bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2026–08–16
sixty-six papers selected by
Gavin McStay, Liverpool John Moores University
  1. Exercise Regulates Mitochondrial Quality Control: Maintenance and Remodeling of Skeletal Muscle Homeostasis.
  2. Oxidative Damage Induced Disruption of Mitochondrial Quality Control Underlying Abnormal Energy Metabolism in Peripheral Leukocytes of Schizophrenia Patients.
  3. Regulation and roles of mammalian mitophagy.
  4. Polystyrene Microplastics Trigger Liver Damage Through Impaired Mitochondrial Biogenesis and Mitochondrial Dynamics.
  5. Corrigendum to: Decreased dynamin-related protein 1-related mitophagy induces myocardial apoptosis in the aging heart.
  6. Mitochondrial dysfunction-driven PANoptosis in doxorubicin-induced cardiotoxicity: mechanistic insights and intervention strategies.
  7. Nrf2 Deficiency Exacerbates Methamphetamine-Induced Neuronal Apoptosis and Cognitive Dysfunction in Male Mice.
  8. TMC6 Protects Against Ischemic Neuronal Injury by Activating Rap1/Rac1 Signaling to Restore Mitochondrial Dynamics and Mitophagy.
  9. Acupuncture regulates mitochondrial homeostasis in traumatic brain injury: current evidence, mechanistic hypotheses, and translational challenges.
  10. Mitochondrial dysfunction as a key mediator of endplate chondrocyte senescence: emerging insights and targeted interventions.
  11. Periodontal ligament stem cells ameliorate experimental colitis by restoring macrophage mitochondrial homeostasis associated with PINK1/Parkin-related mitochondrial quality control.
  12. Plectin-mediated mitochondrial fusion is necessary for hepatocellular carcinoma cell migration promoted by higher matrix stiffness.
  13. Emerging roles of mitophagy in liver fibrosis: Implications for therapy.
  14. Novel mitophagy activator TJ0113 restricts cytosolic mtDNA to suppress ZBP1-driven inflammation in acute lung injury.
  15. Mitochondrial unfolded protein response as a central stress-integration hub: mechanisms and implications in disease contexts.
  16. FOXO1 Promotes Mitophagy in Granulosa Cells by Targeting the METTL3/SMAD4 axis.
  17. PRKCD Orchestrates Sevoflurane-Induced Cognitive Dysfunction in Aged Rats by Regulating PINK1/PRKN Mitophagy Pathway.
  18. Curcumin-preconditioned bone marrow mesenchymal stem cell exosomes ameliorate postmenopausal osteoporosis by activating mitophagy in osteoblast-lineage cells.
  19. PRMT6 drives hearing loss by promoting asymmetric arginine dimethylation-mediated FOXG1 degradation and suppressing mitophagy.
  20. Polydatin in combination with hawthorn flavonoids alleviates atherosclerosis by inhibiting mitochondrial division through the YTHDF2-DRP1 axis.
  21. Rhynchophylline rewires DLAT lipoylation via conformational control to reverse mitochondrial bioenergetic collapse against dopaminergic neuronal injury.
  22. Mechanistic Insights into Aldose Reductase-Dependent Modulation of Hypoxia-Inducible Factor-1α in Promoting Renal Fibrosis.
  23. AMPK as a central regulator of necroptosis: mechanistic insights and therapeutic implications.
  24. ZNF143 suppresses mitophagy to drive MASLD progression by regulating SMURF1/TRPV1 axis.
  25. Mitochondrial dynamics and ion channel regulation of cancer stem cells (CSCs) in metabolic flexibility and therapeutic targeting.
  26. DRP1-mediated mitochondrial fragmentation is a druggable vulnerability in multiple myeloma.
  27. Inhibition of PINK1/Parkin-mediated mitophagy enhances the susceptibility of breast cancer to cuproptosis.
  28. Abnormal glucose metabolism and muscle mass decline by bisphenol A or bisphenol S in skeletal muscle of male mice:inhibition of mitophagy by downregulation of the ERα/AMPK/ULK1 pathway.
  29. A putative rRNA methyltransferase Mrm1 regulates mitochondrial dynamics and pathogenicity in Magnaporthe oryzae.
  30. Mito-TEMPO improves survival rates in npc1-knockout zebrafish by reducing oxidative stress and enhancing mitophagy via Sod2.
  31. The Role of Autophagy in the Pathogenesis of Mitochondrial Diseases.
  32. Silver nanoparticles induce damage in BV2 microglia via the mitochondrial dysfunction-PINK1/Parkin signaling pathway.
  33. The gut-brain-mitophagy axis: Urolithin A as a transcriptional activator of Parkin in Alzheimer's and Parkinson's diseases.
  34. Vitronectin-driven amyloid deposition disrupts mitochondrial homeostasis via integrin-mediated pathway in a humanized mouse model of transthyretin cardiac amyloidosis.
  35. Mitochondrial stress activates ELT-2-dependent lysosomal proteostasis to extend lifespan in C. elegans.
  36. The central role of mitochondrial pathology in sepsis-induced cardiomyopathy: from molecular mechanisms to clinical translation.
  37. Melatonin Suppresses Osteoclastogenesis via Inhibiting Iron/ROS-CREB/PGC-1β-Mediated Mitochondrial Biogenesis.
  38. Loss of Miro1 drives cardiac and mitochondrial dysfunction exacerbated by metabolic stress.
  39. Quercetin Ameliorates Imatinib-Induced Ovarian Damage by Regulating Mitochondrial Dysfunction and PANoptosis via the RAF1-ERK1/2-Drp1 Axis.
  40. Fto-mediated m6A demsupplementethylation of SNHG9 Enhances PINK1-Dependent mitophagy and reverses cisplatin resistance via nuclear EZH2 ubiquitination.
  41. Melatonin attenuates burn-wound progression by inhibiting inflammation via mitophagy-related pathway.
  42. Mitochondrial calcium uniporter as a biomarker in lung adenocarcinoma: regulation of the immune microenvironment, apoptosis, cell cycle and mitophagy.
  43. Dynamic structural profiling of PINK1 mutations (T313M and L347P) reveals a vital molecular perturbation namely phospho-Serine 65 ubiquitin recognition point in mitophagy mediated autosomal recessive Parkinson's disease (ARPD).
  44. Cardiolipin as a Signaling Hub: Evolutionary Conservation and Programmable Platforms Coupling Mitochondrial Stress to Cell Fate.
  45. Senescence-Associated Mitochondrial Dysfunction as a Therapeutic Target in Ovarian Cancer: Challenges and Opportunities.
  46. Host systemic metabolism and cancer metabolic vulnerabilities: mechanisms and therapeutic opportunities.
  47. Hepatocyte hnRNPK preserves mitochondrial integrity to restrain liver injury and fibrosis.
  48. Mitochondrial Morphology Dynamics Remodel Metabolism and Affect TKI Sensitivity in EGFR-Mutated Lung Cancer.
  49. Adenosine Triphosphate Nanoparticles with Blood-Brain Barrier Permeability for Prevention of Cerebral Ischemic Injury via Mitochondrial Homeostasis.
  50. Eucalyptus camaldulensis leaf extract enhances thalidomide efficacy in acute myeloid leukemia cells through modulation of mitochondrial energetics.
  51. Gestational diabetes mellitus amplifies sevoflurane-induced developmental neurotoxicity in offspring mice.
  52. Cardiometabolic stress induces HFpEF with impaired bioenergetics and disrupted proteostasis in aged female mice.
  53. Bioinformatics identification of mitochondrial dynamics-related potential biomarkers in kawasaki disease and prediction of potential regulatory correlations.
  54. Cannabidiol confers neuroprotection against 6-OHDA toxicity by rescuing Nrf2 proteostasis and preserving mitochondrial integrity.
  55. The Tau-mitochondria connection and its impact on cellular energy metabolism in Alzheimer's disease.
  56. Succinate and its carrier Sfc1 mediate metabolic control of mitochondrial protein import by the TIM23 translocase.
  57. Natural Bioactive Compounds Targeting Key Hallmarks of Aging: Functional Food Potential of Spermidine, Fisetin, Berberine, and Urolithin A.
  58. JTE-013 ameliorates allergic asthma by targeting the S1PR2-HDAC3-p53 signaling axis to improve mitochondrial homeostasis.
  59. Glucose/ROS dual-responsive mitochondria-targeting nanozyme microneedles remodel mitochondrial homeostasis to orchestrate immune metabolic reprogramming for diabetic foot ulcer healing.
  60. Ganoderic Acid A Reverses Ultraviolet B Induced Hyperpigmentation via Multi-Targeted Regulation of Mitochondrial Homeostasis and Inflammation.
  61. Breaking Bad and Taking Sides: Chamber-specific mitochondrial remodeling in Dsg2-linked arrhythmogenic cardiomyopathy.
  62. FGF21 attenuates sepsis-induced myocardial injury via AMPK-mediated mitochondrial biogenesis.
  63. Lipidomics Based on HILIC-ESI-HRMS Reveal Subtle Changes in the Mitochondrial Phospholipidome of Mouse Embryonic Fibroblasts Expressing Pathogenic Variants of Human OPA1 Protein.
  64. Nr4a3 Deficiency Disrupts MEK1-ERK1/2-Drp1 Signaling, Driving Adiposity and Glucose Intolerance in Male Mice.
  65. Mitochondrial Dysfunction as a Driver of Meta-Inflammation in Aging: The Emerging Role of PDK4 in Bioenergetic Reprogramming and Inflammatory Amplification.
  66. The role of mitochondrial fusion protein 2 in regulating ER stress in premature placental aging: A case-control study.
  1. Biology (Basel). 2026 Jul 27. pii: 1240. [Epub ahead of print]15(15):
    Exercise Regulates Mitochondrial Quality Control: Maintenance and Remodeling of Skeletal Muscle Homeostasis.
    Huiying Zhao, Min Chen.
      Skeletal muscle, as the largest metabolic organ, maintains its homeostasis highly dependent on the precise regulation of mitochondrial quality control. Mitochondrial quality control (MQC) encompasses three core aspects: mitochondrial biogenesis, dynamic balance, and autophagy. All of these jointly ensure mitochondrial network functional integrity. MQC imbalance is mainly manifested as decreased mitochondrial biosynthesis capacity, disordered fusion and division dynamics, and reduced autophagy clearance efficiency. MQC imbalance can lead to atrophy of skeletal muscles, metabolic dysfunction, and decline in motor function. As a physiological stress stimulus, exercise can precisely regulate MQC through multiple targets and pathways and restore the homeostasis of skeletal muscles. Exercise activates AMPK-PGC-1α to promote mitochondrial biogenesis, regulates MFN1/2, OPA1, and DRP1 to optimize mitochondrial dynamics, and activates the PINK1/Parkin pathway and receptor-mediated autophagy pathway to enhance mitochondrial autophagy. The regulatory effects of different exercise modes on MQC vary significantly. Aerobic exercise focuses on promoting mitochondrial biogenesis and fusion, while high-intensity interval training can more efficiently activate the autophagy pathway. Resistance exercise, on the other hand, requires a longer period to manifest its regulation of dynamic proteins. This article systematically reviews the molecular regulatory mechanism of MQC and its impact on skeletal muscle imbalance and elaborates on the mechanisms by which exercise regulates the remodeling of skeletal muscle through MQC. This article also further compares the differential effects of different exercise modes on the regulation of mitochondrial quality control to maintain skeletal muscle homeostasis. Future research needs to further explore the dose and effect relationship of exercise on regulating MQC and the optimal combination of exercise modes to provide a scientific basis for formulating precise and safe exercise intervention strategies.
    Keywords:  exercise; mitochondria; mitochondrial quality control; skeletal muscle
    DOI:  https://doi.org/10.3390/biology15151240
  2. Schizophr Bull Open. 2026 ;7(1): sgag029
    Oxidative Damage Induced Disruption of Mitochondrial Quality Control Underlying Abnormal Energy Metabolism in Peripheral Leukocytes of Schizophrenia Patients.
    Shuhui Li, Wenli Zhu, Jie Jiang, Yangying Bu, Qian Wang, Minghui Li, Dandan Wang, Yan Gao, Jinfeng Wang, Tianqi Wang, Xiaowen Hu, Chunling Wan.
       Background and Hypothesis: Mitochondrial dysfunction is increasingly implicated in schizophrenia (SZ) pathogenesis. To maintain mitochondrial homeostasis under cellular stress, a sophisticated mitochondrial quality control (MQC) mechanism has developed, encompassing mitochondrial biogenesis, dynamics, and mitophagy.
    Study Design: This study systematically evaluated MQC in peripheral leukocytes of 42 SZ patients and 43 healthy controls through morphological analysis, MQC gene expressions, mitochondrial DNA (mtDNA) maintenance, and oxidative damage. Besides, we validated the regulatory effects of oxidative stress on MQC in vitro using a neuronal model treated with hydrogen peroxide.
    Study Results: We observed mitochondrial fragmentation in SZ, characterized by increased organelle numbers with reduced sizes. This was supported by imbalanced MQC, with expression of biogenesis-related genes SIRT1 and TFAM upregulated (P = .008 and 0.027, respectively), and mitophagy receptor gene PHB2 suppressed (P = .041), indicating enhanced biogenesis but impaired mitophagy. Despite enhanced biogenesis, mtDNA copy number was lower (P < .001) with more oxidative damage (P = .037). Furthermore, we discovered deficits in antioxidant capacity, including reduced coenzyme Q10 levels and superoxide dismutase (SOD) activity, with SOD decline correlating with mtDNA depletion. This suggests redox imbalance contributes to MQC dysregulation, supported by findings from an oxidation-damaged neuronal model. Moreover, disrupted MQC functionally impaired energy metabolism, reflected by downregulated NDUFV1 expression (P = .031) and increased lactate-to-pyruvate ratios (P < .001).
    Conclusions: Our findings demonstrated MQC imbalance in SZ, manifested as mitochondrial fragmentation and mtDNA depletion, probably resulted from oxidative damage. These disruptions may underlie the energy metabolism abnormalities in SZ.
    Keywords:  mitochondrial biogenesis; mitochondrial dynamics; mitophagy; mtDNA copy number; oxidative stress
    DOI:  https://doi.org/10.1093/schizbullopen/sgag029
  3. Nat Rev Mol Cell Biol. 2026 Aug 14.
    Regulation and roles of mammalian mitophagy.
    Sascha Martens, Ian G Ganley.
      Mitochondria are essential metabolic and signalling hubs exposed to stress, and mitochondrial damage is highly detrimental to the cell. Mitophagy - the autophagy of mitochondria - is a key mechanism that maintains both mitochondrial integrity and metabolic flexibility. Mitophagy occurs via multiple pathways that either involve activation of PTEN-induced kinase 1 (PINK1) and the E3 ubiquitin-protein ligase Parkin, or are independent of PINK1 and Parkin. Recessive mutations in PINK1 and PKRN (the gene that encodes Parkin) cause early-onset Parkinson's disease and have provided key mechanistic insights into mitophagy. However, emerging findings indicate that mitophagy is also executed by other molecular routes. Despite these molecular advances in mitophagy characterization, the physiological roles of these pathways in mammals and the specific contexts or conditions in which they operate remain poorly defined. This Review summarizes current understanding of PINK1-Parkin-dependent and independent mitophagy pathways, highlighting mechanistic distinctions and coordinated regulation. We also examine physiological and pathological triggers of mitophagy, as well as the expanding therapeutic potential of targeting mitophagy in disease.
    DOI:  https://doi.org/10.1038/s41580-026-01012-9
  4. J Biomed Mater Res B Appl Biomater. 2026 Aug;114(8): e70143
    Polystyrene Microplastics Trigger Liver Damage Through Impaired Mitochondrial Biogenesis and Mitochondrial Dynamics.
    Fatma Abdel Ghany, Mokhtar I Yousef, Mohamed A M El-Tabakh, Maher A Kamel, Abeer El Wakil.
      Polystyrene microplastics (PS-MPs) are emerging environmental contaminants with increasing evidence of systemic toxicity; however, the mechanisms underlying their hepatic effects remain incompletely understood. The present study investigated the hepatotoxic effects of PS-MPs, focusing on hepatic bioaccumulation, mitochondrial homeostasis, inflammation, apoptosis, and liver functional impairment. Experimental animals were exposed to increasing concentrations of PS-MPs, after which liver tissues were subjected to GC-MS, biochemical, histopathological, and molecular analyses. GC-MS confirmed hepatic accumulation of PS-MPs predominantly in the higher exposure groups (20 and 40 μg), which were subsequently selected for mechanistic investigations. PS-MP exposure induced marked hepatic dysfunction, evidenced by elevated bilirubin, ALT, AST, and GGT levels together with significant reductions in total protein, albumin, and globulin concentrations. Histopathological examination revealed progressive hepatocellular degeneration, inflammatory infiltration, cytoplasmic vacuolation, and necrotic alterations. In parallel, inflammatory and apoptotic signaling were significantly activated, as demonstrated by increased NF-κB and caspase-3 levels. Mechanistically, PS-MPs were associated with transcriptional dysregulation of genes involved in mitochondrial homeostasis, including suppression of mitochondrial biogenesis markers (PGC-1α and TFAM), downregulation of mitochondrial fusion regulators (MFN2 and OPA1), increased DRP1 expression, and reduced PINK1 expression, suggesting altered mitophagy-related signaling. Principal Component Analysis further demonstrated clear separation between control and exposed groups, strongly associating PS-MP exposure with hepatic injury, transcriptional dysregulation of mitochondrial homeostasis-related genes, inflammation, and apoptosis. Collectively, these findings demonstrate that PS-MPs induce significant hepatotoxicity, accompanied by coordinated transcriptional dysregulation of mitochondrial homeostasis-related genes and activation of inflammatory and apoptotic pathways. These findings highlight the liver as a major target of microplastic toxicity and emphasize the need for further studies incorporating protein-level validation, functional mitochondrial assessments, and long-term exposure models to better understand the implications for human health.
    Keywords:  microplastic; mitofusin‐2; mitophagy; nuclear factor kappa B
    DOI:  https://doi.org/10.1002/jbm.b.70143
  5. Acta Biochim Biophys Sin (Shanghai). 2026 Aug 11.
    Corrigendum to: Decreased dynamin-related protein 1-related mitophagy induces myocardial apoptosis in the aging heart.
    Xin Wei, Ye Wu, Wen Wang, Suli Zhang, Dan Liu, Huirong Liu.
      
    DOI:  https://doi.org/10.3724/abbs.2026146
  6. Front Pharmacol. 2026 ;17 1852905
    Mitochondrial dysfunction-driven PANoptosis in doxorubicin-induced cardiotoxicity: mechanistic insights and intervention strategies.
    Xinyu Xue, Xihan Liao, Xing Ji, Kailin Huang, Huanlin Wu, Wei Li.
