bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2026–08–02
72 papers selected by
Gavin McStay, Liverpool John Moores University
  1. β-Elemene Triggers Drp1-Dependent Mitochondrial Fission Through CDK1/Cyclin B1 Signaling in Cervical Cancer Cells.
  2. Interplay between RNA m6A modification and transglutaminase 2 inhibitor effects on mitophagy dysfunction in Alzheimer's disease.
  3. Mitophagy Inhibition Promotes Survival and Mitochondrial Function in MYC-driven HCC.
  4. Mechanisms underlying perfluorooctanoic acid-induced neuronal loss and cognitive deficits: Disruption of mitochondrial dynamics, impaired mitophagy, and blood-brain barrier dysfunction.
  5. The white spot syndrome virus wsv156 protein hijacks Parkin-dependent mitophagy to promote viral infection.
  6. Mitochondrial Quality Control and Pathogenic Signaling Networks in Parkinson's Disease.
  7. The Zuo Jin Wan Formula Reverses Cisplatin Resistance in Gastric Cancer by Inhibiting the Mitochondrial Translocation of Dynamin-Related Protein 1 and Its Mediated Mitochondrial Fission and Mitophagy.
  8. Mitophagy in neurodegeneration: crosstalk between PRKN/parkin-dependent and PRKN-independent pathways.
  9. The Molecular and Cellular Mechanisms of Melatonin: From Physiological Actions to Clinical Applications in Reproductive Medicine.
  10. Naringin reduces mitochondrial fragmentation and excessive mitophagy in cerebral ischemia-reperfusion injury via the S-nitrosylated Dynamin-related protein 1 (SNO-DRP1) / Leucine-rich repeat kinase 2 (LRRK2) / Mitochondrial Calcium Uniporter (MCU) pathway.
  11. Unveiling the AcSirt2-FOXO-Mitophagy Axis: Insights Into Mitochondrial Quality Control and Delayed Aging in Apis cerana.
  12. Mitochondrial quality control in health and disease: mechanisms and therapeutic targets.
  13. Procyanidins A1 and B1 Suppress PEDV CV777 by Modulating Mitophagy.
  14. Erianin Targets PINK1/Parkin-Mediated Mitophagy and Apoptosis to Ameliorate Atopic Dermatitis.
  15. Hyperbaric Oxygen Attenuates Cerebral Ischemia-Reperfusion Injury Through ROS-Dependent Remodeling of Microglial Mitochondrial Dynamics.
  16. PINK1/Parkin-Mediated Mitophagy Participates in High-Altitude Hypoxia Adaptation in Yaks via Energy Metabolism Remodeling.
  17. Exosome-mediated delivery of 3-n-butylphthalide rescues microglial energy crisis and ameliorates neuroinflammation in ischemic stroke.
  18. Targeting TOMM40 unleashes immunogenic mitophagy to facilitate antigen presentation and immunotherapy sensitization.
  19. High-Intensity Interval Training Ameliorates Oxidative Stress and Mitophagy in Heart Tissue of Healthy Rats Following the Combination Use of Methylphenidate and Ethanol.
  20. Mitochondrial programmed cell death in bronchopulmonary dysplasia: mechanisms and therapeutic targets.
  21. Ribosome-associated chaperones integrate co-translational mitochondrial protein import, stress signaling and proteostasis in Saccharomyces cerevisiae.
  22. Rutin rescues oocyte developmental competence in primary ovarian insufficiency by restoring mitophagy and suppressing pyroptosis.
  23. Polystyrene Microplastics Induce Sustained Cardiovascular Redox Imbalance and Alter Mitochondrial Quality Control.
  24. Mitophagy in Hepatic Ischemia-Reperfusion Injury: From Mitochondrial Dysfunction to Therapeutic Targeting.
  25. Exercise alleviates neuroinflammation and cognitive decline in aged mice via hepatic FGF21-driven microglial mitophagy.
  26. MGRN1 alleviates the progression of obesity-related acute lung injury by protecting lung epithelial cells through restoring mitochondrial function.
  27. Oocyte Aging as a Systems-Level Failure of Cellular Quality Control Networks: Insights from Comparative Biology.
  28. Deoxycholic acid impairs mitochondrial fitness and suppresses mitophagy through Parkin ubiquitination driving CD8+ T cell Exhaustion in Colorectal Cancer.
  29. Salidroside alleviates metabolic dysfunction-associated steatohepatitis-induced fibrosis by regulating PI3K/AKT/mTOR pathway-mediated hepatocyte mitophagy.
  30. Mitochondrial dynamics: A promising tool for personalized TNBC management.
  31. Mitochondrial Dysfunction in Metabolic-Syndrome-Related MASLD/MASH: Metabolic Mechanisms and Therapeutic Perspectives.
  32. Restoring Parkin Function: An AAV Gene Therapy Approach for Early-Onset Parkinson's Disease.
  33. The Fly Maggot Antioxidant Peptide (FMP) Alleviates Oxidative Damage in the Intestines of Weaned Piglets by Enhancing Mitochondrial Autophagy Through Activation of the Nrf2 Signaling Pathway.
  34. Mitochondrial Quality Control in Age-Related Diseases: From Molecular Architecture to Precision Therapeutics.
  35. Chemogenetic Activation of Neurons Promotes Axonal Regeneration and Ameliorates Neurological Deficits in Mice with Intracerebral Hemorrhage by Modulating Mitochondrial Function.
  36. A combined stimulus of acute fasting and exercise modulates hippocampal mitochondrial quality control in healthy mice.
  37. New Functions of Mitochondrial Dysfunction in Gastric Cancer: From Molecular Processes to Potential Treatments.
  38. Ylang Ylang Essential Oil in Malignant and Non-Malignant Cells: Comparative Mitophagy-Related Transcriptional Responses.
  39. Measuring PINK1 Activity in Single Cells Using a PINK1 Kinase Activity Reporter.
  40. Mitochondrial pearling is controlled by the inner membrane and mediates segregation of the luminal content and membrane scission.
  41. Correction: SIRT1/PGC-1α signaling promotes mitochondrial functional recovery and reduces apoptosis after intracerebral hemorrhage in rats.
  42. Polystyrene Nanoplastics Induce Early Mitochondrial Dysfunction in H9c2 Cardiomyoblasts Without Substantial Cell Damage.
  43. Evolving role of mitochondrial dysfunction and mitophagy in necrotizing enterocolitis.
  44. Autism Spectrum Disorder: High-Resolution Elucidation of Mitochondrial Dysregulation in Larval Zebrafish Gut.
  45. The embedding of stress: mitophagy as a mechanism for the central nervous system (CNS) programming and lifelong disease vulnerability.
  46. Differential Effects of Turmeric Bioactive Compounds on Neuroinflammation and Mitochondrial Homeostasis in Brain Regions in a Rodent Model of Neuropathic Pain.
  47. Sumoylation profiles and mitochondrial dynamics in in vivo and in vitro models of Parkinson's disease.
  48. Light Exposure Ameliorates Tau-Induced Deficits via Adenosine Signaling and Mitochondrial Quality Control in Drosophila.
  49. Demonstrating Fluorescent Peptidyl Inhibitor Targeting of Mitochondrial ClpXP by Fluorescence Microscopy in Mammalian Cells.
  50. Inhibition of ETS1/DRP1 axis attenuates intervertebral disc degeneration by suppressing excessive mitochondrial fission.
  51. USP8 promotes the progression of sepsis-induced acute lung injury by interacting with the USP24 to suppress PGC-1α deubiquitination and expression.
  52. A coupled TOM-TIM22 supercomplex in human mitochondrial protein import.
  53. Correction: Mesenchymal stem cells inhibit mitochondrial fission by upregulating armadillo repeat containing 1, ameliorating oxidative stress in renal fibrosis.
  54. Artesunate promotes liver regeneration by modulating mitophagy via the AMPKα1/2/mTOR signaling pathway.
  55. Super-resolution live imaging reveals spatiotemporal uncoupling of mitochondria-ER contacts and mitochondrial fission in stem cell aging.
  56. Zhenwu Decoction ameliorates experimental benign prostatic hyperplasia: association with mitochondrial quality control, oxidative stress and apoptosis regulation.
  57. An adaptor for feedback regulation of heme biosynthesis by a mitochondrial protease.
  58. Mitochondrial autophagy promotion contributes to the protective effects of BYHWD glycoside-enriched fraction against OGD/R-induced injury in H9C2 cells.
  59. The Biological Clock-Mitochondria Axis in the Liver: From Molecular Mechanisms to Metabolic Disease.
  60. Health Benefits and Molecular Mechanisms of Urolithin A: From a Gut Microbiota-Derived Metabolite to Translational Applications.
  61. Tumor-Derived Exosomal circAP2B1 Induces M2 Macrophage Polarization by Enhancing Mitochondrial Homeostasis to Promote Esophageal Squamous Cell Carcinoma Progression.
  62. Spatial control of mitochondrial retrograde signaling by nuclear pore-associated contact sites.
  63. The "Mechano-Metabolic-Immune" crosstalk within the skeletal muscle microenvironment: evolution of homeostatic remodeling and quality control mechanisms.
  64. The Central Role of the AMPK/SIRT1/PGC-1α Signaling Axis in Skeletal Muscle Physiology and Pathology and Its Targeted Therapeutic Strategies.
  65. Shugan Tongbian Decoction Ameliorates Constipation and Mental Disorder by Inhibiting UPRmt via Wnt/Retromer Axis.
  66. Microglial Mitochondrial Dysfunction: The Storm Center of Post-Stroke Neuroinflammation.
  67. Complement C3 as a marker for blood-brain barrier leakage after burn injury.
  68. Reprogramming Mitochondrial Adaptation: LONP1 at the Crossroads of Proteostasis, Metabolism, and Disease.
  69. Endothelial Mitochondrial Dysfunction in INOCA and Coronary Microvascular Dysfunction: Mechanisms, Sex Differences, and Therapeutic Implications.
  70. Inhibition of PGC1β-dependent mitochondrial biogenesis enhances EGFR-targeted therapy in lung cancer.
  71. The Role of Inflammation and Immunity in Cardiovascular Disease: Molecular Mechanisms and Therapeutic Targets.
  72. Heat stress promotes myocardial injury and ventricular arrhythmia through DRP1-mediated mitochondrial dysfunction.
  1. J Biochem Mol Toxicol. 2026 Aug;40(8): e71032
    β-Elemene Triggers Drp1-Dependent Mitochondrial Fission Through CDK1/Cyclin B1 Signaling in Cervical Cancer Cells.
    Zhifang Li, Ling Tang, Mingyan Wang, Qiong Yu, Chen Chen, Jiyi Xia, Xiaolan Yu.
      Mitochondrial dynamics, regulated by fission and fusion, are frequently altered in cancers, influencing cell survival and metabolism. The sesquiterpene β-elemene exhibits anti-tumor activity, but its effect on mitochondrial dynamics in cervical cancer is unknown. This study investigated whether β-elemene exerts its anti-tumor effects by disrupting mitochondrial homeostasis. We found that β-elemene treatment dose-dependently reduced viability and increased lactate dehydrogenase release in HT-3 and Caski cervical cancer cells. In HT-3 cells, β-elemene induced mitochondrial oxidative stress, impaired respiratory function, and triggered extensive mitochondrial fragmentation. Mechanistically, β-elemene promoted phosphorylation of dynamin-related protein 1 (Drp1) at Ser616 and its translocation to mitochondria. Furthermore, β-elemene enhanced the interaction between cyclin-dependent kinase 1 (CDK1) and cyclin B1. Genetic silencing of CDK1 abrogated β-elemene-induced Drp1 activation, mitochondrial fragmentation, and bioenergetic deficits. Collectively, these data identify a novel pathway through which β-elemene drives CDK1-dependent Drp1 activation, leading to excessive mitochondrial fission and dysfunction in cervical cancer cells.
    Keywords:  CDK1/Cyclin B1; Drp1; cervical cancer; mitochondrial fission; β‐elemene
    DOI:  https://doi.org/10.1002/jbt.71032
  2. Drug Discov Today. 2026 Jul 27. pii: S1359-6446(26)00153-4. [Epub ahead of print] 104748
    Interplay between RNA m6A modification and transglutaminase 2 inhibitor effects on mitophagy dysfunction in Alzheimer's disease.
    Ankita Chatterjee, Thakur Gurjeet Singh, Shareen Singh, Amritpal Kaur, Sukriti Vishwas.
      Alzheimer's disease (AD) involves amyloid-β aggregation, tau hyperphosphorylation and mitochondrial dysfunction with defective mitophagy. Emerging evidence implicates RNA N6-methyladenosine (m6A) modification and transglutaminase 2 (TG2) as critical regulators of mitochondrial quality control in AD. Downregulation of METTL3/METTL14 and upregulation of fat mass and obesity-associated protein reduce m6A methylation, impair PTEN-induced putative kinase 1/Parkinson protein 2-mediated mitophagy and promote reactive oxygen species accumulation and synaptic loss. Conversely, TG2 overexpression exacerbates mitochondrial stress by crosslinking Aβ and tau, disturbing dynamin-related protein 1- and mitochondrial fission 1 protein-mediated dynamics and suppressing mitophagy. Crosstalk between TG2-induced oxidative stress and m6A dysregulation amplifies neuronal damage. Pharmacological modulation, using TG2 inhibitors (e.g. Z-DON) and m6A enhancers (e.g. METTL3 overexpression), restores mitophagic flux and mitigates pathology in preclinical models, suggesting dual m6A-TG2 targeting as a promising disease-modifying approach in AD.
    Keywords:  Alzheimer’sdisease; m(6)A mRNA modification; mitophagy; neuroprotective effects; transglutaminase2
    DOI:  https://doi.org/10.1016/j.drudis.2026.104748
  3. bioRxiv. 2026 Jul 14. pii: 2026.07.13.738248. [Epub ahead of print]
    Mitophagy Inhibition Promotes Survival and Mitochondrial Function in MYC-driven HCC.
    Nicholas P Lesner, Laura C Kim, Spencer D Shelton, Madelyn Landis, Xuanyan Cai, Denise Zheng, Tanay Parnaik, Caroline Bartman, M Celeste Simon.
      Hepatocellular carcinomas (HCC) are genetically heterogeneous cancers frequently characterized by MYC gene amplification or hyperactivating β-catenin ( CTNNB1 ) mutations. Analysis of TCGA transcriptomics revealed that MYC-driven HCC tumors have decreased expression of mtDNA-encoded genes, but increased expression of nuclear-encoded mitochondrial genes. To investigate this apparent discrepancy, we generated MYC- and CTNNB1-driven murine HCCs, all of which displayed aberrant mitochondrial metabolism. Notably, MYC-driven tumors exhibited significant reductions in OXPHOS and TCA cycle activity that correlated with increased ROS levels, as well as elevated mitochondrial turnover through mitochondrial fission and mitophagy. MYC induces the expression of nuclear respiratory factor 1 (NRF1), which regulates DRP1 and other genes to promote receptor-mediated mitophagy. Knocking out DRP1 reduced mitophagy and ROS levels and promoted survival of HCC-bearing mice. These results identify elevated mitochondrial turnover as a potential therapeutic target in MYC-driven HCC.
    Significance: Hepatocellular carcinoma can arise from multiple oncogenes, making targeted therapy more difficult. Here we show that tumors with MYC amplification lose mitochondrial function via fission and mitophagy upregulation. Targeting mitochondrial quality control results in increased survival suggesting a therapeutic window in MYC-driven HCC.
    DOI:  https://doi.org/10.64898/2026.07.13.738248
  4. Neurotoxicology. 2026 Jul 26. pii: S0161-813X(26)00154-3. [Epub ahead of print]116 103533
    Mechanisms underlying perfluorooctanoic acid-induced neuronal loss and cognitive deficits: Disruption of mitochondrial dynamics, impaired mitophagy, and blood-brain barrier dysfunction.
    Vikrant Rahi, Ravinder K Kaundal.
      Perfluorooctanoic acid (PFOA), a persistent member of the Per- and polyfluoroalkyl substances (PFAS), is widely detected in the environment and human populations and has recently been increasingly associated with neurotoxicity; however, its underlying molecular mechanisms, particularly those involving mitochondrial quality control, remain poorly defined. This study aimed to elucidate the mechanistic basis of PFOA-induced neurotoxicity, focusing on mitochondrial dysfunction, dynamics, and mitophagy, and to determine the downstream effects on neuronal integrity and cognitive function using both in-vitro and in-vivo approaches. In N2a cells, PFOA exposure induced significant oxidative stress, characterized by elevated intracellular and mitochondrial ROS levels and loss of mitochondrial membrane potential (Δψm). These alterations were accompanied by dysregulation of mitochondrial dynamics, evidenced by suppression of fusion proteins (MFN1, MFN2, OPA1) and enhanced activation of fission regulators (DRP1, FIS1). Concurrently, mitophagy was impaired, as indicated by dysregulation of PINK1-Parkin and LC3-p62 signaling, suggesting defective mitochondrial clearance. In-vivo, chronic PFOA exposure disrupted blood-brain barrier integrity, as reflected by increased MMP-9 and reduced tight junction proteins (ZO-1, occludin, claudin-5), and was associated with enhanced neuronal apoptosis, histopathological damage, and cognitive deficits. Collectively, these findings demonstrate that PFOA induces neurotoxicity through mitochondrial dysfunction-driven impairment of mitochondrial dynamics and quality control, leading to neuronal degeneration and neurobehavioral dysfunction.
    Keywords:  Apoptosis; Cognitive impairment; Mitochondrial dysfunction; Mitophagy; Neurotoxicity; PFAS
    DOI:  https://doi.org/10.1016/j.neuro.2026.103533
  5. J Virol. 2026 Jul 29. e0041826
    The white spot syndrome virus wsv156 protein hijacks Parkin-dependent mitophagy to promote viral infection.
    Yan Wang, Lu-Lu Yang, Kai-Ming Cai, Xuan Zeng, Ling-Ke Liu, Hai-Peng Liu.
      White spot syndrome virus (WSSV), a major pathogen causing severe losses in global crustacean aquaculture, ranks among the largest known animal enveloped DNA viruses. While some features of WSSV-host interactions are known, the mechanisms by which the virus exploits host mitochondrial functions to promote its replication remain unclear. Here, using the red claw crayfish (Cherax quadricarinatus) model, we demonstrate that WSSV infection activates host mitophagy. This process is orchestrated by the mitochondria-targeting viral protein wsv156, which acts as a key effector that triggers the formation of mitochondrial aggregates (mito-aggresomes) and initiates mitophagy. Mechanistically, wsv156 recruits and activates dynamin-related protein 1 (CqDrp1) to drive mitochondrial fission and aggregation. Concurrently, wsv156 facilitates the recruitment of the E3 ubiquitin ligase Parkin (CqParkin) to mitochondria, engaging the canonical PTEN-induced putative kinase 1 (CqPINK1)-Parkin pathway to initiate mitophagy. Intriguingly, the viral envelope protein VP26 blocks the final step of autophagic degradation, arresting the process in an incomplete state. We further show that this incomplete mitophagy benefits viral replication through a dual mechanism: it enhances glycolysis to meet the heightened energy and biosynthetic demands of infection while suppressing cell apoptosis to preserve cellular viability. Collectively, our findings uncover how a large DNA virus exploits and precisely modulates host mitophagy, specifically by initiating and then arresting it to craft a supportive intracellular niche for replication. This study not only advances the understanding of WSSV pathogenesis but also provides evolutionary insights into conserved viral strategies for manipulating mitochondrial quality control across diverse hosts, from crustaceans to mammals.IMPORTANCEWhite spot syndrome virus (WSSV) poses the most significant viral threat to global crustacean aquaculture. A major barrier to developing effective countermeasures is the limited understanding of its molecular pathogenesis. This study demonstrates that WSSV actively hijacks host mitochondrial quality control by triggering a stalled form of mitophagy. We identify wsv156 as a key orchestrator of this process, driving mito-aggresome formation and activating Parkin-dependent mitophagy while arresting its completion via VP26, then creating a stalled, incomplete state. Importantly, this incomplete mitophagic response is repurposed to benefit viral replication through a dual mechanism: it enhances glycolysis to fuel viral biosynthesis and concurrently suppresses host cell apoptosis to maintain cell viability. Our findings uncover a novel strategy, whereby an enveloped large DNA virus manipulates mitochondrial turnover to create a favorable replicative niche. These results deepen the mechanistic understanding of WSSV infection and highlight wsv156 as a potential target for future antiviral strategies in aquaculture.
