bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2026–06–14
73 papers selected by
Gavin McStay, Liverpool John Moores University
  1. Mitochondrial Dynamics in Cancer Progression and Therapy Resistance: Emerging Roles in Metabolic Reprogramming, Biomarker Discovery, and Precision Medicine.
  2. Editor's Note: Protective effects of antidepressant citalopram against abnormal APP processing and amyloid beta-induced mitochondrial dynamics, biogenesis, mitophagy and synaptic toxicities in Alzheimer's disease.
  3. Restoration of mitochondrial dynamics and synaptic function by mitophagy enhancers in a tauopathy cell model.
  4. Understanding the OMA1-DELE1-HRI Axis and PINK1-parkin-mediated Mitophagy in Parkinson's Disease.
  5. Mitophagy-mediated immune evasion: Shared strategies of pathogens.
  6. Rejuvenating Inter-organellar Communication Via Mitophagy in Ageing and Neurodegeneration.
  7. Drp1-Dependent Mitochondrial Fission in the Hippocampus Drives Chronic Stress-Induced Depressive-like Behaviors in Mice.
  8. Aerobic Exercise attenuates airway inflammation in allergic asthma by regulating M2 macrophage polarization via drp1-mediated mitophagy.
  9. Mitophagy: an emerging therapeutic target in mitochondrial diseases.
  10. Mechanisms by Which Exercise Delays Brain Aging Through Regulation of the Mitochondrial Quality Control System.
  11. Mitochondrial dysfunction in pulmonary fibrosis: from mechanisms to therapeutic opportunities.
  12. The Role of PINK1/Parkin-Mediated Mitophagy in Cerebral Ischemia-Reperfusion Injury: A Review of Recent Advances.
  13. PARS2 deficiency impairs mitochondrial homeostasis and activates ferroptotic to drive developmental and epileptic encephalopathy.
  14. UBC/UBA52 silencing restores PINK1-Parkin-mediated mitochondrial autophagy in allergic rhinitis.
  15. CLPX acquires an iron-sulfur cluster to sustain mitochondrial proteostasis in cancer cells.
  16. Excessive mitochondrial fission induces postoperative delirium in mice undergoing high-altitude deacclimatization by exacerbating neuroinflammation and synaptic injury.
  17. STING1 senses mitochondrial damage to promote mitophagy.
  18. CDK1 alleviates intrauterine adhesion progression by enhancing glycolysis and mitophagy in endometrial stem cells.
  19. MoCox6 is a potential fungicide target regulating mitophagy in magnaporthe oryzae.
  20. The Legionella effector RidL binds the large fission GTPase Drp1 to promote mitochondrial fragmentation.
  21. Melatonin alleviates mitochondrial damage by regulating SIRT3‑mediated mitochondrial dynamics in granulosa cells under PCOS‑like conditions.
  22. STING-OPTN signaling confers cytoprotection through TBK1-dependent mitophagy.
  23. Linagliptin and/or α-pinene attenuate cisplatin nephrotoxicity in rats via modulating phosphatase and tensin homolog-induced kinase 1/Parkin/microtubule-associated proteins 1A/1B light chain 3II/SQSTM1/sequestosome-1-assisted mitophagy.
  24. RANBP3 promotes mitophagy through the CCAR2/SIRT1 pathway to alleviate pyroptosis in macrophages in TBTB.
  25. Terazosin Attenuates Neuronal Pyroptosis by Regulating the Mitochondrial ROS/NLRP3 Inflammasome Axis Through Mitophagy in Cerebral Ischemia-Reperfusion Injury.
  26. Mitochondrial dynamics in prostatic cells during seasonal hyperplasia and atrophy in wild ground squirrels (Spermophilus dauricus).
  27. Molecular Hydrogen as a Regulator of Mitochondrial Quality Control and Metabolic Reprogramming.
  28. DRP1 and MID49 co-diffusion scans mitochondria for fission.
  29. Pre-Activation of Mitophagy Protects Against Hyperbaric Oxygen-Induced Central Nervous System Oxygen Toxicity.
  30. HSPA1-regulated mitophagy-necroptosis crosstalk determines the fate of brain microvascular endothelial cells after cerebral ischemia.
  31. The Regulatory Role and Mechanism of Myoferlin in Mitophagy During Papillary Thyroid Carcinogenesis.
  32. Retrograde mitochondrial transport is required for mitochondrial biogenesis in zebrafish neurons.
  33. Mycobacterial HBHA drives mitochondrial damage-mediated apoptosis via inhibiting mitophagy in macrophages.
  34. Canagliflozin attenuates cognitive deficits in the streptozotocin-induced mouse model of sporadic Alzheimer's disease via modulating PINK1/Parkin signaling pathway and miR-34a expression.
  35. NOP2-mediated m5C methylation impairs mitophagy and aggravates acute lung injury by targeting PINK1.
  36. Ajugol attenuates acute gouty arthritis by enhancing mitophagy to suppress chondrocyte pyroptosis.
  37. PM2.5 promotes the phenotypic transition of vascular smooth muscle cells in atherosclerosis by activating pro-ferroptotic signaling via DRP1/PINK1/Parkin-dependent mitophagy.
  38. TRMT10C promotes mitochondrial fission through transferrin receptor m1A methylation modification and aggravates the progression of atrial fibrillation.
  39. Blueberry anthocyanin extract inhibits platelet activation and FUNDC1-mediated mitophagy in Type 2 diabetes mellitus via AMPK pathway.
  40. Cis-3-hexen-1-ol suppresses bladder cancer progression by inducing mitophagy via the PCK2/AMPK/mTOR signaling pathway.
  41. Senescent BMSC-Derived Thbs1 Drives Inflammaging and Impairs Bone Regeneration by Suppressing PINK1/Parkin-Mediated Mitophagy in Macrophages.
  42. Tissue Effects of the Mitochondrial Division Inhibitor Mdivi-1 on the Substantia Nigra in a Laboratory Model of Dopaminergic System Damage.
  43. Drp1-driven fragmentation of scleral mitochondria promotes myopia development.
  44. Correction: KAP1-associated transcriptional inhibitory complex regulates C2C12 myoblasts differentiation and mitochondrial biogenesis via miR-133a repression.
  45. Olfactory Mucosa MSCs-Derived Exosomal RPL6 Attenuates Seizure-Induced Neuronal Damage via FGF2-Mediated Oxidative Stress and Mitophagy.
  46. The Role of Mitochondria in Polycystic Kidney Disease.
  47. Generation and characterization of the hiPSC line CSSi023-A (16154) from a patient with ADOA caused by an OPA1 variant.
  48. Hydroxysafflor Yellow A Regulates SIRT1-FOXO3-BNIP3 Signaling Pathway to Promote Mitophagy: A Novel Therapeutic Strategy for Myocardial Ischemia-Reperfusion Injury.
  49. Engineered Tan-CDs@AS-IV Nanosystem Orchestrates Mitochondrial Biogenesis and Intercellular Transfer to Restore Endothelial Function via PGC-1α and Cx43 Signaling Pathways.
  50. Elevated maternal non-esterified fatty acid concentrations during late gestation are associated with altered skeletal muscle development and mitochondrial dynamics related-markers in calves.
  51. Differential Activation of Pro-Survival Pathways by NIX/BNIP3L: An Expression-Level-Dependent Mechanism Governing PC12 Cell Fate During H2O2-Induced Oxidative Stress.
  52. E2F4 Mediates Mitophagy to Inhibit Ferroptosis in Esophageal Cancer Cells by Activating GPR176.
  53. A DPEP1-Binding and mitochondria-targeted nanocomposite relieves acute respiratory distress syndrome by inhibiting Drp1-mediated mitochondria fission.
  54. ClpP Ensures Mitochondrial Integrity and Spermatocyte Meiotic Progression in Mice.
  55. Glutamyl-tRNA synthetase 2 regulates mitochondrial biogenesis and reactive oxygen species homeostasis mediatingenzalutamide resistance by targeting striatin 4 in prostate cancer cells.
  56. Sex Differences in Mitochondrial Function: Endocrine Regulation, Immunometabolic Signaling, and Implications for Health and Disease.
  57. Electron transport chain complex I and mitochondrial fusion regulate ROS for differentiation in Drosophila neural stem cells.
  58. Stage-dependent DNA damage and mitochondrial dysfunction under simulated microgravity constrain oocyte maturation and are mitigated by melatonin.
  59. Selenium nanoparticle-loaded microneedle patches promote diabetic oral ulcer healing by regulating the inflammatory microenvironment through upregulation of SELENBP1-mediated mitophagy.
  60. Metformin activates AMPK-TFEB signaling to restore lysosomal and mitochondrial homeostasis and suppress EMT in oxidative stress-injured retinal pigment epithelium.
  61. San Wei Tan Xiang (SWTX) ameliorates depressive-like behaviors by modulating 6-phosphogluconate dehydrogenase (6PGD) activity in mice.
  62. ac4C modification of PDK4 by NAT10 promotes pulmonary fibrosis by reprogramming mitochondrial dynamics in fibroblasts.
  63. Dental Pulp Stem Cell-Derived Intracellular Vesicles Inhibit OSCC by Delivering PTEN to Suppress PI3K/AKT/mTOR Signalling Pathway.
  64. DRP1/p53 interaction mediated mitochondrial regulation of TFRC-SLC39A14 drives mechanical overload-induced temporomandibular joint osteoarthritis via ferroptosis.
  65. A mitochondria-driven quality control mechanism for peroxisomal membrane proteins.
  66. Chitosan-Functionalized Liposome-Mediated Fundus Delivery of Epigallocatechin-3-Gallate for Diabetic Retinopathy Therapy.
  67. Fasting requires Peroxiredoxin 2 and Peroxiredoxin 6 to coordinate redox dependent mitochondrial and lipid remodelling in Caenorhabditis elegans.
  68. Divergent Role of ULK1 to Balance Mitochondrial Homeostasis and Bioenergetics in Ovarian Cancer Spheroids.
  69. eIF3 Orchestrates a Biphasic Stress Response Linking Translational Control to Mitochondrial Integrity in Skeletal Muscle.
  70. Mitochondrial homeostasis in bone aging: Unraveling dysfunctional pathways and developing precision therapies.
  71. Corrigendum to "Mitochondrial ribosomal protein L12 potentiates hepatocellular carcinoma by regulating mitochondrial biogenesis and metabolic reprogramming" [Metabolism. 2024 Mar; 152: 155761. doi:10.1016/j.metabol.2023.155761].
  72. Particulate matter induced cell death: Current understanding of molecular drivers that lead to lung damage.
  73. Autophagy in cancer cachexia: From mechanisms to therapeutic opportunities.
  1. Cells. 2026 Jun 02. pii: 1026. [Epub ahead of print]15(11):
    Mitochondrial Dynamics in Cancer Progression and Therapy Resistance: Emerging Roles in Metabolic Reprogramming, Biomarker Discovery, and Precision Medicine.
    Vasudevarao Penugurti, Rajni Kant, Che-Chia Hsu.
      Mitochondria play essential roles in cellular metabolism and signaling, regulating biosynthetic pathways, calcium homeostasis, redox balance, and cell fate beyond ATP production. Their continual remodeling through fusion, fission, and mitophagy maintains mitochondrial quality control and adapts organelle function to cellular demands. Here, we review how mitochondrial dynamics, fusion, fission, and mitophagy modulate metabolic reprogramming and signaling to drive cancer progression and therapy resistance. Emerging evidence indicates that in cancer, mitochondrial fusion enhances respiratory efficiency and oxidative phosphorylation, whereas fission promotes glycolytic adaptation, rapid biomass accumulation, and stress tolerance. Mitophagy further refines metabolic fitness by eliminating damaged mitochondria and sustaining redox homeostasis. Together, these processes underscore that dysregulation of mitochondrial dynamics is a hallmark of cancer and a key driver of metabolic reprogramming and therapeutic resistance. In this review, we summarize how mitochondrial fusion, fission, and mitophagy govern metabolic circuitry in cancer development and therapy resistance. We highlight their functional impact on tumor progression and discuss emerging therapeutic strategies targeting mitochondrial dynamics and associated machinery. Understanding this dynamic metabolic crosstalk may reveal new vulnerabilities and guide the development of mitochondria-targeted cancer therapies.
    Keywords:  TCA cycle; bioenergetics; cancer; cell death; cell survival; drug resistance; immune evasion; mitochondria-targeted therapy; mitochondrial DNA (mtDNA); mitochondrial dynamics; mitochondrial dysfunction; mitochondrial fission; mitochondrial fusion; mitochondrial metabolism; mitophagy; oxidative phosphorylation (OXPHOS); reactive oxygen species (ROS)
    DOI:  https://doi.org/10.3390/cells15111026
  2. Hum Mol Genet. 2026 Jun 12. pii: ddag051. [Epub ahead of print]35(12):
    Editor's Note: Protective effects of antidepressant citalopram against abnormal APP processing and amyloid beta-induced mitochondrial dynamics, biogenesis, mitophagy and synaptic toxicities in Alzheimer's disease.
      
    DOI:  https://doi.org/10.1093/hmg/ddag051
  3. Mitochondrion. 2026 Jun 11. pii: S1567-7249(26)00074-7. [Epub ahead of print] 102184
    Restoration of mitochondrial dynamics and synaptic function by mitophagy enhancers in a tauopathy cell model.
    Sudhir Kshirsagar, Arubala P Reddy, P Hemachandra Reddy.
       OBJECTIVES: To evaluate whether mitophagy enhancers-including urolithin A, actinonin, tomatidine, and nicotinamide riboside-can counteract mitochondrial dysfunction and synaptic damage induced by phosphorylated Tau in Alzheimer's disease.
    METHODS: We Used immortalized mouse hippocampal primary HT22 neurons expressing mutant Tau (mTau-HT22). We treated cells with mitophagy enhancers and measured gene and protein levels of mitochondrial dynamics, biogenesis, mitophagy, synaptic markers, assessed cell viability, mitochondrial respiration, and examined mitochondrial morphology via transmission electron microscopy.
    RESULTS: Compared to controls, mTau-HT22 cells exhibited increased mitochondrial fission and reduced fusion, diminished mitochondrial biogenesis, impaired mitophagy and synaptic gene expression, reduced cell survival, lower respiration, and fragmented mitochondria. Treatment with all mitophagy-enhancing compounds improved mitochondrial dynamics-, biogenesis-, and mitophagy-related marker expression together with mitochondrial functional outcomes, with urolithin A showing the strongest effects. Notably, a combined treatment of urolithin A with EGCG further enhanced respiratory function beyond single-agent treatments.
    CONCLUSIONS: Mitophagy enhancers, particularly urolithin A alone or in combination with EGCG, restore mitochondrial and synaptic health in Tau-induced toxicity models. These findings position mitophagy enhancement as a potential therapeutic approach requiring further validation in Alzheimer's disease.
    Keywords:  Alzheimer's disease; Mitochondrial dynamics; Mitochondrial fragmentation; Mitophagy enhancers; Urolithin A
    DOI:  https://doi.org/10.1016/j.mito.2026.102184
  4. CNS Neurol Disord Drug Targets. 2026 Jun 08.
    Understanding the OMA1-DELE1-HRI Axis and PINK1-parkin-mediated Mitophagy in Parkinson's Disease.
    Shalini Singh, Anisha Sharma, Ravi Kumar Rajan, Manodeep Chakraborty, Ananya Bhattacharjee.
       INTRODUCTION: Mitochondrial dysfunction plays a crucial role in the pathogenesis of Parkinson's disease (PD). PINK1-Parkin-mediated mitophagy is a quality-control system for mitochondria that protects neurons by getting rid of damaged mitochondria. The OMA1-DELE1-HRI axis has recently been recognized as a vital regulatory checkpoint that limits excessive mitophagy and prevents metabolic failure during mitochondrial stress. The aim of this review is to analyze the mechanistic interplay between the PINK1-Parkin pathway and the OMA1-DELE1-HRI signaling axis. This study aims to synthesize current research on the influence of the stress-response pathway on the initiation of mitophagy, maintenance of mitochondrial homeostasis, and neuronal survival in PD.
    METHODS: A comprehensive literature review was conducted of molecular, genetic, and pharmacological studies on OMA1, DELE1, and HRI. A thorough analysis of data from kinome-wide screening assays, genetic knockdown experiments, multi-omics profiling, and structural biology studies was performed to elucidate the regulatory interactions between HRI and PINK1 under mitochondrial stress conditions.
    RESULT: The OMA1-DELE1-HRI pathway stops PINK1 from being stable by controlling how mitochondria make proteins and how they respond to stress. This inhibition serves as a metabolic safeguard that regulates mitophagy levels, preventing harmful overactivation. HRI seems to change PINK1-dependent mitophagy while having little effect on other pathways that clear things at the same time. This suggests that HRI has different substrate preferences and signaling specificity.
    DISCUSSION: The OMA1-DELE1-HRI axis is an important negative regulator of mitophagy that PINK1 and Parkin mediate. It stops too much mitochondrial clearance and metabolic failure in Parkinson's disease. This mechanism preserves bioenergetic homeostasis and promotes neuronal survival, suggesting that HRI is a promising therapeutic target. Inhibitors like ISRIB or heme mimetics may selectively restore mitophagy, thereby enhancing neuroprotection and enabling precision therapies guided by biomarkers such as phosphorylated eIF2.
    CONCLUSION: The OMA1-DELE1-HRI axis is a distinctive regulatory mechanism for mitochondrial quality control, significantly impacting neuroprotection in Parkinson's disease. Understanding its dual role in controlling mitophagy and maintaining bioenergetic homeostasis opens new possibilities for targeted drug development. Subsequent research should focus on structural and pharmacological modifications of HRI to enhance mitophagy while preventing mitochondrial depletion.
    Keywords:  DELE1; HRI (heme-regulated inhibitor kinase); ISR (integrated stress response); OMA1; PINK1; Parkin; Parkinson’s Disease (PD).; mitophagy
    DOI:  https://doi.org/10.2174/0118715273469080260515103009
  5. Redox Biol. 2026 Jun 05. pii: S2213-2317(26)00245-4. [Epub ahead of print]95 104247
    Mitophagy-mediated immune evasion: Shared strategies of pathogens.
    Jun Li, Weijian Li, Dan Wang, Yulan Liu.
      Mitophagy selectively eliminates dysfunctional mitochondria, playing a pivotal role in mitochondrial quality control and cellular homeostasis. Emerging evidence reveals that certain pathogens exploit mitophagy to evade host immune defenses. Here, we provide novel insights into the regulatory mechanisms of mitophagy by integrating it with mitochondrial dynamics, and systematically review the mechanisms by which intracellular bacteria, viruses, and parasites utilize mitophagy to subvert host innate immunity. Notably, some pathogens dynamically regulate mitophagy at different infection stages to facilitate their survival, and the mitophagy show a positive correlation with mitochondrial fission/fragmentation. This review further summarizes four therapeutic strategies to counteract pathogen-induced immune evasion via mitophagy: 1) pharmacological modulation of mitophagy pathways; 2) mitochondria-targeted nanomaterials delivery systems; 3) mitochondria transplantation; 4) nanoengineered mitochondria. Moreover, two core mechanistic questions that remain to be addressed: (1) The mechanisms of time-dependent mitophagy-mediated immune evasion during infection, and (2) the mechanistic connection between mitochondrial dynamics and mitophagy. Future studies could employ label-free holographic tomography microscopy combined with artificial intelligence to visualize and quantify pathogen-induced subcellular alterations, enhancing our understanding of how mitophagy is manipulated, particularly through stage-specific regulation. These insights may open new avenues for treating infections resistant to conventional therapies.
