bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2026–08–09
fifty-one papers selected by
Gavin McStay, Liverpool John Moores University
  1. Mitochondrial quality control in acute liver injury and its therapeutic implications (Review).
  2. Herbal targeting of mitochondrial dynamic proteins in low-density lipoprotein driven atherosclerosis in vitro.
  3. N-Acetylcysteine, Dichloroacetate, and Metformin Restore Mitochondrial Homeostasis by Counteracting Oxidative Stress and Fusion-Fission Imbalance in Palmitic Acid-Induced Lipotoxicity.
  4. Mas receptor activation promotes mitophagy and preserves neuronal function after traumatic brain injury.
  5. Pro-developmental role of AMPK-PINK1/Parkin-mediated mitophagy in the morula-to-blastocyst transition during early embryonic development: Dual-omics evidence for the beneficial effects of GSH.
  6. Fraxinellone suppresses inflammatory bowel disease by targeting PINK1 and activating PINK1/Parkin-mediated mitophagy.
  7. Mitochondria-enriched BMSC exosomes restore microglia-neuron cross-talk in Parkinson's disease via PINK1/parkin and PI3K/Akt/mTOR pathways.
  8. Effects of exercise in a fed or fasted state on mitochondrial dynamics regulators in the skeletal muscle of recreationally active males.
  9. Mitochondrial homeostasis dysregulation: Potential mechanisms of Alzheimer's disease mediated by TDP-43.
  10. The role of the HB-EGF-regulated EGFR-mitophagy axis in maintaining cartilage homeostasis and osteoarthritis.
  11. FUNDC1-mediated mitochondrial quality control protects against immune checkpoint inhibitor-associated cardiac injury.
  12. Sestrin2 alleviates age-related hearing loss through mediating PINK1/Parkin related mitophagy.
  13. Porcine epidemic diarrhea virus induces Vero cell mitophagy by regulating ROS-mediated PINK1/Parkin signal pathway.
  14. [Psoralen promotes osteogenic differentiation of MC3T3-E1 cells by regulating mitophagy via PINK1/Parkin pathway].
  15. IGFBP2 Knockdown Ameliorates Diabetic Gastroparesis by Inhibiting VDAC1-Dependent Mitophagy in Interstitial Cells of Cajal.
  16. Cyanidin chloride activates mitophagy to delay aging via PINK1/parkin pathway.
  17. Crosstalk between mitophagy and metabolism in cancer: Mechanisms and therapeutic opportunities.
  18. Targeted Restoration of Mitophagy Reinvigorates Aged Hematopoietic Stem Cells.
  19. Ckb-Cryab-Drp1 axis enhances BMSC osteogenic differentiation and mouse alveolar bone healing through mitochondrial fission modulation.
  20. The microbiome-mitochondria axis: the context-dependent role of urolithin A in aging and cancer via mitophagy.
  21. Progressive mitochondrial and autophagic dysfunction during RGC development driven by a LHON-associated mitochondrial tRNAThr mutation.
  22. Integrative phosphoproteomics reveals kinase-mediated regulation of OCIAD1 and its roles in mitochondrial quality control.
  23. Yiqi Huoxue Jiedu formula protects against sepsis-associated lung injury by modulating macrophage mitophagy and mtDNA-STING signaling.
  24. Asiaticoside attenuates endothelial cells senescence in diabetic retinopathy via CCND1-mediated mitophagy through the PI3K/AKT/mTOR pathway.
  25. Catalpol protects against MPP+-induced neurotoxicity by targeting PINK1/DJ-1-mediated mitophagy and the TrkB/Akt/BDNF/Bcl-2 axis.
  26. Corrigendum to "Mitophagy suggesting a possible association with oocyte maturation: A study of granulosa cells from follicular fluid of normoresponder and diminished ovarian reserve cases".
  27. Protocatechuic acid protects neural stem cells against cerebral ischemia-reperfusion injury by suppressing JAK2/STAT3 signaling and restoring mitophagy.
  28. FOXO3 Counteracts Oxidative Stress-Induced Nucleus Pulposus Cell Senescence via BNIP3-Mediated Mitophagy in Intervertebral Disc Degeneration.
  29. A 3-n-butylphthalide-based nanoagent modulates PINK1/Parkin-associated mitophagy signaling in ischemia-reperfusion brain injury.
  30. African swine fever virus pMGF360-3 L suppresses innate immunity by facilitating CMA-dependent SKP1 degradation to promote BNIP3-mediated mitophagy.
  31. Triphenylphosphonium-functionalized ferric-tannic acid nanometallic framework delivers optic atrophy 1 protein to restore mitochondrial homeostasis in diabetic erectile dysfunction.
  32. Urolithin B Ameliorates Depressive-like Behavior and Hippocampal Neuronal Damage in Depressed Rats via regulation of the SLP2/PINK1/Parkin Signaling Pathway.
  33. Type 2 Diabetes Mellitus: Molecular Pathogenesis and Therapeutic Interventions.
  34. [Costunolide improves sorafenib-induced cardiomyocyte injury by inhibiting mitophagy].
  35. Targeting the AMPK signalling pathway: Honokiol modulated energy metabolism to mitigate pulmonary injury induced by airborne microplastics through regulating autophagy and mitophagy.
  36. Miro1 Protects Against Acute Kidney Injury Through Modulating Mitochondrial Homeostasis via Interaction With Sirt6.
  37. Dusquetide Regulates SQSTM1/p62-Mediated Mitophagy to Alleviate PM2.5-Aggravated Airway Inflammation in Asthma.
  38. Ion-Driven Regulation of Ca2 + Flow by Ti/Zn Composite Activates ERK/MAPK Signaling and Maintains Mitochondrial Homeostasis to Promote Macrophage-Mediated Bone Regeneration.
  39. Beyond the Pump: Unravelling Immunometabolic Crosstalk and Organelle Dynamics in Sepsis-Induced Cardiomyopathy.
  40. Targeting FOSL1-KCa3.1 inhibits ferroptosis and cartilage destruction by suppressing mitochondrial hyperfusion.
  41. The identification of drp1 patient mutations that limit interactions with mff.
  42. Identification and validation of mitophagy and astrocyte-related molecular signature in the pathogenesis of Alzheimer's disease: evidence from ensemble learning-driven multi-omics and clinical validation.
  43. Integrating UHPLC-HRMS with SSA-BP neural network identifies optimal components of Astragali Radix‑Salviae Miltiorrhizae combination for mitigating cerebral ischemia-reperfusion injury via mitophagy and ferroptosis pathways.
  44. Research progress on the association of maternal high-fat diet with offspring neurodevelopment and susceptibility to Parkinson's disease.
  45. HNRNPC Succinylation Influences the Neurodegeneration of Alzheimer's Disease Through YME1L1-Mediated Mitochondrial Metabolism.
  46. Mechanistic basis for calmodulin‑dependent allosteric activation of the neuropathy-associated formin INF2.
  47. The Microbiome-Mitochondria Axis in aging: a self-reinforcing vicious cycle linking metabolic dysregulation, mitochondrial quality control failure, and inflammaging.
  48. [Huangqi Guizhi Wuwu Detection regulates mitochondrial quality control and autophagy-lysosome flux to ameliorate skeletal muscle pathology in rheumatoid arthritis-associated sarcopenia].
  49. RETRACTION: SIRT5-Related Desuccinylation Modification Contributes to Quercetin-Induced Protection against Heart Failure and High Glucose-Prompted Cardiomyocytes Injured through Regulation of Mitochondrial Quality Surveillance.
  50. Correction: Bendless is essential for PINK1-Park mediated Mitofusin degradation under mitochondrial stress caused by loss of LRPPRC.
  51. HO-1 Up-regulation and PINK1/Parkin-Mediated Mitophagy Contribute to the Anti-tumor Effects of Metochalcone in Colorectal Cancer.
  1. Mol Med Rep. 2026 Oct;pii: 273. [Epub ahead of print]34(4):
    Mitochondrial quality control in acute liver injury and its therapeutic implications (Review).
    Ziqiang Chen, Yunhe Wang, Yijing Li, Gang Cong, Yunhang Chu, Yunhui Bai, Yishuo Zhang, Liya Zhou.