    Keywords:  Drp1; Parkin; incomplete mitophagy; mito-aggresome; mitochondria; mitophagy; white spot syndrome virus; wsv156
    DOI:  https://doi.org/10.1128/jvi.00418-26
  6. Curr Issues Mol Biol. 2026 Jun 23. pii: 645. [Epub ahead of print]48(7):
    Mitochondrial Quality Control and Pathogenic Signaling Networks in Parkinson's Disease.
    Xiaobing Zhang, Huiyu Li, Jiaxin Zhao, Jiawen Tang, Xiaoqing Li, Pengjing Li, Qingyun Zhao, Qi Wang, Wei Zou.
      The second most prevalent neurodegenerative illness in the world, Parkinson's disease (PD), currently has no viable treatments. Although it is yet unknown if mitochondrial dysfunction is an initial event or evolves as a result of neurodegeneration, it is thought to be a crucial component of Parkinson's disease etiology. From the perspective of mitochondrial quality control (MQC), which includes PINK1/Parkin-mediated mitophagy, mitochondrial dynamics, and mitochondrial proteostasis, this article examines mitochondrial dysfunction. Together, these processes preserve mitochondrial homeostasis and prevent the buildup of damaged mitochondria. Dysfunctional mitochondria gradually build up and cause oxidative stress and aberrant cellular signaling when mitochondrial quality control is compromised. According to available data, mitochondrial reactive oxygen species (mtROS) primarily worsen pre-existing mitochondrial damage by encouraging α-synuclein aggregation, cardiolipin remodeling, and dopamine oxidation. In addition, innate immune pathways like cGAS-STING and TLR9 signaling can be triggered by mitochondrial damage-associated molecular patterns (mtDAMPs), especially mitochondrial DNA, which can lead to long-term neuroinflammatory reactions in PD. While new research suggests that m6A RNA modification may be involved in the regulation of mitochondrial stress, the PINK1/Parkin pathway is crucial for maintaining mitochondrial homeostasis. Therapeutic approaches that target mitophagy augmentation, neuroinflammatory signaling, and mitochondrial protection have garnered increasing attention. In an attempt to improve mitochondrial function and lessen persistent neuroinflammatory activation, future research will probably need to concentrate on combination treatment techniques.
    Keywords:  PINK1/Parkin pathway; Parkinson’s disease; m6A modification; mitochondrial malfunction; neuroinflammation; oxidative stress; therapeutic target
    DOI:  https://doi.org/10.3390/cimb48070645
  7. Cancer Med. 2026 Aug;15(8): e72131
    The Zuo Jin Wan Formula Reverses Cisplatin Resistance in Gastric Cancer by Inhibiting the Mitochondrial Translocation of Dynamin-Related Protein 1 and Its Mediated Mitochondrial Fission and Mitophagy.
    Zhuo Zhao, Meijie Yuan, Xiao Yang, Qing Ji, Guobin Liu, Qingfeng Tang, Jian Sun.
       BACKGROUND: Gastric cancer is a major global health concern characterized by high incidence and mortality rates. One of the key challenges in treating gastric cancer is the development of resistance to chemotherapy drugs like cisplatin (DDP). This study aimed to investigate the efficacy of Zuo Jin Wan (ZJW), a traditional Chinese medicine, in overcoming DDP resistance in gastric cancer cells.
    METHODS: The research employed gastric cancer cells with DDP resistance, namely SGC7901/DDP and AGS/DDP, to explore the molecular mechanisms underlying ZJW's effects.
    RESULTS: ZJW significantly reduced DDP resistance by inhibiting the phosphorylation and preventing mitochondrial translocation of Dynamin-related protein 1 (DRP1). ZJW treatment suppressed DRP1-mediated mitochondrial fission and mitophagy, thereby enhancing the sensitivity of resistant cells to DDP. Additionally, ZJW was observed to downregulate the AMPK signaling pathway, which plays a crucial role in DRP1 activation.
    CONCLUSIONS: By modulating mitochondrial dynamics, ZJW disrupts protective mechanisms in resistant cancer cells, highlighting its potential as an adjunct therapy. This study underscores the therapeutic potential of integrating traditional Chinese medicine with conventional chemotherapy to combat drug resistance in gastric cancer.
    Keywords:  DRP1; Zuo Jin Wan; cisplatin; drug resistance; gastric cancer
    DOI:  https://doi.org/10.1002/cam4.72131
  8. Autophagy. 2026 Jul 31.
    Mitophagy in neurodegeneration: crosstalk between PRKN/parkin-dependent and PRKN-independent pathways.
    Laura Kristine Rasmussen, Diana Gomes Moreira, Justyna Okarmus, Anne Simonsen, Morten Meyer.
      Mitochondrial quality control is essential for cellular homeostasis, particularly in neurons, where mitochondrial dysfunction is implicated in the pathogenesis of neurodegenerative diseases. Mitophagy, the selective degradation of damaged or superfluous mitochondria, plays a central role in maintaining mitochondrial integrity and metabolic balance. This review provides a comprehensive overview of the best-characterized PINK1-PRKN/parkin-dependent mitophagy pathway and the expanding repertoire of PRKN-independent mechanisms, including additional ubiquitin-dependent, receptor-mediated, and lipid-mediated pathways. We explore how these pathways intersect and compensate for one another, highlighting the complexity and adaptability of mitochondrial quality control networks. Furthermore, we discuss how dysregulated mitophagy contributes to the onset and progression of neurodegenerative diseases. By examining the interplay between mitophagy pathways and their regulation under physiological and pathological conditions, this review underscores the therapeutic potential of targeting mitophagy in neurodegeneration. Future studies should aim to decode the spatiotemporal dynamics of these pathways to uncover novel opportunities for clinical intervention.
    Keywords:  Autophagy receptors; E3 ubiquitin ligases; PINK-PRKN/parkin pathway; PRKN-independent mitophagy; mitochondrial dysfunction; mitochondrial quality control; mitophagy; neurodegeneration; therapeutic targets
    DOI:  https://doi.org/10.1080/15548627.2026.2711596
  9. Int J Mol Sci. 2026 Jul 22. pii: 6524. [Epub ahead of print]27(14):
    The Molecular and Cellular Mechanisms of Melatonin: From Physiological Actions to Clinical Applications in Reproductive Medicine.
    Kelly I-Rong Lee, Jie-Hong Chen, Kuo-Hu Chen.
      Melatonin has evolved from its classical role as a pineal-derived circadian regulator to a molecule increasingly recognized for its mitochondrial and cytoprotective functions. This review examines the molecular mechanisms and translational implications of melatonin within a mitochondria-centered framework, with particular emphasis on reproductive medicine. Available evidence suggests that melatonin may influence mitochondrial quality control (MQC) through multiple interconnected processes, including ROS regulation, mitochondrial dynamics, mitophagy, biogenesis, and mitochondrial inflammatory signaling. In mitochondria, melatonin can attenuate electron transport chain-derived oxidative stress through direct radical-scavenging reactions, antioxidant metabolite formation, and indirect activation of endogenous antioxidant systems. Experimental studies further suggest that melatonin may modulate Drp1-mediated fission, OPA1- and Mfn1/2-associated fusion, PINK1/Parkin-mediated mitophagy, and SIRT1/PGC-1α-related mitochondrial biogenesis. In reproductive medicine, melatonin has been investigated as a potential adjunctive strategy in assisted reproductive technology, endometriosis, and polycystic ovary syndrome. However, clinical evidence remains heterogeneous, and most human studies have evaluated reproductive or biochemical outcomes rather than direct MQC-related biomarkers. Therefore, although melatonin represents a promising mitochondria-targeted adjunct, standardized dosing strategies, tissue-level pharmacodynamic assessment, and validated mitochondrial biomarkers are needed to determine whether these mechanisms translate into reproducible clinical benefit.
    Keywords:  melatonin; mitochondria; mitochondrial quality control; reproductive medicine
    DOI:  https://doi.org/10.3390/ijms27146524
  10. Phytomedicine. 2026 Jul 22. pii: S0944-7113(26)00854-8. [Epub ahead of print]160 158623
    Naringin reduces mitochondrial fragmentation and excessive mitophagy in cerebral ischemia-reperfusion injury via the S-nitrosylated Dynamin-related protein 1 (SNO-DRP1) / Leucine-rich repeat kinase 2 (LRRK2) / Mitochondrial Calcium Uniporter (MCU) pathway.
    Ting Lei, Kaimei Tan, Xu He, Dandan Li, Manshu Zou, Tao Yi, Feng Qiu, Pan Meng, Lijuan Hu, Rui Fang, Zhigang Mei, Xiuli Zhang.
       BACKGROUND: Mitophagy is vital for preventing cerebral ischemia-reperfusion (CI/R) injury. Naringin, a flavanone glycoside, reduces CI/R injury by blocking harmful mitophagy induced by peroxynitrite (ONOO⁻). Our earlier studies identified that mitochondrial calcium (mtCa2+) efflux stabilizes mitochondrial endosymbiosis and initiates protective mitophagy. However, it is unclear whether and how naringin inhibits harmful mitophagy in association with mtCa2+.
    PURPOSE: This study aimed to examine the influence of the S-nitrosylated dynamin-related protein 1 (SNO-DRP1)/leucine-rich repeat kinase 2 (LRRK2)/mitochondrial calcium uniporter (MCU) pathway on harmful mitophagy, which is inhibited by naringin in CI/R injury.
    METHODS: To validate the hypotheses, a transient middle cerebral artery occlusion/reperfusion (tMCAO/R) model in rats and oxygen-glucose deprivation/reoxygenation (OGD/R)-induced PC12 cells were used to investigate the effects of naringin. Specifically, linsidomine hydrochloride (SIN-1) was used to enhance SNO-DRP1, whereas spermine (Spm) was used to activate MCU. Mitochondrial fragmentation was assessed by measuring the average mitochondrial diameter via transmission electron microscopy (TEM) and evaluating the protein levels of mitofusin 1 (MFN1) and dynamin-related protein 1 (DRP1) through western blotting (WB). The SNO-DRP1 formation was determined by a biotin switch assay. The extent of SNO-DRP1-mediated excessive mitophagy was examined by quantifying the number of autophagosomes using TEM and assessing the colocalization of translocase of the outer mitochondrial membrane complex subunit 20 (TOMM20)-DRP1-3-NT and 3-NT-DRP1-LC3 via immunofluorescence (IF). The interaction between SNO-DRP1 and LRRK2 was confirmed using co-immunoprecipitation and IF colocalization. MtCa2+ overload induced by MCU was evaluated by analyzing MCU protein levels, measuring mtCa2+ fluorescence intensity following Rhod-2 AM treatment, and assessing the opening of the mitochondrial permeability transition pore. The mitochondrial reactive oxygen species and mitochondrial DNA release were used to evaluate the mitochondrial endosymbiosis failure.
    RESULTS: Naringin exhibited a dose-dependent protective effect against CI/R injury in rats subjected to the tMCAO/R model. It effectively reduced mitochondrial fragmentation and SNO-DRP1-mediated mitophagy, attenuated the interaction between SNO-DRP1 and LRRK2, and decreased the protein level of MCU in the penumbra region of the cortex. SIN-1 and Spm counteracted the neuronal protection of naringin in OGD/R-induced PC12 cells. They also mitigated the impact of naringin on mitochondrial fragmentation, harmful mitophagy, and MCU-mediated mtCa2+ overload and mitochondrial endosymbiosis disruption. Notably, only SIN-1 reversed naringin's suppression of SNO-DRP1 formation and its interaction with LRRK2 in vitro.
    CONCLUSIONS: This study demonstrates that naringin reduces ONOO⁻-caused harmful mitophagy in CI/R injury by blocking the SNO-DRP1/LRRK2/MCU pathway, which helps prevent mitochondrial fragmentation and preserve mitochondrial endosymbiosis. This pathway may be among the mechanisms by which naringin exerts its protective effects.
    Keywords:  CI/R injury; Harmful mitophagy; Mitochondrial endosymbiosis; Mitochondrial fragmentation; mtCa(2+) overload
    DOI:  https://doi.org/10.1016/j.phymed.2026.158623
  11. Aging Cell. 2026 Aug;25(8): e70645
    Unveiling the AcSirt2-FOXO-Mitophagy Axis: Insights Into Mitochondrial Quality Control and Delayed Aging in Apis cerana.
    Qiang Ma, Zhengang Ma, Tingyue Huang, Qianmin Hai, Xiaoqun Dang, Jinshan Xu, Jialing Bao, Zachary Y Huang, Zeyang Zhou.
      Cellular senescence is closely associated with mitochondrial dysfunction. Sirtuin 2 (Sirt2), a member of the Sirtuin deacetylases family, plays a pivotal role in regulating energy metabolism and aging in mammals. However, its function in social insect aging remains unclear. Here, using the Eastern honey bee (Apis cerana) as a model, we demonstrate that the age-related downregulation of A. cerana Sirt2 (AcSirt2) in brain tissue is coupled with progressive mitochondrial damage, reactive oxygen species (ROS) accumulation, and a biphasic change in autophagy activity. Conversely, overexpression of AcSirt2 alleviates cellular senescence by promoting mitochondrial fusion/fission balance (via Mfn1, Mfn2, and Drp1), activating the PINK1/Parkin-mediated mitophagy pathway, improving mitochondrial integrity, reducing oxidative stress, and enhancing ATP production. In vivo, AcSirt2 knockdown shortens honey bee lifespan and impairs locomotor ability, whereas its activation reverses these aging phenotypes. Furthermore, we show that AcSirt2 interacts with the transcription factor FOXO and mediates its deacetylation. This study reveals for the first time that the AcSirt2-FOXO-mitophagy axis delays aging by maintaining mitochondrial homeostasis in a social insect, providing novel insights into the development of anti-aging strategies and the promotion of healthy beekeeping.
    Keywords:   Apis cerana ; FOXO; Sirt2; aging; mitochondrial dynamics; mitophagy
    DOI:  https://doi.org/10.1111/acel.70645
  12. Signal Transduct Target Ther. 2026 Jul 29. pii: 295. [Epub ahead of print]11(1):
    Mitochondrial quality control in health and disease: mechanisms and therapeutic targets.
    Agustina Creus, Shrestha Mohapatra, Leonardo Ortega, David Sebastián.
      Mitochondria are essential for cellular homeostasis, integrating various signals to control key cellular functions such as metabolism, apoptosis, inflammation, cell proliferation and redox balance. Given their multifaceted functions, it is not surprising that mitochondrial dysfunction has been implicated as a key contributor to the pathogenesis of numerous human diseases. Consequently, preserving mitochondrial integrity and functionality is vital for overall organismal health. Mitochondrial health is safeguarded by a sophisticated and tightly regulated network of quality control systems. These include mitochondrial proteostasis, which ensures proper protein folding and degradation; mitochondrial biogenesis, which governs the synthesis of new mitochondria; mitochondrial dynamics, encompassing fusion and fission processes; and mitophagy, the selective autophagic removal of damaged mitochondria. Additionally, these core systems are intricately connected to other crucial mitochondrial processes, such as the maintenance of mitochondrial DNA integrity, the regulation of cristae architecture, and the control of mitochondrial permeability transition, all of which are indispensable for optimal mitochondrial performance. Preclinical and clinical studies consistently demonstrate a strong link between impairments in these quality control mechanisms and both aging and the development of a wide spectrum of diseases. These include cancer, metabolic disorders, cardiovascular conditions, neurodegenerative diseases and autoimmune pathologies. In this review, we explore the different facets of mitochondrial quality control and discuss their implications in disease progression and aging. Furthermore, we highlight recent advances in interventions and therapies aimed at modulating mitochondrial quality control, providing an overview of their potential to mitigate disease burden and promote healthy aging.
    DOI:  https://doi.org/10.1038/s41392-026-02813-2
  13. Viruses. 2026 Jul 10. pii: 758. [Epub ahead of print]18(7):
    Procyanidins A1 and B1 Suppress PEDV CV777 by Modulating Mitophagy.
    Yujing Weng, Jialin Li, Cong Ma, Jiufeng Wang, Xiaojia Wang.
      Porcine epidemic diarrhea virus (PEDV) causes severe enteric disease and high mortality in piglets, yet effective therapeutic options remain scarce. To identify novel antivirals, we evaluated the inhibitory potential and molecular mechanisms of four procyanidin subtypes (A1, A2, B1, and B2) in Vero cells. Our results indicate that procyanidins A1 and B1 possess superior anti-PEDV activity compared with their analogs, acting primarily through direct virucidal inactivation (p < 0.001) and by blocking viral adsorption (p < 0.001), internalization (p < 0.001), and replication (p < 0.05). The SI of procyanidin A1 and B1 in Vero cells are 22.4 and 10.8. At the cellular level, mitochondrial membrane dynamics proteins regulate mitophagy-related proteins. PEDV infection disrupts mitochondrial dynamics and hijacks the autophagic machinery, which is characterized by the upregulation of the fission protein DRP1 and the mitophagy regulator Parkin, concurrent with the decrease of p62 and the increase in LC3-II. Treatment with procyanidins A1 and B1 effectively counteracted these alterations, restoring p62 levels (p < 0.05), decreasing LC3-II levels (p < 0.001), reducing autolysosome formation, and reversing the aberrant upregulation of DRP1 (p < 0.001) and Parkin (p < 0.05) to maintain mitochondrial homeostasis. Molecular docking results suggested that the potential binding affinity between procyanidin A1 and the mitochondrial protein Parkin was significantly higher than that of other configurations. Structural analysis further indicated that the presence of an additional ether bond and the trans configuration of the terminal catechin unit in procyanidin A1 might be important factors contributing to its superior antiviral efficacy. These results suggest that procyanidins may inhibit PEDV by inactivating viral particles or blocking their adsorption and internalization to prevent viral entry, while simultaneously modulating host mitochondrial proteins to suppress the replication of viruses that have already entered the cells, thereby supporting the potential of procyanidins A1 and B1 as effective antiviral candidates.
    Keywords:  mitophagy; molecular docking; porcine epidemic diarrhea virus; procyanidin
    DOI:  https://doi.org/10.3390/v18070758
  14. Food Sci Nutr. 2026 Jul;14(7): e72158
    Erianin Targets PINK1/Parkin-Mediated Mitophagy and Apoptosis to Ameliorate Atopic Dermatitis.
    Kexin Xu, Lianhua Zhu, Shan Jin, Wenyu Jin, Zhehu Jin, Guanghai Yan, Liangchang Li.