    Keywords:  Immune evasion; Mitophagy; Pathogen infection; Therapy
    DOI:  https://doi.org/10.1016/j.redox.2026.104247
  6. Curr Neuropharmacol. 2026 Jun 08.
    Rejuvenating Inter-organellar Communication Via Mitophagy in Ageing and Neurodegeneration.
    Katerina Kitopoulou, Antonis Roussos, Ioannis P Trougakos, Vilhelm A Bohr, Konstantinos Palikaras.
      Ageing and neurodegeneration are characterized by the progressive breakdown of organellar communication between mitochondria, the endoplasmic reticulum (ER), and lysosomes. Recent findings underline mitophagy as a central modulator of this interconnected network. Impaired mitophagy induces ER fragmentation, lysosomal dysfunction, imbalanced mitochondrial dynamics, and deregulation of calcium homeostasis, suggesting that mitochondrial turnover is essential for the maintenance of global organellar architecture. Conversely, restoring mitophagy re-establishes structural integrity and functional coordination across subcellular compartments. Notably, Urolithin A (UA) rejuvenates inter-organelle crosstalk through a defined calcium-dependent mechanism. UA promotes ER-derived calcium release via ITR-1/ITPR/InsP3R, EMC-3/EMC3, and TMCO-1/TMCO1, and enhances calcium uptake into mitochondria through MCU-1/MCU. This calcium flux activates DRP-1/DRP1-mediated mitochondrial fission, facilitating mi-tophagy initiation. In parallel, calcium-dependent activation of the UNC-43/CaMKII-SKN-1/Nrf2 axis stimulates mitochondrial biogenesis and metabolic adaptation. Furthermore, UA increases ER-mitochondrial contact sites (MAMs) and restores lysosomal activity, thereby re-establishing functional inter-organellar communication in nematodes and mammalian cells. These findings establish mitophagy as a central node of cellular and tissue homeostasis, acting through the stabilization of the organellar communication network to promote healthspan and lifespan while highlighting the need for future studies to validate these mechanisms across human tissues and disease-relevant cellular contexts.
    Keywords:  Ageing; ER; MAMs; lysosome; mitochondria; mitophagy; neurodegeneration; urolithin A.
    DOI:  https://doi.org/10.2174/011570159X473929260605103158
  7. Int J Mol Sci. 2026 Jun 04. pii: 5085. [Epub ahead of print]27(11):
    Drp1-Dependent Mitochondrial Fission in the Hippocampus Drives Chronic Stress-Induced Depressive-like Behaviors in Mice.
    Qiao Peng, Lijun Ai, Chang Chen, Jiayan Zhang, Qingya Sun, Tiantian Gao, Ming Zhao, Jiarui Zhang.
      The mechanism of action of mice in chronic stress-induced depressive like behavior remains unclear. In this study, we found that chronic social defeat stress (CSDS) upregulates Drp1 expression in mouse hippocampal tissue, leading to excessive mitochondrial fission, which further impairs bioenergetics, induces oxidative stress, disrupts mitochondrial autophagy, and reduces excitatory synaptic transmission. Stereotactic injection of Drp1 inhibitor Mdivi-1 into the hippocampus reversed the aforementioned neuronal defects and alleviated CSDS-induced depressive-like behaviors, including social avoidance, anhedonia, and behavioral despair. Our findings indicate that elevated Drp1 triggers mitochondrial fission, representing a key pathophysiological mechanism underlying stress-induced depression. Therefore, targeting the regulation of mitochondrial dynamics may represent a viable therapeutic strategy.
    Keywords:  Drp1; Mdivi-1; chronic social defeat stress; depression-like behaviors; mitochondrial fission
    DOI:  https://doi.org/10.3390/ijms27115085
  8. Immunol Lett. 2026 Jun 06. pii: S0165-2478(26)00071-4. [Epub ahead of print] 107198
    Aerobic Exercise attenuates airway inflammation in allergic asthma by regulating M2 macrophage polarization via drp1-mediated mitophagy.
    Linfang Ding, Nannan Wu, Jie Lin.
       BACKGROUND: Allergic asthma is a chronic respiratory condition characterized by persistent airway inflammation and dysregulated macrophage activation. Although aerobic exercise is known to exert anti-inflammatory effects, its influence on macrophage polarization and mitochondrial dynamics in asthma remains poorly defined METHODS: : Using a rat model of ovalbumen (OVA)-induced allergic asthma, we investigated the impact of aerobic exercise on macrophage polarization and mitophagy regulation. Animals were divided into four experimental groups: control, OVA-induced asthma, OVA with aerobic exercise intervention, and OVA with Drp1 inhibitor (Mdivi-1) treatment. We evaluated airway inflammation, macrophage phenotypes, mitochondrial function, and key mitophagy-related proteins RESULTS: : Aerobic exercise significantly attenuated allergic airway inflammation, as evidenced by reduced inflammatory cell infiltration, decreased mucus production, and a shift in macrophage polarization from the M2 towards the M1 phenotype. At the molecular level, exercise suppressed mitophagy activation, reduced Drp1 phosphorylation, and downregulated the expression of mitophagy-related proteins. These effects were mirrored by Drp1 inhibition with Mdivi-1, confirming the crucial role of Drp1-mediated mitophagy in exercise-induced modulation of macrophage polarization CONCLUSION: : Our findings indicate that aerobic exercise alleviates allergic airway inflammation by inhibiting Drp1-dependent mitophagy and rebalancing macrophage polarization. These results provide novel mechanistic insights into the therapeutic potential of exercise in asthma and highlight mitophagy as a promising target for inflammatory respiratory diseases.
    Keywords:  Drp1; aerobic exercise; airway inflammation; allergic asthma; macrophage polarization; mitophagy
    DOI:  https://doi.org/10.1016/j.imlet.2026.107198
  9. Biochem J. 2026 Jul 08. 483(7): 1193-1220
    Mitophagy: an emerging therapeutic target in mitochondrial diseases.
    Brígida R Pinho, Michael R Duchen, Jorge M A Oliveira.
      Mitophagy is a crucial autophagic process that degrades dysfunctional or unnecessary mitochondria, thereby maintaining cellular homeostasis. Mitophagy occurs through both basal mitophagy and stress-induced pathways, highly regulated by a complex network of proteins. In mitochondrial diseases, which are genetic disorders lacking effective treatments, mitophagy is often defective or insufficient. This permits the accumulation of dysfunctional mitochondria that negatively impact cell homeostasis. While some experimental therapeutic strategies have enhanced mitophagy in mitochondrial disorders by targeting broadly acting signaling pathways, such as mTORC1 inhibition or AMPK activation, pharmacological approaches directly targeting the mitophagy process remain underexplored in these disorders. Given the growing understanding of mitophagy regulation, targeting key proteins involved in this process may offer novel therapeutic opportunities for mitochondrial diseases. Here, we explore the molecular mechanisms of mitophagy, examining distinct pathways and regulatory checkpoints that might present potential therapeutic targets. Additionally, we review recent studies evaluating the effects of mitophagy modulation in mitochondrial diseases.
    Keywords:  autophagy; mitochondria; pathway; pharmacology; receptors; ubiquitins
    DOI:  https://doi.org/10.1042/BCJ20260161
  10. Biology (Basel). 2026 May 29. pii: 854. [Epub ahead of print]15(11):
    Mechanisms by Which Exercise Delays Brain Aging Through Regulation of the Mitochondrial Quality Control System.
    Xinyi Zhu, Lei Shi, Yahong Dong, Yingjie Sun, Qiguan Jin.
      Brain aging is a complex biological process characterised by progressive neuronal and synaptic decline, in which disruption of mitochondrial quality control plays a central role. This system encompasses multiple synergistic components, including mitochondrial biogenesis, dynamic equilibrium, autophagic clearance, and energy metabolism. Aging induces dysfunction across these processes, precipitating mitochondrial fragmentation, functional decline, and energy crises, ultimately driving cognitive deterioration. Exercise is a promising non-pharmacological intervention for preserving brain health during aging, and its benefits may be mediated, at least in part, through modulation of mitochondrial quality control. Specifically, exercise has been shown to activate key signaling pathways such as AMPK/SIRT1/PGC-1α, thereby promoting mitochondrial biogenesis and metabolic adaptation. It may also regulate mitochondrial dynamics and mitophagy via pathways including cAMP/PKA/Drp1 and AMPK/mTOR. In addition, emerging evidence indicates that exercise may influence brain mitochondrial function through activity-dependent regulation of mitochondrial gene expression and systemic signaling factors. Furthermore, this review discusses potential differences between exercise modalities and highlights future directions for personalised intervention strategies, providing a theoretical basis for the application of exercise in delaying brain aging and preventing neurodegenerative diseases.
    Keywords:  brain aging; exercise intervention; mitochondrial autophagy; mitochondrial dysfunction; mitochondrial quality control; neuromuscular axis
    DOI:  https://doi.org/10.3390/biology15110854
  11. Biochem Pharmacol. 2026 Jun 12. pii: S0006-2952(26)00501-0. [Epub ahead of print] 118164
    Mitochondrial dysfunction in pulmonary fibrosis: from mechanisms to therapeutic opportunities.
    Xingyu Jin, Le Sang, Jiayi Zhu, Zuoqaun Zhong, Jian Sun.
      Pulmonary fibrosis (PF) is a progressive and often fatal interstitial lung disease characterized by excessive extracellular matrix deposition and irreversible remodeling of lung architecture. Although current antifibrotic therapies can slow disease progression, they remain unable to halt or reverse fibrosis, underscoring the need for a deeper mechanistic understanding and new therapeutic strategies. Mitochondria are increasingly recognized as central regulators of PF pathogenesis, extending beyond their canonical role in energy production. Emerging evidence indicates that mitochondrial dysfunction contributes to epithelial injury, fibroblast activation, immune dysregulation, and the persistence of a profibrotic microenvironment. Alterations in mitochondrial biogenesis, dynamics, mitophagy, redox homeostasis, and oxidative phosphorylation constitute interconnected processes that converge on mitochondrial quality control (MQC) failure. These defects may establish self-amplifying pathogenic circuits that sustain fibrotic progression. Notably, mitochondrial dysfunction in PF shows clear cell type-dependent features, supporting the concept that mitochondrial dysregulation operates within a multicellular network rather than as an isolated cellular defect. Therapeutically, targeting mitochondrial pathways-including enhancement of biogenesis, correction of dynamic imbalance, restoration of mitophagy, and redox modulation-has demonstrated antifibrotic potential in experimental models. However, key questions remain regarding causality, stage-specific roles, and the long-term safety of mitochondrial modulation. This review summarizes recent advances in understanding mitochondrial dysfunction in PF, highlights its integration across metabolic and signaling networks, and discusses emerging mitochondria-targeted interventions. A systems-level perspective on mitochondrial quality control may help refine future research directions and support the development of more precise antifibrotic therapies.
    Keywords:  Mitochondrial dynamics; Mitochondrial dysfunction; Mitophagy; Oxidative stress; Pulmonary fibrosis
    DOI:  https://doi.org/10.1016/j.bcp.2026.118164
  12. Mol Neurobiol. 2026 Jun 11. pii: 687. [Epub ahead of print]63(1):
    The Role of PINK1/Parkin-Mediated Mitophagy in Cerebral Ischemia-Reperfusion Injury: A Review of Recent Advances.
    Liping Xing, Annan Liu, Jianhui Li, Mingyuan Yao, Jing Song, Peihan Duan, Honglin Li.
      Mitophagy, the selective clearance of damaged mitochondria, is a critical mechanism for mitochondrial quality control in cerebral ischemia-reperfusion injury (CIRI). The PINK1/Parkin signaling pathway is the primary ubiquitin-dependent pathway mediating mitochondrial autophagy, and its functional status directly influences the pathological progression of CIRI. This review systematically examines the molecular activation mechanisms of PINK1/Parkin-mediated mitophagy in CIRI and analyzes its interactions with core pathological processes, including oxidative stress, calcium homeostasis disruption, ferroptosis, and neuroinflammation. Furthermore, we summarize the latest advances over the past 5 years in modern medical strategies, traditional Chinese medicine interventions, and gene and protein-targeted therapies directed at this pathway. By integrating existing evidence, this review is aimed at deepening our understanding of the molecular mechanisms underlying CIRI and providing a theoretical foundation for developing novel neuroprotective therapies that target this pathway.
    Keywords:  Cerebral ischemia-reperfusion injury; Mitophagy; PINK1/Parkin signaling pathway; Pathological mechanisms; Potential interventions
    DOI:  https://doi.org/10.1007/s12035-026-05997-4
  13. Free Radic Biol Med. 2026 Jun 07. pii: S0891-5849(26)00870-1. [Epub ahead of print]
    PARS2 deficiency impairs mitochondrial homeostasis and activates ferroptotic to drive developmental and epileptic encephalopathy.
    Ziheng Li, Zhao Xu, Genfu Zhang, Ang Ma, Zongpu Zhou, Jiong Qin, Zhixian Yang.
      PARS2 , encodes a mitochondrial aminoacyl-tRNA synthetase associated with developmental and epileptic encephalopathy (DEE), a severe neurological disorder characterized by refractory epilepsy and intellectual disability. While genetic associations between PARS2 and DEE have been established, the underlying molecular mechanisms remain poorly understood. This study integrates genetic analyses of clinical cases of infantile epileptic spasms syndrome (IESS) with functional assessments in PARS2-deficient animal models and cell models to elucidate these mechanisms. Our findings indicate that PARS2 deficiency disrupts mitochondrial integrity and impairs oxidative phosphorylation, resulting in elevated intracellular calcium levels. This calcium overload activates CaMKK2-AMPK-Drp1 signaling, promoting excessive mitochondrial fission and PINK1-Parkin-mediated mitophagy, ultimately leading to degradation of GPX4 and subsequent ferroptosis. Notably, pharmacological inhibition of Drp1 using Mdivi-1 successfully rescued mitochondrial fragmentation and mitigated ferroptosis. These results unveil a novel calcium-mitophagy-ferroptosis pathway as a crucial mechanism in PARS2-related DEE and propose a potential therapeutic strategy for DEE.
    Keywords:  ( Developmental and epileptic encephalopathy; PARS2; ferroptosis); mitochondrial dysfunction; mitophagy
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.06.019
  14. PLoS One. 2026 ;21(6): e0350815
    UBC/UBA52 silencing restores PINK1-Parkin-mediated mitochondrial autophagy in allergic rhinitis.
    Qinhui Lu, Yanli Yang, Biao Ruan.
      Allergic rhinitis (AR) is a common chronic inflammatory disease of the upper respiratory tract, and recent studies suggest that mitochondrial dysfunction may play a role in its pathogenesis. This study aimed to identify key genes related to AR and mitochondrial autophagy through bioinformatics analysis and to verify their functional roles in vitro. Transcriptomic data from the GEO database were analyzed, and ubiquitin C (UBC) and ubiquitin A-52 residue ribosomal protein fusion product 1 (UBA52) were identified as potential genes associated with AR and mitophagy. In vitro, IL-13-stimulated human nasal epithelial cells (HNEpCs) were used to establish an AR model. RT-qPCR and Western blotting showed that UBC and UBA52 were significantly upregulated, while mitophagy-related genes PINK1 and Parkin were downregulated. Flow cytometry and TMRE staining demonstrated increased ROS levels and reduced mitochondrial membrane potential (MMP), indicating mitochondrial dysfunction. Co-immunoprecipitation confirmed an interaction between UBC and UBA52. Silencing UBC downregulated UBA52 expression, restored PINK1 and Parkin levels, decreased ROS accumulation, and improved MMP, suggesting potential reactivation of the PINK1-Parkin-mediated mitophagy pathway. These findings suggest that UBC and UBA52 may be involved in the regulation of mitophagy and contribute to mitochondrial dysfunction in AR. Targeting the UBC-UBA52 axis may provide a novel therapeutic strategy for restoring mitochondrial homeostasis in allergic inflammation.
    DOI:  https://doi.org/10.1371/journal.pone.0350815
  15. Nat Commun. 2026 Jun 09. pii: 5072. [Epub ahead of print]17(1):
    CLPX acquires an iron-sulfur cluster to sustain mitochondrial proteostasis in cancer cells.
    Chengquan Huang, Yixue Zhang, Han Gao, Yuxin Song, Shunchang Hu, Chaoyue Sun, Shiwen Duan, Dongxiao Ma, Xiumei Jiang, Gang Liu.
      Mitochondrial proteostasis-maintaining mechanisms are crucial for protecting cells from the toxicity of misfolded protein accumulation. Although excessive stress is known to inactivate these mechanisms and thereby induce mitophagy in cancer cells, the detailed molecular mechanisms coordinating these mitochondrial quality control processes remain unclear. Herein, we identify CLPX, a mitochondrial protease subunit, as an iron-sulfur protein, which requires a [4Fe-4S] cluster to bind with CLPP to exert proteolysis function. Iron chelation impairs the assembly of the [4Fe-4S] cluster onto CLPX, thereby disrupting mitochondrial proteostasis maintenance and inducing mitophagy. Furthermore, cysteine deprivation caused by excessive reactive oxygen species accumulation hinders iron-sulfur cluster biosynthesis, thereby undermining CLPX function and inducing mitophagy. Our research elucidates an iron-sulfur cluster-dependent mechanism sustaining mitochondrial proteostasis.
    DOI:  https://doi.org/10.1038/s41467-026-74080-2
  16. Brain Res Bull. 2026 Jun 10. pii: S0361-9230(26)00284-4. [Epub ahead of print]243 111997
    Excessive mitochondrial fission induces postoperative delirium in mice undergoing high-altitude deacclimatization by exacerbating neuroinflammation and synaptic injury.
    Hui Ma, Yu Zhao, Minghui Yin, Xin Ran, Yu Du, Shuzhi Zhou.
      Postoperative delirium (POD) is a common complication after surgery. High-altitude deacclimatization (HADA), a physiological adaptation process, is associated with pathophysiological changes that may increase POD susceptibility. However, the underlying molecular mechanisms remain poorly understood. This study investigated the role of mitochondrial dynamics in POD pathogenesis in mice undergoing HADA and explored the neuroprotective effects of the mitochondrial fission inhibitor, Mdivi-1. C57BL/6 mice were subjected to simulated high-altitude exposure for 4 weeks, followed by anesthesia and surgery to induce a POD model. Mice undergoing HADA and surgery exhibited significant postoperative delirium-like behaviors. These behavioral deficits were accompanied by excessive mitochondrial fission, exacerbated neuroinflammation (evidenced by microglial and astrocyte activation), and synaptic injury within the hippocampus. Notably, pretreatment with Mdivi-1 effectively attenuated these pathological changes. It reduced mitochondrial fission, suppressed neuroinflammation, restored key synaptic proteins, and consequently, alleviated the postoperative delirium-like behaviors. In conclusion, this study suggests that excessive mitochondrial fission contributes to HADA-associated POD, potentially via exacerbating neuroinflammation and synaptic damage. Targeting mitochondrial fission presents a potential therapeutic strategy to prevent this serious postoperative complication.
    Keywords:  High-altitude deacclimatization; Mitochondrial dynamics; Neuroinflammation; Postoperative delirium; Synapse
    DOI:  https://doi.org/10.1016/j.brainresbull.2026.111997
  17. Autophagy. 2026 Jun 13.
    STING1 senses mitochondrial damage to promote mitophagy.
    Ze-Bo Huang, Jin-Yi Lin, Ling-Jun Cheng, Hayden Weng Siong Tan, Han-Ming Shen, Guang Lu.