      Doxorubicin (DOX) is a broad-spectrum anthracycline chemotherapeutic agent, and its clinical application is severely limited by dose-dependent cardiotoxicity (DIC), for which there are currently no effective clinical interventions. Mitochondria are the central organelles regulating myocardial energy metabolism and cell survival, and mitochondrial dysfunction is considered the initiating and core mechanism underlying DIC. DOX disrupts the mitochondrial quality control (MQC) system and induces mitochondrial metabolic reprogramming, thereby leading to mitochondrial dysfunction. This results in excessive production of mitochondrial reactive oxygen species (mROS) and leakage of mitochondrial DNA (mtDNA), ultimately inducing PANoptosis. PANoptosis is a newly defined inflammatory programmed cell death pathway that integrates key features of apoptosis, pyroptosis, and necroptosis. This review delves into the molecular mechanisms by which mitochondrial dysfunction triggers PANoptosis in DIC, focusing on key aspects such as impaired mitochondrial protein homeostasis, mitochondrial dynamics imbalance, suppressed mitochondrial biogenesis, inhibited mitophagy, and mitochondrial metabolic reprogramming. It systematically discusses DIC-targeted intervention strategies against mitochondrial homeostasis and PANoptosis, including mitochondrial-targeted antioxidants, mitochondrial dynamics regulators, mitophagy activators, mitochondrial biogenesis promoters, mitochondrial transplantation, PANoptosis inhibitors, nanomedicine delivery systems, and gene/cell therapy. The aim is to balance the antitumor efficacy of DOX and reduce its cardiac adverse effects, thereby providing a new theoretical basis and potential therapeutic targets for the clinical prevention and treatment of DIC.
    Keywords:  PANoptosis; doxorubicin; doxorubicin-induced cardiotoxicity; mitochondrial dysfunction; mitochondrial quality control
    DOI:  https://doi.org/10.3389/fphar.2026.1852905
  7. Int J Mol Sci. 2026 Jul 23. pii: 6565. [Epub ahead of print]27(15):
    Nrf2 Deficiency Exacerbates Methamphetamine-Induced Neuronal Apoptosis and Cognitive Dysfunction in Male Mice.
    Qianyun Nie, Wenjuan Dong, Peng Zhang, Genmeng Yang, Di Jing, Zhenping Hou, Yanxia Peng, Yang Yu, Lihua Li, Shijun Hong.
      Methamphetamine (MA) abuse, a growing global public health concern, has been linked to the emergence of neuropsychiatric effects, largely attributed to MA-induced neurotoxicity. Despite its significant impact, the precise mechanisms underlying this neurotoxicity remain poorly understood, and current therapeutic options for MA abusing patients are limited. In the present study, primary mouse neurons with 400 μM MA treatment and Nrf2 knockout C57BL/6J mice with 10 mg/kg MA treatment were used to investigate the regulatory mechanisms of Nrf2 in MA-induced cognitive impairment and neuronal apoptosis. Results revealed that Nrf2 activation occurred with in vitro and in vivo exposure to MA, with pronounced cognitive dysfunction in mice. In both primary neurons and prefrontal cortex and hippocampus tissues, MA exposure induced oxidative stress, disrupted mitochondrial dynamics (characterized by elevated Drp1 and p-Drp1 expression and reduced Mfn1 expression), enhanced mitophagy (characterized by high PINK1 and Parkin expression), and increased apoptosis. Notably, silencing or knocking out Nrf2 exacerbated MA-induced cognitive dysfunction, oxidative stress, and disruptions in mitochondrial dynamics, while further impairing mitophagy through reduced PINK1 and Parkin expression, ultimately leading to increased apoptosis. These results suggest that Nrf2 deficiency exacerbates MA-induced neuronal apoptosis and cognitive dysfunction. Consequently, Nrf2 may represent a promising therapeutic target for mitigating neurotoxic effects induced by MA.
    Keywords:  Nrf2; methamphetamine; mitochondrial dynamics; mitophagy; neurotoxic damage
    DOI:  https://doi.org/10.3390/ijms27156565
  8. Mol Neurobiol. 2026 Aug 13. pii: 832. [Epub ahead of print]63(1):
    TMC6 Protects Against Ischemic Neuronal Injury by Activating Rap1/Rac1 Signaling to Restore Mitochondrial Dynamics and Mitophagy.
    Xuemei Quan, Huo Liang, Haiyin Long, Xiawei Wang, Liling Feng, Xia Zhou, Yuan Chen, Yanhua Li, Xiaofeng Li.
      Ischemic stroke (IS) is a leading cause of neurological disability, yet the molecular basis of neuronal injury and repair remains unclear. Three Gene Expression Omnibus datasets (GSE22255, GSE58294, and GSE37587) were integrated for differential expression analysis. Candidate genes were identified by combining protein-protein interaction network analysis with weighted gene co-expression network analysis and validated in GSE16561. The effects of transmembrane channel-like 6 (TMC6) were investigated in oxygen-glucose deprivation/reoxygenation (OGD/R)-treated HT22 cells and a rat middle cerebral artery occlusion (MCAO) model. Rap1/Rac1-related signaling was examined using geranylgeranyltransferase I inhibitor-298 (GGTI-298) and Rac1 knockdown. TMC6 was downregulated in IS. TMC6 overexpression reduced cortical and striatal infarction and mitigated neurological deficits in the MCAO rat. TMC6 overexpression alleviated neuronal apoptosis and improved cell viability in OGD/R-treated HT22 cells. Inflammatory response was suppressed, and mitochondrial membrane potential was preserved after TMC6 overexpression. TMC6 reprogrammed mitochondrial dynamics and quality control by increasing mitofusin 1 (MFN1) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), suppressing dynamin-related protein 1 (DRP1), and restoring the expression of the mitophagy-associated proteins PTEN-induced putative kinase 1 (PINK1) and Parkin RBR E3 ubiquitin-protein ligase (Parkin). TMC6 knockdown exacerbated OGD/R-induced injury.. Pharmacological inhibition of Rap1 using GGTI-298 or genetic silencing of Rac1 markedly abrogated TMC6-mediated neuroprotection. TMC6 alleviates experimental ischemic neuronal injury and preserves mitochondrial homeostasis. Rap1/Rac1-related signaling may be involved in these protective effects. These findings identify TMC6 as a potential therapeutic target for IS.
    Keywords:  Ischemic stroke; Mitochondrial dysfunction; Rap1/Rac1 signaling; Transmembrane channel-like 6
    DOI:  https://doi.org/10.1007/s12035-026-06102-5
  9. Chin Med. 2026 Aug 14. pii: 208. [Epub ahead of print]21(1):
    Acupuncture regulates mitochondrial homeostasis in traumatic brain injury: current evidence, mechanistic hypotheses, and translational challenges.
    Guanglei Li, Luxi Cao, Sisi Zhao, Yingyu Fang, Zhentao Peng, Feidan Deng, Peng Qing, Mingmin Zhu, Yimin Zhang, Shujun Lin.
       BACKGROUND: Traumatic brain injury (TBI) is associated with high morbidity, disability, and long-term neurological sequelae. Mitochondrial dysfunction is a central component of secondary injury after TBI, contributing to impaired energy metabolism, oxidative stress, calcium dysregulation, neuroinflammation, and neuronal apoptosis.
    MAIN BODY: This review summarizes current evidence regarding acupuncture-mediated regulation of mitochondrial homeostasis after TBI, focusing on structural homeostasis, quantitative homeostasis, and functional/metabolic homeostasis. We distinguish direct evidence from TBI models, indirect evidence from related brain injury models, and hypothesis-generating mechanisms. Particular attention is given to mitochondrial dynamics, mitochondrial biogenesis, mitophagy, energy metabolism, oxidative stress, calcium signaling, mitochondrial membrane potential, apoptosis, intercellular mitochondrial transfer, and putative upstream neural and humoral pathways.
    CONCLUSION: Current preclinical evidence suggests that acupuncture, particularly electroacupuncture, may influence mitochondrial homeostasis after TBI through multidimensional and context-dependent mechanisms. However, direct TBI-specific evidence remains limited, and several proposed mechanisms require further validation before acupuncture-mediated mitochondrial regulation can be considered a clinically established therapeutic strategy.
    Keywords:  Acupuncture; Electroacupuncture; Mitochondrial homeostasis; Mitophagy; Neuroprotection; Traumatic brain injury
    DOI:  https://doi.org/10.1186/s13020-026-01481-2
  10. Exp Gerontol. 2026 Aug 13. pii: S0531-5565(26)00255-X. [Epub ahead of print]223 113276
    Mitochondrial dysfunction as a key mediator of endplate chondrocyte senescence: emerging insights and targeted interventions.
    Ruohui Tang, Jin Yin, Shidan Li, Shaochuan Wang, Jun Fei, Zhaowen Zhou.
      Intervertebral disc degeneration (IVDD) is a leading global cause of chronic pain and functional impairment. The senescence of endplate chondrocytes (EPCs) associated with the IVDD cascade, with mitochondrial homeostatic imbalance serving as the central pathological key mediator. EPCs inhabit a physiological niche defined by hypoxia, limited nutrients, and high mechanical loads, requiring precise metabolic regulation and mitochondrial quality control. This review integrates recent advances in mitochondrial biology to clarify how organelle dysfunction promotes EPC senescence. We first analyze the metabolic shift from oxidative phosphorylation to glycolysis and its impact on extracellular matrix stability. We then examine the mechanisms by which mitochondrial reactive oxygen species activate the NLRP3 inflammasome and NF-κB pathways to drive the senescence-associated secretory phenotype. Furthermore, the review discusses how fusion-fission imbalance and mitophagy failure lead to the accumulation of damaged mitochondria, and how mito-nuclear communication facilitates epigenetic remodeling to sustain senescent transcriptional programs. Finally, we evaluate therapeutic interventions targeting mitochondrial homeostasis, including targeted antioxidants, NAD+ precursors, and mitochondrial transplantation. To address the delivery challenges of avascular cartilage, the potential of cartilage-penetrating nanocarriers and gene-editing technologies is also discussed. This review establishes a theoretical framework for developing etiology-based precision therapies for IVDD.
    Keywords:  Endplate cartilage; Mitochondrial dynamics; Mitophagy; Oxidative stress; Senescence
    DOI:  https://doi.org/10.1016/j.exger.2026.113276
  11. Biochim Biophys Acta Mol Basis Dis. 2026 Aug 12. pii: S0925-4439(26)00270-X. [Epub ahead of print] 168407
    Periodontal ligament stem cells ameliorate experimental colitis by restoring macrophage mitochondrial homeostasis associated with PINK1/Parkin-related mitochondrial quality control.
    Zekun Li, Yuhui Sun, Juefei Wu, Jixiao Wang, Jichang Li, Wenting Zhang, Tianyi Li, Shuai Tang, Fulan Wei, Gang Ding.
      Inflammatory bowel disease (IBD) is characterized by persistent mucosal inflammation and dysregulated macrophage responses, in which mitochondrial dysfunction reinforces inflammatory activation. Periodontal ligament stem cells (PDLSCs) possess immunomodulatory potential, but whether they regulate macrophage inflammation by restoring mitochondrial homeostasis in colitis remains unclear. Here, human PDLSCs were indirectly co-cultured with lipopolysaccharide-stimulated THP-1-derived macrophages, and their therapeutic effects were further examined in dextran sulfate sodium (DSS)-induced colitis mice. PDLSCs suppressed macrophage pro-inflammatory activation while enhancing anti-inflammatory mediator expression. RNA sequencing combined with MitoCarta3.0 analysis revealed that PDLSC-regulated genes were enriched in mitochondrial function, mitophagy, oxidative stress, ferroptosis, and metabolic adaptation pathways. Mechanistically, PDLSCs alleviated mitochondrial ultrastructural injury, restored mtTFA expression and mitochondrial membrane potential, enhanced respiratory chain complex I/III activity and ATP production, and attenuated intracellular and mitochondrial oxidant-sensitive signals. PDLSCs also decreased OMA1 and Drp-1, restored OPA1 and Mfn1, and promoted PINK1-Parkin signaling, whereas Mdivi-1 attenuated their anti-inflammatory effects. In vivo imaging revealed PDLSC-associated fluorescence in the inflamed colon, and PDLSC treatment mitigated DSS-induced weight loss, disease activity, colonic shortening, MPO activation, histological injury, mucus barrier disruption, and collagen deposition. PDLSC treatment also suppressed M1-associated macrophage activation while promoting M2-associated macrophage polarization, preserved mitochondrial ultrastructure, improved mitochondrial respiratory function and ATP generation, and restored the expression of PINK1 and Parkin in colonic tissue. In conclusion, PDLSCs ameliorate experimental colitis by reshaping macrophage inflammatory responses and restoring mitochondrial quality control, with potential involvement of PINK1/Parkin-associated mitophagy.
    Keywords:  Inflammatory bowel disease; Macrophages; Mitochondrial function; PINK1-Parkin pathway; Periodontal ligament stem cells
    DOI:  https://doi.org/10.1016/j.bbadis.2026.168407
  12. Histochem Cell Biol. 2026 Aug 08. pii: 73. [Epub ahead of print]164(1):
    Plectin-mediated mitochondrial fusion is necessary for hepatocellular carcinoma cell migration promoted by higher matrix stiffness.
    Zhihui Wang, Wenbin Wang, Xu Zhang, Qing Luo, Guanbin Song.
      Increased matrix stiffness is a key physical signal affecting the migration of hepatocellular carcinoma (HCC) cells, and mitochondrial dynamics and function also play important roles in cell migration. Plectin may influence mitochondrial dynamics and function through its cytoskeletal cross-linking function. However, the relationship between these two factors remains unclear. HCC cells were seeded on hydrogels with stiffness of 7 kPa and 53 kPa, respectively, to investigate the effects of matrix stiffness on plectin expression, mitochondrial dynamics and function, and cell migration. Moreover, plectin was knocked down to further assess its specific impacts on mitochondrial dynamics and function, as well as cell migration under different matrix stiffness. Compared with 7 kPa, high matrix stiffness (53 kPa) promotes HCC cell migration by upregulating plectin expression, promoting mitochondrial fusion, and enhancing mitochondrial function. Under high matrix stiffness, plectin knockdown weakens mitochondrial fusion capacity and function, reducing cell migration. Subsequently, we treated cells with carbonyl cyanide 3-chlorophenylhydrazone (CCCP) to inhibit mitochondrial function. This treatment significantly suppressed cell migration on high- matrix stiffness. Then, when mitochondrial dynamics were disrupted by the mitochondrial fusion inhibitor 8 (MFI8), mitochondrial function was compromised, and cell migration decreased. High matrix stiffness enhances mitochondrial function by driving mitochondrial fusion through increasing plectin expression, thereby promoting the migration of HCC cells. It provides new insights into the mechanobiological mechanisms underlying matrix stiffness affected HCC cell migration.
    Keywords:  Hepatocellular carcinoma; Matrix stiffness; Migration; Mitochondria; Plectin
    DOI:  https://doi.org/10.1007/s00418-026-02527-0
  13. Acta Pharmacol Sin. 2026 Aug 10.
    Emerging roles of mitophagy in liver fibrosis: Implications for therapy.
    Zi-Yang Zhao, Shu-Na Tong, Run-Hao Lin, Shi-Yi Feng, Ying Yang, Xing-Juan Shi.
      Liver fibrosis, a pathological process characterized by excessive production of extracellular matrix (ECM) and sustained activation of hepatic stellate cells (HSCs), can further progress into cirrhosis and hepatocellular carcinoma. The disorder has imposed a heavy burden on global public health, resulting in millions of deaths annually. Mitophagy maintains mitochondrial function by eliminating dysfunctional mitochondria and regulating the biogenesis of new ones. It has been reported that mitophagy participates in the progression of liver diseases. However, the exact function of mitophagy in liver fibrosis remains unclear. In this review, we first outline the current knowledge regarding mitophagy regulatory mechanism. We then focus on the effect of mitophagy in the progression of liver fibrosis by regulating HSCs activation, oxidative stress, inflammatory signaling cascades, lipid metabolism reprogramming, and the modulation of the immune microenvironment. We further highlight that mitophagy mainly plays a protective role against liver fibrosis, whereas excessive mitophagy may exacerbate liver fibrosis by clearing healthy mitochondria aberrantly. Moreover, we summarize clinical data supporting mitophagy-targeted therapeutic strategies for liver fibrosis. Elucidation of these issues will offer new perspectives on the function of mitophagy during liver fibrosis, as well as potential strategies for anti-fibrotic therapy.
    Keywords:  hepatic stellate cells; liver disease; liver fibrosis; mitochondria; mitophagy
    DOI:  https://doi.org/10.1038/s41401-026-01908-4
  14. Redox Biol. 2026 Aug 06. pii: S2213-2317(26)00336-8. [Epub ahead of print]96 104337
    Novel mitophagy activator TJ0113 restricts cytosolic mtDNA to suppress ZBP1-driven inflammation in acute lung injury.
    Xiaohan Chen, Shunpeng Xing, Xufeng Cen, Jikai Shen, Jiwei Zhu, Xu Lin, Le Xu, Fengqi Wang, Yanan Tian, Xuan Lai, Yuejia Luo, Hongguang Xia, Jian Hu, Luming Wang.
      Acute lung injury (ALI) is driven by excessive inflammation and mitochondrial dysfunction, but how mitochondrial DNA (mtDNA) release engages inflammatory signaling remains incompletely understood. Here, we demonstrate that TJ0113, a novel mitophagy activator, confers protection against LPS-induced ALI by promoting mitochondrial quality control and limiting cytosolic mtDNA accumulation. Transcriptomic and ultrastructural analyses showed that TJ0113 restored mitophagy and reduced oxidative stress. Single-cell transcriptomic profiling identified ZBP1 as the most prominently induced cytosolic nucleic acid sensor in injured lungs, revealing inflammatory alveolar macrophages as a major ZBP1-enriched population. Mechanistically, cytosolic mtDNA accumulation triggered ZBP1 activation, leading to necroptotic (MLKL) and pyroptotic (GSDMD) signaling. TJ0113 suppressed ZBP1 activation by enhancing mitophagy and reducing mtDNA release, and inhibition of mitophagy abolished its protective effects. Consistently, ZBP1 knockdown recapitulated the anti-inflammatory effects of TJ0113, as evidenced by reduced downstream inflammatory signaling and decreased cytosolic Z-NA puncta, and pharmacological mitochondrial depletion (EB) similarly attenuated the inflammatory phenotype. Our findings identify the mtDNA-ZBP1 axis as a critical link between mitochondrial dysfunction and inflammation in ALI, and position TJ0113 as a promising therapeutic candidate targeting this axis.
    Keywords:  Acute lung injury; Alveolar macrophages; Mitochondrial DNA; Mitophagy; ZBP1
    DOI:  https://doi.org/10.1016/j.redox.2026.104337
  15. Burns Trauma. 2026 ;14 tkag037
    Mitochondrial unfolded protein response as a central stress-integration hub: mechanisms and implications in disease contexts.