      Acute liver injury (ALI) is a clinically important syndrome with limited mechanism‑based therapies. Notably, mitochondrial dysfunction is increasingly recognized as a central driver of hepatocellular damage and repair failure. The present narrative review aims to summarize the current evidence on mitochondrial quality control (MQC) in ALI, with an emphasis on mitophagy, mitochondrial biogenesis, mitochondrial dynamics, etiology‑specific regulation and therapeutic implications. For the present review, relevant experimental and translational studies addressing MQC‑related mechanisms and interventions in major forms of ALI, including drug‑induced liver injury, ischemia‑reperfusion injury and viral ALI, were reviewed and integrated. The findings indicated that MQC operates as an interconnected network rather than as isolated pathways. Mitophagy, mitochondrial dynamics and mitochondrial biogenesis are temporally coordinated to remove damaged mitochondria, remodel mitochondrial networks and restore bioenergetic capacity. However, MQC responses differ across ALI etiologies, and inappropriate or excessive activation may become maladaptive. In conclusion, understanding MQC as a dynamic and context‑dependent repair system may provide a conceptual basis for precision interventions in ALI. Future studies should clarify spatiotemporal MQC regulation, establish reliable biomarkers and validate MQC‑targeted therapies in clinically relevant settings.
    Keywords:  acute liver injury; mitochondrial biogenesis; mitochondrial dynamics; mitochondrial quality control; mitophagy
    DOI:  https://doi.org/10.3892/mmr.2026.13984
  2. Front Cardiovasc Med. 2026 ;13 1855659
    Herbal targeting of mitochondrial dynamic proteins in low-density lipoprotein driven atherosclerosis in vitro.
    Zhanna Dzampaeva, Rodion Saveljev.
       Background: Mitochondrial dysfunction is a critical early driver of endothelial injury in atherogenesis. Natural plant-derived products targeting mitochondrial quality control represent a promising therapeutic approach, yet their mechanisms in oxidized LDL (ox-LDL)-induced endothelial damage remain underexplored.
    Methods: We evaluated ethanolic extracts from Rosmarinus officinalis, Cynara cardunculus, and Myrtus communis on ox-LDL-induced mitochondrial damage in human umbilical vein endothelial cells (HUVECs). Cell viability (MTT), proliferation (acridine orange staining), and mitochondrial membrane potential (Δψm; Rhodamine 6G) were assessed across therapeutic-equivalent concentrations (×0.1-×100). In a pathophysiologically relevant ox-LDL model (80 μg/mL, 48 h), RT-qPCR analyzed expression of genes regulating mitochondrial dynamics (DRP1, FIS1, MFF, MFN2, OPA1), mitophagy (PINK1, PARKIN, FUNDC1, OPTN, SQSTM1/p62), and antioxidant defense (CAT).
    Results: All three extracts preserved Δψm and mitochondrial network architecture in healthy HUVECs in a dose-dependent manner. In the ox-LDL model, extracts reversed the pro-fission transcriptional shift by downregulating DRP1, FIS1, and MFF while restoring MFN2 and OPA1 expression (p < 0.05-0.001). C. cardunculus robustly upregulated PINK1 and PARKIN, indicating enhanced ubiquitin-dependent mitophagy, whereas R. officinalis and M. communis preferentially increased FUNDC1 and OPTN, suggesting receptor-mediated clearance pathways. Extract treatment concurrently upregulated endogenous antioxidant enzymes (CAT), suppressed pro-inflammatory MAPK8 (JNK).
    Conclusions: Polyphenol-rich herbal extracts protect endothelial cells from ox-LDL-induced injury by rebalancing mitochondrial fission/fusion dynamics, activating complementary mitophagy pathways, and fortifying antioxidant defenses. These findings support the potential of standardized herbal formulations as targeted adjunctive strategies for early atherosclerosis prevention through mitochondrial quality control.
    Keywords:  Cynara cardunculus; HUVEC; atherosclerosis; fission; fusion; inflammation; mitochondria; mitophagy
    DOI:  https://doi.org/10.3389/fcvm.2026.1855659
  3. J Oleo Sci. 2026 ;75(8): 921-932
    N-Acetylcysteine, Dichloroacetate, and Metformin Restore Mitochondrial Homeostasis by Counteracting Oxidative Stress and Fusion-Fission Imbalance in Palmitic Acid-Induced Lipotoxicity.
    Zhixing Cai, Yue Chen, Lili Chen, Danyang Zhu.
       BACKGROUND: Palmitic acid (PA)-driven lipotoxicity in skeletal muscle is associated with excessive reactive oxygen species (ROS) and disturbed mitochondrial dynamics. This study aimed to characterize PA-induced alterations in oxidative status and fusion-fission balance in C2C12 skeletal muscle cells and to test whether N-acetylcysteine (NAC), dichloroacetate (DCA), or metformin mitigate these changes.
    METHODS: Differentiated C2C12 myotubes were exposed to PA under conditions detailed in the Methods. Intracellular ROS was quantified, antioxidant defenses were assessed by activities of catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD), and mitochondrial dynamics were evaluated by expression of the fusion protein mitofusin 1 (MFN1) and the fission protein dynamin-related protein 1 (DRP1), together with morphological assessment of mitochondrial fragmentation.
    RESULTS: PA exposure increased ROS and was accompanied by decreases in CAT, GPx, and SOD activities. PA shifted mitochondrial dynamics toward fission, with reduced MFN1, elevated DRP1, and increased mitochondrial fragmentation. Co-treatment with NAC, DCA, or metformin attenuated PA-induced ROS accumulation, improved antioxidant enzyme activities relative to PA alone, and partially normalized MFN1 and DRP1 expression, with reduced fragmentation.
    CONCLUSIONS: In an in vitro C2C12 model, PA-induced lipotoxicity is associated with oxidative stress and a fusion-fission imbalance favoring mitochondrial fragmentation. NAC, DCA, and metformin mitigate these alterations and help preserve mitochondrial homeostasis. These findings support targeting oxidative stress and mitochondrial dynamics as a potential approach to counteract mitochondrial dysfunction under lipotoxic conditions.
    Keywords:  insulin resistance; mitochondrial dysfunction; oxidative stress; palmitic acid
    DOI:  https://doi.org/10.5650/jos.ess25268
  4. Mitochondrion. 2026 Aug 06. pii: S1567-7249(26)00090-5. [Epub ahead of print] 102200
    Mas receptor activation promotes mitophagy and preserves neuronal function after traumatic brain injury.
    Ruili Dang, Lei Wang, Changshui Wang, Jinxiu Guo, Pei Jiang.
      Traumatic brain injury (TBI) is a leading global cause of death and long-term disability, primarily due to secondary injury mechanisms such as mitochondrial dysfunction and impaired mitophagy，the selective degradation of damaged mitochondria. While the ACE2/Angiotensin-(1-7)/Mas receptor (MasR) axis is recognized for its neuroprotective effects in various neurological disorders, its role in regulating mitochondrial quality control after TBI remains unclear. In this study, we investigated the regulatory function of MasR in post-traumatic mitophagy using controlled cortical impact (CCI) mice and scratch-injured neuronal cultures. We employed MasR knockdown (MasR-KD) and pharmacological activation with the selective MasR agonist AVE0991 to assess neurobehavioral outcomes, neuronal survival, and mitophagy flux. Activation of MasR significantly improved motor coordination, cognitive performance, and reduced anxiety-like behaviors following TBI, whereas MasR deficiency exacerbated neurological deficits. Histologically, MasR-KD mice exhibited increased neuronal loss, dendritic degeneration, and oxidative stress. In contrast, AVE0991 treatment preserved neuronal integrity and mitochondrial ultrastructure, effects that were abolished in MasR-KD animals. Mechanistically, MasR activation promoted PINK1/Parkin-mediated mitophagy, enhanced TOMM20-LC3 colocalization, stabilized mitochondrial membrane potential, reduced mitochondrial ROS production, and improved respiratory capacity. In vitro, Ang-(1-7) restored mitophagy flux through MasR-dependent clearance of damaged mitochondria, as confirmed by mt-Keima assays. Collectively, these findings identify MasR as an endogenous regulator of PINK1/Parkin-mediated mitophagy and mitochondrial homeostasis following TBI and demonstrate that MasR signaling is required for preserving mitochondrial function and neurological outcomes after injury.
    Keywords:  Mas receptor; Mitochondrial dysfunction; Mitophagy; Oxidative stress; Traumatic brain injury
    DOI:  https://doi.org/10.1016/j.mito.2026.102200
  5. Theriogenology. 2026 Aug 03. pii: S0093-691X(26)00313-4. [Epub ahead of print]265 118123
    Pro-developmental role of AMPK-PINK1/Parkin-mediated mitophagy in the morula-to-blastocyst transition during early embryonic development: Dual-omics evidence for the beneficial effects of GSH.
    Tianhao Li, Xuefeng Bai, Yuejiao Liao, Qiyong Zuo, Xin Liu, Yan Cui, Sijiu Yu, Yangyang Pan.
