bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2026–06–28
84 papers selected by
Gavin McStay, Liverpool John Moores University
  1. The irisin-PINK1/Parkin axis plays an essential role in mediating microglial mitophagy: A crucial mechanism for exercise-induced neuroprotection against Parkinson's disease.
  2. Traditional Chinese medicine-derived monomers protect chondrocytes and delay osteoarthritis progression by regulating mitochondrial quality control.
  3. The therapeutic effect of nicotinamide riboside chloride on ameliorating alcohol-induced neuronal damage with a focus on mitochondrial unfolded protein response and mitophagy.
  4. Molecular diversity of mitochondrial autophagy receptors: context-dependent effects in human health and disease.
  5. Mitochondrial quality control in health and disease: Updates 2026.
  6. Role of recombinant S100A13 expression in regulating mitochondrial fission and fusion in lung epithelial cells.
  7. Exercise as a Bidirectional Regulator of Drp1: A Goldilocks Principle for Mitochondrial Adaptation in Skeletal Muscle.
  8. [Progress on mechanism of mitochondrial autophagy in pathogenesis of intervertebral disc degeneration based on PINK1/Parkin signaling pathway].
  9. Mitophagy mitigates tau acetylation via the ULK1-NAD+/SIRT1 axis in Alzheimer's disease.
  10. Muscone Promotes PINK1/Parkin-Associated Mitophagy to Suppress NLRP3 Inflammasome Activation: Implications for Endotoxemia Therapy.
  11. FUBL-3/FUBP1 mediates mitochondrial stress-induced chromatin remodeling and longevity.
  12. Mdivi-1-Sensitive Mitochondrial Remodeling Contributes to B Cell Immune Synapse Formation and Antigen Presentation.
  13. Physical exercise as a precision strategy for targeted PINK1 recruitment- a mechanistic review.
  14. Stage- and compartment-specific remodeling of autophagy and selective mitophagy in glaucoma: from aqueous outflow dysfunction to retinal ganglion cell neurodegeneration.
  15. Mitigating nucleus pulposus cell senescence in intervertebral disk degeneration: the role of nodakenin in SIRT6 and PINK1/Parkin-associated mitophagy signaling.
  16. Robust and sensitive ELISA detection of total and activated PRKN.
  17. Black Bean Peptide Alleviates Lead-Induced Hippocampal Neurotoxicity in Mice by Regulating PINK1/Parkin-Mediated Mitophagy.
  18. PIM1-induced Drp1 phosphorylation disrupts microglial mitophagy and aggravates neuroinflammation.
  19. Targeting Dynamin-Related Protein 1 and Glucose Metabolism Reverses Acquired Resistance to Sorafenib in Liver Cancer.
  20. Hypoxia-induced MIC19 myristoylation promotes PRKN-dependent VDAC2 ubiquitination and activates mitophagy in non-small cell lung cancer.
  21. Oxidative stress-preconditioned exosomes target BMF to restore mitophagy for alleviating intervertebral disc degeneration.
  22. The Interplay of Splicing and Metabolism in Cancer.
  23. Suppression of STING by Acacetin attenuates renal fibrosis via balancing mitophagy and protective nucleoid-phagy.
  24. Correction to "Shenlian Extract Decreases Mitochondrial Autophagy to Regulate Mitochondrial Function in Microvascular to Alleviate Coronary Artery No-Reflow".
  25. Exploring Key Regulators of Mitochondrial Dynamics and Immune Response in SARS-CoV-2 Infection.
  26. PINK1 loss in astrocytes triggers inflammatory dysfunction and neuronal death.
  27. Cisplatin-Induced Nephrotoxicity Attenuation by Schizophyllum commune Through Regulating Mitochondria-Associated Signaling, Apoptosis, Autophagy, and PINK1/Parkin-Mediated Mitophagy.
  28. DRP1 mutations associated with EMPF1 encephalopathy perturb the transcriptional profile and maturation of cortical neurons.
  29. Copper and PFOS Co-Exposure Induces Synergistic Neurotoxicity via ROS-Mediated Mitophagy in C. elegans.
  30. Disrupted mitochondrial dynamics activate RNA-sensing innate immunity through mitochondrial RNA release.
  31. Lamivudine ameliorates neuropathology in 5×FAD mice via coordinated inhibition of the cGAS-STING pathway with enhancement of mitophagy.
  32. Oxymatrine alleviates cerebral ischemia-reperfusion injury by inhibiting microglia ferroptosis via NRF2 pathway activation.
  33. Regular exercise improves cardiac dysfunction in Drosophila by inhibiting excessive mitochondrial fission through RalA.
  34. Pterostilbene mitigates intervertebral disc degeneration via dual regulation of mitophagy and NLRP3 ubiquitination to inhibit nucleus pulposus cell pyroptosis.
  35. Mitochondrial Adaptations to Exercise Training in Equine Skeletal Muscle: A Narrative Review.
  36. The mitochondrial unfolded protein response in human microglia disrupts neuronal-glial communication and promotes senescence.
  37. Desmoglein-2 Deficiency Drives Mitochondrial Morphological Remodeling in Cardiomyocytes.
  38. HIF-1α-mediated mitochondrial autophagy in the post-treatment protective effect of thyroxine against myocardial ischemia-reperfusion injury.
  39. Salvia miltiorrhiza Bunge Alleviates Pulmonary Fibrosis by Promoting Fibroblast Mitophagy.
  40. Differential effects of tropomyosin paralogs on mitochondrial dynamics in Saccharomyces cerevisiae.
  41. Targeting mitochondria as a potential therapeutic strategy against radioresistance in cancer.
  42. C/EBP alpha agonist ICCB280 overcomes doxorubicin resistance in osteosarcoma through mitochondrial dynamics-dependent GREM1-MAPK activation.
  43. Myeloid DRP1 Sulfenylation Drives Reparative Macrophage Polarization and Neovascularization in Ischemic Muscle.
  44. Dysregulation of the HSF1-Mediated UPRmt Pathway in Colonic Smooth Muscle Cells Drives Motility Dysfunction in Functional Constipation.
  45. Mitochondrial Dynamics and SLC25 Transporters in Neurodegeneration: From Mechanisms to Therapeutic Opportunities.
  46. Targeting Grx1 by hyperoside regulates Ncf4 post-translational modification to enhance mitophagy and accelerate diabetic wound healing.
  47. Avian Pathogenic Escherichia coli T6SS Effector Protein Hcp2 Induces Mitochondrial Dysfunction and Activates Mitophagy in Chicken Tracheal Mucosal Epithelial Cells.
  48. Interrupting a mitochondrial DNA-driven innate immune circuit attenuates hepatic tissue remodeling and fibrotic architecture in experimental steatohepatitis.
  49. Immunomodulatory cytoskeleton of bionic periosteum affects mitochondrial dynamics to promote osteogenesis.
  50. Photobiomodulation Targets Mitochondrial Homeostasis for Diabetic Wound Healing.
  51. Senp1 O-GlcNAcylation Promotes Mitochondrial Fragmentation by Regulating Fis1 SUMO1-ylation Underlying Diabetic Cataract.
  52. Mitochondrial-derived compartments buffer outer membrane protein load during acute mitochondrial adaptation.
  53. GPR124 promotes NLRP3 inflammasome activation through impaired mitochondrial autophagy homeostasis in ox-LDL-treated endothelial cells.
  54. Selenium nanoparticles alleviate ulcerative colitis by regulating macrophage mitochondrial dynamics.
  55. Recombinant myonectin ameliorates sepsis‑induced cardiomyopathy by alleviating mitochondrial dysfunction via the AdipoR1/AMPK pathway.
  56. Bioinformatics and network pharmacology to explore Huangqi Guizhi Wuwu Decoction in regulating mitophagy to ameliorate doxorubicin-induced cardiotoxicity the potential mechanism.
  57. Local Mitochondrial Growth Initiated by Femtosecond Laser-Evoked Ca2+ Signaling.
  58. Imbalanced mitochondrial fusion/fission in human placenta: a potential link to preeclampsia.
  59. Rosmarinic acid attenuates hyperuricemia-induced intestinal damage by activating mitophagy via the p38 MAPK/mTOR pathway.
  60. Ketone-Dependent Restoration of Autophagy and Mitochondrial Quality Control Through VPS35 in a Drosophila Model of C99-Induced Neurodegeneration.
  61. Perfluorooctanoic acid induces mitochondrial dysfunction-driven apoptosis and PINK1/Parkin-mediated mitophagy in testicular cells.
  62. EGR1 mediates neuronal damage via suppressing HIF1A-induced mitophagy following traumatic brain injury.
  63. Prohibitins in cancer: Multifaceted regulators of mitochondrial homeostasis, oncogenic signaling, tumor microenvironment, and therapeutic resistance.
  64. E4BP4 safeguards brown fat mitochondria from obesity-induced fragmentation via ceramide repression.
  65. The role of ESRRA and JUNB in oxyphil cells: insights from spatial transcriptomics and single-cell transcriptomics in uremic secondary hyperparathyroidism.
  66. Retraction notice to "SNP alleviates mitochondrial homeostasis dysregulation-mediated developmental toxicity in diabetic zebrafish larvae" [Biomedicine & Pharmacotherapy 177 (2024) 117117].
  67. Mitochondria-associated endoplasmic reticulum membrane (MAM): roles in innate immunity dysregulation.
  68. Disruption of a GalR2-mitochondrial axis in the ventral hippocampus contributes to depression-like phenotypes after prenatal stress.
  69. Corrigendum to "Integrative single-cell analysis reveals Bu-Shen-Huo-Xue Formula rescues iron-overloaded ovarian function via rewiring IFN-γ/JAK/STAT/CXCL10-driven immune-stromal interactions and BNIP3-mediated mitophagy in endometriosis" [Phytomedicine 2026 May:157:158343].
  70. Bacoside-A from Bacopa monnieri (L.) Wettst. in Parkinson's disease: In Silico and preclinical insights into dopaminergic neuroprotection.
  71. Mitochondrial Dysfunction and Oxidative Stress in Retinal Degeneration: Mechanisms, Biomarkers, and Therapeutic Perspectives.
  72. miRNA family miR-29 inhibits PINK1-PRKN signaling via ATG9A.
  73. Comparative Cochlear-Vestibular Aging Reveals Age-Aligned Mitochondrial Ultrastructural Burden, Mitophagy-Autophagy Remodeling, Synaptic Uncoupling, and Sensory Functional Decline.
  74. Proteolytic coordination of the OXPHOS Life Cycle.
  75. Norepinephrine regulates hippocampal mitochondrial biogenesis via β2-adrenergic receptor signaling and PGC-1α.
  76. Emerging Cardioprotective Strategies Beyond Dexrazoxane: SGLT2 Inhibitors, Drug Repurposing, and Mitochondrial Approaches in Doxorubicin Cardiotoxicity.
  77. Mitochondrial stress response drives microglial senescence.
  78. De Novo MFN2 p.Arg95Met in Severe Charcot-Marie-Tooth Disease Type 2A.
  79. Tuning the Fire: Context-Dependent Mitochondrial ROS Signaling, Mitohormesis, and Redox-Modulating Interventions.
  80. Liqi Huoxue dripping pills alleviate myocardial ischemia-reperfusion injury with improved mitochondrial biogenesis and reduced ferroptosis: Involvement of S100A8/A9-TLR4-ERK signaling.
  81. ADP-ribosylation factor 1 sustains regulatory T cell function and mucosal immune homeostasis in ulcerative colitis.
  82. Metformin Partially Attenuates Simvastatin-Induced Myotoxic Responses in C2C12 Myotubes Through Metabolic Adaptation.
  83. Carob pod aqueous extract potentiates cisplatin efficacy and reduces toxicity in experimental hepatocellular carcinoma via mitochondrial and inflammatory pathway modulation.
  84. Interplay of Mitochondrial Dynamics, Nutrition, and Vitamins: Evidence From Experimental and Human Studies With Implications for Women's Health.
  1. Biochim Biophys Acta Mol Basis Dis. 2026 Jun 24. pii: S0925-4439(26)00198-5. [Epub ahead of print] 168335
    The irisin-PINK1/Parkin axis plays an essential role in mediating microglial mitophagy: A crucial mechanism for exercise-induced neuroprotection against Parkinson's disease.
    Bin Wang, Xin Liu, Xin Tian, Junjie Lin, Qian Li, Yue Wu, Renqing Zhao.
      The progression of Parkinson's disease (PD) is primarily driven by chronic neuroinflammation in microglia and impaired mitochondrial quality control. Here, we show that 10 weeks of treadmill running ameliorates motor deficits, dopaminergic neuron loss, and α-synuclein (α-syn) pathology in MPTP-induced PD mice. Exercise enhances PINK1/Parkin-dependent mitophagy in microglia, evidenced by increased LC3/Iba1 colocalization, p62 clearance, and direct LC3/Tom20 colocalization, thereby suppressing proinflammatory activation. These effects are mediated by exercise-induced upregulation of FNDC5/irisin. In vitro, recombinant irisin rescues impaired mitophagy and alleviates neuroinflammation in α-syn-exposed microglia. Crucially, pharmacological blockade of irisin receptors with RGDyk abolishes exercise-induced neuroprotection, mitophagy restoration, and behavioral improvements. Our findings reveal: (1) Exercise alleviates PD pathology by enhancing mitochondrial autophagy to reprogram microglial function; (2) Irisin is a key myokine activating microglial mitochondrial autophagy via the PINK1/Parkin pathway; (3) The irisin-mitochondrial autophagy axis represents a novel and promising therapeutic target for PD. This work provides the first evidence that exercise-induced irisin directly regulates microglial mitochondrial homeostasis, establishing a mechanistic basis for exercise-based PD interventions.
    Keywords:  Exercise; Irisin; Microglial mitophagy; Neuroinflammation; Parkinson's disease
    DOI:  https://doi.org/10.1016/j.bbadis.2026.168335
  2. Front Mol Biosci. 2026 ;13 1857635
    Traditional Chinese medicine-derived monomers protect chondrocytes and delay osteoarthritis progression by regulating mitochondrial quality control.
    Xinhui Yang, Ying Li.
      Osteoarthritis is a common degenerative joint disease characterized by progressive cartilage degeneration, joint structural damage, and functional impairment. Despite its high prevalence, effective therapies capable of slowing structural progression remain limited. Increasing evidence suggests that mitochondrial quality control is a key mechanism in maintaining chondrocyte homeostasis and plays an important role in the development and progression of osteoarthritis. In osteoarthritis chondrocytes, mitochondrial quality control is mainly manifested through impaired mitochondrial biogenesis, dysregulated mitochondrial fusion and fission, abnormal mitophagy, and oxidative stress-related mitochondrial dysfunction. These alterations can lead to reduced ATP production, excessive reactive oxygen species accumulation, decreased mitochondrial membrane potential, enhanced chondrocyte senescence and apoptosis, and extracellular matrix degradation, thereby accelerating osteoarthritis progression. In recent years, traditional Chinese medicine-derived monomers have attracted increasing attention because of their relatively clear chemical composition and multitarget pharmacological activities. Accumulating studies indicate that TCM-derived monomers, such as quercetin, resveratrol, curcumin, baicalin, berberine, and icariin, can protect chondrocytes and delay osteoarthritis progression by regulating key processes involved in mitochondrial quality control. This review focuses on the role of mitochondrial quality control in osteoarthritis chondrocytes and summarizes current research on the protective effects of TCM-derived monomers from the perspectives of mitochondrial biogenesis, mitochondrial dynamics, mitophagy, and oxidative stress-related homeostasis, with the aim of providing a reference for future mechanistic studies and potential therapeutic development.
    Keywords:  chondrocytes; mitochondrial biogenesis; mitochondrial quality control; osteoarthritis; traditional Chinese medicine-derived monomers
    DOI:  https://doi.org/10.3389/fmolb.2026.1857635
  3. Genes Dis. 2026 Sep;13(5): 101886
    The therapeutic effect of nicotinamide riboside chloride on ameliorating alcohol-induced neuronal damage with a focus on mitochondrial unfolded protein response and mitophagy.
    Jinyang Wang, Jianan Wang, Wei Xie, Qi Shen, Chengbin Wang, Ruibing Li, Shixiong Deng.
      Excessive alcohol consumption leads to neurodegeneration, driven primarily by oxidative stress and mitochondrial dysfunction, yet no specific treatment exists. Nicotinamide riboside chloride (NRC), a nicotinamide adenine dinucleotide precursor, has demonstrated therapeutic potential in mitigating mitochondrial dysfunction in heart failure, but its role in alcohol-induced neurodegeneration remains unexplored. This study investigated NRC's neuroprotective effects using behavioral tests, serum ethanol and inflammatory marker analysis, hematoxylin-eosin staining, and molecular assays of in vitro models. Proteomics and GEO database analysis further elucidated the mechanisms of alcohol-induced brain injury. Results showed that NRC significantly improved alcohol-related cognitive impairment and neuroinflammation. Both our experimental data and external datasets identified mitochondrial dysfunction as a key driver of alcohol-induced neuronal damage, characterized by impaired mitophagy and disrupted mitochondrial unfolded protein response (UPRmt). NRC supplementation restored mitochondrial homeostasis by enhancing UPRmt and Fundc1-dependent mitophagy. Mechanistically, UPRmt inhibition abolished NRC's protective effects by suppressing Fundc1 expression and mitophagy, whereas mitophagy inhibition did not affect UPRmt, suggesting a hierarchical regulation where UPRmt governs Fundc1-mediated mitophagy. In conclusion, alcohol disrupts mitochondrial quality control, but NRC counteracts neuronal toxicity by activating UPRmt and restoring Fundc1-driven mitophagy, offering a promising therapeutic strategy for alcohol-related neuronal damage.
    Keywords:  Alcohol; Mitophagy; Neuron; Nicotinamide riboside chloride; Unfolded protein response
    DOI:  https://doi.org/10.1016/j.gendis.2025.101886
  4. Cell Death Discov. 2026 Jun 25.
    Molecular diversity of mitochondrial autophagy receptors: context-dependent effects in human health and disease.
    Ana Rožić, Mija Marinković, Ivana Novak.
      Mitophagy receptors are central regulators of mitochondrial quality control, integrating metabolic, stress-related, and developmental cues to maintain cellular homeostasis. Accumulating evidence indicates that their dysregulation contributes to a broad spectrum of human diseases through highly context-dependent mechanisms. In cardiovascular and neurological disorders, receptor-mediated mitophagy shapes cell survival, synaptic function, stress adaptation, and tissue integrity, with both insufficient and excessive activity proving detrimental. In cancer, mitophagy receptors display dual and stage-specific roles, acting as tumor suppressors in early disease while later supporting metabolic adaptation, stemness, and therapy resistance. Metabolic diseases highlight the tissue-specific complexity of mitophagy regulation, where precise control of mitochondrial turnover is essential for insulin sensitivity, calcium signaling, and energy homeostasis. In hematological, inflammatory, and autoimmune disorders, receptor-mediated mitophagy emerges as a fundamental determinant of lineage commitment, immune cell function, and inflammatory balance. Collectively, these findings position mitophagy receptors not as uniform stress responders, but as dynamic modulators of disease progression, whose precise and context-sensitive targeting may offer novel therapeutic opportunities across diverse pathological conditions.
    DOI:  https://doi.org/10.1038/s41420-026-03207-7
  5. Chin Med J (Engl). 2026 Jun 24.
    Mitochondrial quality control in health and disease: Updates 2026.
    Zhengzhao Liu, Wenbao Hu, Lin Sun, Huafeng Liu.
       ABSTRACT: Mitochondria are central to cellular energy metabolism, and their functional integrity is essential for maintaining cellular homeostasis and life processes. Mitochondrial quality control (MQC) encompasses a complex network of mechanisms-including mitochondrial biogenesis, mitochondrial dynamics, mitophagy, mitochondrial proteostasis, and mitochondrial-derived vesicles-that collectively preserve the structural and functional balance of mitochondria. Recent studies have revealed that dysregulation of MQC is closely associated with a broad spectrum of diseases, such as neurodegenerative disorders, cardiovascular diseases, kidney diseases, metabolic syndrome, and cancers, highlighting its critical role in pathological processes. Despite significant progress in elucidating the molecular regulation of MQC, many aspects of its complexity and multilayered regulatory mechanisms remain unresolved. This review provides a comprehensive overview of the major molecular pathways involved in MQC and their functional alterations under physiological and pathological conditions. It emphasizes the abnormalities of MQC in various diseases and explores potential therapeutic targets. Moreover, integrating the latest research advances, this article discusses emerging treatment strategies aimed at restoring and optimizing MQC, with the goal of offering theoretical insights and clinical translation avenues for future disease prevention and management.
    Keywords:  Cardiovascular disease; Kidney disease; Mitochondria; Mitochondrial dynamics; Mitochondrial quality control; Mitophagy; Neurodegenerative disease; Therapeutic strategies
    DOI:  https://doi.org/10.1097/CM9.0000000000004169
  6. BBA Adv. 2026 ;10 100195
    Role of recombinant S100A13 expression in regulating mitochondrial fission and fusion in lung epithelial cells.
    Somaya Alqattan, Mona Alonazi, Eid Almutairy, Vineesh V Raveendran, Abdulaziz Alamri, Futwan Al-Mohanna.
      S100A13, a calcium-binding protein containing two EF-hand motifs, contributes to intracellular calcium homeostasis, a key determinant of mitochondrial quality control. We previously showed that S100A13 modulates mitochondrial membrane potential (ΔΨm) in patient-derived skin fibroblasts carrying S100A13 (p.I80Gfs*13) and S100A3 (p.R77C) mutations. However, its role in regulating mitochondrial dynamics remains unclear. Here, we investigated whether S100A13 regulates mitochondrial fusion-fission balance in human bronchial epithelial cells (BEAS-2B) using Myc-tagged wild-type or p.I80Gfs*13 S100A13 constructs. The S100A13 p.I80Gfs*13 mutant markedly attenuated bradykinin- and ionophore-induced intracellular calcium transients and reduced ΔΨm compared with wild-type S100A13 (p < 0.05). These alterations were associated with severe mitochondrial ultrastructural abnormalities, disrupted cristae organization, and increased mitochondrial fragmentation (p < 0.05). Interestingly, both wild-type and p.I80Gfs*13 mutant S100A13 increased expression of the mitochondrial fusion-associated proteins MFN1/2 and OPA1 while reducing expression of the fission mediator MFF. However, despite these apparently pro-fusion molecular changes, the S100A13 p.I80Gfs*13 mutant failed to maintain mitochondrial fusion competency, suggesting a functional uncoupling between fusion protein abundance and mitochondrial fusion competency. Collectively, these findings identify S100A13 as an important regulator of intracellular calcium-dependent mitochondrial dynamics and demonstrate that C-terminal truncation disrupts calcium-dependent regulation of mitochondrial fusion and cristae integrity in lung epithelial cells.
    Keywords:  Calcium transients; Cristae; Lung epithelial cells; Mitochondrial dynamics; S100A13; p.I80Gfs*13; ΔΨm
    DOI:  https://doi.org/10.1016/j.bbadva.2026.100195
  7. Cells. 2026 Jun 16. pii: 1091. [Epub ahead of print]15(12):
    Exercise as a Bidirectional Regulator of Drp1: A Goldilocks Principle for Mitochondrial Adaptation in Skeletal Muscle.
    Mei Ma, Jialin Li, Wentao Pang, Ziyi Zhang, Yong Zhang, Hai Bo.