    Yanmin Xin, Yiting He, Xingguo Liu.
      The mitochondrial unfolded protein response (UPRmt) is a conserved mitochondrial stress response that is activated by mitochondrial dysfunction to maintain proteostasis. Although UPRmt has been extensively studied in aging and cancer, its role in trauma and critical illness remains poorly understood. Here, we propose a unifying conceptual framework in which UPRmt functions as a central stress-integration hub that senses and coordinates adaptive responses following acute injury. We systematically review the mechanisms of UPRmt activation triggered by diverse insults and highlight how UPRmt integrates mitochondrial-nuclear communication, and crosstalk with other stress-responses such as the integrated stress response and mitophagy. Beyond cell-autonomous regulation, UPRmt also coordinates systemic adaptation through mitokine-mediated interorgan signaling. Importantly, we emphasize the context-dependent role of UPRmt in trauma and critical illness. Moderate activation promotes mitochondrial recovery, limits reactive oxygen species accumulation, and supports immune cell function, thereby enhancing tissue resilience and repair. In contrast, sustained or dysregulated UPRmt contributes to mitochondrial failure, sterile inflammation, and the progression to systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS). Furthermore, we discuss emerging evidence linking UPRmt to immune regulation and inflammatory responses, and propose that targeting key regulatory nodes within this stress-integration network may offer novel therapeutic strategies for a broad spectrum of human diseases. Crucially, we synthesize how UPRmt mechanisms contribute to post-traumatic mitochondrial damage, sterile inflammation, SIRS, and MODS. We propose that targeting key regulatory nodes within this stress-integration network may offer novel therapeutic strategies for trauma, burns, and critical illness.
    Keywords:  Immunity; MODS; SIRS; Trauma; UPRmtproteostasis
    DOI:  https://doi.org/10.1093/burnst/tkag037
  16. Cell Biochem Biophys. 2026 Aug 14.
    FOXO1 Promotes Mitophagy in Granulosa Cells by Targeting the METTL3/SMAD4 axis.
    Lan Luo, Mi Tang, Yanli Peng, Xi Chen, Yaqi Liu, Jialan Cui.
      Diminished ovarian reserve decreases the chance of fertility, but the mechanisms regulating ovarian function remain unclear. This study aimed to explore the mechanism through which FOXO1 regulates mitochondrial function in ovarian granulosa cells. KGN cells were transfected with FOXO1, METTL3, and/or SMAD4 vectors, and then their proliferation and apoptosis were detected using CCK-8 and EdU assays and flow cytometry, respectively. Molecular binding was detected by immunoprecipitation. The effect of FOXO1 on METTL3 promoter activity was analyzed using luciferase reporters. SMAD4 m6A was quantified using MeRIP-qPCR. ROS and MMP were measured using immunofluorescence, ATP and mtDNA levels were determined using their respective kits, and the expression of mitophagy-related proteins, including DRP1, PINK1, and parkin, was quantified using Western blotting. FOXO1 overexpression or SMAD4 knockdown reduced the proliferation of KGN cells and enhanced their apoptosis. FOXO1 inhibited METTL3 transcription via binding. METTL3 promoted SMAD4 m6A modification. FOXO1 repressed METTL3 and SMAD4 expression, while METTL3 upregulated SMAD4 expression. In FOXO1-overexpressing cells, METTL3 or SMAD4 overexpression enhanced proliferation, suppressed apoptosis, reduced ROS production, elevated ATP, mtDNA, and MMP levels, and downregulated DRP1, PINK1, and parkin expression. In conclusion, FOXO1 targeted METTL3 to downregulate SMAD4 and modulated the expression of mitophagy-related proteins, thereby promoting mitophagy and mitochondrial damage in granulosa KGN cells.
    Keywords:  FOXO1; Mitochondrial autophagy; Ovarian dysfunction; SMAD4; m6A
    DOI:  https://doi.org/10.1007/s12013-026-02143-8
  17. J Cell Mol Med. 2026 Aug;30(15): e71315
    PRKCD Orchestrates Sevoflurane-Induced Cognitive Dysfunction in Aged Rats by Regulating PINK1/PRKN Mitophagy Pathway.
    Yang Yu, Wei Zhang, Yingying Zhao, Yue Zhang, Pingle Li, Zepeng He.
      Post-operative cognitive dysfunction (POCD) is a cognitive disorder characterized by a decline in cognitive function following surgical procedures, with mitophagy identified as a significant underlying mechanism. Protein kinase C delta (PRKCD), localized within the mitochondria, is implicated in the regulation of PINK1/PRKN mitophagy pathway; however, the potential regulatory role of PRKCD in POCD through this pathway remains to be elucidated. Neurons and rats were exposed to sevoflurane (SEV) to illuminate the function and mechanism of PRKCD in POCD. Various methodologies were employed, including immunofluorescence, quantitative real-time PCR, CCK-8 assays, mitochondrial membrane potential (MMP) assessments, MitoSOX generation detection, Seahorse metabolic flux analysis, co-immunoprecipitation, western blotting and behavioural experiments like Morris water maze, novel object recognition and fear conditioning, along with haematoxylin and eosin and immunohistochemical staining. PRKCD was expressed in neurons and that SEV administration led to an upregulation of PRKCD expression. Furthermore, interference with PRKCD was found to restore cell viability in SEV-treated neurons. Additionally, inhibition of PRKCD resulted in the recovery of LC3 expression and the normalization of p62 levels in neurons subjected to SEV treatment. Suppressing PRKCD restored MMP and OCR, reduced MitoSOX in SEV-affected neurons and interacted with PRKN and PINK1, decreasing their expression. Overexpressing PRKN mitigated PRKCD inhibition's impact on mitochondrial damage. In vivo, SEV increased PRKCD, PINK1 and PRKN levels, but PRKCD knockdown improved behavioural and pathological outcomes, reversing changes in LC3-II, PINK1, PRKN and p62 expression. PRKCD enhanced SEV-induced POCD in aged rats via the regulation of PINK1/PRKN mitophagy pathway.
    Keywords:  PRKCD; PRKN; mitophagy; post‐operative cognitive dysfunction; sevoflurane
    DOI:  https://doi.org/10.1111/jcmm.71315
  18. Front Cell Dev Biol. 2026 ;14 1891247
    Curcumin-preconditioned bone marrow mesenchymal stem cell exosomes ameliorate postmenopausal osteoporosis by activating mitophagy in osteoblast-lineage cells.
    Chao Li, Xufeng Jiang, Kechong Zhou, Quan Sun, Huaqing Shen.
       Background: Postmenopausal osteoporosis, driven by oxidative stress and impaired osteoblast function, remains a major health crisis with limited anabolic therapies. Exosomes from curcumin-preconditioned mesenchymal stem cells (MSCs) are promising cell-free therapeutics, yet their cellular targets and molecular mechanisms remain elusive.
    Methods: BMSCs were isolated, pretreated with curcumin, and exosomes were purified by ultracentrifugation. Exploratory scRNA-seq, in vitro H2O2 stress assays, and ovariectomized (OVX) mouse models were employed.
    Results: Curcumin pretreatment enhanced exosomal osteogenic potential without altering physicochemical properties. scRNA-seq identified osteoblast-lineage cells as major transcriptional responders. Cur-BMSC-Exo activated PINK1/Parkin-mediated mitophagy, eliminated damaged mitochondria, and restored mitochondrial function. This effect was abrogated by Mdivi1. Systemic Cur-BMSC-Exo administration significantly increased bone volume and trabecular thickness in OVX mice, whereas Mdivi1 abolished these benefits.
    Conclusion: Cur-BMSC-Exo ameliorates osteoporosis by activating mitophagy in osteoblast-lineage cells, offering a novel cell-free therapeutic strategy.
    Keywords:  PINK1/parkin pathway; curcumin; mesenchymal stem cell exosomes; mitophagy; postmenopausal osteoporosis; single-cell RNA sequencing
    DOI:  https://doi.org/10.3389/fcell.2026.1891247
  19. Exp Gerontol. 2026 Aug 12. pii: S0531-5565(26)00257-3. [Epub ahead of print]223 113278
    PRMT6 drives hearing loss by promoting asymmetric arginine dimethylation-mediated FOXG1 degradation and suppressing mitophagy.
    Jin Wu, Zhi Liu.
       OBJECTIVE: Age-related hearing loss (ARHL) is a progressive and irreversible sensorineural impairment with incompletely understood mechanisms. This study investigates the role of protein arginine methyltransferase 6 (PRMT6) and its regulatory mechanisms in ARHL.
    METHODS: In vivo, D-galactose (D-gal)-induced aging mouse models were established. Auditory brainstem response (ABR), cochlear β-galactosidase activity, and PRMT6 expression were measured, and the therapeutic effects of the PRMT6 inhibitor EPZ020411 were evaluated. In vitro, D-gal-treated HEI-OC1 cells were employed. PRMT6 was silenced using siRNA. Cellular senescence and apoptosis were assessed by SA-β-gal staining and TUNEL assay. Mitochondrial function was evaluated by JC-1 staining, ROS levels, ATP content, and transmission electron microscopy. Mitophagy was determined by LC3-TOM20 co-localization and the GFP-LC3-RFP-LC3ΔG reporter system. Asymmetric arginine dimethylation of FOXG1 was measured by immunoprecipitation with the D6A8 antibody, and FOXG1 protein stability was assessed by a cycloheximide chase assay.
    RESULTS: Aging mice exhibited elevated ABR thresholds, increased β-gal activity, and upregulated PRMT6, all reversed by EPZ020411. PRMT6 silencing attenuated cellular senescence and apoptosis, improved mitochondrial membrane potential, elevated ATP content, reduced ROS accumulation, and ameliorated mitochondrial damage. PRMT6 silencing also enhanced autophagic flux. Notably, PRMT6 silencing did not alter FOXG1 mRNA but upregulated FOXG1 protein and decreased its asymmetric arginine dimethylation, prolonging FOXG1 half-life. FOXG1 knockdown partially reversed the enhanced mitophagy, impaired mitochondrial function, and abrogated the anti-apoptotic protection conferred by PRMT6 silencing.
    CONCLUSION: PRMT6 exacerbates D-gal-induced cochlear aging by promoting asymmetric arginine dimethylation of FOXG1, accelerating FOXG1 degradation, and inhibiting mitophagy. The PRMT6-FOXG1-mitophagy axis represents a potential therapeutic target for D-gal-induced cochlear aging.
    Keywords:  Age-related hearing loss; FOXG1; Mitophagy; PRMT6
    DOI:  https://doi.org/10.1016/j.exger.2026.113278
  20. J Adv Res. 2026 Aug 13. pii: S2090-1232(26)00669-7. [Epub ahead of print]
    Polydatin in combination with hawthorn flavonoids alleviates atherosclerosis by inhibiting mitochondrial division through the YTHDF2-DRP1 axis.
    Yujuan Li, Xiaonan Zhang, Shengjie Yang, Xin Bai, Xiaoya Li, Lanqing Hu, Changxin Sun, Yu Cao, Tong Li, Yongfang Yuan, Lingling Li, Longtao Liu, Min Wu.
       INTRODUCTION: The combination of polydatin and hawthorn flavonoids (PH), a traditional Chinese medicine formulation for activating blood circulation and detoxification, has shown the potential to counteract atherosclerosis, but the mechanisms underlying its effects remain unclear.
    PURPOSE: To investigate the protective effects of pH on atherosclerosis and identify the key targets underlying mitochondrial homeostasis.
    METHODS: An ApoE-/- mouse model fed a high-fat diet (HFD) was established to evaluate the effect of pH on aortic plaques, and an oxidized low-density lipoprotein (ox-LDL)-induced human umbilical vein endothelial cell (HUVEC) injury model was established. Dynamin-related protein 1 (DRP1) knockdown, YTHDF2 knockdown, and overexpression models were used to identify the key targets.
    RESULTS: PH exerted potent dose-dependent anti-atherosclerotic effects in high-fat diet-challenged ApoE-/-mice, reducing atherosclerotic lesion burden by 44.8%, 49.29%, and 72.99% at low, medium, and high doses, respectively. In vivo, PH ameliorated systemic dyslipidemia by lowering circulating total cholesterol, triglycerides, low-density lipoprotein cholesterol, and very-low-density lipoprotein levels, while robustly suppressing proinflammatory cytokine expression. PH also rescued aortic mitochondrial damage, mitigated mitochondrial fragmentation, and restored mitochondrial structural integrity, as evidenced by increased mitochondrial length, improved aspect ratio, and elevated mtDNA abundance. In ox-LDL-injured human umbilical vein endothelial cells (HUVECs), PH rescued endothelial mitochondrial dysfunction and restored normal mitochondrial architecture by reversing the ox-LDL-induced declines in mitochondrial matrix diameter and aspect ratio. Mechanistically, PH inhibited DRP1 expression and Ser616 phosphorylation, blocked mitochondrial translocation of phosphorylated DRP1, and thereby preserved mitochondrial membrane potential and mtDNA content. DRP1 knockdown abrogated PH's endothelial protective functions, verifying DRP1 as a core downstream effector. PH significantly upregulated YTHDF2 expression in ox-LDL-stimulated HUVECs. Functional assays confirmed a negative YTHDF2-DRP1 regulatory axis: YTHDF2 depletion increased DRP1 and phosphorylated DRP1 levels by 31.92% and 30.79%, whereas YTHDF2 overexpression reduced their levels by 43.88% and 38.31%. Notably, YTHDF2 loss abolished PH-mediated DRP1 suppression, indicating PH alleviates DRP1-dependent mitochondrial dysfunction via a YTHDF2-dependent mechanism.
    CONCLUSION: PH exerts a protective effect on HUVECs and prevents AS by regulating the YTHDF2/DRP1 axis to restore mitochondrial homeostasis, thereby providing a novel therapeutic approach for AS.
    Keywords:  Atherosclerosis; DRP1; Mitochondrial dynamics; Polydatin combined with hawthorn flavonoids; YTHDF2
    DOI:  https://doi.org/10.1016/j.jare.2026.08.037
  21. Acta Pharm Sin B. 2026 Aug;16(8): 5276-5296
    Rhynchophylline rewires DLAT lipoylation via conformational control to reverse mitochondrial bioenergetic collapse against dopaminergic neuronal injury.
    Xiaomin Liang, Xunfang Yang, Shuhui Wang, Fangfang Zhuo, Xingzi Hou, Pengfei Tu, Yang Liu, Kewu Zeng, Qingying Zhang.
      Parkinson's disease (PD), the second most prevalent neurodegenerative disorder, is characterized by progressive loss of dopaminergic neurons in the substantia nigra. Although the molecular mechanisms of PD remain incompletely understood, mitochondrial dysfunction has emerged as a central pathological driver, highlighting the urgent need for therapies targeting mitochondrial homeostasis. In this study, we demonstrate that rhynchophylline (Rhy), a bioactive alkaloid from Uncaria species, exerts neuroprotective effects by restoring mitochondrial dynamics. Thermal proteome profiling identified dihydrolipoamide acetyltransferase (DLAT) as a direct target of Rhy. Genetic ablation of DLAT induced mitochondrial fragmentation and abolished Rhy-mediated beneficial effects on mitochondrial structure and function. Mechanically, Rhy binds to the N-terminal lipoyl domain of DLAT, allosterically disrupting its interaction with sirtuin 4 (SIRT4) and subsequently enhancing DLAT lipoylation, a critical post-translational modification for mitochondrial energy metabolism. In vivo, Rhy administration ameliorated motor deficits and dopaminergic neurodegeneration in both the 6-OHDA-induced and A53T α-synuclein transgenic PD mouse models. Single-nucleus RNA sequencing further highlighted the clinical relevance of DLAT dysregulation in PD. Collectively, our findings establish Rhy as a promising PD therapeutic candidate and delineate DLAT as a pivotal node in therapeutic targets by promoting mitochondrial fusion and bioenergetics, offering a novel mechanistic avenue for neuroprotection.
    Keywords:  DLAT; Lipoylation; Mitochondrial dynamics; Neuroprotection; Parkinson's disease; Rhynchophylline; Target identification; Thermal proteome profiling
    DOI:  https://doi.org/10.1016/j.apsb.2026.06.016
  22. Cell Biochem Biophys. 2026 Aug 14.
    Mechanistic Insights into Aldose Reductase-Dependent Modulation of Hypoxia-Inducible Factor-1α in Promoting Renal Fibrosis.
    Wenke Zhao, Haoyu Wang, Jingjing Yan, Lutan Zhou, Wei Xu, Xianwei Li.
      Renal fibrosis (RF) represents the common pathological endpoint of all chronic kidney diseases. According to recent evidence, impaired mitophagy, which facilitates epithelial-mesenchymal transition (EMT) in renal tubular epithelial cells (RTECs), substantially contributes to RF progression, although the underlying mechanisms remain unclear. We previously demonstrated that mitophagy mediated by aldose reductase (AR) promotes EMT of hepatocytes. Further investigations are warranted to elucidate whether AR affects RF and EMT in RTECs through the regulation of impaired mitophagy. In the in vivo study, AR knockout remarkably reduced Phosphoinositide 3-kinase (PI3K) and serine/threonine kinase (AKT) phosphorylation and attenuated hypoxia-inducible factor-1α (HIF-1α) expression, while increasing Pink1 and Parkin expression in unilateral ureteral obstruction (UUO)-exposed renal tissues. These changes were linked with a higher expression ratio of microtubule-associated protein 1 light chain 3 (LC3) II/I; low p62 expression; decreased Snail, α-smooth muscle actin‌ (α-SMA), and vimentin expression; enhanced E-cadherin expression; and a reduction in mitochondrial damage, which collectively contributed to mitigate RF. In the in vitro study, knockdown of AR through siRNA or pharmacological inhibition markedly reduced transforming growth factor-beta 1 (TGF-β1)-induced HIF-1α expression, inhibited PI3K/AKT pathway activation, restored mitochondrial autophagy function, decreased levels of reactive oxygen species (ROS) and mitochondrial permeability transition pore (MPTP) opening, and increased mitochondrial membrane potential (ΔΨm) and adenosine triphosphate (ATP) production, thereby reversing EMT in RTECs. Conversely, AR overexpression exacerbated TGF-β1-induced HIF-1α expression, enhanced PI3K/AKT pathway activation, lowered efficiency of mitophagy, increased MPTP opening and ROS levels, reduced ΔΨm and ATP production, and promoted EMT. These findings highlight AR's role as a facilitator of EMT in RTECs and emphasize its critical contribution to RF progression. This process may be mediated by AR-induced expression of HIF-1α, which stimulates the PI3K/AKT signaling pathway, leading to inhibition of Pink1 and Parkin expression, ultimately decreasing mitophagy occurrence in RTECs.