      The cGAS-STING1 pathway is essential for innate immunity, while its functions beyond immune activation have emerged as a key research topic. Recent studies have revealed the non-canonical roles of this pathway in autophagy. However, whether it participates in organelle quality control through selective autophagy processes such as mitophagy remains largely unexplored. In our study, we identify the cGAS-STING1 pathway as an essential upstream regulator of PINK1-PRKN-dependent mitophagy. We demonstrate that upon mitochondrial damage, STING1 is recruited to damaged mitochondria in a process requiring PINK1- and VCP/p97-mediated degradation of outer mitochondrial membrane proteins. STING1 at damaged mitochondria then activates TBK1, which phosphorylates the mitophagy receptor OPTN at Ser177, enhancing its recruitment to damaged mitochondria and driving efficient mitophagy. Disruption of the STING1-TBK1-OPTN axis impairs mitophagy and shifts the cellular response from pro-survival mitophagy to apoptosis. Our findings therefore uncover a non-canonical, pro-survival function of the cGAS-STING1 pathway in mitophagy, extending its role beyond innate immunity to the regulation of selective autophagy and cell fate decisions. Abbreviations: BafA1: bafilomycin A1; cGAS: cyclic GMP‑AMP synthase; ER: endoplasmic reticulum; GABARAP: GABA type A receptor-associated protein; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MQC: mitochondrial quality control; mtDNA: mitochondrial DNA; NAC: N-Acetylcysteine; Nec-1: Necrostatin-1; OMM: outer mitochondrial membrane; OPTN: optineurin; PINK1: PTEN induced kinase 1; PRKN: parkin RBR E3 ubiquitin protein ligase; RIPK1: receptor interacting serine/threonine kinase 1; ROS: reactive oxygen species; STING1: stimulator of interferon response cGAMP interactor 1; TBK1: TANK binding kinase 1; TFEB: transcription factor EB; VCP/p97: valosin containing protein; Z-VAD-FMK: benzyloxycarbony (Cbz)-l-ValAla-Asp (OMe)-fluoromethylketone.
    Keywords:  Cell death; OPTN; PINK1-PRKN-dependent mitophagy; cGAS-STING1 pathway; innate immunity; mitochondrial quality control
    DOI:  https://doi.org/10.1080/15548627.2026.2689463
  18. Cell Signal. 2026 Jun 06. pii: S0898-6568(26)00314-1. [Epub ahead of print]146 112659
    CDK1 alleviates intrauterine adhesion progression by enhancing glycolysis and mitophagy in endometrial stem cells.
    Xicui Long, Lijuan Yang, Jianghong Zhou, Sujie Wang, Mingjie Wu, Xuesong Han.
       BACKGROUND AND OBJECTIVE: Intrauterine adhesion (IUA) often leading to recurrent miscarriage or infertility. The glycolytic activity and mitophagy level of endometrial stem cells (EnSCs) are crucial for endometrial regeneration. Although cyclin-dependent kinase 1 (CDK1) regulates both processes, its role in IUA is unknown. This study aimed to elucidate how CDK1 modulates EnSCs glycolysis and mitophagy during IUA progression.
    METHODS: Experiments were performed using a lipopolysaccharide (LPS)-stimulated cellular injury model in vitro, as well as an IUA rat model in vivo. Uterine pathological damage and collagen deposition were assessed by HE and Masson staining. Mitochondrial membrane potential and autophagosome formation were examined using flow cytometry and transmission electron microscopy. Immunofluorescence, ELISA, Western blotting, CCK-8 assays, and various biochemical kits were used to detect relevant proteins, inflammatory cytokines, and glycolytic activity.
    RESULTS: A reduced number of EnSCs was observed in IUA tissues, accompanied by impaired glycolysis and defective mitophagy. LPS stimulation markedly decreased EnSCs viability and proliferation, suppressed the stemness-related genes Oct4, Nanog, and Sox2, upregulated pro-apoptotic proteins Bax and cleaved caspase-3 as well as the pro-inflammatory cytokines TNF-α, IL-6, and IL-1β, and downregulated the anti-apoptotic protein Bcl-2. CDK1 was lowly expressed in IUA, whereas CDK1 overexpression alleviated uterine injury, fibrosis, and inflammation in IUA rats, reduced stem cell loss, restored EnSCs proliferation and stemness, enhanced glycolysis and mitophagy, and inhibited apoptosis and inflammation. The beneficial effects of CDK1 overexpression were attenuated by the dynamin-related protein 1 (DRP1) inhibitor mitochondrial division inhibitor 1 (Mdivi-1) or the autophagy inhibitor 3-methyladenine (3-MA).
    CONCLUSION: CDK1 restores EnSCs function and alleviates IUA progression by promoting DRP1-mediated mitophagy and enhancing glycolysis.
    Keywords:  Cyclin-dependent kinase 1; Endometrial stem cells; Glycolysis; Intrauterine adhesion; Mitophagy
    DOI:  https://doi.org/10.1016/j.cellsig.2026.112659
  19. Autophagy. 2026 Jun 13.
    MoCox6 is a potential fungicide target regulating mitophagy in magnaporthe oryzae.
    Ming-Hua Wu, Xue-Ming Zhu, Daniel J Klionsky, Fu-Cheng Lin, Xiao-Hong Liu.
      Mitophagy is a key mitochondrial quality-control pathway required for stress adaptation, but how damaged mitochondria are recognized and cleared in Magnaporthe oryzae remains poorly understood. In our recent study, we found that upon outer mitochondrial membrane disruption, inner mitochondrial membrane (IMM) protein MoCox6 is rendered available for engagement with cytosolic MoAtg5 and MoAtg14 to drive mitophagy, whereas MoSirt5-mediated desuccinylation of MoCox6 at K144 weakens these interactions and thereby restrains mitophagic flux. Further analyses identified Asp95 at the MoSirt5-MoCox6 interface as a pivotal residue coupling mitochondrial metabolic control to mitophagy. A high-throughput virtual screening targeting an Asp95-centered pocket in MoCox6 identified Pan-RAS-IN-1, a small molecule that effectively suppresses rice blast incidence and exhibits broad-spectrum antifungal activity. Collectively, these findings identify MoCox6 as an IMM regulator of mitophagy whose succinylation state links mitochondrial metabolic cues to mitochondrial turnover, while highlighting mitochondrial quality control as a potential target for fungal disease management.
    Keywords:  Fungicide target; MoCox6; magnaporthe oryzae; mitophagy; succinylation
    DOI:  https://doi.org/10.1080/15548627.2026.2689458
  20. EMBO Rep. 2026 Jun 06.
    The Legionella effector RidL binds the large fission GTPase Drp1 to promote mitochondrial fragmentation.
    Ana Katic, Elizabeth Teresa Vittori, Stefanie Halter, Kevin Steiner, A Leoni Swart, Milad Radiom, Francisco Javier García-Rodríguez, Tobias Jäggi, Xiaodan Li, Jason A Mears, Carmen Buchrieser, Pedro Escoll, Vikram Govind Panse, Hubert Hilbi.
      Intracellular pathogens such as Legionella pneumophila secrete effector proteins that manipulate host cell processes to promote bacterial survival. One such effector, RidL, is known to inhibit retrograde trafficking by interacting with the retromer complex via its N-terminal domain. Here, we identify a second function of RidL mediated by its C-terminal domain, which directly binds to the mitochondrial fission GTPase dynamin-related protein 1 (Drp1) and related large GTPases. In vitro, RidL reduces Drp1 GTPase activity and disrupts its oligomerization. During infection, RidL localizes to mitochondria, enhances the accumulation of Drp1 and the outer membrane protein Tom20, and impairs mitochondrial dynamics and function. Moreover, in L. pneumophila-infected cells, RidL promotes phosphorylation of Drp1 at Ser616, leading to Drp1 activation and mitochondrial fragmentation. These findings establish RidL as a bifunctional effector that targets both the retromer complex and Drp1 through distinct domains. By interfering with host mitochondrial dynamics, RidL enables L. pneumophila to remodel host organelles and optimize conditions for intracellular replication.
    DOI:  https://doi.org/10.1038/s44319-026-00823-3
  21. Mol Med Rep. 2026 Aug;pii: 227. [Epub ahead of print]34(2):
    Melatonin alleviates mitochondrial damage by regulating SIRT3‑mediated mitochondrial dynamics in granulosa cells under PCOS‑like conditions.
    Congcong Xie, Zehao Liu, Tong Chen, Hui Lu, Xiujia Zhang, Wenbo Yu, Jiaxin Zhang, Dandan Shang, Xueying Wang.
      The present study investigated the role of melatonin (MT) in regulating mitochondrial function via sirtuin 3 (SIRT3) in granulosa cells (GCs) from patients with polycystic ovary syndrome (PCOS), with a focus on mitochondrial protection. Notably, GCs isolated from patients with PCOS exhibited mitochondrial dysfunction. Using an in vitro PCOS model established by treating KGN cells with dihydrotestosterone (DHT), decreased SIRT3 expression, dysregulated mitochondrial dynamics and hyperactivation of mitophagy were observed. Both SIRT3 overexpression and MT treatment restored the mitochondrial membrane potential, rebalanced mitochondrial dynamics and suppressed excessive autophagy in DHT‑treated cells. Additionally, MT levels were shown to be reduced in the follicular fluid of patients with PCOS. Notably, the protective effects of MT on proteins associated with both mitochondrial dynamics and autophagy were abolished upon SIRT3 inhibition. In conclusion, mitochondrial dysfunction and aberrant mitophagy in GCs may serve a role in the pathogenesis of PCOS. MT appears to ameliorate these defects by modulating mitochondrial dynamics and function in a SIRT3‑dependent manner. Moreover, the current study identified SIRT3 as a key molecular target of MT in PCOS.
    Keywords:  melatonin; mitochondrial function; polycystic ovary syndrome; sirtuin 3
    DOI:  https://doi.org/10.3892/mmr.2026.13937
  22. Cell Rep. 2026 Jun 09. pii: S2211-1247(26)00593-0. [Epub ahead of print]45(6): 117515
    STING-OPTN signaling confers cytoprotection through TBK1-dependent mitophagy.
    Ze-Bo Huang, Jin-Yi Lin, Ling-Jun Cheng, Yong Wu, Xiang-Zheng Gao, Yichi Zhang, Guan-Lin He, He-Yu Ling, Hayden Weng Siong Tan, Yuxiong Guo, Chuang Wang, Haihe Wang, Evandro F Fang, Han-Ming Shen, Guang Lu.
      The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway plays an essential role in innate immunity. While recent studies have revealed its critical role in non-canonical autophagy independent of its immune function, its role in selective autophagy remains elusive. Here, we identify the cGAS-STING pathway as an upstream positive regulator of mitophagy. We demonstrate that activation of TANK-binding kinase 1 (TBK1) during mitophagy is strictly dependent on the cGAS-STING pathway. Mechanistically, TBK1 activation involves the mitochondrial recruitment of STING, which requires valosin-containing protein (VCP)/p97-mediated degradation of outer mitochondrial membrane proteins. Activated TBK1 then phosphorylates optineurin (OPTN), resulting in the efficient clearance of damaged mitochondria via the autophagosome-lysosome pathway. Disruption of the STING-OPTN axis impairs mitophagy, which switches cellular response from mitophagy to apoptosis. Our work thereby defines a non-canonical, pro-survival function of the cGAS-STING pathway in mitochondrial quality control.
    Keywords:  CP: cell biology; OPTN; PINK1; TBK1; VCP/p97; cGAS-STING; cell death; mitophagy
    DOI:  https://doi.org/10.1016/j.celrep.2026.117515
  23. J Pharmacol Exp Ther. 2026 May 05. pii: S0022-3565(26)01132-8. [Epub ahead of print]393(6): 104933
    Linagliptin and/or α-pinene attenuate cisplatin nephrotoxicity in rats via modulating phosphatase and tensin homolog-induced kinase 1/Parkin/microtubule-associated proteins 1A/1B light chain 3II/SQSTM1/sequestosome-1-assisted mitophagy.
    Alaa A Elgendy, Hisham A Nematalla, Mona Elharoun, Ihab T Abdel-Raheem.
      Acute kidney injury is considered the most harmful and prevalent type of cisplatin-induced nephrotoxicity. In the current research, the potential prophylactic effects of linagliptin and/or α-pinene were investigated on cisplatin-induced functional, biochemical, and structural changes in rat kidneys. Forty Sprague-Dawley male rats were separated into five groups (n = 8): (1) normal group; (2) model group (cisplatin 7.5 mg/kg, i.p., single dose); (3) linagliptin group (3 mg/kg, p.o. for 18 days); (4) α-pinene group (50 mg/kg, p.o. for 18 days); and (5) linagliptin + α-pinene group (linagliptin 3 mg/kg + α-pinene 50 mg/kg, p.o.) for 18 days. Cisplatin was administered to all groups on day 15, excluding the normal group. Possible antioxidant, anti-inflammatory, and antiapoptotic activities were evaluated. In addition, mitophagy and mitochondrial biogenesis boosting mechanisms of both drugs were examined. Cisplatin administration produced a marked elevation in serum creatinine, urea, and renal kidney injury molecule-1 levels. Oxidative stress was markedly increased in the kidney homogenate. Similarly, cisplatin elevated renal inflammatory markers, activated the inflammasome, and increased apoptotic markers. It diminished mitophagy and mitochondrial biogenesis by reducing phosphatase and tensin homolog-induced kinase 1, Parkin, and peroxisome proliferator-activated receptor γ coactivator 1α levels. Contrarily, cisplatin raised microtubule-associated proteins 1A/1B light chain 3II and SQSTM1/sequestosome-1 levels. Coadministration of linagliptin and α-pinene demonstrated a potential prophylactic strategy in this preclinical model, likely through attenuation of oxidative stress, inflammation, apoptosis, and enhancement of mitophagy. However, this combination requires further validation in additional experimental models, including optimization of dosing regimens and evaluation of potential interactions with chemotherapy outcomes. SIGNIFICANCE STATEMENT: Linagliptin and/or α-pinene attenuate cisplatin-induced nephrotoxicity in rats by modulation of mitochondrial biogenesis and mitophagy.
    Keywords:  Acute kidney injury; Cisplatin; Linagliptin; Mitophagy; Oxidative stress; α-Pinene
    DOI:  https://doi.org/10.1016/j.jpet.2026.104933
  24. Sci Rep. 2026 Jun 11.
    RANBP3 promotes mitophagy through the CCAR2/SIRT1 pathway to alleviate pyroptosis in macrophages in TBTB.
    Lei Zhou, Lin-Zi Luo, Zhi-Bin Lu, Hai-Long Luo, Dan Feng, Limei Gong, Yang-Bao Xiao, Li Luo.
      Mycobacterium tuberculosis infection of the trachea causes tracheobronchial tuberculosis (TBTB), a chronic inflammatory illness, and its pathological features include macrophage pyroptosis. RanBP3, as a potential regulator, participates in cell stress, but its specific mechanism of action in TBTB has not been clarified. The mouse and bone marrow-derived macrophages (BMDMs) models were constructed by infecting with M. smegmatis. RanBP3 protein level and the levels of pyroptosis-related proteins were measured by Western blotting (WB). The levels of inflammatory factors were measured by ELISA. Pearson's correlation analysis was employed to evaluate their correlation with RanBP3, and the interaction of RanBP3/CCAR2/SIRT1 was verified by Co-immunoprecipitation (Co-IP). The detection of macrophage pyroptosis and mitophagy was done using flow cytometry, and mitophagy was further assessed by transmission electron microscopy. Bacterial survival in BMDMs was evaluated by colony-forming unit assays. Hematoxylin and eosin (H&E) and Masson staining were used to assess lung tissue damage. RanBP3 was down-regulated in TBTB mucosa. At the cellular level, RanBP3 overexpression alleviated BMDM's pyroptosis by promoting mitophagy and reduced intracellular bacterial survival, whereas RanBP3 knockdown exacerbated pyroptosis and increased bacterial survival. Mechanistically, RanBP3 competitively binds to CCAR2, disrupts the CCAR2-SIRT1 interaction, and promotes SIRT1 release, thereby activating mitophagy. At the animal level, RanBP3 overexpression promoted mitophagy, alleviated macrophage pyroptosis, and alleviated TBTB, but the SIRT1 inhibitor reversed these effects. RanBP3 mediates the release of SIRT1 through the CCAR2-SIRT1 axis, thereby activating mitophagy and inhibiting pyroptosis, providing a new target for TBTB treatment.
    Keywords:  CCAR2/SIRT1 pathway; Macrophage pyroptosis; Mitophagy; RANBP3; TBTB
    DOI:  https://doi.org/10.1038/s41598-026-55696-2
  25. Kaohsiung J Med Sci. 2026 Jun 09. e70242
    Terazosin Attenuates Neuronal Pyroptosis by Regulating the Mitochondrial ROS/NLRP3 Inflammasome Axis Through Mitophagy in Cerebral Ischemia-Reperfusion Injury.
    Wei Wang, Xin-Yue Han, Li-An Huang, Yu-Sheng Zhang, Heng Meng, An-Ding Xu.
      Cerebral ischemia-reperfusion injury (CI/RI) is a major cause of secondary neuronal damage following ischemic stroke. This study investigated whether terazosin (TZ) exerts neuroprotective effects by regulating mitophagy and the reactive oxygen species (ROS)/NOD-like receptor protein 3 (NLRP3) inflammasome axis. A mouse model of CI/RI was established and treated with TZ alone or in combination with the mitophagy inhibitor Mdivi-1 or the NLRP3 activator nigericin. Neurological function, infarct volume, histopathological changes in the hippocampal CA1 region, mitophagy (Mito-Tracker+LC3B+), and neuronal pyroptosis (NeuN+GSDMD-N+) were evaluated. In parallel, an oxygen-glucose deprivation/reperfusion (OGD/R) model was established in HT-22 cells to assess cell viability, cytotoxicity, mitochondrial membrane potential, ROS production, inflammatory cytokine release, and expression of autophagy- and pyroptosis-related proteins. The CI/RI exhibited was characterized by worsened neurological deficits, increased infarct volume, enhanced neuronal pyroptosis, and elevated interleukin-1β (IL-1β), IL-18, ROS, p62, and pyroptosis proteins, as well as prominent vacuolation and edema in the hippocampal CA1 region. These changes were accompanied by reduced mitophagy and decreased expression of LC3B II/I and Beclin-1. TZ treatment markedly ameliorated these abnormalities. Mechanistic analyses showed that TZ inhibited OGD/R-induced neuronal pyroptosis by promoting mitophagy, which reduced ROS accumulation and subsequently suppressed NLRP3 inflammasome activation. Importantly, blockade of mitophagy or activation of NLRP3 weakened the protective effects of TZ. Collectively, these findings indicate that TZ mitigates CI/RI-induced neuronal injury by enhancing mitophagy and inhibiting ROS/NLRP3-dependent pyroptosis.
    Keywords:  cerebral ischemia–reperfusion injury; mitophagy; pyroptosis; reactive oxygen species‐NOD‐like receptor protein 3; terazosin
    DOI:  https://doi.org/10.1002/kjm2.70242
  26. Comp Biochem Physiol A Mol Integr Physiol. 2026 Jun 09. pii: S1095-6433(26)00071-1. [Epub ahead of print] 112035
    Mitochondrial dynamics in prostatic cells during seasonal hyperplasia and atrophy in wild ground squirrels (Spermophilus dauricus).
    Pengyu Chen, Houyi Chen, Huan Yu, Maria Daniela Artigas Ramirez, Yuning Liu, Qiang Weng, Haolin Zhang.