      Dynamin-related protein 1 (Drp1) is essential for mitochondrial dynamics in skeletal muscle, particularly in regulating fission, mitophagy, and maintaining mitochondrial function. Exercise is crucial for sustaining muscle function, promoting mitochondrial adaptations that enhance energy metabolism and oxidative capacity in skeletal muscle. In this Review, we discuss the role of Drp1 in exercise-induced mitochondrial adaptations and its potential implications for skeletal muscle health. We first address the evidence that Drp1 activity must be maintained within a narrow physiological range. Both Drp1 deficiency and overabundance provoke muscle atrophy and dysfunction, establishing a Goldilocks principle for mitochondrial fission. We then examine the multi-layered post-translational modification code that governs Drp1 activity, including canonical phosphorylation, redox-sensing modifications, and the receptor selectivity model that may specify distinct fission programs. A three-stage model of exercise-induced mitochondrial adaptation is presented, describing how Drp1 activity is temporally orchestrated from acute fragmentation through short-term remodeling to long-term network optimization, and how these morphological transitions govern substrate metabolism and determine exercise performance. The pathological consequences of Drp1 dysregulation are examined in metabolic disease, where Drp1 is chronically hyperactivated, and in aging, where Drp1 activity is deficient. Finally, we analyze the ROS-Drp1 signaling axis as the mechanistic basis for the bidirectional regulation of Drp1 by exercise. Moderate exercise-induced ROS production activates Nrf2 and AMPK signaling, which suppress excessive fission in metabolic disease while restoring insufficient fission in aging, thereby moving Drp1 activity toward the physiological Goldilocks zone in both contexts. This context-dependent, bidirectional regulation distinguishes exercise from pharmacological inhibitors and identifies the ROS-Drp1 axis as a therapeutic target for conditions at opposite ends of the Drp1 activity continuum, such as sarcopenia and type 2 diabetes.
    Keywords:  Drp1; ROS; exercise; mitochondrial adaptation; skeletal muscle atrophy
    DOI:  https://doi.org/10.3390/cells15121091
  8. Zhongguo Gu Shang. 2026 Jun 25. 39(6): 642-8
    [Progress on mechanism of mitochondrial autophagy in pathogenesis of intervertebral disc degeneration based on PINK1/Parkin signaling pathway].
    Jie Guo, Ling Lei, Hongjing Tian, Tiefeng Guo, Linzhao Luo, Yanjun Zhang.
      Intervertebral disc degeneration (IVDD) is one of the main causes of lower back pain. The chronic accumulation of aging and apoptosis of nucleus pulposus cells (NPCs) is believed to be related to IVDD. In recent years, mitochondrial autophagy which as an important clearance mechanism within cells, has gradually attracted attention. The PINK1/Parkin signaling pathway is regarded as the key pathway regulating mitochondrial autophagy, and it plays a significant role in physiological and pathological processes of NPCs. The mechanism by which PINK1/Parkin signaling pathway mediates mitochondrial autophagy could be understood as follows, PINK1, as the sensor for mitochondrial quality regulation, is activated. It recruits and activates Parkin to the mitochondrial membrane through phosphorylation of ubiquitin, and then undergoes Parkin-dependent substrate ubiquitination, recruitment of autophagy receptors, formation of autophagosomes, and fusion with lysosomes, ultimately completing the extremely important autophagy process. Current research indicates that abnormality of PINK1/Parkin signaling pathway may be closely related to IVDD, but the specific mechanism still requires further exploration. The paper explores research progress of mechanism by which mitochondrial autophagy affects IVDD based on PINK1/Parkin signaling pathway, with the aim of providing new strategies and targets for the treatment of IVDD.
    Keywords:  Intervertebral disc degeneration; Mitophagy; Nucleus pulposus cells; PINK1/Parkin signaling pathway; Review
    DOI:  https://doi.org/10.12200/j.issn.1003-0034.20241146
  9. Autophagy. 2026 Jun 21. 1-3
    Mitophagy mitigates tau acetylation via the ULK1-NAD+/SIRT1 axis in Alzheimer's disease.
    Jun-Ping Pan, Jianying Zhang, Ping-Jie Wang, Guobing Chen, Evandro Fei Fang.
      Autophagy preserves neuronal integrity by clearing damaged proteins and other subcellular components, yet it declines with age and exacerbates in Alzheimer's disease (AD). Although autophagy reduces tauopathy, whether it can proactively restrict early tau pathology via post-translational modifications (PTMs) has remained unclear. In a recent paper, we have identified a mitophagy-based metabolic signaling mechanism linking the autophagy-initiating kinase Unc-51-like autophagy activating kinase 1 (ULK1) to the inhibition of pathogenic tau acetylation via the ULK1-NAD+/SIRT1 axis. Analyses of human biofluidic to postmortem and transcriptomic data reveal an age-associated decline of ULK1; this situation gets worse in AD with the extent of ULK1 reduction positively correlates with Tau-based Braak stage progression, consistent with a bidirectional vicious cycle in which pathological tau disrupts mitochondrial homeostasis and impairs autophagy. Restoring ULK1-dependent mitophagy breaks this cycle in the upstream: in the hTau.P301S mice, ULK1 overexpression reduces ac‑tauK174 leading to reduced tau pathology and improved cognition. Mechanistically, ULK1 activates PINK1- and FUNDC1- as well as AMBRA1-dependent mitophagy to eliminate damaged mitochondria, restore bioenergetics, and elevate intracellular NAD+, which activates the deacetylase SIRT1 to directly deacetylate tau at Lys174. Pharmacological ULK1 activation with a small molecule Rac‑BL‑918 phenocopies these protective effects in a mitophagy- and SIRT1-dependent manner. Collectively, our recent findings position mitophagy as a metabolic signaling hub that couples mitochondrial turnover to NAD+/SIRT1 activity to shape neuronal tau PTMs, supporting ULK1-mitophagy activation as an upstream strategy to limit tauopathy before overt aggregation.
    Keywords:  Ac‑tauK174; Mitophagy; NAD+; SIRT1; ULK1
    DOI:  https://doi.org/10.1080/15548627.2026.2689031
  10. Pharmaceuticals (Basel). 2026 May 23. pii: 816. [Epub ahead of print]19(6):
    Muscone Promotes PINK1/Parkin-Associated Mitophagy to Suppress NLRP3 Inflammasome Activation: Implications for Endotoxemia Therapy.
    Ziwei Yan, Minrui Li, Dan Li, Wentian Hua, Haoxue Cao, Yufei Li, Li Che, Xiyi Chen, Zhicheng Lai, Yi Wang, Guofang Shen, Jing Qian.
      Background: The NLRP3 inflammasome drives pathological inflammation in various diseases. PINK1/Parkin-associated mitophagy serves as a critical negative regulator of NLRP3 activation, yet pharmacological enhancers remain scarce. Muscone, a natural macrocyclic ketone with blood-brain barrier permeability, exhibits potent anti-inflammatory properties; however, its mechanistic role within the NLRP3-mitophagy axis remains undefined. Methods: LPS/ATP-stimulated macrophages were employed to assess stage-specific effects of muscone on NLRP3 priming (NF-κB signaling, NLRP3, and pro-IL-1β expression) and activation (ASC oligomerization, ASC-pro-caspase 1 complex formation, and IL-1β secretion). RNA sequencing and bioinformatic analysis were performed for pathway enrichment. Mitophagy was characterized by MitoSOX Red staining for mt-ROS detection, electron microscopy, Western blotting of LC3B-II in isolated mitochondria and PINK1 and Parkin in whole-cell lysates, and live-cell mitochondria-lysosome tracking. In vivo protective efficacy was assessed in an LPS-induced endotoxemia mouse model. Results: Muscone dose-dependently suppressed both the priming and activation stages of the NLRP3 inflammasome, maximally reducing IL-1β secretion by ~60% at 50 μM. Mechanistically, muscone amplified PINK1/Parkin-associated mitophagy, scavenging excessive mt-ROS and attenuating NLRP3 activation. These effects were corroborated by RNA-seq and comprehensive functional assays. In vivo, muscone (30 mg/kg) significantly improved survival (3/8 mice alive at 98 h when all LPS controls had died; 2/8 survived to the 132-h endpoint), with concomitant enhancement of mitophagy markers in peritoneal macrophages. Conclusions: Muscone functions as a PINK1/Parkin-associated mitophagy enhancer that maintains mitochondrial quality control during NLRP3-driven inflammatory responses. Its unique macrocyclic structure and blood-brain barrier permeability provide a promising scaffold for developing therapeutics against inflammatory disorders associated with NLRP3 inflammasome activation.
    Keywords:  NLRP3 inflammasome; PINK1/Parkin-associated mitophagy; endotoxemia; macrophages; mitochondrial quality control; muscone
    DOI:  https://doi.org/10.3390/ph19060816
  11. Sci Adv. 2026 Jun 26. 12(26): eaec8143
    FUBL-3/FUBP1 mediates mitochondrial stress-induced chromatin remodeling and longevity.
    Qian Zhang, Hangyu Dong, Yayun Jiang, Zihao Wang, Jiasheng Li, Ye Tian.
      Mitochondrial stress activates nuclear transcriptional programs to restore homeostasis and promote longevity; yet, the nuclear effector that directly reshapes chromatin during stress remains unclear. Through a forward genetic screen in Caenorhabditis elegans, we identify FUBL-3, the homolog of human far-upstream elements binding protein 1 (FUBP1), as a conserved regulator that couples mitochondrial stress to chromatin remodeling. FUBL-3 translocates to intestinal nuclei upon stress, where it drives nucleosome remodeling and deacetylase-dependent chromatin condensation and activates mitochondrial unfolded protein response (UPRmt). Loss of fubl-3 disrupts chromatin compaction and abolishes stress-induced lifespan extension, while its overexpression is sufficient to restructure chromatin, trigger UPRmt, and extend lifespan. Notably, human FUBP1 rescues fubl-3 mutants in worms and mediates chromatin remodeling in mammalian cells under mitochondrial stress. FUBP1 binds promoters of proteostasis and mitochondrial quality control genes, supporting its role in nuclear adaptation. Our study identifies FUBL-3/FUBP1 as a conserved mitochondrial-to-nuclear communicator that reprograms chromatin architecture to promote stress resilience and healthy aging.
    DOI:  https://doi.org/10.1126/sciadv.aec8143
  12. Cells. 2026 Jun 19. pii: 1114. [Epub ahead of print]15(12):
    Mdivi-1-Sensitive Mitochondrial Remodeling Contributes to B Cell Immune Synapse Formation and Antigen Presentation.
    Juan Pablo Bozo, Teemly Contreras, Antonio Sánchez-Squella, Jheimmy Diaz-Muñoz, María-Isabel Yuseff.
      B cell activation requires the formation of an immune synapse (IS), where coordinated cytoskeletal remodeling and organelle dynamics enable antigen extraction and presentation. While mitochondria are known to regulate cellular metabolism during activation, their role in IS function remains poorly understood. Here, we investigated how mitochondrial dynamics influence antigen processing and presentation in B cells. We show that B cell receptor (BCR) engagement induces rapid phosphorylation of the mitochondrial fission GTPase Drp1 at Ser616. Treatment with mdivi-1, a compound used to perturb Drp1-associated mitochondrial fission that can also affect mitochondrial complex I activity, altered mitochondrial morphology, reduced mitochondrial activity, and decreased their stable accumulation at the synapse. This was accompanied by increased tubulin acetylation, lysosome retention near the MTOC, and reduced delivery to the synaptic membrane. Accordingly, lysosome fusion, antigen extraction, and presentation to T cells were significantly diminished in mdivi-1-treated B cells. Together, our findings suggest that mdivi-1-sensitive mitochondrial fission and activity are associated with mitochondrial positioning, lysosomal trafficking, and exocytosis at the B cell immune synapse, supporting a model in which mitochondrial dynamics contribute to efficient antigen extraction and presentation.
    Keywords:  B cell immune synapse; Drp1; mitochondria
    DOI:  https://doi.org/10.3390/cells15121114
  13. Front Physiol. 2026 ;17 1836651
    Physical exercise as a precision strategy for targeted PINK1 recruitment- a mechanistic review.
    Jing Zhu, Ligang Tong, Anand Thirupathi.
      PTEN-induced kinase 1 (PINK1) is a mitochondrial serine/threonine kinase that orchestrates ubiquitin-dependent mitophagy together with the E3 ligase Parkin. Both physiological and pathological conditions rapidly recruit PINK1, and timely PINK1 degradation in healthy mitochondria determines whether it supports or harms the cell. Thus, the tight regulation of PINK1 balances its negative effects. In this context, introducing physical exercise as one of the strategies can fine-tune PINK1/Parkin pathways by triggering transient energy stress and moderate increases in reactive oxygen species (ROS) that promote PINK1 stabilization on the outer mitochondrial membrane, enhance Parkin recruitment via sensitizing various molecular signaling, such as AMPK-PGC-1α and FOXOs. However, the mechanism underlying a specific exercise mode that triggers PINK1-mediated selective removal of mitochondrial damage remains unknown. Therefore, this review will synthesize mechanistic approaches to how different exercise paradigms modulate PINK1 function, recruit PINK1 dynamics, and regulate downstream signaling, to define exercise prescriptions as adjunctive strategies.
    Keywords:  PINK1; Parkin; mitochondria; mitophagy; neurons; physical exercise
    DOI:  https://doi.org/10.3389/fphys.2026.1836651
  14. Front Cell Dev Biol. 2026 ;14 1842496
    Stage- and compartment-specific remodeling of autophagy and selective mitophagy in glaucoma: from aqueous outflow dysfunction to retinal ganglion cell neurodegeneration.
    Pai Zhou, Ying Deng, Yasha Zhou, Jing Lu, Qinghua Peng, Yijing Yang.
       Background: Glaucoma is a leading cause of irreversible blindness and is increasingly understood as a chronic neurodegenerative disorder rather than a disease explained solely by elevated intraocular pressure (IOP). Although IOP lowering remains the cornerstone of treatment, many patients continue to progress despite apparently adequate pressure control, indicating that additional mechanisms shape retinal ganglion cell (RGC) vulnerability and disease course. Among these, autophagy and mitophagy have emerged as central regulators of cellular stress adaptation in both anterior and posterior ocular tissues.
    Main Body: This review argues that glaucoma can be more coherently interpreted through a stage- and compartment-specific framework of autophagy and selective mitophagy. In the conventional outflow pathway, autophagy contributes to mechanoadaptation, proteostasis, and extracellular matrix homeostasis, whereas chronic oxidative and biomechanical stress may impair lysosomal function and autophagic flux, thereby promoting outflow dysfunction and ocular hypertension. In the posterior segment, RGCs and their axons are highly dependent on autophagy for proteostasis and mitochondrial quality control because of their polarized morphology and substantial metabolic demand. Experimental work suggests that autophagy may be protective during early or acute stress but become insufficient, stalled, or maladaptive during chronic injury. Recent human stem cell and animal studies further implicate optineurin-linked autophagic-lysosomal dysfunction, AMPK-mTORC1 imbalance, and reduced PINK1/Parkin-associated mitophagy as mechanistic nodes linking mitochondrial stress to RGC degeneration. These observations support a model in which glaucoma progression reflects not simply more or less autophagy, but failure to maintain effective quality control across distinct ocular compartments and disease stages.
    Conclusion: A compartment-aware and time-resolved view of autophagy and mitophagy offers a more nuanced framework for glaucoma pathogenesis and therapy. Future progress will likely depend less on indiscriminate pathway modulation than on restoring selective, flux-competent quality control, particularly mitochondrial turnover, in the appropriate tissue and at the appropriate stage of disease.
    Keywords:  autophagy; glaucoma; mitophagy; neurodegeneration; retinal ganglion cell; trabecular meshwork
    DOI:  https://doi.org/10.3389/fcell.2026.1842496
  15. Cell Mol Biol Lett. 2026 Jun 26.
    Mitigating nucleus pulposus cell senescence in intervertebral disk degeneration: the role of nodakenin in SIRT6 and PINK1/Parkin-associated mitophagy signaling.
    Daqian Zhou, Liquan Wang, Yang Zhou, Jiale Lv, Chao Song, Yongliang Mei, Tao Liu, Taotao Wu, Fei Yu, Zongchao Liu.
      Intervertebral disc degeneration (IVDD) is a common and challenging chronic condition in orthopedics, primarily characterized by the aging of nucleus pulposus cells (NPC). Current treatment strategies for IVDD, particularly those targeting NPC senescence, remain underdeveloped. Research has shown that NPC senescence is closely associated with mitochondrial damage, leading to the accumulation of cytoplasmic reactive oxygen species (ROS) and mitochondrial DNA (mtDNA). Mitochondrial autophagy, as a key mechanism of mitochondrial quality control, regulates ROS and mtDNA levels by eliminating dysfunctional and damaged mitochondria, thereby delaying cellular aging. Notably, mitophagy signaling associated with Sirtuin 6 (SIRT6) and PTEN-induced kinase 1 (PINK1)/Parkin has been implicated in this process. Traditional Chinese Medicine (TCM), with its holistic approach and unique theoretical system of syndrome differentiation and treatment, offers significant advantages in preventing and treating degenerative diseases such as IVDD. However, research into TCM formulations aimed at NPC senescence remains limited. In preliminary studies, we observed that Nodakenin, the primary active compound from the TCM formula Duhuo Jisheng decoction (DHJSD), exerts protective effects in a SIRT6-associated manner and appears to be associated with activation of PINK1/Parkin-related mitophagy signaling. In this study, we used single-cell analysis to construct human NPC senescence and rat IVDD models, assessing mitochondrial morphology, mitochondrial membrane potential, cell senescence, and autophagy-related gene expression. We further evaluated the effects of Nodakenin (Nod) on H2O2-induced NPC senescence and determined the optimal intervention concentration, followed by assessment of mitochondrial phenotypes and SIRT6- and PINK1/Parkin-associated markers. These findings provide new theoretical support for the clinical application of TCM in the treatment of IVDD.
    Keywords:  Cell senescence; Intervertebral disc degeneration; Mitochondrial autophagy; Reactive oxygen species; SIRT6
    DOI:  https://doi.org/10.1186/s11658-026-00968-y
  16. Autophagy. 2026 Jun 24.
    Robust and sensitive ELISA detection of total and activated PRKN.
    Jens O Watzlawik, Bernardo A Bustillos, Claudia Rodriguez Martinez, Dennis W Dickson, Zbigniew K Wszolek, Owen A Ross, Wolfdieter Springer, Fabienne C Fiesel.
      Parkinson disease (PD) is closely linked to disruptions in mitochondrial quality control, a process regulated by the ubiquitin kinase PINK1 and the E3 ubiquitin ligase PRKN/parkin. Upon mitochondrial damage, PINK1 phosphorylates ubiquitin, which in turn recruits and activates PRKN. Full activation of PRKN is mediated by PINK1-dependent phosphorylation of PRKN at serine 65, which leads to widespread ubiquitination of mitochondrial substrates and amplifies the mitophagy response. Disruption of this pathway results in mitochondrial accumulation, oxidative stress, and neuronal death, all key mechanisms of PD pathogenesis. Genetic studies have shown biallelic loss-of-function mutations in PRKN are the most common cause of early-onset PD. Although the role of haploinsufficiency remains under investigation, PRKN protein becomes insoluble and inactive with aging or post-translational modifications, indicating that functional protein levels are a key determinant of disease risk. Reliable quantification of total and activated PRKN in samples has not been feasible, limiting research and clinical assessment. To address this, we developed and validated knockout (KO)-verified sandwich ELISA assays that quantify both total PRKN and PINK1-phosphorylated p-S65-PRKN. These assays provide absolute quantification of PRKN, improving functional diagnosis, and patient stratification in PD. Application of these methods established the concentration of PRKN in cells and in brain and revealed significant effects of a common genetic PRKN variant, further highlighting the importance of determining functional PRKN protein levels. The developed immunoassays complement previously established PINK1 and p-S65-Ub measurements, enhancing mechanistic insight into mitophagy and enabling effective monitoring of PD therapies and other neurodegenerative diseases.
    Keywords:  Autophagy; P-S65-PRKN; PARK2; PINK1; biomarker; mitochondria; mitophagy; parkin; parkinson disease; ubiquitin
    DOI:  https://doi.org/10.1080/15548627.2026.2694658
  17. J Food Sci. 2026 Jun;91(6): e71233
    Black Bean Peptide Alleviates Lead-Induced Hippocampal Neurotoxicity in Mice by Regulating PINK1/Parkin-Mediated Mitophagy.
    Jiawen Sun, Qian Li, Tiange Li, Xing Li, Xianqing Huang, Yongxia Cheng, Guangshan Zhao, Lianjun Song, Mingwu Qiao, Gianni Galaverna, Peijun Zhao, Ning Li.
      Lead (Pb) exposure is a major environmental risk factor for cognitive impairment. This effect is mainly caused by oxidative stress, mitochondrial dysfunction in the hippocampus, and neuronal apoptosis. This study examined whether black bean peptide (BSP) reduces Pb-induced hippocampal neurotoxicity by regulating PINK1/Parkin-mediated mitophagy. A mouse model of Pb exposure was established by oral gavage. The effects of BSP were assessed using biochemical assays, Western blot, immunofluorescence, and molecular docking. Results showed that BSP significantly increased total antioxidant capacity (T-AOC) and restored the activities of superoxide dismutase (SOD) and catalase (CAT). PINK1/Parkin-dependent mitophagy was activated, as shown by increased levels of PINK1, Parkin, and LC3B-II and decreased p62 accumulation. BSP also significantly inhibited Pb-induced neuronal apoptosis. This was demonstrated by reduced expression of BCL2-associated X protein (Bax) and cysteine-aspartic acid protease 3 (Caspase-3) and increased expression of B-cell lymphoma 2 (Bcl-2) (p < 0.05). Molecular docking predicted a binding free energy of -6.9 kcal/mol for the BSP-PINK1 complex, indicative of a moderate and thermodynamically favorable interaction that may underpin its neuroprotective effect. No significant difference was found between the BSP (200 mg/kg/day) and resveratrol (RSV, 80 mg/kg/day) groups (p > 0.05). In conclusion, these results suggest that BSP improves mitochondrial quality control, reduces oxidative damage, and inhibits apoptosis in a mouse model of Pb-induced neurotoxicity, highlighting its potential as a candidate dietary strategy for further investigation in the context of heavy metal-related cognitive decline.
    Keywords:  PINK1/Parkin pathway; black bean peptide; lead (Pb) neurotoxicity; mitophagy; molecular docking
    DOI:  https://doi.org/10.1111/1750-3841.71233
  18. Pharmacol Res. 2026 Jun 22. pii: S1043-6618(26)00228-8. [Epub ahead of print]230 108313
    PIM1-induced Drp1 phosphorylation disrupts microglial mitophagy and aggravates neuroinflammation.
    Xiaofang Liu, Lili Ma, Xueying Ma, Xiaomeng Ma, Xiqin Fang, Yingying Liu, Zhumin Su, Xiaoyun Liu, Zhiling Yu, Xiaohong Chen.