      Early embryonic development depends on precise redox homeostasis and mitochondrial quality control; however, how AMPK regulates embryonic fate through mitophagy remains unclear. In this study, integrated transcriptomic and proteomic analyses of Tibetan sheep embryos from the morula to blastocyst stages identified a GSH-AMPK-PINK1/PARKIN-mediated mitophagy axis as a key pathway governing mitochondrial homeostasis. Subsequently, functional validation was performed using in vitro embryo culture models with either GSH synthesis inhibition or AMPK inhibition. Under GSH synthesis inhibition, endogenous antioxidant capacity was markedly impaired, as evidenced by a 53% reduction in GCLC expression, while GPX4 expression showed no significant change. The energy-sensing molecules AMPK and phosphorylated AMPK (p-AMPK) were downregulated by 71.32% and 46.38%, respectively, accompanied by decreased expression of PINK1 (66.5%) and PARKIN (29.2%), consistent with multi-omics enrichment results. Mitochondrial functional assays revealed elevated mitochondrial membrane potential, increased MitoSOX fluorescence, reduced mitochondria-lysosome colocalization, and decreased LC3-positive puncta, indicating pronounced suppression of selective mitophagy. To further verify the central regulatory role of AMPK, an AMPK inhibition model was established. AMPK suppression did not significantly alter GSH levels but reproduced mitochondrial dysfunction and mitophagy defects highly similar to those observed under GSH synthesis inhibition, demonstrating that AMPK serves as a critical signaling hub linking redox imbalance to mitochondrial quality control. Collectively, this study systematically elucidates a causal cascade-GSH depletion→AMPK inactivation→inhibition of PINK1/PARKIN-mediated mitophagy→mitochondrial dysfunction→impaired embryonic development-and provides robust multi-omics and functional evidence for a redox-energy regulatory mechanism essential for early embryonic development.
    Keywords:  AMP-Activated protein kinase (AMPK); Glutathione (GSH); PINK1/Parkin
    DOI:  https://doi.org/10.1016/j.theriogenology.2026.118123
  6. Int Immunopharmacol. 2026 Aug 05. pii: S1567-5769(26)01089-1. [Epub ahead of print]187 117243
    Fraxinellone suppresses inflammatory bowel disease by targeting PINK1 and activating PINK1/Parkin-mediated mitophagy.
    Hongzhen Chen, Linying Hu, Yonghu Chen, Xuezheng Li, Zhe Jiang.
      The onset and progression of inflammatory bowel disease (IBD) are closely associated with mitochondrial dysfunction and oxidative stress, and an imbalance in PINK1/Parkin-mediated mitophagy is considered a key pathogenic mechanism; however, effective intervention strategies targeting this pathway are limited. Therefore, this study aims to investigate the protective effects of the natural bioactive compound Fraxinellone (FRA) against IBD and its underlying molecular mechanisms. In vivo experiments demonstrated that FRA significantly alleviated Dextran Sulfate Sodium (DSS)-induced colitis in mice, improving weight loss, colonic shortening and histopathological damage, whilst effectively reducing oxidative stress levels. In vitro model of LPS-mediated intestinal epithelial cell damage revealed that FRA significantly improved mitochondrial dysfunction, inhibited ROS accumulation, inflammatory responses and cell death, whilst restoring intestinal epithelial barrier function. Further studies using molecular docking and cell-based Cellular Thermal Shift Assay (CETSA) confirmed that FRA exerts its protective effects by directly binding to PINK1 and activating PINK1/Parkin-dependent mitophagy; conversely, its mitochondrial protective and anti-inflammatory effects were markedly attenuated following PINK1 knockdown. In summary, FRA exerts its anti-IBD effects by targeting PINK1 and activating PINK1/Parkin-dependent mitophagy, thereby improving mitochondrial homeostasis and alleviating oxidative stress and inflammatory damage. This study not only reveals a novel mechanism by which FRA regulates mitochondrial quality control to improve IBD, but also provides a new theoretical basis for precision therapeutic strategies targeting the PINK1/Parkin pathway, whilst offering a potential direction for the clinical translation of natural products in the prevention and treatment of IBD.
    Keywords:  Fraxinellone (FRA); Inflammatory bowel disease; Mitophagy; PINK1/Parkin
    DOI:  https://doi.org/10.1016/j.intimp.2026.117243
  7. Brain Res. 2026 Aug 05. pii: S0006-8993(26)00349-5. [Epub ahead of print] 150487
    Mitochondria-enriched BMSC exosomes restore microglia-neuron cross-talk in Parkinson's disease via PINK1/parkin and PI3K/Akt/mTOR pathways.
    Shanshan Shi, Ruyue Liu, Chang Liu, Yuyao Chen, Yujun Pan, Chunyan Wang.
       BACKGROUND: Mitochondrial dysfunction and neuroinflammation drive dopaminergic neuron loss in Parkinson's disease (PD). While BMSC-derived small extracellular vesicles (BMSC-Exo) are neuroprotective, their ability to repair mitochondrial deficits is limited. We engineered mitochondrial-enriched sEVs (Exo-Mito) to evaluate their effects on microglia-neuron interactions in a PD-relevant model.
    METHODS: BMSC-Exo-Mito were characterized via TEM, NTA, and immunoblotting. Their therapeutic efficacy was assessed using an MPP + -induced BV2/SH-SY5Y transwell co-culture model. Assessments included ROS levels, mitochondrial membrane potential, ATP quantification, mitophagy flux, and signaling pathway analysis.
    RESULTS: Exo-Mito significantly restored mitochondrial homeostasis by reducing ROS, preserving membrane potential, and increasing ATP production. Mechanistically, Exo-Mito enhanced PINK1/Parkin-dependent mitophagy and PGC-1alpha/TFAM-mediated biogenesis. In BV2 microglia, Exo-Mito suppressed the NF-kappaB/NLRP3 axis, reduced proinflammatory cytokines, and promoted M2 polarization. In SH-SY5Y cells with dopaminergic phenotype, Exo-Mito was associated with reactivated PI3K/Akt/mTOR signaling, preserved tyrosine hydroxylase expression, and inhibited apoptosis. Functionally, Exo-Mito improved SH-SY5Y cell and restored microglial migratory capacity, showing superior efficacy to unmodified BMSC-Exo.
    CONCLUSION: Mitochondria-enriched BMSC sEVs protect SH-SY5Y cells by coordinating mitochondrial quality control and modulating neuroinflammation. These findings support Exo-Mito as a promising cell-free therapeutic strategy for Parkinson's disease.
    Keywords:  Mesenchymal stem cells; Mitochondria; Mitophagy; Neuroinflammation; PI3K/Akt/mTOR; Parkinson’s disease; Small extracellular vesicles
    DOI:  https://doi.org/10.1016/j.brainres.2026.150487
  8. Exp Physiol. 2026 Aug 06.
    Effects of exercise in a fed or fasted state on mitochondrial dynamics regulators in the skeletal muscle of recreationally active males.
    Elya J Ritenis, Christos G Stathis, Matthew B Cooke, Stephen Keenan, Andrew Philp, Donny M Camera.
      Exercise and nutritional modulation favourably alter mitochondrial quantity and quality in skeletal muscle. Mitochondrial dynamics, the coordination of fission and fusion events, are poised to mediate key aspects of organelle adaptation that arise from exercise. However, the molecular basis by which exercise affects mitochondrial dynamics remains poorly understood. The objective of this work was to further elucidate the signalling response of mitochondrial dynamics regulators to exercise and explore the synergistic potential to combine exercise and nutritional modulation. In a randomized crossover design, eight healthy, recreationally active men (age 25.8 ± 5.3 years, BMI 24.4 ± 1.2 kg/m2, V̇O2peak 39.2 ± 5.7 ml/kg/min) performed a 1-h bout of workload-matched aerobic exercise on a cycle ergometer at 50-70% of Wmax, either in a fasted or a fed (i.e., following a carbohydrate rich breakfast) state. Gas exchange was measured throughout, and blood samples were collected intermittently. Vastus lateralis muscle biopsies were collected pre-, post- and 3 h post-exercise. Western blotting was performed on cytosolic and mitochondrial fractions. Fasted exercise was accompanied by increased cytosolic acetyl-CoA carboxylase Ser79 phosphorylation (P ≤ 0.001), an effect not observed in the fed group (P > 0.05). The subcellular location of mitochondrial fission effector dynamin-related protein 1 (DRP1) was unchanged (P > 0.05) following exercise. However, group differences (i.e., Fed vs. Fasted) in DRP1 subcellular localization and phosphorylation at residues Ser616 and Ser637 were observed post-exercise. Substrate availability may potentially influence the mitochondrial dynamics signalling response in skeletal muscle to acute aerobic exercise.
    Keywords:  exercise; mitochondrial dynamics; skeletal muscle
    DOI:  https://doi.org/10.1113/EP093336
  9. Ageing Res Rev. 2026 Aug 05. pii: S1568-1637(26)00282-5. [Epub ahead of print] 103290
    Mitochondrial homeostasis dysregulation: Potential mechanisms of Alzheimer's disease mediated by TDP-43.