    Keywords:  Aldose reductase; Epithelial-mesenchymal transition; Hypoxia-inducible factor-1α; Mitophagy; Renal fibrosis
    DOI:  https://doi.org/10.1007/s12013-026-02149-2
  23. J Physiol Biochem. 2026 Aug 12. pii: 78. [Epub ahead of print]82(1):
    AMPK as a central regulator of necroptosis: mechanistic insights and therapeutic implications.
    Wenjing Song, Zhifei Ke.
      Adenosine monophosphate-activated protein kinase (AMPK) is an evolutionarily conserved serine/threonine kinase that links cellular energy stress with metabolic adaptation, autophagy, redox homeostasis, and cell fate decisions. Necroptosis is a regulated lytic form of cell death driven by receptor-interacting serine/threonine kinases 1 and 3 (RIPK1 and RIPK3), with mixed lineage kinase domain-like protein (MLKL) serving as the terminal executor. Increasing evidence suggests that AMPK modulates necroptosis through multiple interconnected mechanisms. AMPK directly phosphorylates RIPK1, thereby influencing necroptotic signaling in a context- and time-dependent manner. Through the AMPK-mTOR axis, AMPK also regulates autophagy and mitophagy, affecting inhibitory control of RIPK1 and autophagic turnover of RIPK3. In parallel, AMPK suppresses necroptosis through SIRT1- and PGAM5-related pathways, limiting necrosome assembly, mitochondrial dysfunction, and Drp1-dependent mitochondrial fission. AMPK further shapes reactive oxygen species (ROS)-associated necroptotic responses through downstream effectors, including mTOR and Nrf2. In this review, we summarize recent advances in the mechanisms by which AMPK regulates necroptosis and highlight unresolved questions, including the cell-type-specific roles of AMPK subunits, the contribution of additional autophagy regulators, the balance between mTORC1-dependent protective signaling and RIPK3 stability, and the in vivo relevance of the AMPK-SIRT1-PGAM5 axis. Clarifying this regulatory network may facilitate the development of therapeutic strategies for necroptosis-related diseases, including metabolic disorders, ischemia-reperfusion injury, and neurodegeneration. Collectively, the available evidence indicates that AMPK acts as a context-dependent regulator of necroptosis rather than a universally protective kinase.
    Keywords:  AMPK; Autophagy; Mitochondrial fission; Mitophagy; Necroptosis; Oxidative stress
    DOI:  https://doi.org/10.1007/s13105-026-01221-y
  24. Mol Genet Genomics. 2026 Aug 11. pii: 169. [Epub ahead of print]301(1):
    ZNF143 suppresses mitophagy to drive MASLD progression by regulating SMURF1/TRPV1 axis.
    Mei Long, Kewei Tan, Yujie Dong.
      Metabolically dysfunction-associated steatotic liver disease (MASLD), a globally prevalent metabolic condition, is increasingly linked to impaired mitophagy. However, its regulatory mechanisms in MASLD are not fully elucidated. This study investigated the role of Zinc finger protein 143 (ZNF143) in regulating hepatocyte mitophagy during MASLD development and the mechanisms involved. We employed two complementary MASLD models: (1) C57BL/6J mice fed a high-fat diet (HFD) for 16 weeks and (2) Huh-7 cells exposed to free fatty acid (FFA). Pathological changes were detected by H&E Staining. Cellular lipid deposition and mitochondrial damage were assessed using Oil Red O, JC-1 staining and transmission electron microscope (TEM), respectively. The intermolecular interaction was identified by dual-luciferase reporter assay, ChIP, and Co-IP. ZNF143 was upregulated in MASLD models, and its knockdown mitigated lipid accumulation and liver injury by activating hepatocyte mitophagy. ZNF143 promoted SMAD-specific E3 ubiquitin-protein ligase 1 (SMURF1) transcription by binding to its promoter region. Moreover, SMURF1 mediated transient receptor potential vanilloid type 1 (TRPV1) ubiquitination and degradation. Finally, knockdown of TRPV1 or overexpression of SMURF1 reversed the promoting effect of ZNF143 knockdown on mitophagy in FFA-treated Huh-7 cells. In short, ZNF143 upregulation exacerbated MASLD progression by mediating TRPV1 ubiquitination and degradation through transcriptionally activating SMURF1.
    Keywords:  Metabolically dysfunction-associated steatotic liver disease; Mitophagy; SMURF1; TRPV1; ZNF143
    DOI:  https://doi.org/10.1007/s00438-026-02501-4
  25. Stem Cells. 2026 Aug 13. pii: sxag046. [Epub ahead of print]
    Mitochondrial dynamics and ion channel regulation of cancer stem cells (CSCs) in metabolic flexibility and therapeutic targeting.
    Krishna Samanta, Pulak Kar.
      Cancer stem cells (CSCs) constitute a rare yet highly adaptable tumour subpopulation that drives tumour initiation, intratumorally heterogeneity, metastasis, recurrence, and therapy resistance. Emerging evidence indicates that mitochondrial dynamics and mitochondrial ion signalling form an interconnected regulatory network that enables CSCs to remodel their metabolic and signalling states in response to environmental and therapeutic stress. Mitochondrial architectural remodelling through fission, fusion, biogenesis, and mitophagy cooperates closely with mitochondrial Ca2+ signalling and ion transport systems, including the mitochondrial calcium uniporter (MCU), voltage-dependent anion channels (VDACs), and mitochondrial K+ channels, to regulate mitochondrial membrane potential, oxidative phosphorylation (OXPHOS), reactive oxygen species (ROS) signalling, and bioenergetic adaptation. Selected plasma membrane and ER-associated ion channels further contribute by modulating mitochondrial signalling pathways. Together, these processes govern CSC plasticity, adaptive stress tolerance, and stemness-associated programs, facilitating survival under hypoxia, nutrient deprivation, and anticancer therapy. In this review, we explore how mitochondrial dynamics and ion signalling converge to shape CSC metabolic flexibility and therapeutic resistance. We further discuss emerging diagnostic and therapeutic opportunities targeting mitochondrial dynamics-ion signalling crosstalk, while highlighting key challenges, including CSC heterogeneity, metabolic adaptability, and the need for selective strategies capable of eliminating CSCs while sparing normal stem-cell populations.
    Keywords:  Cancer stem cells; Ion channels; Metabolic plasticity; Mitochondrial dynamics; Therapy resistance
    DOI:  https://doi.org/10.1093/stmcls/sxag046
  26. Blood. 2026 Aug 03. pii: blood.2025030349. [Epub ahead of print]
    DRP1-mediated mitochondrial fragmentation is a druggable vulnerability in multiple myeloma.
    Maria Eugenia Gallo Cantafio, Noemi Puccio, Roberta Torcasio, Ilenia Valentino, Ludovica Ganino, Yuanyuan Jin, Anil Aktas Samur, Pierpaolo Murfone, Alessia Gallo, Mehmet K Samur, Nicola Cuscino, Cesarina Giallongo, Ida Daniela Perrotta, Alessia Ciarrocchi, Federico Tallarigo, Ernestina Marianna De Francesco, Davide Barbuto, Ross David Jansen-van Vuuren, Luka Jedlovčnik, Danchen Wu, Enrica Antonia Martino, Daniele Tibullo, Francesco Di Raimondo, Massimo Gentile, Antonino Neri, Stephen L Archer, Eugenio Morelli, Nikhil C Munshi, Giuseppe Viglietto, Mariateresa Fulciniti, Nicola Amodio.
      Mitochondrial dynamics is a key regulator of cellular homeostasis, orchestrating metabolic reprogramming that fuels tumor progression and treatment resistance. In multiple myeloma (MM), however, the functional relevance of mitochondrial remodeling has not been fully defined. Using ultrastructural analyses, we reveal that MM cells display a highly fragmented mitochondrial network, a phenotype further exacerbated in both cell lines and primary MM cells resistant to proteasome inhibitors. Transcriptomic profiling across multiple patient-derived datasets consistently demonstrated upregulation of DNM1L gene, which encodes the mitochondrial fission GTPase DRP1, particularly in relapsed and refractory MM, and revealed a significant association with inferior overall survival. Disrupting mitochondrial fission, either through genetic targeting of DNM1L or pharmacologic inhibition of DRP1 with the selective small molecule inhibitor Drpitor1a, resulted in pronounced mitochondrial dysfunction, impaired oxidative phosphorylation, and potent anti-myeloma activity in vitro, culminating in a hybrid cell death program with a predominant apoptotic component accompanied by ferroptotic features. These effects were recapitulated in vivo in a bortezomib-resistant xenograft model, where either DNM1L depletion or DRP1 inhibition produced similar outcomes. Mechanistically, the transcription factor c-MYC upregulated DNM1L expression, and DRP1-dependent mitochondrial fragmentation sustained MYC-driven oxidative metabolism and lipid synthesis. Altogether, these findings establish aberrant mitochondrial fission as a pathogenic hallmark of MM and highlight DRP1 inhibition as a promising therapeutic approach, especially for relapsed or refractory disease.
    DOI:  https://doi.org/10.1182/blood.2025030349
  27. Oncogene. 2026 Aug 13.
    Inhibition of PINK1/Parkin-mediated mitophagy enhances the susceptibility of breast cancer to cuproptosis.
    Chaoyi Tang, Ka Su, Zexu Zhan, Rongzhi Huang, Ming Luo, Jiehua Li.
      Cuproptosis is a novel form of programmed cell death characterized by the accumulation of copper ions in the mitochondria, the formation of DLAT oligomers, and the depletion of Fe-S cluster proteins. However, the alterations in mitochondrial morphology and function during cuproptosis and the potential role of mitophagy in cuproptosis remain insufficiently elucidated. In this study, we induced cuproptosis of breast cancer cells using Elesclomol (ES) and assessed changes in mitochondrial reactive oxygen species, mitochondrial membrane potential, and oxygen consumption rate. Stable cell lines with overexpression or knockdown of PINK1/Parkin genes were constructed to elucidate the impact of mitophagy on cuproptosis. Subcutaneous mouse xenograft models were employed to identify drugs that may synergize with ES and enhance antitumor effects. Our results demonstrated that ES induced cuproptosis of breast cancer cells, which was associated with the activation of PINK1/Parkin-mediated mitophagy. Both gene knockdown and pharmacological inhibition of mitophagy enhanced the sensitivity of breast cancer cells to cuproptosis in vitro and in vivo. The combination of dichloroacetate (DCA) and ES exhibited a synergistic antitumor effect without significant tissue damage on the brain, heart, liver, and kidneys in subcutaneous mouse xenograft models. Collectively, our findings reveal that inhibiting PINK1/Parkin-mediated mitophagy enhances the sensitivity of breast cancer to cuproptosis, offering a novel combined treatment strategy for breast cancer.
    DOI:  https://doi.org/10.1038/s41388-026-03945-z
  28. Environ Res. 2026 Aug 09. pii: S0013-9351(26)01723-8. [Epub ahead of print]306(Pt 4): 125392
    Abnormal glucose metabolism and muscle mass decline by bisphenol A or bisphenol S in skeletal muscle of male mice:inhibition of mitophagy by downregulation of the ERα/AMPK/ULK1 pathway.
    Mingyue Zhao, Jiarong Song, Jiaqi Wang, Yishan Chen, Yue Zhao, Youdan Dong, Lingling Zhai, Lihong Jia.
      The comorbidity of type 2 diabetes mellitus (T2DM) and sarcopenia is becoming increasingly prominent. Studies have shown that bisphenol A (BPA) or bisphenol S (BPS) exposure increases the risk of T2DM. However, the mechanisms by which BPA or BPS affect skeletal muscle glucose metabolism had remained limited and few investigations have addressed their impacts on skeletal muscle mass. In this study, male mice were administered 50 μg/kg bw/d BPA or BPS via drinking water for 16 weeks. Our results demonstrated that BPA or BPS exposure increased FBG and GHbA1c levels while reducing muscle glycogen content, which were attributed to the inhibition of insulin signaling in skeletal muscle. BPA or BPS exposure impaired motor function and skeletal muscle fiber structure, and disrupted the balance of myocyte apoptosis and differentiation, manifested by increased expression of apoptosis-related proteins and Mstn, while downregulating Myog and Myod. Mitochondrial damage and oxidative stress were observed in both BPA and BPS groups. BPA or BPS exposure impaired mitophagy, as indicated by increased levels of LC3B, p62, TOM20 and COXIV, as well as decreased PINK1 and Parkin expression. Moreover, the ERα/AMPK/ULK1 pathway was inhibited in the BPA and BPS groups. Our results revealed that BPA or BPS exposure could impair glucose metabolism and reduce muscle mass, which might be associated with abnormal mitophagy induced by the downregulation of the ERα/AMPK/ULK1 pathway.
    Keywords:  Bisphenol A; Bisphenol S; Glucose metabolism; Mitophagy; Muscle mass
    DOI:  https://doi.org/10.1016/j.envres.2026.125392
  29. Virulence. 2026 Dec;17(1): 2715237
    A putative rRNA methyltransferase Mrm1 regulates mitochondrial dynamics and pathogenicity in Magnaporthe oryzae.
    Mi Shen, Xiaowen Xu, Shikun Xiang, Xiao-Lin Chen.
      Rice blast disease, a major global threat to staple crops, is caused by the ascomycete fungus Magnaporthe oryzae. This pathogen has complex mechanisms to invade rice, with mitochondrial function crucial for infection energy. Our study looks at the impact of Mrm1, a putative rRNA methyltransferase, on mitochondrial dynamics and pathogenicity of M. oryzae. Mrm1 deficiency delays appressorium formation and reduces turgor pressure for host penetration and infection hypha expansion. The N-terminal sequence of Mrm1, with a mitochondrial targeting sequence (MTS), is vital for its localization and function. Deletions cause impaired growth and lower pathogenicity. Deleting MRM1 leads to abnormal mitochondrial morphology, with more filamentous mitochondria during invasive growth, disrupting the balance of fission and fusion. This imbalance reduces the fungus's infection ability. Furthermore, loss of Mrm1 alters the steady-state protein levels of mitochondrial dynamics regulators Dnm1 and Fzo1, likely through translational regulation, while their transcript abundances remain unchanged. In the absence of Mrm1, the levels of these proteins are significantly reduced. Our findings deepen the understanding of epitranscriptomic regulation in fungal pathogenicity and represent a potential candidate for future target-based intervention strategies, pending validation through chemical or genetic approaches.
    Keywords:  Magnaporthe oryzae; Mrm1; mitochondrial dynamics; pathogenicity; rRNA methylation; rice blast disease
    DOI:  https://doi.org/10.1080/21505594.2026.2715237
  30. Sci Adv. 2026 Aug 14. 12(33): eaee0509
    Mito-TEMPO improves survival rates in npc1-knockout zebrafish by reducing oxidative stress and enhancing mitophagy via Sod2.
    Wenhao Zhao, Xudong Hu, Ruyi Wang, Han Zhang, Man Zhou, Hong Cao.
      Niemann-Pick type C (NPC) disease is a lysosomal storage disorder primarily caused by mutations in the NPC1 gene. Most patients present with early-life symptoms including hepatosplenomegaly and digestive system impairment, followed by progressive neurodegeneration. However, effective therapeutic approaches to improve survival in NPC disease remain limited. In this study, using an npc1-knockout (NPC1-KO) zebrafish model established in our laboratory, our team suggests that npc1 deficiency appears to correlate with marked down-regulation of superoxide dismutase 2 (Sod2) expression, concurrent with excessive oxidative stress (OS), mitochondrial dysfunction, and defective mitophagy. Treatment with Mito-TEMPO, a mitochondria-targeted antioxidant acting on SOD, increased survival rates and ameliorated cholesterol accumulation and liver function impairment in early-stage NPC1-KO zebrafish. The underlying mechanism may involve attenuation of OS and promotion of PINK1/Parkin-dependent mitophagic flux through SOD2 enhancement. Our findings support Mito-TEMPO as a potential therapeutic agent and SOD2 as a possible target for NPC disease.
    DOI:  https://doi.org/10.1126/sciadv.aee0509
  31. Cells. 2026 Jul 29. pii: 1371. [Epub ahead of print]15(15):
    The Role of Autophagy in the Pathogenesis of Mitochondrial Diseases.
    Elena D Avdonina, Sergey I Kutsev, Aleksandr V Shestopalov.
      Mitochondrial diseases are a heterogeneous group of inherited disorders caused by defects in the mitochondrial genome or nuclear genes encoding proteins essential for mitochondrial function. These conditions are characterised by progressive dysfunction of tissues with high energy demands, particularly the nervous and muscular systems. In recent years, increasing consideration has been paid to the role of autophagy-the cellular mechanism for the degradation and recycling of intracellular components in the pathogenesis of mitochondrial diseases. This review synthesizes current knowledge on molecular mechanisms of macroautophagy and selective forms of au-tophagy targeting specific organelles and structures: mitophagy, pexophagy, ribophagy, ER-phagy, aggrephagy, lipophagy, lisophagy, and nucleophagy. Using classic mitochondrial syndromes-Kearns-Sayre syndrome (KSS), MERRF, and MELAS, as well as various mitochondrial myopathies-as examples, we discuss experimental evidence indicating both compensatory activation of autophagy and its insufficiency or blockade at different stages. Furthermore, we examine the link between deficiencies of key fatty acid β-oxidation enzymes (VLCAD, MCAD, CPT2) and impaired autophagic flux, including secondary defects of mitophagy mediated by energy deficiency. The review systematises current understanding of how dysregulation of selective autophagy promotes the accumulation of damaged mitochondria, oxidative stress, inflammation, and cell death in mitochondrial diseases. Prospects for therapeutic modulation of autophagy as a potential approach to treating these disorders are discussed.
    Keywords:  autophagy; fatty acid oxidation disorders; mitochondrial diseases; mitophagy; selective autophagy
    DOI:  https://doi.org/10.3390/cells15151371
  32. Food Chem Toxicol. 2026 Aug 11. pii: S0278-6915(26)00405-9. [Epub ahead of print] 116330
    Silver nanoparticles induce damage in BV2 microglia via the mitochondrial dysfunction-PINK1/Parkin signaling pathway.
    Mengting Shang, Shuyan Niu, Menghao Guo, Xiaoru Chang, Yuying Xue.