      Current disease-modifying therapies for multiple sclerosis (MS) primarily target peripheral immune responses but exhibit limited efficacy in mitigating the compartmentalized neuroinflammation driven by central nervous system (CNS)-resident microglia. By integrating clinical sample analysis with experimental autoimmune encephalomyelitis (EAE) model studies, we have demonstrated that the proviral integration site for Moloney murine leukemia virus 1 (PIM1) is significantly upregulated, particularly in microglia, in both MS patients and the spinal cords of EAE mice. This upregulation positively correlates with disease severity and levels of proinflammatory cytokines such as IL-1β, TNF-α, and IL-6. Utilizing a multimodal research approach-including pharmacological inhibition (SMI-4a), genetic knockdown, RNA sequencing, and HIS-SIM super-resolution imaging-we confirmed that PIM1 inhibition effectively attenuates neuroinflammatory responses, improves clinical symptoms in EAE mice, and promotes activation of the mitophagy pathway while suppressing inflammation-related molecules. Mechanistically, PIM1 enhances the phosphorylation of dynamin-related protein 1 (Drp1) at Ser616 while suppressing its phosphorylation at Ser637, which disrupts LC3-mitochondria colocalization and autophagosome-lysosome fusion. This leads to mitophagy dysfunction, loss of mitochondrial membrane potential, and accumulation of reactive oxygen species. Notably, the combined administration of PIM1 and Drp1 inhibitors did not yield synergistic therapeutic effects, suggesting that PIM1 likely functions as an upstream master regulator of Drp1. These findings not only elucidate the molecular mechanism by which PIM1 interacts with Drp1 to regulate microglial activation and mitophagy but also establish PIM1 as a promising CNS-intrinsic therapeutic target for restoring mitochondrial homeostasis in MS.
    Keywords:  Lysosomal function; Microglia; Mitophagy; Multiple sclerosis; Neuroinflammation; PIM1
    DOI:  https://doi.org/10.1016/j.phrs.2026.108313
  19. Oncol Res. 2026 ;34(7): 21
    Targeting Dynamin-Related Protein 1 and Glucose Metabolism Reverses Acquired Resistance to Sorafenib in Liver Cancer.
    Jinhui Che, Zhiyuan Chen, Feng Zhang, Shuo Zhu, Shengya Cao, Ou Li, Rong Li, Jun Zheng, Yubin Liu.
      Objective: Advanced liver cancer, a highly lethal and increasingly prevalent malignancy, frequently develops sorafenib resistance, with aberrant mitochondrial dynamics and metabolism implicated in its pathogenesis. This study aimed to investigate their interplay and assess combination therapies against sorafenib-resistant liver cancer. Methods: Mitochondrial morphology was assessed using immunofluorescent staining. Besides, the mitochondrial metabolic profile was evaluated by measuring the oxygen consumption rate, glucose uptake, and lactate production. Dynamin-related protein 1 (Drp1) expression was determined through immunohistochemical staining, western blotting, and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Cell counting, colony formation, and cell cycle assays were conducted to evaluate in vitro cell growth. Furthermore, time-lapse cell motility and Transwell assays were employed to assess cell migration and invasion capacities, respectively. Orthotopic xenograft models were utilized to demonstrate the therapeutic effects of the combined administration of the oxidative phosphorylation (OXPHOS) inhibitor IACS-010759 and the Drp1 inhibitor mdivi-1. Result: Importantly, our findings revealed that Drp1-mediated mitochondrial fission and the metabolic switch from OXPHOS to aerobic glycolysis were dominant in sorafenib-resistant liver cancer cells and strongly correlated with tumor prognosis (hazard ratio = 3.899, 95% confidence interval: 1.167-13.022, p = 0.027). Drp1 knockdown or inhibition impaired the invasive and metastatic capabilities of these cancer cells but promoted cell cycle progression and cellular growth, attributed to a metabolic shift from aerobic glycolysis to OXPHOS. Notably, the combined administration of the OXPHOS inhibitor IACS-010759 with mdivi-1 significantly attenuated tumor progression in sorafenib-resistant liver cancer, affecting both proliferation and metastasis. Conclusion: The results of this study collectively indicate that mitochondrial dynamics regulate metabolism in sorafenib-resistant liver cancer, which displays an aggressive hybrid metabolic phenotype. Accordingly, the combined targeting of mitochondrial dynamics and metabolism may represent an effective strategy to overcome sorafenib resistance in liver cancer.
    Keywords:  IACS-010759; Sorafenib-resistant hepatocellular carcinoma; glucose metabolism; mdivi-1; mitochondrial dynamics
    DOI:  https://doi.org/10.32604/or.2026.067443
  20. Oncogene. 2026 Jun 20.
    Hypoxia-induced MIC19 myristoylation promotes PRKN-dependent VDAC2 ubiquitination and activates mitophagy in non-small cell lung cancer.
    Hua Huang, Chen Ding, Zexia Zhao, Wenhao Zhao, Guorui He, Hongbing Zhang, Peijie Chen, Yongwen Li, Hongyu Liu, Jun Chen.
      Tumor hypoxia drives mitophagy reprogramming to support mitochondrial quality control in non-small cell lung cancer (NSCLC) cells, yet the role of the mitochondrial cristae organizers remains poorly understood. Here, we identified MIC19, a key subunit of mitochondrial contact site and cristae organizing system complex, as an essential regulator of hypoxia-induced mitophagy in NSCLC. We demonstrate that prolonged hypoxia induces MIC19 protein expression in a HIF-1α-dependent manner and that elevated MIC19 promotes NSCLC cell proliferation and metastasis. MIC19 sustains mitochondrial morphology and mitophagy activation under hypoxic stress. Mechanistically, HIF-1α transcriptionally upregulates NMT1, an N-myristoyltransferase that catalyzes N-myristoylation at Gly2 of MIC19 protein, which is essential for the mitochondrial localization and protein stability of MIC19. MIC19 facilitates PRKN-dependent K48-linked ubiquitination of the outer mitochondrial membrane protein voltage-dependent anion channel 2 (VDAC2), thereby promoting mitophagy progression under hypoxic stress. Therapeutically, suppression of MIC19 via shRNA combined with pharmacological inhibition of autophagy using chloroquine synergistically impairs NSCLC tumor growth in vivo. Collectively, these findings uncover a previously unrecognized HIF-1α-NMT1-MIC19-VDAC2 axis that drives hypoxia-adaptive mitophagy and reveals a potential therapeutic vulnerability in hypoxic NSCLC.
    DOI:  https://doi.org/10.1038/s41388-026-03847-0
  21. Autophagy. 2026 Jun 22.
    Oxidative stress-preconditioned exosomes target BMF to restore mitophagy for alleviating intervertebral disc degeneration.
    Yun Teng, Tianyi Wu, Yanglin Wu, Jun Ge, Rui Chen, Xiao Sun, Leyu Zhao, Xianggu Zhong, Qi Yan, Qi Zhang, Huilin Yang, Junjie Niu, Jun Zou.
      Exosomes derived from bone marrow mesenchymal stem cells (BMSCs) represent a promising cell-free strategy for intervertebral disc degeneration (IDD). Here, we obtained oxidative stress-preconditioned exosomes (O-Exos) from BMSCs exposed to low-concentration hydrogen peroxide. Compared with exosomes from untreated cells (N-Exos), O-Exos more effectively delayed nucleus pulposus (NP) cell senescence and attenuated IDD in vitro and in vivo. The superior effects of O-Exos were associated with restoration of mitophagy and improved mitochondrial homeostasis in TNF/TNF-α-treated NP cells. BMF (Bcl2 modifying factor) was identified as a functionally relevant downstream target suppressed by O-Exos, and Bmf deficiency promoted mitophagy and alleviated IDD. Further analyses showed that O-Exos relieved the inhibitory effect of BMF on BCL2L13-LC3B coupling, thereby restoring mitophagy. In addition, exosomal Mir29a-3p was required for BMF suppression and the superior activity of O-Exos. Together, these findings identify oxidative stress preconditioning as an effective strategy to enhance exosome potency against IDD.
    Keywords:  BMF; Mir29a-3p; exosomes; intervertebral disc degeneration; mitophagy; nucleus pulposus cells
    DOI:  https://doi.org/10.1080/15548627.2026.2693774
  22. Cells. 2026 Jun 20. pii: 1117. [Epub ahead of print]15(12):
    The Interplay of Splicing and Metabolism in Cancer.
    Dillon M Voss, Yange Cui, Peter S Klein.
      Aberrant RNA splicing and metabolic reprogramming are defining hallmarks of cancer that were historically studied as parallel processes. Increasing evidence now reveals extensive crosstalk between these pathways, whereby RNA splicing reshapes metabolic circuits, and metabolic states reciprocally influence splice-site selection and spliceosome activity. In this review, we synthesize recent mechanistic insights into how splicing programs regulate metabolic adaptation across diverse cancer contexts. We discuss recurrent oncogenic mutations in spliceosomal components and dysregulation of RNA-binding proteins (RBPs) that drive alternative splicing events in key metabolic regulators, which promote metabolic plasticity required for tumor growth. We further examine how metabolites and nutrient-sensing pathways directly modulate splicing factor activity, spliceosome dynamics, and RNA processing. We also summarize a new mechanism of mitochondrial quality control mediated by retrograde signals from mitochondria to the spliceosome to enhance mitophagy of dysfunctional mitochondria.
    Keywords:  PINK1; cancer; leukemia; metabolism; mitophagy; myelodysplasia; pyruvate kinase; retrograde signaling; spliceosome; splicing
    DOI:  https://doi.org/10.3390/cells15121117
  23. J Ethnopharmacol. 2026 Jun 22. pii: S0378-8741(26)00948-7. [Epub ahead of print]371 122094
    Suppression of STING by Acacetin attenuates renal fibrosis via balancing mitophagy and protective nucleoid-phagy.
    Yujiu Gao, Linjie Mu, Chen Liu, Yue Zhao, Rui Cai, Liting Zhu, Fu Rao, Hanxiao Bao, Jinfang Chen, Meixia Fan, Congcong Zeng, Zhengzhong Yuan, Tingting Wei, Jinguo Cheng.
       ETHNOPHARMACOLOGICAL RELEVANCE: Acacetin (5,7-dihydroxy-4'-methoxyflavone) is a primary active flavonoid extracted from traditional medicinal plants such as Agastache rugosa and Saussurea involucrata. Historically, these herbs have been utilized in Traditional Chinese Medicine to clear heat, eliminate dampness, and treat inflammatory and kidney-related ailments. Despite its potent anti-inflammatory properties, the direct molecular targets of Acacetin and its specific mechanisms regarding mitochondrial quality control (MQC) in the progression of renal fibrosis (RF) remain undefined.
    AIM OF THE STUDY: This study aimed to evaluate the anti-fibrotic efficacy of Acacetin and elucidate whether it directly targets the cGAS-STING cascade to restore organelle homeostasis by balancing mitophagy and protective nucleoid-phagy.
    METHODS: Molecular dynamics (MD) simulations, microscale thermophoresis (MST), and drug affinity responsive target stability (DARTS) assays were utilized to verify the direct binding between Acacetin and STING. In vivo, wild-type (WT) and STING-knockout (STING-/-) mice were subjected to unilateral ureteral obstruction (UUO) and folic acid nephropathy (FAN) models, and administered Acacetin (40 and 80 mg/kg/d). In vitro, human renal tubular epithelial (HK-2) cells were stimulated with TGF-β or cGAMP. Mitochondrial function, ultrastructure, and dynamic autophagic flux were evaluated using Seahorse XF analysis, transmission electron microscopy (TEM), bafilomycin A1 (BafA1) blockade, tandem fluorescence imaging, and immunofluorescence. Protein and gene expressions were measured via Western blotting and RT-qPCR.
    RESULTS: Biophysical assays identified Acacetin as a direct STING inhibitor that bound to the STING protein pocket (Kd = 1.57 μM) and effectively antagonized its cGAMP-induced phosphorylation. Consequently, Acacetin dose-dependently alleviated UUO- and FA-induced renal fibrogenesis, suppressed oxidative stress, and restored mitochondrial respiratory capacity. Mechanistically, Acacetin promoted a functional shift in MQC: it suppressed the initiation phase of maladaptive PINK1/Parkin-mediated "exhaustive over-mitophagy" while facilitating TFAM-LC3-associated "nucleoid-phagy" to selectively clear immunogenic leaked mitochondrial DNA (mtDNA). Crucially, the anti-fibrotic, anti-inflammatory, and MQC-restoring benefits of Acacetin were completely abolished in STING-/- mice, establishing STING as its indispensable pharmacological target.
    CONCLUSION: Acacetin ameliorates renal fibrogenesis by directly inhibiting STING, thereby regulating the balance between pathological over-mitophagy and protective nucleoid-phagy. These findings validate the traditional use of Acacetin-rich herbs in treating inflammatory conditions and highlight the monomer as a promising mechanism-based therapeutic candidate for the treatment of chronic kidney disease.
    Keywords:  Acacetin; Mitophagy; Nucleoid-phagy; Renal fibrosis; STING
    DOI:  https://doi.org/10.1016/j.jep.2026.122094
  24. Phytother Res. 2026 Jun 25.
    Correction to "Shenlian Extract Decreases Mitochondrial Autophagy to Regulate Mitochondrial Function in Microvascular to Alleviate Coronary Artery No-Reflow".
      
    DOI:  https://doi.org/10.1002/ptr.70399
  25. Viruses. 2026 Jun 16. pii: 675. [Epub ahead of print]18(6):
    Exploring Key Regulators of Mitochondrial Dynamics and Immune Response in SARS-CoV-2 Infection.
    Thatiana Corrêa de Melo, Hellen Paula Valerio, Dilza Trevisan-Silva, Marcelo Medina de Souza, Amanda Teixeira de Melo, Miryam Paola Alvarez-Flores, Douglas Souza Oliveira, Renata Nascimento Gomes, Glaucia Maria Machado-Santelli, Beatriz Fumelli Monti Ribeiro, Viviane Fongaro Botosso, Soraia Attie Calil Jorge, Ana Marisa Chudzinski-Tavassi.
      Mitochondria are central hubs of antiviral immunity and cellular metabolism, yet the links between SARS-CoV-2-induced mitochondrial remodeling, antiviral gene regulation, and post-translational control remain incompletely understood. Here, we investigated mitochondrial-immune remodeling in SARS-CoV-2-infected lung-derived LC-HK2 cells at 48 and 96 h post-infection using confocal and high-content imaging, colocalization analysis, CellProfiler quantification, RT-qPCR, proteomics, cytokine profiling, and conditioned-medium analysis. Infection induced a time-dependent mitochondrial phenotype. At 48 hpi, cells displayed early mitochondrial stress and fission-associated signatures, including increased DRP1, transient upregulation of mitochondrial respiratory genes, and reduced MFN1/2. At 96 hpi, mitochondria shifted toward elongated perinuclear networks, accompanied by increased fusion/biogenesis markers and partial ISG15-MFN2 colocalization, indicating a spatial association between ISG15-related antiviral/stress responses and mitochondrial remodeling. Antiviral and ISG-related transcripts were consistently upregulated, but IFN-α2 secretion remained limited, suggesting partial uncoupling between antiviral transcriptional activation and downstream interferon output. SUMO2/3 was dynamically modulated and showed time-dependent colocalization with mitochondrial dynamics proteins and MAVS. Together, these data support a coordinated mitochondrial-immune regulatory axis involving mitochondrial remodeling, ISG15-associated responses, and SUMO-dependent regulation during SARS-CoV-2 infection.
    Keywords:  ISG15; LC-HK2 cells; MAVS; MFN2; SARS-CoV-2; SUMO2/3; innate immunity; mitochondrial dynamics; post-translational modifications; proteomics
    DOI:  https://doi.org/10.3390/v18060675
  26. bioRxiv. 2026 Jun 09. pii: 2026.06.04.729996. [Epub ahead of print]
    PINK1 loss in astrocytes triggers inflammatory dysfunction and neuronal death.
    Gabriella Fiorino, Damian N Di Florio, Deshaun H Hadley, Owen A Ross, Fabienne C Fiesel, Wolfdieter Springer.
      Genetic loss of the mitochondrial control enzyme PINK1 leads to Parkinson's disease, characterized by dopaminergic neuron degeneration and neuroinflammation, yet its role in glia remains poorly understood. To address this gap, we investigated how the function of astrocytes and their ability to support neurons is influenced by PINK1 deficiency. For the first time, we demonstrate that human astrocytes exhibit robust PINK1 activity. Next, the first bulk transcriptomic study of human PINK1 mutant astrocytes was performed followed by biochemical validation at the protein level, uncovering homeostatic collapse. Co-culture experiments demonstrated that this astrocyte dysfunction drives neuronal damage through non-cell-autonomous mechanisms. Notably, pharmacological enhancement of autophagy successfully mitigated this inflammatory secretome, indicating that mitochondrial quality control deficits are reversible. These findings establish an unexpected role for PINK1 in glial biology, reveal that astrocytes are vulnerable to mitophagy deficits, and highlight a novel mechanistic link connecting mitochondrial dysfunction, neuroinflammation, and neurodegeneration.
    DOI:  https://doi.org/10.64898/2026.06.04.729996
  27. Int J Mol Sci. 2026 Jun 11. pii: 5302. [Epub ahead of print]27(12):
    Cisplatin-Induced Nephrotoxicity Attenuation by Schizophyllum commune Through Regulating Mitochondria-Associated Signaling, Apoptosis, Autophagy, and PINK1/Parkin-Mediated Mitophagy.
    Yu-Wen Sun, Te-Kai Sun, Wen-Ping Jiang, Guan-Jhong Huang.
      Associated with high morbidity and mortality, cisplatin-induced acute kidney injury (AKI) is a common clinical complication characterized by oxidative stress, inflammation, and mitochondria-associated signaling. Although multiple signaling pathways have been implicated in AKI progression, effective interventions targeting these complex mechanisms are still lacking. As a medicinal fungus with antioxidant and anti-inflammatory properties, Schizophyllum commune (SC) has shown potential biological activities; however, its renoprotective effects in cisplatin-induced AKI remain unclear. Therefore, this study aimed to investigate SC's protective effects and underlying mechanisms in a cisplatin-induced AKI mouse model. SC treatment improved renal function and attenuated histopathological damage. It reduced oxidative stress and inflammatory responses, as evidenced by the modulation of malondialdehyde (MDA), glutathione (GSH), nitric oxide (NO), and pro-inflammatory cytokines. Mechanistically, SC regulated multiple signaling pathways, including mitogen-activated protein kinase (MAPK), toll-like receptor 4/nuclear factor kappa B (TLR4/ NF-κB), PI3K/AKT, nuclear factor erythroid 2-related factor 2/heme oxygenase-1 (Nrf2/HO-1), and the calcium/calmodulin-dependent protein kinase kinase-AMP-activated protein kinase-sirtuin 1 (CaMKK-AMPK-Sirt1) axis. In addition, SC modulated apoptosis, autophagy, and PTEN-induced kinase 1 (PINK1)/Parkin-mediated mitophagy, suggesting improved mitochondrial homeostasis. These findings indicate that SC exerts renoprotective effects and may contribute to cisplatin-induced nephrotoxicity mitigation strategies.
    Keywords:  Schizophyllum commune; acute kidney injury; cisplatin; mitochondria; mitophagy; oxidative stress
    DOI:  https://doi.org/10.3390/ijms27125302
  28. J Neurodev Disord. 2026 Jun 26.
    DRP1 mutations associated with EMPF1 encephalopathy perturb the transcriptional profile and maturation of cortical neurons.
    T B Baum, J Costanzo, C Bodnya, D P Boulton, M C Caino, D Mogilenko, A Zhelonkin, V Gama.
      With the advent of exome sequencing, a growing number of children are being identified with de novo loss-of-function mutations in the dynamin 1-like (DNM1L) gene, which encodes the large GTPase essential for mitochondrial fission, dynamin-related protein 1 (DRP1). Mutations in DRP1 result in severe neurodevelopmental phenotypes, such as developmental delay, optic atrophy, and epileptic encephalopathies. Though it is established that mitochondrial fission is an essential precursor to the rapidly changing metabolic needs of the developing cortex, it is not understood how identified mutations in different domains of DRP1 uniquely disrupt cortical development and synaptic maturation. We leveraged the power of human induced pluripotent stem cells (iPSCs) harboring DRP1 mutations in either the GTPase or stalk domains to model early stages of cortical development in vitro. High-resolution time-lapse imaging of transport in neuronal projections revealed mutation-specific changes in mitochondrial motility of severely hyperfused mitochondrial structures. Transcriptional profiling of mutant DRP1 cortical neurons during maturation also implicated mutation-dependent alterations in synaptic development and gene expression of calcium-regulatory genes. Disruptions in calcium dynamics were confirmed using live functional recordings of 65-200 days in vitro (DIV) mutant DRP1 cortical neurons. These findings strongly suggest that altered mitochondrial morphology in DRP1 mutant neurons leads to pathogenic dysregulation of synaptic development and activity.
    Keywords:  DRP1; Mitochondria; Mitochondrial fission; Neurons
    DOI:  https://doi.org/10.1186/s11689-026-09713-0
  29. Toxics. 2026 May 27. pii: 469. [Epub ahead of print]14(6):
    Copper and PFOS Co-Exposure Induces Synergistic Neurotoxicity via ROS-Mediated Mitophagy in C. elegans.
    Peixin Lu, Ying Zhang, Ruo Zhang, Kejia Liu, Wei Shi, Lu Lu, Qian Zhou, Yuepu Pu, Lihong Yin.
      Copper (Cu) and perfluorooctanesulfonic acid (PFOS) are ubiquitous environmental pollutants that frequently co-occur, each capable of inducing neurotoxicity individually. However, the combined toxicity and interactive mechanisms of their co-exposure remain unclear, hindering an accurate assessment of their combined environmental health risks. Using the Caenorhabditis elegans model, we investigated the effects of co-exposure to environmentally relevant concentrations. Compared to individual exposures, co-exposure triggered synergistic neurotoxicity, characterized by the loss of dopaminergic (DAergic) and glutamatergic (GLUergic) neurons, aggravated locomotor deficits, massive accumulation of reactive oxygen species (ROS), and a severe decline in mitochondrial membrane potential, accompanied by substantial mitochondrial ultrastructural damage and accumulation of autophagosomes. Mechanistically, the excessive oxidative stress induced by co-exposure aberrantly and persistently activated the ROS-mediated mitophagy pathway, thereby impairing mitochondrial quality control. Critically, intervention with N-acetylcysteine (NAC), an antioxidant, effectively mitigated the co-exposure-induced deficits, identifying oxidative stress as the central driver of the synergistic toxicity. Our findings reveal a novel mechanism by which Cu and PFOS exert synergistic neurotoxicity via the oxidative-stress-mitophagy axis, providing key scientific evidence for refining the assessment of their combined environmental pollution risks.
    Keywords:  C. elegans; Cu; PFOS; mitophagy; neurotoxicity
    DOI:  https://doi.org/10.3390/toxics14060469
  30. Cell Rep. 2026 Jun 26. pii: S2211-1247(26)00685-6. [Epub ahead of print]45(7): 117607
    Disrupted mitochondrial dynamics activate RNA-sensing innate immunity through mitochondrial RNA release.
    Tatsuki Yasuda, Aoi Ichikawa, Kenta Onoue, Emi Ogasawara, Takaya Ishihara, Hidetaka Kosako, Naotada Ishihara.
      Mitochondria are dynamic organelles that continuously remodel their morphology through fusion and fission in response to cellular cues. While this dynamic behavior is essential for diverse cellular functions, how mitochondrial dynamics influence innate immune responses remains incompletely understood. Here, we show that mitochondrial hyperfusion-induced by loss of the fission factor DRP1 or by cellular stress, including cycloheximide or doxorubicin treatment-is associated with activation of a RIG-I-MAVS-dependent innate immune response and BAX-dependent cytosolic release of mitochondrial RNA. Functionally, our data suggest that this pathway contributes to enhanced susceptibility to NK cell-mediated cytotoxicity in vitro and reduced tumor growth in a xenograft model. Collectively, our findings identify mitochondrial hyperfusion-induced mtRNA release as a mechanism that engages innate immune signaling downstream of impaired mitochondrial dynamics.