      Atopic dermatitis (AD) is a chronic inflammatory skin lesions. Mitochondrial dysregulation is associated with various pathologic conditions, including inflammation in the skin. Prior research has indicated that Erianin, a naturally occurring compound derived from Dendrobium plants, has antioxidant and anti-inflammatory effects. Generally, Erianin has been demonstrated to be effective in cutaneous melanoma and ulcerative colitis. However, there is limited knowledge regarding its biological components and the mechanisms by which it prevents and treats AD. To investigate the protective effects of Erianin against AD and to elucidate the potential mechanism of inflammation in AD, with a particular focus on the role of mitochondrial impairment pathways. Combined with vivo and vitro models of inflammation was employed to assess skin conditions, oxidative stress, and mitochondrial dysfunction. The mitochondrial homeostasis was analyzed, and the effects of Erianin treatment on these processes were evaluated using histological analysis, biochemical assays, molecular techniques, and targeting inflammatory cytokines, oxidative stress, mitophagy, and apoptosis. Erianin effectively alleviated AD, and computational simulations suggested a potential interaction with PINK1. Treatment with Erianin significantly reversed these dysfunctional states by promoting mitophagy activity, thereby alleviating mitochondrial dysfunction and reducing ROS levels, which ultimately suppressed apoptosis. These findings demonstrate that Erianin exerts therapeutic potential in AD by targeting mitophagy, with PINK1/Parkin-mediated mitophagy playing a crucial role in the pathogenesis of AD.
    Keywords:  PINK1; atopic dermatitis; erianin; mitochondrial apoptosis; mitophagy
    DOI:  https://doi.org/10.1002/fsn3.72158
  15. Int J Mol Sci. 2026 Jul 16. pii: 6334. [Epub ahead of print]27(14):
    Hyperbaric Oxygen Attenuates Cerebral Ischemia-Reperfusion Injury Through ROS-Dependent Remodeling of Microglial Mitochondrial Dynamics.
    Haotian Wei, Xingyue Du, Shushu Xu, Qiuli Bo, Yanan Guo, Lihua Xu, Zhenglin Jiang, Xia Li, Yuan Yuan.
      Hyperbaric oxygen (HBO) shows neuroprotective potential in cerebral ischemia-reperfusion (CIR) injury, but its variable efficacy suggests that the underlying cellular mechanisms remain incompletely defined. We previously showed that HBO suppresses microglial NLRP3 inflammasome activation after CIR injury in a reactive oxygen species (ROS)-dependent manner; yet, how ROS couples to this effect remains unclear. Since mitochondria regulate ROS and inflammasome signaling, we investigated whether HBO modulates microglial mitochondrial dynamics in CIR injury. In adult male ICR mice (n = 71, 8-12 weeks) subjected to 60 min middle cerebral artery occlusion followed by 24 h reperfusion, HBO improved neurological function, reduced infarct area, and decreased ASC-positive microglia/macrophages. In lipopolysaccharide/nigericin-stimulated primary microglia, HBO suppressed IL-1β release, reduced mitochondrial fragmentation, preserved mitochondrial membrane potential, maintained mitofusin 2 (MFN2) protein level, and reduced DRP1 Ser616 phosphorylation without altering total DRP1 or FIS1 expression. MitoTEMPOL abolished HBO-mediated protection against mitochondrial fragmentation, MFN2 reduction, and DRP1 Ser616 phosphorylation in vitro. Edaravone, when combined with HBO, attenuated HBO-mediated neuroprotection and counteracted HBO-induced regulation of MFN2 and DRP1 Ser616 phosphorylation in vivo. These findings support ROS-dependent remodeling of microglial mitochondrial dynamics as a mechanism contributing to HBO-mediated suppression of inflammasome-associated inflammation after CIR injury.
    Keywords:  cerebral ischemia–reperfusion injury; hyperbaric oxygen; microglia; mitochondrial dynamics; neuroinflammation; reactive oxygen species
    DOI:  https://doi.org/10.3390/ijms27146334
  16. Animals (Basel). 2026 Jul 08. pii: 2121. [Epub ahead of print]16(14):
    PINK1/Parkin-Mediated Mitophagy Participates in High-Altitude Hypoxia Adaptation in Yaks via Energy Metabolism Remodeling.
    Zheng-Bo Li, Tian-Shuai Li, Miao-Ran Li, Zhong-Duo Li, Jia-Lin Wang, Guo-Xiu Li, Jian-Shu Lv, Ling-Xia Li, Xiang-Dong Ye, Xiao-Dong Ling.
      Yaks are an ideal model for investigating mammalian adaptation to high-altitude hypoxia; however, the underlying adaptive mechanisms remain unclear. Therefore, this study aimed to investigate the mechanisms underlying yak adaptation to high altitudes, focusing on the role of the PINK1/Parkin pathway. In particular, we established normoxic and hypoxic models of yak skeletal muscle satellite cells (SMSCs). In addition, we examined the relationship between PINK1/Parkin-mediated mitophagy and the activities of key enzymes involved in mitochondrial energy metabolism. At the tissue level, an increase in altitude significantly decreased p62 expression and upregulated LC3B-II expression. Notably, mitophagy levels and the expression of PINK1 and Parkin in the skeletal muscle, lungs, and myocardial tissues increased with altitude. At the cellular level, hypoxia markedly elevated the expression of PINK1 and Parkin proteins in SMSCs, induced the conversion of LC3-I to LC3-II, decreased p62 accumulation, significantly increased the number of autolysosomes, and enhanced autophagic flux. Hypoxia altered mitochondrial electron transport chain function, resulting in compensatory elevation of key enzyme activities in the mitochondrial respiratory chain. However, 3-methyladenine (3-MA) treatment reversed these hypoxia-induced changes. In conclusion, yak SMSCs sustain mitochondrial functional homeostasis under hypoxia via PINK1/Parkin-mediated mitophagy, effectively managing hypoxic stress.
    Keywords:  PINK1/Parkin; hypoxia; mitophagy; normoxia; skeletal muscle satellite cells; yaks
    DOI:  https://doi.org/10.3390/ani16142121
  17. Neurotherapeutics. 2026 Jul 29. pii: S1878-7479(26)00147-9. [Epub ahead of print]23(5): e00977
    Exosome-mediated delivery of 3-n-butylphthalide rescues microglial energy crisis and ameliorates neuroinflammation in ischemic stroke.
    Bangyue Wang, Muchen Xi, Keyi Lin, Qinglong Guo, Yuyang Wang.
      Stroke remains the second leading cause of death and the primary cause of long-term disability worldwide, with ischemic stroke accounting for the majority of cases. Ischemia triggers robust microglial activation, yet the precise regulatory mechanisms underlying microglial functional reprogramming remain incompletely understood. Here, we demonstrate that excessive mitophagy drives metabolic energy failure in microglia following cerebral ischemia, resulting in impaired phagocytosis and exacerbated neuroinflammation. Analysis of single-cell RNA-sequencing data from mouse brains in the sham, transient middle cerebral artery occlusion (tMCAO, mMCAO), and permanent middle cerebral artery occlusion (pMCAO, sMCAO) groups revealed that mitophagy was markedly activated in microglia under sustained ischemia and was associated with impaired phagocytic and cytoskeletal pathways. In vitro oxygen-glucose deprivation (OGD) assays showed that phagocytosis of apoptotic neurons by microglia induced upregulation of Drp1, triggering excessive mitochondrial fission and mitophagy, which caused ATP depletion and reduced clearance capacity. The mitophagy inhibitor 3-methyladenine alleviated inflammatory responses but failed to restore mitochondrial quality. In contrast, 3-n-butylphthalide (NBP) stabilized mitochondrial membrane potential, restored ATP production, and improved microglial phagocytic defects and inflammation. To achieve targeted delivery, we constructed BV2 microglia-derived exosomes encapsulating NBP (BV2exo@ NBP), which efficiently enhanced drug accumulation in ischemic lesions and significantly improved neurological outcomes in stroked mice. These results identify excessive mitophagy as a core mechanism underlying microglial energy crisis after cerebral ischemia and provide a mitochondria-targeted therapeutic strategy for ischemic stroke. Importantly, the neuroprotective efficacy, mitochondrial restoration, and anti-inflammatory effects of BM@NEB were fully recapitulated in 18-month-old aged mice, a clinically relevant model that more closely reflects the stroke patient population, supporting the translational potential of this exosome-based therapeutic strategy.
    Keywords:  3-n-butylphthalide; Cerebral ischemia; Energy metabolism; Microglia; Mitophagy
    DOI:  https://doi.org/10.1016/j.neurot.2026.e00977
  18. J Immunother Cancer. 2026 Jul 27. pii: e015462. [Epub ahead of print]14(7):
    Targeting TOMM40 unleashes immunogenic mitophagy to facilitate antigen presentation and immunotherapy sensitization.
    Zhiwei Zhang, Yu-An Xie, Chenglin Mu, Shiying Sheng, Jinyuan Zhang, Jie Han, Jiwen Li, Zhengfu He, Xia Liu.
       BACKGROUND: Mitophagy is a mitochondrial quality control process that maintains cellular homeostasis in cancer, yet whether its dysregulation can be exploited to induce tumor immunogenicity remains unclear.
    METHODS: We integrated pancancer single-cell transcriptomic analyses with genetic perturbation strategies in hepatocellular carcinoma models, including CRISPR/Cas9-mediated gene depletion, in vivo syngeneic tumor systems, and RNA-based lipid nanoparticle delivery. Mechanistic investigations combined mitochondrial functional assays, imaging-based mitophagy analysis, flow cytometry, and transcriptional profiling, together with evaluation of immune checkpoint blockade responses in preclinical and clinical cohorts.
    RESULTS: We identify translocase of the outer mitochondrial membrane 40 (TOMM40) as a mitochondrial import gatekeeper that restrains PINK1-Parkin-dependent mitophagy. Loss of TOMM40 induces catastrophic mitochondrial dysfunction and triggers a lethal form of hyperactivated mitophagy. This process is immunogenic and converts immune-cold tumors into immune-inflamed states characterized by enhanced CD8+ T-cell infiltration and activation. Mechanistically, TOMM40 deficiency leads to intracellular reactive oxygen species accumulation, which activates NF-κB signaling and drives upregulation of major histocompatibility complex class I antigen presentation machinery, thereby increasing tumor visibility to cytotoxic T cells. In parallel, TOMM40 loss induces programmed death-ligand 1 upregulation, establishing an adaptive immune resistance program. Functionally, TOMM40-deficient tumors exhibit markedly increased responsiveness to immune checkpoint blockade and generate systemic antitumor immune protection. Clinically, a TOMM40-loss transcriptional signature is associated with improved immunotherapy outcomes across multiple independent patient cohorts.
    CONCLUSIONS: TOMM40 functions as a mitochondrial immune checkpoint that controls the threshold of immunogenic mitophagy. Its loss reprograms mitochondrial stress into antigen presentation and immune activation, providing a strategy to convert immune-cold tumors into immune-responsive states.
    Keywords:  Antigen Presentation; Immunotherapy; Mitochondria
    DOI:  https://doi.org/10.1136/jitc-2026-015462
  19. J Stud Alcohol Drugs. 2026 Jul 27.
    High-Intensity Interval Training Ameliorates Oxidative Stress and Mitophagy in Heart Tissue of Healthy Rats Following the Combination Use of Methylphenidate and Ethanol.
    Sara Shirazpour, Gholamreza Sepehri, Farzaneh Rostamzadeh, Sobhan Mansouri, Homa Jafari, Maryam Iranpour.
       OBJECTIVE: The concurrent consumption of methylphenidate (MPD) and ethanol are prevalent among young individuals and those diagnosed with attention deficit hyperactivity disorder (ADHD). This study investigated the effects of high-intensity interval training (HIIT) on probable cardiac complications caused by the combined use of MPD and ethanol (ET), with a particular focus on oxidative stress and mitochondrial fission, fusion and mitophagy.
    MATERIALS AND METHODS: This study was carried on male Wistar rats that received saline (CTL), HIIT, MPD, ET, MPD+ET, or a combination of HIIT with MPD, ET, or MPD+ET. Cardiac tissue damage and fibrosis were assessed using hematoxylin and eosin and Masson's trichrome staining. The expression of mRNAs was quantified using Real-time PCR, and the activities of superoxide dismutase (SOD) and glutathione peroxidase (GPX) and malondialdehyde (MDA) levels were measured, calorimetrically.
    RESULTS: The combination of ET and MPD increased the levels of MDA, decreased the activity of SOD and GPX, and increased mRNA expression of DRP1, PINK, and Parkin compared to the CTL group. HIIT was associated with a significant reduction in oxidative stress and mitochondrial fission and mitophagy parameters in ethanol and MPD treated groups. HIIT reduced histopathological changes in MDA+ET group and fibrosis in groups receiving ET and combination of MDA and ET.
    CONCLUSION: The findings of this study showed that HIIT intervention could be associated with significant reduction in adverse effects of concurrent consumption of MPD and ethanol on oxidative stress, mitochondrial fission and mitophagy, and injury in heart of healthy male rats.
    Keywords:  Ethanol; Fission; Fusion; High-intensity interval training; Methylphenidate; Mitophagy
    DOI:  https://doi.org/10.15288/jsad.25-00195
  20. Front Physiol. 2026 ;17 1765819
    Mitochondrial programmed cell death in bronchopulmonary dysplasia: mechanisms and therapeutic targets.
    Jianfeng Jiang, Mingyan Wang, Huici Yao, Ying Zhu, Hongyan Lu.
      Bronchopulmonary dysplasia (BPD) is a prevalent chronic lung disease in preterm infants, primarily characterized by arrested alveolarization and dysregulated pulmonary microvascular development. Mitochondria are crucial for normal lung development, supporting cellular energy and homeostasis. In BPD, mitochondrial homeostasis is severely disrupted, characterized by excessive fission, suppressed fusion, deficient biogenesis, imbalanced mitophagy, a collapsed antioxidant system, and a consequent energy crisis. Following mitochondrial damage, a spectrum of mitochondria-associated programmed cell death pathways is activated in pulmonary cells, including mitophagy-dependent death, apoptosis, necroptosis, pyroptosis, and ferroptosis. Within alveolar epithelial cells, vascular endothelial cells, and other pulmonary cells, these death pathways operate both independently and through extensive crosstalk, forming a complex regulatory network. This network synergistically disrupts pulmonary cell survival, proliferation, and differentiation, ultimately arresting lung development. Therapeutic strategies aim to restore mitochondrial homeostasis, inhibit specific death pathways, and utilize regenerative approaches like exosome-based delivery. This review examines the role of mitochondrial dysfunction and interconnected cell death pathways in BPD pathogenesis and discusses emerging treatments.
    Keywords:  apoptosis; bronchopulmonary dysplasia; ferroptosis; mitochondrial dysfunction; mitophagy; necroptosis; pyroptosis
    DOI:  https://doi.org/10.3389/fphys.2026.1765819
  21. Genetics. 2026 Aug 01. pii: iyag200. [Epub ahead of print]
    Ribosome-associated chaperones integrate co-translational mitochondrial protein import, stress signaling and proteostasis in Saccharomyces cerevisiae.
    J Ernesto Bravo-Arévalo, Ariann E Mendoza-Martínez, Teresa Ballado, Ericka Moreno-Méndez, Alexander DeLuna, Soledad Funes.
      Mitochondrial biogenesis requires the coordinated synthesis, targeting, and import of nuclear-encoded mitochondrial precursor proteins. Although ribosome-associated chaperones support co-translational protein folding, their genetic contributions to mitochondrial protein import and cellular homeostasis remain incompletely defined. Here, we investigate the roles of the nascent polypeptide-associated complex (NAC) and the ribosome-associated Hsp70 system Ssb1/2 in Saccharomyces cerevisiae. We show that NAC and Ssb1/2 have distinct yet partially overlapping functions in the handling of mitochondrial precursor proteins. Loss of NAC activates the mitochondrial retrograde pathway and enhances growth on ethanol as a non-fermentable carbon source without compromising respiratory competence, indicating metabolic adaptation rather than overt mitochondrial dysfunction. In contrast, Ssb1/2 deficiency disrupts cytosolic proteostasis, sensitizes cells to TORC1 inhibition, and impairs autophagy and mitophagy. Using a TEV protease-based import reporter, we show that Ssb1/2 promotes efficient co-translational distribution of precursor proteins, whereas NAC limits the accumulation of misfolded proteins at the mitochondrial surface. Biochemical analyses further reveal that Ssb1/2 supports the association of translating cytosolic ribosomes with the mitochondrial outer membrane, while NAC loss partially restores this interaction in the absence of Ssb1/2. Together, these findings establish NAC and Ssb1/2 as key components of an integrated network linking co-translational targeting, mitochondrial signaling, and cellular homeostasis.
    Keywords:   Saccharomyces cerevisiae ; Ribosome-associated chaperones; TORC1 signaling; co-translational targeting; mitochondrial protein import; proteostasis; retrograde signaling
    DOI:  https://doi.org/10.1093/genetics/iyag200
  22. Front Cell Dev Biol. 2026 ;14 1872070
    Rutin rescues oocyte developmental competence in primary ovarian insufficiency by restoring mitophagy and suppressing pyroptosis.
    Ying Zhao, Zhuo Yang, Chenyun Miao, Yuanyuan Zhang, Wenjun Xiao, Ruye Wang, Yun Chen, Ning Ren, Liuqing Yang, Haimo Qian, Heng Dai, Xiaoyi Zhu, Qin Zhang, Jing Ma.
      Primary ovarian insufficiency (POI) is a major cause of female infertility and endocrine dysfunction, for which effective therapies remain limited. We investigated whether rutin, a bioactive compound from traditional Chinese medicine, protects ovarian function in POI by regulating mitochondrial homeostasis and pyroptosis. In vitro assays using chemically injured oocytes showed that rutin alleviated mitochondrial defects, rescued developmental arrest, enhanced antioxidant signaling, promoted mitophagy, and reduced inflammatory cell death. In a cyclophosphamide-induced murine POI model, rutin restored estrous cyclicity, improved follicle development, normalized hormone levels, and enhanced ovulation, litter outcome, and in vitro-fertilization (IVF)-related developmental competence. Ovarian histological and molecular analyses further showed reduced inflammasome-related pyroptotic signaling, lower oxidative stress levels, and improved mitochondrial integrity. These findings identify rutin as a promising ovarian-protective candidate in POI-associated infertility and support further investigation of its therapeutic potential in female reproductive disorders.
    Keywords:  mitophagy; oxidative stress; primary ovarian insufficiency; pyroptosis; rutin
    DOI:  https://doi.org/10.3389/fcell.2026.1872070
  23. Antioxidants (Basel). 2026 Jun 29. pii: 816. [Epub ahead of print]15(7):
    Polystyrene Microplastics Induce Sustained Cardiovascular Redox Imbalance and Alter Mitochondrial Quality Control.
    Ting-Yu Tsai, Pei-Hsuan Lu, Eddy Owaga, Yi-Sheng Tsai, Chia-Wen Chen, Rong-Hong Hsieh.