    Wendi Huang, Juan Huang, Nanyu Kuang, Jingjing Wu, Fei Feng, Yong Luo, Nanqu Huang.
      Alzheimer's disease (AD) exhibits substantial clinical and pathological heterogeneity that is not fully explained by amyloid-β and tau pathology alone. TAR DNA-binding protein 43 (TDP-43) is increasingly recognized as a frequent copathology in AD, particularly in limbic regions, where its presence is associated with accelerated cognitive decline. Disruption of mitochondrial homeostasis is also an early and consistent feature of AD and contributes to neuronal vulnerability. In this review, we summarize current evidence linking TDP-43 pathology to impaired mitochondrial homeostasis in AD. We outline key features of mitochondrial homeostasis in neurons, review neuropathological and clinical data supporting the relevance of TDP-43 in AD, and synthesize emerging mechanisms by which TDP-43 may perturb mitochondrial homeostasis, including effects on expression, aggregation and localization, quality control, organelle dynamics, and endoplasmic reticulum-mitochondria communication.
    Keywords:  Alzheimer's Disease; Mitochondrial fission; Mitochondrial fusion; Mitochondrial homeostasis; Mitophagy; TDP-43
    DOI:  https://doi.org/10.1016/j.arr.2026.103290
  10. J Mol Histol. 2026 Aug 04. pii: 256. [Epub ahead of print]57(4):
    The role of the HB-EGF-regulated EGFR-mitophagy axis in maintaining cartilage homeostasis and osteoarthritis.
    JunHua Wang, ChiShou Mo, Qiang Wang, Jia Qin, Yong Li, WuXun Peng.
      This study investigates the mechanism by which heparin-binding epidermal growth factor (HB-EGF) maintains cartilage homeostasis in osteoarthritis (OA) through the epidermal growth factor receptor (EGFR)-mitochondrial autophagy axis. Given the challenges in OA treatment and the critical role of impaired mitochondrial autophagy in disease progression, this research first identified key regulators using transcriptomic data from human OA cartilage and GEO databases. An in vitro OA model was established via IL-1β induction in chondrocytes, through which HB-EGF was found to reverse the IL-1β-induced metabolic imbalance by downregulating catabolic markers (Mmp13, Adamts5) and upregulating anabolic markers (Acan, Col2a1). Further analysis revealed that HB-EGF enhanced mitophagy, as indicated by increased levels of Pink1, Parkin, and Lc3-II alongside decreased P62. These protective effects were attenuated by the mitophagy inhibitor Mdivi-1, confirming the dependence on this pathway. In conclusion, HB-EGF activates EGFR signaling to promote PINK1/ PARKIN-mediated mitophagy, which facilitates the clearance of damaged mitochondria and improves mitochondrial function, thereby restoring chondrocyte metabolic balance and delaying OA progression, suggesting the EGFR-mitophagy axis as a potential therapeutic target for OA.
    Keywords:  Chondrocytes; EGFR; HB-EGF; Mitochondrial autophagy; Osteoarthritis; Synthesis and catabolism
    DOI:  https://doi.org/10.1007/s10735-026-10916-x
  11. Immunol Res. 2026 Aug 06. pii: 78. [Epub ahead of print]74(1):
    FUNDC1-mediated mitochondrial quality control protects against immune checkpoint inhibitor-associated cardiac injury.
    Nengfeng Zhang, Yao Zhou, Hailing Li, Haiyun Liu.
      Immune checkpoint inhibitors (ICIs) targeting PD-1 are effective cancer therapies but can cause severe myocarditis. The molecular mechanisms linking PD-1 blockade to cardiomyocyte damage are incompletely understood. We established a murine model of anti-PD-1-associated cardiac injury and used human AC16 cardiomyocytes in co-culture with CD8+ T cells. Global Fundc1 knockout (Fundc1-/-) mice and cardiac-specific Fundc1 reconstitution via AAV9 were employed to investigate the role of this mitophagy receptor. Cardiac function was assessed by echocardiography, and injury was evaluated through serum biomarkers, histology, and molecular analyses. Anti-PD-1 treatment induced cardiac dysfunction, myocardial T-cell infiltration, and reduced myocardial FUNDC1 expression in mice. FUNDC1 deficiency, both in vitro and in vivo, aggravated anti-PD-1-associated cardiomyocyte injury, cardiac dysfunction, inflammation, and fibrosis. Conversely, FUNDC1 overexpression or cardiac-specific Fundc1 restoration attenuated these pathological changes. Mechanistically, FUNDC1 loss was associated with altered mitophagy-related marker profiles, mitochondrial protein accumulation, increased oxidative stress, and mitochondrial functional impairment. FUNDC1-mediated mitochondrial quality control may represent an endogenous protective mechanism against anti-PD-1 antibody-associated cardiac injury.
    Keywords:  Cardiotoxicity; FUNDC1; Fibrosis; Immune checkpoint inhibitor; Mitophagy; Myocarditis
    DOI:  https://doi.org/10.1007/s12026-026-09819-6
  12. Nagoya J Med Sci. 2026 May;88(2): 297-311
    Sestrin2 alleviates age-related hearing loss through mediating PINK1/Parkin related mitophagy.
    Liwen Wang, Yuenong Jiao, Tianqi Nie, Linlan Jiang, Shuyi Gao, Jinyu Wang.
      Age-related hearing loss (ARHL) is closely linked to mitochondrial dysfunction in cochlear hair cells; however, its molecular regulation remains unclear. Sestrin2 (SESN2), a stress-inducible protein crucial for regulating energy metabolism, has not been comprehensively studied in the context of ARHL. To investigate SESN2's role, cochlea-specific SESN2 overexpression and knockout mouse models were established via adeno-associated virus 9 (AAV9) delivery through posterior semicircular canal injection. These models, combined with an H2O2-induced accelerated-aging paradigm and H2O2-treated House Ear Institute-organ of Corti 1 (HEI-OC1) cellular oxidative injury system, were systematically evaluated using auditory brainstem response (ABR), immunofluorescence (IF), mitochondrial membrane potential assays, western blotting, and other methods. Analysis of ARHL mouse cochleae revealed downregulation of SESN2 in hair cells, accompanied by mitochondrial membrane disruption and increased apoptosis. In aged mice, SESN2 overexpression significantly improved low-frequency hearing thresholds (p < 0.01). Mechanistically, SESN2 reduced oxidative stress, restored mitochondrial function, and suppressed excessive PTEN-induced putative kinase 1 (PINK1)-Parkin-mediated mitophagy, thereby maintaining mitochondrial quality control. This study is the first to show that SESN2 protects against ARHL through a tripartite cascade: antioxidant defense, mitochondrial functional restoration, and dynamic mitophagy regulation. These findings highlight SESN2's pivotal role in auditory preservation and identify it as a promising new therapeutic target for age-related hearing deterioration.
    Keywords:  SESN2; Sestrin2; age-related hearing loss; mitochondrial function; mitophagy
    DOI:  https://doi.org/10.18999/nagjms.88.2.297
  13. Front Vet Sci. 2026 ;13 1892510
    Porcine epidemic diarrhea virus induces Vero cell mitophagy by regulating ROS-mediated PINK1/Parkin signal pathway.
    Yuhe Jin, Ao Sun, Ye Jin, Xinxu Li, Mingyue Han, Haoran Zhang, Hanfan Qiao, Wenli Bai, Yue Zhang, Dahan Yang.
       Introduction: Porcine epidemic diarrhea (PED) is a highly contagious enteric disease caused by the porcine epidemic diarrhea virus (PEDV), with mortality rates exceeding 80% in piglets. While the pathogenesis of PEDV is well-documented, its relationship with mitophagy remains unclear.
    Methods: We used transmission electron microscopy (TEM) to observe ultrastructural changes in PEDV-infected Vero cells. Western blotting and biochemical assays were employed to analyze mitophagy-related markers (LC3-II, PINK1, Parkin, Beclin1) and oxidative stress indicators (ROS, MDA, antioxidant enzymes). The role of the PINK1/Parkin pathway was further validated through siRNA knockdown and overexpression.
    Results: PEDV infection was found to trigger PINK1/Parkin-dependent mitophagy, evidenced by the accumulation of damaged mitochondria and upregulation of mitophagy markers. This process was driven by ROS-induced oxidative stress, as ROS scavenging significantly attenuated mitophagy. Furthermore, we demonstrated that mitophagy facilitates PEDV replication, with Parkin expression acting as a critical regulator of this viral-induced autophagic pathway.
    Discussion: This study reveals that PEDV exploits PINK1/Parkin-mediated mitophagy via ROS accumulation to promote viral replication. These findings provide a scientific basis for understanding PEDV pathogenesis and offer a technical reference for optimizing high-titer virus production in vaccine development.