    Keywords:  CP: immunology; DRP1; RIG-I; innate immunity; mitochondrial RNA; mitochondrial dynamics; mitochondrial hyperfusion; molecular biology
    DOI:  https://doi.org/10.1016/j.celrep.2026.117607
  31. Brain Res Bull. 2026 Jun 23. pii: S0361-9230(26)00301-1. [Epub ahead of print]243 112014
    Lamivudine ameliorates neuropathology in 5×FAD mice via coordinated inhibition of the cGAS-STING pathway with enhancement of mitophagy.
    Yang Zhang, Xiuqing Zhang, Junsong Huang, Zhongsheng Sun.
      Alzheimer's disease is a neurodegenerative disorder for which there is currently no effective treatment available. Epidemiological and clinical evidence suggests that lamivudine, a nucleoside reverse transcriptase inhibitor, is associated with a reduced risk of Alzheimer's disease and shows potential in alleviating neuroinflammation. This study therefore aims to employ AD mouse models to further investigate the molecular mechanisms by which lamivudine ameliorates AD-related phenotypes. In this study, we showed that lamivudine administration inhibited cGAS-STING activation and attenuated mitochondrial damage in the 5 ×FAD mouse model, as supported by improved mitochondrial morphology and enhanced mitophagy. These changes were associated with improved spatial memory, alongside reduced neuronal apoptosis and synaptic loss. Our findings underscore the neuroprotective potential of lamivudine in AD via coordinated preservation of mitochondrial integrity and suppression of innate immune signaling, suggesting its promise for clinical translation in neurodegenerative disorders.
    Keywords:  Alzheimer’s disease; CGAS-STING pathway; Lamivudine; Mitophagy
    DOI:  https://doi.org/10.1016/j.brainresbull.2026.112014
  32. Phytomedicine. 2026 Jun 17. pii: S0944-7113(26)00681-1. [Epub ahead of print]159 158450
    Oxymatrine alleviates cerebral ischemia-reperfusion injury by inhibiting microglia ferroptosis via NRF2 pathway activation.
    Nanding Wu, Yutong Wang, Mengjie Guo, Ruili Ran, Dewei Wang, Junqiu Song, Lishan Hui, Jing Yang, Yue Yang.
       BACKGROUND: Cerebral ischemia-reperfusion injury (CIRI) involves secondary damage following blood flow restoration. Ferroptosis, an iron-dependent cell death process, is implicated in CIRI, with mitochondrial dynamics imbalance playing a critical role. Oxymatrine (OMT), a quinolizidine alkaloid extracted from the root of Sophora flavescens, exhibits neuroprotective properties, yet its role in modulating microglia ferroptosis and mitochondrial homeostasis during CIRI remains unclear.
    PURPOSE: This study aimed to investigate whether OMT attenuates microglia ferroptosis in CIRI by activating the nuclear factor erythroid 2-related factor 2 (NRF2) pathway and restoring mitochondrial dynamic balance.
    METHODS: Using a rat middle cerebral artery occlusion/reperfusion model and BV-2 microglia under oxygen-glucose deprivation/reoxygenation, we evaluated the effects of OMT alone or with NRF2 inhibitor ML385 or ferroptosis inducer Erastin. Assessments included neurological scores, infarct volume, Reactive Oxygen Species, ferrous iron, malondialdehyde, glutathione, mitochondrial membrane potential, and related protein expression, including NRF2, kelch-like ECH-associated protein 1 (KEAP1), heme oxygenase-1, solute carrier family 7 member 11, ferritin heavy chain, glutathione peroxidase 4, dynamin-related protein 1, optic atrophy 1. Molecular docking, surface plasmon resonance, and co-immunoprecipitation were used to examine OMT-KEAP1 binding. Finally, in vitro rescue experiments using KEAP1 overexpression and CDDO-ME (a specific KEAP1 inhibitor) confirmed the KEAP1/NRF2 dependency by re-assessing cell viability and ferroptosis markers.
    RESULTS: OMT improved neurological outcomes and suppressed ferroptosis in vivo and in vitro. Mechanistically, OMT disrupted KEAP1-NRF2 binding, promoting NRF2 nuclear translocation and upregulating solute carrier family 7 member 11, heme oxygenase-1, ferritin heavy chain, and glutathione peroxidase 4. This restored mitochondrial homeostasis by balancing optic atrophy 1 and dynamin-related protein 1, thereby reducing lipid peroxidation. Crucially, these effects were abolished by ML385 or Erastin, while KEAP1 overexpression and CDDO-ME respectively mimicked KEAP1-mediated suppression and NRF2-driven protection. These findings confirm OMT acts via a KEAP1/NRF2-dependent anti-ferroptotic axis.
    CONCLUSIONS: OMT protects against CIRI by inhibiting microglia ferroptosis through NRF2 pathway activation and improvement of mitochondrial homeostasis, supporting its potential as a therapeutic agent for ischemic stroke.
    Keywords:  Cerebral ischemia-reperfusion injury; Ferroptosis; Microglia; Mitochondrial dynamics; Oxymatrine
    DOI:  https://doi.org/10.1016/j.phymed.2026.158450
  33. Biochim Biophys Acta Mol Basis Dis. 2026 Jun 26. pii: S0925-4439(26)00201-2. [Epub ahead of print] 168338
    Regular exercise improves cardiac dysfunction in Drosophila by inhibiting excessive mitochondrial fission through RalA.
    Wenqing Huang, Meng Ding, Qin Yi, Yuepeng Li, Wenzhi Gu, Ping Zhang, Rui Tian, Zhilong Zhang, Lan Zheng.
      Metabolic disorders leading to cardiac dysfunction have become a global health challenge, and the cardioprotective mechanisms of regular exercise remain unclear. This study focused on the small GTPase RalA and revealed its critical role in exercise-mediated improvement of high-fat-induced cardiac dysfunction. Using a high-fat-fed drosophila heart model, combined with genetic manipulation and exercise intervention, it was demonstrated that a high-fat diet upregulates RalA expression in the myocardium, accompanied by excessive mitochondrial fission and impaired cardiac function. Regular exercise not only effectively reversed these pathological phenotypes but also exerted its protective effects in a RalA -dependent manner within the myocardium. Mechanistically, RalA appeared to exert its effects not through traditional energy metabolism pathways, but rather through the regulation of Drp1-mediated mitochondrial fission, thereby preserving mitochondrial network homeostasis and energy supply in cardiomyocytes. This study is the first to propose a novel "exercise-RalA-mitochondrial dynamics" signaling axis, providing new mechanistic insight into the cardioprotective effects of exercise and suggesting that targeting the RalA pathway may represent a promising therapeutic strategy for metabolic heart disease.
    Keywords:  Cardiac function; Drp1; Exercise; Mitochondrial fission; RalA
    DOI:  https://doi.org/10.1016/j.bbadis.2026.168338
  34. Phytomedicine. 2026 Jun 17. pii: S0944-7113(26)00690-2. [Epub ahead of print]159 158459
    Pterostilbene mitigates intervertebral disc degeneration via dual regulation of mitophagy and NLRP3 ubiquitination to inhibit nucleus pulposus cell pyroptosis.
    Yang Zhang, Shuanggong Liu, Shuhang Dong, Guangxu Song, Kewen Wang, Zhi Zhou, Guowei Yang, Xu Yang, Shuai Peng, Yingze Zhang, Dongjin Wu.
       BACKGROUND: Intervertebral disc degeneration (IVDD) is a major contributor to low back pain and is characterized by mitochondrial dysfunction, inflammation, and regulated cell death in nucleus pulposus (NP) cells. NLRP3 inflammasome-mediated pyroptosis plays a pivotal role in disc degeneration, whereas mitophagy limits mitochondrial damage and inflammasome activation. Emerging evidence indicates that pterostilbene (PTE) exhibits diverse pharmacological activities; however, its role in attenuating IVDD remains insufficiently understood.
    OBJECTIVE: To investigate whether PTE attenuates IVDD by regulating mitophagy and NLRP3 inflammasome-mediated pyroptosis, and to elucidate the underlying molecular mechanisms.
    STUDY DESIGN: This study combined network pharmacology analysis, in vitro cellular experiments, and an in vivo rat IVDD model to evaluate the therapeutic effects and mechanisms of PTE.
    METHODS: Network pharmacology was used to predict the cytoprotective potential of PTE. In vitro, LPS-stimulated NP cells were employed to evaluate inflammation, extracellular matrix degradation, pyroptosis, mitochondrial function, and mitophagic flux. Pharmacological inhibitors were used to interrogate mitophagy-dependent mechanisms, while Western blotting, co-immunoprecipitation, and related assays were performed to assess signaling pathways, protein stability, and ubiquitination. In vivo, a rat IVDD model was established to evaluate the therapeutic effects of PTE through radiological and histopathological analyses.
    RESULTS: PTE attenuated LPS-induced inflammatory responses and extracellular matrix degradation in NP cells. It suppressed NLRP3 inflammasome-mediated pyroptosis and restored mitochondrial function by enhancing mitophagic flux, whereas inhibition of mitophagy partially reversed these protective effects. Mechanistically, PTE activated the AMPK/mTOR/ULK1 signaling pathway to promote mitophagy. In parallel, PTE facilitated ubiquitination and proteasomal degradation of NLRP3, predominantly through K48-linked polyubiquitination, while K63-linked modification may contribute to regulatory signaling. Notably, this ubiquitination-mediated degradation occurred independently of mitophagy. In vivo, PTE significantly alleviated disc degeneration, reduced NLRP3, caspase-1, and p-mTOR expression, and increased collagen II, SOX9, PINK1, LC3, and p-AMPK levels.
    CONCLUSION: PTE attenuates IVDD progression by coordinately enhancing mitophagy and promoting K48-linked ubiquitin-proteasome-dependent degradation of NLRP3. These two mechanisms operate independently yet synergistically to suppress inflammasome activation, providing mechanistic insight into PTE as a potential disease-modifying therapeutic strategy for IVDD.
    Keywords:  AMPK/mTOR/ULK1 signaling pathway; IVDD; Mitophagy; PTE; Pyroptosis; Ubiquitin-proteasome pathway
    DOI:  https://doi.org/10.1016/j.phymed.2026.158459
  35. Life (Basel). 2026 Jun 16. pii: 1008. [Epub ahead of print]16(6):
    Mitochondrial Adaptations to Exercise Training in Equine Skeletal Muscle: A Narrative Review.
    Vlad Cocioba, Paula Nistor, Daniel George Bratu, Șerban Blaga, Bianca Cornelia Zanfira, Călin Mircu, Ioan Huțu.
      The horse represents one of the most physiologically specialized athletic mammals, capable of sustaining both high-intensity and prolonged exercise. Central to this remarkable performance capacity is the metabolic adaptability of skeletal muscle and its mitochondrial network. This narrative review synthesizes current evidence from equine, human, and rodent studies on exercise-induced mitochondrial remodeling in equine skeletal muscle. A comprehensive literature search was conducted across PubMed, Web of Science, and Scopus using terms related to equine exercise physiology, mitochondrial biology, and skeletal muscle metabolism. Preference was given to peer-reviewed original research and review articles. Mitochondria regulate oxidative phosphorylation, substrate oxidation, redox signaling, and cellular responses to metabolic stress induced by exercise. Training induces extensive mitochondrial adaptations, including mitochondrial biogenesis, remodeling of the respiratory chain, enhanced oxidative phosphorylation efficiency, and increased metabolic flexibility. These adaptations are believed to contribute to improvements in aerobic capacity, delayed fatigue onset, and enhanced recovery following exercise, although direct mechanistic evidence in horses remains limited. In equine skeletal muscle, mitochondrial plasticity is closely linked to muscle fiber composition and the distribution of oxidative and glycolytic fibers. Exercise-induced signaling pathways involving AMP-activated protein kinase (AMPK), Ca2+-dependent kinases, and the transcriptional coactivator PGC-1α regulate mitochondrial biogenesis and metabolic remodeling. In addition, mitochondrial dynamics, including fusion, fission, and mitophagy, maintain mitochondrial quality and functional efficiency during repeated training stimuli. Experimental studies in Thoroughbred and Standardbred horses demonstrate that training has been associated with increases in mitochondrial density and respiratory capacity in equine skeletal muscle, contributing directly to improved aerobic performance and metabolic efficiency. However, mitochondrial adaptations must be interpreted within the broader context of musculoskeletal adaptation, as metabolic improvements may occur faster than structural adaptation of tendons and ligaments. This review synthesizes current knowledge on exercise-induced mitochondrial remodeling in equine skeletal muscle, while highlighting the limited mechanistic evidence available in horses and the need for more standardized longitudinal studies.
    Keywords:  equine athletes; equine exercise physiology; exercise adaptation; metabolic flexibility; mitochondria; mitochondrial biogenesis; oxidative phosphorylation; skeletal muscle
    DOI:  https://doi.org/10.3390/life16061008
  36. Nat Neurosci. 2026 Jun 26.
    The mitochondrial unfolded protein response in human microglia disrupts neuronal-glial communication and promotes senescence.
    Maria Jose Perez J, Alicia Lam, Christin Weissleder, Federico Bertoli, Hariam Raji, Mariella Bosch, Ivan Nemazanyy, Stefanie Kalb, Mohammed Kehili, Insa Hirschberg, Dario Brunetti, Indra Heckenbach, Morten Scheibye-Knudsen, Michela Deleidi.
      Mitochondria have evolved a specialized mitochondrial unfolded protein response (UPRmt) to maintain proteostasis and promote recovery under stress. Studies in simple organisms have shown that UPRmt activation in glial cells supports proteostasis through beneficial non-cell-autonomous communication with neurons. However, the role of mitochondrial stress responses in the human brain remains unclear. To address this gap, we investigated the cell-type-specific effects of mitochondrial proteotoxic stress using human induced pluripotent stem cell-derived neuronal and glial cultures, as well as brain organoids. Here we show that mitochondrial proteotoxic stress induces metabolic rewiring in human microglia, marked by depletion of S-adenosylmethionine and lipid remodeling, ultimately leading to a senescent phenotype. Using human neuronal-glial tricultures and microglia-containing brain organoids, we identified the specific contributions of microglia to brain senescence and mitochondrial stress-driven neurodegenerative processes. UPRmt activation disrupts microglial communication with neighboring cells, triggering inflammatory signaling and impairing proteostasis. Together, these findings reveal how impaired mitochondrial proteostasis alters intercellular networks and identify a critical role for the UPRmt in neurodegenerative disease pathogenesis.
    DOI:  https://doi.org/10.1038/s41593-026-02320-1
  37. Am J Physiol Heart Circ Physiol. 2026 Jun 27.
    Desmoglein-2 Deficiency Drives Mitochondrial Morphological Remodeling in Cardiomyocytes.
    Alexandre Gonçalves, Elaine Zhelan Chen, Hosna Rastegarpouyani, Aurélia Araújo Fernandes, Inês N Alves, Vasco Sequeira, Chulan Kwon, Stephen P Chelko, Maicon Landim-Vieira.
      Pathogenic variants in desmoglein-2 (DSG2) are a major cause of arrhythmogenic cardiomyopathy (ACM), a disease plagued by ventricular arrhythmias, contractile dysfunction, myocardial inflammation, and fibrofatty remodeling. Additionally, increasing evidence implicates mitochondrial dysfunction in DSG2-associated disease. However, whether mitochondrial remodeling occurs uniformly across ventricles remains less well defined. Here, we utilized a homozygous Dsg2 mutant (Dsg2mut/mut) mouse to define chamber-specific mitochondrial remodeling in DSG2-linked ACM. Re-analysis of our previously generated cardiomyocyte snRNAseq dataset revealed broad downregulation of mitochondrial transcripts involved in fusion/fission dynamics, calcium handling, mitophagy, structural organization, and electron transport chain (ETC) assembly, findings that are consistent with impaired mitochondrial homeostasis and bioenergetic capacity. Ultrastructural analyses by transmission electron microscopy showed that Dsg2mut/mut hearts contained an increased number of mitochondria, which were smaller, irregularly shaped, and more disorganized than wildtype (WT) counterparts. Importantly, these alterations were chamber-dependent, with the right ventricle (RV) displaying more pronounced reductions in mitochondrial circularity and greater mitochxondrial abundance than the left ventricle (LV), indicating increased RV susceptibility. Together, these findings unveil mitochondrial remodeling as a feature of DSG2-deficiency and support a desmosomal-mitochondrial axis in ACM pathogenesis, further supporting mitochondrial pathways as candidate therapeutic targets.
    Keywords:  Desmoglein-2; arrhythmogenic cardiomyopathy; mitochondria
    DOI:  https://doi.org/10.1152/ajpheart.00368.2026
  38. J Cardiothorac Surg. 2026 Jun 26.
    HIF-1α-mediated mitochondrial autophagy in the post-treatment protective effect of thyroxine against myocardial ischemia-reperfusion injury.
    Hongbo Yu, Jingsheng Feng, Kepeng Wang, Xuehui Zhang.
       BACKGROUND: This study aimed to investigate the role of HIF-1α-regulated mitochondrial autophagy in the protective effect of Thyroxine against myocardial ischemia-reperfusion injury.
    METHODS: Male Sprague-Dawley rats were randomly divided into five groups (n = 10 each): Sham, I/R, L-Thyroxine (T4) post-treatment (20 µg/kg i.p. immediately after reperfusion), 2ME2 + I/R (15 mg/kg 2ME2 i.p. 30 min before ischemia), and 2ME2 + Thyroxine groups. The I/R model was established by ligating the left anterior descending coronary artery for 40 min followed by 120 min of reperfusion.
    RESULTS: Compared with the I/R group, Thyroxine treatment significantly up-regulated HIF-1α (2.<0.01) and BNIP3 (1.8 < 0.01) protein expressions, reduced the LC3-II/LC3-I ratio (0.6-fold, P < 0.01), Beclin-1 (0.<0.01) and P62 (0.40.01) accumulation, while increasing LAMP2 expression (1.6-fold, P < 0.01). Thyroxine treatment reduced ROS production from 80% to 40% DHE-positive nuclei (P < 0.01), increased ATP content from 45% to 75% of sham levels (P < 0.05), restored mitochondrial membrane potential (JC-1 red/green ratio increased from 0.4 to 0.8, P < 0.01), and decreased myocardial infarct size from 45% to 20% of the area at risk (P < 0.01). These protective effects were abolished by the HIF-1α inhibitor 2ME2 pre-treatment.
    CONCLUSION: Thyroxine reduced the area of myocardial infarction and promoted mitochondrial autophagy by activating the HIF-1α/BNIP3 signaling pathway.
    Keywords:  HIF-1α/BNIP3; Mitophagy; Myocardial ischemia-reperfusion; Thyroxine
    DOI:  https://doi.org/10.1186/s13019-026-04463-5
  39. J Ethnopharmacol. 2026 Jun 26. pii: S0378-8741(26)00949-9. [Epub ahead of print] 122095
    Salvia miltiorrhiza Bunge Alleviates Pulmonary Fibrosis by Promoting Fibroblast Mitophagy.
    Zhang Xing, Duan Naifan, Xue Yan, Chen Feng, Zhou Ziyi, Lin Jiacheng, Zhang Wei.
       ETHNOPHARMACOLOGICAL RELEVANCE: Salvia miltiorrhiza Bunge (SM), a traditional medicinal herb, demonstrates potential in treating pulmonary fibrosis (PF). Although preclinical studies suggest anti-fibrotic properties, its mechanisms remain unclear. This study elucidates the efficacy and molecular pathways of SM in pulmonary fibrosis.
    MATERIALS AND METHODS: A rodent model of pulmonary fibrosis and an in vitro lung fibroblast system were established. RNA sequencing and gene interference were used to investigate the core mechanism of SM action.
    RESULTS: We found that SM remarkably alleviated pulmonary fibrosis by reducing pulmonary edema and inflammation in PF rats. SM inhibited TGF-β1-induced fibroblast activation and collagen formation. Mechanistically, SM inhibited TGF-β1-induced Smad2/3 signaling. RNA-seq analysis revealed that SM enhanced mitophagy, thereby preserving mitochondrial membrane potential, a process implicated in fibroblast activation. Moreover, we observed that SM activated PINK1/parkin signaling in cultured fibroblasts and in fibroblasts isolated from fibrotic lungs. SM promoted PINK1 spot formation and increased the mitochondrial LC3BII/I ratio. Furthermore, we found that PINK1 knockdown or AKT inhibition weakens the anti-activating effect in fibroblasts.
    CONCLUSIONS: Taken together, our results showed that SM could alleviate pulmonary fibrosis. SM promotes mitophagy to reduce mitochondrial dysfunction, thereby inhibiting fibroblast activation. These effects of SM may depend on the regulation of AKT/PINK1 signaling. Taken together, we suggest that SM is a substitution therapy for pulmonary fibrosis with a protective effect on mitochondria.
    Keywords:  Mitophagy; Pulmonary fibrosis; Salvia miltiorrhiza Bunge
    DOI:  https://doi.org/10.1016/j.jep.2026.122095
  40. Mol Biol Cell. 2026 Jun 24. mbcE25090461
    Differential effects of tropomyosin paralogs on mitochondrial dynamics in Saccharomyces cerevisiae.
    Freya Cardozo, Aakansha Paliwal, Adwaita Bose, Swagata Adhikary, Sunil Laxman, Patrick D'Silva, Saravanan Palani.
      The actin cytoskeletal network is closely associated with mitochondria and performs crucial functions in mitochondrial movement, inheritance, and fission-fusion. Although its role in mitochondrial division is established, the specific contributions of actin-binding proteins (ABPs) remain unclear. Here, we report the role of tropomyosin, an ABP, in modulating mitochondrial morphology and dynamics. We demonstrate that loss of Tpm1 and Tpm2 in Saccharomyces cerevisiae differentially alters mitochondrial morphology. Tpm1 deletion results in fragmented mitochondria, whereas Tpm2 deletion produces an elongated tubular morphology. Through live-cell imaging, we show the localization of both paralogs to mitochondria, providing direct evidence of their association with the organelle. Microscopy-based analysis of fission-fusion frequencies revealed no change in the Tpm1 deletion, whereas Tpm2 deletion showed a decrease in these events, with a concomitant increase in the fusion factor Mgm1. Further, we characterized the overall health of mitochondria in the Tpm deletion mutants. Fragmented mitochondria in the Tpm1 deletion were hyperpolarized and exhibited increased mass and activity with elevated OCR, ATP levels, and basal ROS. In contrast, the tubular morphology of the Tpm2 deletion did not impair mitochondrial health. Overall, our findings suggest that Tpm modulates mitochondrial morphology and dynamics through its association with the actin cytoskeletal network.
    DOI:  https://doi.org/10.1091/mbc.E25-09-0461
  41. Front Oncol. 2026 ;16 1849057
    Targeting mitochondria as a potential therapeutic strategy against radioresistance in cancer.
    Nazia Nazam, Shaikh Sadiya, Saba Khan, Aroonima Misra, Niti Sureka, Kirti Panwar, Neelam Sahani, Sufian Zaheer.