      Seasonal remodeling of reproductive organs is ideal for studying adaptive metabolic regulation under physiological conditions. The wild ground squirrel (Spermophilus dauricus), a typical seasonal breeder, shows pronounced prostate hypertrophy in the breeding season and marked atrophy in the non-breeding season, serving as a natural model for reversible prostate remodeling. Using morphological, histological, immunofluorescence (with MitoTracker staining), immunohistochemical analyses and RT-qPCR, we examined seasonal changes in mitochondrial biogenesis, dynamics, antioxidant capacity, prostate structure and mitochondrial indicators in the squirrel prostate. Results showed seasonal structural differences: epithelial expansion with suggested enhanced secretory activity in the breeding season vs stromal predominance in the non-breeding season; increased mitochondrial content in breeding-season epithelial cells; consistent epithelial localization of PGC-1α and PGC-1β across seasons, with breeding-season-specific strong epithelial expression of TFAM; predominance of MFN1/OPA1 (fusion-related) in the breeding season and upregulated DRP1 (fission-related) in the non-breeding season; and seasonal differences in the transcription of Tfam, Mfn2, Drp1, Opa1 and Sod2. In conclusion, mitochondrial biogenesis, fusion-fission balance and antioxidant capacity are seasonally coordinated in the prostate to match tissue demands, providing the first systematic characterization of mitochondrial remodeling in a seasonally breeding mammal's prostate and new insights into adaptive mitochondrial regulation of reversible prostate plasticity.
    Keywords:  Comparative physiology; Fusion–fission balance; Mitochondrial biogenesis; Mitochondrial dynamics; Prostate plasticity; Seasonal breeding
    DOI:  https://doi.org/10.1016/j.cbpa.2026.112035
  27. Int J Mol Sci. 2026 May 29. pii: 4948. [Epub ahead of print]27(11):
    Molecular Hydrogen as a Regulator of Mitochondrial Quality Control and Metabolic Reprogramming.
    Fangfang Li, Yue Jing, Chao Xia, Ruping Zhao, Mengyu Liu, Pengxiang Zhao, Xuemei Ma, Fei Xie.
      The biological effects of molecular hydrogen are moving beyond the traditional explanatory framework of "selective antioxidation." This article systematically integrates the basic, preclinical, and preliminary clinical evidence for hydrogen in metabolic diseases, neurodegenerative disorders, and cancer, centering on the two major themes of mitochondrial quality control and metabolic reprogramming. Current studies indicate that hydrogen can reshape redox homeostasis, coordinate mitochondrial biogenesis, dynamic balance, and mitophagy, and modulate key signaling axes such as AMPK/Sirtuins, PGC-1α, and PPARα, aimed at optimizing mitochondrial function, thereby influencing adaptive glucose and lipid metabolism as well as cellular bioenergetic homeostasis. Although its upstream initiating events and context dependency remain to be clarified, existing evidence supports the view that hydrogen is an important network regulator linking redox regulation, mitochondrial homeostasis, and metabolic adaptation.
    Keywords:  mitochondrial quality control; molecular hydrogen; redox homeostasis
    DOI:  https://doi.org/10.3390/ijms27114948
  28. Nat Cell Biol. 2026 Jun 11.
    DRP1 and MID49 co-diffusion scans mitochondria for fission.
    Cristiana Zollo, David Gomez Suarez, Elmira Parvindokht Bararpour, Andreas Jenner, Pratima Verma, Jan Koch, Sabine Wilhelm, Christian Jüngst, Lukas Faber, Faye White, Ana J García-Sáez.
      DRP1 is a dynamin-related large GTPase responsible for mitochondrial fission, which ensures proper mitochondrial distribution, morphology and quality control. Despite its relevance, the mechanism of mitochondrial division, especially regarding the dynamic regulation of DRP1, remains elusive. Here we report that DRP1 oligomers diffuse in helical-like trajectories along mitochondria, browsing the organelle surface and stalling at preconstricted fission sites, in what we call 'mito-scanner' motion. Molecular dynamics simulations support a geometry-mediated diffusion mechanism emerging from surface confinement. Perturbation of DRP1 motility results in elongated mitochondria, underscoring the functional importance of DRP1 scanning dynamics in mitochondrial division. We also show that DRP1 dynamics on mitochondria are differentially regulated by interactions with its adaptors, where co-diffusion of MID49/MID51 with DRP1 promotes its motility. Our findings support a model in which receptor-regulated mitochondrial surveillance by DRP1 enables balanced organelle division, with potential implications for targeting this process in disease.
    DOI:  https://doi.org/10.1038/s41556-026-01986-w
  29. Int J Mol Sci. 2026 May 30. pii: 4982. [Epub ahead of print]27(11):
    Pre-Activation of Mitophagy Protects Against Hyperbaric Oxygen-Induced Central Nervous System Oxygen Toxicity.
    Wei Ding, Qi Zhu, Houyu Zhao, Guanning Wei, Guoyang Huang, Jing Shi, Longfei Wang, Nan Zhao, Jin Ding, Yiqun Fang.
      Central nervous system oxygen toxicity (CNS-OT) is a major complication of hyperbaric oxygen (HBO) characterized by seizures and neuronal damage, yet the underlying mechanisms remain incompletely understood. Using male Sprague Dawley rats (n = 6 per group) and HT22 neurons exposed to either HBO (6 ATA, 100% O2) or hyperbaric normoxia (HNO), our results demonstrate that HBO, but not HNO, caused mitochondrial structural damage and loss of mitochondrial membrane potential (ΔΨm). Transcriptomic analysis revealed enrichment of apoptosis and mitogen-activated protein kinase (MAPK) signaling pathways. Using HeLa cells stably overexpressing Parkin and Mito-Keima, a pH-sensitive mitochondrial probe system for monitoring mitophagy, we observed that mitophagic flux was initiated but proceeded too slowly to clear damaged mitochondria in a timely manner in HBO-exposed neurons. Pharmacological preconditioning to activate mitophagy enabled the prompt elimination of dysfunctional mitochondria and rescued HBO-induced mitochondrial dysfunction and cell death. In vivo, everolimus treatment promoted timely mitophagic clearance, prolonged seizure latency, attenuated ΔΨm loss, and suppressed p-p38 activation. These findings demonstrate that HBO exposure disrupts mitochondrial homeostasis and activates pro-apoptotic MAPK signaling. Meanwhile, endogenous mitophagy is initiated but fails to clear damaged mitochondria in a timely manner. Pre-activation of mitophagy by everolimus enables the timely clearance of damaged mitochondria, protecting against CNS-OT and highlighting a promising therapeutic strategy.
    Keywords:  central nervous system oxygen toxicity (CNS-OT); hyperbaric oxygen; mitophagy; neuroprotection
    DOI:  https://doi.org/10.3390/ijms27114982
  30. Exp Neurol. 2026 Jun 12. pii: S0014-4886(26)00240-2. [Epub ahead of print] 115875
    HSPA1-regulated mitophagy-necroptosis crosstalk determines the fate of brain microvascular endothelial cells after cerebral ischemia.
    Qiuyue Yang, Yuxiang Wu, Hui Zhao, Qiuxia Zhang.
      Ischemic stroke triggers brain microvascular endothelial dysfunction. Necroptosis (RIP3-MLKL) and PINK1-Parkin mitophagy are both implicated, but their coordination and the role of HSPA1/HSP70 remain unclear. Using oxygen-glucose deprivation (OGD) in hCMEC/D3 cells and a rat permanent middle cerebral artery occlusion (pMCAO) model, we tested whether stress-inducible HSPA1 mediates a mitochondrial "tug-of-war" between necroptosis and mitophagy. Time-course analysis identified a 4-h OGD window in which RIP3/MLKL activation and mitochondrial MLKL oligomerization peaked, while PINK1-Parkin and HSPA1 increased later. Within this window, necrostatin-1 (Nec-1) suppressed RIP3/MLKL signalling and mitochondrial MLKL oligomers, improved cell viability, and partially reshaped mitophagy markers. Rapamycin (RAPA) improved viability, upregulated PINK1, LC3-II/LC3-I and HSPA1, and reduced mitochondrial MLKL oligomers despite increased total RIP3/MLKL, consistent with enhanced autophagy and attenuated necroptotic execution. The mitochondrial HSP70 inhibitor MKT-077 reduced both MLKL oligomers and PINK1, suggesting that both pathways may be influenced by HSPA1-related activity. In pMCAO rats, Nec-1 and MKT-077, and to a lesser extent RAPA, improved neurological outcomes and reduced infarct volume; immunofluorescence further revealed increased necroptosis- and mitophagy-related signals in the peri-infarct cortex, with overlapping MLKL and PINK1 signals observed in CD31-positive endothelial cells/microvascular structures. Collectively, HSPA1 may function as a shared and limited chaperone resource that shifts from supporting necroptosis early to facilitating mitophagy as its abundance rises, thereby protecting endothelium after cerebral ischemia.
    Keywords:  Brain microvascular endothelial cells; Cerebral ischemia; HSPA1/HSP70; Mitophagy; Necroptosis
    DOI:  https://doi.org/10.1016/j.expneurol.2026.115875
  31. Kaohsiung J Med Sci. 2026 Jun 10. e70245
    The Regulatory Role and Mechanism of Myoferlin in Mitophagy During Papillary Thyroid Carcinogenesis.
    Wen-Chao Lyu, Yang-Shuai Wang, Chun-Yang Shang, Ming Qi, Tong-Chang Li, Li-Xin Lian, Hai-Quan Qiao.
      Papillary thyroid carcinoma (PTC) is the most prevalent subtype of thyroid cancer; however, the regulatory mechanisms by which mitophagy influences its progression remain inadequately elucidated. This study sought to examine the role of myoferlin (MYOF) in mitophagy and its molecular basis during PTC development. Utilizing three paired PTC and adjacent normal tissues, we observed elevated MYOF expression at both protein and mRNA levels through western blot and qRT-PCR analyses. Stable MYOF knockdown cell lines were established in PTC (TPC-1, KTC-1) and normal thyroid (Nthy-ori 3-1) cells using lentiviral shRNA. Functional assays, including CCK-8, wound healing, transwell, flow cytometry, immunofluorescence, and mitophagic flux analysis, along with a xenograft mouse model, were employed. Subsequent evaluations involved hematoxylin and eosin staining, immunohistochemistry, western blot, and qRT-PCR. As a result, MYOF was significantly upregulated in PTC tissues and TPC-1 cells. Knockdown of MYOF inhibited PTC cell proliferation, invasion, migration, and colony formation, while promoting apoptosis. Mechanistically, MYOF was found to regulate PTC progression through the PINK1/Parkin-mediated mitophagy pathway. In vivo xenograft experiments demonstrated that MYOF silencing suppressed tumor growth and increased the expression of mitophagy-related proteins BNIP3 and NIX. In conclusion, MYOF drives PTC progression by repressing mitophagy. Targeted inhibition of MYOF activates tumor-suppressive mitophagy via the PINK1-Parkin axis, indicating MYOF as a potential therapeutic target in PTC.
    Keywords:  PINK1‐Parkin pathway; mitochondrial dysfunction; mitophagy; myoferlin; papillary thyroid carcinoma
    DOI:  https://doi.org/10.1002/kjm2.70245
  32. Nat Commun. 2026 Jun 12.
    Retrograde mitochondrial transport is required for mitochondrial biogenesis in zebrafish neurons.
    Angelica E Lang, Chris Stein, Roger Schultz, Catherine M Drerup.
      To maintain a functional mitochondrial population in a long-lived cell like a neuron, mitochondria must be continuously replenished through the process of mitochondrial biogenesis. Because most mitochondrial proteins are nuclear encoded, mitochondrial biogenesis requires communication between mitochondria and the nucleus. This can be a challenge in a large, compartmentalized cell like a neuron in which a significant portion of the mitochondrial population is in neuronal compartments far from the nucleus. Using in vivo assessments of mitochondrial biogenesis in zebrafish neurons, we determined that mitochondrial transport between distal axonal compartments and the cell body is required for sustained mitochondrial biogenesis. Estrogen-related receptor transcriptional activation links transport with nuclear expression of mitochondrial genes. Together, our data support a role for retrograde feedback between axonal mitochondria and the nucleus for regulation of mitochondrial biogenesis in neurons.
    DOI:  https://doi.org/10.1038/s41467-026-74127-4
  33. Mol Immunol. 2026 Jun 09. pii: S0161-5890(26)00136-7. [Epub ahead of print]196 55-64
    Mycobacterial HBHA drives mitochondrial damage-mediated apoptosis via inhibiting mitophagy in macrophages.
    Jialian Zhou, Qiumei Wu, Wenjuan Li, Jiali Yang, Longshun Xiao, Yong Yang, Nan Wang, Shun Feng.
      Heparin-binding hemagglutinin adhesin (HBHA), an important adhesion protein located on the surface of Mycobacterium tuberculosis (Mtb), plays a critical role in the pathogen infection process. Macrophages serve as the primary effector cells that modulate the host immune response. It has been established that HBHA can regulate macrophage autophagy and apoptosis; however, the precise mechanism underlying HBHA's effect on macrophage apoptosis remains to be fully elucidated. In this study, HBHA was employed to stimulate mouse macrophage RAW 264.7 cells. Subsequently, apoptosis (including DNA fragmentation, the rate of apoptosis, and apoptosis-related proteins), mitochondrial damage (including mitochondrial morphology, membrane potential, and permeability transition), reactive oxygen species (ROS) generation, and mitophagy (including mitochondrial-lysosome formation and mitophagy-related pathway proteins) were systematically evaluated. The ROS scavenger N-acetyl cysteine (NAC) and the mitophagy inducer Carbonylcyanide 3-chlorophenylhydrazone (CCCP) were utilized to investigate the specific mechanism by which HBHA regulates macrophage apoptosis. The results demonstrated that HBHA stimulation significantly promoted apoptosis and ROS production in RAW 264.7 cells, leading to mitochondrial structural damage, decreased membrane potential, and increased permeability. Additionally, HBHA inhibited the formation of mitophagy-lysosome complexes and the activation of mitophagy-related pathways. NAC intervention partially reversed the effects of HBHA on ROS production, mitochondrial dysfunction, and apoptosis in RAW 264.7 cells. However, CCCP intervention effectively suppressed HBHA-induced apoptosis in RAW 264.7 cells by activating mitophagy. HBHA induces mitochondrial damage through the promotion of ROS production and the inhibition of mitophagy, ultimately leading to macrophage apoptosis. Our findings offer a novel perspective on the molecular mechanism by which Mtb evades macrophage immune clearance.
    Keywords:  Apoptosis; Heparin-binding hemagglutinin adhesin; Mitophagy; Mycobacterium tuberculosis; Reactive oxygen species
    DOI:  https://doi.org/10.1016/j.molimm.2026.06.005
  34. Prog Neuropsychopharmacol Biol Psychiatry. 2026 Jun 11. pii: S0278-5846(26)00179-X. [Epub ahead of print]148 111781
    Canagliflozin attenuates cognitive deficits in the streptozotocin-induced mouse model of sporadic Alzheimer's disease via modulating PINK1/Parkin signaling pathway and miR-34a expression.
    Rania I Nadeem, Rabab H Sayed, Eman M Elbaz, Amina A S Abdel Rahman, Marwa M Saeed.
      Mitochondrial deficits and impairments in mitophagy, a specialized form of mitochondrial degradation by autophagy, contribute to Alzheimer's disease (AD). Furthermore, dysregulated miR-34a was reported to contribute to AD progression. Sodium-glucose cotransporter-2 inhibitors are evolving as potential therapeutic agents in AD. To date, no data are available to elucidate the role of gliflozins in the mitophagy cascade in AD. Accordingly, this work was designed to investigate the central impact of canagliflozin (Cana) on PINK1/Parkin signaling in mice with streptozotocin (STZ)-induced cognitive impairment. Animals were arbitrarily allocated into 4 groups; the first received saline, while the other groups were injected intracerebroventricularly with STZ (3 mg/kg) once and then a daily oral administration of saline in the second group, Cana (30 mg/kg) in the third group and Cana together with the commonly used mitophagy/autophagy blocker 3-methyladenine (3-MA, 30 mg/kg/day, i.p.) in the fourth group, for 21 days. Cana alleviated cognitive impairments in the novel object recognition and Morris water maze tests, while also restoring the histological architecture. Cana induced a marked reduction in the amyloid beta deposition and phosphorylated tau protein. The neuroprotective role of Cana was manifested by modulation of mitophagy signaling through amplifying PINK1/Parkin protein expression, modifying the autophagic markers Beclin1 and LC3 II expression, and down-regulating miR-34a. Interestingly, co-administration of 3-MA hindered Cana's actions. Therefore, this study presents Cana as a potential therapeutic candidate for AD, possibly via modulation of mitophagy signaling.
    Keywords:  Alzheimers disease; Canagliflozin; Mice; Mitophagy; STZ
    DOI:  https://doi.org/10.1016/j.pnpbp.2026.111781
  35. Sci Rep. 2026 Jun 10.
    NOP2-mediated m5C methylation impairs mitophagy and aggravates acute lung injury by targeting PINK1.
    Xiaoyuan Chen, Rui Zhao, Hong Zhu, Yang Lu.
      Sepsis-induced acute lung injury (ALI) involves complex pathological mechanisms. 5-methylcytosine (m5C) RNA modification, catalyzed by methyltransferases like NOP2, plays a crucial role in regulating inflammation and cellular processes. However, the role of NOP2 and its potential regulation of m5C modification in sepsis-induced ALI remains unclear. An in vitro ALI model was established by treating human pulmonary epithelial A549 cells with lipopolysaccharide (LPS). Inflammatory cytokine levels (IL-1β, IL-6, TNF-α) were measured by ELISA. Apoptosis was assessed by flow cytometry. Mitophagy was evaluated via immunofluorescence staining for mitochondrial Parkin and western blot analysis of Parkin, LC3-II, COX IV, and p62. The m5C modification of PINK1 mRNA was analyzed by m5C-RIP-PCR. The specific m5C site was identified using bioinformatics and validated by dual-luciferase reporter assays. LPS treatment significantly upregulated NOP2 expression in A549 cells. Knockdown of NOP2 attenuated LPS-induced inflammation, apoptosis, and promoted mitophagy, as evidenced by increased Parkin translocation, elevated LC3-II levels, and decreased p62 and COX IV levels. Mechanistically, NOP2 knockdown reduced m5C modification on PINK1 mRNA, particularly at site 197, thereby enhancing PINK1 mRNA stability and increasing its expression. Furthermore, knockdown of PINK1 reversed the protective effects of NOP2 knockdown on inflammation, apoptosis, and mitophagy in LPS-treated A549 cells. NOP2 is upregulated in LPS-induced ALI models. Its knockdown alleviates cellular injury by reducing the m5C modification of PINK1 mRNA, which enhances PINK1 expression and promotes mitophagy. The NOP2/m5C/PINK1 axis represents a novel regulatory pathway in sepsis-induced ALI, suggesting potential therapeutic targets for its treatment.
    Keywords:  Acute lung injury; NOP2; PINK1; Sepsis
    DOI:  https://doi.org/10.1038/s41598-026-56994-5
  36. Biochim Biophys Acta Mol Basis Dis. 2026 Jun 09. pii: S0925-4439(26)00183-3. [Epub ahead of print]1872(7): 168320
    Ajugol attenuates acute gouty arthritis by enhancing mitophagy to suppress chondrocyte pyroptosis.
    Yang Zhang, Yi Liu, Weiping Xie, Yingqiang Fu, Zhonghao Liu, Qingfeng Yin, Zengxin Gao, Wenguang Liu.