      Microplastic exposure is an emerging environmental risk factor for cardiovascular health; however, whether cardiovascular alterations can be detected after exposure cessation remains unclear. This study investigated subclinical cardiovascular alterations following repeated oral exposure to polystyrene microplastics (PSMPs), with particular emphasis on redox imbalance and mitochondrial function in delayed cardiovascular alterations. Male Sprague-Dawley rats were administered 0.5 μm PSMPs via oral gavage at varying dosages of 5 or 20 mg/kg every 5 days for 70 days, followed by a 35-day exposure-free period. Repeated exposure to PSMPs did not affect body or organ weights but altered cardiac serum biochemical markers. Cardiac tissue exhibited elevated NADPH oxidase 4 (NOX4) expression and decreased superoxide dismutase 1 (SOD1), SOD2, and catalase (CAT) activities, whereas malondialdehyde (MDA) levels remained unchanged, indicating a state of chronic, low-level oxidative stress. Mitochondrial respiratory chain activities, including nicotinamide adenine dinucleotide cytochrome c reductase (NCCR) and succinate cytochrome c reductase (SCCR), were significantly reduced. Ultrastructural analysis revealed mitochondrial swelling and cristae disruption. In parallel, mitochondrial biogenesis-related proteins, including peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α), nuclear respiratory factor 1 (NRF-1), and mitochondrial transcription factor A (TFAM), were downregulated, while mitophagy markers, including PTEN-induced kinase 1 (PINK1), Parkin RBR E3 ubiquitin protein ligase (Parkin), microtubule-associated protein 1 light chain 3 (LC3), and sequestosome 1 (p62), were upregulated. Notably, most significant alterations were primarily observed in the high-dose group. Furthermore, the aorta showed increased oxidative stress markers without overt structural remodeling. These findings suggest that repeated exposure to PSMP is associated with subclinical cardiac redox-mitochondrial dysregulation, potentially involving redox imbalance, impaired mitochondrial respiratory chain activity, reduced mitochondrial biogenesis, and altered mitochondrial quality-control markers.
    Keywords:  NOX4; mitochondrial biogenesis; mitochondrial dysfunction; mitochondrial respiratory chain; mitophagy; redox imbalance
    DOI:  https://doi.org/10.3390/antiox15070816
  24. Biomolecules. 2026 Jun 24. pii: 941. [Epub ahead of print]16(7):
    Mitophagy in Hepatic Ischemia-Reperfusion Injury: From Mitochondrial Dysfunction to Therapeutic Targeting.
    Xinlei Zou, Tianjie Zhang, Nan Wang, Yuanyue Li, Xingming Jiang, Xiangyu Zhong.
      Hepatic ischemia-reperfusion injury (HIRI) is a major cause of postoperative liver dysfunction and adverse outcomes in hepatectomy, liver transplantation, and hemorrhagic shock. Among the multiple mechanisms implicated in HIRI, mitochondria are recognized as central organelles that integrate metabolic failure, oxidative stress, inflammation, and cell death. During ischemia, interruption of oxygen and nutrient supply impairs oxidative phosphorylation, depletes ATP, disrupts ionic homeostasis, and renders mitochondria highly vulnerable to subsequent injury. Upon reperfusion, reoxygenation triggers excessive reactive oxygen species production, calcium overload, mitochondrial permeability transition pore opening, and release of damage-associated molecular patterns, thereby amplifying hepatocellular injury and sterile inflammatory responses. As a key component of mitochondrial quality control, mitophagy plays a context-dependent role in HIRI. Appropriate activation of mitophagy facilitates the clearance of damaged mitochondria, limits oxidative stress, restrains inflammasome activation, and preserves hepatocellular homeostasis, whereas insufficient or dysregulated mitophagy contributes to mitochondrial accumulation and aggravates liver injury. This review summarizes mitochondrial alterations during the ischemic and reperfusion phases, outlines the major mitophagy pathways involved in HIRI and discusses recent advances in upstream regulation, disease-specific dysregulation, and mitophagy-targeted interventions. A better understanding of the dynamic and biphasic nature of mitophagy in HIRI may provide a stronger theoretical basis for precision liver-protective strategies and future translational therapies.
    Keywords:  hepatic ischemia–reperfusion injury; mitochondria; mitophagy; therapy
    DOI:  https://doi.org/10.3390/biom16070941
  25. Brain Behav Immun. 2026 Jul 30. pii: S0889-1591(26)00683-5. [Epub ahead of print] 106935
    Exercise alleviates neuroinflammation and cognitive decline in aged mice via hepatic FGF21-driven microglial mitophagy.
    Pengda Li, Tao Wu, Mengjie Chen, Nan Wang, Xiaopeng Jia, Zengqiang Chen, Rui Duan.
      Aging-associated neuroinflammation is a major contributor to cognitive decline, and exercise is an effective non-pharmacological intervention against it. However, the molecular mechanisms linking peripheral adaptations to exercise with central neuroprotection in the aged brain remain incompletely understood. In this study, using aged male C57BL/6J mice subjected to 16-week treadmill exercise, we show that aerobic exercise improves cognitive function and attenuates hippocampal neuroinflammation. Through bioinformatic analysis, we identified fibroblast growth factor 21 (FGF21) as an exercise-induced yet aging-suppressed hepatokine. Notably, hepatic FGF21 knockdown eliminated the capacity of exercise to enhance hippocampal mitophagy, along with its beneficial effects on cognition and neuroinflammation. Pharmacological blockade of mitophagy recapitulated the loss of FGF21 function, similarly abolishing the exercise-induced cognitive improvements and attenuation of neuroinflammation. These findings suggest that the neuroprotective effects of FGF21 may be mediated through the promotion of mitophagy. Mechanistically, FGF21 activated the AMPK-transcription factor EB (TFEB) axis in microglia to restore lysosomal function and mitophagy. Restoration of microglial mitophagy was accompanied by reduced cytosolic mtDNA accumulation and attenuated cGAS-STING-driven neuroinflammation in the aged hippocampus. Together, our findings reveal a liver-brain axis through which exercise-induced hepatic FGF21 reshapes microglial homeostasis in the aging brain, and identify FGF21 as a potential therapeutic target for age-related cognitive decline.
    Keywords:  Aerobic exercise; FGF21; Liver-brain axis; Mitophagy; Neuroinflammation
    DOI:  https://doi.org/10.1016/j.bbi.2026.106935
  26. Cytotechnology. 2026 Oct;78(5): 169
    MGRN1 alleviates the progression of obesity-related acute lung injury by protecting lung epithelial cells through restoring mitochondrial function.
    Yingping Wang, Liming Lu, Hui Jin, Jie Wu, Xin Li, Zhijuan Chen, Lisi Luo.
      Acute lung injury (ALI) is a common respiratory disease worldwide, and obesity is a significant factor contributing to its progression. However, there is still a lack of effective clinical interventions specifically targeting this condition. This study aims to investigate the role of MGRN1 in obesity-related ALI. An obesity-related ALI mouse model was induced by a high-fat diet (HFD) and intratracheal instillation of lipopolysaccharide (LPS). An in vitro model was constructed using palmitic acid (PA) and LPS to stimulate mouse lung epithelial cells (MLE-12). Lung wet/dry weight ratio and HE staining were used to assess pathological changes in lung tissue. Cell damage was evaluated through CCK-8 and LDH release assays. Mitochondrial function was assessed via JC-1, Mito-Tracker Green, MitoSOX Red staining, and ATP content measurement. Additionally, RT-qPCR, Western blot, ELISA, immunofluorescence, and immunohistochemistry were employed to detect the expression of related genes and proteins.MGRN1 is downregulated in obesity-related ALI, and its overexpression alleviates LPS-induced lung histopathological damage in obese mice, reduces TNF-α, IL-1β, IL-6, ROS, and LDH levels, and inhibits PA-LPS-induced MLE-12 cell injury. Additionally, overexpression of MGRN1 restores mitochondrial function in PA-LPS-induced MLE-12 cells and suppresses PINK1/Parkin signaling pathway-mediated mitophagy. Further studies found that treatment with the PINK1 activator MTK458 attenuates the protective effect of MGRN1 overexpression on MLE-12 cells exposed to PA-LPS. MGRN1 restores mitochondrial function by inhibiting PINK1/Parkin-mediated mitophagy, thereby suppressing lung epithelial cell injury and ultimately alleviating obesity-related ALI. These findings suggest that MGRN1 may be a promising therapeutic target and that strategies aimed at restoring MGRN1 or pharmacologically restraining PINK1/Parkin-mediated mitophagy may offer a novel intervention for obese patients at risk of ALI, providing a theoretical basis for future clinical drug development.
    Supplementary Information: The online version contains supplementary material available at 10.1007/s10616-026-01038-z.
    Keywords:  MGRN1; Mitochondrial dysfunction; Mitophagy; Obesity-related acute lung injury; PINK1/Parkin signaling pathway
    DOI:  https://doi.org/10.1007/s10616-026-01038-z
  27. Biology (Basel). 2026 Jul 14. pii: 1143. [Epub ahead of print]15(14):
    Oocyte Aging as a Systems-Level Failure of Cellular Quality Control Networks: Insights from Comparative Biology.
    Magda Sochaczewska, Waclaw Tworzydlo.
      Oocyte aging is a conserved biological process that limits reproductive success across animal taxa. While most research has focused on mammalian systems, particularly humans, comparative studies reveal both shared molecular mechanisms and lineage-specific adaptations that shape oocyte longevity. Here, we synthesise current knowledge on chromosomal instability, mitochondrial dysfunction, proteostasis collapse and epigenetic alterations, integrating insights from insects, nematodes and vertebrates. We argue that these phenomena should not be viewed as independent hallmarks of reproductive aging but rather as interconnected manifestations of a progressive decline in cellular quality control networks. By comparing taxa, we identify both conserved vulnerabilities, including cohesin loss, mitochondrial deterioration and genome instability, and lineage-specific adaptations that mitigate their effects. We further propose the hypothesis that biomolecular condensates, including the Balbiani body, nuage and recently described endolysosomal assemblies, may function as higher-order organizational hubs coordinating mitochondrial quality control, proteostasis and genome defence. This perspective provides a unifying framework for understanding oocyte aging as a systems-level process and highlights new directions for future studies of reproductive longevity.
    Keywords:  biomolecular condensates; epigenetic drift; germline aging; mitochondrial quality control; mitophagy; oocyte aging; proteostasis; reproductive aging
    DOI:  https://doi.org/10.3390/biology15141143
  28. Redox Biol. 2026 Jul 25. pii: S2213-2317(26)00321-6. [Epub ahead of print]96 104322
    Deoxycholic acid impairs mitochondrial fitness and suppresses mitophagy through Parkin ubiquitination driving CD8+ T cell Exhaustion in Colorectal Cancer.
    Yang Gao, Jiaxin Wang, Shihui Lai, Mingwei Li, Jiaqi Shi, Xianjun Li, Ying Guo, Sainan Ma, Xinxin Wang, Shule Zhang, Tianyu He, Yu Hong, Shuang Li, Caiqi Liu, Lijuan Cao, Haiping Hao, Chujie Ding.
      Colorectal cancer (CRC) exhibits significant heterogeneity in response to immunotherapy that cannot be fully explained by microsatellite status alone. Although elevated bile acid levels are recognized as an important risk factor for CRC, their impact on immunotherapy responsiveness remains poorly understood. Here, we demonstrate that high bile acid levels profoundly impair anti-PD-1 efficacy in both CRC patient cohort and mouse models, accompanied by reduced infiltration and functional impairment of tumor-infiltrating CD8+ T cells. Bile acid profiling identified deoxycholic acid (DCA) as the key bile acid species mediating this immunosuppressive effect. In vitro and in vivo studies have shown that DCA not only suppressed CD8+ T cell effector function but also drove them toward terminal exhaustion, thereby limiting responsiveness to anti-PD-1. Mechanistically, DCA disrupted mitochondrial fitness in CD8+ T cells by suppressing oxidative phosphorylation and inducing excessive mitochondrial reactive oxygen species (mtROS) production. In parallel, DCA enhanced ubiquitination-dependent degradation of Parkin, thereby inhibiting mitophagy and causing the accumulation of damaged mitochondria. These convergent defects in mitochondrial homeostasis ultimately promoted CD8+ T cell dysfunction and terminal exhaustion. Notably, pharmacological reactivation of mitophagy via Urolithin A reversed these defects and restored the antitumor efficacy of anti-PD-1 in vivo. Collectively, our findings identified a DCA-Parkin-mitophagy axis that drives CD8+ T cell terminal exhaustion and compromises immunotherapy efficacy, providing a potential metabolic intervention strategy to improve immunotherapy responses in CRC patients with elevated bile acid levels.
    Keywords:  Anti-PD-1 therapy; CD8(+) T cell terminal exhaustion; Colorectal cancer; Deoxycholic acid; Mitochondrial dysfunction; Mitophagy
    DOI:  https://doi.org/10.1016/j.redox.2026.104322
  29. Phytomedicine. 2026 Jul 20. pii: S0944-7113(26)00851-2. [Epub ahead of print]160 158620
    Salidroside alleviates metabolic dysfunction-associated steatohepatitis-induced fibrosis by regulating PI3K/AKT/mTOR pathway-mediated hepatocyte mitophagy.
    Zhanyang Xia, Hongliang Liu, Zheyun He, Jing Zhou, Sijia Zhang, Yingfei Xi, Changgui Zhou, Xiang Huang, Chunyan Ruan, Kedan Mao, Junping Shi, Xiaobing Dou, Hongshan Li.
       BACKGROUND: Salidroside (SAL), the primary active compound extracted from Rhodiola rosea, has demonstrated potential efficacy against MASH-induced fibrosis; however, its precise pharmacological mechanisms and molecular targets remain incompletely elucidated.
    PURPOSE: The aim of this study was to explore the protective effects of against MASH-induced liver fibrosis and its underlying pharmacological mechanisms.
    METHODS: In this work, a MASH-induced fibrosis model was established using the high-fat diet (HFD) and choline-deficient, L-amino acid-defined (CDAHFD) diet-fed in vivo and palmitic acid/oleic acid-stimulated hepatocytes in vitro. By comprehensively conducting biochemical index measurements, pathological analysis, Western blot, PCR detection, RNA sequencing, 4D-DIA proteomic analyses, molecular docking, and validation experiments, the study revealed the critical association of PI3K/AKT/mTOR-mediated autophagy-associated mitochondrial quality control with the treatment of MASH-related liver fibrosis.
    RESULTS: Sal treatment significantly ameliorates hepatic steatosis, inflammatory infiltration, and liver fibrosis induced by CDAHFD and HFD. Integrated RNA sequencing and 4D-DIA proteomics analysis revealed that the anti-fibrotic effect of Sal on MASH-induced liver fibrosis may be associated with regulation of the PI3K/AKT/mTOR signaling pathway, thereby enhancing autophagy-associated mitochondrial quality control in hepatocytes, preventing cytoplasmic accumulation of mitochondrial DNA (mtDNA), and ultimately blocking the activation of the cGAS-STING pathway and subsequent production of pro-inflammatory cytokines, including TNF-α and IL-1β. Further in vivo and in vitro andvalidation experiments demonstrated that the anti-fibrotic effects of Sal could be reversed by combined treatment with PI3K or mTOR agonists, specifically manifested as activation of the PI3K/AKT/mTOR signaling pathway, reduced hepatocyte mitochondrial autophagy, restoration of cGAS-STING pathway activity, and increased production of pro-inflammatory cytokines.
    CONCLUSION: In summary, Our findings demonstrate that SAL mitigates MASH-induced liver fibrosis by targeting hepatocyte autophagy-associated mitochondrial quality control to suppress the mtDNA-dependent cGAS-STING inflammatory pathway, thereby revealing a novel therapeutic strategy.
    Keywords:  Hepatocyte mitophagy; Liver fibrosis; Metabolic dysfunction-associated steatohepatitis; PI3K/AKT/mTOR; Salidroside; cGAS–STING
    DOI:  https://doi.org/10.1016/j.phymed.2026.158620
  30. Genes Dis. 2026 Nov;13(6): 102157
    Mitochondrial dynamics: A promising tool for personalized TNBC management.
    Harshit Mishra, Anshu Yadav, Veena B Kushwaha, Manish Pratap Singh.
      Triple-negative breast cancer (TNBC) is an aggressive and highly metastatic form of breast cancer and is associated with poor prognosis due to the lack of targeted therapies. Mitochondrial dysfunction is a crucial factor contributing to tumor growth and chemoresistance in TNBC. Dysregulation in mitochondrial dynamics leads to disruption of the normal process of oxidative phosphorylation, elevated reactive oxygen species generation, and resistance to apoptosis, contributing to TNBC aggressiveness. Moreover, alterations in mitochondrial energetics, including elevated glycolysis and glutamine addiction, provide metabolic advantages for TNBC growth and survival. Emerging therapeutic strategies targeting mitochondrial vulnerabilities have shown potential for TNBC management. Inhibitors targeting mitochondrial dynamics, including Mdivi-1, dynasore, and cepharanthine, act by restoring mitochondrial homeostasis and impairing excessive fission to stimulate apoptosis. Mitochondrial energetics inhibitors, such as 2DG, 3BP, clotrimazole, and etomoxir, disrupt mitochondrial metabolic processes and reduce tumor growth in TNBC. This review highlights the latest advancements in mitochondrial dynamics and energetics in TNBC and explores the molecular mechanisms underlying their dysregulation. It also explores the therapeutic potential of targeting mitochondrial function for personalized strategies leading to improved clinical management of TNBC.
    Keywords:  Mitochondrial dynamics; Mitochondrial energetics; Personalized medicine; TNBC; Targeted therapy
    DOI:  https://doi.org/10.1016/j.gendis.2026.102157
  31. Metabolites. 2026 Jul 11. pii: 489. [Epub ahead of print]16(7):
    Mitochondrial Dysfunction in Metabolic-Syndrome-Related MASLD/MASH: Metabolic Mechanisms and Therapeutic Perspectives.
    Jin Jin, Yang Cheng.
       BACKGROUND/OBJECTIVES: Metabolic-dysfunction-associated steatotic liver disease (MASLD) and metabolic-dysfunction-associated steatohepatitis (MASH) arise in the setting of obesity, insulin resistance, type 2 diabetes, and metabolic syndrome. This review examines how mitochondrial dysfunction participates in the transition from lipid accumulation to hepatocyte injury, inflammation, and fibrosis, and how evidence from human, animal, and in vitro studies should be interpreted.
    METHODS: We provide a narrative synthesis of mechanistic, translational, and clinical studies on hepatic mitochondrial metabolism, fatty acid oxidation, oxidative phosphorylation, redox stress, organelle crosstalk, mitophagy, mitochondrial biogenesis and proteostasis, mitochondrial danger signals, the gut-liver-mitochondria axis, and mitochondria-related therapeutic strategies.
    RESULTS: In early metabolic overload, mitochondrial oxidation may increase as an adaptive response. With persistent substrate pressure, this adaptation can become inefficient, with impaired fatty acid disposal, less efficient oxidative phosphorylation, reactive oxygen species production, redox imbalance, defective mitochondrial quality control, altered mitochondrial biogenesis, mitochondrial unfolded protein response (UPRmt)-related proteostatic stress and mtDNA instability. Mitochondrial DNA and RNA released from damaged organelles may also activate cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING), inflammasome, and RNA-sensing pathways, linking hepatocyte stress to macrophage activation, stellate cell activation, extracellular matrix deposition, and fibrosis.
    CONCLUSIONS: The current evidence supports mitochondria as a stage-dependent amplifier of metabolic liver injury rather than a uniform initiating event. Clinically, the strongest evidence remains with upstream metabolic unloading and liver-directed metabolic therapy, whereas direct mitochondrial restoration and quality-control targeting remain promising but less mature.