    Keywords:  PINK1; ROS; mitophagy; parkin; porcine epidemic diarrhea virus
    DOI:  https://doi.org/10.3389/fvets.2026.1892510
  14. Zhongguo Zhong Yao Za Zhi. 2026 Jul;51(14): 4093-4102
    [Psoralen promotes osteogenic differentiation of MC3T3-E1 cells by regulating mitophagy via PINK1/Parkin pathway].
    Jun Cheng, Yan-Tao Guo, Lu Ma, Lei Yang.
      This study aims to investigate the protective effect of psoralen against hydrogen peroxide(H_2O_2)-induced oxidative stress injury in mouse cranial apical osteoblasts(MC3T3-E1) and explore its molecular mechanism in promoting osteogenic differentiation through PTEN-induced putative kinase 1(PINK1)/Parkin-mediated mitophagy regulation. An oxidative injury model in MC3T3-E1 cells was established with 200 μmol·L~(-1) H_2O_2. The experiment was conducted with four groups: normal, model, psoralen, and inhibitor groups. Cell viability and proliferation were assessed by the CCK-8 assay and EdU incorporation assay, respectively. Apoptosis was analyzed by Annexin V-FITC/PI double-staining flow cytometry. Mitochondrial membrane potential was evaluated with the JC-1 probe, and reactive oxygen species(ROS) levels were measured by the DCFH-DA probe. Early osteogenic differentiation markers and late mineralized nodule formation were observed by alkaline phosphatase(ALP) staining and alizarin S staining, respectively. Transmission electron microscopy was employed to examine mitochondrial ultrastructure changes. Immunofluorescence staining and Western blot were employed to determine the expression levels of PINK1, Parkin, p62, Runt-related transcription factor 2(Runx2), and Osterix. Molecular docking and 100 ns molecular dynamics simulations were conducted to validate the binding mode and stability of psoralen with PINK1. The results showed that psoralen ameliorated H_2O_2-induced cell damage in a concentration-dependent manner, with the optimal concentration being 80 μmol·L~(-1). Psoralen significantly promoted cell proliferation, upregulated the expression of Runx2, Osterix, PINK1, and Parkin, enhanced mitochondrial membrane potential, increased mitophagy levels and osteogenic differentiation capacity, and enlarged mineralized nodule area. Simultaneously, it inhibited apoptosis, reduced intracellular ROS content, and downregulated the expression of autophagy substrate p62. Molecular docking results showed that the binding energy between psoralen and PINK1 was-7.024 kcal·mol~(-1), and 100 ns molecular dynamics simulations further confirmed the structural stability of the formed complex with persistent hydrogen bond interactions. In conclusion, psoralen directly targets and activates the PINK1/Parkin pathway to mediate mitophagy, clear damaged mitochondria, improve the oxidative stress microenvironment, promote the expression of osteogenic marker proteins and mineralization, thereby enhancing osteogenic differentiation of MC3T3-E1 cells, providing a new target and candidate drug for the prevention and treatment of osteoporosis.
    Keywords:  mitophagy; molecular docking; molecular dynamics simulation; osteoporosis; psoralen
    DOI:  https://doi.org/10.19540/j.cnki.cjcmm.20260305.403
  15. Endocr Metab Immune Disord Drug Targets. 2026 Jul 27.
    IGFBP2 Knockdown Ameliorates Diabetic Gastroparesis by Inhibiting VDAC1-Dependent Mitophagy in Interstitial Cells of Cajal.
    Xiao Yuan, Yuting Chen, Zhengran Qin, Hong Zhang.
       INTRODUCTION/OBJECTIVE: Although insulin-like growth factor binding protein 2 (IGFBP2) is significantly upregulated in diabetic gastroparesis (DGP) and may regulate ICC mitophagy through its interaction with VDAC1, the precise mechanism of action remains unclear. This study aims to investigate the role and mechanism of IGFBP2 in the pathogenesis of DGP, with a specific focus on its impact on mitochondrial quality control in interstitial cells of Cajal (ICCs).
    METHODS: An in vivo DGP model was established. IGFBP2 expression was knocked down to assess its effects on systemic metabolism (blood glucose, HbA1c), gastric motor function (gastric emptying, motility, blood flow), and ICC integrity. In vitro, cell viability, apoptosis, mitochondrial membrane potential (MMP), and key proteins in the PINK1/Parkin mitophagy pathway were analyzed using CCK-8, flow cytometry, fluorescent probes, and Western blot.
    RESULTS: IGFBP2 knockdown significantly ameliorated hyperglycemia, promoted gastric emptying, enhanced contractile activity, and improved gastric perfusion. Mechanistically, it enhanced ICC survival, suppressed apoptosis, reduced mitochondrial oxidative stress, and stabilized MMP. Crucially, these benefits were mediated by the downregulation of voltage-dependent anion channel (VDAC1) and subsequent inhibition of PINK1/Parkin-dependent mitophagy.
    DISCUSSION: These findings indicate that IGFBP2 drives mitochondrial dysfunction and ICC loss via a VDAC1-dependent mitophagy pathway, revealing a previously underrecognized mechanism in DGP. The observed functional recovery and cytoprotection following IGFBP2 knockdown suggest that targeting this pathway may offer a potential therapeutic strategy for DGP.
    CONCLUSION: IGFBP2 acts as a potential upstream regulator that drives mitochondrial dysfunction and ICC loss in DGP via a VDAC1-mitophagy axis. These findings unveil IGFBP2 as a promising therapeutic target for intervening in the progression of DGP.
    Keywords:  Diabetic gastroparesis; insulin-like growth factor binding protein 2; interstitial cells of cajal; mitochondrial dysfunction; mitophagy; voltage dependent anion channel
    DOI:  https://doi.org/10.2174/0118715303448109260613173507
  16. Food Res Int. 2026 Oct 01. pii: S0963-9969(26)01398-0. [Epub ahead of print]241 119715
    Cyanidin chloride activates mitophagy to delay aging via PINK1/parkin pathway.
    Zhaotun Hu, Yan Ran, Xiaocong Li, He Zha, Yi Xiao.
      Food-derived bioactive compounds are increasingly recognized as promising nutritional candidates for modulating aging-associated functional decline. Among them, anthocyanidins, a major class of polyphenolic pigments widely present in dark-colored fruits, vegetables, and grains, have attracted attention because of their antioxidant, anti-inflammatory, and metabolic regulatory activities. Cyanidin chloride is a representative food-derived anthocyanidin found in edible plants such as blueberries, blackberries, purple cabbage, and black rice. However, whether Cyanidin chloride influences lifespan and aging-associated physiological decline, and how it affects mitochondrial homeostasis, remain incompletely understood. In this study, Caenorhabditis elegans and naturally aging mice were used to evaluate the effects of Cyanidin chloride. Cyanidin chloride extended lifespan in Caenorhabditis elegans and improved selected age-associated physiological readouts, including locomotor activity, lipofuscin accumulation, fertility preservation, and proteotoxicity-associated paralysis. Genetic analyses showed that these effects were largely dependent on the PINK-1/PDR-1 axis and were accompanied by increased expression of downstream autophagy-related genes (bec-1, lgg-1, and lgg-2), reduced reactive oxygen species (ROS) accumulation, and increased adenosine triphosphate (ATP) production. In aging mice, Cyanidin chloride administration was associated with improved survival, increased PINK1/Parkin-related protein markers, partially reduced the expression of inflammatory-related factors, and enhanced antioxidant-related gene expression. These findings suggest that Cyanidin chloride activates PINK1/Parkin-mediated mitophagy to alleviate aging-associated decline, providing a mechanistic basis for future studies on cyanidin-rich foods and anthocyanidin-based nutritional strategies.
    Keywords:  Aging; Cyanidin chloride; Mitochondrial homeostasis; Mitophagy; PINK1/parkin pathway
    DOI:  https://doi.org/10.1016/j.foodres.2026.119715
  17. Free Radic Biol Med. 2026 Aug 03. pii: S0891-5849(26)00985-8. [Epub ahead of print]255 573-590
    Crosstalk between mitophagy and metabolism in cancer: Mechanisms and therapeutic opportunities.
    Jingyi Cheng, Ting Xiao, Zhangui Tang, Yuhan Chen.