      Gouty arthritis (GA), triggered by monosodium urate (MSU) crystal deposition, is closely associated with oxidative stress, mitochondrial dysfunction, and NLRP3 inflammasome-mediated pyroptosis. This study combined network pharmacology, molecular docking, molecular dynamics simulations, and experimental validation to elucidate the mechanism by which the iridoid glycoside ajugol alleviates GA. Network pharmacology analyses identified the PI3K/AKT/mTOR pathway as a key regulatory axis, and docking results revealed stable binding of ajugol to PI3K, AKT, and mTOR. In LPS/MSU-stimulated human chondrocytes, ajugol significantly restored cell viability, reduced LDH release, and preserved extracellular matrix integrity by increasing Collagen II and Aggrecan expression while decreasing MMP-3 levels. Ajugol markedly inhibited the expression of NLRP3, ASC, caspase-1, and GSDMD-N, reduced the secretion of IL-1β, IL-18, IL-6, and TNF-α, and decreased caspase-1 activity and membrane pore formation, indicating that ajugol suppresses pyroptosis through enhanced mitophagy. The mitophagy inhibitor cyclosporin A (CsA) significantly weakened ajugol-induced mitophagy activation and pyroptosis inhibition, confirming that mitophagy plays a pivotal role in its protective effects. Mechanistically, ajugol inhibited PI3K/AKT/mTOR phosphorylation, upregulated PINK1, Parkin, and LC3-II/LC3-I while reducing p62, thereby activating PINK1/Parkin-dependent mitophagy. PI3K agonist 740YP partially reversed ajugol's effects, whereas PI3K inhibitor LY294002 mimicked them, verifying pathway involvement. In MSU-induced GA mice, oral ajugol administration alleviated joint swelling, reduced inflammatory cytokines and NLRP3 expression, preserved cartilage integrity, and restored autophagy via PI3K/AKT/mTOR suppression. Collectively, ajugol alleviates inflammation and cartilage damage by suppressing the PI3K/AKT/mTOR pathway, activating mitophagy, and inhibiting pyroptosis, providing a promising mitochondrial-targeted therapeutic strategy for gouty arthritis.
    Keywords:  Ajugol; Gouty arthritis; Inflammation; Mitophagy; PI3K/AKT/mTOR signaling pathway; Pyroptosis
    DOI:  https://doi.org/10.1016/j.bbadis.2026.168320
  37. Ecotoxicol Environ Saf. 2026 Jun 10. pii: S0147-6513(26)00683-4. [Epub ahead of print]322 120354
    PM2.5 promotes the phenotypic transition of vascular smooth muscle cells in atherosclerosis by activating pro-ferroptotic signaling via DRP1/PINK1/Parkin-dependent mitophagy.
    Mengqi Zou, Tianyu Lu, Bo Liu, Haotian Wang, Delong Lin, Yibiao Lu, Song Yuan, Lei Bao, Yujie Niu, Yaxian Pang, Rong Zhang.
      Fine particulate matter (PM2.5), as a widespread environmental pollutant, is closely associated with cardiovascular diseases. The adverse effects of PM2.5 on the cardiovascular system and the molecular mechanisms driving PM2.5-aggravated atherosclerosis remain incompletely understood. In this study, in vivo and in vitro PM2.5 exposure models were established to explore the relevant pathogenic mechanisms. Male ApoE⁻/⁻ mice were randomly divided into three groups: filtered air(FA) group, unfiltered air(UA) group, and concentrated PM2.5 air(CA) group. For in vitro experiments, mouse aortic vascular smooth muscle cells were exposed to PM2.5 at concentrations of 0, 25, 50, and 100 μg/ml, meanwhile,group control was set up, DRP1 inhibitor Mdivi-1 and ferroptosis inhibitor Fer-1 were used to intervention, and PINK1 knockdown cell model was constructed. Aortic vascular function was evaluated via ultrasonography after exposure. Histopathological changes, collagen deposition, and lipid accumulation in arterial tissues and cells were evaluated via HE staining, Masson staining, Oil Red O, and BODIPY staining, respectively. Immunofluorescence and Western blot were applied to analyze the expression of related proteins in the arterial wall. The results demonstrated that PM2.5 exposure accelerated atherosclerosis progression and VSMC phenotypic switching.PM2.5 exposure upregulated mitochondrial fission proteins and downregulated fusion proteins, with DRP-1 as a critical regulatory molecule. PM2.5 specifically activated PINK1/Parkin-mediated mitophagy rather than the FUNDC1 pathway. PINK1 knockdown markedly attenuated pro-ferroptotic signaling. Mdivi-1 intervention alleviated PM2.5-induced excessive mitophagy, upregulated pro-ferroptotic signaling and phenotypic switching of VSMC. Fer-1 treatment also efficiently inhibited VSMC phenotypic switching.The results of this study demonstrate that DRP1-driven PINK1/Parkin- mediated mitophagy and inducing pro-ferroptotic signaling to promote the phenotypic switching of VSMCs in PM2.5-aggravated atherosclerosis, These findings provide new insights into the pathogenesis of environmental atherosclerosis and potential targets for therapeutic intervention.
    Keywords:  Atherosclerosis; DRP-1; Mitophagy; PM(2.5); Pro-ferroptotic signaling
    DOI:  https://doi.org/10.1016/j.ecoenv.2026.120354
  38. J Cell Commun Signal. 2026 Jun;20(2): e70059
    TRMT10C promotes mitochondrial fission through transferrin receptor m1A methylation modification and aggravates the progression of atrial fibrillation.
    Nijina Li, Hao Zhang.
      Atrial fibrillation (AF) is a common cardiac arrhythmia often accompanied by structural remodeling of the atria, particularly fibrosis, and disruption of normal mitochondrial function. N(1)-methyladenosine (m1A), a methylation of RNA, is gaining attention for its role in diverse biological processes. This study aimed to explore the role of the m1A methyltransferase tRNA methyltransferase 10C (TRMT10C) in AF pathogenesis. In the study, TRMT10C and m1A methylation levels were upregulated in AF rats, accompanied by excessive mitochondrial fission and myocardial fibrosis. Knockdown of TRMT10C inhibited the expression levels of mitochondrial fission-related proteins Drp1 and Fis1, reduced collagen deposition (collagen I, Postn, collagen III, and fibronectin), and AF progression. In vitro results showed that TRMT10C knockdown inhibited TGF-β1-induced cardiac fibroblasts proliferation and migration, whereas overexpression of transferrin receptor (TFRC) reversed this effect. Mechanistically, TRMT10C enhanced the stability of TFRC mRNA by promoting m1A methylation, driving mitochondrial fission and fibrosis. Collectively, our findings elucidate a novel TRMT10C-TFRC m1A axis driving pathological mitochondrial dynamics and fibrosis in AF, offering new insight into cell-signaling pathways underlying atrial disease and potential therapeutic targets.
    Keywords:  TRMT10C; atrial fibrillation; atrial fibrosis; m1A methylation; mitochondrial fission
    DOI:  https://doi.org/10.1002/ccs3.70059
  39. Xenobiotica. 2026 Jun 08. 1-13
    Blueberry anthocyanin extract inhibits platelet activation and FUNDC1-mediated mitophagy in Type 2 diabetes mellitus via AMPK pathway.
    Qiang Wu, Yushi Bao, Kangkang Peng, Yaping Lou, Lulu Wang.
      1. HPLC analysis was employed to identify the chemical compositions in BAE. Delphinidin, cyanidin, peonidin, and malvidin were detected in BAE.2. After establishment of the T2DM mice model, BAE and metformin were treated. Body weight, fasting blood glucose level and glucose tolerance were monitored, followed by detection of β-TG, PF4, CD62p, mitophagy markers. Both BAE and metformin implement reduced the body weight and fasting blood glucose level, and improved glucose tolerance of T2DM mice. BAE implement significantly reduced the β-TG, PF4 and CD62p levels in T2DM mice. FUNDC1, LC3II/LC3I, Pink1, and Parkin protein levels were both significantly elevated in T2DM mice, while Tomm20 expression was remarkedly reduced. BAE implement effectively reversed the FUNDC1, LC3II/LC3I, Pink1, and other relevant markers in T2DM mice.3. The effect of AMPK pathway involved in the BAE for T2DM treatment was explored. STZ treatment significantly decreased the phospho-AMPK level, while BAE administration reversed the effects of STZ on phospho-AMPK level in mice. Compound C implement effectively abolished the effects of BAE on the expression of platelet activation and mitophagy markers.4. This study suggests that BAE ameliorates T2DM through inhibiting platelet activation and FUNDC1-mediated platelet mitophagy via the AMPK pathway.
    Keywords:  AMPK pathway; FUNDC1; Type 2 diabetes mellitus; blueberry anthocyanin extract; mitophagy; platelet activation
    DOI:  https://doi.org/10.1080/00498254.2026.2686234
  40. Cell Oncol (Dordr). 2026 Jun 08.
    Cis-3-hexen-1-ol suppresses bladder cancer progression by inducing mitophagy via the PCK2/AMPK/mTOR signaling pathway.
    Jingxuan Peng, Quan Zhu, Sha Li, Boyu Xiang, Yu Han, Zhengyan Tang.
       BACKGROUND: Cis-3-hexen-1-ol is a naturally occurring green leaf volatile widely distributed in aromatic and medicinal plants. However, its antitumor activity and underlying mechanisms in bladder cancer (BLCA) remain largely unexplored.
    METHODS: The antitumor effects of cis-3-hexen-1-ol were evaluated using human BLCA cell lines and mouse xenograft and metastasis models. Cell proliferation, migration, invasion, mitochondrial function, and mitophagy were assessed using CCK-8, EdU incorporation, transwell assays, mitochondrial membrane potential and ROS assays, transmission electron microscopy, and immunofluorescence. Transcriptomic profiling, molecular docking, co-immunoprecipitation, immunoblotting, and in vitro kinase assays were performed to elucidate the underlying molecular mechanisms.
    RESULTS: Cis-3-hexen-1-ol significantly inhibited BLCA cell proliferation, migration, and invasion in vitro and suppressed tumor growth and lung metastasis in vivo without overt toxicity. Treatment induced mitochondrial dysfunction and robust mitophagy, as evidenced by mitochondrial fragmentation, loss of membrane potential, increased mitochondrial ROS, and enhanced recruitment of autophagy markers. Mechanistically, cis-3-hexen-1-ol activated mitophagy through the PCK2/AMPK/mTOR signaling axis. Genetic silencing of PCK2 or pharmacological inhibition of autophagic flux using 3-methyladenine markedly attenuated the antitumor and pro-mitophagic effects. Notably, biochemical analyses demonstrated that PCK2 undergoes autophosphorylation and directly phosphorylates AMPK in vitro, supporting a kinase-dependent regulatory mechanism.
    CONCLUSIONS: These findings identify cis-3-hexen-1-ol as a novel mitophagy-inducing phytochemical that suppresses BLCA progression via activation of the PCK2/AMPK/mTOR pathway, highlighting its potential as a natural-product lead for targeted bladder cancer therapy.
    Keywords:   Cis-3-hexen-1-ol; Bladder cancer; Mitophagy; Natural products; PCK2/AMPK/mTOR signaling
    DOI:  https://doi.org/10.1007/s13402-026-01233-2
  41. Aging Cell. 2026 Jun;25(6): e70575
    Senescent BMSC-Derived Thbs1 Drives Inflammaging and Impairs Bone Regeneration by Suppressing PINK1/Parkin-Mediated Mitophagy in Macrophages.
    Yifeng Xing, Jingjing Su, Yanjun Lin, Nengwen Huang, Sihui Zhang, Yuwei Zhou, Jie Lu, Weiping Chen, Kaixun He, Wenxiu Yuan, Yang Li, Geyuan Zheng, Pengyuan Hu, Dong Wu, Yanjing Ou, Jiang Chen.
      The aging bone marrow microenvironment is characterized by chronic low-grade inflammation ("inflammaging"), which disrupts skeletal homeostasis and impairs bone regeneration. However, the stromal-immune crosstalk mechanisms sustaining this pathological state remain poorly defined. Here, transcriptomic analysis identified thrombospondin-1 (Thbs1) as a key upregulated component of the senescence-associated secretory phenotype (SASP) in aged bone mesenchymal stromal cells (BMSCs). We demonstrate that BMSC-derived Thbs1 drives pro-inflammatory M1 macrophage polarization by suppressing PINK1/Parkin-mediated mitophagy. Mechanistically, Thbs1 binds to the TGF-β type II receptor (Tgfbr2) on macrophages to activate Smad3 signaling, which transcriptionally represses the mitophagy regulator Pink1. This repression leads to mitochondrial superoxide accumulation and redox imbalance, thereby skewing macrophages toward an M1-like phenotype. These Thbs1-activated M1 macrophages, in turn, secrete IL-6, which activates the JAK/STAT3 pathway in BMSCs to inhibit osteogenic differentiation. Crucially, activated Stat3 directly binds the Thbs1 promoter, establishing a self-amplifying loop that perpetuates inflammaging and osteogenic decline. In vivo, AAV9-mediated Thbs1 knockdown in aged rat bone defects restored mitochondrial homeostasis, promoted an M2 macrophage transition, and significantly enhanced bone repair. Our study reveals a vicious cycle involving the Thbs1/TGF-β/Smad3/PINK1-IL-6/JAK/STAT3 axis that sustains inflammaging and osteogenic decline, highlighting Thbs1 as a promising therapeutic target for age-related bone regeneration.
    Keywords:  bone regeneration; cellular senescence; inflammaging; macrophage polarization; mitophagy; thrombospondin‐1
    DOI:  https://doi.org/10.1111/acel.70575
  42. Int J Mol Sci. 2026 Jun 01. pii: 5003. [Epub ahead of print]27(11):
    Tissue Effects of the Mitochondrial Division Inhibitor Mdivi-1 on the Substantia Nigra in a Laboratory Model of Dopaminergic System Damage.
    Anna V Egorova, Dmitry N Voronkov, Maria S Ryabova, Alla V Stavrovskaya, Artem S Olshansky, Anastasia K Pavlova, Tatiana I Baranich, Dmitry A Kharlamov, Vladimir S Sukhorukov.
      The use of substances that modulate mitochondrial dynamics in cells of nervous tissue represents a new direction in targeted therapy for neurodegeneration. The aim of this study was to evaluate the effect of mitochondrial division inhibitor-1 (Mdivi-1) on neurons and microgliocytes of the substantia nigra under conditions of partial damage to the dopaminergic system. This study was conducted using the 6-hydroxydopamine model of parkinsonism in rats; a separate experimental group of animals received Mdivi-1 intraperitoneally at a dose of 20 mg/kg for 5 days. The intensity of immunofluorescence staining for Tomm20, MTCO1, pDrp1, and Mfn2 was evaluated in neurons of the substantia nigra, and microglial activation was morphologically assessed. It was found that unilateral administration of 6-OHDA led to pro-inflammatory changes in microglia and changes in mitochondrial markers of neurons on the side of the substantia nigra contralateral to the toxin injection. Mdivi-1 did not affect the damage and mitochondrial proteins of neurons in pars compacta of the substantia nigra; however, it changed mitochondrial markers in nervous cells of the pars reticulata. The use of Mdivi-1 to address abnormal processes in neurodegeneration requires additional studies that include a differential assessment of its effects on various cell types.
    Keywords:  6-hydroxydopamine; Mdivi-1; Parkinson’s disease; microglia; mitochondrial dynamics; substantia nigra
    DOI:  https://doi.org/10.3390/ijms27115003
  43. Proc Natl Acad Sci U S A. 2026 Jun 16. 123(24): e2511427123
    Drp1-driven fragmentation of scleral mitochondria promotes myopia development.
    Zhenqi Guan, Wenting Li, Shengcong Liu, Xingxing Yang, Yuejia Peng, Long Ye, Luyao Wang, Yuan Lu, Sisi Dong, Huihui Liu, Jian Yuan, Jianzhong Su, Jia Qu, Xianqun Fan, Fei Zhao, Miaozhen Pan, Xiangtian Zhou.
      The global epidemic of myopia constitutes a growing public health concern worldwide. Myopia development is characterized by pathological scleral remodeling through fibroblast-myofibroblast transdifferentiation (FMT) and extracellular matrix (ECM) degradation. Since myopia is progressive, the development of sustainable and safe preventive interventions is imperative. While mitochondrial dynamics critically regulate fibrotic processes in other organs, their role in scleral homeostasis has remained unexplored. Here, we identify pathological mitochondrial fragmentation, caused by increased mitochondrial fission, as a key driver of myopia progression. Using two mammalian animal models, we demonstrate that both genetic and pharmacological enhancement of mitochondrial fission (inducing mitochondrial fragmentation) exacerbates collagen loss and accelerates axial elongation, whereas genetic and pharmacological inhibition of mitochondrial fission prevents collagen degradation and attenuates myopia progression. Hypoxia-induced FMT in cultured human scleral fibroblasts (HSFs) requires activation of mitochondrial fission, revealing overproduction of reactive oxygen species (ROS) as the downstream effector on HSFs and in both animal models. Our multilevel analyses identify the mitochondrial fission-ROS axis as a key pathway linking scleral hypoxia to ECM remodeling. Lycopene, a naturally occurring carotenoid antioxidant, significantly attenuated scleral ROS levels and was found suitable for long-term application, highlighting its potential as a therapeutic agent for myopia control. Collectively, these findings have identified a therapeutic target and agent for controlling myopia progression.
    Keywords:  Drp1; ROS; mitochondria; myopia; sclera
    DOI:  https://doi.org/10.1073/pnas.2511427123
  44. Cell Death Dis. 2026 Jun 11. pii: 563. [Epub ahead of print]17(1):
    Correction: KAP1-associated transcriptional inhibitory complex regulates C2C12 myoblasts differentiation and mitochondrial biogenesis via miR-133a repression.
    Jialing Zhang, Chaoju Hua, Yu Zhang, Peng Wei, Yaping Tu, Taotao Wei.
      
    DOI:  https://doi.org/10.1038/s41419-026-08844-5
  45. Neurochem Res. 2026 Jun 12. pii: 191. [Epub ahead of print]51(3):
    Olfactory Mucosa MSCs-Derived Exosomal RPL6 Attenuates Seizure-Induced Neuronal Damage via FGF2-Mediated Oxidative Stress and Mitophagy.
    Zijie Wang, Xiqi Hu, Yuchang Liang, Guoao Tan, Wenqi Fan, Jun Peng, Ya-Nan Ma, Ying Xia.
      Evidence suggests that olfactory mucosa-derived mesenchymal stem cells (OM-MSCs) can benefit epilepsy treatment in both clinical patients and mouse models, although their precise mechanism remains unclear. Given the advantages of exosomes in precise cellular regulation, ease of storage, and long-term stability, this study investigated the role of OM-MSCs-derived exosomes (OM-MSCs-exos) in status epilepticus (SE) models. Here, SE mouse models were induced by intraperitoneal injection of pilocarpine. OM-MSCs, differentially treated OM-MSCs-exos, and recombinant FGF2 protein were injected into SE model mice to investigate the effects of OM-MSCs-exos on SE models and their potential mechanisms. Functionally, treatment with OM-MSCs and OM-MSCs-exos significantly improved cognitive function, as evidenced by increased target quadrant duration, decreased escape latency, increased average speed, and more platform crossings in behavioral tests. Furthermore, this treatment further alleviated hippocampal tissue damage by reversing pilocarpine-induced oxidative damage, neuronal injury, and excessive mitophagy. Consistent outcomes were confirmed in vitro. Mechanistically, RPL6 was screened and confirmed as a key protein in OM-MSCs-exos, which interacts with FGF2 to promote FGF2 expression, thereby alleviating oxidative stress and mitochondrial dysfunction induced by H2O2. In conclusion, the RPL6 protein derived from OM-MSCs-exos improves neuronal damage post-SE by activating FGF2 to suppress oxidative stress and mitophagy, laying a theoretical foundation for the development of exosome-related drugs for treating epilepsy clinically.
    Keywords:  Epilepsy; Exosomes; Mitophagy; OM-MSCs; RPL6; Seizure
    DOI:  https://doi.org/10.1007/s11064-026-04809-4
  46. Int J Mol Sci. 2026 May 26. pii: 4774. [Epub ahead of print]27(11):
    The Role of Mitochondria in Polycystic Kidney Disease.
    Yuhe Wang, Jianhua Mao, Fei Liu.