      Radioresistance remains a major barrier to effective cancer therapy, contributing to tumor persistence, recurrence, and poor clinical outcomes. Increasing evidence identifies mitochondria as central regulators of radiation response through their multifaceted roles in cellular bioenergetics, redox homeostasis, mitochondrial DNA (mtDNA) maintenance, apoptotic signaling, and mitochondrial dynamics. Radioresistant tumor cells undergo profound metabolic reprogramming characterized by enhanced oxidative phosphorylation (OXPHOS), glycolytic plasticity, glutaminolysis, and pentose phosphate pathway activation, enabling sustained ATP generation, antioxidant defense, and efficient DNA repair under radiation stress. In parallel, mitochondrial reactive oxygen species (ROS) signaling is tightly modulated by antioxidant systems including glutathione, superoxide dismutase, catalase, and NRF2-driven pathways, thereby limiting radiation-induced oxidative injury. Alterations in mitochondrial fusion and fission dynamics, particularly Drp1-mediated fission, further support tumor survival by promoting mitophagy, metabolic adaptation, and resistance to apoptosis. Additionally, enhanced mtDNA repair and mitochondrial biogenesis preserve mitochondrial integrity in irradiated cancer cells. Dysregulation of mitochondria-mediated intrinsic apoptotic pathways, including aberrant expression of Bcl-2 family proteins, further facilitates evasion of radiation-induced cell death. This review comprehensively examines the molecular mechanisms by which mitochondria contribute to tumor radioresistance and critically discusses emerging mitochondria-targeted therapeutic strategies aimed at improving radiosensitivity. These include OXPHOS inhibitors, glycolytic and glutaminase inhibitors, ROS-modulating agents, mitochondrial dynamics regulators, nanoparticle-based mitochondrial targeting systems, and combinatorial approaches integrating radiotherapy with immunotherapy or DNA damage response inhibitors. By integrating mechanistic insights with emerging preclinical and clinical evidence, this review highlights mitochondria as actionable therapeutic vulnerabilities and underscores the translational potential of mitochondrial-targeted radiosensitization strategies for improving outcomes in resistant malignancies.
    Keywords:  cancer; mitochondria; radioresistance; radiosensitization; radiotherapy
    DOI:  https://doi.org/10.3389/fonc.2026.1849057
  42. Cell Death Dis. 2026 Jun 25.
    C/EBP alpha agonist ICCB280 overcomes doxorubicin resistance in osteosarcoma through mitochondrial dynamics-dependent GREM1-MAPK activation.
    Yuchen Han, Hui Li, Chunyuan Xue, Lu Pan, Li Liu, Hui Chen, Zhendong Wang, Fengkun Ji, Yinglong Zhang, Xiaofeng Kang, Ying Lu, Yimeng Du, Jianxiong Li, Wenchao Li.
      The resistance of doxorubicin (DOX), the first-line chemotherapeutic drug for osteosarcoma (OS), stands as a pivotal obstacle in the effective treatment of OS. Alterations in mitochondrial dynamics and thereby affecting reactive oxygen species (ROS) accumulation play critical roles in DOX-induced cell death. However, the novel targets and pharmacological agents combating DOX resistance in OS via mitochondrial homeostasis and DOX-induced cell death manipulation is poorly understood. Herein, we showed that the C/EBPα/GREM1/p-ERK signaling pathway sensitizes OS to DOX by promoting mitochondrial fission and causing ROS-induced apoptosis. C/EBPα agonist ICCB280 and ERK pathway inhibitor PD98059 both played a DOX sensitivity augmentation role in OS in vitro and in vivo. The combined application of these two agents synergistically amplifies the cytotoxic impact of DOX, potentially overcoming DOX resistance and offering innovative therapeutic strategies for treating DOX-resistant OS.SCHEME： ICCB280 and PD98059 co‑administration counteracts doxorubicin resistance in osteosarcoma. When ICCB280 and PD98059 are co-administered, the activation of GREM1 by C/EBPα and the inhibition of ERK phosphorylation are intensified. This suppresses OPA1 expression, promotes mitochondrial fission, and effectively counteracts chemotherapy resistance in osteosarcoma.
    DOI:  https://doi.org/10.1038/s41419-026-08980-y
  43. Antioxidants (Basel). 2026 Jun 19. pii: 768. [Epub ahead of print]15(6):
    Myeloid DRP1 Sulfenylation Drives Reparative Macrophage Polarization and Neovascularization in Ischemic Muscle.
    Shikha Yadav, Rajagopal Kamarajan, Varadarajan Sudhahar, Sheela Nagarkoti, Archita Das, Stephanie Kelley Spears, Rajalakshmi Veeranan Karmegam, Tohru Fukai, Masuko Ushio-Fukai.
      Reparative macrophage polarization and macrophage-derived reactive oxygen species (ROS) are required for ischemia-induced revascularization in peripheral artery disease (PAD). Our previous study showed that mitochondrial fission protein dynamin-related protein 1 (DRP1) promotes reparative polarization and metabolic reprogramming in macrophages and post-ischemic neovascularization. However, the redox-dependent mechanism governing DRP1 activation in this context remains elusive. Here, using a mouse hindlimb ischemia (HLI) model of PAD, we identify cysteine sulfenylation (CysOH) of DRP1 as a critical redox modification induced in ischemic bone marrow (BM)-derived cells. BM chimeric mice reconstituted with CRISPR/Cas9-generated "redox-dead" DRP1-C631A knock-in mutant (Drp1C/A) BM exhibited markedly reduced limb perfusion recovery and CD31+ capillary density in ischemic muscles following HLI. These defects were associated with enhanced Ly6G+ neutrophil accumulation, pro-inflammatory F4/80+CD80+ M1-like macrophages and reduced anti-inflammatory F4/80+CD206+ M2-like macrophages in ischemic muscle. Mechanistically, using an in vitro PAD model, hypoxia serum starvation (HSS) rapidly induced NADPH oxidase 2-dependent cytosolic ROS production and DRP1-CysOH formation in wild-type macrophages. In contrast, Drp1C/A macrophages failed to undergo DRP1-CysOH-dependent mitochondrial fission under HSS, resulting in aberrant metabolic reprogramming characterized by enhanced glycolysis and mitochondrial ROS, pro-inflammatory p-NF-κB and M1-genes, and suppressed anti-inflammatory p-AMPK, efferocytosis and M2-genes. Thus, our findings establish DRP1 sulfenylation as a previously unrecognized redox-sensing mechanism that links ischemia-induced ROS to reparative macrophage reprogramming and revascularization, identifying a novel therapeutic target for PAD.
    Keywords:  DRP1; hindlimb ischemia; inflammation; macrophage; metabolic reprogramming; mitochondrial fission; peripheral arterial disease; post-translational modification; sulfenylation
    DOI:  https://doi.org/10.3390/antiox15060768
  44. Biomolecules. 2026 Jun 12. pii: 868. [Epub ahead of print]16(6):
    Dysregulation of the HSF1-Mediated UPRmt Pathway in Colonic Smooth Muscle Cells Drives Motility Dysfunction in Functional Constipation.
    Junpeng Yao, Wen Wang, Wei Zhang, Hang Dong, Yujun Hou, Qianhua Zheng, Ying Li, Fang Zeng.
      Mitochondrial dysfunction in colonic smooth muscle cells (SMCs) is closely associated with impaired gut motility in functional constipation (FC), but the underlying molecular mechanisms remain incompletely understood. The mitochondrial unfolded protein response (UPRmt) is a critical pathway for maintaining mitochondrial proteostasis, and heat shock factor 1 (HSF1) acts as an important upstream regulator of this response. In the present study, we employed a loperamide-induced FC mouse model, combined with single-cell transcriptomic, molecular, and functional analyses to characterize the HSF1-UPRmt pathway in colonic SMCs and to investigate its role in FC. Single-cell transcriptomic analysis of colon tissue from FC mice revealed marked downregulation of UPRmt-associated genes in colonic SMCs. Immunofluorescence, Western blotting, and RT-qPCR analyses of colonic tissue confirmed that HSF1 expression was reduced in colonic SMCs, along with the downregulation of the UPRmt components, including HSP60, mtHSP70, and LONP1. These molecular changes were accompanied by mitochondrial structural damage, seen by transmission electron microscopy, and by functional impairments, including reduced mitochondrial membrane potential, elevated mtROS production, decreased ATP levels, and diminished activities of respiratory chain complexes I-V. AAV9-mediated overexpression of HSF1 reactivated the UPRmt pathway, improved mitochondrial function, and ameliorated constipation, whereas shRNA-mediated knockdown of HSF1 further suppressed UPRmt activity and aggravated mitochondrial damage, indicating that HSF1 bidirectionally regulates this pathway. Complementary experiments in primary colonic SMCs confirmed that this regulatory mechanism operates in a cell-autonomous manner, as modulation of HSF1 expression produced corresponding changes in the UPRmt pathway, in the expression of mitochondrial respiratory chain complex subunits (ATP5A, NDUFA9, COX1, SDHA, UQCRC1), and in ATP production, mirroring the in vivo findings. Collectively, these results demonstrate that HSF1 plays a pivotal role in maintaining mitochondrial homeostasis in colonic SMCs through regulation of the UPRmt pathway and that HSF1 dysfunction is closely associated with slowed gut motility in FC. These findings offer a new mechanistic perspective on FC and point to the HSF1-UPRmt axis as a potential therapeutic target.
    Keywords:  functional constipation; gut motility; heat shock factor 1; mitochondrial unfolded protein response; smooth muscle cell
    DOI:  https://doi.org/10.3390/biom16060868
  45. Biomolecules. 2026 Jun 09. pii: 842. [Epub ahead of print]16(6):
    Mitochondrial Dynamics and SLC25 Transporters in Neurodegeneration: From Mechanisms to Therapeutic Opportunities.
    Giampaolo Morciano, Ruggiero Gorgoglione, Vito Porcelli, Amer Ahmed, Pasquale Scarcia, Angelo Vozza, Francesco Massimo Lasorsa, Giuseppe Fiermonte, Luigi Palmieri.
      Neurodegenerative diseases are increasingly recognized as disorders of due to disrupted cellular homeostasis, with mitochondrial dysfunction playing a central and early role in disease progression. This review explores the intricate relationship between mitochondrial function and neuronal health, emphasizing the pivotal role of the solute carrier family 25 (SLC25) transporters in maintaining mitochondrial homeostasis. We provide a comprehensive overview of mitochondrial biology in the central nervous system, including energy metabolism, calcium signaling, redox regulation, organelle interactions and mitochondrial dynamics. We delve into the SLC25 transporter family, highlighting their transport mechanisms, substrates and roles in brain metabolism and neuroprotection. SLC25 on one hand and proteins involved in the regulation of mitochondrial morphology and calcium signaling on the other hand are two sides of the same coin influencing each other. A critical analysis follows, examining how mitochondrial dysfunction contributes to mitochondrial abnormalities in a spectrum of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, ALS and rare mitochondrial encephalopathies. Finally, we assess emerging therapeutic strategies targeting mitochondrial pathways and SLC25 function, including metabolic modulation, gene therapies, antioxidants and pharmacological agents. This review underscores mitochondria and the SLC25 transporters as promising targets for disease-modifying interventions in neurodegeneration and raises key questions about the causality between mitochondrial failure and neuronal death.
    Keywords:  SLC25 carriers; metabolism; mitochondrial dynamics; neurodegeneration
    DOI:  https://doi.org/10.3390/biom16060842
  46. Int Immunopharmacol. 2026 Jun 26. pii: S1567-5769(26)00920-3. [Epub ahead of print]186 117074
    Targeting Grx1 by hyperoside regulates Ncf4 post-translational modification to enhance mitophagy and accelerate diabetic wound healing.
    Nan Chen, Jie Deng, Yongbing Cao, Caihua Sun, Tong Hou.
       INTRODUCTION: Diabetic wound healing impairment is a devastating diabetic complication with high amputation and mortality rates, and current therapies lack effective targeted agents.
    OBJECTIVES: To define the pro-healing efficacy of hyperoside and elucidate its underlying molecular mechanism in diabetic wound repair.
    METHODS: A type 2 diabetic mouse wound model was established via high-fat diet combined with low-dose streptozotocin. Mechanistic studies employed high glucose-stimulated bone marrow-derived macrophages, integrated DIA quantitative proteomics and single-cell RNA sequencing, molecular dynamics simulation, CETSA/DARTS binding assays, co-immunoprecipitation, and Grx1 gain/loss-of-function experiments.
    RESULTS: Hyperoside dose-dependently accelerated wound closure and ameliorated systemic metabolic disorders. Concurrently, hyperoside attenuated the intensity of inflammatory responses in the wound bed, upregulated the expression of collagens including Col1a1 and Col3a1, and promoted ordered collagen remodeling. It normalized redox homeostasis by elevating the GSH/GSSG and NADPH/NADP+ ratios, and suppressed the secretion of pro-inflammatory cytokines TNF-α, IL-1β and IL-6. Integrated multi-omics analysis identified the Grx1/Ncf4/Bnip3l axis as the regulatory pathway. Mechanistically, in vitro studies demonstrated that hyperoside bound to Grx1 to enhance its protein stability, shifted the post-translational modification of Ncf4 from phosphorylation to glutathionylation to inhibit NOX2 activation, and augmented Bnip3l-mediated mitophagy to reverse macrophage dysfunction.
    CONCLUSION: Hyperoside exerted robust pro-healing effects via targeting the Grx1/Ncf4/Bnip3l axis, establishing it as a promising therapeutic candidate for refractory diabetic wounds.
    Keywords:  Diabetic wound healing; Glutathionylation; Grx1/Ncf4/Bnip3l axis; Hyperoside; Mitophagy
    DOI:  https://doi.org/10.1016/j.intimp.2026.117074
  47. Transbound Emerg Dis. 2026 ;2026(1): e4882962
    Avian Pathogenic Escherichia coli T6SS Effector Protein Hcp2 Induces Mitochondrial Dysfunction and Activates Mitophagy in Chicken Tracheal Mucosal Epithelial Cells.
    Bingyu Zhao, Ziqi Li, Liyang Dai, Yifei Huang, Yaqin Tian, Xiyang Wei, Chenchen Sheng, Zhenyu Wang, Ying Shao, Jiumeng Sun, Jian Tu, Xiangjun Song.
      The secretion system of avian pathogenic Escherichia coli (APEC) plays a key role in bacterial colonization and invasion of the host. The core structural component of the type VI secretion system (T6SS), hemolysin-coregulatory protein (Hcp), functions both as a T6SS structural component and a secreted virulence effector. However, the pathogenic mechanisms by which Hcp2 affects host cell function remain poorly understood. In this study, we focused on the impact of Hcp2 on mitochondrial function in chicken tracheal mucosal epithelial (CTE) cells to reveal the mechanism of APEC-induced host cell damage. Hcp2 exposure led to significant mitochondrial dysfunction, as evidenced by elevated levels of reactive oxygen species, mitochondrial membrane potential depolarization, and intracellular calcium overload. These findings suggest that Hcp2 induces mitochondrial oxidative stress and disrupts cellular homeostasis. Notably, when mitochondrial function is impaired, cells initiate a selective autophagic mechanism, a process that may be closely related to the pathogenic mechanism of Hcp2 protein. Transmission electron microscopy (TEM) and immunofluorescence microscopy confirmed the formation of double-membraned autophagosomes. Western blot analysis further revealed increased conversion of LC3-I to LC3-II and a dynamic change in p62/SQSTM1 expression. Additionally, the degradation of mitochondrial proteins and the increased colocalization of mitochondria with autophagosomes and lysosomes confirmed the activation of mitophagy. Our study reveals that Hcp2 disrupts mitochondrial functional homeostasis and activates mitophagy in CTE cells.
    Keywords:  avian pathogenic Escherichia coli; hemolysin-coregulatory protein 2; mitochondrial dysfunction; mitophagy; type VI secretion system
    DOI:  https://doi.org/10.1155/tbed/4882962
  48. Tissue Cell. 2026 Jun 24. pii: S0040-8166(26)00427-1. [Epub ahead of print]103 103733
    Interrupting a mitochondrial DNA-driven innate immune circuit attenuates hepatic tissue remodeling and fibrotic architecture in experimental steatohepatitis.
    Rabab S Hamad, Sura Akram Mohammed, Waseem Ali Hasan, Norhan Ahmed AbuoHashish, Sherin Refat El Afify, Mohamed A M Ali, Alaa Eldin Ahmed Mohamed, Attalla F El-Kott, Mohammed A AlShehri, Kareem Morsy, Alshaimaa A Farrag, Karem Mohamed Salem, Nesreen Elsayed Morsy, Rasha Elmowafy, Ahmed Abdel-Monem Elmetwally, Walid Mostafa Sayed Ahmed, Lubna Jamil, Ahmed Shata, Anis Ahmad Chaudhary, Hanan Eissa, Sameh Saber.
      Steatohepatitis integrates metabolic stress and mitochondrial damage, but single-node interventions often incompletely quell inflammation and fibrosis. We tested a dual-node strategy that reduces the trigger and blocks the adaptor of the mtDNA-cGAS-STING pathway in a high-fat diet plus streptozotocin mouse model. Male C57BL/6 J mice with steatohepatitis (SH) received urolithin A (UA; mitophagy enhancer), C176 (murine STING inhibitor), or their combination. Endpoints included liver injury (ALT/AST), lipids (serum and hepatic triglycerides, cholesterol), glycemia/insulin resistance (fasting glucose, insulin, HOMA-IR), cGAS-STING/type-I interferon signaling (Ifnb1, Cxcl10, IFN-β, CXCL10; p-STING, p-TBK1, p-IRF3), mitochondrial damage signals (cytosolic mtDNA, mtTFA), autophagy/mitophagy (LC3-II/I, cleaved-PINK1, p-PARKIN, p62), inflammasome/cytokines (NLRP3, IL-1β, TNF-α), and fibrosis (hydroxyproline, Col1a1, Tgfb1/TGF-β1). Compared with SH, UA or C176 monotherapy improved injury, lipid, interferon, and fibrotic readouts, with UA preferentially lowering mtDNA/mtTFA and C176 more strongly suppressing p-STING-TBK1-IRF3 and IFN-β/CXCL10. The combination produced the largest, pathway-concordant effects across domains, frequently approaching CTRL. Formal combination analysis on fractional inhibition showed predominant synergistic activity (ΔBliss and ΔHSA > 0 for most endpoints). A precision-weighted correlation map linked insulin resistance, mitochondrial stress, cGAS-STING activation, and fibrosis, while mitophagy restoration markers correlated inversely. By pairing a mitophagy enhancer with a STING inhibitor, we provide first evidence in this model that coordinated upstream and downstream targeting of the mtDNA-cGAS-STING axis yields superior, multi-domain control of disease biology and is immediately translatable via IFN-β/CXCL10, cell-free mtDNA, and imaging readouts.
    Keywords:  Extracellular matrix; Hepatic tissue remodeling/Fibrotic architecture; Innate immune sensing; Mitochondrial damage; Mitophagy; Steatohepatitis
    DOI:  https://doi.org/10.1016/j.tice.2026.103733
  49. Bioact Mater. 2026 Nov;65 663-690
    Immunomodulatory cytoskeleton of bionic periosteum affects mitochondrial dynamics to promote osteogenesis.
    Tianyu Zhou, Zhengxia Ni, Yiyang Huang, Ziyan Huang, Qiangqiang Guo, Jie Wu, Hongyi Zhu, Xinzhao Jiang, Liang Zhou, Wei Wang, Kun Xi, Yong Gu, Wenguo Cui, Liang Chen.
       Purpose: Periosteum is a key regulatory hub in the immune microenvironment of bone repair and the mitochondrial dynamics of bone marrow mesenchymal stem cells (BMSCs) directly determine the osteogenic efficiency; therefore, how to promote bone healing through the immunomodulation of mitochondrial dynamics is a key challenge.
    Methods: Inspired by the natural periosteum, we designed a bionic periosteum that integrates topology and controlled Semaphorin 3 A (Sema3A) release. Hyaluronic acid-coated Sema3A granular microsols spontaneously formed a nucleus-sheath structure under a high-voltage electric field to facilitate efficient drug loading.
    Results: The periosteum controlled Sema3A release and oriented topography, which drived macrophage M2 polarization via the PI3K/Akt/mTOR pathway, reconstructed the BMSC skeleton via the ROCK2 pathway, and synergistically promoted bone formation by driving mitochondrial fusion through material-appropriate stiffness. In vivo experiments further demonstrated that this biomimetic periosteum efficiently repaired bone defects by activating the immune microenvironment to remodel the BMSC skeleton and modulating mitochondrial dynamics, an endogenous repair cascade.
    Conclusion: This immunomodulatory drug delivery strategy utilizing bionic periosteum offers a novel approach for regenerative medicine to regulate immune-osteogenic crosstalk, which is promising for potential applications.
    Keywords:  Biomimetic periosteum; Bone immunity; Cytoskeleton; Macrophage polarization; Mitochondrial dynamics; Osteogenesis
    DOI:  https://doi.org/10.1016/j.bioactmat.2026.05.041
  50. Tissue Eng Part B Rev. 2026 Jun 27. 19373368261460337
    Photobiomodulation Targets Mitochondrial Homeostasis for Diabetic Wound Healing.
    Feng Lai, Yuxiu Mai, Zhaodan Wang, Chao Wang, Shulan Xu.
      Diabetes mellitus is a global public health problem, and impaired wound healing is a complication that significantly reduces patients' quality of life. Dysregulation of mitochondrial homeostasis is a key pathological feature contributing to impaired wound healing in diabetes. This dysregulation increases oxidative stress, resulting in impaired energy metabolism, endothelial dysfunction, and prolonged inflammatory responses. Photobiomodulation (PBM) is a noninvasive therapy that has been successfully used to promote diabetic wound healing by modulating mitochondrial homeostasis via multiple mechanisms. In this review, we have systematically summarized the following roles of PBM in restoring mitochondrial homeostasis to accelerate diabetic wound healing: improving mitochondrial dysfunction and oxidative stress through cytochrome C oxidase in the electron transport chain, thereby enhancing oxidative phosphorylation and adenosine triphosphate production; modifying mitochondrial dynamics by inhibiting the expression of dynamin-related protein 1 and promoting mitofusin-2 expression to restore mitochondrial morphology and function; reducing inflammation and promoting macrophage polarization from the M1 to M2 phenotype; activating signaling pathways (e.g., VEGF, PI3K/AKT/mTOR/GSK3-β, AMPK, RAS/MAPK, JAK/STAT, NF-κB, TGF-β/Smad) to enhance cell proliferation and angiogenesis and resolve inflammation. Beyond monotherapy, this review synthesizes the burgeoning field of PBM in combination with advanced therapeutic strategies, such as hydrogels, nanomaterials, small-molecule drugs, adipose-derived stem cells, and extracellular vesicles, highlighting their synergistic potential for enhanced efficacy. Finally, this review critically addresses the prevailing challenges in clinical translation, particularly the lack of standardized treatment parameters, and proposes future research directions. This comprehensive overview aims to solidify the scientific foundation of PBM and inspire the design of integrated, precision therapeutic strategies for diabetic wound management.
    Keywords:  angiogenesis; diabetic wound healing; endothelial dysfunction; mitochondrial homeostasis; oxidative stress; photobiomodulation
    DOI:  https://doi.org/10.1177/19373368261460337
  51. Invest Ophthalmol Vis Sci. 2026 Jun 01. 67(6): 44
    Senp1 O-GlcNAcylation Promotes Mitochondrial Fragmentation by Regulating Fis1 SUMO1-ylation Underlying Diabetic Cataract.
    Zaoxia Guo, Xinnan Li, Xi Chen, Xiaopan Ma, Hong Yan.
       Purpose: Cataract is a major cause of blindness among patients with diabetes mellitus. The pathology underlying diabetic cataract (DC) is complex because of changes in biological processes caused by chronic hyperglycemia. O-GlcNAcylation is highly dependent on glucose availability and regulates mitochondrial functions. Dysregulation of O-GlcNAcylation has been reported in DC. Mitochondria in lens epithelial cells are key organelles for energy supply and redox homeostasis of the lens. Mitochondrial dysfunction is a hallmark of DC. However, whether O-GlcNAcylation regulates mitochondrial function underlying DC has not been fully studied.