      Research remains limited regarding the potential mechanisms by which silver nanoparticle (AgNPs) induced nerve injury, specifically mitochondrial damage in microglia. This study investigates the mitochondrial damaging effects of AgNPs in BV2 cells. BV2 cells were treated with AgNPs to evaluate their impact. Their mitochondrial morphological alterations were observed via transmission electron microscopy, and mitochondrial functional changes were assessed using various assays, including JC-1 labeling, ATP measurement, mitochondrial reactive oxygen species (mtROS) detection. The result demonstrated that BV2 cells treated with AgNPs showed vacuolization, damaged mitochondrial cristae, and even ruptured the outer membrane. In addition, AgNPs leads BV2 cells mitochondrial membrane to potential collapsed, marked elevation of total cellular ROS and mtROS, and reduced their ATP production. Furthermore, the mitochondrial division inhibitor-1 effectively reduced the rise in mitochondrial fission caused by AgNPs. Interestingly, it also reduced the mtROS, the activation of PINK1/Parkin pathway, and apoptosis caused by AgNPs. These results clearly demonstrated that AgNPs triggered neurotoxicity by targeting mitochondria which disrupts mitochondrial homeostasis. Our study shows that AgNPs induce neurotoxicity in BV2 cells through the activation ofmitochondrial dysfunction-PINK1/Parkin signaling pathway. These findings offer novel insights into the mechanisms underlying AgNPs-induced neurotoxicity, which could present potential strategies to lessen their harmful consequences.
    Keywords:  AgNPs; Microglia; Mitochondria; Neuroinflammation
    DOI:  https://doi.org/10.1016/j.fct.2026.116330
  33. Mol Cell Neurosci. 2026 Aug 08. pii: S1044-7431(26)00042-4. [Epub ahead of print]138 104112
    The gut-brain-mitophagy axis: Urolithin A as a transcriptional activator of Parkin in Alzheimer's and Parkinson's diseases.
    Mustafa M Shokr, Mohamed N Fawzy.
      Mitochondrial dysfunction is a cardinal, causative, and convergent hallmark in both Alzheimer's disease (AD) and Parkinson's disease (PD). However, therapeutics that target the process of mitophagy, the selective removal of damaged mitochondria, are relatively undeveloped. Prior work has largely centered around post-translational modifications of the PINK1-Parkin signaling pathway while ignoring the key need for sustained protein synthesis of Parkin. In this review, we explore an innovative transcriptional circuit involving the gut microbiome, AMP-activated protein kinase (AMPK), sirtuin 1 (SIRT1), and mitophagy: gut-derived metabolites, such as Urolithin A (UA), activate AMPK and SIRT1, both of which converge to deacetylate and phosphorylate peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). The transcription of the mitophagy protein, Parkin, is then driven by activation of PGC-1α. This UA/AMPK/SIRT1/PGC-1α/Parkin/mitophagy pathway is disrupted in multiple layers in AD and PD; this includes impaired gut function, lowering the level of UA produced in the body, proteinopathy leading to reduced PGC-1α activity, and decreased transcription of Parkin. Therapeutic targets of these various nodes include UA, PGC-1α activator ZLN005, and SIRT1 activators, such as resveratrol or nicotinamide riboside. By shifting the paradigm from post-translational activation to transcriptional restoration of Parkin, this gut-brain metabolic axis offers a unifying, testable, and therapeutically tractable framework for mitigating mitophagy failure in AD and PD.
    Keywords:  AMPK/SIRT1 signaling; Gut–brain axis; Mitophagy; PGC-1α activation; Urolithin A
    DOI:  https://doi.org/10.1016/j.mcn.2026.104112
  34. Eur Heart J. 2026 Aug 11. pii: ehag598. [Epub ahead of print]
    Vitronectin-driven amyloid deposition disrupts mitochondrial homeostasis via integrin-mediated pathway in a humanized mouse model of transthyretin cardiac amyloidosis.
    Zeping Qiu, Yingze Fan, Jiabin Qin, Haikun Qi, Qinfang Miao, Shudong Zheng, Zhiyan Wang, Zhihong Sun, Yutong Wu, Wenbo Yang, Yanjia Chen, Sha Hua, Marish I F J Oerlemans, Alain van Mil, Wei Jin.
       BACKGROUND AND AIMS: Transthyretin (TTR) amyloid cardiomyopathy (ATTR-CM) is a progressive cause of heart failure, especially in the ageing society, but cellular biological mechanism studies are limited by the lack of robust animal models. Vitronectin (VTN), an extracellular matrix (ECM) glycoprotein enriched in amyloid deposits, may contribute to amyloidogenesis, yet its pathogenic role in ATTR-CM remains undefined.
    METHODS: Humanized knock-in mice expressing either wild-type (hTTRWT) or V142I mutant transthyretin (hTTRV142I) were generated. Amyloid burden, cardiac structure, and function were assessed by Congo red staining, electron microscopy, echocardiography, and cardiac magnetic resonance. The functional role of VTN and integrin signalling was studied using genetic silencing and pharmacological intervention with low-dose cilengitide.
    RESULTS: Both hTTRWT and hTTRV142I mice developed age-dependent cardiac amyloidosis with diastolic dysfunction and reduced survival, especially in the hTTRV142I strain. VTN co-localized with TTR fibrils, promoted fibril aggregation, reduced amyloid burden upon its knockdown, and preserved cardiac function. Mechanistically, TTR amyloid suppressed integrin αvβ3/FAK/Akt signalling, leading to marked mitochondrial dysregulation characterized by excessive fission, enhanced mitophagy, and impaired oxidative phosphorylation. Restoration of αvβ3 signalling with cilengitide normalized mitochondrial dynamics, improved bioenergetics, and ameliorated diastolic dysfunction despite persistent amyloid stress.
    CONCLUSIONS: Two reproducible ATTR-CM models that recapitulate the steadily progressive course of human disease were established. Furthermore, VTN actively drives cardiac amyloid deposition, and disruption of integrin αvβ3/FAK/Akt signalling links amyloid-ECM interactions to mitochondrial dysfunction. Therefore, modulation of integrin signalling represents a potential complementary therapeutic strategy in ATTR-CM beyond TTR suppression.
    Keywords:  ATTR-CM; Integrin αvβ3; Mitochondrial fission; Vitronectin
    DOI:  https://doi.org/10.1093/eurheartj/ehag598
  35. Sci Adv. 2026 Aug 14. 12(33): eaeh0657
    Mitochondrial stress activates ELT-2-dependent lysosomal proteostasis to extend lifespan in C. elegans.
    Rendan Yang, Yu Sun, Wenzheng Wang, Yuxuan Lei, Lin Chen, Xiaoxu Li, Raya B Liu, Ang Zhou, Arwen W Gao, Liangshan Mu, Johan Auwerx, Terytty Yang Li.
      Mild mitochondrial stress could extend lifespan across species, yet the underlying mechanism remains unclear. Here, we show that inhibition of mitochondrial respiration induces a sustained transcriptional program that enhances lysosomal proteolysis during aging in Caenorhabditis elegans. Mechanistically, this response is primarily regulated by the intestinal GATA transcription factor ELT-2, which retains high expression and directly binds to GATA motifs in the promoters of lysosomal protease genes to promote their transcriptional activation. Moreover, we identified R249 within the conserved zinc-finger DNA binding domain of ELT-2 as a key residue required for its transcriptional activity. Notably, this mitochondrion-ELT-2-lysosome axis operates largely independently of the mitochondrial unfolded protein response (UPRmt) to counteract aging. Furthermore, increased lysosomal activity, as well as the lysosomal proteases CPR-5 and CPR-8, is essential for mitochondrial stress-induced clearance of toxic polyglutamine (polyQ) aggregates and lifespan extension. Together, our findings reveal a previously unrecognized ELT-2-dependent lysosomal proteostasis pathway that acts downstream of mitochondrial stress to maintain protein homeostasis and promote longevity.
    DOI:  https://doi.org/10.1126/sciadv.aeh0657
  36. Front Cardiovasc Med. 2026 ;13 1856434
    The central role of mitochondrial pathology in sepsis-induced cardiomyopathy: from molecular mechanisms to clinical translation.
    Linghong Xu, Jun Zhang, Huijing Tong, Xusheng Teng.
      Sepsis-induced cardiomyopathy (SIC) affects approximately 50% of severe sepsis patients, with mortality rates approaching 80%. This review examines mitochondrial pathology as the central orchestrator of SIC progression. Mitochondrial dysfunction encompasses impaired oxidative phosphorylation (OXPHOS), causing bioenergetic failure; mitochondrial DNA (mtDNA) release activating cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes, Toll-like receptor 9, and NOD-like receptor family pyrin domain containing 3 pathways; ETC dysfunction generating explosive reactive oxygen species (ROS); defective mitophagy leading to damaged mitochondria accumulation; and disturbed mitochondrial dynamics with excessive fission and suppressed fusion. Intercellular mitochondrial transfer through tunneling nanotubes (TNTs) exhibits paradoxical dual effects. Mitochondria-targeted antioxidants selectively accumulate within mitochondria to scavenge ROS and preserve membrane potential. Nrf2 activators enhance endogenous antioxidant defenses. Melatonin modulates mitochondrial function through Ripk3 inhibition. Clinical translation faces substantial obstacles due to sepsis heterogeneity, animal model limitations, and disease complexity. This review integrates mitochondrial biology, immunometabolism, and translational medicine to identify promising directions for improving patient outcomes.
    Keywords:  inflammation; mitochondrial dynamics; mitochondrial dysfunction; mitophagy; oxidative stress; sepsis-induced cardiomyopathy; therapeutic targets
    DOI:  https://doi.org/10.3389/fcvm.2026.1856434
  37. J Pineal Res. 2026 Sep;78(5): e70182
    Melatonin Suppresses Osteoclastogenesis via Inhibiting Iron/ROS-CREB/PGC-1β-Mediated Mitochondrial Biogenesis.
    Jiancheng Yang, Jingmin Che, Ming Yang, Yan Feng, Qingmei Li, Yuhong Zeng.
      Postmenopausal osteoporosis (PMOP) is linked to iron accumulation. Melatonin has iron-chelating and antioxidant properties, but its mechanism against osteoclastogenesis remains unclear. This study investigated whether melatonin suppresses osteoclast formation by targeting the iron/ROS-CREB-PGC-1β-mediated mitochondrial biogenesis pathway. In vitro, bone marrow-derived macrophages (BMMs) were treated with RANKL and melatonin (10-1000 nM). Melatonin concentration-dependently inhibited osteoclast differentiation, reduced intracellular ferrous and total iron levels, decreased ROS and oxidative stress markers, and suppressed mitochondrial biogenesis. Mechanistically, melatonin indirectly suppressed PGC‑1β expression via inhibition of CREB phosphorylation, without affecting PGC‑1α expression. The CREB activator forskolin reversed melatonin's effects, whereas the CREB inhibitor 666-15 mimicked them. In vivo, ovariectomized (OVX) mice received weekly injections of iron dextran to model moderate iron overload, with or without oral melatonin. Melatonin ameliorated iron‑induced bone loss, improved bone microarchitecture and biomechanical properties, reduced tissue iron stores and bone ROS levels, and suppressed osteoclast mitochondrial biogenesis and the CREB/PGC-1β pathway; these effects were counteracted by forskolin. In conclusion, melatonin prevents osteoclastogenesis and counters bone loss due to iron accumulation in estrogen‑deficient conditions by chelating iron, scavenging ROS, and blocking the iron/ROS‑activated CREB/PGC‑1β axis, thereby suppressing mitochondrial biogenesis. This study offers a mechanistic explanation for using melatonin as a possible treatment for PMOP, particularly when accompanied by iron overload.
    Keywords:  iron accumulation; melatonin; mitochondrial biogenesis; osteoclast; osteoporosis; reactive oxygen species
    DOI:  https://doi.org/10.1111/jpi.70182
  38. J Mol Cell Cardiol. 2026 Aug 12. pii: S0022-2828(26)00122-7. [Epub ahead of print]
    Loss of Miro1 drives cardiac and mitochondrial dysfunction exacerbated by metabolic stress.
    Sarah Kassab, Zainab Albalawi, Asim M Khojah, Connor D Stonall, Wei Liu, Florence Baudoin, Sukhpal Prehar, Hind AlMalki, Yoshimi Tokuyama, Gina Galli, Elizabeth J Cartwright, Ashraf Kitmitto.
      Cardiac mitochondrial remodelling is a hallmark of type 2 diabetes-linked heart failure (T2DM-HF). We previously reported that mitochondrial morphological changes occur in early-stage disease and identified down-regulation of the mitochondrial protein Miro1 (Rhot1). Neuronal Miro1 regulates mitochondrial movement but the role of cardiac Miro1 remains poorly understood. Therefore, we generated a cardiac-specific Miro1 knockout (Miro1cko) mouse model to investigate how cardiomyocyte-Miro1 deficiency affects cardiac and mitochondrial structure-function. Miro1cko mice compared to controls develop mild diastolic and systolic dysfunction and electrical abnormalities, cellular hypertrophy and fibrosis. Miro1cko leads to aberrant mitochondrial respiration and elevated H₂O₂ production, consistent with electron microscopy showing disrupted cristae morphology, with putative links to Myosin19 down-regulation. Three-dimensional electron microscopy identified mitochondrial remodelling with interfibrillar mitochondria (IFM) ~50% smaller with an increased surface complexity. Since fusion-fission protein expression was unchanged these data identify Miro1 as a regulator of mitochondrial morphology. Mitochondrial density increases (34% Miro1cko; 30% control), with abnormal IFM clustering, which we suggest is associated with impaired mitophagy since PINK1 and Parkin are down-regulated (~80% and ~ 60% respectively) and imaging flow cytometry of isolated primary cardiomyocytes identified an ~2-fold reduction to mitochondrial clearance indicative of blunted mitophagy. Heterozygous knockout mice, which display a milder cardiac phenotype, rapidly developed HF symptoms when given a high fat diet with L-NAME. In conclusion, loss of Miro1 drives multiple aberrant mitochondrial remodelling events culminating in cardiac dysfunction and predisposes towards accelerated metabolic-HF development. Loss of Miro1 may represent a critical mechanistic link in T2DM-HF pathogenesis and therefore a potential therapeutic target.
    Keywords:  Cristae; Heart failure; Metabolic stress; Miro1; Mitochondria; Mitophagy; electron microscopy
    DOI:  https://doi.org/10.1016/j.yjmcc.2026.08.004
  39. Free Radic Biol Med. 2026 Aug 11. pii: S0891-5849(26)01019-1. [Epub ahead of print]
    Quercetin Ameliorates Imatinib-Induced Ovarian Damage by Regulating Mitochondrial Dysfunction and PANoptosis via the RAF1-ERK1/2-Drp1 Axis.
    Qing-Hui Li, Min Ji, Yan Zhou, Shi-Qi Weng, Yao Kong, Qin Xiao, Tao Luo, Zhao-Xia Liu.
      Imatinib (IMA), a front-line targeted therapy, was demonstrated by our prior study to potentially cause premature ovarian insufficiency (POI) after long-term administration. Additionally, we found that quercetin (QUE) may ameliorate IMA-induced ovarian injury by regulating mitophagy. Previous studies have shown that mitochondrial dysfunction may be involved in various cell death pathways. PANoptosis is a recently identified form of cell death that exhibits characteristics of pyroptosis, apoptosis, and necroptosis simultaneously. The present study further investigates whether IMA induces PANoptosis via mitochondrial dysfunction and explores the underlying mechanisms and potential therapeutic targets. In vitro experiments on granulosa cells revealed that IMA induced PANoptosis, characterized by membrane blebbing and swelling, pyknosis, as well as rupture of the nuclear and plasma membranes observed via transmission electron microscopy and confocal microscopy. This was accompanied by increased lactate dehydrogenase release, an elevated proportion of propidium iodide positive cells, and activation of caspase-3 (apoptosis), gasdermin D (GSDMD, pyroptosis), and mixed lineage kinase domain-like protein (MLKL, necroptosis). Network pharmacology revealed that the related genes associated with IMA, QUE, mitochondrial function, and POI were enriched in the MAPK pathway, with RAF1 identified as a key target. Western blot analysis demonstrated that IMA upregulated phosphorylation of RAF1, its downstream effector ERK1/2, and the mitochondrial fission mediator Drp1 (Ser616) in granulosa cells and ovarian. GW5074 (a RAF1 inhibitor), Mdivi1 (a Drp1 inhibitor), and QUE restored mitochondrial membrane potential and mitochondrial superoxide levels in granulosa cells and oocytes, suppressed IMA-induced PANoptosis, and improved granulosa cell viability and oocyte quality. These findings provide new insights into potential strategies for protecting ovarian function during IMA treatment.
    Keywords:  Imatinib; Mitochondrial function; PANoptosis; Premature ovarian insufficiency; Quercetin; RAF1-ERK1/2-Drp1 axis
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.08.017
  40. Biochem Pharmacol. 2026 Aug 14. pii: S0006-2952(26)00684-2. [Epub ahead of print] 118345
    Fto-mediated m6A demsupplementethylation of SNHG9 Enhances PINK1-Dependent mitophagy and reverses cisplatin resistance via nuclear EZH2 ubiquitination.
    Zihan Jing, Xingmei Ren, Ruqiong Wang, Bo An, Weitong Gao, Yan Jin, Lihua Shang, Dexin Jia, Yan Yu.
      Cisplatin (CDDP) resistance in lung adenocarcinoma (LUAD) is associated with increased N6-methyladenosine (m6A) RNA modification. Although proteolysis-targeting chimeras (PROTACs) that recruit E3 ligases have shown therapeutic potential, the role of nuclear ubiquitination in CDDP resistance remains unclear. Here, m6A-epitranscriptomic profiling identified the long non-coding RNA small nucleolar RNA host gene 9 (SNHG9) as a key target of the m6A demethylase fat mass and obesity-associated protein (FTO). Clinically, elevated SNHG9 expression was associated with poor prognosis and CDDP resistance. Mechanistically, SNHG9 bound to and inhibited the E3 ligase von Hippel-Lindau tumor suppressor protein (VHL), thereby blocking VHL-mediated ubiquitination and proteasomal degradation of enhancer of zeste homolog 2 (EZH2). Ubiquitination assays and subcellular fractionation further demonstrated that VHL promotes nuclear accumulation of K63-linked ubiquitinated EZH2 (ub-EZH2), leading to proteasome-dependent degradation and reduced EZH2 abundance. Nuclear EZH2 transcriptionally repressed PTEN-induced kinase 1 (PINK1) via trimethylated histone H3 at lysine 27 (H3K27me3), thereby impairing Parkin activation (Ser65 phosphorylation) required for mitophagy. Functionally, FTO destabilized SNHG9 in an m6A-YTH domain family protein 2 (YTHDF2)-dependent manner, which restored VHL-mediated EZH2 ubiquitination, reactivated mitophagy, and ultimately reversed CDDP resistance. Importantly, pharmacological m6A inhibition and EZH2 degradation effectively suppressed SNHG9 signaling and improved chemosensitivity in preclinical models. Collectively, these findings reveal a previously underappreciated mechanism of CDDP resistance driven by the FTO/SNHG9/VHL/EZH2/PINK1/Parkin axis and support the therapeutic potential of targeting this pathway in LUAD.