      Polycystic kidney disease (PKD) is a genetic disorder characterized by renal cyst formation and progressive renal dysfunction, where inflammation, immune responses, and metabolic dysregulation critically drive disease progression, while emerging evidence increasingly links its pathogenesis to mitochondrial dysfunction. Mitochondria, central to cellular energy production, metabolism, and redox homeostasis, exhibit profound abnormalities in PKD, contributing to disease pathogenesis. Current evidence on mitochondrial mechanisms driving PKD progression includes metabolic reprogramming, oxidative stress, disrupted mitochondrial dynamics, and impaired mitophagy. Polycystic kidney disease is caused by mutations in the PKD1 or PKD2 genes, which encode polycystin 1 and polycystin 2. The formation of dysfunctional polycystins (PC1/PC2) is a key event in the pathogenesis of this disease, triggering impaired calcium signaling, increased production of mitochondrial reactive oxygen species (ROS), and reduced oxidative phosphorylation, thereby promoting cyst growth and fibrosis. Key signaling pathways such as mTORC1 hyperactivation, AMPK suppression, and disrupted calcium homeostasis further exacerbate mitochondrial defects. Emerging therapeutic strategies targeting mitochondrial pathways, such as mitochondrial antioxidants, modulators of mitophagy, calcium signaling regulators, and metabolic reprogramming agents, show promise in preclinical models. However, challenges remain in translating these findings to clinical applications, including drug specificity and minimizing off-target effects. This review underscores mitochondria as pivotal players in PKD pathogenesis and highlights their potential as therapeutic targets to mitigate cystogenesis and disease progression.
    Keywords:  cell signaling; metabolic reprogramming; mitochondria; mitophagy; oxidative stress; polycystic kidney disease
    DOI:  https://doi.org/10.3390/ijms27114774
  47. Stem Cell Res. 2026 Jun 01. pii: S1873-5061(26)00118-2. [Epub ahead of print]94 104022
    Generation and characterization of the hiPSC line CSSi023-A (16154) from a patient with ADOA caused by an OPA1 variant.
    Angela Maria Giada Giovenale, Ilaria Ferrone, Silvia Tomaselli, Elisa Maria Turco, Martina Mazzoni, Barbara Torres, Paola Zanfardino, Edvige Vulcano, Daniela Ferrari, Devid Damiani, Filippo M Santorelli, Alessandro De Luca, Maria Pennuto, Angelo Luigi Vescovi, Vittoria Petruzzella, Jessica Diana Rosati.
      Autosomal Dominant Optic Atrophy plus syndrome (ADOA, OMIM #125250) is a mitochondrial optic neuropathy characterized by progressive degeneration of retinal ganglion cells (RGCs), leading to worsening visual impairment. The disease is caused by pathogenic variants in the Optic Atrophy 1 (OPA1) gene, a member of the guanosine triphosphatase (GTPase) family that plays a central role in mitochondrial fusion and fission, mitophagy regulation, and mitochondrial DNA (mtDNA) maintenance. To model this disorder, we generated and characterized a human induced pluripotent stem cell (hiPSC) line from primary fibroblasts obtained from a patient affected by ADOA syndrome.
    DOI:  https://doi.org/10.1016/j.scr.2026.104022
  48. Nutrients. 2026 May 31. pii: 1780. [Epub ahead of print]18(11):
    Hydroxysafflor Yellow A Regulates SIRT1-FOXO3-BNIP3 Signaling Pathway to Promote Mitophagy: A Novel Therapeutic Strategy for Myocardial Ischemia-Reperfusion Injury.
    Dongdong Meng, Wencong Xia, Feng Tian, Qi Huang, Chaowen Ge, Ning Wang.
       BACKGROUND: Hydroxysafflor Yellow A (HSYA), the major bioactive component from Carthamus tinctorius L., exerts significant protective effects against myocardial ischemia-reperfusion injury (MIRI). Mitophagy is pivotal in the pathological process of MIRI, yet the specific molecular mechanism underlying HSYA-mediated mitophagy regulation remains unclear.
    OBJECTIVE: This study aimed to investigate the association between HSYA treatment and mitochondrial autophagy in murine MIRI and to explore the potential mechanistic role of the SIRT1-FOXO3-BNIP3 signaling pathway using functional loss-of-function and rescue experiments. These findings may provide preliminary evidence supporting the clinical translational potential in MIRI therapy.
    METHODS: Mouse myocardial ischemia-reperfusion injury (MIRI) model and oxygen-glucose deprivation/reoxygenation (OGD/R)-induced AC16 cardiomyocyte injury models were established. Metabolomics, molecular docking, and surface plasmon resonance (SPR) techniques were combined to screen the potential targets of HSYA. The SIRT1 inhibitor EX527 and SIRT1 siRNA were used to verify the underlying mechanism. Cardiac function, myocardial infarct size, mitochondrial function, the expression of autophagy-related proteins, and protein-protein interaction were detected and analyzed.
    RESULTS: Compared with the MIRI group, HSYA significantly improved cardiac function in mice, as evidenced by increased left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) (p < 0.01), attenuated ST-segment elevation, and improved myocardial perfusion. HSYA also markedly reduced myocardial infarct size (p < 0.01) and serum levels of CK-MB, LDH, and cTnI (all p < 0.01) and ameliorated myocardial histopathological damage and mitochondrial ultrastructural integrity. Mechanistic studies revealed that HSYA significantly upregulated the expression of SIRT1, FOXO3, BNIP3, Beclin-1, and the LC3II/I ratio while downregulating p62 expression (p < 0.01), consistent with enhanced mitophagy-related activity. Furthermore, these protective effects were markedly attenuated upon SIRT1 inhibition or siRNA-mediated silencing, whereas HSYA intervention partially reversed these alterations. Additionally, co-immunoprecipitation (Co-IP) and pull-down assays demonstrated that HSYA promoted protein-protein interactions between SIRT1-FOXO3, FOXO3-BNIP3, and BNIP3-LC3B.
    CONCLUSIONS: These findings highlight that HSYA is associated with improved cardiac function, enhanced mitophagy-related activity, and upregulated SIRT1-FOXO3-BNIP3 signaling, providing robust experimental evidence for its clinical translational application in MIRI treatment.
    Keywords:  AC16 cell; Hydroxysafflower Yellow A (HSYA); SIRT1-FOXO3-BNIP3 signaling pathway; mitophagy; myocardial ischemia-reperfusion injury (MIRI)
    DOI:  https://doi.org/10.3390/nu18111780
  49. Nanomaterials (Basel). 2026 Jun 04. pii: 698. [Epub ahead of print]16(11):
    Engineered Tan-CDs@AS-IV Nanosystem Orchestrates Mitochondrial Biogenesis and Intercellular Transfer to Restore Endothelial Function via PGC-1α and Cx43 Signaling Pathways.
    Haoran Wang, Xiaoyu Wang, Shuo Liu, Chunzhao Liu.
      Ischemic diseases are characterized by the functional collapse of endothelial cells (ECs) triggered by insufficient tissue perfusion. Given that mitochondria serve as the metabolic hub of ECs, their homeostatic imbalance, which is manifested by adenosine triphosphate (ATP) depletion, reactive oxygen species (ROS) bursts, and mitochondrial permeability transition pore opening, serves as the initiating factor driving impaired angiogenesis and tissue necrosis. In this study, we engineered an integrated nanosystem (Tan-CDs@AS-IV) by transforming Tanshinone into antioxidant carbon dots to encapsulate Astragaloside IV, achieving multi-level synergistic regulation of mitochondrial function. Our results demonstrate that Tan-CDs@AS-IV possesses superior structural stability and cellular internalization capabilities, significantly enhancing the migration and tubulogenesis of ECs under ischemic stress. Mechanistically, Tan-CDs@AS-IV effectively scavenges mitochondrial ROS and restores membrane potential and ATP production. Crucially, the nanosystem orchestrates mitochondrial biogenesis via peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) upregulation while simultaneously facilitating intercellular mitochondrial transfer through Connexin 43 (Cx43)-mediated gap junctions. This synergistic "endogenous amplification and intercellular replenishment" model establishes a robust mitochondrial quality control relay. By reconstructing cellular energy homeostasis, this study provides a novel nanoengineering strategy for the targeted therapy of ischemic diseases.
    Keywords:  PGC-1α/Cx43 signaling; carbon dot-based nanosystem; endothelial function; intercellular mitochondrial transfer; mitochondrial biogenesis
    DOI:  https://doi.org/10.3390/nano16110698
  50. J Anim Sci Biotechnol. 2026 Jun 09. pii: 114. [Epub ahead of print]17(1):
    Elevated maternal non-esterified fatty acid concentrations during late gestation are associated with altered skeletal muscle development and mitochondrial dynamics related-markers in calves.
    Yu Zhang, Guiling Ma, Xiangyi Zhao, Zhiyong Hu, Yang Gai, Rui He, Shilong Huang, Shengyong Mao, Zhaobing Gu, Yanting Chen.
       BACKGROUND: Late gestation represents an important developmental window for fetal skeletal muscle formation, which is associated with postnatal body growth, metabolic health and mobility in offspring. Although elevated circulating non-esterified fatty acids (NEFA) in dairy cows have been extensively studied in relation to milk production, their associations with fetal and neonatal skeletal muscle development remain unclear.
    METHODS: Sixty healthy Holstein cows with similar body weight, parity and calving dates were enrolled in this study after dry-off, and retrospectively assigned to low NEFA (n = 30, 263 ± 8.8 μmol/L) and high NEFA group (n = 30, 379 ± 9.1 μmol/L) according to serum NEFA concentrations at 1, 3, 5, and 7 weeks after dry-off. Skeletal muscle was collected from calves at birth and at one month of age to assess the impacts on offspring muscle mass, fiber morphology and metabolic functions. C2C12 myoblasts were also used to assess the NEFA addition on myogenesis in vitro.
    RESULTS: Cows with high NEFA (within the physiological prepartum range) in the dry period had no effect on calf birth weight (P = 0.15), but exhibited reduced biceps femoris (P = 0.05) and semitendinosus muscle mass (P < 0.01). Moreover, calves in the high-NEFA group shifted the muscle fiber composition, characterized by a lower proportion of fast-twitch fibers (P < 0.01) and a higher proportion of slow-twitch fibers (P = 0.01). The protein abundance of mitochondrial fission-related markers dynamin-related protein 1 (DRP1) and mitochondrial fission protein 1 (FIS1), as well as stimulator of interferon genes (STING)-associated inflammatory markers, was increased in skeletal muscle tissue of calves born to high-NEFA cows (P < 0.01). These alterations were persistently observed at one month of age. In vitro, NEFA supplementation reduced myogenic differentiation and fast-twitch myofiber formation (P < 0.01), while increasing the expression of mitochondrial dynamics-related genes and inflammatory markers (P < 0.01).
    CONCLUSION: Overall, this study reveals that the calves born to mothers with elevated NEFA during the dry period are associated with altered skeletal muscle development and changes in the expression of mitochondrial dynamics- and inflammation-related markers.
    Keywords:  Cows; Fetuses; Myogenesis; Non-esterified fatty acids; Skeletal muscle
    DOI:  https://doi.org/10.1186/s40104-026-01422-x
  51. Biology (Basel). 2026 May 31. pii: 867. [Epub ahead of print]15(11):
    Differential Activation of Pro-Survival Pathways by NIX/BNIP3L: An Expression-Level-Dependent Mechanism Governing PC12 Cell Fate During H2O2-Induced Oxidative Stress.
    Fanghui Ge, Jingxuan Shu, Ziqian Liu, Haixiang Ma, Minghong Cai, Xinyan Deng, Hong Zhang, Jiandong Wang.
      Oxidative stress is a major contributor to neuronal apoptosis and subsequent neurofunctional deficits. This study investigates the dual role of the mitochondrial membrane-anchored protein NIX in PC12 cells, a model for mature neurons. We demonstrate that both overexpression and knockdown of NIX attenuate apoptosis under oxidative stress, albeit through distinct mechanisms. Overexpression of NIX promotes cell survival by activating NIX-mediated mitophagy, which clears damaged mitochondria and intracellular reactive oxygen species (ROS), thereby maintaining redox homeostasis. Conversely, knockdown of NIX reduces apoptosis primarily by diminishing the intrinsic pro-apoptotic function of the protein. Collectively, these findings reveal that NIX expression levels critically gate PC12 cell fate under oxidative stress by differentially activating pro-survival or anti-apoptotic pathways.
    Keywords:  NIX/BNIP3L; apoptosis; mitophagy; oxidative stress
    DOI:  https://doi.org/10.3390/biology15110867
  52. Hum Mutat. 2026 ;2026 9418012
    E2F4 Mediates Mitophagy to Inhibit Ferroptosis in Esophageal Cancer Cells by Activating GPR176.
    Weilang Xu, Fang Su, Luxuan Xie, Tao Ding, Xiao Qi, Peiqiang Chen, Zaiyuan Ye, Wenfa Lin.
      Esophageal cancer (EC) is driven by complex dysregulated molecular networks, and ferroptosis-an iron-dependent, non-apoptotic form of regulated cell death-has emerged as a critical modulator of tumorigenesis. However, the functional contribution and mechanistic basis of GPR176 in ferroptosis regulation during EC progression remain largely unexplored. Here, we integrated computational and experimental approaches to delineate the role of GPR176 and its upstream regulator E2F4 in EC ferroptosis. Bioinformatic analysis revealed consistent upregulation of both GPR176 and E2F4 in EC tissues, which was further confirmed by molecular validation. Functional assays demonstrated that GPR176 overexpression conferred resistance to ferroptosis in EC cells, as reflected by reduced malondialdehyde, intracellular Fe2+, and lipid reactive oxygen species (ROS) accumulation, alongside altered expression of core ferroptosis mediators. This protective effect was associated with the suppression of mitophagy, as indicated by alterations in mitochondrial function and autophagy-related markers. Mechanistically, we demonstrated that E2F4 directly binds to the GPR176 promoter and transcriptionally activates its expression. Rescue experiments further validated that GPR176 overexpression abrogated the enhanced mitophagy and ferroptosis induced by E2F4 depletion. Collectively, our findings define an E2F4/GPR176/mitophagy axis that acts to suppress ferroptosis in EC, highlighting this pathway as a novel therapeutic target for inducing ferroptosis in EC intervention.
    Keywords:  E2F4; GPR176; esophageal cancer; ferroptosis; mitophagy
    DOI:  https://doi.org/10.1155/humu/9418012
  53. Mater Today Bio. 2026 Jun;38 103291
    A DPEP1-Binding and mitochondria-targeted nanocomposite relieves acute respiratory distress syndrome by inhibiting Drp1-mediated mitochondria fission.
    Ming He, Peng Zhang, Suya Bao, Rui Luo, Li Chen, Wenqi Huang, Weixi Jiang, An Zhang.
      Acute respiratory distress syndrome (ARDS), a severe condition associated with high mortality, is characterized by uncontrollable inflammation and oxidative stress linked to mitochondrial dysfunction. Dynamin-related protein 1 (Drp1) drives pathological mitochondrial fission in patients with ARDS, leading to a sustained inflammatory response and excessive mitochondrial reactive oxygen species (mtROS) production. However, the specific inhibition of Drp1 in lung mitochondria remains challenging. Here, a multifunctional nanocomposite (DTP-LSA@MTC NPs) was developed by integrating the Drp1 inhibitor Mdivi-1 with a mitochondria-targeting tannic acid-cerium (TA-Ce) nanozyme network. Additionally, surface functionalization with an LSA peptide enabled specific binding to DPEP1 on the inflamed pulmonary endothelium, enhancing site-specific accumulation and competitively inhibiting neutrophil recruitment. Following intravenous administration, these nanoparticles efficiently targeted both pulmonary microvascular endothelial cells and mitochondria, suppressed the activity of the Drp1-NLRP3 inflammasome axis, and scavenged ROS, ultimately preventing the development of cytokine storms in preclinical models of ARDS. This targeted nanotherapeutic strategy offers a potent and translatable approach for treating ARDS and related inflammatory disorders.
    Keywords:  Acute respiratory distress syndrome; Dynamin-related protein 1; Mitochondria fission; Nanozyme
    DOI:  https://doi.org/10.1016/j.mtbio.2026.103291
  54. Andrology. 2026 Jun 11.
    ClpP Ensures Mitochondrial Integrity and Spermatocyte Meiotic Progression in Mice.
    Hai-Wei Feng, Yan-Lin Gao, Bin-Jie Jiang, Muhammad Zubair, Dong-Teng Liu, Zhi-Shen Xu, Zheng-Zhu Wang, Hong-Ling Wang, Xue-Mei Wang, Jing-Xia Sun, Guo-Hua Zeng, Li-Jun Huo.
       BACKGROUND: Caseinolytic peptidase P (ClpP) plays a key role in maintaining cellular homeostasis for mitochondrial quality control. However, the specific function of ClpP during meiosis and its subcellular localization in spermatocytes remain poorly understood.
    OBJECTIVE: To investigate the function of ClpP in spermatocyte meiosis.
    MATERIALS AND METHODS: ClpP expression was examined in mouse spermatocytes, and tamoxifen was utilized to achieve spatiotemporal-specific deletion of Clpp mediated by Ddx4-CreERT2 in spermatocytes. We analyzed the meiotic progression of Clpp conditional KO (ClppcKO) using spermatocyte chromosome spreading, combined with immunofluorescence and transmission electron microscopy, to determine the morphology and number of spermatocyte mitochondria in ClppcKO mice.
    RESULTS: A progressive increase in ClpP expression levels was evident from the leptotene stage to the pachytene stage in mouse spermatocytes, and a decrease in ClpP expression was observed from the diplotene stage to the metaphase I (MI) stage. Compared with wild-type male mice, adult ClppcKO male mice had reduced testis size and no mature spermatozoa in their epididymides. A large proportion of pachytene and diplotene spermatocytes, as well as round or elongated spermatids, were eliminated from the seminiferous tubules of the ClppcKO mice. The mitochondria of ClppcKO spermatocytes appeared as "giant mitochondria." However, ClppcKO spermatocytes exhibited normal meiotic synapsis and impaired recombination, with reduced RAD51 foci and abnormal MLH1 localization.
    CONCLUSIONS: ClpP is critical for spermatocyte survival and mitochondrial integrity during meiosis. As a consequence of its deficiency, meiotic progression and spermatogenesis are disrupted, highlighting its essential role in the meiosis of spermatocytes.
    Keywords:  ClpP; meiotic recombination ; mitochondrial morphology ; spermatogenesis
    DOI:  https://doi.org/10.1111/andr.70274
  55. J Physiol Pharmacol. 2026 Apr;77(2): 249-264
    Glutamyl-tRNA synthetase 2 regulates mitochondrial biogenesis and reactive oxygen species homeostasis mediatingenzalutamide resistance by targeting striatin 4 in prostate cancer cells.
    B Q Wang, X Wang, W Liu, L Jin.