    Methods: An animal model of DC was established in Sprague-Dawley male rats by feeding a 60% high-fat diet and injecting streptozotocin. Mitochondria were visualized using confocal laser scanning microscope and transmission electron microscope. O-GlcNAcylated proteins were verified using liquid chromatography tandem mass spectrometry and immunoprecipitation assays. Lentivirus-encapsulated plasmids were constructed to generate stable transfected cell lines. The histomorphology of the lens was assessed by hematoxylin and eosin staining.
    Results: High glucose levels promoted mitochondrial fission by upregulating Senp1 O-GlcNAcylation at the S137 site. Senp1 S137 O-GlcNAcylation inhibited Fis1 deSUMO1-ylation. Fis1 SUMO1-ylation decreased its interaction with Mfn2, which reduced the contact between mitochondria-associated ER membranes (MAMs), thereby promoting mitochondrial fragmentation. Site-specific mutation of Senp1 S137A released the inhibitory effect on Fis1 deSUMOylation and mitigated high-glucose induced mitochondrial fragmentation.
    Conclusions: Senp1 S137 O-GlcNAcylation regulates mitochondrial fragmentation in lens epithelial cells underlying DC. Senp1 O-GlcNAcylation increase mediates mitochondrial fragmentation by upregulating Fis1 SUMO1-ylation, which in turn reduces the contact of mitochondria-associated endoplasmic reticulum membranes and promotes mitochondrial fragmentation.
    DOI:  https://doi.org/10.1167/iovs.67.6.44
  52. bioRxiv. 2026 Jun 10. pii: 2026.06.09.731211. [Epub ahead of print]
    Mitochondrial-derived compartments buffer outer membrane protein load during acute mitochondrial adaptation.
    Bo J Price, Sai Sangeetha Balasubramaniam, Adam L Hughes.
      Cells undergoing metabolic transitions rapidly remodel mitochondria through coordinated expansion and reorganization of the mitochondrial proteome. How the outer mitochondrial membrane (OMM) accommodates acute increases in newly synthesized proteins before organelle adaptation is complete remains poorly understood. Here we show that mitochondrial-derived compartments (MDCs), multilamellar domains that form from the OMM and selectively sequester OMM-associated cargo, arise during metabolic perturbations associated with acute mitochondrial biogenesis, including glucose restriction, carbon-source switching, and salt stress. In these situations, MDC formation requires the energy-sensing kinase Snf1 and derepression of the transcriptional repressor Mig1, linking MDC induction to transcriptional programs that increase mitochondrial protein expression. Activation of mitochondrial biogenesis in the absence of metabolic changes is sufficient to trigger MDCs, whereas disruption of mitochondrial protein targeting and import prevents MDC formation and causes mislocalization of outer membrane cargos. Together, these findings, combined with previous observations that MDCs are induced by hydrophobic protein overexpression, mistargeting, and metabolic perturbations, support an emerging model in which MDCs function as adaptive outer-membrane remodeling domains that buffer outer membrane protein load during mitochondrial adaptation.
    DOI:  https://doi.org/10.64898/2026.06.09.731211
  53. Sci Rep. 2026 Jun 24.
    GPR124 promotes NLRP3 inflammasome activation through impaired mitochondrial autophagy homeostasis in ox-LDL-treated endothelial cells.
    Jie Qu, Yangyang Pang, Xinyin Fu, Yiqian Xu, Qingyun Guo, Xingyue Fang, Yingmei Lu, Qingwen Meng, Qibing Liu.
      G protein-coupled receptor 124 (GPR124) has been implicated in endothelial dysfunction, but its role in ox-LDL-induced endothelial inflammatory injury remains incompletely understood. This study investigated whether GPR124 contributes to endothelial cell injury through disruption of mitochondrial autophagy homeostasis and subsequent activation of the NLRP3 inflammasome. Using an ox-LDL-treated EA.hy926 endothelial cell model, we found that GPR124 expression was significantly upregulated under injurious conditions. GPR124 overexpression aggravated ox-LDL-induced cellular dysfunction, as reflected by reduced proliferative activity, increased reactive oxygen species (ROS) production, and enhanced lipid accumulation. Mechanistically, GPR124 dysregulation was associated with impaired mitochondrial homeostasis, including loss of mitochondrial membrane potential, excessive ROS generation, and altered mitochondrial autophagy flux, accompanied by increased NLRP3 inflammasome activation and IL-1β release. In contrast, GPR124 knockdown partially attenuated these abnormalities and alleviated endothelial cell injury. In addition, pharmacological intervention with Mdivi-1 supported the involvement of mitochondrial autophagy-related processes in the inflammatory phenotype observed under ox-LDL stimulation. Bioinformatics analyses further suggested that GPR124-associated differentially expressed genes were enriched in pathways related to mitochondrial homeostasis, metabolic regulation, and inflammatory signaling. Taken together, these findings suggest that GPR124 may contribute to ox-LDL-induced endothelial inflammatory injury through dysregulation of the mitochondrial autophagy-NLRP3 axis and identify GPR124 as a potential target for further mechanistic investigation in endothelial dysfunction.
    Keywords:  Autophagic flux; Endothelial dysfunction; Mitochondria༛GPR124; NLRP3 inflammasome
    DOI:  https://doi.org/10.1038/s41598-026-59173-8
  54. Free Radic Biol Med. 2026 Jun 22. pii: S0891-5849(26)00895-6. [Epub ahead of print]254 323-341
    Selenium nanoparticles alleviate ulcerative colitis by regulating macrophage mitochondrial dynamics.
    Jiajing Chang, Xiaonan Zeng, Runan Zhang, Tiantian Li, Qianqian Gao, Chunlan Xu.
      Ulcerative colitis (UC) progression is closely associated with aberrant macrophage polarization and mitochondrial dysfunction. Here, we explored how biogenic selenium nanoparticles (SeNPs) protect against experimental colitis, using dextran sulfate sodium (DSS)-challenged mice, together with lipopolysaccharide (LPS)-activated THP-1-derived macrophages as complementary in vivo and in vitro models. We found that selenium deficiency markedly aggravated DSS-induced intestinal barrier disruption, mucosal injury, and mitochondrial damage, underscoring the critical role of selenium homeostasis in mucosal immunity. Compared with inorganic selenium (Na2SeO3), biogenic SeNPs showed superior efficacy in alleviating colitis severity, preserving intestinal barrier integrity, restoring the intestinal stem cell niche, and promoting epithelial regeneration. Mechanistically, SeNPs shifted macrophage polarization away from the pro-inflammatory M1 state toward a more restorative profile. Transcriptomic and molecular analyses further suggested that these immunometabolic benefits were associated with preserved selenoprotein expression and peroxidase (GPx)/thioredoxin reductase (TrxR) activities, particularly restoration of the endoplasmic reticulum (ER)-resident selenoproteins selenoprotein K (SELENOK) and selenoprotein T (SELENOT), together with modulation of inositol 1,4,5-trisphosphate receptor (IP3R)-voltage-dependent anion channel 1 (VDAC1)-mediated mitochondria-associated membrane (MAM) signaling. This stabilization of inter-organelle communication effectively blunted LPS-induced cytosolic calcium overload, thereby facilitating the molecular rebalancing of mitochondrial dynamics, as reflected by reduced dynamin-related protein 1 (DRP1) and increased mitofusin 2 (MFN2) expression, and was accompanied by attenuation of reactive oxygen species (ROS) overproduction and NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation. Furthermore, a Transwell co-culture system confirmed that SeNP-pretreated macrophages indirectly preserved NCM460 intestinal epithelial barrier integrity through paracrine mechanisms. Collectively, these results suggest that SeNPs may serve as a potential nanotherapeutic approach for UC by restoring intestinal homeostasis through modulation of macrophage mitochondrial dynamics and enhancement of immune-epithelial crosstalk.
    Keywords:  ER-mitochondria communication; Macrophage polarization; Mitochondrial dynamics; NLRP3 inflammasome; Selenium nanoparticles; Ulcerative colitis
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.06.040
  55. Int J Mol Med. 2026 Aug;pii: 229. [Epub ahead of print]58(2):
    Recombinant myonectin ameliorates sepsis‑induced cardiomyopathy by alleviating mitochondrial dysfunction via the AdipoR1/AMPK pathway.
    Peipei Li, Rui Chen, Hanmo Zhang, Lihong Li, Huiling Luo, Beibei Du, Ping Yang.
      Sepsis‑induced cardiomyopathy (SIC) is a common complication of sepsis and is associated with a high mortality rate; however, effective therapies remain lacking. Mitochondrial dysfunction is a key pathogenic mechanism. Myonectin, also known as C1q tumor necrosis factor‑related protein 15, is a novel member of the C1q/TNF‑related protein family. It has been demonstrated to exert cardioprotective effects by suppressing inflammatory response, inhibiting apoptosis and attenuating cardiac fibrosis. Despite these known functions, whether myonectin protects against SIC remains unclear. The present study aimed to investigate the protective potential of recombinant myonectin (rMyonectin) against SIC. Lipopolysaccharide (LPS)‑induced and cecal ligation and puncture‑induced SIC models were established in C57BL/6J mice, and LPS‑stimulated neonatal mouse cardiomyocytes (NMCMs) were used for in vitro validation. Mice and NMCMs were pretreated with rMyonectin prior to the respective challenge. The results showed that rMyonectin improved cardiac function, attenuated myocardial injury, inhibited apoptosis and preserved the integrity of myocardial mitochondria in SIC mice. Furthermore, rMyonectin inhibited LPS‑induced apoptosis in cardiomyocytes. It concurrently promoted mitochondrial biogenesis, maintained mitochondrial dynamics and stabilized mitochondrial membrane potential, thereby improving mitochondrial function and enhancing ATP production. Importantly, these protective effects were abolished by either adiponectin receptor 1 (AdipoR1) knockdown or AMP‑activated protein kinase (AMPK) inhibition. These findings suggest that rMyonectin protects against SIC by alleviating mitochondrial dysfunction via the AdipoR1/AMPK pathway, highlighting its promise as a protective agent.
    Keywords:  apoptosis; mitochondrial biogenesis; mitochondrial dynamics; myonectin; sepsis‑induced cardiomyopathy
    DOI:  https://doi.org/10.3892/ijmm.2026.5900
  56. Medicine (Baltimore). 2026 Jun 26. 105(26): e49502
    Bioinformatics and network pharmacology to explore Huangqi Guizhi Wuwu Decoction in regulating mitophagy to ameliorate doxorubicin-induced cardiotoxicity the potential mechanism.
    Jian Yu, Jiangtao Wang, Xinya Liu, Jing Shi, Mengjiao Gao, Li Wu, Yuanming Zhang.
      While studies suggested that Huangqi Guizhi Wuwu Decoction (HGWD) can mitigate doxorubicin-induced cardiotoxicity (DIC), the specific mechanism of action remains unclear. GSE106297, GSE157282, and GSE206803 were downloaded to screen for differentially expressed genes (DEGs), followed by gene set enrichment analysis and immune infiltration analysis. DIC-related genes were obtained by the intersection of weighted gene co-expression network analysis and DEGs. The active ingredients and target genes of HGWD were obtained from the Traditional Chinese Medicine System Pharmacology Database and Analysis Platform database, and HGWD-DIC common targets were identified by intersecting them with DIC-related genes. A drug-active ingredient-target network was constructed to select the core components of HGWD. Mitophagy-related genes were obtained from GeneCards, PHARMGKB, and OMIM databases, and intersecting them with common targets yielded the core genes, which were then subjected to enrichment analyses. A protein-protein interaction network was constructed to identify key genes, further assessing their diagnostic value. The effect of HGWD on the expression of key genes was further validated using prepared medicated serum. The interactions between the core components and key genes were validated through molecular docking and molecular dynamics simulation. A total of 2344 DEGs were identified, with gene set enrichment analysis results primarily enriched in categories such as apoptosis, p53 signaling pathway, cell cycle, PLK1 pathway, mitochondrial translation, and metabolism of RNA. Immune infiltration analysis suggested that the immune response may also be involved in the pathogenesis of DIC. We identified 2969 key modular genes by weighted gene co-expression network analysis, and intersecting these with DEGs yielded 1569 DIC-related genes. Network pharmacology analysis revealed 74 active ingredients and 692 target genes of HGWD, resulting in 64 common targets when intersected with DIC-related genes. The core components of HGWD were identified as quercetin and kaempferol. By intersecting the obtained mitophagy-related genes with common targets, 13 core genes were identified, with enrichment analyses indicating significant associations with cellular response to mitophagy and autophagy. Further analysis showed that 5 key genes: AKT1, TP53, BCL2L1, FASN, and HRAS, all demonstrated good diagnostic value, and their DOX-induced expression alterations were reversed by HGWD. Molecular docking and molecular dynamics simulation showed a strong binding affinity between the core components and key genes. HGWD may alleviate DIC by regulating mitophagy.
    Keywords:  DOX-induced cardiotoxicity (DIC); Huangqi Guizhi Wuwu Decoction (HGWD); bioinformatics; mitophagy; molecular docking; molecular dynamics simulation; network pharmacology
    DOI:  https://doi.org/10.1097/MD.0000000000049502
  57. J Biophotonics. 2026 Jun;19(6): e70313
    Local Mitochondrial Growth Initiated by Femtosecond Laser-Evoked Ca2+ Signaling.
    Bingyi Li, Zichuan Tang, Hao He.
      Mitochondrial structural remodeling is closely coupled to intracellular Ca2+ signaling, and precise spatiotemporal control of this process is critical for understanding mitochondrial physiology. Here, we report an optical approach based on femtoSOC (femtosecond laser-controlled store-operated calcium channel) activation to induce localized Ca2+ influx and trigger region-specific mitochondrial growth in living cells. The Ca2+-regulated mitochondrial growth relies on MCU-dependent Ca2+ uptake and OPA1-mediated fusion but is not primarily mediated by the AMPK/CaMKKβ pathway. This study provides a minimally invasive strategy for precise optical control of mitochondrial dynamics and reveals an AMPK-distinct pathway linking localized Ca2+ signaling to mitochondrial structural remodeling.
    Keywords:  Ca2+ signaling; femtosecond laser; mitochondrial growth; photoexcitation
    DOI:  https://doi.org/10.1002/jbio.70313
  58. Sci Rep. 2026 Jun 26.
    Imbalanced mitochondrial fusion/fission in human placenta: a potential link to preeclampsia.
    Jianying Liu, Yujing Xu, Hong Sun, Shasha Yu, Rong Hou, Ruofan Wang, Qian Li, Xiaoyi Yin, Yuchun Zhu, Guanglei Wang.
      We aimed to examine how placental dysfunction and impaired mitochondrial fusion/fission balance correlate with preeclampsia (PE) in human placentas, shedding light on the underlying etiology of PE. Twenty-eight pregnant women who received antenatal care at the Obstetrics Medical Center of Weifang People's Hospital between November 2024 and May 2025. They were divided into a PE group (n = 14) and a normal control group (n = 14). Placental tissues from pregnant women with PE or with healthy control were analyzed. Compared to controls, the PE group exhibited impaired placental function (evidenced by decreased PlGF and increased sFlt-1) and disrupted mitochondrial dynamics (characterized by reduced MFN1/2 and elevated p-DRP1). These alterations were accompanied by increased oxidative stress and apoptosis, alongside decreased ATP production. Imbalanced mitochondrial fusion/fission may contribute to placental dysfunction through mechanisms involving oxidative stress, disturbed energy metabolism, and cell apoptosis, leading to the occurrance of PE.
    Keywords:  Fission; Fusion; Mitochondrial; Oxidative stress; Placenta; Preeclampsia
    DOI:  https://doi.org/10.1038/s41598-026-57067-3
  59. Bioorg Chem. 2026 Jun 18. pii: S0045-2068(26)00667-X. [Epub ahead of print]180 110131
    Rosmarinic acid attenuates hyperuricemia-induced intestinal damage by activating mitophagy via the p38 MAPK/mTOR pathway.
    Jian Guo, Meihan Zhang, Yuanhang Cheng, Yunqi Gu, Ningbo Qin, Xiaodong Xia.
      Intestinal damage is commonly associated with hyperuricemia (HUA). This study investigated the effect of rosmarinic acid (RA) on intestinal damage in a high-purine diet (HPD)-induced HUA mouse model and the underlying mechanisms. RA effectively alleviated HUA and its related intestinal mucosal damage, epithelial cell apoptosis, and mitochondrial dysfunction in mice. RA also restored the membrane localization of ATP-binding cassette subfamily G member 2 (ABCG2) in epithelial cells. Mechanistically, RA inhibited intestinal epithelial cell apoptosis by modulating the p38 MAPK/mTOR signaling pathway and activating mitophagy. Cellular thermal shift assay (CETSA) and drug affinity responsive target stability (DARTS) assay supported the direct interaction between RA and dual specificity phosphatase 1 (DUSP1), while functional validation further reinforced the involvement of DUSP1 in RA-mediated regulation of the p38 MAPK/mTOR pathway. These findings suggest that RA could be developed as a therapeutic option for HUA and its associated intestinal damage.
    Keywords:  Hyperuricemia; Intestinal damage; Mitophagy; Rosmarinic acid; p38 MAPK/mTOR
    DOI:  https://doi.org/10.1016/j.bioorg.2026.110131
  60. Cells. 2026 Jun 15. pii: 1082. [Epub ahead of print]15(12):
    Ketone-Dependent Restoration of Autophagy and Mitochondrial Quality Control Through VPS35 in a Drosophila Model of C99-Induced Neurodegeneration.
    Hao Huang, Kaijing Xu, Michael Lardellia.
       BACKGROUND: Early endolysosomal and autophagic defects are among the earliest cellular alterations observed in Alzheimer's disease (AD). However, the molecular mechanisms linking amyloid precursor protein (APP) metabolism to vesicle trafficking dysfunction remain incompletely understood. The APP-derived fragment C99 has emerged as a potential upstream mediator of intracellular toxicity, but its impact on organelle homeostasis and its modulation by metabolic interventions remain unclear.
    METHODS: To investigate these mechanisms, we expressed human C99 in Drosophila neurons and examined intracellular pathology using ultrastructural analysis, fluorescent reporters of autophagy and mitochondrial turnover, and proteomic interactome mapping. The effects of the ketone body β-hydroxybutyrate (BHB) were evaluated to assess the impact of metabolic intervention.
    RESULTS: Neuronal C99 expression induced pronounced vesicular abnormalities, impaired autophagic turnover, and disrupted mitochondrial quality control. Transmission electron microscopy revealed extensive accumulation of enlarged vesicular compartments, accompanied by reduced mitochondrial turnover and accumulation of aged mitochondria. BHB treatment restored autophagic cargo clearance, improved mitochondrial turnover, and normalized vesicular ultrastructure. These protective effects required neuronal ketone transport, indicating a neuron-intrinsic metabolic mechanism. Proteomic analysis of the C99-associated interactome revealed that ketone treatment remodels networks enriched for vesicle trafficking and proteostasis pathways. Network prioritization identified the retromer component VPS35 as a candidate regulatory hub. Functional analyses demonstrated that depletion of VPS35 abolished the BHB-dependent restoration of autophagy, mitochondrial turnover, and vesicle morphology.
    CONCLUSIONS: Ketone treatment restores mitochondrial quality control and autophagic homeostasis through a VPS35-dependent mechanism in C99-induced neurodegeneration. These findings provide mechanistic insight into how metabolic interventions may restore intracellular homeostasis in Alzheimer's disease.
    Keywords:  Alzheimer’s disease; C99; β-hydroxybutyrate
    DOI:  https://doi.org/10.3390/cells15121082
  61. Toxicology. 2026 Jun 23. pii: S0300-483X(26)00137-X. [Epub ahead of print]526 154530
    Perfluorooctanoic acid induces mitochondrial dysfunction-driven apoptosis and PINK1/Parkin-mediated mitophagy in testicular cells.
    Banu Orta Yilmaz, Yasemin Aydin.
      Per- and polyfluoroalkyl substances (PFAS) have become an important focus of research in recent years due to their widespread use and environmental persistence. Perfluorooctanoic acid (PFOA) has attracted considerable attention due to its effects on the reproductive system, yet its molecular mechanisms in testicular cells remain unclear. This study aimed to investigate the effects of PFOA on oxidative stress, mitochondrial function, and interconnected programmed cell death pathways. Mouse Sertoli (TM4) and spermatogonial (GC-1) cells were exposed to PFOA at concentrations of 200-800 µM for 24 h, and its effects on cell viability and cytotoxicity were evaluated. Oxidative stress levels were determined by measuring reactive oxygen species production, malondialdehyde levels, antioxidant enzyme activities, and mitochondrial membrane potential. In addition, the potential cell death pathways, including apoptosis, autophagy, mitophagy, and ferroptosis, were assessed by analyzing gene and protein expression using RT-qPCR and Western blot. PFOA exposure resulted in a concentration-dependent and significant increase in intracellular ROS levels, accompanied by a significant decrease in mitochondrial membrane potential in both cell lines. The antioxidant defense system and NRF2 signaling were markedly suppressed. PFOA exposure also significantly activated intrinsic apoptotic pathways, as supported by increased apoptotic gene expression and elevated caspase-3 protein levels. A clear increase in autophagy- and mitophagy-related markers was observed, suggesting that cells develop an adaptive response to mitochondrial damage. These findings provide important mechanistic insights into mitochondrial dysfunction and associated cell death processes in PFOA-exposed testicular cells.
    Keywords:  Apoptosis; Ferroptosis; Mitochondrial dysfunction; Mitophagy; Oxidative stress; Perfluorooctanoic acid; Testicular cells
    DOI:  https://doi.org/10.1016/j.tox.2026.154530
  62. Autophagy. 2026 Jun 21.
    EGR1 mediates neuronal damage via suppressing HIF1A-induced mitophagy following traumatic brain injury.
    Xiaoxiang Hou, Danfeng Zhang, Xianzheng Sang, Chaogui Peng, Wen Chen, Jing Xu, Yichao Ye, Yangu Guo, Hantong Shi, Chengzi Yang, Hanzi Cai, Yijian Wang, Guangxin Chu, Haoxiang Xu, Liquan Lv, Hai Jin, Chunhui Wang, Xiaolin Qu.