    Keywords:  MASH; MASLD; fibrosis; insulin resistance; metabolic syndrome; metabolomics; mitochondrial dysfunction; mitochondrial quality control; mitophagy; oxidative stress
    DOI:  https://doi.org/10.3390/metabo16070489
  32. bioRxiv. 2026 Jul 13. pii: 2026.07.09.737487. [Epub ahead of print]
    Restoring Parkin Function: An AAV Gene Therapy Approach for Early-Onset Parkinson's Disease.
    Sambuddha Basu, Tyler G Demarest, Nicholas J Gattone, Alexandra J Gilsrud, Brittany Wicks, Apeksha Khatiwada, Mohammad Nayal, Renee Gentzel, Daniel Cohen, Eric W Kostuk, Derek P Narendra, Pedro Gonzalez-Alegre, Maria-Grazia Biferi, Elizabeth A Ramsburg.
       Background: Biallelic loss-of-function mutations in PRKN gene (encoding Parkin protein) cause early-onset Parkinson's disease (EOPD). Parkin is a crucial component of PINK1-Parkin pathway, which marks damaged mitochondria for degradation via mitophagy. Without functional Parkin, damaged mitochondria accumulate, causing oxidative stress and neurodegeneration.
    Objective: Investigate Parkin gene replacement via AAV gene therapy as a potential treatment for Parkin-dependent EOPD.
    Methods: We initially validated phosphorylated ubiquitin Ser65 (pUb Ser65 ) as an indicator of Parkin-mediated mitophagy initiation. We evaluated AAV-mediated PRKN replacement (hereafter, AAV-Parkin) in a Parkin knockout neuroblastoma cell line (SH-SY5Y cells) and feasibility of delivery in mouse and rat models.
    Results: Our research showed pUb Ser65 signal was reduced in Parkin-KO SH-SY5Y cells when compared to wild-type cells after mitochondrial stress, indicating deficiency in initiation of mitophagy. AAV-mediated human PRKN gene replacement successfully restored these pUb Ser65 levels in knockout cells. We saw restoration in patient-derived fibroblasts following AAV-Parkin overexpression. We developed a translatable gene therapy approach using rodents. We demonstrated the feasibility of delivering AAV-Parkin directly into the substantia nigra (SN) of wild-type rats. Using an AAV1 capsid with Ef1a promoter, we achieved dose-dependent Parkin expression and identified a well-tolerated dose. We also evaluated multiple promoters in a proprietary Spark100 capsid, finding Ef1a and Synapsin1 (Syn1) were most effective for transducing dopaminergic neurons in the SN of mice without causing adverse effects. These findings established a well-tolerated vector dose and an optimal capsid-promoter combination.
    Conclusions: Our results support the potential of AAV-Parkin gene therapy as a disease-modifying approach for Parkin-deficient EOPD.
    DOI:  https://doi.org/10.64898/2026.07.09.737487
  33. Antioxidants (Basel). 2026 Jun 24. pii: 791. [Epub ahead of print]15(7):
    The Fly Maggot Antioxidant Peptide (FMP) Alleviates Oxidative Damage in the Intestines of Weaned Piglets by Enhancing Mitochondrial Autophagy Through Activation of the Nrf2 Signaling Pathway.
    Xingke Wang, Ruiying Bao, Qingchao Yang, Qian Yang, Sheng Gao, Qingying Cai, Yang Zhang, Haiwen Zhang, Huiyu Shi, Xuemei Wang.
      Intestinal oxidative stress severely compromises the health and growth of weaned piglets. The fly maggot-derived antioxidant peptide FMP was previously identified, but its protective mechanisms remain unclear. Here, we explored how FMP alleviates oxidative intestinal injury. In IPEC-J2 cells, FMP pretreatment significantly attenuated H2O2-induced cytotoxicity, ROS accumulation, and apoptosis, while enhancing antioxidant enzyme activities and activating Nrf2 signaling (p < 0.05). Co-treatment with the Nrf2 inhibitor ML385 abolished FMP-mediated mitophagy enhancement and cytoprotection, revealing that FMP enhances PINK1/Parkin-dependent mitophagy via Nrf2 activation. In diquat-challenged weaned piglets, oral FMP administration restored serum SOD and GSH-Px activities, reduced MDA and DAO levels (p < 0.05), upregulated jejunal tight junction proteins, and enriched Lactobacillus populations. These findings demonstrate that FMP targets the Nrf2-mitophagy axis to protect against intestinal oxidative damage, supporting its application as a green feed additive.
    Keywords:  antioxidant peptide; intestinal barrier; mitophagy; oxidative stress; weaned piglets
    DOI:  https://doi.org/10.3390/antiox15070791
  34. Antioxidants (Basel). 2026 Jun 30. pii: 830. [Epub ahead of print]15(7):
    Mitochondrial Quality Control in Age-Related Diseases: From Molecular Architecture to Precision Therapeutics.
    Jingmin Che, Ye Sun, Fang Wang, Qing Feng, Cuixiang Xu, Xuhui Li.
       BACKGROUND: Mitochondria are the primary organelles that regulate cellular bioenergetic metabolism and maintain homeostasis, providing essential structural support for optimal cell survival. Nonetheless, advancing age leads to cumulative damage to mitochondrial structure and functional integrity, which is a defining characteristic of biological aging and is closely linked to the emergence and progression of numerous age-related diseases, including neurodegenerative disorders, cardiovascular diseases, and metabolic disorders.
    SCOPE OF REVIEW: This article offers a thorough summary and review of mitochondrial quality control (MQC), emphasizing numerous critical processes, including mitochondrial biosynthesis, dynamic remodeling (fusion and fission), and mitophagy. We thoroughly elucidate the molecular pathways that regulate MQC and demonstrate how age-related dysregulation precipitates cellular senescence, highlighting the transition from physiological maintenance to pathological malfunction, which ultimately culminates in cellular aging.
    CONCLUSIONS AND IMPLICATIONS: This study systematically elaborates the pathophysiological mechanisms in the field, comprehensively evaluates the clinical translational potential of targeting the MQC pathway, highlights the key objectives of "restoring mitochondrial plasticity and removing dysfunctional mitochondria", and explores novel intervention strategies. The restoration of normal mitochondrial function in cells throughout aging is a very promising path for precision medicine therapeutics with great translational potential, according to recent state-of-the-art research. The development of novel therapeutic approaches to improve functional healthy mitochondria can effectively delay aging and reduce the rising global burden of age-related diseases.
    Keywords:  age-related diseases; cellular senescence; metabolic homeostasis; mitochondrial quality control; mitophagy; therapeutic targets
    DOI:  https://doi.org/10.3390/antiox15070830
  35. Neuromolecular Med. 2026 Jul 26. pii: 44. [Epub ahead of print]28(1):
    Chemogenetic Activation of Neurons Promotes Axonal Regeneration and Ameliorates Neurological Deficits in Mice with Intracerebral Hemorrhage by Modulating Mitochondrial Function.
    Jinpeng Wang, Li Zhou, Chunxiao Pang, Hui Liu, Yongli Wang, Zengwu Wang, Wenyuan Ling.
      Intracerebral hemorrhage (ICH) is a devastating neurological condition characterized by high morbidity and mortality, with limited treatment options for promoting neurological recovery. Enhancing cortical excitability has emerged as a potential strategy for promoting neurological recovery. However, the role of neuronal activation in mitochondrial regulation and axonal regeneration after ICH remains unclear. A chemogenetic approach using adeno-associated virus (AAV)-human M3 muscarinic designer receptor exclusively activated by designer drugs (hM3Dq) was employed to selectively activate cortical excitatory neurons in an ICH mouse model. Behavioral assessments, histological analyses, and molecular evaluations of mitochondrial function and axonal integrity were performed. In vitro, PC12 cells were transfected with hM3Dq and subjected to Hemin-induced injury to assess mitochondrial dynamics and neurite outgrowth. Dynamin-related protein 1 (DRP1) overexpression was used to investigate the role of mitochondrial fission in hM3Dq-mediated effects. hM3Dq activation significantly improved motor and cognitive functions in ICH mice, reduced neuronal apoptosis, and enhanced axonal regeneration. These effects were associated with restored mitochondrial membrane potential, reduced oxidative stress, increased adenosine triphosphate (ATP) production, and partially restored mitochondrial dynamics-related protein expression. In vitro, hM3Dq overexpression mitigated mitochondrial dysfunction and promoted neurite elongation in PC12 cells. Importantly, DRP1 overexpression reversed these beneficial effects, suggesting that inhibition of mitochondrial fission is critical for hM3Dq-mediated neuroprotection. Chemogenetic activation of cortical neurons promotes neurological recovery after ICH and is associated with improved mitochondrial function and enhanced axonal regeneration. Modulation of DRP1-related mitochondrial fission signaling may partially contribute to these effects, suggesting a potential neuron-mitochondria interaction that may serve as a therapeutic target for hemorrhagic stroke.
    Keywords:  Axonal regeneration; Chemogenetics; DRP1; HM3Dq; Intracerebral hemorrhage; Mitochondrial dynamics
    DOI:  https://doi.org/10.1007/s12017-026-08942-9
  36. Cell Signal. 2026 Jul 30. pii: S0898-6568(26)00431-6. [Epub ahead of print] 112774
    A combined stimulus of acute fasting and exercise modulates hippocampal mitochondrial quality control in healthy mice.
    Vivien Csikos, Brittany Hauger, Taylor Strope, Colton Lysaker, Keith Smith, Julie Allen, Colin S McCoin, John P Thyfault, Heather M Wilkins.
       BACKGROUND AND AIMS: Exercise and fasting are recognized for their ability to improve brain health and mitigate neurodegeneration. However, little is known about how these interventions acutely impact mitochondrial quality control mechanisms including mitophagy.
    METHODS: We examined the effects of a single bout of fasting and exercise (FEx) on hippocampal mitochondrial function and proteomic remodeling in male and female mice. To assess in vivo autophagy dynamics, we combined proteomics with chloroquine (CQ) inhibition of autophagic flux. Mice were assigned to sedentary (Sed), fasting (F), exercise (Ex), or combined FEx groups and received unilateral intrahippocampal injections of CQ or PBS following treatments. Four hours later, hippocampi were collected for analysis.
    RESULTS: LC3-II levels significantly increased in the FEx group only following CQ treatment, indicating enhanced autophagic flux. Proteomic profiling showed sedentary males failed to mount a robust response to FEx however females exhibited upregulation of proteins involved in the TCA cycle, glutathione metabolism, and oxidative phosphorylation, suggesting greater mitochondrial adaptability. Functional assays supported these findings, females showed increased complex IV activity post-FEx. The mitochondrial DNA / nuclear DNA ratio increased after FEx regardless of sex, and upstream regulator analysis predicted activation of mitochondrial biogenesis.
    CONCLUSIONS: Together, these data reveal sex-specific mitochondrial remodeling in response to acute fasting and exercise. Defining these normative responses is critical for understanding how mitochondrial adaptability shapes resilience or vulnerability to neurological challenges.
    Keywords:  Brain; Exercise; Fasting; Mitochondria; Mitophagy
    DOI:  https://doi.org/10.1016/j.cellsig.2026.112774
  37. Int J Mol Sci. 2026 Jul 15. pii: 6305. [Epub ahead of print]27(14):
    New Functions of Mitochondrial Dysfunction in Gastric Cancer: From Molecular Processes to Potential Treatments.
    Huanhuan Liu, Yating Zhang, Juan Wang, Min Qiao, Qinghong Guo.
      Through multifaceted reprogramming, mitochondria, the fundamental organelles of eukaryotic cells, can drive the malignant growth of malignancies. They also control energy metabolism, redox balance, and cell fate determination. Due to its high heterogeneity and primary/acquired drug resistance, gastric cancer (GC), a highly deadly and common cancer worldwide, continues to present significant clinical treatment challenges. Current targeted and immunotherapy strategies have been unable to significantly improve long-term patient survival. Thus, the pathological roles and molecular mechanisms of mitochondrial dysfunction (including mutations in mitochondrial DNA, imbalances in mitochondrial dynamics, aberrant mitophagy, abnormalities in mitochondrial permeability transition pores, and metabolic disorders) in the development of GC are systematically reviewed in this article. The specific mitochondrial phenotypic remodeling of various molecular subtypes of GC, abnormalities in membrane contact interactions between mitochondria and other organelles, the regulatory roles of mitochondrial dysfunction in tumor microenvironment (TME) immune evasion, maintenance of tumor stemness, and ferroptosis, as well as their major effects on the malignant progression and treatment resistance of GC, are all thoroughly examined. In order to provide important theoretical references and novel research perspectives for identifying therapeutic targets with greater precision, clarifying resistance mechanisms, and developing novel combination strategies in GC, this article summarizes the current research status and translational potential of anti-GC therapeutic strategies targeting mitochondria. It also explores the translational challenges currently faced in this field and the core future research directions.
    Keywords:  gastric cancer; metabolic reprogramming; mitochondrial dynamics; mitochondrial dysfunction; targeted therapy; tumor microenvironment
    DOI:  https://doi.org/10.3390/ijms27146305
  38. Pharmaceuticals (Basel). 2026 Jun 28. pii: 1002. [Epub ahead of print]19(7):
    Ylang Ylang Essential Oil in Malignant and Non-Malignant Cells: Comparative Mitophagy-Related Transcriptional Responses.
    Goksu Kasarci-Kavsara, Timur Hakan Barak, Baris Ertugrul, Tugba Buse Senturk, Bedia Cakmakoglu, Sinem Bireller.
      Background: Mitophagy is a mitochondrial quality-control pathway whose contribution to cancer stress tolerance may vary by cellular context. For essential oils, mechanistic interpretation is often limited by compositional variability and the limited number of studies addressing malignant and non-malignant comparisons under matched exposure conditions. Methods: Ylang Ylang essential oil (YY EO) was characterized by GC-MS-FID. Lung cancer cells (A549) and a salivary gland carcinoma model (HTB-41), together with non-malignant lung-related cells (BEAS-2B, MRC-5), were exposed to YY EO. Functional outcomes were assessed by WST-1 and LDH assays. Mitophagy-related and mitochondrial quality-control-associated genes were quantified by RT-qPCR (2-ΔΔCt). Results: GC-MS-FID identified a terpenoid-rich mixture (99.31%), with germacrene D and β-caryophyllene among the major constituents. YY EO was associated with dose- and cell-type-dependent functional responses, with malignant cells showing reductions in WST-1 signal and stronger LDH-associated responses under the tested conditions, while non-malignant cells showed less pronounced functional changes. Transcriptional responses were context-dependent, with differential changes in mitophagy-related genes across cell lines. Conclusions: These findings provide comparative evidence of greater functional sensitivity in malignant cells, alongside cell-context-dependent mitophagy-related transcriptional responses. These observations are hypothesis-generating and remain limited to functional readouts and mRNA-level data. Within these limits, the present study provides a composition-anchored comparative dataset that may support future mechanistic studies in this area.
    Keywords:  GC-MS-FID; Ylang Ylang essential oil; lung cancer; mitochondrial quality control; mitophagy; salivary gland carcinoma
    DOI:  https://doi.org/10.3390/ph19071002
  39. Bio Protoc. 2026 Jul 20. 16(14): e5746
    Measuring PINK1 Activity in Single Cells Using a PINK1 Kinase Activity Reporter.
    Katie G Vineall, Danielle L Schmitt.
      Phosphatase and tensin homolog-induced kinase 1 (PINK1) is a serine/threonine kinase that plays a key role in mitophagy initiation. Loss-of-function autosomal recessive mutations in PINK1 cause early onset Parkinson's disease (EOPD). Current approaches for studying PINK1 function depend on bulk techniques that can only provide snapshots of activity and could miss the dynamics and cell-to-cell heterogeneity of PINK1 activity or provide an indirect readout of PINK1 activity. Here, we present a protocol using our newly developed phase separation-based PINK1 biosensor (PINK1-SPARK) to observe real-time activity of endogenous PINK1 in single cells. Following transfection of live cells with PINK1-SPARK, cells are treated with mitochondrial depolarizing agents and visualized using widefield or confocal fluorescence microscopy, either following the same cells over time for time-lapse imaging of PINK1 activity or end-point measurements. Thus, PINK1-SPARK is a new tool that enables the measurement of PINK1 activity in single live cells, allowing for further elucidation of the role of PINK1 in mitophagy and cell function. Key features • Detailed protocol for use of PINK1-SPARK, a new PINK1 biosensor introduced in Vineall et al. [1]. • PINK1-SPARK, based on phase separation, has a high signal-to-noise, enabling robust detection of PINK1 activity in multiple cell types under multiple activating conditions. • Enables measurement of real-time endogenous PINK1 activation at the single-cell level.
    Keywords:  Biosensor; Fluorescence microscopy; Functional imaging; Kinase activity reporter; Mitophagy; PINK1
    DOI:  https://doi.org/10.21769/BioProtoc.5746
  40. Proc Natl Acad Sci U S A. 2026 Aug 04. 123(31): e2602775123
    Mitochondrial pearling is controlled by the inner membrane and mediates segregation of the luminal content and membrane scission.
    Wasi Iqbal, Ben Zucker, Xiaoying Liu, Ruiru Wang, Hongfei Zhu, Sijie Chen, Renjie Zhou, Xingguo Liu, Michael M Kozlov, Liting Duan.
      Membrane pearling, the transformation of a smooth tubule into a chain of bead-like swellings connected by narrow membrane tethers, is a widely observed shape change. While it has been well studied for synthetic lipid and unilamellar intracellular membranes, the mechanism underlying the pearling of the peculiar double-membrane architecture of tubular mitochondria remained elusive. Here, we addressed the role of the strongly convoluted inner mitochondrial membrane (IMM) in pearling driven by stretching. Using a light-gated, mitochondria-specific mechanostimulator to apply stretching forces to mitochondria in live cells, we demonstrated that stretching triggers pearling of whole tubular mitochondria. Moreover, we found that pearling requires the presence of the IMM, as unilamellar tubules derived solely from the mitochondrial outer membrane elongate uniformly under stretching and never undergo pearling. To understand the physical mechanism by which IMM controls pearling, we developed a theoretical model that considers the lumen, effectively spanned and volumetrically stiffened by cristae, as an elastic continuum. Our computations show that pearling requires the luminal volume to be sufficiently resistant to change, with its effective bulk rigidity modulus exceeding a critical value. Our experimental observations further revealed the functionally important consequences of stretching-induced pearling. mtDNA nucleoids partitioned into the bulges of pearled configurations, suggesting a role for pearling in the reorganization of luminal components. In addition, the membrane fission GTPase DRP1 accumulated at the constrictions of pearled shapes, leading to membrane scission and mitochondrial fragmentation. Our work uncovers the unique biophysical mechanism of mitochondrial pearling and its functional significance for organelle dynamics.
    Keywords:  membrane elasticity; membrane pearling; membrane tension; mitochondria; mitochondrial fission
    DOI:  https://doi.org/10.1073/pnas.2602775123
  41. Front Mol Neurosci. 2026 ;19 1903556
    Correction: SIRT1/PGC-1α signaling promotes mitochondrial functional recovery and reduces apoptosis after intracerebral hemorrhage in rats.
    Yang Zhou, Shaohua Wang, Yixin Li, Shanshan Yu, Yong Zhao.
      [This corrects the article DOI: 10.3389/fnmol.2017.00443.].