      Although enzalutamide (ENZA) has improved the overall survival of patients with metastatic prostate cancer, ENZA resistance (ENZA-resistant) inevitably develops, largely limiting its efficacy. Alternative oncogenic pathways may bypass androgen receptor (AR) signaling to promote ENZA-resistant. Glutamyl-tRNA synthetase 2 (EARS2) is involved in mitochondrial biogenesis and is associated with cancer, but its action mechanism in prostate cancer (PCa) is not well defined. EARS2 expression was detected in primary PCa and castrate-resistant prostate cancer samples, ENZA-resistant cell lines, and ENZA-resistant xenograft models, and the prognostic relationship of EARS2 in patients with PCa was analyzed. In AR-sensitive LNCaP cells, changes in EARS2 expression were explored before and after stimulation with dihydrotestosterone (DHT) or bicalutamide. AR was knocked down in AR-positive LNCaP and C4-2B cells to explore the relationship between EARS2 and AR. The effect of EARS2 on PCa cells was further explored. ENZA-resistant xenograft model was built to explore the effect of EARS2 on tumorigenesis in vivo. EARS2 was knocked down in C4-2B-ENZA-resistant, and the relationship between EARS2 and mitochondrial biogenesis and reactive oxygen species (ROS) homeostasis was investigated in PCa cells. Finally, the relationship between EARS2 and striatin 4 (STRN4) was explored. EARS2 expression was elevated in PCa and correlated with ENZA-resistant, and high EARS2 expression was associated with poorer patient prognosis. In androgen-sensitive LNCaP cells, DHT inhibited EARS2 expression, and silencing AR increased EARS2 expression. Suppressing EARS2 inhibited the proliferation, colony formation, migration and invasion ability, down-regulated the IC50 of ENZA in ENZA-resistant cells, and promoted apoptosis. Stable EARS2 downregulation in C4-2B-ENZA-resistant significantly inhibited tumor growth. Suppressing EARS2 in ENZA-resistant cells may lead to increased mitochondrial biogenesis and ROS generation. Mechanistically, EARS2 inhibited mitochondrial biogenesis and ROS generation in PCa cells by targeting STRN4. EARS2 targets STRN4 to modulate mitochondrial biogenesis and ROS homeostasis mediating ENZA-resistant.
    Keywords:  androgen receptor; enzalutamide resistance; glutamyl-tRNA synthetase 2; homeostasis; mitochondrial biogenesis; prostate cancer; reactive oxygen species; striatin 4
    DOI:  https://doi.org/10.26402/jpp.2026.2.07
  56. Int J Mol Sci. 2026 May 30. pii: 4966. [Epub ahead of print]27(11):
    Sex Differences in Mitochondrial Function: Endocrine Regulation, Immunometabolic Signaling, and Implications for Health and Disease.
    Hanna Bynum, Kristin S Edwards.
      Mitochondria are central regulators of cellular bioenergetics, redox balance, and signaling pathways that integrate metabolic and immune responses. Emerging evidence indicates that biological sex is an important determinant of mitochondrial function, in part through the regulatory effects of sex hormones on mitochondrial biogenesis, oxidative phosphorylation, reactive oxygen species production, and quality control mechanisms. Estrogen, testosterone, and progesterone differentially modulate mitochondrial dynamics, substrate utilization, antioxidant capacity, and immune signaling, resulting in distinct mitochondrial phenotypes that may influence disease susceptibility across the lifespan. In this review, we synthesize current knowledge on the mechanistic basis of sex differences in mitochondrial function and highlight mitochondria as key mediators linking endocrine signaling to immunometabolic regulation. We discuss how mitochondrial-derived signals, including mitochondrial reactive oxygen species, mitochondrial DNA release, and cardiolipin exposure, activate inflammatory pathways such as NF-κB, cGAS-STING, and NLRP3 inflammasome signaling. These pathways may contribute to chronic inflammation, gut barrier dysfunction, and systemic metabolic disruption. We further examine the impact of major endocrine transitions, including pregnancy, the postpartum period, menopause, and androgen imbalance in conditions such as polycystic ovary syndrome, on mitochondrial function and disease risk. Particular emphasis is placed on the gastrointestinal tract as a metabolically active and mitochondria-dependent interface, where mitochondrial dysfunction may contribute to epithelial barrier disruption, microbial dysbiosis, and systemic inflammation. Finally, we discuss emerging therapeutic strategies targeting mitochondrial function, including exercise, hormone-based therapies, mitochondria-targeted antioxidants, and interventions aimed at improving mitochondrial quality control. Understanding sex-specific mitochondrial regulation may provide a framework for improved endocrine stratification, mitochondrial phenotyping, and precision medicine approaches across diverse clinical contexts.
    Keywords:  endocrine disorders; estrogen; immunometabolism; mitochondria; mitochondrial dynamics; mitochondrial reactive oxygen species; oxidative phosphorylation; sex differences; sex hormones; testosterone
    DOI:  https://doi.org/10.3390/ijms27114966
  57. Stem Cell Reports. 2026 Jun 11. pii: S2213-6711(26)00162-1. [Epub ahead of print] 102951
    Electron transport chain complex I and mitochondrial fusion regulate ROS for differentiation in Drosophila neural stem cells.
    Rahul Kumar Verma, Atharva Bhingare, Dnyanesh Dubal, Richa Rikhy.
      Mitochondrial fusion and electron transport chain complex I are each essential for differentiation in Drosophila neuroblasts, but the mechanism by which they interact to mediate differentiation is unknown. We found that complex I subunit depletion did not affect type II neuroblast numbers but reduced their proliferation and decreased their lineage cells. Complex I depletion decreased the mitochondrial membrane potential and cristae numbers, increased fragmentation and ROS, and inhibited Notch signaling in lineage cells. Similarly, antioxidant enzyme depletion increased ROS and reduced lineage cells. Both complex I and antioxidant proteins promoted the G1/S transition and nuclear cyclin E levels. Additional mitochondrial fusion via Drp1 mutants restored ROS levels, proliferation, and differentiation defects in complex I and antioxidant protein-depleted neuroblasts. Overexpression of antioxidant proteins and an increase in Notch signaling alleviated ROS and the complex I depletion-driven defect in neuroblast proliferation and differentiation. Complex I and mitochondrial fusion together restrict ROS to support neuroblast proliferation and differentiation.
    Keywords:  Drosophila; Drp1; Notch; complex I; differentiation; mitochondria; mitochondrial fragmentation; mitochondrial fusion; neural stem cells; neuroblasts
    DOI:  https://doi.org/10.1016/j.stemcr.2026.102951
  58. Cell Commun Signal. 2026 Jun 11.
    Stage-dependent DNA damage and mitochondrial dysfunction under simulated microgravity constrain oocyte maturation and are mitigated by melatonin.
    Yuqing Gao, Lei Ge, Tianxia Xiao, Feifei Du, Jie Chen, Mengxia Li, Wakam Chang, Yali Yang, Jian V Zhang.
      During spaceflight, the female reproductive system undergoes substantial adaptation to microgravity and faces an increased risk of reproductive impairment. Mammalian oocytes remain arrested for extended periods at the first meiotic prophase, a stage particularly vulnerable to DNA damage, yet whether simulated microgravity (SMG) directly induces oocyte genomic damage and how such damage, together with the associated meiotic arrest, can be mitigated remain unclear. Melatonin (MLT), a pineal hormone with broad physiological roles, has shown benefits in improving oocyte quality in vivo and in vitro. Using SMG as a stress model, we demonstrate that during the prophase-arrested stage, SMG exposure induces DNA double-strand breaks with activation of the ATM-CHK2 DNA damage response, without detectable elevation of global cellular ROS or mitochondrial superoxide. These changes were accompanied by abnormal mitochondrial distribution and increased early apoptosis. In vitro MLT supplementation during SMG exposure alleviated DNA damage through a DNA-PKcs-associated NHEJ repair response, improved mitochondrial distribution, and this protective effect was largely independent of canonical MT1 or MT2 receptor signaling. During meiotic maturation, MLT improved SMG-induced spindle assembly defects, promoted MTOC coalescence, suppressed mitochondrial unfolded protein response overactivation, reduced SMG-induced mitochondrial hyperpolarization, and reduced early apoptosis. Consequently, oocytes exposed to MLT exhibited increased first polar body extrusion, improved spindle integrity, and enhanced oocyte-intrinsic developmental competence, as reflected by increased blastocyst formation after parthenogenetic activation. Together, these findings show that SMG induces DNA damage in prophase-arrested oocytes and identify MLT as a stage- and dose-sensitive modulator of DNA repair and mitochondrial homeostasis, offering a potential strategy to protect female reproductive health during spaceflight.
    Keywords:  DNA damage; Melatonin; Mitochondrial homeostasis; Oocyte maturation; Simulated microgravity
    DOI:  https://doi.org/10.1186/s12964-026-02976-z
  59. J Nanobiotechnology. 2026 Jun 06.
    Selenium nanoparticle-loaded microneedle patches promote diabetic oral ulcer healing by regulating the inflammatory microenvironment through upregulation of SELENBP1-mediated mitophagy.
    Xia Wang, Haiyin Wan, Xujie Cui, Bo Tan, Haofeng Wang, Jing He, Zichen Yang, Xiaoxuan Han, Jingang Xiao, Gang Tao, Yun He, Rui Cai.
      Diabetes mellitus (DM) is frequently complicated by refractory oral ulcers, which are characterized by persistent inflammation and impaired healing. We first identified that diabetic oral ulcer tissues exhibit significant selenium deficiency, downregulated SELENBP1 expression, and substantial mitochondrial damage - key factors contributing to the pathogenesis. To address this pathological condition, we developed a sericin-selenium nanoparticle-loaded microneedle patch (Ser-SeNPs@MN) for efficient selenium delivery and targeted therapy of diabetic oral ulcers. The Ser-SeNPs were synthesized using a green sericin-based method, demonstrating enhanced stability and biosafety. The Ser-SeNPs@MN enabled mucosal adhesion and sustained release of Ser-SeNPs, significantly improving selenium bioavailability. In vitro experiments revealed that Ser-SeNPs@MN promoted the expression of SELENBP1 and key selenoproteins (GPX1, GPX2, TXNRD1, TXNRD2), activated PINK1/Parkin-mediated mitophagy, and restored mitochondrial function. Consequently, it suppressed pro-inflammatory responses and facilitated M2 macrophage polarization. In both diabetic oral ulcer and skin wound rat models, Ser-SeNPs@MN accelerated wound closure, enhanced collagen deposition, and promoted angiogenesis. These findings underscore the therapeutic potential of Ser-SeNPs@MN as a multifunctional platform for diabetic wound management through selenium-mediated mitochondrial recovery and immune modulation.
    Keywords:  Diabetic oral ulcer; Microneedle patch; Mitophagy; SELENBP1; Selenium nanoparticles; Wound healing
    DOI:  https://doi.org/10.1186/s12951-026-04586-w
  60. Am J Pathol. 2026 Jun 11. pii: S0002-9440(26)00167-7. [Epub ahead of print]
    Metformin activates AMPK-TFEB signaling to restore lysosomal and mitochondrial homeostasis and suppress EMT in oxidative stress-injured retinal pigment epithelium.
    Sumin Son, Yoonha Kim, Kyoung-Jin Jang, Dong-Eun Kim.
      Disruption of lysosomal homeostasis and accumulation of dysfunctional mitochondria contribute to degenerative pathologies including age-related macular degeneration (AMD). Here, we investigated how inhibition of autophagic lysosome reformation (ALR) alters lysosomal dynamics, mitophagy, and downstream stress signaling in retinal pigment epithelial (RPE) cells, and whether these changes are pharmacologically reversible. In ARPE-19 cells, ALR inhibition by nocodazole or siRNA-mediated depletion of kinesin-1 (UKHC) and dynamin-2 (DNM2) induced enlarged lysosomes with reduced degradative capacity, impaired mitophagic turnover, and accumulation of dysfunctional mitochondria. ALR blockade increased reactive oxygen species (ROS) and cytosolic Ca2+, promoted activation and mitochondrial translocation of protein kinase C (PKC), and triggered phosphorylation of glycogen synthase kinase-3β with subsequent stabilization of SNAIL, consistent with epithelial-to-mesenchymal transition (EMT). Metformin restored lysosomal homeostasis by activating AMPK and enhancing transcription factor EB (TFEB)-dependent lysosome biogenesis, thereby improving autophagic flux, limiting ROS/Ca2+ accumulation, suppressing PKC activation, and attenuating EMT-associated marker changes. In a sodium iodate-induced oxidative injury model, metformin preserved RPE microtubule architecture and reduced lysosomal and mitochondrial abnormalities. Although these findings rely on a prolonged monolayer culture system and an acute injury model, they support a protective role for AMPK-TFEB-driven lysosome restoration in RPE stress resilience and suggest lysosome-directed repurposing potential for metformin in degenerative retinal disease.
    Keywords:  Autophagic lysosome reformation (ALR); Epithelial–mesenchymal transition (EMT); Lysosomal homeostasis; Mitochondrial dysfunction; Retinal pigment epithelium (RPE)
    DOI:  https://doi.org/10.1016/j.ajpath.2026.05.009
  61. J Ethnopharmacol. 2026 Jun 11. pii: S0378-8741(26)00875-5. [Epub ahead of print] 122021
    San Wei Tan Xiang (SWTX) ameliorates depressive-like behaviors by modulating 6-phosphogluconate dehydrogenase (6PGD) activity in mice.
    Yuyan Ling, Ling Gu, Shuxun Feng, Manjia Dong, Lei Li, Xingjian Zhang, Xiongfei Zhang, Ruiting Ma, Meijuan Chen, Lijun Tong.
       ETHNOPHARMACOLOGICAL RELEVANCE: San Wei Tan Xiang (SWTX), known as Zandansong Tang in Tibetan medicine, is recorded in the Four Medical Classics and is commonly used in Tibetan medicine. Recently, it has been found to exhibit good therapeutic efficacy in patients with depression.
    AIM OF THE STUDY: This study aims to assess the therapeutic benefits of SWTX for depression and to elucidate the underlying mechanism whereby SWTX improves depressive-like behavior via regulation of 6-phosphogluconate dehydrogenase (6PGD).
    MATERIALS AND METHODS: A depression model was established via corticosterone (CORT) stimulation, followed by treatment with San Wei Tan Xiang (SWTX). Behavioral tests were conducted to evaluate emotional changes, while Nissl staining and ELISA were employed to assess histopathological alterations and biochemical indices, respectively. 6PGD activity was measured using commercial enzyme activity assay kits. Protein expression levels were analyzed by immunofluorescence and western blotting. Furthermore, oxidative stress status in mouse brain was evaluated through malondialdehyde, superoxide dismutase, and glutathione assays, along with ROS levels using flow cytometry.
    RESULTS: SWTX exhibited significant antidepressant activity in a mouse model of depressive-like behavior by activating 6PGD to restore cerebral redox homeostasis. This activation enhanced pentose phosphate pathway (PPP) metabolism and NADPH generation, consequently ameliorating mitochondrial function and attenuating mitophagy. In addition, the potential active ingredient in SWTX, naringenin, is associated with increasing 6PGD activity and promoting NADPH biosynthesis, thereby restoring redox homeostasis, maintaining mitochondrial integrity, and thus weakening the compensatory upregulation of mitochondria mediated by PINK1/Parkin. Through molecular docking and Bio-Layer Interferometry (BLI) assays, we identified naringenin as a potential bioactive component in the therapeutic effects of SWTX. Naringenin also demonstrated beneficial effects in investigating mitochondrial damage caused by oxidative stress due to 6PGD downregulation and excessive activation of PINK1/PARK2/Parkin. Therefore, naringenin may be one of the active components responsible for the antidepressant effects of SWTX.
    CONCLUSIONS: SWTX ameliorates depressive-like behaviors by coordinating 6PGD activity and mitochondrial function, including restoring NADPH generation via the PPP to alleviate oxidative stress, and improving mitochondrial quality through the PARK2/Parkin/PINK1 pathway. These findings highlight SWTX as a promising holistic therapeutic approach for depression, reflecting the multi-component and multi-target pharmacological characteristics of traditional formulations. Further exploratory analysis suggested that naringenin, one of the SWTX-derived absorbable constituents, may contribute to 6PGD/NADPH pathway regulation and neuronal protection in CORT-treated primary hippocampal neurons. However, the naringenin-related results should be interpreted cautiously because additional pharmacokinetic, dose-response, and direct structural validation studies are required.
    Keywords:  6-phosphogluconate dehydrogenase (6-PGD); Antioxidant; Depression; PARK2/Parkin/PINK1; San Wei Tan Xiang (SWTX); mitophagy
    DOI:  https://doi.org/10.1016/j.jep.2026.122021
  62. Free Radic Biol Med. 2026 Jun 08. pii: S0891-5849(26)00871-3. [Epub ahead of print]
    ac4C modification of PDK4 by NAT10 promotes pulmonary fibrosis by reprogramming mitochondrial dynamics in fibroblasts.
    Dongyu Liu, Yanqun Li, Tianyang Liu, Yuhan Du, Jinzhong Zhuo, Jiangzhou Du, Qi Yu, Huimin Yang, Liping Huang, Haohua Huang, Yixin Chen, Minxuan Hu, Xiaoxiao Jiang, Jie Chen, Shiya Liang, Qingmei Wang, Zhuman Wu, Shaoxi Cai, Jinming Zhang, Hangming Dong.
      Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disorder with limited therapeutic options, necessitating the identification of novel pathogenic mechanisms and therapeutic targets. Here, we report a critical role for the RNA acetyltransferase NAT10 in driving pulmonary fibrosis through epitranscriptomic regulation of mitochondrial metabolism. We found that NAT10 and its catalyzed N4-acetylcytidine (ac4C) modification were significantly upregulated in fibrotic lungs from IPF patients and bleomycin-challenged mice, particularly within activated fibroblasts. Genetic ablation of NAT10 in fibroblasts markedly attenuated fibrotic progression, whereas its overexpression exacerbated the pathology. Mechanistically, integrated transcriptomic and biochemical analyses identified pyruvate dehydrogenase kinase 4 (PDK4) as a key downstream target whose mRNA stability was enhanced by NAT10-mediated ac4C modification. This post-transcriptional regulation led to PDK4 upregulation, which in turn promoted mitochondrial fission and reactive oxygen species production, thereby facilitating fibroblast-to-myofibroblast transition and excessive extracellular matrix deposition. Furthermore, we delineated the upstream regulation of NAT10, demonstrating that TGF-β1 transcriptionally induces NAT10 expression via direct Smad3 binding to its promoter, forming a positive feedback loop that sustains fibrotic activation. Our study unveils the NAT10-ac4C-PDK4 axis as a central regulator of mitochondrial dynamics in pulmonary fibrosis and highlights NAT10 as a promising therapeutic target for restoring metabolic homeostasis and ameliorating fibrotic lung remodeling.
    Keywords:  Idiopathic pulmonary fibrosis; Mitochondrial dynamics; NAT10; PDK4; ac4C modification
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.06.020
  63. Cell Prolif. 2026 Jun 10. e70248
    Dental Pulp Stem Cell-Derived Intracellular Vesicles Inhibit OSCC by Delivering PTEN to Suppress PI3K/AKT/mTOR Signalling Pathway.
    Yu Luo, Qiang Qin, Wenting She, Xiangying Wang, Xiqin Li, Chenxuan Shu, Ruohan Li, Ziwei Li, Dongjie Fu, Yan He, Qingsong Ye.
      Oral squamous cell carcinoma (OSCC) represents a globally predominant type of oral malignancy with escalating incidence, featuring aggressive biological behaviour, prominent metastatic potential and poor clinical outcomes. Emerging evidence positions dental pulp stem cell-sourced intracellular vesicles (DPSC-IVs) as novel therapeutic vectors in regenerative oncology, citing their low immunogenicity, favourable safety profile and ability to modulate tumour microenvironment. In this study, DPSC-IVs significantly inhibited OSCC progression both in vitro and in vivo, suppressing tumour cell proliferation, invasion and colony formation while simultaneously promoting apoptosis. Notably, the antitumor effect of DPSC-IVs was further enhanced by combining them with autophagy inhibitor 3-methyladenine (3-MA), which synergistically suppressed the PI3K/AKT/mTOR pathway and enhanced mitochondrial stress while suppressing residual cytoprotective autophagy. Mechanistically, DPSC-IVs served as carriers of PTEN into OSCC cells, which in turn suppressed oncogenic PI3K/AKT signalling and induced excessive mitophagy. Taken together, this study indicated that DPSC-IVs could suppress OSCC through dual mechanisms, highlighting their potential as a promising and clinically translatable therapeutic option with advantages in safety and scalable production.