      Traumatic brain injury (TBI) remains a leading cause of neurological morbidity and mortality, characterized by complex pathophysiological cascades. Here, we investigate the role of the transcription factor EGR1 (early growth response 1) in modulating mitochondrial homeostasis via the HIF1A (hypoxia inducible factor 1, alpha subunit)-BNIP3 (BCL2/adenovirus E1B interacting protein 3) axis following TBI. Using integrated transcriptomic and epigenomic analyses, we identified EGR1 as a critical regulator of TBI pathology, with its expression acutely upregulated in neurons post-injury. Genetic ablation of Egr1 in mice significantly reduced neuronal apoptosis, preserved dendritic integrity, and ameliorated cognitive and sensorimotor deficits. Mechanistically, chromatin immunoprecipitation and luciferase assays revealed that EGR1 directly binds to the Hif1a promoter, repressing its transcription. Loss of EGR1 enhanced HIF1A-BNIP3-mediated mitophagy, reducing mitochondrial dysfunction and oxidative stress both in vitro and in vivo. Conversely, silencing HIF1A or BNIP3 abrogated the neuroprotective effects of EGR1 deficiency. These findings establish a novel EGR1-HIF1A-mitophagy signaling axis as a key determinant of TBI outcomes, highlighting EGR1 as a potential therapeutic target. Abbreviations: AAV: adeno-associated virus; ACTB/β-actin: actin, beta; AIF1/IBA1: allograft inflammatory factor 1; BAF: bafilomycin A1; BNIP3: BCL2/adenovirus E1B interacting protein 3; CCI: controlled cortical impact; COX8: cytochrome c oxidase subunit 8; CUT&Tag: cleavage under targets and tagmentation; DAPI: 4,'6-diamidino-2-phenylindole; DEGs: differentially expressed genes; eGFP: enhanced green fluorescent protein; EGR1: early growth response 1; GFAP: glial fibrillary acidic protein; GO: gene ontology; GSEA: gene set enrichment analysis; HCQ: hydroxychloroquine; HIF1A/HIF-1α: hypoxia inducible factor 1, alpha subunit; IGV: integrative genomics viewer; KEGG: Kyoto encyclopedia of genes and genomes; KO: knockout; LAMP1: lysosomal-associated membrane protein 1; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; Lv: lentivirus; MAP2: microtubule-associated protein 2; mCherry: monomeric cherry fluorescent protein; mRFP: monomeric red fluorescent protein; MTOR: mechanistic target of rapamycin kinase; MUT: mutant; MWM: Morris water maze; NAB1: Ngfi-A binding protein 1; NAB2: Ngfi-A binding protein 2; RBFOX3/NeuN: RNA binding protein, fox-1 homolog (C. elegans) 3; OGD: oxygen-glucose deprivation; OLIG2: oligodendrocyte transcription factor 2; PBS: phosphate-buffered saline; PECAM1/CD31: platelet/endothelial cell adhesion molecule 1; PFA: paraformaldehyde; PPI: protein-protein interaction; Puro: puromycin; ROI: region of interest; ROS: reactive oxygen species; SEM: standard error of the mean; SQSTM1/p62: sequestosome 1; TBI: traumatic brain injury; TOMM20: translocase of outer mitochondrial membrane 20; TSA: tyramide signal amplification; TUNEL: terminal deoxynucleotidyl transferase dUTP nick end labeling; VDAC1: voltage-dependent anion channel 1; WT: wild-type.
    Keywords:  EGR1; HIF1A; mitophagy; neuron; traumatic brain injury
    DOI:  https://doi.org/10.1080/15548627.2026.2693261
  63. Cancer Genet. 2026 Jun 16. pii: S2210-7762(26)00073-6. [Epub ahead of print]306-307 130-159
    Prohibitins in cancer: Multifaceted regulators of mitochondrial homeostasis, oncogenic signaling, tumor microenvironment, and therapeutic resistance.
    Lijun Fang, Yufan Yang, Xin Tian, Jian Guan, Yunmei Liu, Ziyi Luo, Wangrui Lu, Yiqi Du, Zhaoshen Li, Bin Song, Lei Huang.
      Prohibitin 1 (PHB1) and prohibitin 2 (PHB2) are highly conserved, ubiquitously expressed scaffold proteins that play central roles in cellular physiology by forming heterodimeric ring-shaped complexes. Their subcellular localization to mitochondria, the nucleus, cytoplasm, and plasma membrane underpins a remarkable functional pleiotropy that is profoundly exploited in cancer. This review provides a comprehensive synthesis of the current understanding of PHBs in tumor biology, spanning structural features, post-translational modifications, and their integration into multiple oncogenic signaling networks. We systematically describe how PHB1 directly activates the RAS-RAF-MEK-ERK cascade through regulated phosphorylation, how both PHB1 and PHB2 fine-tune the PI3K/Akt/mTOR axis through ubiquitination-dependent scaffolding and degradation of negative regulators, and how they exert bidirectional control over Wnt/β-catenin and NF-κB pathways. A major focus is the dual role of the mitochondrial PHB complex: protecting cristae architecture and regulating the OMA1-OPA1 axis, orchestrating respiratory chain supercomplex assembly, metabolic substrate switching, and mitophagy, while simultaneously suppressing or, in specific contexts, promoting reactive oxygen species signaling and ferroptosis. The review further dissects how dynamic nucleocytoplasmic shuttling of PHBs couples metabolic status to cell cycle progression, stemness, and epigenetic remodeling through interactions with transcription factors (E2F1, p53, Sp1) and chromatin modifiers (MLL2, HDAC1). Within the tumor microenvironment, PHBs emerge as critical immunometabolic hubs that influence macrophage polarization, cGAS-STING activation, and sexual dimorphism in immune responses. We summarize the cancer-type-specific expression patterns of PHB1/2 and their prognostic value, and provide an in-depth analysis of the mechanisms by which PHBs confer resistance to platinum drugs, paclitaxel, PARP inhibitors, and radiotherapy through stabilization of anti-apoptotic proteins, mitochondrial protection, and maintenance of cancer stem cell properties. Finally, we catalogue the expanding armamentarium of PHB-targeted interventions, including small-molecule ligands, stapled peptides, DNA aptamers, and siRNA delivery platforms, and discuss the challenges and opportunities for clinical translation. By integrating molecular mechanisms with translational perspectives, this review highlights PHBs as unique regulatory nodes at the intersection of metabolism, signaling, and immunity, and advocates for precision strategies that exploit context-specific PHB functions to overcome therapy resistance and improve cancer treatment.
    Keywords:  Cancer; Drug resistance; Mitochondrial homeostasis; Mitophagy; Post-translational modifications; Prohibitin; Targeted therapy; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.cancergen.2026.06.005
  64. EMBO Rep. 2026 Jun 22.
    E4BP4 safeguards brown fat mitochondria from obesity-induced fragmentation via ceramide repression.
    Fernando Valdivieso-Rivera, Vanessa O Furino, Carlos E Leher, Ariane M Zanesco, Monara Kaélle Cruz, Flavia C Gan, Adriana Leandra Santoro, Lara Regina-Ferreira, Giovanna Leite Santos, Tiago Gonçalves, Luiz Osório Leiria, Pedro M Moraes-Vieira, Roger Frigério Castilho, Shingo Kajimura, Marcelo A Mori, Licio A Velloso, Carlos H Sponton.
      Brown adipose tissue (BAT) counteracts obesity-related metabolic dysfunction through both thermogenic and non-thermogenic means. However, substantial evidence indicates that obesity negatively affects BAT mitochondrial morphology and oxidative capacity, impairing systemic energy homeostasis. Motivated by this apparent contradiction, we investigate the relationship between obesity and mitochondrial dynamics, as the underlying mechanisms remain incompletely understood. Here, we identify E4BP4 as a transcriptional repressor that prevents obesity-induced mitochondrial fragmentation and oxidative dysfunction by inhibiting ceramide synthesis in brown fat. Specifically, E4BP4 interacts with PRDM16 to repress Cers6 mRNA expression and consequently reduces C16:0 ceramide levels by binding to a 65 kb upstream enhancer region of the Cers6 gene. Notably, the preservation of mitochondrial integrity in BAT by E4BP4 gain-of-function improves systemic glucose homeostasis, independent of weight loss. Collectively, our findings establish E4BP4 as a molecular safeguard against obesity-induced mitochondrial fragmentation and oxidative dysfunction, primarily by suppressing ceramide synthesis in brown fat.
    DOI:  https://doi.org/10.1038/s44319-026-00826-0
  65. Biol Direct. 2026 Jun 24.
    The role of ESRRA and JUNB in oxyphil cells: insights from spatial transcriptomics and single-cell transcriptomics in uremic secondary hyperparathyroidism.
    Zeyu Zhang, Xiangyuan Qiu, Botao Sun, Xinying Li, Fada Xia.
      Oxyphil cells are a primary cellular component of the parathyroid gland. Due to the limitations of techniques for separating oxyphil cells from chief cells, the characteristics and functions of oxyphil cells in uremic secondary hyperparathyroidism (SHPT) remain largely unclear. Therefore, we integrated spatial transcriptomics and single-cell transcriptomics to investigate the characteristics of oxyphil cells and the association between oxyphil cells and calcitriol resistance in SHPT. 6 uremic SHPT samples and 3 normal parathyroid samples were used for single-cell transcriptomics, while the most suitable SHPT sample was used for spatial transcriptomics. By integrating spatial transcriptomics with single-cell transcriptomics data (93073 cells), we identified a subset of 7653 cells with high confidence as oxyphil cells. Both transcriptomic data indicated a higher mitochondrial transcript proportion in oxyphil cells, and further investigation revealed that the transcription factor estrogen related receptor alpha (ESRRA), participated in mitochondrial biogenesis in these cells. Meanwhile, lower VDR expression and calcitriol resistance were observed in oxyphil cells. Further investigation demonstrated that the transcription factor JUNB promoted the transcription of VDR gene by binding to the promoter area of VDR gene, thus ameliorating calcitriol resistance of oxyphil cells in SHPT. These findings offer reliable evidence and new insights into the characteristics of oxyphil cells and their potential role in SHPT, and provide JUNB as a potential target for calcitriol resistance in SHPT.
    Keywords:  Calcitriol; Chief cells; Mitochondrial biogenesis; Oxyphil cells; Secondary hyperparathyroidism
    DOI:  https://doi.org/10.1186/s13062-026-00876-3
  66. Biomed Pharmacother. 2026 06 23. pii: S0753-3322(26)00719-5. [Epub ahead of print] 119683
    Retraction notice to "SNP alleviates mitochondrial homeostasis dysregulation-mediated developmental toxicity in diabetic zebrafish larvae" [Biomedicine & Pharmacotherapy 177 (2024) 117117].
    Yingying Jiang, Yu Cao, Yaoqi Li, Liuliu Bi, Lv Wang, Qianqian Chen, Yue Lin, Huanzhi Jin, Xiaoming Xu, Renyi Peng, Zheyan Chen.
      
    DOI:  https://doi.org/10.1016/j.biopha.2026.119683
  67. Cell Commun Signal. 2026 Jun 22.
    Mitochondria-associated endoplasmic reticulum membrane (MAM): roles in innate immunity dysregulation.
    Qingqi Zhang, Junyan Gao, Yiting Yang, Ping Guo, Huiqin Gao, Shuaiyong Zhao, Shuanglin Zhang, Yaping Shi, Guanxing Xie, Yutong Han, Hao Liu, Yunzeng Zou.
      Mitochondria-associated endoplasmic reticulum membrane (MAM), which serves as a signaling hub for interactions between the endoplasmic reticulum (ER) and mitochondria, dynamically coordinates innate immune processes by regulating calcium homeostasis, lipid metabolism, mitochondrial dynamics, mitochondrial protein modifications, and autophagy. MAM regulates calcium homeostasis to govern mitochondrial energy metabolism and inflammasome activation; maintains lipid metabolism for membrane integrity to support antiviral signaling pathways; controls mitochondrial fission and fusion dynamics, processes that are closely associated with mitochondrial DNA (mtDNA) release; regulates mitochondrial protein modifications to fine-tune the function of proteins localized at MAM; and facilitates the clearance of damaged mitochondria and leaked mtDNA through autophagy. Most critically, MAM dysfunction and innate immune dysregulation form a vicious cycle: immune activation disrupts MAM integrity, and MAM abnormalities exacerbate the release of mitochondrial damage-associated molecules, continuously driving overactivation of pathways such as inflammasomes and the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, thereby promoting the development of autoimmune diseases. This review synthesizes current literature on the molecular mechanisms by which MAM regulates innate immunity. We summarize how disruptions in MAM-mediated mitochondrial homeostasis contribute to innate immune imbalance. By integrating these findings, we highlight potential intervention nodes. This underscores the clinical relevance of targeting MAM in immune-related pathological conditions.
    Keywords:  Innate immunity; Mitochondria-associated endoplasmic reticulum membrane (MAM); Mitochondrial homeostasis; MtDNA
    DOI:  https://doi.org/10.1186/s12964-026-03013-9
  68. Front Psychiatry. 2026 ;17 1809262
    Disruption of a GalR2-mitochondrial axis in the ventral hippocampus contributes to depression-like phenotypes after prenatal stress.
    Jingjing Yue, Jing Zhang, Xiaoyi Yu, Zhiheng Li, Yanhua Wang, Siyi Zhao, Yunfei Bai, Xiaoxiao Li, Hui Li, Yutao Yang, Zhi-Qing David Xu.
       Background: Prenatal stress (PS) is a major risk factor for depression later in life, yet the cellular mechanisms linking early-life adversity to long-term affective vulnerability remain incompletely understood. Neuropeptide receptors have emerged as important modulators of stress-related psychopathology, but their roles in mitochondrial regulation within limbic circuits remain largely unexplored.
    Methods: A rat model of PS was established to assess depression-like behaviors in adulthood. Mitochondrial ultrastructure, ATP production, and the expression of Galanin receptor 2 (GalR2) and key components of the PINK1/Parkin mitochondrial quality control machinery were examined in the ventral hippocampus (vHPC). The effects of intranasal administration of the GalR2 agonist AR-M1896 on behavioral and mitochondrial alterations were evaluated in vivo. To directly test whether the vHPC mediates these effects, we performed unilateral intra-vHPC infusion of AR-M1896. In vitro, glucocorticoid exposure and pharmacological manipulation of GalR2 were used to assess their impact on mitochondrial function and PINK1/Parkin signaling.
    Results: PS induced persistent anhedonia-like behavior and behavioral despair phenotypes in adult offspring, accompanied by marked mitochondrial structural abnormalities, reduced ATP production, and downregulation of GalR2 and PINK1/Parkin-associated mitochondrial quality control signaling in the vHPC. Intranasal AR-M1896 partially normalized reward-related behavioral deficits and ameliorated mitochondrial dysfunction. Importantly, direct intra-vHPC infusion of AR-M1896 elevated ATP, PINK1 and Parkin levels in the ipsilateral vHPC, providing causal evidence that the vHPC is a critical site for GalR2-mediated PINK1/Parkin-related mitophagy-restoring effects. In cell-based assays, glucocorticoid exposure suppressed, whereas GalR2 activation enhanced, mitochondrial membrane potential and PINK1/Parkin-related signaling.
    Conclusion: These findings identify a GalR2-mitochondrial axis in the ventral hippocampus that is disrupted by PS and associated with vulnerability to depression-like phenotypes. The complementary intra-vHPC infusion experiments establish a causal role for vHPC GalR2 signaling in rescuing mitochondrial deficits, directly demonstrating that intranasal AR-M1896 acts at least in part via the vHPC. This receptor-organelle pathway may represent a neurobiological mechanism linking early-life adversity to long-term affective dysfunction.
    Keywords:  depression; galanin receptor 2; mitochondrial quality control; prenatal stress (PS); ventral hippocampus
    DOI:  https://doi.org/10.3389/fpsyt.2026.1809262
  69. Phytomedicine. 2026 Jun 26. pii: S0944-7113(26)00676-8. [Epub ahead of print]159 158445
    Corrigendum to "Integrative single-cell analysis reveals Bu-Shen-Huo-Xue Formula rescues iron-overloaded ovarian function via rewiring IFN-γ/JAK/STAT/CXCL10-driven immune-stromal interactions and BNIP3-mediated mitophagy in endometriosis" [Phytomedicine 2026 May:157:158343].
    Zhexin Ni, Qianqian Zhao, Yangshuo Li, Shanshan Mei, Jin Yu, Jie Ding, Xiaolan Liang, Shuai Sun, Yuqing Wang, Wen Cheng, Wei Zhou, Chaoqin Yu.
      
    DOI:  https://doi.org/10.1016/j.phymed.2026.158445
  70. Biomed Pharmacother. 2026 Jun 23. pii: S0753-3322(26)00748-1. [Epub ahead of print]201 119712
    Bacoside-A from Bacopa monnieri (L.) Wettst. in Parkinson's disease: In Silico and preclinical insights into dopaminergic neuroprotection.
    Abhishek Dadhich, Abhishek Kumar Verma, Irra Dhar, Sunidhi Bhatt, Neeraj Agarwal, Madan Mohan Sharma.
      Parkinson's disease (PD) presents a formidable therapeutic challenge rooted not in a singular pathogenic event but in the convergent failure of mitochondrial homeostasis, redox balance, α-synuclein proteostasis, autophagy-lysosomal integrity, and neuroinflammatory amplification within substantia nigra dopaminergic neurons. Existing dopaminergic pharmacotherapies address symptomatic deficits while leaving the underlying neurodegenerative cascade unchecked, underscoring the need for disease-modifying strategies with multi-target mechanistic reach. This review examines bacoside-A, the principal triterpenoid saponin complex of Bacopa monnieri (L.) Wettst., as a structurally distinctive, polypharmacological neuroprotective scaffold whose biological relevance emerges from convergence with core vulnerability pathways driving dopaminergic degeneration. Integrating in silico, in vitro, and in vivo evidence, we examine how bacoside-A engages molecular targets including α-synuclein aggregation intermediates, monoamine oxidase-B, LRRK2 kinase, PINK1-Parkin mitophagy regulators, and the redox sensor DJ-1, with computational predictions providing a coherent mechanistic framework for findings observed across MPP⁺-, rotenone-, and 6-OHDA-based preclinical models, including attenuation of mitochondrial dysfunction, oxidative amplification, and apoptotic signalling, and partial nigrostriatal preservation with motor improvement in vivo. This review reframes bacoside-A as a stress-buffering, network-active modulator most relevant during early, pre-degenerative disease stages. While no clinical trial has yet evaluated bacoside-A in PD, and findings from cognitive or other non-PD indications cannot be extrapolated as efficacy evidence, the convergent mechanistic, computational, and preclinical evidence presented here provides a strong rationale for advancing bacoside-A toward systems pharmacology-guided preclinical and clinical evaluation as an adjunct neuroprotective candidate.
    Keywords:  Dopaminergic neurodegeneration; Mitophagy dysregulation; Polypharmacological neuroprotection; Substantia nigra pars compacta; Triterpenoid saponin scaffold
    DOI:  https://doi.org/10.1016/j.biopha.2026.119712
  71. Curr Issues Mol Biol. 2026 Jun 11. pii: 612. [Epub ahead of print]48(6):
    Mitochondrial Dysfunction and Oxidative Stress in Retinal Degeneration: Mechanisms, Biomarkers, and Therapeutic Perspectives.
    Feliciana Menna, Stefano Lupo, Laura De Luca, Antonio Baldascino, Enzo Maria Vingolo, Alessandro Meduri.
      Mitochondrial dysfunction and oxidative stress are increasingly recognized as key contributors to the development and progression of retinal degenerative diseases, including age-related macular degeneration and inherited retinal dystrophies. Growing evidence suggests that alterations in mitochondrial function, excessive production of reactive oxygen species, defective mitophagy, and chronic inflammatory responses are closely interconnected processes that contribute to retinal cell damage and degeneration. This review provides an overview of the current understanding of the molecular mechanisms linking mitochondrial dysfunction to retinal degeneration, with particular emphasis on the impact of oxidative stress, mitochondrial quality-control pathways, and inflammatory signaling. Available evidence indicates that mitochondrial DNA damage, impaired bioenergetics, and dysregulated mitochondrial dynamics play a crucial role in the degeneration of photoreceptors and retinal pigment epithelium cells. In turn, oxidative stress further exacerbates mitochondrial impairment, creating a self-sustaining cycle that promotes disease progression. Recent advances have also highlighted the therapeutic potential of targeting mitochondrial pathways. Although several mitochondria-directed strategies have shown encouraging results in experimental models, their translation into clinical practice remains at an early stage. Overall, the available data identify mitochondria as a promising therapeutic target and support the development of precision medicine approaches aimed at preserving retinal function and slowing disease progression in patients with retinal degenerative disorders.
    Keywords:  biomarkers; mitochondrial dysfunction; mitochondrial therapy; mitophagy; oxidative stress; reactive oxygen species; retinal degeneration; retinal pigment epithelium
    DOI:  https://doi.org/10.3390/cimb48060612
  72. Mol Neurodegener Adv. 2026 ;2(1): 31
    miRNA family miR-29 inhibits PINK1-PRKN signaling via ATG9A.
    Briana N Markham, Chloe Ramnarine, Songeun Kim, William E Grever, Alexandra I Soto-Beasley, Michael G Heckman, Yingxue Ren, Andrew C Osborne, Mohammed Kehili, Aditya V Bhagwate, Yuanhang Liu, Chen Wang, Jungsu Kim, Zbigniew K Wszolek, Owen A Ross, Wolfdieter Springer, Fabienne C Fiesel.
      Loss-of-function mutations in the genes encoding PINK1 and PRKN result in early-onset Parkinson disease (EOPD). Together, the encoded enzymes direct a neuroprotective pathway that ensures the elimination of damaged mitochondria via autophagy. We performed a genome-wide high-content imaging miRNA screen for inhibitors of the PINK1-PRKN pathway and identified all three members of the miRNA family 29 (miR-29). RNA sequencing revealed target genes regulated by miR-29 and identified ATG9A as a candidate gene. SiRNA-mediated ATG9A silencing phenocopied the effects of miR-29 and suppressed the initiation of PINK1-PRKN-mediated mitophagy. In addition, expression of ATG9A was able to rescue the effects of miR-29a, suggesting that ATG9A is primarily responsible for the inhibitory effect of miR-29. In an EOPD patient cohort, we further discovered two rare, potentially deleterious, ATG9A missense variants (p.R631W and p.S828L) and tested them experimentally in cells. Strikingly, neither EOPD ATG9A variant was able to rescue the phenotype suggesting they both act as loss-of-function mutations and might contribute to the etiology of disease. Together, our study validates miR-29 and its target gene ATG9A as novel regulators of PINK1-PRKN signaling. It further serves as proof-of-concept with the identification of novel, potentially disease-relevant EOPD variants specifically in mitophagy-regulating genes. The nomination of biological pathways is important for the stratification and treatment of patients that suffer from devastating diseases, such as EOPD.
    Supplementary Information: The online version contains supplementary material available at 10.1186/s44477-026-00029-w.
    Keywords:  ATG9A; Hsa-miR-29; Mitophagy; PINK1; PRKN; Parkin; Parkinson’s disease
    DOI:  https://doi.org/10.1186/s44477-026-00029-w
  73. Aging Cell. 2026 Jul;25(7): e70593
    Comparative Cochlear-Vestibular Aging Reveals Age-Aligned Mitochondrial Ultrastructural Burden, Mitophagy-Autophagy Remodeling, Synaptic Uncoupling, and Sensory Functional Decline.
    Jingyi Xie, Xujia Zhang, Jinyi Tian, Yulu Yan, Ke Shi, Yongqi Pan, Yanni Zhang, Zichen Chen, Jianbin Sun, Hui Lv, Jingguo Chen, Xiaoyong Ren, Teru Kamogashira, Xiaotong Zhang, Ying Gao.
      Age-related hearing loss and balance decline are prevalent features of organismal aging, yet how the cochlea and vestibular organs converge on shared cellular liabilities remains insufficiently resolved. In particular, whether mitochondrial ultrastructural injury and mitochondrial quality-control programs co-vary with synaptic vulnerability and sensory functional decline across these systems within an age-resolved framework has not been clearly delineated. Here, we compared cochlear and vestibular aging in SAMP8 mice of different ages using integrated functional assays, region-resolved quantification of hair cells and CtBP2/GluA2 synapses, cochlear NF200+ fiber area fraction, transmission electron microscopy, and targeted qPCR of mitophagy/autophagy-lysosome genes. The results show that ABR thresholds rose progressively across 5.6-32 kHz. VsEP exhibited age-dependent threshold shifts and prolonged P-wave latency. Relative to the magnitude of synaptic and functional changes, cochlear hair-cell numbers were broadly preserved, although regional OHC loss was observed in middle-to-basal turns, whereas vestibular macular hair-cell density declined with age. Ultrastructurally, the proportion of pathological mitochondria increased with age, featuring electron-lucent matrix, disrupted cristae organization, and rounded/swollen profiles. What's more, guided by an adult-versus-aged transcriptomic screen nominating the Ca2+ extrusion gene Atp2b4, we derived z-scored molecular indices, including a flux-burden signature (z(p62)-z(Lc3b)) and a TFEB-lysosome module. Descriptive coupling across age-group means indicated that mitochondrial pathology burden aligned closely with high-frequency ABR loss and basal synaptic uncoupling, and tracked the flux-burden signature more consistently than the TFEB-lysosome module. Together, these findings support age-aligned associations among mitochondrial ultrastructural injury, molecular remodeling, synaptic vulnerability, and progressive sensory decline across cochlear and vestibular systems.