    Keywords:  PGC-1α; SIRT1; apoptosis; intracerebral hemorrhage; mitochondrial biogenesis
    DOI:  https://doi.org/10.3389/fnmol.2026.1903556
  42. Antioxidants (Basel). 2026 Jun 26. pii: 801. [Epub ahead of print]15(7):
    Polystyrene Nanoplastics Induce Early Mitochondrial Dysfunction in H9c2 Cardiomyoblasts Without Substantial Cell Damage.
    Ming-Hung Shen, Pei-Hsuan Lu, Ting-Yu Tsai, Eddy Owaga, Yi-Sheng Tsai, Chia-Wen Chen, Rong-Hong Hsieh.
      Global plastic production has led to widespread contamination by micro- and nanoplastics, with polystyrene nanoplastics (PSNPs) increasingly being detected in human biological samples, including blood and cardiac tissue. Given the critical role of mitochondria in cardiac energy metabolism, this study investigated whether 100 nm PSNPs interact with mitochondria and affect mitochondrial function in H9c2 cardiomyoblasts. Cellular uptake and intracellular distribution were examined, followed by an evaluation of mitochondrial ultrastructure, intracellular and mitochondrial reactive oxygen species (ROS) production, mitochondrial membrane potential, mitochondrial dynamics and mitophagy-related gene expression, mitochondrial DNA copy number, and metabolic function. PSNPs were internalized but did not directly localize to mitochondria within 24 h. No significant cytotoxicity, increase in intracellular or mitochondrial ROS production, or alteration in basal metabolic activity was observed. However, PSNP exposure resulted in intracellular accumulation, an altered mitochondrial ultrastructure characterized by crista loosening and vacuole-like structural changes. These changes were accompanied by reduced mitochondrial membrane potential; the upregulation of mitochondrial dynamics-related genes, including optic atrophy 1 (Opa1) and dynamin-related protein 1 (Drp1); the suppression of PTEN-induced kinase 1 (PINK1)/Parkin RBR E3 ubiquitin protein ligase (Parkin)-mediated mitophagy-related genes; and decreased maximal respiratory capacity. Lactate production and the extracellular acidification rate remained unchanged, suggesting that compensatory glycolysis was not activated. These findings indicate that PSNP exposure induces early mitochondrial structural and functional alterations without substantial cell damage, suggesting a potential reduction in cardiac adaptive capacity under PSNP-induced stress conditions.
    Keywords:  cardiomyoblasts; cellular uptake; environmental toxicology; mitochondrial dysfunction; mitochondrial quality control; nanoplastics; polystyrene nanoplastics
    DOI:  https://doi.org/10.3390/antiox15070801
  43. Pediatr Res. 2026 Jul 25.
    Evolving role of mitochondrial dysfunction and mitophagy in necrotizing enterocolitis.
    Srinivasan Mani, Jeffrey Shenberger, Parvesh Mohan Garg.
      Necrotizing enterocolitis (NEC) is a severe, multifactorial disease of prematurity characterized by a heterogeneous pathophysiology. A dysregulated cytokine-driven inflammatory response is central to its progression, underscoring the need to identify key molecular triggers and pathways. Emerging evidence suggests that mitochondrial dysfunction represents a central nidus linking microbial signals to immune responses, and ultimately to epithelial injury. Future studies defining the timing and mechanisms of mitochondrial dysfunction and the role of mitophagy to better understand the interplay of the microbiome, immune responses, and mitochondria in the pathogenesis of NEC are greatly needed. IMPACT: Mitochondrial dysfunction is central to NEC pathogenesis, linking dysbiosis, immune dysregulation, and epithelial injury, and redefining NEC as an immunometabolic disease. ACSL1 emerges as a promising biomarker and therapeutic target, with potential to guide early diagnosis and modulate inflammation and oxidative stress. Future focus on timing and mitophagy may enable early detection and targeted interventions before irreversible intestinal injury develops, improving outcomes in NEC.
    DOI:  https://doi.org/10.1038/s41390-026-05350-4
  44. Cells. 2026 Jul 21. pii: 1305. [Epub ahead of print]15(14):
    Autism Spectrum Disorder: High-Resolution Elucidation of Mitochondrial Dysregulation in Larval Zebrafish Gut.
    Johanna A Coetzee, Lesha Pretorius, Janica Theron, Angela Latakgomo, Carine Smith.
      Although gastrointestinal distress is both common and debilitating in individuals with autism spectrum disorder (ASD), underpinning mechanisms-and therefore effective management strategies-are not fully elucidated. The current study employed well-established valproic acid ASD model in larval zebrafish to more comprehensively characterize mitochondrial dysregulation. Whole body redox status and mitochondrial respiration, as well as protein expression in the mitophagy-lysosomal axis in the mid-intestine was assessed. In addition, high-resolution microscopy of the gut was used to assess mitochondrial morphometrics and distribution. Redox imbalance was evident from increased oxygen radical levels and decreased endogenous antioxidant capacity, as well as depression of whole body mitochondrial respiration. Upregulation of endo-lysosomal pathway markers (Rab5, LAMP1) together with reduced expression in mitophagy and autophagy markers (PINK1, LC3B) suggests a potential impairment of canonical mitophagy in the ASD-like gut. High-resolution imaging further revealed smaller, more circular mitochondria, indicative of a morphological fission bias. Abnormal mitochondrial distribution patterns were also evident. Together, current data points to primary mitochondrial dysfunction as a potential feature of the ASD-like gut. Furthermore, data suggest potential insufficiencies in mitochondrial recycling as potential role player in ASD-associated (gut) mitochondrial pathology.
    Keywords:  LC3B; PINK1; autophagy; confocal microscopy; fission; mitochondrial respiration; mitophagy-lysosomal axis; redox imbalance; transmission electron microscopy
    DOI:  https://doi.org/10.3390/cells15141305
  45. Front Cell Dev Biol. 2026 ;14 1808059
    The embedding of stress: mitophagy as a mechanism for the central nervous system (CNS) programming and lifelong disease vulnerability.
    Meiling Wang, Ziyan Zhang, Zhou Sha, Fengfeng Zhang, Kaifan Bao.
      Growing epidemiological evidence shows that psychological stress is strongly associated with pathogenesis in modern society a correlational finding). Its effects on CNS are highly age- and cell-type specific. This review outlines how stress regulates mitophagy and dynamically disrupt CNS homeostasis across different life stages, including fetal development, adolescence, and aging, as well as across distinct cell types such as neurons, astrocytes, and microglia. These alterations ultimately increase susceptibility to neurodevelopmental and neurodegenerative disorders.): We propose an integrated "cell-age-stress" framework (Hypothesis 1) that highlights the bidirectional crosstalk between stress-induced mitochondrial damage and nuclear epigenetic reprogramming. We also present a "lifespan intervention hypothesis" (Hypothesis 2) and discuss precision fine-tuning strategies targeted to specific life stages and cell types, offering new directions for neuroprotective therapies.
    Keywords:  CNS; epigenetic reprogramming; lifespan; mitophagy; psychological stress
    DOI:  https://doi.org/10.3389/fcell.2026.1808059
  46. Metabolites. 2026 Jun 25. pii: 442. [Epub ahead of print]16(7):
    Differential Effects of Turmeric Bioactive Compounds on Neuroinflammation and Mitochondrial Homeostasis in Brain Regions in a Rodent Model of Neuropathic Pain.
    Xiaobo Liu, Julianna M Santos, Takaki Kiritoshi, Guangchen Ji, Volker Neugebauer, Chwan-Li Shen.
      Background: Managing neuropathic pain (NP) is particularly challenging in the context of opioid use, and the mechanisms behind chronic pain remain unclear. Objective: This study evaluated the impact of turmeric bioactive compounds on brain regions including frontal cortex (FC), hippocampus (HPC), and hypothalamus (HPT) in the spinal nerve ligation (SNL) in a rat model of NP. Methods: Twenty-four SD rats were assigned to four groups (N = 6 per group), namely sham+vehicle (Sham-V), SNL+vehicle (SNL-V), SNL + 100 mg/kg curcumin (SNL+100CUR), and SNL + 50 mg/kg bisdemethoxycurcumin (SNL+50BDMC), treated daily for four weeks via oral gavage. Gene expression levels related to neuroinflammation, oxidative stress, and mitochondrial homeostasis were measured using qRT-PCR. Protein-level or functional mitochondrial assays were not performed due to limited sample availability. Results: In the FC, SNL decreased the expression level of NRF1 and OPA1, but only OPA1 was increased by BDMC. In the HPC, SNL increased CD11b, NRF2, and MFN1; BDMC decreased CD11b and increased IBA1, NRF1, TFAM, PGC1α and Complex I; and CUR increased NRF1, TFAM, DRP1 and Complex I levels. In the HPT, SNL decreased GFAP and MFN1, with CUR and BDMC further decreasing GFAP but not affecting MFN1. Additionally, CUR and BDMC decreased the expression of several key markers of neuroimmune signaling and mitochondrial homeostasis, including IBA1, CD11b, NFkB, NRF1/2, DRP1, OPA1, PGC1α, TFAM, and PINK1. Conclusions: CUR and BDMC induced region-specific transcriptional remodeling of mitochondrial homeostasis across FC, HPC, and HPT in SNL rats, with somewhat limited effects in the FC, mixed effects in the HPC, and broader downregulation in the HPT.
    Keywords:  animals; brain; mitochondria homeostasis; neuroinflammation; neuropathy; turmeric
    DOI:  https://doi.org/10.3390/metabo16070442
  47. Neurosci Lett. 2026 Jul 29. pii: S0304-3940(26)00193-X. [Epub ahead of print]884 138693
    Sumoylation profiles and mitochondrial dynamics in in vivo and in vitro models of Parkinson's disease.
    Letícia Y Queiroz, Stella C Junqueira, Ericks S Soares, Jaquelini B Canever, Kevin A Wilkinson, Jeremy M Henley, Rui Daniel S Prediger, Helena I Cimarosti.
      Parkinson's disease (PD) is characterized by progressive dopaminergic neuron loss and motor and non-motor impairments. Mitochondrial dysfunction and altered post-translational modifications, including SUMOylation, have emerged as key mechanisms in PD pathogenesis. Here, we investigated global SUMOylation changes in in vivo and in vitro PD models induced by MPTP and MPP+, respectively. Intranasal MPTP administration in rats induced region- and time-dependent changes in Ubc9 and SENP3 across the olfactory bulb, prefrontal cortex, striatum, and hippocampus. In primary cortical neurons, MPP+ reduced SUMO-2/3 conjugation, Ubc9 and SENP3 levels, along with the mitochondrial fission proteins Drp1 and Mff. Notably, SENP3 showed opposite regulation in vivo and in vitro, highlighting model-specific SUMOylation responses to neurotoxic stress. These findings suggest that context-dependent alterations in SUMOylation and mitochondrial dynamics contribute to PD pathogenesis.
    Keywords:  MPP(+); Mitochondria; Parkinson’sdisease; SUMO; intranasal MPTP
    DOI:  https://doi.org/10.1016/j.neulet.2026.138693
  48. Biomedicines. 2026 Jul 02. pii: 1502. [Epub ahead of print]14(7):
    Light Exposure Ameliorates Tau-Induced Deficits via Adenosine Signaling and Mitochondrial Quality Control in Drosophila.
    Su Zhang, Yuanhang Xiang, Xinxin Huang, Chuncao Ao, Linfeng Chen, Xinhui Zhang, Zhong Li.
      Background: Accumulating evidence suggests that environmental light cues influence brain function and neurodegenerative processes; however, the underlying cellular mechanisms remain incompletely understood. Methods: Here, using a Tau-overexpressing Drosophila model, we investigated how light exposure modulates neurodegeneration-associated phenotypes, with a particular focus on adenosine signaling and mitochondrial homeostasis. We performed behavioral assays, biochemical measurements, genetic interference targeting the adenosine receptor, and mito-QC reporter analysis to assess mitochondrial quality control. Results: We show that light exposure ameliorates Tau-induced behavioral impairments and neuropathological features, reducing climbing time by approximately 29% in males and 45% in females, and extending median lifespan by ~29% in males and ~26% in females. Notably, biochemical analyses revealed that light exposure significantly increases brain adenosine levels at ZT12 by approximately 5 to 6 nmol/L in both sexes (p < 0.01), suggesting a light-dependent modulation of adenosine availability. To further examine the role of adenosine signaling, we performed genetic interference experiments targeting the adenosine receptor. These results indicate that adenosine receptor-associated signaling is functionally involved in the beneficial effects of light, as disruption of this pathway attenuates the light-induced improvements in behavioral and mitochondrial phenotypes. Using a mito-QC reporter system, we further show that light exposure enhances mitochondrial quality control, as reflected by a ~2.3-fold increase in mitolysosome density (p < 0.001). Importantly, this effect is modulated by the functional state of adenosine signaling, suggesting a potential interaction between these processes. Conclusions: Together, our findings indicate that light exposure is associated with coordinated changes in adenosine signaling and mitochondrial quality control, which may contribute to the attenuation of Tau-induced deficits in Drosophila. This work provides insight into how environmental light cues may influence neurodegeneration-related cellular processes and highlights the potential relevance of light-based interventions for future mechanistic and translational studies.
    Keywords:  Drosophila melanogaster; adenosine signaling; light exposure; mitochondrial quality control; tau
    DOI:  https://doi.org/10.3390/biomedicines14071502
  49. J Vis Exp. 2026 Jul 07.
    Demonstrating Fluorescent Peptidyl Inhibitor Targeting of Mitochondrial ClpXP by Fluorescence Microscopy in Mammalian Cells.
    Zhou Sha, Stephen Benkovic, Irene Lee.
      Mitochondrial ATP-dependent proteases are essential for maintaining protein homeostasis through degradation of damaged or misfolded proteins. Among these, the ClpXP protease complex locates in mitochondrial matrix and contributes to mitochondrial quality control under physiological and stress conditions. This work demonstrates a quantitative fluorescence microscopy workflow to assess mitochondrial targeting of the fluorescent peptidyl inhibitor FAM-FAPAL-CMK and evaluate mitochondrial morphological changes associated with ClpXP inhibition in mammalian cells. HeLa cells were treated with FAM-FAPAL-CMK and analyzed using confocal microscopy combined with immunofluorescence staining of mitochondrial markers and quantitative image analysis. Colocalization analysis using Costes thresholding and Manders' overlap coefficients demonstrated mitochondrial enrichments of the inhibitor signal. As a consequence, inhibition of ClpP altered mitochondrial morphology. Immunoblot analysis showed no significant change in ClpP protein abundance upon inhibitor treatment. Taken together, this work describes a reproducible imaging-based workflow that will enable interrogation of mitochondrial ClpXP functions in intact cells in response to perturbations of homeostasis, such as oxidative stress.
    DOI:  https://doi.org/10.3791/72089
  50. Cell Signal. 2026 Jul 29. pii: S0898-6568(26)00426-2. [Epub ahead of print] 112769
    Inhibition of ETS1/DRP1 axis attenuates intervertebral disc degeneration by suppressing excessive mitochondrial fission.
    Pengfei Li, Yichen Que, Shuhao Zhang, Ganggang Zhang, Rui Tang, Han Jia, Yasong Zhao, Hongjian Liu, Yuqiang Wang, Yilin Liu.
      Intervertebral disc degeneration (IVDD) is a predominant contributor to low back pain, characterized by nucleus pulposus cell (NPC) senescence, extracellular matrix (ECM) metabolic dysfunction, and chronic inflammation. Excessive mitochondrial fission contributes to IVDD, yet the underlying regulatory mechanisms remain unclear. Herein, we identified ETS proto-oncogene 1 (ETS1) as a critical regulator of mitochondrial fission in human NPCs. ETS1 was upregulated in severe human IVDD and correlated with disc degeneration severity and NPC senescence. Mechanistically, inflammatory cytokines induced ETS1 upregulation, which directly bound to the dynamin 1-like (DNM1L, encoding DRP1) promoter and activated its transcription. Increased DRP1 triggered excessive mitochondrial fission, leading to reactive oxygen species accumulation, NPC senescence, and ECM catabolism. Inhibition of ETS1 via AAV5-mediated RNA interference or targeting DRP1 with CRISPR/dCas9-KRAB system or Mdivi-1 alleviated mitochondrial dysfunction, cellular senescence, ECM degradation, and attenuated IVDD progression. Collectively, our findings revealed the ETS1/DRP1 axis as a novel pathogenic mechanism and a potential therapeutic target in IVDD.
    Keywords:  Cellular senescence; DRP1; ETS1; Intervertebral disc degeneration; Mitochondrial fission
    DOI:  https://doi.org/10.1016/j.cellsig.2026.112769
  51. Redox Biol. 2026 Jul 29. pii: S2213-2317(26)00328-9. [Epub ahead of print]96 104329
    USP8 promotes the progression of sepsis-induced acute lung injury by interacting with the USP24 to suppress PGC-1α deubiquitination and expression.
    Wei Lai, Xin Xing, Songhela Ahan, Yan Liu, Wanli Jiang.
      Sepsis is a life-threatening condition with high morbidity and mortality, in which acute lung injury (ALI) represents one of the earliest and most severe complications, yet effective therapeutic strategies remain limited. The molecular mechanisms underlying ALI pathogenesis are still incompletely understood. In this study, we identify ubiquitin-specific protease 8 (USP8) as a critical regulator of mitochondrial homeostasis and ferroptosis during sepsis-induced ALI. Mechanistically, USP8 modulates mitochondrial biogenesis and promotes ferroptosis by interfering with the interaction between USP24 and PGC-1α in a manner independent of its deubiquitinase activity. Notably, genetic ablation of USP8 markedly attenuates ALI; however, this protective effect is strictly dependent on the presence of USP24. Collectively, our findings uncover a previously unrecognized regulatory mechanism by which USP8 controls ferroptotic signaling and highlight USP8 and USP24 as potential therapeutic targets for sepsis-associated acute lung injury.
    Keywords:  Acute lung injury; Mitochondrial biogenesis; PGC-1α; USP24; Ubiquitination
    DOI:  https://doi.org/10.1016/j.redox.2026.104329
  52. Nat Struct Mol Biol. 2026 Jul 31.
    A coupled TOM-TIM22 supercomplex in human mitochondrial protein import.
    Doron Rapaport, Johannes M Herrmann.
      
    DOI:  https://doi.org/10.1038/s41594-026-01852-1
  53. Stem Cell Res Ther. 2026 Jul 30. pii: 262. [Epub ahead of print]17(1):
    Correction: Mesenchymal stem cells inhibit mitochondrial fission by upregulating armadillo repeat containing 1, ameliorating oxidative stress in renal fibrosis.
    Tao Li, Chuan Guo, Qin Liu, Fengting Jing, Min Zhao, Hemin Xiong, Chang Li, Wei Zhang, Bo Chen.
      
    DOI:  https://doi.org/10.1186/s13287-026-05164-5
  54. Cytotechnology. 2026 Oct;78(5): 166
    Artesunate promotes liver regeneration by modulating mitophagy via the AMPKα1/2/mTOR signaling pathway.
    Xinkai Li, Chuntao Li, Chao Fang, Yong Guo, Changyou Lu.