      Mitophagy is a highly selective autophagic process that eliminates dysfunctional mitochondria to enforce stringent cellular quality control, acting as a context-dependent modulator of stress adaptation in cancer cells. Concurrently, to thrive in hostile microenvironments, cancer cells undergo extensive metabolic reprogramming to fulfill the immense bioenergetic and anabolic demands of rapid proliferation. Rather than operating independently, mitophagy and metabolism are intrinsically coupled to form a highly sophisticated and bidirectional regulatory circuit. Metabolic disturbances trigger mitophagy, while mitophagy reciprocally remodels metabolic landscape. This crosstalk functions as a critical metabolic rheostat, equipping cancer cells with the dynamic plasticity required to cope with the dynamic physicochemical stresses. Furthermore, this mitophagy-metabolism crosstalk extends beyond cancer cells into the tumor microenvironment, orchestrating systemic metabolic symbiosis and driving immune evasion. In this review, we summarize the molecular mechanisms underpinning this crosstalk, and highlight how therapeutic targeting of these vulnerabilities offer opportunities for overcoming therapeutic resistance and improving clinical outcomes.
    Keywords:  Cancer; Metabolic reprogramming; Mitophagy; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.08.004
  18. Antioxid Redox Signal. 2026 Aug 05. 15230864261475098
    Targeted Restoration of Mitophagy Reinvigorates Aged Hematopoietic Stem Cells.
    Jin Liu, Aiwei Wu, Jieyu Ling, Liquan Hong, Mingwei Wang, Xinyi Chen, Jianpin Zhou, Zhenyu Ju, Yue Sheng, Hongguang Xia, Hu Wang.
       AIMS: Aging-related functional decline in hematopoietic stem cells (HSCs) is closely associated with mitochondrial dysfunction and impaired mitophagy. This study aimed to investigate whether targeted restoration of mitophagy via the myeloid cell leukemia 1 (MCL-1)/light chain 3A pathway could rejuvenate aged HSCs and improve their regenerative capacity.
    RESULTS: We identified MCL-1 as the most highly expressed mitophagy receptor in aged HSCs. Treatment with UMI-77, a selective MCL-1 agonist, significantly enhanced mitophagy, reduced mitochondrial mass, improved mitochondrial membrane potential, and reduced reactive oxygen species levels in aged HSCs both in vitro and in vivo. Single-cell RNA sequencing revealed that UMI-77 upregulated mitophagy-related genes (Sqstm1, Fundc1, Bnip3) and restored stemness signatures in long-term HSCs. Transplantation assays demonstrated that UMI-77-treated aged HSCs exhibited superior hematopoietic reconstitution capacity compared with those from control mice. However, this intervention also increased the proportion of myeloid-biased CD150high HSCs, a hallmark of aging.
    CONCLUSION: Targeted mitophagy restoration via MCL-1 activation improves mitochondrial fitness and stemness in aged HSCs but does not reverse myeloid bias. These findings highlight mitophagy enhancement as a viable therapeutic approach, while suggesting combinatorial strategies may be needed to fully restore lineage balance in aging hematopoiesis. Antioxid. Redox Signal. 00, 000-000.
    Keywords:  MCL-1; UMI-77; aging; hematopoietic stem cells; mitophagy
    DOI:  https://doi.org/10.1177/15230864261475098
  19. Stem Cells Transl Med. 2026 Jul 20. pii: szag056. [Epub ahead of print]15(8):
    Ckb-Cryab-Drp1 axis enhances BMSC osteogenic differentiation and mouse alveolar bone healing through mitochondrial fission modulation.
    Mingxi Wang, Long Wang, Jingchan Wang, Shan Gao, Guoqing Li, Chunbo Tang.
      Repairing bone defects resulting from trauma, infection, or tumor resection remains a significant challenge in clinical practice. Particularly in the oral and maxillofacial region, achieving predictable bone regeneration is especially difficult due to the complex anatomical structure and the critical need for optimal aesthetic and functional outcomes. A deeper understanding of the molecular mechanisms governing osteogenic differentiation is therefore essential to develop effective strategies for bone repair. Although creatine kinase B (Ckb) is known for its role in energy metabolism, its function in bone regeneration remains poorly understood. In this investigation, we found that Ckb is specifically expressed in jaw mesenchymal cells. Functional assays demonstrated that Ckb promoted osteogenic differentiation of bone marrow mesenchymal stem cells in vitro. Consistently, Ckb overexpression promoted alveolar bone healing in a mouse tooth-extraction model, while Ckb knockdown impaired bone regeneration. We discovered that Ckb localized to mitochondria and enhanced mitochondrial fission by increasing dynamin-related protein 1 (Drp1) Ser616 phosphorylation. The pro-osteogenic impact of Ckb was reduced by pharmacologically inhibiting mitochondrial fission with Mdivi-1. This result was replicated by Drp1 knockdown, indicating that Drp1 is essential for Ckb-mediated osteogenesis. Transcriptome sequencing identified αB-crystallin (Cryab) as a key downstream effector of Ckb, and co-immunoprecipitation confirmed a physical interaction between Ckb and Cryab. Crucially, Cryab overexpression rescued the osteogenic and mitochondrial dysfunction caused by Ckb knockdown. Collectively, our research reveals a unique Ckb-Cryab-Drp1 axis that controls mitochondrial dynamics to coordinate osteogenesis, offering a molecular basis for guiding MSC-based bone regeneration techniques.
    Keywords:  BMSCs; Ckb-Cryab-Drp1 axis; alveolar bone healing; mitochondrial fission; osteogenic differentiation
    DOI:  https://doi.org/10.1093/stcltm/szag056
  20. Mol Biol Rep. 2026 Aug 04. pii: 1331. [Epub ahead of print]53(1):
    The microbiome-mitochondria axis: the context-dependent role of urolithin A in aging and cancer via mitophagy.
    Jiayuan Wu, Xinxin Ye, Wei Hua, Yuyang Yao, Lu Sun, Hongyu Ma, Congcong Yu, Yanling Cheng, Shengquan Mi.
      Urolithin A (UA) is a gut microbiota-derived metabolite formed from dietary ellagitannins and ellagic acid. It has drawn sustained interest because it can influence mitochondrial quality control, but the evidence does not support a simple anti-aging or anticancer label. In this review, UA is examined across microbial metabolism, urolithin metabotypes, pharmacokinetic exposure, mitophagy biology, aging-related phenotypes, and cancer. The emphasis is placed on what has been shown, what remains model-dependent, and where translational claims are still premature. Preclinical work links UA to PINK1/Parkin-, TFEB-, AMPK-, sirtuin-, and Nrf2-associated pathways, with reported improvements in mitochondrial turnover and inflammatory signaling. Human data are narrower: most trials have been short and have focused on safety, muscle performance, mitochondrial signatures, and circulating biomarkers. Evidence for cancer prevention or cancer therapy still comes mainly from cell and animal studies. Because mitophagy can limit early mitochondrial damage but may also help established tumors survive hypoxia, nutrient restriction, dormancy, and therapy-induced stress, UA is better regarded as a microbiome-dependent mitochondrial modulator whose effects depend on biological setting. The next step is to define direct molecular targets, test native and conjugated UA at human-relevant exposure ranges, account for UM-A, UM-B, and UM-0 metabotypes, and evaluate cancer-specific endpoints before making therapeutic claims.
    Keywords:  Aging; Cancer; Gut microbiota; Mitophagy; Urolithin A; Urolithin metabotype
    DOI:  https://doi.org/10.1007/s11033-026-12542-y
  21. Cell Signal. 2026 Aug 02. pii: S0898-6568(26)00436-5. [Epub ahead of print]148 112778
    Progressive mitochondrial and autophagic dysfunction during RGC development driven by a LHON-associated mitochondrial tRNAThr mutation.
    Wei Guan, Wenxu Li, Zijun Li, Lu Peng, Shidan Shao, Juanjuan Zhang.
      Leber's hereditary optic neuropathy (LHON) is a genetically inherited disease of the eye triggered by mtDNA mutations, leading to degeneration of RGCs. We previously reported that the mitochondrial tRNAThr (MT-TT) 15927G > A homoplasmic mutation disrupted the base pairing (28C-42G) conserved in the anticodon stem of tRNAThr, impairing t6A modification, aminoacylation, and steady-state tRNAThr levels, ultimately resulting in mitochondrial dysfunction. However, the absence of suitable animal and cell models for LHON has delayed efforts to elucidate disease pathophysiology, particularly tissue-specific effects. In this study, RGC-like cells were generated from iPSCs derived from a Chinese family member carrying the m.15927G > A mutation and from a control subject without this mutation. Mitochondrial dysfunction and autophagy/mitophagy defects were investigated at three differentiation stages: iPSCs, NPCs, and RGC-like cells. Both iPSCs and NPCs harboring this mutation exhibited abnormal mitochondrial dynamics, mitochondrial dysfunction, and defects in autophagy and mitophagy. RGC-like cells carrying the mutation showed significant abnormalities, including shorter neurites, imbalanced mitochondrial dynamics, elevated ROS production, reduced mitochondrial membrane potential, and impaired autophagy and mitophagy. These results indicate that the m.15927G > A mutation induces progressive mitochondrial dysfunction and developmental defects in RGCs, providing new insights into LHON pathogenesis and establishing a valuable model for future therapeutic development.