    Keywords:  CDDP resistance; Lung adenocarcinoma; M(6)A; Mitophagy; Nuclear ubiquitination; SNHG9
    DOI:  https://doi.org/10.1016/j.bcp.2026.118345
  41. J Burn Care Res. 2026 Aug 13. pii: irag132. [Epub ahead of print]
    Melatonin attenuates burn-wound progression by inhibiting inflammation via mitophagy-related pathway.
    Weixue Jin, Danyang Ren, Celia Ho, Meirong Yu, Songxue Guo.
      Burn-wound progression contributes to early deterioration of burn severity and is closely associated with oxidative stress-induced inflammation in the zone of stasis, where mitochondria play a central role in regulating inflammatory responses and tissue damage. Melatonin is known to exert antioxidant and anti-inflammatory effects and to protect organelles from injury, suggesting a potential role in mitigating ischemia-related tissue damage. In this study, a "comb" scald rat model was used to investigate whether melatonin could prevent early burn-wound progression and to elucidate the underlying mechanisms. Melatonin was administered intraperitoneally at different doses immediately after injury, and wound conversion was assessed by histological analysis. Oxidative stress markers, inflammatory cytokines, and autophagy/mitophagy-related signals were evaluated using ELISA, immunostaining, qRT-PCR, and western blotting, with additional pharmacological modulation of autophagy and mitophagy to clarify mechanistic involvement. The results showed that melatonin significantly attenuated burn-induced activation of the HMGB1-NLRP3 inflammasome and reduced inflammatory cytokine release, while also alleviating oxidative stress, as indicated by decreased malondialdehyde (MDA) levels and restored superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities. These protective effects were closely associated with preservation of mitochondrial integrity and regulation of reactive oxygen species (ROS) through autophagy, particularly PINK1-PARKIN-dependent mitophagy. Importantly, the autophagy inhibitor 3-MA abolished the beneficial effects of melatonin, confirming the essential role of autophagy-related pathways. Together, these findings demonstrate that melatonin prevents early burn-wound progression by promoting mitophagy-mediated mitochondrial repair and suppressing downstream inflammatory responses.
    Keywords:  burn-wound progression; inflammation; mitochondrion; mitophagy; oxidative stress
    DOI:  https://doi.org/10.1093/jbcr/irag132
  42. Am J Cancer Res. 2026 ;16(7): 2783-2800
    Mitochondrial calcium uniporter as a biomarker in lung adenocarcinoma: regulation of the immune microenvironment, apoptosis, cell cycle and mitophagy.
    Yihao Liu, Zexia Zhao, Hua Huang, Chenxuan Zhao, Zhixuan Duan, Min Wang, Chen Ding, Wenhao Zhao, Yanzhan Liu, Hongbing Zhang, Yongwen Li, Wenjun Meng, Yin Li, Xiaobin Shang, Jun Chen, Haoling Zhang, Honglin Zhao.
      The mitochondrial calcium uniporter (MCU) complex is essential for maintaining mitochondrial calcium homeostasis and regulating cellular metabolism, apoptosis, proliferation, and mitochondrial quality control. Although MCU has been implicated in multiple malignancies, its biological role and regulatory mechanisms in lung adenocarcinoma (LUAD), a major subtype of non-small cell lung cancer (NSCLC), remain insufficiently defined. In this study, MCU expression was analyzed using pan-cancer and LUAD datasets from TCGA, GEO, UALCAN, and tissue microarray cohorts. GO, KEGG, and GSEA were performed to explore MCU-associated biological pathways, while ssGSEA, CIBERSORT, and TIDE algorithms were used to evaluate immune infiltration and predicted immunotherapy response. In vitro assays, including CCK-8, EdU, colony formation, Transwell assays, flow cytometry, qRT-PCR, Western blotting, immunofluorescence staining, JC-1 staining, and reactive oxygen species (ROS) detection, were conducted to assess the effects of MCU on LUAD cell behavior, mitophagy, and mitochondrial function. MCU was significantly upregulated in LUAD tissues and cell lines compared with normal controls. High MCU expression was associated with reduced immune cell infiltration, decreased immune checkpoint and HLA gene expression, and lower predicted sensitivity to immunotherapy. Functionally, MCU knockdown markedly inhibited LUAD cell proliferation, migration, and invasion, promoted apoptosis, and induced G1-phase cell cycle arrest, accompanied by increased p21 and cleaved caspase-3 expression and decreased CDK4 and Cyclin D1 expression. Conversely, MCU overexpression enhanced malignant phenotypes and suppressed apoptosis. Mechanistically, GSEA indicated that MCU was closely associated with mitophagy-related pathways. Further validation showed that MCU knockdown reduced PINK1 and PRKN expression, decreased mitochondrial LC3B accumulation, and weakened LC3B-mitochondria co-localization, indicating impaired mitophagy. MCU depletion also caused mitochondrial membrane potential dissipation and increased intracellular ROS accumulation. Collectively, these findings suggest that MCU promotes LUAD progression by remodeling the tumor immune microenvironment, enhancing malignant cellular behaviors, inhibiting apoptosis, and maintaining mitophagy-dependent mitochondrial homeostasis, highlighting MCU as a potential prognostic biomarker and therapeutic target in LUAD.
    Keywords:  Mitochondrial calcium uniporter (MCU); apoptosis; cell cycle; immune microenvironment; lung adenocarcinoma (LUAD); mitophagy
    DOI:  https://doi.org/10.62347/PGQK3358
  43. Front Mol Neurosci. 2026 ;19 1875988
    Dynamic structural profiling of PINK1 mutations (T313M and L347P) reveals a vital molecular perturbation namely phospho-Serine 65 ubiquitin recognition point in mitophagy mediated autosomal recessive Parkinson's disease (ARPD).
    Deborah Vincent, C Sudandiradoss.
       Introduction: Autosomal recessive Parkinson's disease (ARPD) arises from impaired mitophagy due to dysfunction of the PINK1/Parkin pathway, where PINK1-mediated phosphorylation of ubiquitin at Ser65 is essential for pathway activation. However, experimental limitations obscure the effects of disease-associated mutations on intrinsically disordered regions (IDRs) and post-translational modification (PTM) dynamics.
    Methods: An integrated computational pipeline was employed to screen 825 PINK1 missense variants, identifying two high-confidence deleterious mutations, T313M and L347P, within the kinase domain. Variant prioritization was complemented by conserved residue, IDR, and PTM analyses, followed by protein-protein docking, molecular dynamics simulations, MM/PBSA binding free-energy calculations, principal component analysis (PCA), and dynamic cross-correlation matrix (DCCM) analysis.
    Results: T313M overlapped a conserved phosphorylation site, whereas L347P mapped to conserved active-site residues, with complementary support from IDR analysis. Docking analysis revealed a progressive reduction in binding affinity from the wild type (-88.4 ± 8.2) to L347P (-81.9 ± 3.4) and T313M (-77.4 ± 4.9), accompanied by decreased electrostatic stabilization (-357.6 → -260.6 → -235.5 kcal/mol) and buried surface area (1741.6 → 1624.1 → 1547.4 Å2). Molecular dynamics simulations demonstrated that T313M produced the greatest structural and dynamic perturbations, whereas L347P induced moderate destabilization with increased solvent exposure. Although MM/PBSA analysis indicated broadly comparable binding energetics across all systems, PCA and DCCM analyses revealed increased conformational flexibility and altered residue communication in the mutant complexes, particularly T313M.
    Discussion: These findings establish a mechanistic link between mutation-induced structural dynamics and impaired PINK1-ubiquitin recognition at Ser65, providing a mutation-specific framework for understanding early mitophagy impairment in ARPD and supporting future molecular assessment and targeted therapeutic development.
    Keywords:  IDR; PINK1; PTM; SNP; autosomal recessive Parkinson’s disease (ARPD); mitophagy; molecular dynamics; ubiquitin phosphorylation (Ser65)
    DOI:  https://doi.org/10.3389/fnmol.2026.1875988
  44. Int J Mol Sci. 2026 Jul 31. pii: 6868. [Epub ahead of print]27(15):
    Cardiolipin as a Signaling Hub: Evolutionary Conservation and Programmable Platforms Coupling Mitochondrial Stress to Cell Fate.
    Patrice X Petit.
      Cardiolipin (CL), a dimeric phospholipid with four acyl chains and a small polar head group, is one of the most striking examples of evolutionary continuity in cell biology. Present in the plasma membrane of α-proteobacteria and retained without fundamental modification in the inner mitochondrial membrane (IMM) of every eukaryote examined, CL has persisted across roughly two billion years of evolution, a period over which the mitochondrion shed the great majority of its ancestral genes. This review develops, as an organizing hypothesis rather than an established fact, the proposal that CL acts as a programmable signaling hub: a lipid whose physical chemistry and membrane address allow it to nucleate distinct supramolecular platforms in response to discrete stress signals, each platform coupling a specific mitochondrial state to a defined cell fate outcome. Three CL-dependent platforms are examined, together with a fourth, emerging axis, and the evidence supporting each is explicitly graded. Platform 1, the catalytic peroxidase platform, converts the constitutive CL-cytochrome c (cyt c) structural complex into an enzymatic reaction under oxidative stress, generating oxidized CL (oxCL) species that contribute to cyt c release from the IMM; this platform is the best supported of the four. Platform 2, the receptor-like mitophagy platform, exploits NME4-dependent CL scramblase activity to translocate CL from the IMM to the outer mitochondrial membrane (OMM) surface upon membrane potential dissipation, creating an externalized "eat-me" signal recognized by LC3-II; the evidence here is moderate and largely cell-based. Platform 3, the caspase-8/BID activation platform, is proposed to assemble a CL microdomain scaffold at the OMM that recruits caspase-8, markedly accelerates BID cleavage, and couple extrinsic apoptotic signals to mitochondrial outer membrane permeabilization (MOMP); this model rests substantially on reconstituted systems and requires further validation in intact cells and in vivo. A fourth, still-debated axis links CL externalization to innate immune activation through NLRP3 recruitment, for which alternative membrane-recruitment models exist. The argument advanced here is that the conservation of CL is unlikely to be explained by its structural roles alone, although those roles are themselves sufficient to impose strong selection; disentangling structural from signaling contributions remains an open problem, and the comparative genomic work needed to do so has not yet been performed.
    Keywords:  Barth syndrome; Bid; NLRP3; apoptosis; cardiolipin; caspase-8; evolutionary conservation; mitochondria; mitophagy; signaling hub
    DOI:  https://doi.org/10.3390/ijms27156868
  45. Eur J Pharmacol. 2026 Aug 13. pii: S0014-2999(26)00732-6. [Epub ahead of print] 179250
    Senescence-Associated Mitochondrial Dysfunction as a Therapeutic Target in Ovarian Cancer: Challenges and Opportunities.
    Hanieh Sadat Khalili, Banafshe Abadi, Nima Rezaei.
      Senescence-associated mitochondrial dysfunction (SAMD) links aging, metabolic reprogramming, and therapy resistance in ovarian cancer. Persistent damage to mitochondrial DNA (mtDNA), impaired mitochondrial quality control, and disrupted mitochondrial fusion and fission dynamics compromise electron transport (ET) and membrane potential, yielding chronic mitochondrial reactive oxygen species. This, in turn, drives a senescence-associated secretory phenotype, which includes proinflammatory cytokines, matrix proteases, and pro-angiogenic factors. This secretory phenotype alters the tumor microenvironment in ways that make the cells more resistant to cell death. In this review, we provide comprehensive insights from preclinical and translational clinical studies to map mechanistic connections and outline pragmatic measurement strategies. Our goal is to explore whether SAMD can move from being merely a descriptive hallmark to a measurable biomarker and a practical therapeutic target for restoring chemosensitivity.
    Keywords:  Ovarian cancer; mitochondrial dynamics; mitochondrial dysfunction; targeted therapy; therapy resistance
    DOI:  https://doi.org/10.1016/j.ejphar.2026.179250
  46. Front Oncol. 2026 ;16 1897564
    Host systemic metabolism and cancer metabolic vulnerabilities: mechanisms and therapeutic opportunities.
    Rashid Mir, Jameel Barnawi, Naseh A Algehainy, Mohammed M Jalal, Malik A Altayar, Reema M Almotairi, Faris J Tayeb, Mamdoh S Moawadh, Ruqaiah I Bedaiwi, Kholoud S Almasoudi, Ibrahim Altedlawi Albalawi, Abdulrahman Alasmari, Mohammad Muzaffar Mir.
       Background: Central molecular mediators-including hypoxia-inducible factors (HIF-1α/HIF-2α), MYC, wild-type and mutant p53, NF-κB, STAT3, SREBPs, NRF2, and KRAS-orchestrate these pathways by linking nutrient availability to oncogenic signalling, epigenetic reprogramming, and immune-metabolic crosstalk within the tumour microenvironment. Key metabolic enzymes including HK2, PKM2, LDH-A, IDH1/2, GLS1, and FASN serve as direct effectors and therapeutic targets. Mitochondrial dynamics-biogenesis (PGC-1α), fission (DRP1), fusion (MFN1/2, OPA1), and mitophagy (PINK1-Parkin)-constitute a critical regulatory layer. The bidirectional epigenetic-metabolic axis, mediated by acetyl-CoA, SAM, α-ketoglutarate, 2-hydroxyglutarate, and lysine lactylation, amplifies oncogenic transcriptional programs and locks cells into malignant states. Central to this review is the thesis that metabolic plasticity-the capacity of cancer cells to dynamically switch between and co-opt multiple metabolic programs-is the primary driver of tumour progression, immune evasion, and resistance to therapy. Understanding and targeting this plasticity represents the central translational challenge of cancer metabolic oncology.
    Methods: A comprehensive narrative literature review was conducted across PubMed, Scopus, and Web of Science (2015-2025) using terms including metabolic reprogramming, Warburg effect, oncometabolites, mitochondrial dynamics, epigenetic metabolism, immunometabolism, and metabolic therapeutics. Peer-reviewed primary research and comprehensive reviews were evaluated. Limitations include restriction to English-language literature (2015-2025), potential publication bias toward high-impact journals, and the rapidly evolving nature of the field.
    Conclusion: Metabolic reprogramming is governed by an interconnected network of transcription factors, signalling cascades, epigenetic regulators, mitochondrial dynamics, and TME-immune crosstalk. FDA-validated targets include IDH1/2 (ivosidenib, enasidenib, vorasidenib-August 2024), HIF-2α (belzutifan), and mTOR (everolimus). An expanding clinical pipeline encompasses GLS1, MCT1, OXPHOS Complex I, FASN, and metabolic immune checkpoints. Future advances require single-cell/spatial metabolomics, AI-driven patient stratification, and rational combination strategies that preempt adaptive metabolic escape. Future advances require AI-driven genome-scale metabolic modelling for patient stratification, single-cell and spatial metabolomics to resolve intra-tumoral metabolic heterogeneity, and rational combination strategies targeting multiple metabolic nodes simultaneously to preempt adaptive resistance. Integration of circadian pharmacology, host metabolic comorbidity management (obesity, diabetes, gut microbiome modulation), and TME metabolic normalisation into cancer treatment frameworks will drive the next generation of precision metabolic oncology.
    Keywords:  HIF-1α; cancer therapeutics; epigenetic regulation; metabolic reprogramming; mitochondrial dynamics; oncometabolites; tumour microenvironment; warburg effect
    DOI:  https://doi.org/10.3389/fonc.2026.1897564
  47. Hepatology. 2026 Aug 10.
    Hepatocyte hnRNPK preserves mitochondrial integrity to restrain liver injury and fibrosis.
    Qian Peng, Sujuan Wang, Yufeng Zhang, Yangjun Luo, Beiwu Lan, Nan Wang, Wei Jiao, Zhiqin Xie, Yaming Yuan, Wei Duan, Huijuan Sun, Ping Yang, Zhigang Li, Yewei Ji, Yufei Gao, Ben Zhou, Lifeng Yang, Yongfang Jiang, Ming Lu, Ying Feng, Zhangsen Zhou.
       BACKGROUND AIMS: Liver fibrosis is a global health issue with unclear unified drivers. The RNA-binding protein hnRNPK is critical for hepatic homeostasis, but its role in chronic fibrosis remains undefined. This study investigated hnRNPK-mediated splicing dysregulation in liver fibrosis and its therapeutic potential.
    APPROACH RESULTS: We mapped hepatocellular hnRNPK expression across a broad spectrum of human and murine fibrotic etiologies. Mechanistic insights were obtained by integrating snRNA-seq, hepatocyte-specific alternative splicing profiling, untargeted and spatial metabolomics, and 3D mitochondrial reconstruction using AT-SEM. We identified reduced hepatocellular hnRNPK abundance as a conserved hallmark of liver fibrosis across distinct pathogenic insults, including MASH, ALD, HBV, and DILI. Hepatocyte-specific Hnrnpk ablation in mice induced aberrant Opa1 splicing, specifically promoting exon 4b inclusion. This disrupted the balance of OPA1 isoforms, depleting L-OPA1 and driving severe mitochondrial fragmentation characterized by distinct "spheroid" ultrastructures. This loss of mitochondrial integrity triggered HSC activation through the cytosolic mtDNA-cGAS-STING pro-inflammatory signaling cascade and the mitochondria-containing pellet. Notably, restoring the hnRNPK-Opa1 axis via AAV-mediated overexpression of Hnrnpk or the Opa1-Δ4b isoform (lacking exon 4b), together with pharmacological promotion of mitochondrial fusion, effectively arrested and regressed established liver fibrosis in multiple murine models.
    CONCLUSIONS: Our findings establish the loss of hnRNPK as a central, unifying mechanism in liver fibrogenesis. By governing the Opa1 splicing axis, hnRNPK maintains mitochondrial integrity and prevents the pro-inflammatory signaling and secretome that fuel HSC activation. Targeting this RNA-mitochondria axis represents a potent, etiology-independent therapeutic strategy for chronic liver disease.
    Keywords:  ; Alternative splicing; Hepatic stellate cells; Liver disease; Mitochondrial dynamics
    DOI:  https://doi.org/10.1097/HEP.0000000000001836
  48. Cancer Sci. 2026 Aug 13.
    Mitochondrial Morphology Dynamics Remodel Metabolism and Affect TKI Sensitivity in EGFR-Mutated Lung Cancer.
    Yu Zhao, Yuqiang Liu, Mingxuan Xie, Zhiming Ye, Hong Huang, Maojin Yao, Feng Zhou, Jianzhu Zhao, Jun Tang.