      Partial hepatectomy (PH) triggers acute liver insufficiency and a tightly-orchestrated regenerative program. Here we show that artesunate (ART) markedly accelerates liver mass restoration in mice subjected to PH. ART elevated the liver index, normalized serum total protein and albumin, and curbed ALT/AST leakage. Histologically, ART attenuated hepatocellular necrosis and reduced lesion scores in a dose-dependent manner. Mechanistically, ART amplified Ki67-positive hepatocytes, suppressed apoptosis, and shifted cell-cycle distribution from G1 arrest toward G2/M progression. These regenerative effects were associated with enhanced mitophagy-related changes, as evidenced by increased TOM20/LC3B co-localization, elevated LC3-II/I ratio, increased PINK1 and Parkin expression, and reduced p62 accumulation. A chloroquine-based lysosomal inhibition assay further supported that ART enhanced mitophagy-associated flux. Docking analysis suggested a potential interaction between ART and AMPKα1/2, with docking energies of - 6.41 and - 6.45 kcal mol- 1 for PRKAA1 and PRKAA2, respectively. ART increased p-AMPKα1/2 and suppressed mTOR signaling, as further supported by reduced p-S6 expression. Pharmacological inhibition of AMPK with Compound C attenuated ART-induced PINK1/Parkin-associated mitophagy-related signaling, suppressed ART-enhanced hepatocyte proliferation, increased apoptosis, and partially reversed the ART-mediated reduction in p-S6 expression. Collectively, these findings suggest that ART promotes post-PH liver regeneration by activating AMPKα1/2-associated signaling and enhancing mitophagy-associated flux, positioning ART as a potential adjunct strategy for liver regeneration after hepatectomy.
    Keywords:  AMPKα1/2/mTOR signaling pathway; artesunate; hepatocyte proliferation; liver regeneration; mitophagy
    DOI:  https://doi.org/10.1007/s10616-026-01039-y
  55. Protein Cell. 2026 Jul 31. pii: pwag054. [Epub ahead of print]
    Super-resolution live imaging reveals spatiotemporal uncoupling of mitochondria-ER contacts and mitochondrial fission in stem cell aging.
    Tianling Cao, Quan Meng, Tiantian Sun, Yaobin Jing, Ping Yang, Zeming Wu, Bin Zhang, Baohu Zhang, Amin Jiang, Shuai Ma, Si Wang, Jing Qu, Dong Li, Guang-Hui Liu.
      
    DOI:  https://doi.org/10.1093/procel/pwag054
  56. J Ethnopharmacol. 2026 Jul 28. pii: S0378-8741(26)01104-9. [Epub ahead of print]372 122249
    Zhenwu Decoction ameliorates experimental benign prostatic hyperplasia: association with mitochondrial quality control, oxidative stress and apoptosis regulation.
    Xianzhao Zhou, Jinben Yu, Huan He, Xingyu Jiang, Mingfeng Xie, Jie Sun, Min Xiao.
       ETHNOPHARMACOLOGICAL RELEVANCE: Zhenwu Decoction (ZWD), first recorded in the Shang Han Lun, is a classical formula used to warm Yang and promote water metabolism. It has traditionally been used for Yang deficiency with water retention, impaired Qi transformation and dysuria. Benign prostatic hyperplasia (BPH) can be classified under the traditional categories of "Longbi" and "dysuria", and its pathogenesis is closely related to kidney Yang deficiency, impaired bladder Qi transformation and water retention in the lower Jiao. Given that BPH is not merely a proliferative lesion but a chronic process involving androgenic stimulation, oxidative stress, insufficient apoptosis and tissue remodelling, investigating the modern pharmacological basis by which ZWD improves BPH through multiple pathological links has clear ethnopharmacological relevance.
    AIM OF THE STUDY: This study aimed to evaluate the therapeutic effect of ZWD on TP-induced experimental BPH and to determine whether this effect is accompanied by changes in oxidative stress, apoptosis and markers of HIF-1α/BNIP3-related mitochondrial quality control.
    MATERIALS AND METHODS: UPLC-MS/MS was used to characterise the chemical constituents of ZWD, and network pharmacology analysis was performed based on the experimentally detected candidate compounds. A testosterone propionate (TP)-induced rat model of BPH was established to evaluate the effects of ZWD on prostatic hyperplasia, tissue remodelling, androgen levels, oxidative stress and apoptosis. Western blotting, qPCR, immunohistochemistry, immunofluorescence co-localisation, mCherry-GFP-LC3 autophagy flux-related assays and medicated serum experiments in BPH-1 cells were further used to assess changes associated with mitochondrial quality control.
    RESULTS: UPLC-MS/MS combined with database cross-matching identified 49 ZWD-related candidate compounds, of which 24 met the criteria of OB ≥ 20% and DL ≥ 0.10. Network pharmacology analysis identified 135 overlapping ZWD-BPH targets. These targets were mainly enriched in processes related to the MAPK cascade, reactive oxygen species response, AGE-RAGE signalling, HIF-1 signalling, EGFR-related signalling and endocrine regulation. In vivo, ZWD reduced prostate volume, prostate weight and prostate index in TP-induced BPH rats. It also improved epithelial thickening, glandular architectural disruption and collagen deposition, decreased serum T, DHT and prostatic MDA levels, and increased SOD activity. ZWD treatment also enhanced TUNEL-positive signals, up-regulated Bax and cleaved caspase-3, down-regulated Bcl-2, and was accompanied by changes in mitochondrial quality control-related markers, including HIF-1α, BNIP3, Beclin-1, LC3B-II/LC3B-I and p62. In vitro, ZWD-medicated serum reduced BPH-1 cell viability and ROS accumulation, improved mitochondrial membrane potential status, promoted apoptosis-related changes, and enhanced the spatial association between mitochondria and the autophagy-lysosome system.
    CONCLUSION: ZWD ameliorated prostatic hyperplasia and tissue remodelling in experimental BPH. These effects were accompanied by reduced androgenic stimulation, decreased oxidative stress, enhanced apoptosis-related changes and restoration of mitochondrial quality control-related markers. HIF-1α/BNIP3-related mitochondrial quality control may represent an important observational node in the action of ZWD, although its causal role requires further clarification through targeted intervention and dynamic flux validation.
    Keywords:  Apoptosis; Benign prostatic hyperplasia; Ethnopharmacology; Mitochondrial quality control; Oxidative stress; Zhenwu decoction
    DOI:  https://doi.org/10.1016/j.jep.2026.122249
  57. Science. 2026 Jul 30. 393(6810): eads5397
    An adaptor for feedback regulation of heme biosynthesis by a mitochondrial protease.
    Thomas Cottle, Lydia Joh, Cori Posner, Adam DeCosta, Dean R Campagna, Mark D Fleming, Sarah Ducamp, Julia R Kardon.
      Heme biosynthesis is tightly coordinated to support essential functions without accumulating toxic porphyrins and depleting cellular iron. Heme induces degradation of the heme biosynthetic enzyme, 5-aminolevulinate synthase (ALAS), by the mitochondrial caseinolytic protease complex CLPX-CLPP (CLPXP), but the mechanism for heme-triggered degradation had not been elucidated. We found that polymerase delta-interacting protein 2 (POLDIP2) is a heme-sensing adaptor protein sufficient to reconstitute negative feedback degradation of ALAS by CLPXP. POLDIP2 was necessary to support ALAS turnover in cells and regulate heme production during erythropoiesis. POLDIP2 directly recognized and recruited heme-bound ALAS to CLPXP. Degradation initiation required a carboxyl-terminal element of ALAS, truncations of which cause an erythropoietic protoporphyria. Our findings establish a mechanism for conditional degradation by CLPXP that underlies erythropoietic protoporphyrias linked to CLPX and ALAS.
    DOI:  https://doi.org/10.1126/science.ads5397
  58. Exp Ther Med. 2026 Sep;32(3): 244
    Mitochondrial autophagy promotion contributes to the protective effects of BYHWD glycoside-enriched fraction against OGD/R-induced injury in H9C2 cells.
    Xujiao Hu, Jingjing Fang, Tong Sun, Jiheng Feng, Fangmei Zhou, Mingyuan Zhou, Zhishan Ding.
      Myocardial ischemia-reperfusion injury is a major cause of mortality among patients with cardiovascular diseases and critically ill individuals. Its pathogenesis is complex and effective preventive or therapeutic strategies remain limited. Buyang Huanwu Decoction (BYHWD) is a classical Traditional Chinese Medicine formula used to tonify deficiency and promote blood circulation and is widely applied in the treatment of cardiovascular and cerebrovascular disorders. The total glycosides extracted from BYHWD, which mainly comprise astragaloside IV, paeoniflorin and amygdalin, represent its key bioactive components. Notably, the extract used is a glycoside-enriched fraction, in which astragaloside IV, paeoniflorin and amygdalin are the three major quantified components, rather than a pure mixture of these three compounds. In the present study, an H9C2 cell model of ischemia-reperfusion injury was established by 21 h of hypoxia followed by 6 h of reoxygenation to evaluate the cardioprotective effects of BYHWD glycosides. Autophagy and reactive oxygen species levels were analyzed by flow cytometry, while malondialdehyde and superoxide dismutase activities were measured using appropriate assay kits. Mitochondrial membrane potential changes were observed by fluorescence microscopy. The expression of PINK1 and Parkin pathway-associated proteins and genes was examined by western blotting and reverse transcription-quantitative PCR. Overall, BYHWD glycosides significantly reduced oxidative damage in H9C2 cells and protected cardiomyocytes from reperfusion injury, potentially by promoting mitochondrial autophagy. These protective effects may therefore be associated with regulation of the PINK1/Parkin-mediated mitochondrial autophagy pathway.
    Keywords:  Buyang Huanwu Decoction; PTEN-induced kinase 1/Parkin; glycosides; mitochondrial autophagy; myocardial ischemia-reperfusion injury
    DOI:  https://doi.org/10.3892/etm.2026.13239
  59. Biology (Basel). 2026 Jul 20. pii: 1197. [Epub ahead of print]15(14):
    The Biological Clock-Mitochondria Axis in the Liver: From Molecular Mechanisms to Metabolic Disease.
    Virginia Manuti, Emanuele Murgo, Anna Alessia Saponaro, Umberto Sfregola, Moris Sangineto, Rosanna Villani, Gaetano Serviddio, Gianluigi Mazzoccoli, Tommaso Colangelo.
      The liver ranks among the peripheral organs exhibiting the most robust circadian rhythmicity, with glucose homeostasis, lipid metabolism, and bile acid turnover governed by tightly phased diurnal oscillations. Mitochondria execute these programs, their output coordinated with the hepatocyte circadian state. The mitochondrial network undergoes dynamic remodeling across the 24 h cycle, encompassing oscillatory changes in bioenergetics, fusion-fission balance, and quality control. This interplay is bidirectional: core clock components drive rhythmic remodeling via cyclin-dependent kinase 1/mitogen-activated protein kinase (CDK1/MAPK)-dependent phosphorylation of dynamin-related protein 1 (DRP1) and the NAD+-SIRT1/SIRT3 axis, while retrograde signals modulate clock amplitude and entrainment. Circadian disruption is associated with mitochondrial dysfunction implicated in MASLD onset and progression to MASH and HCC, though this evidence remains largely correlative and derives predominantly from rodent models. This review integrates clock-mitochondria coupling with metabolic liver disease. Restoring this coupling has been proposed as a candidate chronotherapeutic strategy, supported by preliminary rhythmicity data in primary human hepatocytes and a hepatocellular carcinoma cell line, though causal validation in healthy human liver is lacking. Time-restricted feeding, NAD+ precursors, PPAR agonists, and ACC inhibitors converge on clock-regulated pathways and may benefit from circadian-informed timing, though this remains unverified.
    Keywords:  MASH; MASLD; NAD+–sirtuin axis; chronopharmacology; chronotherapy; circadian clock; hepatic mitochondria; mitochondrial dynamics
    DOI:  https://doi.org/10.3390/biology15141197
  60. Food Sci Nutr. 2026 Jul;14(7): e72167
    Health Benefits and Molecular Mechanisms of Urolithin A: From a Gut Microbiota-Derived Metabolite to Translational Applications.
    Zijiang Yang, Chenggen Guo, Ziao Deng, Xinxuan Xue.
      Urolithin A (UA) is an important bioactive metabolite generated by the gut microbiota from ellagic acid and ellagitannins. In recent years, it has attracted widespread attention because of its potential value in aging intervention and the prevention and treatment of multisystem diseases. This review systematically summarizes the molecular mechanisms of UA, its effects in disease intervention, and progress in human clinical studies. Existing studies have shown that, with mitochondrial quality control as the core, UA exerts multi-target biological effects through the synergistic regulation of pathways related to inflammatory responses, oxidative stress, mitophagy, and programmed cell death. Findings from in vitro mechanistic studies and animal models suggest that UA may influence pathological processes relevant to degenerative musculoskeletal diseases, cardiovascular diseases, neurological disorders, and cancers, whereas current human clinical evidence remains preliminary and is mainly concentrated in muscle function, exercise-related outcomes, selected metabolic biomarkers, and short- to medium-term safety and tolerability. In addition, this review discusses the bioavailability of UA and its relationship with individual gut microbiota metabolic phenotypes. Future research should focus on high-quality, long-term randomized controlled trials with extended follow-up to promote the application of UA in precision nutrition and its clinical translation.
    Keywords:  Urolithin A; aging‐related diseases; clinical translation; gut microbiota; mitophagy
    DOI:  https://doi.org/10.1002/fsn3.72167
  61. Adv Sci (Weinh). 2026 Jul 31. e76903
    Tumor-Derived Exosomal circAP2B1 Induces M2 Macrophage Polarization by Enhancing Mitochondrial Homeostasis to Promote Esophageal Squamous Cell Carcinoma Progression.
    Yiru Wang, Gang Feng, Youyu Wang, Ruihao Liang, Haixia Pan, Kai Lei.
      Esophageal squamous cell carcinoma (ESCC) remodels the immunosuppressive tumor microenvironment via exosome-mediated intercellular communication. In this study, circular RNA circAP2B1 is identified as a critical regulatory molecule that is markedly upregulated in ESCC tissues and patient serum and strongly associated with poor prognosis. Mechanistically, tumor-derived exosomes efficiently deliver circAP2B1 to tumor-associated macrophages (TAMs), where it serves as a distinct molecular scaffold that simultaneously binds the transcription factor ESRRA and the nuclear import receptor KPNA1, facilitating ternary complex formation and ESRRA nuclear translocation. Once in the nucleus, ESRRA directly activates the transcription of Mitofusin 2 (MFN2), a pivotal regulator of mitochondrial fusion, thereby enhancing mitochondrial oxidative phosphorylation, improving ATP production efficiency, and establishing a metabolically optimized intracellular environment that ultimately drives TAMs toward a pro-tumor M2 phenotype. Both in vitro and in vivo experiments demonstrate that targeted intervention of the circAP2B1/ESRRA/KPNA1/MFN2 signaling axis effectively reverses M2 polarization and markedly suppresses tumor progression. This study uncovers a novel exosomal circRNA-mediated metabolic-immune regulatory pathway and offers new avenues for the diagnosis and treatment of ESCC. The findings not only expand the understanding of circRNA functions in tumor immunity but also provide a theoretical basis for the development of therapies targeting the metabolic-immune axis.
    Keywords:  circAP2B1; esophageal squamous cell carcinoma; exosomes, mitochondrial homeostasis; tumor‐associated macrophages
    DOI:  https://doi.org/10.1002/advs.76903
  62. bioRxiv. 2026 Jul 24. pii: 2026.07.23.740218. [Epub ahead of print]
    Spatial control of mitochondrial retrograde signaling by nuclear pore-associated contact sites.
    Sahana Mitra, Giulia Burrone, Surya Rubarajan, Christophe Klein, Tyler Kwok, Suchit Gutta, Keyu Chloe Li, Elizaveta Berson, Joseph Orofino, Maria Dafne Cardamone, Michael Blower, Valentina Perissi.
      Mitochondria relay their functional state to the nucleus via retrograde signaling, yet whether the spatial organization of the mitochondrial network plays a role in this process remains unclear. Here, we show that stress-induced clustering of mitochondria around the nucleus is a crucial part of the retrograde response. Perinuclear clustering facilitates the formation of mitochondria- nucleus contact sites (MNCS) and the nuclear entry of GPS2, a key mediator of mitochondrial retrograde signaling essential for activating nuclear-encoded mitochondrial and stress-response genes in response to various mitochondrial stressors. Unexpectedly, TSPO-driven MNCS are dispensable for GPS2-based retrograde signaling. Instead, we identify the mitochondrial import receptor TOMM70 and the nucleoporin RanBP2/NUP358 as components of a stress-induced nuclear pore-associated tethering complex required for promoting GPS2 nuclear translocation and activation of downstream programs. These findings establish MNCS as a functional gateway for mitochondrial retrograde signaling, highlighting that organelle positioning and tethering at the nuclear pore provide an unexpected layer of stress regulation.
    DOI:  https://doi.org/10.64898/2026.07.23.740218
  63. Front Immunol. 2026 ;17 1875468
    The "Mechano-Metabolic-Immune" crosstalk within the skeletal muscle microenvironment: evolution of homeostatic remodeling and quality control mechanisms.
    Manli Yan, Xin Zhang, Zhixi Zhu, Hao Liu, Jincheng Zeng, Hua Wei, Lei Huang, Xiang Li.
      Skeletal muscle functions not only as a mechanical apparatus for locomotion but also serves as a pivotal metabolic hub and endocrine organ essential for systemic homeostasis. While traditional perspectives focused on macro-volumetric measurements, contemporary biology posits that muscle quality is fundamentally an integration of mechanotransduction, biochemical metabolism, and ultrastructural coupling. Under comorbidity conditions, the progressive decline of skeletal muscle is intricately linked to multi-systemic dysfunction. In chronic inflammatory environments, mechanical imbalance and metabolic derangements are not merely additive; instead, they construct a sophisticated "mechano-metabolic-immune" network by co-regulating immune cell phenotypes and inflammatory thresholds. Pathological remodeling represents the destabilization of this homeostatic axis: lipotoxic metabolic stress induces the phenotypic deviation of fibro-adipogenic progenitors (FAPs) and M1 polarization of macrophages, establishing a pro-inflammatory priming state. Furthermore, the leakage of mitochondrial DNA (mtDNA) resulting from impaired mitochondrial quality control amplifies local metabolic disturbances into cGAS-STING pathway activation that secondary drives macrophage M1 polarization, serving as a critical driver of muscle atrophy. Within this pathological context, mechanical signals act not only as physical stimuli but as active variables that remodel microenvironmental stability. Through molecular transducers such as Piezo1, FAK, and TRPV4, kinetic loading facilitates mechano-chemical transduction and activates the energy sensor AMPK, thereby maintaining mitochondrial dynamic equilibrium and suppressing inflammatory cascades. This metabolic remodeling promotes the transition of macrophages toward a pro-regenerative/anti-inflammatory phenotype, supporting functional maintenance by resolving chronic inflammation and restoring tissue homeostasis. This review proposes the "mechano-metabolic-immune" axis as a pivotal regulatory framework governing skeletal muscle quality. Given that the biological benefits of mechanical intervention are constrained by physiological thresholds, precisely defining exercise load parameters across diverse pathological backgrounds is a rational foundation for transitioning from macro-rehabilitation to mechanism-driven precision interventions targeting FAPs adipogenic differentiation, intramuscular fat accumulation, and AMPK-mediated mitochondrial quality control, providing essential criteria for developing safe and effective clinical exercise prescriptions.