    Keywords:  Autophagy; Induced pluripotent stem cells (iPSCs); Leber's hereditary optic neuropathy (LHON); Neural progenitor cells (NPCs); Retinal ganglion cells (RGCs)
    DOI:  https://doi.org/10.1016/j.cellsig.2026.112778
  22. Front Bioinform. 2026 ;6 1770712
    Integrative phosphoproteomics reveals kinase-mediated regulation of OCIAD1 and its roles in mitochondrial quality control.
    Amal Fahma, Suhail Subair, Fathimathul Lubaba, Athira Perunelly Gopalakrishnan, Prathik Basthikoppa Shivamurthy, Rajesh Raju.
       Background: The ovarian cancer immunoreactive antigen domain-containing protein 1 (OCIAD1) is a mitochondrial protein implicated in mitochondrial morphology, energy metabolism, and differentiation. Although understudied, recent studies position it as a critical player in carcinogenesis and neurodegenerative disorders, making it a potentially druggable node in cellular signaling networks. However, the phosphoregulatory networks and the upstream kinases governing OCIAD1 remain unknown.
    Methods: A large-scale literature mining and analysis of 177 phosphoproteomic datasets with differential expression of OCIAD1 was carried out to map its phosphoregulatory network. The predominant phosphosites were determined based on localization probability, detection frequency, and differential regulation. Multipronged computational approaches were employed to gather novel candidate kinases that may target OCIAD1 phosphosites. Co-differential phosphorylation analysis was conducted with other proteins, including interactors and candidate upstream kinases, to infer functional and regulatory associations.
    Results: The sites S108 and S123 emerged as predominant, together accounting for 70% of OCIAD1 phosphorylation. Co-differential phosphorylation analysis revealed associations with proteins involved in the cell cycle, DNA repair, autophagy, mitophagy, endocytosis, and apoptosis. Novel candidate kinases for OCIAD1 phosphosites were identified; notably, SRMS and YES1 emerged as potential upstream regulators of Y199. Furthermore, the phosphosites in the candidate kinases of sites, including PLK1 (T210), CDK13 (S383, S397), PRKD2 (S200), CIT (S1343), and RPS6KA3 (T577), showed strong positive co-differential regulation with OCIAD1 predominant sites, supporting their potential involvement as upstream kinases.
    Conclusion: This study presents the first systematic map of the OCIAD1 phosphoregulatory network and provides candidate upstream kinases that may contribute to its phosphorylation, which warrant further experimental validation. The strong co-differential regulation of proteins involved in autophagy, mitophagy, endocytosis, and neurodegenerative pathways, as well as of kinases that orchestrate these processes, suggests that OCIAD1 phosphoregulatory network maybe involved in mitochondrial quality control and mitochondria-associated neurodegeneration, establishing a foundation for therapeutic investigations targeting OCIAD1 signaling.
    Keywords:  OCIAD1; co-differential regulation; mitochondrial quality control; phosphoproteomics; upstream kinases
    DOI:  https://doi.org/10.3389/fbinf.2026.1770712
  23. Chin Med. 2026 Aug 04. pii: 207. [Epub ahead of print]21(1):
    Yiqi Huoxue Jiedu formula protects against sepsis-associated lung injury by modulating macrophage mitophagy and mtDNA-STING signaling.
    Shuqi Ma, Qiusha Pan, Jingnan Lin, Ruifeng Zeng, Xiaotu Xi, Ye Ye, Zhuoxu Gu, Kaiqiang Zhong, Suyi Yang, Lin Wang, Jun Li, Rui Chen.
       BACKGROUND: Yiqi Huoxue Jiedu Formula (YHJF) is a traditional Chinese medicine formula that has been used as an adjunctive therapy for sepsis for nearly two decades. Previous clinical studies showed that YHJF improves Sequential Organ Failure Assessment (SOFA) scores and modulates gut microbiota in elderly patients with pneumonia-associated sepsis. However, the mechanism by which YHJF protects against sepsis-associated acute lung injury (SALI) remains unclear.
    METHODS: A murine SALI model was established by cecal ligation and puncture (CLP). Therapeutic effects were evaluated by histopathology, micro-CT, pulmonary function assessment, and ELISA. Mechanistic studies included proteomic analysis of lung tissues and LPS-stimulated MH-S macrophages, pharmacological modulation with Mdivi-1 and urolithin A (UA), macrophage-epithelial co-culture, HPLC fingerprinting, UPLC-HRMS, and molecular docking.
    RESULTS: YHJF significantly improved 7-day survival and ameliorated lung injury, pulmonary edema, respiratory dysfunction, and systemic inflammation in mice with CLP-induced SALI. Proteomic profiling and subsequent functional assays suggested that enhanced mitophagy in macrophages represents a central protective mechanism. In vivo, YHJF increased autophagosome formation and PINK1/Parkin co-localization in BALF-derived alveolar macrophages. In vitro, YHJF restored mitochondrial homeostasis by activating PINK1/Parkin-dependent mitophagy in macrophages. This was accompanied by reduced cytoplasmic mtDNA leakage, downregulated cGAS expression, and suppression of the STING-TBK1-IRF3 pathway and subsequent type I interferon responses. Pharmacological inhibition of mitophagy with Mdivi-1 abolished these protective effects of YHJF, whereas activation with UA augmented them, demonstrating that mitophagy is necessary for YHJF-mediated protection. In a macrophage-epithelial co-culture system, YHJF-treated macrophages alleviated LPS-induced apoptosis in MLE-12 alveolar epithelial cells. Furthermore, chemical analysis integrated with molecular docking identified aloe-emodin, rhein, and genistein as candidate bioactive constituents of YHJF that likely contribute to its regulation of macrophage mitophagy.
    CONCLUSION: YHJF protects against SALI by restoring macrophage mitophagy and suppressing mtDNA-STING-mediated inflammatory signalling. These findings support YHJF as a potential therapeutic strategy for sepsis-associated lung injury.
    Keywords:  Mitophagy; Sepsis-associated acute lung injury; Yiqi Huoxue Jiedu formula; mtDNA-STING inflammatory axis
    DOI:  https://doi.org/10.1186/s13020-026-01475-0
  24. J Ethnopharmacol. 2026 Aug 01. pii: S0378-8741(26)01111-6. [Epub ahead of print]373 122256
    Asiaticoside attenuates endothelial cells senescence in diabetic retinopathy via CCND1-mediated mitophagy through the PI3K/AKT/mTOR pathway.
    Zhouyang Chen, Yuxin Luo, Xueying Lou, Songwei Chen, Yan Qian, Xiaowei Yang, Ying Yu.
       ETHNOPHARMACOLOGICAL RELEVANCE: Diabetic retinopathy (DR), a predominant microvascular complication of diabetes mellitus, is pathologically characterized by endothelial dysfunction and blood-retinal barrier (BRB) disruption. Asiaticoside (AC), a bioactive phytochemical constituent derived from traditional Chinese medicinal herbs, has shown promising therapeutic potential against a spectrum of diabetic complications. Nevertheless, the explicit molecular targets and the detailed pharmacological mechanisms underlying the protective effects of this herbal ingredient against DR have not yet been fully elucidated.
    AIM OF THE STUDY: This study aimed to investigate the therapeutic effects and underlying mechanisms of AC in attenuating the progression of DR by targeting Cyclin D1 (CCND1) to negatively regulate the PI3K-AKT-mTOR pathway and activating mitophagy, thereby providing a promising therapeutic strategy for DR treatment.
    MATERIALS AND METHODS: C57BL/6J mice were utilized to establish diabetic mouse model via intraperitoneal injection of streptozotocin (STZ) then treated with AC. Human microvascular endothelial cells (HMECs) were exposed to high glucose (HG; 35 mM) to construct high-glucose model and treated with AC, mitophagy inhibitor 3-MA, mitophagy agonist CCCP and PI3K agonist 740-YP. Genetic knockdown via siRNA was performed to validate CCND1 effect on cellular senescence and mitophagy. The senescence level of retina, mice visual contrast sensitivity and retinal vascular leakage were evaluated by western blotting, immunofluorescence, OptoDrum eyes tracker system and evans blue staining respectively. Cell viability, cellular senescence, cell migratory capacity, apoptosis, mitophagy, mitochondrial morphology, mitochondrial function, and ultrastructural changes were assessed by CCK8 assays, wound-healing assay, western blotting, immunofluorescence, and transmission electron microscopy (TEM) respectively.