    Keywords:  DPSC‐IVs; OSCC; PI3K/AKT/mTOR signalling pathway; PINK1/parkin mediated mitophagy
    DOI:  https://doi.org/10.1111/cpr.70248
  64. Clin Sci (Lond). 2026 Jun 08. pii: CS20260714. [Epub ahead of print]
    DRP1/p53 interaction mediated mitochondrial regulation of TFRC-SLC39A14 drives mechanical overload-induced temporomandibular joint osteoarthritis via ferroptosis.
    Yidi Wang, Yutong Guo, Xiaotong Yu, Shengjie Cui, Xi Wen.
      Condylar cartilage maintains the structure and function of temporomandibular joint (TMJ), with disturbances leading to potential osteoarthritis (OA). Though current research has indicated that Transferrin receptor (TFRC) regulating ferroptosis affects the progression of TMJOA, its role in cartilage homeostasis remains unclear. Therefore, we constructed unilateral anterior crossbite (UAC) and cartilage-specific Tfrc conditional knockout (Tfrc-cKO) mice. The expressions of iron transportation-associated genes including TFRC and SLC39A14, and ferroptosis-related markers were detected in TMJ cartilage through immunofluorescence, immunohistochemical staining, western blot and qPCR assays. Knockdown of Tfrc and knockdown of Drp1 by small interfering RNA in ATDC5 cell line under mechanical overloading were used to investigate the mechanism in vitro through western blot, qPCR and flow cytometry assays. Deferiprone was utilized to verify the pathway in vitro and in vivo. Both the control and Tfrc-cKO mice with UAC developed cartilage degradation and subchondral bone resorption. While the former showed upregulated TFRC and SLC39A14 expression in condylar chondrocytes, the latter exhibited increased SLC39A14 expression alone with elevated ferroptosis markers. Under normal circumstances, cytoplasmic p53 induced ubiquitinated degradation of SLC39A14 mediated by SIAH1. However, under Tfrc knockdown and mechanical overloading, increased DRP1 expression and its Ser616 phosphorylation promoted mitochondrial p53 translocation and reduced SLC39A14 ubiquitination degradation. Both siDrp1-mediated knockdown and deferiprone treatment modulated DRP1 expression to attenuate mitochondrial p53 translocation and alleviate TMJOA progression by suppressing ferroptosis. Our findings demonstrate the role of TFRC and SLC39A14 in maintenance of cartilage homeostasis with DRP1-mediated mitochondrial p53 translocation, offering insights into potential treatment strategies for TMJOA.
    Keywords:  SLC39A14; cartilage homeostasis; ferroptosis; mitochondrial dynamics; p53; transferrin receptor
    DOI:  https://doi.org/10.1042/CS20260714
  65. Nat Commun. 2026 Jun 10.
    A mitochondria-driven quality control mechanism for peroxisomal membrane proteins.
    Sarin Segev-Nakar, Itay Koren.
      Peroxisomes are essential organelles involved in lipid and reactive oxygen species metabolism, and their function requires proper targeting of peroxisomal membrane proteins (PMPs). When peroxisome biogenesis fails, as occurs in peroxisome biogenesis disorders, PMP levels decrease markedly, yet the underlying mechanisms remain unclear. Here, using quantitative proteomics and transcriptomics in peroxisome-deficient cells, we observe widespread post-transcriptional downregulation of PMPs driven by increased protein turnover via ubiquitination and proteasomal degradation. An unbiased CRISPR screen uncovers a mitochondrial quality control axis. PMPs that fail to reach their native peroxisomal destination are rerouted to mitochondria, where the mitochondrial outer membrane E3 ligases MUL1 and MARCH5 act redundantly to promote their degradation. Importantly, the transmembrane domain of PMPs is sufficient to drive their mitochondrial turnover. Functionally, simultaneous loss of peroxisomes and mitochondrial E3 ligases severely impairs cell proliferation, underscoring the essential role of this pathway. Together, these findings provide insight into the pathology of organelle dysfunction and reveal an inter-organelle quality control axis in which mitochondria act as a surveillance hub to clear PMPs and maintain cellular proteostasis when peroxisomes are absent.
    DOI:  https://doi.org/10.1038/s41467-026-74117-6
  66. Adv Healthc Mater. 2026 Jun 12. e05083
    Chitosan-Functionalized Liposome-Mediated Fundus Delivery of Epigallocatechin-3-Gallate for Diabetic Retinopathy Therapy.
    Xingxiu Jiang, Haoliang Shi, Binbin Chu, Yulan Gu, Yicheng Zhang, Li Wang, Yao He, Xiaofeng Zhang.
      Among working-age adults in the contemporary era, more than 30% of individuals with diabetes are at risk of developing diabetic retinopathy (DR), a progressive ocular disorder that is the leading cause of visual impairment and blindness. Despite its high prevalence, treatment options remain limited. Current therapeutic strategies only focus on the inhibition of neovascularization or prevention of vascular leakage. Additionally, the majority of conventional eye drop formulations fail to deliver drugs efficiently to the retina, further limiting clinical applicability. To address these issues, we herein designed and developed an eye drop formulation based on the chitosan-modified liposomes encapsulating epigallocatechin-3-gallate (EGCG), capable of transporting EGCG from the ocular surface to the retina. Mechanistic studies revealed that efficient retinal delivery of EGCG could protect Müller cells against high glucose (HG)-induced injury via SIRT1-BNIP3-mediated mitophagy. In vivo, the developed EGCG@CS-LIP showed enhanced fundus delivery and therapeutic efficacy compared with conventional liposomes or free EGCG systems, attributed to the transient modulation of corneal tight junctions. More importantly, the EGCG@CS-LIP eye drops could effectively increase the expression level of SIRT1 protein and inhibit the apoptosis and damage in retina, thus exerting significant in vivo therapeutic effects for the effective treatments of DR. Lastly, the constructed EGCG@CS-LIP indicated the excellent ocular biocompatibility, highlighting its promise for future clinical translation in DR therapy.
    Keywords:  EGCG; diabetic retinopathy; eyedrops; fundus delivery; liposomes; mitophagy
    DOI:  https://doi.org/10.1002/adhm.202505083
  67. Redox Biol. 2026 May 22. pii: S2213-2317(26)00229-6. [Epub ahead of print]95 104231
    Fasting requires Peroxiredoxin 2 and Peroxiredoxin 6 to coordinate redox dependent mitochondrial and lipid remodelling in Caenorhabditis elegans.
    Penglin Li, Yating Zheng, Jose C Casas-Martinez, Qin Xia, Antonio Miranda-Vizuete, Katarzyna Goljanek-Whysall, Brian McDonagh.
      Fasting induces conserved metabolic and redox adaptations that promote stress resistance and longevity. However, the molecular mechanisms linking transient redox changes and altered metabolism to downstream signalling events remain incompletely understood. Using Caenorhabditis elegans, the roles of peroxiredoxins in coordinating redox-dependent responses to fasting and refeeding were determined. A 4-hr fasting protocol over 5 days extended lifespan, improved late-life physiological activity, reduced age-related lipofuscin and lipid accumulation. The fasting protocol generated a transient increase in mitochondrial ROS, promoted mitochondrial turnover, and attenuated age-related mitochondrial fragmentation. These adaptive responses required the activation and nuclear localisation of the stress-responsive transcription factors DAF-16/FOXO and SKN-1/Nrf2. However, these adaptive responses were abolished in prdx-2 and prdx-6 mutant strains, which exhibited persistent redox imbalance, mitochondrial fragmentation, altered stress resistance, and disrupted DAF-16 and SKN-1 signalling. Mechanistically, loss of 2-Cys PRDX-2 impaired activation of the p38 MAPK PMK-1 pathway, resulting in defective SKN-1 activation. In contrast, loss of 1-Cys PRDX-6 disrupted lipid metabolic signalling, preventing induction of NHR-80 and downstream fatty acid desaturases required for metabolic adaptations. Despite distinct initial signalling pathways, both peroxiredoxins converged on the regulation of DAF-16 and SKN-1. Together, these findings identify PRDX-2 and PRDX-6 as redox sensors that translate a fasting-induced transient ROS signature into mitochondrial and lipid remodelling pathways to promote healthy ageing.
    Keywords:  Ageing; Fasting; Lipid remodelling; Mitochondrial dynamics; Oleic acid; Peroxiredoxin
    DOI:  https://doi.org/10.1016/j.redox.2026.104231
  68. Cancers (Basel). 2026 May 27. pii: 1746. [Epub ahead of print]18(11):
    Divergent Role of ULK1 to Balance Mitochondrial Homeostasis and Bioenergetics in Ovarian Cancer Spheroids.
    Jack D Webb, Matthew J Borrelli, Yudith Ramos Valdés, Trevor G Shepherd.
       BACKGROUND/OBJECTIVES: Epithelial ovarian cancer (EOC) is the deadliest gynaecologic malignancy, largely due to late-stage diagnosis and ineffective therapy. EOC commonly spreads through the peritoneal cavity as multicellular spheroids, which are metastatic structures that enhance survival under detachment stress, promote dissemination, and contribute to therapeutic resistance. We previously showed that ULK1, a serine/threonine kinase classically linked to macroautophagy initiation, supports EOC progression, suggesting non-canonical roles in spheroid biology and pathogenesis.
    METHODS: CRISPR/Cas9 ULK1 knockout (ULK1KO) models were generated in OVCAR8, HEYA8, and ES2 cells. Mitochondrial degradation phenotypes were assessed in spheroids by immunoblotting and fluorescence microscopy. Label-free proteomics with bioinformatic pathway analysis identified ULK1-associated programs in EOC spheroids. Bioenergetic consequences were quantified using Seahorse ATP-Rate assays. Therapeutic interactions were evaluated using multi-dose combination matrices testing the ULK1 inhibitor DCC-3116 with metformin.
    RESULTS: ULK1 modulated mitochondrial degradation in a cell-line-specific manner, either promoting or protecting against mitochondrial loss through mechanisms that were uncoupled from canonical autophagy machinery. Proteomic and bioinformatic analyses revealed significant alterations in mitochondria-related processes, aligning with emerging ULK1 functions in mitochondrial homeostasis. ULK1 loss broadly reduced OXPHOS complex proteins in EOC spheroids and consistently decreased hexokinase 2 (HK2), indicating coordinated metabolic remodeling. Seahorse profiling mirrored these shifts: OVCAR8 ULK1KO spheroids showed reduced OCR and ATP production, whereas HEYA8 and ES2 ULK1KO spheroids exhibited increased mitochondrial ATP production. Combination matrices showed potential synergy between DCC-3116 and metformin.
    CONCLUSIONS: These data show that ULK1 differentially regulates mitochondrial degradation across EOC spheroid models through potential mechanisms alternative to canonical autophagy machinery, while reshaping spheroid metabolism and revealing potential therapeutic vulnerabilities in advanced EOC.
    Keywords:  ULK1; autophagy; mitochondria; ovarian cancer; oxidative phosphorylation; spheroids
    DOI:  https://doi.org/10.3390/cancers18111746
  69. FASEB J. 2026 Jun 30. 40(12): e71972
    eIF3 Orchestrates a Biphasic Stress Response Linking Translational Control to Mitochondrial Integrity in Skeletal Muscle.
    Yingying Lin, Jianing Xia, Man Li, Junhao Zhang, Yonghao Mu, Lenian Ling, Minghao Lu, Jiahuan Wang, Kexin Liao, Yefeng Cai.
      Skeletal muscle adaptation to physiological and pathological stressors requires precise coordination of protein synthesis and mitochondrial function. While the roles of canonical translation regulators such as eIF2α and 4E-BP1 in exercise-induced protein synthesis modulation are well established, the contribution of eIF3, the largest eukaryotic initiation factor complex, to muscle stress responses remains poorly understood. Eukaryotic initiation factor 3 (eIF3) regulates mRNA translation and mitochondrial homeostasis, yet how individual eIF3 subunits respond to distinct modes of skeletal muscle stress remains unclear. Here, we systematically characterized eIF3 dynamics and mitochondrial function using two complementary mouse models: acute exhaustive training and dexamethasone (DEX)-induced atrophy. Integrated proteomic, transcriptional, and imaging analyses revealed a biphasic regulatory pattern: DEX treatment caused broad downregulation of eIF3a, eIF3b, eIF3c, eIF3g, and eIF3l, concurrent with comprehensive mitochondrial electron transport chain (ETC) impairment, while acute training selectively decreased eIF3d, eIF3e, eIF3g, and eIF3l but uniquely preserved eIF3f expression alongside adaptive ETC remodeling. This differential response pattern distinguishes eIF3 from other stress-responsive translation factors, as eIF2α phosphorylation typically causes global translation suppression whereas eIF3 dysregulation selectively impairs mitochondrial protein synthesis. Notably, eIF3f preservation under both conditions suggests a compensatory mechanism to maintain translational capacity. siRNA-mediated knockdown of eIF3e or eIF3f in C2C12 myotubes demonstrated their differential effects on mitochondrial protein expression and atrophy signaling, with eIF3f knockdown causing more severe mitochondrial protein suppression. Seahorse XF analysis confirmed that eIF3 subunit loss directly impairs mitochondrial oxygen consumption, while SUnSET assays demonstrated attenuated global protein synthesis upon eIF3e or eIF3f depletion. Furthermore, eIF3 knockdown suppressed mTORC1 signaling (p-mTOR, p-4EBP1, p-S6K, p-S6) and differentially modulated ubiquitin-proteasome activity without altering bulk autophagy. These findings establish eIF3 as a molecular integrator linking translational control to mitochondrial integrity in skeletal muscle physiology, positioning this complex as a potential therapeutic target for conditions ranging from exercise-induced adaptation to muscle wasting disorders.
    Keywords:  ETC complex; eIF3; mitochondria; muscle adaptation; skeletal muscle; translation regulation
    DOI:  https://doi.org/10.1096/fj.202600161R
  70. Fundam Res. 2026 May;6(3): 1893-1912
    Mitochondrial homeostasis in bone aging: Unraveling dysfunctional pathways and developing precision therapies.
    Yu Zhang, Xishui Liu, Zijie Xiang, Yuqing Yang, Lei Xing, Yu Chen, Siming Zhang, Shixiang Zhao, Youzhi Hong, Yusen Qiao, Jiaxiang Bai.
      Mitochondria have complex functional and information-processing networks that play key roles in both health regulation and disease progression. However, the multiple properties and complex thresholds of mitochondrial dysfunction and quality control make the contribution of mitochondria to bone aging elusive. These factors prevent mitochondria from being among the most important precision therapies. Currently, many strategies that target mitochondrial homeostasis have entered clinical trials. In mitochondria, mitochondrial DNA (mtDNA) and its associated proteins are potential therapeutic agents for immunometabolic diseases and tissue injury, with the aim of enhancing mitochondrial function. Here, we comprehensively review the intrinsic mechanisms of mitochondrial dysfunction and quality control leading to bone aging and summarize current strategies for the treatment of skeletal aging disorders and the clinical translation of relevant agents in terms of unraveling dysfunctional pathways and developing precision therapies. In this review, we offer a general overview of the progress of clinical application in the treatment of skeletal senescence diseases, and we also provide prospects for the challenges associated with the role of mitochondrial dysfunction in bone senescence in clinical application and future trends in this field.
    Keywords:  Bone aging; Clinical application; Mitochondrial DNA (mtDNA); Mitochondrial dysfunction; Precision therapy; Quality control
    DOI:  https://doi.org/10.1016/j.fmre.2025.12.021
  71. Metabolism. 2026 Jun 06. pii: S0026-0495(26)00157-5. [Epub ahead of print]182 156647
    Corrigendum to "Mitochondrial ribosomal protein L12 potentiates hepatocellular carcinoma by regulating mitochondrial biogenesis and metabolic reprogramming" [Metabolism. 2024 Mar; 152: 155761. doi:10.1016/j.metabol.2023.155761].
    Xingzhao Ji, Zhen Yang, Chensheng Li, Suwei Zhu, Yu Zhang, Fuyuan Xue, Shengnan Sun, Tingting Fu, Can Ding, Yi Liu, Qiang Wan.
      
    DOI:  https://doi.org/10.1016/j.metabol.2026.156647
  72. Next Res. 2026 Jul;9
    Particulate matter induced cell death: Current understanding of molecular drivers that lead to lung damage.
    Durgesh N Das, Dhruv Mitroo.
      Particulate matter (PM), ubiquitous in indoor and outdoor air parcels, is an environmental hazard and poses a risk to human health. The proclivity for PM to be continuously inhaled is what leads to adverse human outcomes. This is because often if not always, PM is chemically laden with toxins. The scientific literature is impressively growing with studies in vitro and in vivo that probe PM-induced cellular deaths, resulting in improved knowledge of disease onset. New cell death mechanisms are being proposed, including revisions of canonical definitions (e.g., necrosis). It is helpful in our view if the current knowledge of the processes within a cell initiated by PM insults and leading to cell death are summarized and supplemented to the literature. Such a summary should highlight proteins that act as death activators or gatekeepers in a given affected transduction pathway. Additionally, this summary should discern how PM dose can promote cell death versus lead to signaling that restores cell function. The result should underscore cell resiliency and provide insight on therapeutic strategies. To this end, the objective of this review is to present reception, transduction, and the response of a cell to PM exposure. We emphasize cellular transduction pathways that have been reported by the literature as impacted significantly by PM uptake (that would otherwise occur during homeostasis in a well-regulated manner) and the resulting defined cell deaths: autophagy, apoptosis, necrosis, and cuproptosis. We find that while reactive oxygen species (ROS) and subsequent inflammatory cytokine release are commonly studied and subject to therapeutic research, damage to organelles such as the mitochondrion (and leading to mitophagy) is receiving equivalent attention as attractive research targets. We conclude the review by scaling cell death to organ or organism pathophysiology and the importance of a genetic mutations for burden of PM-induced disease. That is, while air pollution or PM might not directly cause mutations, it can be a driver by creating an environment within the cell that favors the growth and progression of cells with these mutations.
    Keywords:  Apoptosis; Cell death; Cytotoxicity; Mitophagy; Necrosis; Particulate matter; Review
    DOI:  https://doi.org/10.1016/j.nexres.2026.101769
  73. Int Rev Cell Mol Biol. 2026 ;pii: S1937-6448(25)00114-5. [Epub ahead of print]403 85-121
    Autophagy in cancer cachexia: From mechanisms to therapeutic opportunities.
    Riccardo Ballarò, Fabio Penna, Marc Beltrà.
      Cancer cachexia is a multifactorial syndrome characterized by body weight loss, muscle wasting, and systemic metabolic alterations, significantly contributing to patient morbidity and mortality. A key feature of cachexia is the excessive degradation of muscle proteins and mitochondria, largely mediated by autophagy. Although hyperactivation of autophagy has been widely recognized as a hallmark of cancer cachexia, its precise role in exacerbating muscle atrophy through enhanced proteolysis and mitochondrial disposal remains a subject of ongoing debate. This review provides a comprehensive overview of previous milestones and recent advancements in understanding autophagy's role in cancer cachexia, with particular focus on its impact on skeletal muscle and liver, as well as its contribution to tumor metabolic flexibility. Additionally, the review explores emerging therapeutic strategies aimed at modulating autophagy, including exercise, exercise mimetics, and novel molecules to selectively target specific branches of autophagy. By synthesizing current evidence, this review highlights the need for further research into the mechanisms underlying autophagy dysregulation in cancer cachexia and the potential for autophagy-based interventions to improve patient outcomes.
    Keywords:  Autophagy; Cancer cachexia; Diet therapy; Exercise; Liver metabolism; Mitophagy; Muscle wasting; Tumor metabolism
    DOI:  https://doi.org/10.1016/bs.ircmb.2025.08.008
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