    Keywords:  immunometabolism; lipotoxicity; mechanotransduction; mitochondrial homeostasis; precision exercise intervention; skeletal muscle quality
    DOI:  https://doi.org/10.3389/fimmu.2026.1875468
  64. Pharmaceuticals (Basel). 2026 Jul 08. pii: 1056. [Epub ahead of print]19(7):
    The Central Role of the AMPK/SIRT1/PGC-1α Signaling Axis in Skeletal Muscle Physiology and Pathology and Its Targeted Therapeutic Strategies.
    Jie Wang, Jiayi Gu, Xia Li, Hualin Sun, Xiaoming Yang.
      Considered by some to be the largest metabolic organ of the body, the functional integrity of skeletal muscle is highly dependent on its exceptional plasticity, which is primarily governed by mitochondrial quality control. The signaling axis composed of AMP-activated protein kinase (AMPK), sirtuin 1 (SIRT1), and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) serves as a critical hub that senses cellular energy status, coordinates mitochondrial biogenesis, regulates muscle fiber type switching, and maintains protein homeostasis. This review systematically delineates the structural functions and synergistic regulatory network of the AMPK/SIRT1/PGC-1α signaling axis. It further elucidates the regulatory roles of this pathway under physiological conditions-such as exercise adaptation and muscle fiber-type transformation-and its dysregulated mechanisms in the pathogenesis of various skeletal muscle disorders, including sarcopenia, disuse atrophy, cachexia, neurogenic atrophy, muscular dystrophy, and type 2 diabetes mellitus-related myopathy. Building on this foundation, this review critically analyzes current multifaceted therapeutic strategies targeting this pathway, encompassing exercise and physical therapy, nutritional and natural products, and small molecule drugs, as well as gene and cell-based therapies. Finally, this review delves into the challenges facing clinical translation in this field, such as the complexity of the signaling network, individual variability, and bioavailability issues. It also proposes future research directions focused on developing precision intervention tools, establishing effective biomarker systems, and exploring combination intervention strategies. Collectively, the AMPK/SIRT1/PGC-1α signaling axis is central to maintaining skeletal muscle metabolic homeostasis, and targeting this pathway provides a robust theoretical foundation and broad application prospects for the prevention and treatment of skeletal muscle-related diseases.
    Keywords:  metabolic regulation; mitochondrial biogenesis; muscle atrophy; skeletal muscle; therapeutic strategies
    DOI:  https://doi.org/10.3390/ph19071056
  65. J Ethnopharmacol. 2026 Jul 28. pii: S0378-8741(26)01102-5. [Epub ahead of print] 122247
    Shugan Tongbian Decoction Ameliorates Constipation and Mental Disorder by Inhibiting UPRmt via Wnt/Retromer Axis.
    Jiali Liu, Dehao Wang, Hongxia Mi, Sihang Chen, Yanting Cao, Guanlu Li, Yunzhi Qian, Haihua Qian, Dan Zhang.
       ETHNOPHARMACOLOGICAL RELEVANCE: The Shugan Tongbian Decoction (SGTBD), a Traditional Chinese Medicine (TCM), has demonstrated potential efficacy in alleviating constipation with anxiety and depression; however, its pharmacological action on functional constipation (FC) with anxiety and depression has received little attention.
    AIM OF THE STUDY: FC is increasing, and its course is positively correlated with emotional disorders, which affect the quality of life of patients. We studied brain and intestine protective effects of SGTBD and explored its underlying molecular mechanisms using network pharmacology analyses and experimental validation.
    MATERIALS AND METHODS: Network pharmacology analyses were performed. SGTBD composition was determined using analytical methods, and its main compounds were identified using high-performance liquid chromatography coupled with mass spectrometry (HPLC- MS). A rat model of FC with anxiety and depression was established using compound diphenoxylate combined with chronic unpredictable mild stress (CUMS) to evaluate SGTBD effects on constipation and behavioral indicators and pathological changes [hematoxylin and eosin (HE), alcian blue stain, periodic acid schiff (AB-PAS) and Nissl staining]. Neurotransmitter testing was performed using an enzyme linked immunosorbent assay (ELISA) for 5-HT. Mitochondrial damage was evaluated using western blotting (WB) and transmission electron microscopy. The impact of SGTBD on the Wnt/retromer pathway was evaluated using WB and quantitative real-time polymerase chain reaction (qRT-PCR).
    RESULTS: SGTBD may have pharmacological effects, including the regulation of neurodevelopment and oxidative stress-induced cell apoptosis. SGTBD significantly improved behavioral indicators, reduced constipation, and mitigated pathological damage. It inhibited mitochondrial unfolded protein response (UPRmt) and enhanced neurotransmitter. qRT-PCR, Transmission electron microscopy (TEM), and WB results revealed that SGTBD could inhibit mitochondrial damage by repairing mitochondrial structures, with the Wnt/Retromer signaling pathway playing a key role in this process.
    CONCLUSIONS: SGTBD regulates the balance between brain and gut UPRmt. It reduces mitochondrial damage and is associated with restoring the levels of the Wnt/Retromer pathway. This improved the mitochondrial structures of the brain-gut axis, providing multifaceted protective effects in FC rats with anxiety and depression. This study provides a new perspective on the development of protective measures and the prevention of constipation in patients with emotional disorders and diseases in daily life.
    Keywords:  Brain-gut aixs; FC with anxiety and depression; Shugan Tongbian Decoction; UPR(mt); Wnt/Retromer signaling pathway
    DOI:  https://doi.org/10.1016/j.jep.2026.122247
  66. CNS Neurosci Ther. 2026 Jul;32(7): e71060
    Microglial Mitochondrial Dysfunction: The Storm Center of Post-Stroke Neuroinflammation.
    Ruchong Fan, Chuan Wang, Zi Lin, Shiling Chen, Chao Pan, Hao Nie, Chuan Qin, Xuan Wu, Zhouping Tang.
       BACKGROUND: Stroke remains a major global cause of death and disability, with many patients either missing the therapeutic window or responding poorly to current first-line treatments. Consequently, secondary neurological injury, driven predominantly by neuroinflammation, has emerged as a critical therapeutic target. Microglia rapidly sense post-stroke microenvironmental changes and adopt distinct inflammatory phenotypes that shape pathophysiological outcomes.
    RESULTS: Accumulating evidence, including high-resolution spatial profiling and single-cell omics, positions mitochondrial dysfunction at the core of these responses. This review synthesizes recent findings on microglial mitochondrial dysfunction in stroke, introducing the concept of a microglial mitochondrial "storm center". In this model, reactive oxygen species (ROS) trigger an inflammatory cascade, while impairments in mitochondrial quality control (MQC) exacerbate pathogenic signaling. Metabolic reprogramming further sustains inflammatory polarization, influencing interactions with neurons, astrocytes, and endothelial cells.
    CONCLUSIONS: This "storm center" provides a conceptual framework for developing strategies to mitigate secondary brain injury. Finally, this review highlights key molecular mechanisms, potential therapeutic targets, and translational opportunities, providing a stronger foundation for future stroke research and therapeutic innovation.
    Keywords:  fusion/fission dynamics; metabolic reprogramming; microglia; mitochondrial dysfunction; mitochondrial transplantation; mitophagy; neuroinflammation; stroke
    DOI:  https://doi.org/10.1002/cns.71060
  67. J Adv Res. 2026 Jul 26. pii: S2090-1232(26)00608-9. [Epub ahead of print]
    Complement C3 as a marker for blood-brain barrier leakage after burn injury.
    Hongyu Li, Jie Yang, Yitong Li, Zhiyan Zhang, Jiwei Hao, Xiaobing Fu, Siming Yang.
       BACKGROUND: Burns can lead to blood-brain barrier (BBB) disruption, triggering severe neurological complications. However, not all patients with mild thermal injury develop BBB leakage, and reliable peripheral biomarkers to identify concomitant BBB disruption remain lacking.
    OBJECTIVES: This study aimed to identify a peripheral blood biomarker for detecting post-burn BBB disruption and to elucidate the molecular mechanisms driving this endothelial dysfunction.
    METHODS: Mass spectrometry and Enzyme-Linked Immunosorbent Assay (ELISA) techniques were employed to screen potential circulating biomarkers. Diagnostic value was assessed via receiver operating characteristic (ROC) curve analysis using independent training and validation cohorts. Cellular mechanisms were investigated using in vivo and in vitro models, combined with transcriptomics, transmission electron microscopy, and behavioral assessments.
    RESULTS: Proteomic analysis identified complement C3 as a highly specific rule-in biomarker for detecting post-burn BBB disruption. C3 demonstrated robust diagnostic accuracy, yielding an area under the curve (AUC) of 0.978 in the training cohort and 0.855 in the validation cohort (with 100% specificity), particularly for cortical BBB leakage within the optimal 0-6 h post-injury window. Mechanistically, activation of the C3a/C3aR axis promoted mitochondrial dysfunction and maladaptive mitophagy in endothelial cells, leading to compromised BBB integrity, enhanced neuroinflammation, and cognitive impairment.
    CONCLUSION: Peripheral blood C3 serves as a highly specific biomarker for the early risk stratification of burn-induced cortical BBB disruption. Furthermore, the C3a/C3aR-mediated maladaptive mitophagy pathway drives this endothelial injury, offering novel targets for timely clinical intervention.
    Keywords:  BBB; Burn; Cognitive impairment; Complement C3; Mitophagy; Neuroinflammation
    DOI:  https://doi.org/10.1016/j.jare.2026.07.063
  68. Antioxidants (Basel). 2026 Jun 25. pii: 793. [Epub ahead of print]15(7):
    Reprogramming Mitochondrial Adaptation: LONP1 at the Crossroads of Proteostasis, Metabolism, and Disease.
    Hsu-Hung Chang, Phebe Ting Syuan Chang, Chung-Che Tsai, Chan-Yen Kuo.
      Mitochondrial Lon peptidase 1 (LONP1) is an ATP-dependent AAA+ (ATPases associated with diverse cellular activities) protease that has emerged as a key regulator of mitochondrial proteostasis, with functions extending beyond protein quality control. In addition to degrading misfolded and oxidized proteins, LONP1 coordinates mitochondrial DNA maintenance, metabolic remodeling, and stress-responsive signaling. Recent structural and functional advances have expanded the biological significance of LONP1 beyond protein quality control, highlighting its roles in mitochondrial metabolism, genome maintenance, and stress responses. LONP1 dysregulation is increasingly implicated in cancer, metabolic disorders, neurodegeneration, and aging, where it exerts context-dependent effects on cell survival and disease progression. In cancer, LONP1 supports metabolic plasticity, redox adaptation, and therapeutic resistance, whereas in degenerative conditions, its decline contributes to mitochondrial dysfunction and tissue damage. Here, we synthesize recent insights into the structure, mechanisms, and biological functions of LONP1 and discuss their implications for human disease. We further discuss emerging therapeutic strategies and key challenges for targeting LONP1 in human disease.
    Keywords:  LONP1; cancer metabolism; mitochondrial metabolism; mitochondrial proteostasis; stress response
    DOI:  https://doi.org/10.3390/antiox15070793
  69. J Cardiovasc Dev Dis. 2026 Jul 10. pii: 321. [Epub ahead of print]13(7):
    Endothelial Mitochondrial Dysfunction in INOCA and Coronary Microvascular Dysfunction: Mechanisms, Sex Differences, and Therapeutic Implications.
    Roko Santic, Lovre Martinovic, Marko Kumric, Nikola Pavlovic, Dinko Martinovic, Lovre Jukic, Zenon Pogorelic, Josko Bozic.
      Ischemia with non-obstructive coronary arteries (INOCA) and coronary microvascular dysfunction (CMD) are increasingly recognized causes of angina, reduced quality of life, and elevated cardiovascular risk, yet mechanistic heterogeneity complicates diagnosis and treatment. This narrative review synthesizes evidence from clinical guidelines, consensus documents, landmark trials, cohorts, mechanistic studies, and high-quality reviews identified through structured, non-exhaustive searches of PubMed/MEDLINE, Google Scholar, and major cardiovascular society documents. Current evidence indicates that endothelial mitochondria function primarily as signaling organelles, regulating reactive oxygen species, nitric oxide bioavailability, endothelium-dependent hyperpolarization, calcium signaling, inflammatory activation, mitophagy, and endothelial survival. Cardiometabolic risk factors, aging, chronic kidney disease, and postmenopausal hormonal changes may converge on mitochondrial quality-control and redox pathways, contributing to CMD susceptibility and sex-specific vulnerability. However, direct human evidence linking endothelial mitochondrial dysfunction causally to CMD defined by invasive coronary function testing remains limited. Coronary physiological testing and acetylcholine provocation are validated tools for CMD endotyping, whereas mitochondrial biomarkers remain investigational. Endotype-guided diagnosis and management remain central, while mitochondria-targeted strategies require prospective CMD-specific validation.
    Keywords:  INOCA; coronary function testing; coronary microvascular dysfunction; endothelial dysfunction; endothelial mitochondrial dysfunction; mitochondrial biomarkers; mitochondrial reactive oxygen species; mitophagy; nitric oxide; sex differences
    DOI:  https://doi.org/10.3390/jcdd13070321
  70. EMBO Mol Med. 2026 Jul 30.
    Inhibition of PGC1β-dependent mitochondrial biogenesis enhances EGFR-targeted therapy in lung cancer.
    Zhen Chen, Dongsheng Wang, Songqing Fan, Qiming Wang, Yong Huang, Pan Du, Shidong Jia, Suresh S Ramalingam, Shi-Yong Sun.
      Third-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs), including osimertinib, show robust clinical efficacy in EGFR-mutant (EGFRm) non-small cell lung cancer (NSCLC), yet acquired resistance remains inevitable. Here, we demonstrate that osimertinib and other EGFR-TKIs suppress PPARGC1B expression and its regulated mitochondrial biogenesis in EGFRm NSCLC cells through a previously unrecognized FOSL1/AP-1-mediated transactivation mechanism. Upon acquisition of osimertinib resistance, PPARGC1B expression and its encoded protein PGC1β rebound and become refractory to osimertinib-mediated suppression. Enforced overexpression of PPARGC1B confers resistance to osimertinib in sensitive EGFRm NSCLC cells, whereas PPARGC1B knockdown restores drug sensitivity in resistant cells. Moreover, combining osimertinib with the mitochondria-targeting agent CPI-613 synergistically suppresses mitochondrial biogenesis, induces apoptosis, and inhibits the growth of osimertinib-resistant cells and tumors. Collectively, these findings identify PGC1β-dependent mitochondrial biogenesis as a critical determinant of therapeutic response to osimertinib and suggest co-targeting mitochondrial metabolism as a potential strategy to overcome acquired resistance in EGFRm NSCLC.
    DOI:  https://doi.org/10.1038/s44321-026-00493-7
  71. MedComm (2020). 2026 Aug;7(8): e70878
    The Role of Inflammation and Immunity in Cardiovascular Disease: Molecular Mechanisms and Therapeutic Targets.
    Jiaxiang Rong, Zhen Wang, Xiaoxiao Lin, Ziwen Lei, Qianqian Huang, Hang Liu, Fei Luan, Junbo Zou, Yajun Shi.
      Cardiovascular inflammation is increasingly recognized not merely as a secondary response to hemodynamic or metabolic injury, but as a determinant of disease initiation, progression, and remodeling. In the injured heart and vasculature, danger sensing, inflammatory priming, inflammasome activation, nucleic acid recognition, immunometabolic rewiring, immunothrombosis, adaptive immune remodeling, and defective resolution form interdependent circuits rather than isolated pathways. A key challenge is to understand how these circuits shift from adaptive clearance and repair to persistent immune activation, fibrosis, and functional decline. Here, we synthesize evidence on immune landscapes and core inflammatory networks in cardiovascular diseases, focusing on TLR-NF-κB signaling, NLRP3 inflammasomes, cGAS-STING-dependent cytosolic DNA sensing, alternative mitochondrial nucleic acid-sensing platforms, and redox-immunometabolic gating. We highlight mitochondrial quality control and mitochondria-derived DAMPs, including mtDNA, mtROS, ATP, cardiolipin, and oxidized lipids, as an upstream interface linking metabolic stress to sterile immune activation. We further organize disease-specific inflammatory patterns through a stage-cell-threshold perspective across ischemic injury, vascular and metabolic disease, and cardiomyopathic remodeling. Finally, we discuss network-guided therapeutic strategies, translational limitations, biomarkers, endpoints, and safety considerations. This integrated perspective provides a conceptual basis for moving cardiovascular inflammatory therapy from broad suppression toward more precise network regulation.
    Keywords:  cGAS–STING pathway; cardiovascular diseases; immune network; inflammation; mitochondrial danger signaling; mitophagy
    DOI:  https://doi.org/10.1002/mco2.70878
  72. Free Radic Biol Med. 2026 Jul 28. pii: S0891-5849(26)00969-X. [Epub ahead of print]255 423-443
    Heat stress promotes myocardial injury and ventricular arrhythmia through DRP1-mediated mitochondrial dysfunction.
    Jie Xiang, Jiang Han, Jiaru Cao, Shijie Shao, Na Yang, Hexuan Sun, Jinfeng Zhang, Jie Huang, Yangpeng Li, Huaxing Sun, Mujiao Li, Jiangwei Liu, Chuying Huang, Yuhua Lei, Miaoling Li, Shuijie Li, Ling Zhang, Baopeng Tang.
       BACKGROUND: With global warming, extreme summer heat has led to a higher morbidity and mortality of heat stroke (HS). Although heat stress has been linked to arrhythmias and cardiomyocyte injury, the specific molecular mechanisms and effective intervention strategies remain to be clarified.
    METHOD: We retrospectively collected clinical data from HS patients. A rat HS model was established, and the underlying mechanisms were investigated using biochemical and electrophysiological approaches, combined with proteomics and metabolomics analyses of myocardial tissues and cells. In vivo and in vitro intervention experiments were performed using the mitochondrial reactive oxygen species (ROS) scavenger MitoTEMPO and calcineurin inhibitor (FK506).
    RESULTS: Heat stress caused severe myocardial injury and electrocardiographic abnormalities in HS patients. HS rats exhibited increased susceptibility to ventricular arrhythmias (VAs), manifested by prolonged action potential duration (APD), increased Ca2+ transient duration (CaTD) and Ca2+ alternans ratio, and slowed conduction velocity (CV), which were linked to disrupted Ca2+ handling. Proteomics and metabolomics revealed that mitochondrial dysfunction was closely associated with heat stress-induced myocardial injury. Mechanistically, HS triggers intracellular Ca2+ overload, activating calcineurin. Calcineurin dephosphorylates DRP1 at Ser637 site and promotes its mitochondrial translocation, leading to DRP1-mediated mitochondrial fission and dysfunction, excessive mitochondrial ROS generation, and cardiomyocyte apoptosis. In addition, MitoTEMPO and FK506 treatment partially reversed HS-induced myocardial injury and VAs susceptibility by scavenging mitochondrial ROS and restoring mitochondrial function.
    CONCLUSION: Heat stress triggers mitochondrial dysfunction through a Ca2+/calcineurin/p-DRP1(Ser637) axis, resulting in myocardial injury and VAs. The mitochondria-targeted antioxidant MitoTEMPO and FK506 partially alleviate these adverse effects by scavenging mitochondrial ROS and restoring mitochondrial function.
    Keywords:  Calcium; DRP1; Heat stroke; Mitochondrial dysfunction; Myocardial injury; Ventricular arrhythmia
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.07.042
This page is being maintained by Thomas Krichel. It was last updated on 2026‒08‒27 at 9:53.