    Keywords:  age‐related sensory decline; cochlea–vestibular aging; mitochondrial ultrastructural injury; mitophagy–autophagy remodeling; synaptic uncoupling
    DOI:  https://doi.org/10.1111/acel.70593
  74. Biochem J. 2026 Jul 08. 483(7): 1253-1280
    Proteolytic coordination of the OXPHOS Life Cycle.
    Nataliia Nechytailo, Karolina Szczepanowska.
      The mitochondrial oxidative phosphorylation (OXPHOS) system consists of multimeric, highly ordered protein complexes critical for energy production and metabolic wiring in the cell. Recent discoveries in mitochondrial proteolysis, facilitated by advances in proteomic approaches, have transformed the view of mitochondrial proteases from a simple quality-control system into a dynamically coordinated network of enzymes that actively shape the status of the OXPHOS machinery. Mapping OXPHOS-associated proteolytic circuits has uncovered specialized functions of individual proteases and identified key interaction sites. The present review outlines how mitochondrial proteases regulate the OXPHOS life cycle: expression, delivery, assembly, long-term maintenance, and disposal of mitochondrial respiratory complexes. We summarize past findings and highlight emerging concepts, including asynchronous OXPHOS turnover, cofactor-driven proteolysis, and bioenergetics-coupled degradation. Progress in these areas will deepen our understanding of how proteases coordinate the OXPHOS life cycle.
    Keywords:  mitochondria; mitochondrial proteases; mitochondrial respiratory complexes; oxidative phosphorylation; regulatory proteolysis; turnover
    DOI:  https://doi.org/10.1042/BCJ20250120
  75. Neuropsychopharmacology. 2026 Jun 25.
    Norepinephrine regulates hippocampal mitochondrial biogenesis via β2-adrenergic receptor signaling and PGC-1α.
    Darshana Kapri, Amogh Bhaskaran Jayaprasad, Praachi Tiwari, Mukund Sharma, Angarika Balakrishnan, Aastha Singla, Ishanee Mazumder, Ullas Kolthur-Seetharam, Sashaina E Fanibunda, Ashok D B Vaidya, Vidita A Vaidya.
      Neuronal mitochondria are central to not only maintaining cellular bioenergetics, calcium dynamics, and serving as signaling platforms, but are also critical for specialized functions including synaptic plasticity and neurotransmission. While mitochondria are postulated to have a fundamental role in the functioning of neurons, it is only recently that upstream factors that influence mitochondria in neurons have been systematically investigated. Here, we identify the critical role of the neurotransmitter, norepinephrine (NE) in modulating mitochondria in the rodent hippocampus. NE increases the expression of key regulators of mitochondrial biogenesis (SIRT1 and PGC-1α), enhances mitochondrial DNA content and ATP levels in hippocampal neurons in culture. These effects of NE are mediated via the recruitment of a β2-adrenergic receptor-Gs-cAMP-PKA signaling cascade and are dependent on PGC-1α. We find that increasing noradrenergic signaling in vivo, either through direct administration of NE into the hippocampus via osmotic minipumps or treatment with the NE reuptake inhibitor, Atomoxetine, as well administration of the β2-adrenergic receptor agonist, Formoterol, enhances mitochondrial DNA content in the hippocampus. Furthermore, increased spatial memory recall with Atomoxetine treatment was significantly correlated with both mitochondrial DNA content and ATP levels in the hippocampus. Our findings identify a novel role for NE in impacting mitochondrial biogenesis in the hippocampus, and suggest a link between bioenergetic status and spatial memory performance.
    DOI:  https://doi.org/10.1038/s41386-026-02470-7
  76. J Appl Toxicol. 2026 Jun 22.
    Emerging Cardioprotective Strategies Beyond Dexrazoxane: SGLT2 Inhibitors, Drug Repurposing, and Mitochondrial Approaches in Doxorubicin Cardiotoxicity.
    Bahareh Basirpour, Hamidreza Mohammadi, Nasibeh Hemati, Milad Chahardori.
      Doxorubicin (DOX) remains a foundation of cancer treatment; however, its clinical utility is seriously restricted by measurements of subordinate and frequently irreversible cardiotoxicity. In spite of the fact that dexrazoxane is as of now the as it were affirmed cardioprotective specialist, its limited viability and clinical restrictions highlight the require for elective methodologies. Developing prove shows that DOX-induced cardiotoxicity could be a systems-level clutter driven essentially by mitochondrial brokenness, metabolic resoluteness, disabled quality control, and controlled cell passing pathways. This audit fundamentally looks at rising cardioprotective methodologies past dexrazoxane, with a center on sodium glucose cotransporter 2 (SGLT2) inhibitors, medicate repurposing approaches, and mitochondrial-targeted treatments. We synthesize unthinking bits of knowledge and translational prove to compare these techniques in terms of robotic breadth and clinical status. SGLT2 inhibitors rise as the most clinically developed and robotically integrator choice, though repurposed drugs and mitochondrial-directed mediations offer complementary but variable potential. Finally, we highlight future bearings emphasizing combination treatments and accuracy cardioprotection to realize solid cardiac conservation in anthracycline-treated patients.
    Keywords:  DOX cardiotoxicity; SGLT2 inhibitors; cardio‐oncology; dexrazoxane; exactness cardioprotection; ferroptosis; mitochondrial brokenness; mitochondrial elements; mitophagy; sedate repurposing
    DOI:  https://doi.org/10.1002/jat.70295
  77. Nat Neurosci. 2026 Jun 26.
    Mitochondrial stress response drives microglial senescence.
    Luca Peruzzotti-Jametti, Stefano Pluchino.
      
    DOI:  https://doi.org/10.1038/s41593-026-02264-6
  78. J Peripher Nerv Syst. 2026 Sep;31(3): e70136
    De Novo MFN2 p.Arg95Met in Severe Charcot-Marie-Tooth Disease Type 2A.
    Hsi-Yen Lee, Wen-Ling Cheng, Shin-Hung Pan, Chia-Ju Lee, Yau-Huei Wei, Chin-San Liu.
       BACKGROUND AND AIMS: Mitofusin 2 (MFN2)-related Charcot-Marie-Tooth disease type 2A (CMT2A) is often associated with early onset, severe progressive weakness, distal wasting, and reduced motor and sensory response amplitudes.
    CASE REPORT: We report a 30-year-old Taiwanese woman with infancy-onset, severe axonal sensorimotor neuropathy, progressive distal weakness and wasting, optic atrophy, bilateral sensorineural hearing loss, hypophonia, and wheelchair dependence from adolescence. Nerve conduction study was consistent with severe chronic axonal sensorimotor polyneuropathy. Whole-exome sequencing identified a heterozygous de novo Mitofusin 2 (MFN2) variant, NM_014874.4:c.284G>T, predicting p.Arg95Met.
    INTERPRETATION: This case expands the genotypic spectrum of MFN2-related Charcot-Marie-Tooth disease type 2A and supports the clinical importance of the Arg94/Arg95 region in severe early-onset MFN2 neuropathy.
    Keywords:  Charcot–Marie–tooth disease type 2A; MFN2; optic atrophy; p.Arg95Met; sensorineural hearing loss
    DOI:  https://doi.org/10.1111/jns.70136
  79. Biomolecules. 2026 Jun 12. pii: 867. [Epub ahead of print]16(6):
    Tuning the Fire: Context-Dependent Mitochondrial ROS Signaling, Mitohormesis, and Redox-Modulating Interventions.
    Evelina Charidemou, Eleni Andreou, Christos Papaneophytou.
      Mitochondrial reactive oxygen species (mtROS) are central regulators of cellular function, yet their biological roles are often reduced to an oxidative-stress/antioxidant dichotomy. This review reframes mtROS through the concept of mitohormesis, in which outcomes are neither inherently harmful nor beneficial but are determined by a defined set of contextual variables. We present a mechanistic framework in which mtROS effects depend on chemical species identity, sub-mitochondrial site of production, temporal dynamics, redox-buffering capacity, and metabolic state; together, these variables determine whether mtROS promote adaptive eustress or pathological distress. We then show that, across polyphenols, isothiocyanates, terpenoids, alkaloids, and quinones, the biologically relevant effects of natural redox-modulating compounds are mediated less by direct radical scavenging than by pro-hormetic mechanisms, including mild electron transport chain perturbation, nuclear factor erythroid 2-related factor 2/Kelch-like ECH-associated protein 1 (NRF2/KEAP1) activation, modulation of mitochondrial membrane potential, mitochondrial quality control, and NAD+/NADPH regulation. Applying this framework to disease reveals strong tissue and state dependence: neurodegeneration favors buffering expansion and mitophagy; metabolic disease may benefit from exercise-mimetic and NRF2-activating strategies; cardiovascular disease illustrates mitohormesis through ischemic preconditioning and CoQ10 supplementation; and cancer requires distinction between prevention and therapy because redox buffering can either protect normal tissue or support tumor survival. Finally, we argue that the failure of non-specific antioxidant supplementation is mechanistically predictable and propose context-aware, biomarker-guided, temporally optimized, and compartment-targeted redox interventions as a more rational translational path.
    Keywords:  NRF2/KEAP1 pathway; mitochondria-targeted therapeutics; mitochondrial ROS; mitohormesis; phytochemicals; redox buffering; redox signaling; reverse electron transport
    DOI:  https://doi.org/10.3390/biom16060867
  80. Phytomedicine. 2026 Jun 18. pii: S0944-7113(26)00699-9. [Epub ahead of print]159 158468
    Liqi Huoxue dripping pills alleviate myocardial ischemia-reperfusion injury with improved mitochondrial biogenesis and reduced ferroptosis: Involvement of S100A8/A9-TLR4-ERK signaling.
    Qianying Hao, Jiashu Yue, Ping Li, Qingyong He.
       BACKGROUND: S100A8/A9, a critical danger-associated molecular pattern, amplifies inflammatory responses and exacerbates myocardial ischemia-reperfusion injury (MIRI) through Toll-like receptor 4 (TLR4) signaling. Although S100A8/A9-TLR4-related signaling has been implicated in MIRI pathogenesis, effective pharmacological interventions for MIRI remain limited.
    PURPOSE: This study investigated whether Liqi Huoxue Dripping Pills (Lqhxdw), a traditional Chinese medicine, alleviates MIRI in association with modulation of the S100A8/A9-TLR4-ERK-related signaling axis and elucidated the downstream mechanisms involving mitochondrial dysfunction and ferroptosis.
    METHODS: A rat MIRI model was established by temporary LAD ligation, followed by 7-day Lqhxdw treatment. An in vitro hypoxia/reoxygenation (H/R) model was established using drug-containing serum. Transcriptomic profiling, network pharmacology, and molecular docking were performed to identify candidate therapeutic targets. Rescue experiments with recombinant S100A8/A9 (rS100A8/A9), pharmacological pathway validation using U0126, ferroptosis inhibitor rescue using ferrostatin-1, and in vivo pharmacological validation using TAK-242 were performed to support the proposed mechanistic framework. Mitochondrial function and ferroptosis were assessed by Seahorse XF analysis, biochemical assays, fluorescent probes, and transmission electron microscopy.
    RESULTS: Lqhxdw treatment dose-dependently improved cardiac function, attenuated histopathological damage, and reduced myocardial injury biomarkers. Transcriptomic analysis identified S100a8/S100a9 as significantly upregulated genes following MIRI, with negative correlations to mitochondrial Complex I subunits. Molecular docking predicted favorable binding affinity of Lqhxdw components to TLR4. Experimentally, Lqhxdw reduced S100A8/A9-TLR4 co-localization, suppressed TLR4/ERK phosphorylation, and restored the PGC-1α/NRF1/NDUFA9 axis. Seahorse analysis demonstrated restored mitochondrial respiration. Ferroptosis markers were markedly attenuated by Lqhxdw treatment. Critically, exogenous rS100A8/A9 partially reversed these protective effects. Pharmacological validation using U0126 partly restored PGC-1α and NRF1 expression under rS100A8/A9 stimulation, supporting the involvement of ERK upstream of mitochondrial regulatory changes. Ferrostatin-1 rescue experiments provided functional support for the involvement of ferroptosis. In vivo validation with TAK-242 showed regulatory directions broadly consistent with those of Lqhxdw on iron homeostasis markers and NF-κB-associated inflammatory readouts.
    CONCLUSION: This study provides pharmacological and functional evidence supporting a mechanistic framework in which Lqhxdw attenuates MIRI in association with suppression of S100A8/A9-TLR4-ERK-related signaling, restoration of PGC-1α-mediated mitochondrial biogenesis, and attenuation of ferroptosis. These findings identify S100A8/A9-TLR4-ERK as a biologically relevant signaling framework in MIRI and support the potential clinical application of Lqhxdw in ischemic heart disease.
    Keywords:  Ferroptosis; Liqi Huoxue Dripping Pills; Mitochondrial biogenesis; Myocardial ischemia-reperfusion injury; PGC-1α; S100A8/A9; TLR4
    DOI:  https://doi.org/10.1016/j.phymed.2026.158468
  81. Mucosal Immunol. 2026 Jun 25. pii: S1933-0219(26)00070-X. [Epub ahead of print] 100368
    ADP-ribosylation factor 1 sustains regulatory T cell function and mucosal immune homeostasis in ulcerative colitis.
    Hua-Hua Liu, Shu-Pei Wang, Shuang-Shuang Liu, Yue-Tong Wang, Xiang-Guo Shen, Ji-Min Zhu, Xi-Zhong Shen, Li-Hao Huang, Tao-Tao Liu.
      Dysregulation of regulatory T cells (Tregs) is a hallmark of immune imbalance in ulcerative colitis (UC), in which their suppressive function relies heavily on post-translational modifications and the stabilization of the transcription factor Foxp3. However, the upstream regulatory mechanisms remain poorly understood. Here, we identify ADP-ribosylation factor 1 (Arf1) as a key regulator of Treg function. Clinical samples from UC patients revealed an inverse correlation between ARF1 expression in Tregs and disease severity. Using a Treg-specific Arf1 knockout mouse model, we demonstrate that Arf1 deficiency impairs induced Treg (iTreg) differentiation, disrupts suppressive function, and aggravates T cell transfer-induced colitis. Mechanistically, Arf1 sustains mitochondrial integrity and represses histone deacetylase 9 (Hdac9), thereby enhancing FOXP3 acetylation and protein stability. These findings establish Arf1 as a critical upstream modulator of Treg cell function and intestinal immune homeostasis, and highlight the ARF1-HDAC9-FOXP3 axis as a promising target for Treg-based therapeutic strategies in UC.
    Keywords:  ARF1; FOXP3 acetylation; Mitochondrial homeostasis; Regulatory T cells; Ulcerative colitis
    DOI:  https://doi.org/10.1016/j.mucimm.2026.100368
  82. FASEB J. 2026 Jul 15. 40(13): e72075
    Metformin Partially Attenuates Simvastatin-Induced Myotoxic Responses in C2C12 Myotubes Through Metabolic Adaptation.
    Chuqi He, Mike Wesselink, Jelle Y Huijts, Zhenjia Zhong, Moritz Eggelbusch, Richard T Jaspers, Rob C I Wüst.
      Metformin is the first-line therapy for type 2 diabetes mellitus and is commonly co-administered with statins for cardiovascular risk reduction. However, statins can cause statin-associated muscle symptoms, while metformin itself exerts complex effects on skeletal muscle. Because both drugs influence cellular energy metabolism and stress-response pathways in skeletal muscle, their combined effects on muscle cells warrant investigation. C2C12 myotubes were treated with metformin (50 or 1000 μM) in the absence or presence of simvastatin (10 μM) for 24 h. Myotube morphology, differentiation, and fusion indices, myoblast proliferation, and expression of atrophy-, stress-, and metabolism-related genes were assessed. Phosphorylation of key metabolic and anabolic signaling proteins (AMPK/ACC and Akt/mTOR-p70S6K) was analyzed. Mitochondrial respiration was measured using Seahorse respirometry, and mitochondrial network organization was quantified by live-cell imaging. Simvastatin significantly reduced myotube diameter (p < 0.0001), impaired myogenic progression in differentiated myotubes (differentiation index, p < 0.0001; fusion index, p = 0.0152), and inhibited myoblast proliferation (p = 0.003). Simvastatin increased the atrophy markers (Trim63, Fbxo32), stress marker (Perk), and concurrently suppressed myogenic (Myod) and anabolic (p-p70s6k/p70s6k) activity. Simvastatin also induced a broad suppression of mitochondrial and glycolytic metabolism, accompanied by reduced expression of the metabolic genes (Glut4, Hk2) and disruption of mitochondrial network connectivity. Co-exposure with metformin significantly attenuated simvastatin-induced effects, increasing myotube diameter (1.43-fold at low dose, p = 0.0223, and 1.48-fold at high dose, p = 0.0131), differentiation index (low dose: 1.63-fold; high dose: 1.80-fold; both p < 0.0001), and fusion index (low dose: 1.35; high dose: 1.50-fold; both p < 0.01). Compared with simvastatin alone, co-treatment with high-dose metformin increased AMPK and ACC phosphorylation and further suppressed mTOR signaling without amplifying atrophy-related gene expression. Despite deeper suppression of metabolic parameters (routine respiration, ATP production, Hk2 expression), metformin preserved mitochondrial network structure, increased Ppargc1a expression, and reduced cellular stress markers (Hri, Perk, Atf4). Simvastatin induced metabolic suppression, mitochondrial dysfunction, and atrophy-related responses in skeletal muscle cells. Metformin partially attenuated these alterations by preserving myotube structural integrity and reducing cellular stress signaling despite further metabolic suppression. These findings suggest that metformin may promote adaptive metabolic responses that enhance cellular resilience during simvastatin-induced metabolic stress.
    Keywords:  AMPK‐driven metabolic remodeling; metformin; mitochondrial dynamics; muscle atrophy; myotoxicity; statin‐associated muscle symptoms
    DOI:  https://doi.org/10.1096/fj.202600077RRR
  83. Bioresour Bioprocess. 2026 Jun 22. pii: 95. [Epub ahead of print]13(1):
    Carob pod aqueous extract potentiates cisplatin efficacy and reduces toxicity in experimental hepatocellular carcinoma via mitochondrial and inflammatory pathway modulation.
    Wael Sobhy Darwish, Abada El Sayed Khadr, Maher Abd El Naby Kamel, Tamer A Addissouky, Ahmed Zaki Ghareeb, Mabrouk A Abd Eldaim, Mohand K Razzaq, Ibrahim El Tantawy El Sayed, Hamed Mohamed Abdel-Bary, Doaa Ahmed Ghareeb.
       BACKGROUND: Hepatocellular carcinoma (HCC) is a global health challenge with limited therapeutic options. The effectiveness of conventional medication like cisplatin is often compromised by their severe toxicity. This study investigated carob pod aqueous extract (CPAE), a polyphenol-rich natural product, as a potential adjunct therapy to enhance efficacy and mitigate cisplatin toxicity in a preclinical HCC animal model.
    METHODS: A rat model of HCC was established using diethylnitrosamine (DEN) and carbon tetrachloride (CCl₄). Forty-two Wistar rats were divided into seven groups, receiving various treatments: control, CPAE, vehicle, HCC only, HCC+CPAE, HCC+cisplatin, and HCC+CPAE+cisplatin. Liver and kidney function, metabolic profiles, oxidative stress/antioxidant parameters, gene and protein expression (AMPK, PGC-1α, TFAM, SIRT1, iNOS, NF-κB, IκK, p53, SREBP-2), histopathology, and statistical analyses were performed.
    RESULTS: HCC induction caused significant liver dysfunction, metabolic disturbances, oxidative stress, alongside dysregulation of AMPK/PGC-1α/TFAM and NF-κB/iNOS pathways. CPAE, alone or with cisplatin, markedly ameliorated these changes, improving liver and kidney function, restoring antioxidant status, reducing the tumor marker AFP, suppressing pro-inflammatory and oncogenic signaling, and enhancing histological architecture. Furthermore, Combination therapy demonstrated synergistic benefits, with CPAE reducing cisplatin-induced nephrotoxicity and enhancing its antitumor efficacy, primarily via modulation of mitochondrial biogenesis, redox balance, and inflammatory signaling.
    CONCLUSIONS: CPAE exhibits potent hepatoprotective and anti-HCC activity, especially when combined with cisplatin. This combination modulates mitochondrial and inflammatory pathways while mitigating cisplatin-induced toxicity. These finding position CPAE as a promising natural adjuvant for integrative HCC management. Further translational studies are warranted to validate these findings and explore clinical applicability.
    Keywords:  Carob pod aqueous extract; Combination therapy; Hepatocellular carcinoma; Mitochondrial biogenesis; Oxidative stress
    DOI:  https://doi.org/10.1186/s40643-026-01029-0
  84. Oxid Med Cell Longev. 2026 ;2026(1): e8685788
    Interplay of Mitochondrial Dynamics, Nutrition, and Vitamins: Evidence From Experimental and Human Studies With Implications for Women's Health.
    Kunjal Kiran Pai, Shambhavi Shetye, Rakshith Patil, Shravya Acharya, Kishan S Kulal, Ajeetkumar Patil, Saritha U Kamath.
       BACKGROUND: Nutrition is a key modifiable factor supporting mitochondrial health and is essential for ovarian function and women's health across the life course. From menarche to menopause, mitochondrial efficiency underpins physiological balance. The menopausal transition is particularly critical, as hormonal and neuroendocrine changes are associated with impaired mitochondrial function and increased risk of age-related disorders.
    AIM: This review aimed to systematically review and synthesize the available evidence on mitochondrial function across in vitro, animal, and human studies and to evaluate the potential protective role of vitamins and nutrients in maintaining mitochondrial health, with attention to sex-specific findings.
    METHODS: A systematic search was conducted across multiple electronic databases. Forty-six eligible studies were identified and critically reviewed for evidence on mitochondrial function, sex-based differences, and nutritional influences.
    RESULTS: Mitochondrial dysfunction may contribute to the pathophysiology of age-related disorders, including osteoporosis, cardiovascular disease, neurodegenerative conditions, and cancer. Nutritional factors are crucial for preserving mitochondrial integrity. Vitamins C, E, and D, NAD + precursors such as nicotinamide riboside, coenzyme Q10, MitoQ, fucoxanthin, and cabergoline reduce oxidative stress, enhance mitochondrial biogenesis, support electron transport chain activity and ATP production, and maintain redox balance. These actions promote mitochondrial resilience and cellular energy metabolism. Evidence further indicates that women, particularly during the menopausal transition, exhibit heightened vulnerability to mitochondrial dysfunction, highlighting the relevance of nutrition-based interventions.
    CONCLUSION: Optimizing dietary intake of vitamins, antioxidants, and mitochondrial cofactors is a cost-effective, accessible strategy to support mitochondrial health and reduce age-related disease risk in women.
    Keywords:  mitochondria; nutrition; vitamins; women’s health
    DOI:  https://doi.org/10.1155/omcl/8685788
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