      EGFR-mutant non-small cell lung cancer patients often exhibit resistance to TKI therapy. This treatment resistance is a key factor affecting the efficacy of TKIs and a major bottleneck in cancer treatment. The potential underlying cause may be closely related to tumor cell metabolic reprogramming. In this study, we established an EGFR-mutant lung cancer mouse model, isolating and culturing tumor primary cells to explore the cellular and molecular mechanisms of EGFR-mutant lung cancer. Using techniques such as super-resolution microscopy and RNA-seq, we qualitatively and quantitatively analyzed the morphological changes of mitochondria within tumor cells following TKI treatment. Our results indicate that mitochondrial dynamics are remodeled toward increased mitochondrial fission during the early phase of TKI treatment. Furthermore, pharmacological inhibition of mitochondrial fission further sensitizes tumor cells to EGFR-TKIs. Additionally, disrupting oxidative phosphorylation metabolism can increase the sensitivity of tumor cells to TKI treatment and reverse tumor cell resistance to TKI. Overall, these findings suggest that the metabolic reprogramming of mitochondrial OXPHOS in tumor cells mediates energy stress adaptation, altering their response to TKI treatment and providing new metabolic therapeutic targets to overcome EGFR-TKI resistance.
    Keywords:  EGFR‐mutated non‐small cell lung cancer; TKI treatment; combination therapy; mitochondrial fission; oxidative phosphorylation
    DOI:  https://doi.org/10.1111/cas.70488
  49. ACS Nano. 2026 Aug 11. 20(31): 21939-21952
    Adenosine Triphosphate Nanoparticles with Blood-Brain Barrier Permeability for Prevention of Cerebral Ischemic Injury via Mitochondrial Homeostasis.
    Jaewon Ju, Youngkwan Kim, Seung Ju Seo, Yoonhee Jin, Jee-Yin Ahn, Mikyung Shin.
      Cerebral ischemia induces selective neuronal death, largely due to mitochondrial dysfunction and ATP depletion. This energy crisis impairs mitophagy, exacerbates oxidative stress, and accelerates neuronal apoptosis. While exogenous ATP supplementation holds promise for restoring mitochondrial function, its clinical application is hindered by rapid in vivo clearance before brain accumulation occurs. Herein, we report positively charged ATP nanoparticles (ATP-N), formulated via electrostatic interactions with chitosan, that facilitate crossing the blood-brain barrier and subsequent adsorptive-mediated transcytosis following intravenous injection, for the prevention of cerebral ischemic injury. Compared with free ATP, ATP-N exhibited a prolonged circulation time and enhanced brain accumulation. In a mouse model of cerebral ischemia, ATP-N effectively replenished intracellular ATP, restored mitochondrial membrane potential, and activated mitophagy, leading to reduced neuronal apoptosis and attenuated ischemic damage. These findings highlight ATP-N as a promising, minimally invasive therapeutic strategy to prevent ischemic brain injury, enabling rapid and efficient ATP delivery to restore mitochondrial function and promote neuronal survival.
    Keywords:  adenosine triphosphate; cerebral ischemia; mitochondrial homeostasis; nanoparticles; neuroprotection
    DOI:  https://doi.org/10.1021/acsnano.6c05982
  50. BMC Complement Med Ther. 2026 Aug 13. pii: 245. [Epub ahead of print]26(1):
    Eucalyptus camaldulensis leaf extract enhances thalidomide efficacy in acute myeloid leukemia cells through modulation of mitochondrial energetics.
    Samah E Ismail, Ashraf A Hassan, Amany A Elkhedel, Amal M Fakhry, Eman A Khalifa, Soliman M Toto.
       BACKGROUND: Acute myeloid leukemia (AML) is an aggressive hematological malignancy characterized by high relapse rates and poor prognosis. Leukemic stem cells (LSCs), a major driver of therapy resistance, rely predominantly on mitochondrial oxidative phosphorylation (OXPHOS) for survival. Targeting mitochondrial metabolism represents a promising therapeutic strategy. This study investigated the effect of Eucalyptus camaldulensis Dehnh. leaf extract, alone and in combination with thalidomide, on mitochondrial energetics in AML cells.
    METHODS: An in vitro study was conducted using the human AML Kasumi-1 cell line. Cells were divided into four groups: control, thalidomide-treated, E. camaldulensis extract-treated, and combination-treated groups. The ethanolic extract was characterized by GC-MS and HPLC. Cell viability was assessed using WST-1 assay and IC₅₀ values were calculated. Gene expression of CD34, MFN1, MFN2, OPA1, and IL-6 was quantified by qRT-PCR. ATP levels were measured by ELISA. Mitochondrial length was assessed by transmission electron microscopy.
    RESULTS: E. camaldulensis extract significantly reduced Kasumi-1 cell viability in a concentration-dependent manner, both alone and in combination with thalidomide. The combination demonstrated an additive cytotoxic effect (CI = 1). The IC₅₀ values were 197.80 µg/mL for thalidomide, 30.26 µg/mL for the extract, and 28.26 µg/mL for the combination. Thalidomide alone or combined significantly downregulated IL-6 expression, while thalidomide increased MFN1 expression. The extract significantly downregulated IL-6 and mitochondrial fusion genes and reduced CD34 expression. Extract treatment decreased ATP levels and shortened mitochondrial length compared with untreated cells (p < 0.05).
    CONCLUSION: Eucalyptus camaldulensis extract disrupts mitochondrial energetics and LSC-associated pathways in AML cells. Its combination with thalidomide shows additive activity and may represent a complementary strategy to overcome metabolic-driven therapy resistance in AML.
    Keywords:  Acute myeloid leukemia; Eucalyptus camaldulensis; Mitochondrial dynamics; Oxidative phosphorylation; Thalidomide
    DOI:  https://doi.org/10.1186/s12906-026-05503-2
  51. Chem Biol Interact. 2026 Aug 10. pii: S0009-2797(26)00403-5. [Epub ahead of print]438 112295
    Gestational diabetes mellitus amplifies sevoflurane-induced developmental neurotoxicity in offspring mice.
    Xiaoru Sun, Xin Fang, Yun Pan, Yuhan Zheng, Yan Lu, Xinke Guo, Xiaobing Hu, Zhendong Xu.
       OBJECTIVE: Gestational diabetes mellitus (GDM) may increase offspring susceptibility to neurodevelopmental stressors. Sevoflurane is widely used in pediatric anesthesia but carries potential neurotoxicity risks. This study investigated whether maternal GDM exacerbates sevoflurane-induced developmental neurotoxicity in offspring, and explored the underlying mechanisms related to neuroinflammation, microglial activation and mitochondrial dysfunction.
    METHODS: A mouse model of maternal GDM was established, and offspring received sevoflurane exposure during brain development. Cognitive function was assessed by behavioral tests. Neuronal apoptosis and dendritic spine morphology were detected by TUNEL and Golgi-Cox staining. Microglial activation and inflammatory profiles were analyzed using immunofluorescence and multiplex liquid-chip assays. Transcriptomic and proteomic analyses were integrated to identify dysregulated molecular pathways, and key proteins were verified by Western Blot.
    RESULTS: Compared with control and single-treatment groups, combined GDM and sevoflurane exposure significantly worsened long-term cognitive impairment, promoted neuronal apoptosis, and reduced dendritic spine density in the hippocampus. The dual-hit induced robust microglial overactivation and disrupted inflammatory cytokine homeostasis. Multi-omics analyses revealed significant enrichment of pathways governing synaptic vesicle cycling, glutamatergic synaptic function, and immune-inflammatory responses. Mechanistically, the dual-hit caused severe mitochondrial dynamic imbalance characterized by downregulation of the fusion protein Mfn2, together with abnormal expression of the microglial receptor CX3CR1.
    CONCLUSION: Maternal GDM exposure is associated with aggravated sevoflurane-induced developmental neurotoxicity in offspring. Our correlative findings suggest potential underlying links involving altered mitochondrial homeostasis and excessive microglial activation. This study provides potential targets for preventing anesthesia-related neurotoxicity in high-risk children.
    Keywords:  Developmental neurotoxicity; Gestational diabetes mellitus; Microglia; Mitochondrial dynamics; Sevoflurane
    DOI:  https://doi.org/10.1016/j.cbi.2026.112295
  52. J Mol Cell Cardiol. 2026 Aug 11. pii: S0022-2828(26)00123-9. [Epub ahead of print]
    Cardiometabolic stress induces HFpEF with impaired bioenergetics and disrupted proteostasis in aged female mice.
    Kamil A Kobak, Weronika Zarzycka, Catherine J King, Frederick F Peelor, Charlie Burnett, Willard M Freeman, Kenneth M Humphries, Benjamin F Miller, Ying Ann Chiao.
      Heart failure with preserved ejection fraction (HFpEF) predominantly affects older women. The widely used two-hit model of HFpEF has mostly been applied to young animals and fails to induce HFpEF in female mice, limiting clinical and epidemiologic relevance. We challenged 19-month-old female mice with the two-hit protocol. Unlike young female mice, aged mice developed HFpEF, coinciding with impaired cardiac mitochondrial function and disrupted mitochondrial proteostasis. Our findings connect aging with increased female susceptibility to cardiometabolic stress and demonstrate the contribution of mitochondrial dysfunction in HFpEF. Incorporating aging to the two-hit model enables future investigation of sex-specific mechanisms of HFpEF.
    Keywords:  Aging; Cardiometabolic stress; Female sex; HFpEF; Mitochondrial complex II; Mitophagy; Proteostasis
    DOI:  https://doi.org/10.1016/j.yjmcc.2026.08.005
  53. Front Cardiovasc Med. 2026 ;13 1856834
    Bioinformatics identification of mitochondrial dynamics-related potential biomarkers in kawasaki disease and prediction of potential regulatory correlations.
    Tingting Hu, Shaoyong Lin, Rongrong Yang, Xiaofeng Guo.
       Background: Kawasaki disease (KD) is a systemic vasculitis. Mitochondria was found to promote the activation of NLRP3 inflammatory vesicles, which have been shown to be a key driver of vascular disease. And there are few relevant reports of mitochondrial dynamic (MD) in KD. This study aimed to distinguish the potential biomarkers related to MD in KD and supply ideas for the intervention and treatment of KD. Currently, functional experimental verification in this field is lacking, and this study preliminarily explores their potential correlations through bioinformatics analysis.
    Methods: Differential expression analysis, machine learning, and expression validation were employed to identify potential biomarkers. Subsequently, analyses like enrichment analysis, immune infiltration analysis, and molecular regulatory network were applied to probe the underlying mechanisms of potential biomarkers.
    Results: RAP2C, DPM2, and DDX59 were identified as potential biomarkers associated with MD in KD and were mainly involved in inflammation-related pathways. Notably, 13 differential immune cells were gained in KD and control groups, 9 of which showed strong correlation with potential biomarkers, suggesting a relationship between potential biomarkers and the immune microenvironment in KD. For example, DPM2 had the positive relationship with CD8 T cells, while DDX59 had the negative relationship with CD8 T cells. Afterwards, molecular regulatory networks of potential biomarkers were constructed, specifically, they shared 5 common microRNAs (miRNAs) and 3 common transcription factors (TFs). Ultimately, potential biomarkers had 3 common targeting drugs [valproic acid, benzo(a)pyrene, and acetaminophen]; notably, benzo(a)pyrene was excluded due to carcinogenicity, which supplied the basis for targeting potential biomarkers to treat KD.
    Conclusion: The potential biomarkers (RAP2C, DPM2, and DDX59) related to MD in KD were acquired. These findings provide preliminary insights for future drug repurposing studies targeting KD and offer bioinformatic evidence for a potential link between mitochondrial dynamics and the immune microenvironment in KD.
    Keywords:  immune infiltration analysis; kawasaki disease; machine learning; mitochondrial dynamic; molecular regulatory network
    DOI:  https://doi.org/10.3389/fcvm.2026.1856834
  54. Free Radic Biol Med. 2026 Aug 08. pii: S0891-5849(26)01010-5. [Epub ahead of print]255 774-790
    Cannabidiol confers neuroprotection against 6-OHDA toxicity by rescuing Nrf2 proteostasis and preserving mitochondrial integrity.
    Juan Jurado-Coronel, Martin L Duennwald.
      Oxidative stress and the progressive degeneration of dopaminergic neurons are key features of Parkinson's disease (PD). The intrinsically disordered structure of the transcription factor Nuclear factor erythroid 2-related factor 2 (Nrf2), which coordinates the main cellular antioxidant response of the body, makes it highly susceptible to misfolding and aggregation under severe oxidative stress, compromising cellular survival. Cannabidiol (CBD) has potent neuroprotective properties, but its exact molecular mechanism within the dopaminergic redox environment remains unclear. In this study, we investigated the protective effects of CBD against 6-hydroxydopamine (6-OHDA)-induced toxicity in both undifferentiated and mature, post-mitotic differentiated SH-SY5Y cells. We found that CBD confers robust Nrf2-dependent neuroprotection against 6-OHDA. Importantly, we uncover a previously unexplored mechanism of neuroprotection by which CBD actively prevents the stress-induced sequestration of Nrf2 into insoluble cytoplasmic inclusions under oxidative stress. We find that CBD keeps Nrf2 in a soluble, functional state, increases Ser40 phosphorylation, restores nuclear localization, and drives the robust transcriptional upregulation of antioxidant enzymes. This targeted activation of Nrf2 effectively reduces intracellular reactive oxygen species (ROS), significantly attenuates mitochondrial fragmentation, and decreases aberrant mitophagic activity. Overall, our results show that rather than merely scavenging reactive oxygen species, CBD directly increases Nrf2 activity during oxidative stress, enabling a sustained cytoprotective response. We thus identify CBD as a highly specific, targeted molecule with a high potential for neuroprotective therapy in PD.
    Keywords:  6-Hydroxydopamine; Cannabidiol; Mitochondrial dynamics; Neuroprotection; Nrf2; Parkinson's disease; Proteostasis
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.08.012
  55. Int Rev Neurobiol. 2026 ;pii: S0074-7742(26)00054-1. [Epub ahead of print]188 299-361
    The Tau-mitochondria connection and its impact on cellular energy metabolism in Alzheimer's disease.
    Abhay Kumar Singh, Supraja M R, Amal P S, Senthilkumar Krishnamoorthi, Ashok Iyaswamy, Siva Sundara Kumar Durairajan.
      Alzheimer's disease (AD) is a complex multifactorial neurodegenerative disease process resulting in progressive cognitive deterioration and synaptic dysfunction. The primary research approach in AD has traditionally focused on amyloid- pathology however an increasingly evidence suggests that tau protein is a key mediator of neuronal damage via a direct action on mitochondrial bioenergetics. In this chapter we look at the nature of the tau-mitochondrial interface, and propose a paradigm of tau-induced energy failure in AD. Physiologically tau provides stability to the microtubules and is involved in transport mechanisms within cells. In AD, tau is excessively post-translationally modified hyperphosphorylated and truncated tau species form toxic oligomers that incorrectly translocate to mitochondria, interacting pathologically with critical proteins such as voltage-dependent anion channel 1 (VDAC1) and adenine nucleotide translocase (ANT), impeding the mitochondrial ATP/ADP exchange and reducing oxidative phosphorylation efficiency. Tau also further damages mitochondria by excessive fission, inhibition of axonal transport and Inhibition of mitophagy by interrupting PINK1-Parkin signaling. In turn, the build-up of dysfunctional mitochondria leads to ROS production, mtDNA damage and calcium imbalance creating a vicious cycle toward oxidative stress and tau pathology. At the cellular level they cause an energy depletion of the synapse and at the systems level cause glucose hypometabolism and activation of neuroinflammation. The chapter additionally discusses novel therapeutic approaches that target both tau and mitochondrial abnormalities, namely antisense oligonucleotides (ASO), mitochondria targeted compounds and mitophagy modifiers, stressing that it would be more effective to utilize a cocktail of these inhibitors. As a whole, in the context of decreased bioenergetics, the tau-mitochondria axis is an important factor to consider in the successful treatment of AD.
    Keywords:  ATP synthase; Adenine nucleotide translocase; Alzheimer’s disease; Axonal transport; Microglial metabolism; Mitochondria-targeted therapeutics; Mitochondrial bioenergetics; Mitophagy; Neuroinflammation; Neuronal energy metabolism; PINK1-Parkin pathway; Synaptic dysfunction; Tau protein; Tau-targeted therapy; VDAC1
    DOI:  https://doi.org/10.1016/bs.irn.2026.06.002
  56. Cell Rep. 2026 Aug 14. pii: S2211-1247(26)00935-6. [Epub ahead of print]45(8): 117857
    Succinate and its carrier Sfc1 mediate metabolic control of mitochondrial protein import by the TIM23 translocase.
    Koyeli Das, Rituparna Samanta, Tamar Ziv, Johannes M Herrmann, Bella Kalderon, Ophry Pines.
      Tim23 is an essential component of the mitochondrial inner membrane translocase and Sfc1 is a carrier that exchanges succinate for fumarate across that membrane. Sfc1 and succinic acid availability regulate dual targeting of fumarase and aconitase by facilitating mitochondrial import of their newly synthesized precursors, as shown by pulse-chase experiments. Here, we show that Sfc1 associates with Tim23 in vivo, and succinate modulates this association, which in turn affects mitochondrial protein import. Physical interaction between Tim23 and Sfc1 was proven by co-immunoprecipitation, bimolecular fluorescence complementation (BiFC) and biotin-based proximity labeling (TurboID). Proximity labeling and structural modeling-informed mutagenesis allowed us to dissect the carrier activity of Sfc1 from its function as a TIM23 regulator. We performed Rosetta-MP docking of Sfc1 and Tim23 to envisage the interface. Thus, our findings show that metabolites can regulate mitochondrial import and adjust the segregation of key metabolic enzymes between the cytosol and mitochondria.
    Keywords:  CP: cell biology; CP: metabolism; Tim23; aconitase; dual targeting; fumarase; glyoxylate shunt; metabolic signaling; metabolites; mitochondrial protein import; succinate-fumarate carrier; tricarboxylic acid cycle
    DOI:  https://doi.org/10.1016/j.celrep.2026.117857
  57. Nutrients. 2026 Aug 03. pii: 2511. [Epub ahead of print]18(15):
    Natural Bioactive Compounds Targeting Key Hallmarks of Aging: Functional Food Potential of Spermidine, Fisetin, Berberine, and Urolithin A.
    Wojciech Rzeski, Weronika Rzeska.
      Naturally derived bioactive compounds that modulate aging-associated mechanisms have attracted growing research interest, yet few reviews examine how such compounds might act together. This narrative review examines four mechanistically distinct compounds, namely spermidine, fisetin, berberine, and urolithin A, as emerging functional food ingredients with scientifically supported effects on key hallmarks of human aging. Spermidine, a dietary polyamine from wheat germ and fermented foods, induces autophagy through EP300 inhibition and is associated with reduced all-cause mortality in prospective studies. Fisetin, a flavonoid from strawberries and apples, exerts senolytic activity by selectively eliminating senescent cells via PI3K/AKT and Bcl-2/Bcl-xL inhibition, with emerging clinical evidence. Berberine, an isoquinoline alkaloid from Berberis species, modulates metabolic dysfunction via AMP-activated protein kinase (AMPK) activation and reshapes gut microbiota composition through direct high intraluminal exposure, with the most extensive clinical dataset of the four compounds. Urolithin A, a gut microbiome-derived postbiotic from ellagitannins in pomegranates and nuts, induces mitophagy via PINK1/Parkin and has been evaluated in a growing number of registered human clinical trials. Together, the four compounds primarily target distinct but complementary aging-associated pathways (autophagy, senolysis, metabolic regulation, mitophagy), suggesting rational potential for combined functional food formulations. Limited direct evidence for their combined use and the need for dedicated co-administration studies are discussed, alongside bioavailability, safety, and regulatory considerations.
    Keywords:  aging; autophagy; berberine; bioactive compounds; fisetin; functional food; healthspan; mitophagy; senolysis; spermidine; urolithin A
    DOI:  https://doi.org/10.3390/nu18152511
  58. Int Immunopharmacol. 2026 Aug 10. pii: S1567-5769(26)01074-X. [Epub ahead of print]187 117228
    JTE-013 ameliorates allergic asthma by targeting the S1PR2-HDAC3-p53 signaling axis to improve mitochondrial homeostasis.
    Simiao Xu, Kun Guo, Ningpo Ding, Xu Wu, Shuya Wang, Ziwei Qin, Chang Su, Xingmei Wang, Chang Liu, Xinrui Li, Mingshan Zheng, Guanghai Yan, Hong Cui.
       BACKGROUND: Asthma, driven by epithelial mitochondrial dysfunction, lacks effective treatments. JTE-013, a selective sphingosine-1-phosphate receptor 2 (S1PR2) antagonist, has unknown mechanisms in asthma.
    OBJECTIVE: We aimed to evaluate the efficacy of JTE-013 in ovalbumin (OVA)-induced asthmatic mice and elucidate its underlying mechanism, hypothesizing that it may restore mitochondrial homeostasis via the S1PR2-HDAC3-p53 pathway.
    METHODS: We established an in vivo model of OVA-induced mice and an in vitro model of BEAS-2B cells subjected to house dust mite (HDM) treatment. We applied pharmacological and genetic interventions targeting S1PR2, HDAC3, and p53, followed by Western blotting, immunofluorescence (IF), co-immunoprecipitation (Co-IP), flow cytometry, and ROS/MMP quantitative assays.
    RESULTS: In the animal model, JTE-013 significantly alleviated airway inflammation, mucus hypersecretion, and remodeling. At the cellular level, JTE-013 exerted protective effects against HDM-driven damage in BEAS-2B cells by alleviating oxidative stress (restoring Nrf2/HO-1), preventing mitochondrial dysfunction (stabilizing MMP, inhibiting DRP1 fission), and inhibiting apoptosis. These protective effects were highly dependent on HDAC3. To validate the S1PR2-HDAC3-p53 axis, we demonstrated that the cytoprotection from S1PR2 knockdown (mimicking JTE-013) was eliminated by siHDAC3, an effect that was subsequently restored by p53 inhibition (Pifithrin-α).
    CONCLUSION: JTE-013, as an S1PR2 antagonist, potentially modulates HDAC3-mediated p53 deacetylation, mitigating oxidative stress, mitochondrial dysfunction, and apoptosis to ameliorate allergic asthma.
    Keywords:  Allergic asthma; HDAC3; JTE-013; Mitochondrial dysfunction; P53 acetylation
    DOI:  https://doi.org/10.1016/j.intimp.2026.117228
  59. Regen Biomater. 2026 ;13 rbag153
    Glucose/ROS dual-responsive mitochondria-targeting nanozyme microneedles remodel mitochondrial homeostasis to orchestrate immune metabolic reprogramming for diabetic foot ulcer healing.
    Qi Dong, Siyu Xiong, Bing Shu, Zhiwei Cai, Shangqing Wang, Yang Ming, Xiongwei Dong, Peng Chen, Zhaowei Zhang.
      Diabetic foot ulcers (DFUs) develop a persistent vicious loop featuring impaired mitochondrial activity and massive buildup of reactive oxygen species (ROS), accompanied by disordered immune responses; these combined pathological changes hinder the regeneration of damaged tissues. Therapeutic strategies that spatiotemporally target mitochondria to couple redox homeostasis restoration, immunometabolic reprogramming and tissue regeneration remain an unmet clinical need. Here we report a glucose/ROS dual-responsive microneedle patch incorporating mitochondria-targeting metal-phenolic nanozymes for DFU treatment. Tannic acid-cerium (TA-Ce) nano-catalysts possess strong catalytic capacities analogous to natural superoxide dismutase and catalase enzymes. These dual biomimetic functions clear excess ROS, stabilize mitochondrial physiological balance and drive macrophages to shift from pro-inflammatory M1-type toward anti-inflammatory M2 subtypes, which ultimately breaks sustained inflammatory feedback loops. Notably, the nanozyme functions dually as a therapeutic agent and a dynamic crosslinker through reversible boronate ester chemistry, allowing stable loading and microenvironment-responsive, on-demand release aligned with the pathological features of diabetic wounds. In a full-thickness diabetic rat wound model, the microneedle patch achieves 92.64% wound closure on Day 14, significantly outperforming commercial dressings. This work establishes a mitochondria-centered immunometabolic therapeutic strategy and provides a translatable platform for chronic wound regeneration.
    Keywords:  diabetic wound healing; immunometabolic reprogramming; microneedle patches; mitochondrial homeostasis; nanozymes
    DOI:  https://doi.org/10.1093/rb/rbag153
  60. Molecules. 2026 Aug 04. pii: 2705. [Epub ahead of print]31(15):
    Ganoderic Acid A Reverses Ultraviolet B Induced Hyperpigmentation via Multi-Targeted Regulation of Mitochondrial Homeostasis and Inflammation.
    Jingting Wang, Yuerong Qian, Qingna Gong, Rui He, Shanli Tian, Nannan Yu, Yanan Xi, Qiqi Wu, Guang-Li Wang, Jing Wang.
       BACKGROUND: Conventional tyrosinase (TYR) inhibitors irritate skin and trigger rebound pigmentation, necessitating safer and more effective depigmenting agents.
    METHODS: Biocompatibility was assessed by cell viability. Melanin content and TYR activity were measured spectrophotometrically. Reactive oxygen species (ROS), adenosine triphosphate (ATP), and inflammatory cytokines were detected by fluorescence, luminescence, and ELISA. Western blot and RT-qPCR assessed oxidative stress, inflammatory, and melanogenic targets. Molecular docking simulated Ganoderic Acid A (GAA) interactions with key proteins.
    RESULTS: GAA exhibits good biocompatibility, inhibits melanin synthesis and TYR activity in B16-F10 cells, and reverses ultraviolet B-induced pigmentation. Mechanistically, GAA restores mitochondrial homeostasis by scavenging ROS, replenishing ATP, activating the nuclear factor erythroid 2-related factor 2 (Nrf2) axis, and inhibiting nuclear factor kappa-B (NF-κB) and cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) to regulate the inflammatory microenvironment. This synergistic regulation inhibits the mitogen-activated protein kinase (MAPK) signaling pathway and down-regulates the microphthalmia-associated transcription factor (MITF) transcriptional network and the expression of TYR, tyrosinase-related protein 1 (TRP-1), and tyrosinase-related protein 2 (TRP-2).
    CONCLUSION: GAA eliminates ultraviolet B-induced hyperpigmentation through a multi-target mechanism of mitochondrial repair, inflammation inhibition, and direct binding to tyrosinase, and is a potential natural candidate drug for the treatment of skin diseases.
    Keywords:  ganoderic acid A; melanogenesis; mitochondrial homeostasis; tyrosinase; ultraviolet B
    DOI:  https://doi.org/10.3390/molecules31152705
  61. Am J Physiol Heart Circ Physiol. 2026 Aug 12.
    Breaking Bad and Taking Sides: Chamber-specific mitochondrial remodeling in Dsg2-linked arrhythmogenic cardiomyopathy.
    Keaton E Minor, Chi Fung Lee, Hina Lateef Nizami.
      
    Keywords:  Arrhythmogenic cardiomyopathy; Desmoglein-2; Mitochondrial genes; Mitochondrial remodeling
    DOI:  https://doi.org/10.1152/ajpheart.00633.2026
  62. Biochem Biophys Res Commun. 2026 Aug 06. pii: S0006-291X(26)01167-8. [Epub ahead of print]832 154403
    FGF21 attenuates sepsis-induced myocardial injury via AMPK-mediated mitochondrial biogenesis.
    Liping Mao, Dan Dang, Wenjing Wang.
      Sepsis is a life-threatening infection that often leads to myocardial injury. Here we explored the role of fibroblast growth factor 21 (FGF21) in sepsis-induced myocardial injury and its underlying mechanism. A mouse model of sepsis-associated myocardial injury was established by cecal ligation and puncture (CLP). Serum FGF21 levels were upregulated in CLP mice (sham: ∼300 pg/mL; CLP: ∼420 pg/mL). CLP led to myocardial injury, inflammation, and apoptosis. Cardiac-specific overexpression of FGF21 via AAV9-cTnT improved 5-day survival rate from ∼20% (CLP) to ∼60% (CLP + OE-FGF21), reduced histological damage, suppressed apoptosis, and upregulated p-AMPK/AMPK and PGC-1α. In LPS-treated H9C2 cells, FGF21 overexpression reversed the LPS-induced decline in mitochondrial function. The AMPK agonist AICAR mimicked, while the AMPK antagonist Compound C partially reversed, the protective effects of FGF21. In conclusion, FGF21 overexpression alleviates sepsis-associated myocardial injury by restoring mitochondrial function via AMPK/PGC-1α pathway.
    Keywords:  AMPK signaling; Apoptosis; FGF21; Mitochondrial biogenesis; Oxidative stress; Sepsis-associated myocardial injury
    DOI:  https://doi.org/10.1016/j.bbrc.2026.154403
  63. Molecules. 2026 Aug 05. pii: 2719. [Epub ahead of print]31(15):
    Lipidomics Based on HILIC-ESI-HRMS Reveal Subtle Changes in the Mitochondrial Phospholipidome of Mouse Embryonic Fibroblasts Expressing Pathogenic Variants of Human OPA1 Protein.
    Andrea Castellaneta, Ilario Losito, Vito Porcelli, Serena Barile, Alessandra Maresca, Valentina Del Dotto, Penelope Magnoni, Claudia Zanna, Ludovica Sofia Guadalupi, Valeria Cinquepalmi, Cosima Damiana Calvano, David C Chan, Valerio Carelli, Luigi Palmieri, Tommaso R I Cataldi.
      Pathogenic variants of the mammalian optic atrophy 1 (OPA1) protein, a key regulator of mitochondrial fusion, may lead to severe mitochondrial dysfunction and morphological alterations, and have also been proposed to be involved in remodeling the mitochondrial membranes lipid profile. To address this last issue, a lipidomic workflow based on HILIC-ESI-HRMS was applied to profile major classes of mitochondrial membrane phospholipids (PL), namely phosphatidylcholines (PCs), -ethanolamines (PEs), and -inositols (PIs), along with cardiolipins (CLs), in mouse embryonic fibroblasts knocked out for Opa1 gene (Opa1-/- MEFs) and expressing human OPA1 isoform 1 (ISO1) or one of four well-known pathogenic variants (I382M, D603H, G439V and R445H). A total of 122 common sum compositions were recognized for PLs in the four classes across the five sample types. Chemometrics on the respective quantitative data indicated a lower prevalence of alk(en)yl/acyl species (O-PCs and O-PEs) within the PC and PE classes, along with a higher relative contribution of highly unsaturated PI and CL species, when severely pathogenic R445H and G439V variants were expressed. In contrast, the I382M variant was associated with a greater relative contribution of less-unsaturated PI and CL species. These findings indicate that pathogenic OPA1 variants are associated with distinct mitochondrial phospholipid profiles, opening interesting perspectives for future direct experimental validation of an eventual relationship existing between OPA1 variants, inter-organelle phospholipid trafficking, and mitochondrial dysfunction.
    Keywords:  HILIC-ESI-HRMS; OPA1 variants; human OPA1; lipidomics; mitochondria; mouse embryonic fibroblasts
    DOI:  https://doi.org/10.3390/molecules31152719
  64. Am J Physiol Endocrinol Metab. 2026 Aug 09.
    Nr4a3 Deficiency Disrupts MEK1-ERK1/2-Drp1 Signaling, Driving Adiposity and Glucose Intolerance in Male Mice.
    Peter N Ellsworth, Kate E Whalen, Jared D Carter, Jacob A Herring, Kavan H Hess, Kristopher L Wieland, Drake C Watkins, Jeremy Y Saito, Erik D Marchant, Nathan D Marchant, Nathan D Walker, Garritt L Page, Yang Cao, Qin Yang, Benjamin T Bikman, Jeffery S Tessem.
      Obesity is strongly associated with elevated blood glucose levels, glucose intolerance, insulin resistance and type 2 diabetes. The Nr4a family of orphan nuclear receptors are essential for proliferation, cell survival, mitochondrial function, and fuel utilization in a tissue dependent manner. Nr4a3 overexpression has been shown to decrease blood glucose levels and improve glucose tolerance. Here we present the effects of full body Nr4a3 deletion in mice fed a standard chow diet. We demonstrate that male and female Nr4a3 knock out mice fed a standard chow diet have elevated non-fasting blood glucose and impaired glucose tolerance. Male Nr4a3 knock out mice have increased body weight, without changes in body length, food intake, movement or energy expenditure. Interestingly, male, but not female, Nr4a3 knock out mice have increased weight of all adipose depots with increased adipocyte cell size. Furthermore, male Nr4a3 mice have impaired adipose mitochondrial respiration, with normal liver and soleus respiration. Finally, we show a significant decrease in Drp1 mRNA, Drp1 protein, and phosphorylated DRP1 levels. These data suggest that Nr4a3 loss impairs expression of the key mitochondrial fission gene Drp1, resulting in impaired adipose mitochondrial respiration and ultimately increasing adipocyte size, adipose depot mass, and body mass. These data demonstrate that Nr4a3 is critical for proper adipocyte function.
    Keywords:  Adipose tissue; Drp1; Glucose tolerance; Mitochondrial Respiration; Nr4a3
    DOI:  https://doi.org/10.1152/ajpendo.00322.2025
  65. Cells. 2026 Aug 03. pii: 1404. [Epub ahead of print]15(15):
    Mitochondrial Dysfunction as a Driver of Meta-Inflammation in Aging: The Emerging Role of PDK4 in Bioenergetic Reprogramming and Inflammatory Amplification.
    Md Riad Chowdhury, Gui-Hwa Jeong, In-Kyu Lee.
      Aging is accompanied by a progressive decline in mitochondrial quality, bioenergetic flexibility, and stress resilience. Aging mitochondria are increasingly recognized as active inflammatory signaling platforms rather than passive targets of cellular damage. Excess mtROS, leaked mtDNA, defective mitophagy, altered NAD+ metabolism, and impaired pyruvate oxidation together create a cellular environment that favors persistent inflammatory activation. These signals engage NF-κB, NLRP3 inflammasome, cGAS-STING, and SASP pathways, allowing mitochondrial stress to spread from organelle dysfunction to tissue-level inflammation. Within this framework, pyruvate dehydrogenase kinase 4 (PDK4) is of particular interest because it directly controls mitochondrial pyruvate entry through inhibition of the pyruvate dehydrogenase complex. By phosphorylating and inhibiting the pyruvate dehydrogenase complex, PDK4 limits mitochondrial pyruvate oxidation and favors lactate accumulation, fatty acid utilization, and redox-inflammatory signaling. Recent work in senescent cells links PDK4-dependent lactate accumulation to NOX1-derived ROS and SASP activity, suggesting a direct route by which altered fuel handling may reinforce inflammation. Here, we review mitochondrial dysfunction as the organizing principle of age-associated meta-inflammation, discuss PDK4 as a central metabolic checkpoint, examine tissue-specific consequences in muscle, adipose tissue, brain, and kidney, and evaluate therapeutic strategies aimed at restoring mitochondrial function to suppress chronic inflammation and preserve healthspan.
    Keywords:  NLRP3; PDK4; SASP; aging; inflammaging; meta-inflammation; mitochondrial dysfunction; mitophagy; mtROS; pyruvate dehydrogenase
    DOI:  https://doi.org/10.3390/cells15151404
  66. Medicine (Baltimore). 2026 Aug 14. 105(33): e50212
    The role of mitochondrial fusion protein 2 in regulating ER stress in premature placental aging: A case-control study.
    Dandan Sun, Ling Ai, Ping Xu, Jiawei Zhou, Lili Xue.
      Advanced maternal age (AMA) is associated with an increased risk of adverse perinatal outcomes, which may be attributed to premature placental aging. Previous studies have demonstrated that mitochondrial fusion protein 2 (Mfn2) plays a critical role in aging-related neurodegenerative disorders, metabolic diseases, and vascular pathologies. However, its expression in AMA pregnancies and its impact on placental function remain poorly understood. This study aimed to investigate the expression patterns of Mfn2 in placental tissues from AMA pregnancies and elucidate its regulatory role in endoplasmic reticulum (ER) stress through the protein kinase R-like ER kinase (PERK) signaling pathway. The downregulation of Mfn2 expression in AMA exacerbates placental senescence by dysregulating ER stress via PERK. Mfn2 binds to PERK, inhibits phosphorylation, and alleviates oxidative stress and senescence, highlighting its therapeutic potential. Placental tissues from 20 women with AMA and 20 young women were analyzed using real-time quantitative reverse transcription PCR‌. An H2O2-induced HTR-8/SVneo trophoblast cell line senescence model was established. Functional assays (cell counting kit-8, wound healing, Transwell, and β-galactosidase staining) and oxidative stress markers (reactive oxygen species/malondialdehyde/superoxide dismutase) were evaluated. Western blotting was used to assess the expression of PERK pathway proteins (phosphorylated protein kinase R-like endoplasmic reticulum kinase, activating transcription factor 4, and CCAAT/enhancer binding protein homologous protein) and senescence markers (P16 and P53). Immunoprecipitation verified the Mfn2-PERK interaction. Mfn2 expression was significantly downregulated in AMA placentas and negatively correlated with PERK expression. Mfn2 overexpression reversed the H2O2-induced suppression of trophoblast viability, migration, invasion, and senescence while reducing the levels of reactive oxygen species and malondialdehyde and restoring the activity of superoxide dismutase. Mfn2 inhibited PERK pathway activation (phosphorylated protein kinase R-like endoplasmic reticulum kinase, activating transcription factor 4, and CCAAT/enhancer binding protein homologous protein) and the expression of senescence markers (P16/P53). Mfn2 interacted directly with PERK.
    Keywords:  advanced maternal age; endoplasmic reticulum stress; mitochondrial fusion protein 2; placental senescence; protein kinase R-like ER kinase
    DOI:  https://doi.org/10.1097/MD.0000000000050212
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