    RESULTS: AC treatment significantly lowered the visual contrast threshold by approximately 18% and reduced retinal vascular leakage in diabetic mice. In vitro, AC ameliorated high glucose-induced endothelial cell senescence, attenuated cellular and mitochondrial dysfunction as well as reactive oxygen species (ROS) production, and induced mitophagy. Bioinformatics analysis identified CCND1 as one of the key senescence-related genes upregulated in DR, AC intervention significantly inhibited its overexpression. Furthermore, knockdown of CCND1 recapitulated the protective effects of AC, enhancing mitophagy and suppressing senescence phenotypes. Mechanistically, AC treatment or CCND1 knockdown inhibited high glucose-induced activation of the PI3K-AKT-mTOR signaling pathway, while the PI3K agonist 740 YP completely reversed these beneficial effects of AC.
    CONCLUSION: We firstly revealed that AC attenuates DR progression by alleviating cellular senescence in HMECs by modulating CCND1. Notably, the present study is the first to explore the pathological role of CCND1 in DR beyond its classical cell-cycle regulatory function, which provides a novel and promising therapeutic target and intervention strategy for DR treatment.
    Keywords:  Asiaticoside; Diabetic retinopathy; Mitophagy; Senescence
    DOI:  https://doi.org/10.1016/j.jep.2026.122256
  25. Neurochem Int. 2026 Aug 04. pii: S0197-0186(26)00126-9. [Epub ahead of print]199 106235
    Catalpol protects against MPP+-induced neurotoxicity by targeting PINK1/DJ-1-mediated mitophagy and the TrkB/Akt/BDNF/Bcl-2 axis.
    Han-Bin Yang, Yi-Hung Chen, Nguyen Thi Thao Nhung, En-Ya Hung, Shih-Ya Hung.
      Parkinson's disease (PD) is a prevalent neurodegenerative disorder characterized by dopaminergic neuronal death of unclear etiology. While levodopa remains the gold standard for managing PD motor symptoms, it lacks disease-modifying efficacy, necessitating new neuroprotective therapies. Mitochondrial dysfunction and impaired autophagy are key hallmarks of PD. This study utilized 1-methyl-4-phenylpyridinium (MPP+)-treated SH-SY5Y cells to investigate the neuroprotective mechanisms of catalpol, an iridoid glycoside derived from Rehmannia glutinosa. We found that catalpol attenuated MPP+-induced neurotoxicity, mitochondrial membrane depolarization, and ATP depletion. This protection was critically dependent on autophagy; it was enhanced by the activator rapamycin but abolished by the inhibitor wortmannin and the autophagosome-lysosome fusion inhibitor bafilomycin A1. Catalpol activated autophagy by increasing autophagosome formation, elevating Beclin 1 and LC3-II levels, and promoting p62 degradation. Furthermore, catalpol reversed MPP+-induced mitophagy suppression and restored the regulatory protein PINK1 and DJ-1 expression. Given that Akt/BDNF/Bcl-2 and TrkB/BDNF pathways promote neuronal survival, we investigated their involvement. We found that the TrkB agonist 7,8-DHF mimicked catalpol's neuroprotection against MPP+-induced neurotoxicity, whereas the pan-Trk inhibitor GNF-5837 abolished it. Western blotting demonstrated that catalpol reversed MPP+-mediated suppression of TrkB and Akt phosphorylation, as well as BDNF and Bcl-2 expression. Molecular docking indicated that catalpol may interact with the TrkB ligand-binding domain as 7,8-DHF and shares key binding residues. Our findings suggest that catalpol exerts neuroprotection via a dual mechanism: preserving mitochondrial function through PINK1/DJ-1-mediated mitophagy and activating the TrkB/Akt/BDNF/Bcl-2 survival pathway, potentially by interacting with the TrkB receptor, highlighting its therapeutic potential for PD.
    Keywords:  Catalpol; Mitophagy; Neuroprotection; Parkinson's disease; TrkB/Akt/BDNF/Bcl-2 axis
    DOI:  https://doi.org/10.1016/j.neuint.2026.106235
  26. Sci Prog. 2026 Jul-Sep;109(3):109(3): 368504261477908
    Corrigendum to "Mitophagy suggesting a possible association with oocyte maturation: A study of granulosa cells from follicular fluid of normoresponder and diminished ovarian reserve cases".
      
    DOI:  https://doi.org/10.1177/00368504261477908
  27. Free Radic Biol Med. 2026 Aug 05. pii: S0891-5849(26)00998-6. [Epub ahead of print]255 659-674
    Protocatechuic acid protects neural stem cells against cerebral ischemia-reperfusion injury by suppressing JAK2/STAT3 signaling and restoring mitophagy.
    Mengzhen Wei, Jie Hu, Yanxin Ding, Lei Wu, Qiang Wang, Lu Chen, Qiong Zhang, Jian Gu, Zhigao Zhao, Rui Tan.
       BACKGROUND AND OBJECTIVES: Neural stem cells (NSCs) are important for endogenous brain repair but are highly vulnerable to mitochondrial dysfunction during cerebral ischemia-reperfusion injury (CIRI). Preliminary bioinformatics analysis suggested that immune microenvironment remodeling and JAK/STAT signaling activation are involved in CIRI pathology. This study investigated whether protocatechuic acid (PCA) protects NSCs after ischemia-reperfusion injury and explored the underlying mechanisms focusing on the JAK2/STAT3 pathway and mitophagy.
    RESULTS: Bioinformatics analysis identified JAK/STAT signaling as a potential regulatory node in CIRI. Transcriptome sequencing further showed that PCA markedly altered the gene expression profile of NSCs, with differentially expressed genes enriched in the JAK/STAT pathway. In vitro, PCA suppressed OGD/R-induced JAK2/STAT3 activation, restored mitochondrial membrane potential, reduced DCFH-DA and MitoSOX Red oxidation-sensitive fluorescence signals, promoted TOMM20/LC3 colocalization, enhanced PINK1/Parkin-related mitophagy, and improved NSC survival. Co-treatment with the JAK2 inhibitor AG490 further supported the protective and pro-mitophagic effects of PCA, whereas co-treatment with the JAK/STAT pathway activator RO8191 weakened PCA-mediated mitochondrial protection and mitophagy restoration. In vivo, PCA improved neurological function, reduced infarct volume, attenuated hippocampal neuronal injury, preserved endogenous NSCs and NeuN-positive cells, and enhanced mitophagy-related signals in MCAO/R rats. Importantly, in vivo Western blot analysis showed that PCA suppressed MCAO/R-induced JAK2/STAT3 phosphorylation, whereas RO8191 co-treatment attenuated this inhibitory effect and weakened the protective effects of PCA, supporting the involvement of JAK2/STAT3 inhibition in PCA-mediated neuroprotection.
    CONCLUSION: PCA alleviates CIRI and protects NSCs partly by suppressing JAK2/STAT3 activation, restoring mitochondrial function, and promoting PINK1/Parkin-mediated mitophagy. These findings provide experimental evidence supporting mitochondrial quality control and NSC protection as potential therapeutic targets for ischemic stroke.
    Keywords:  CIRI; JAK2/STAT3; Mitophagy; NSCs; PCA
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.08.009
  28. Free Radic Biol Med. 2026 Aug 06. pii: S0891-5849(26)01011-7. [Epub ahead of print]
    FOXO3 Counteracts Oxidative Stress-Induced Nucleus Pulposus Cell Senescence via BNIP3-Mediated Mitophagy in Intervertebral Disc Degeneration.
    Wei Chen, Wenzhe Huang, Libo Chen, Yi Chen, Zhenxin Hu, Jiayuan Wu, Qi Zhang, Yiming Ren, Penglei Cui, Da He.
      Oxidative stress and mitochondrial reactive oxygen species (ROS) accumulation are central drivers of nucleus pulposus (NP) cell senescence and intervertebral disc degeneration (IVDD), yet the transcriptional programs that maintain mitochondrial redox homeostasis in NP cells remain poorly defined. In this study, we investigated the role of forkhead box O3 (FOXO3) in regulating NP cell senescence and mitophagy during IVDD. We found that FOXO3 expression was significantly reduced in degenerated disc tissues and in senescent NP cells. In vitro, FOXO3 overexpression markedly alleviated H2O2-induced senescence, as shown by reduced SA-β-gal positivity, downregulation of p16 and senescence-associated catabolic factors, and partial restoration of extracellular matrix-related proteins. Transcriptomic profiling revealed that FOXO3 suppressed senescence-, NF-κB-, and matrix degradation-associated pathways while activating autophagy-related programs. Mechanistically, FOXO3 enhanced autophagic flux and promoted BNIP3-dependent mitophagy, accompanied by improved mitochondrial ultrastructure, preservation of mitochondrial membrane potential, and reduced mitochondrial reactive oxygen species accumulation. Importantly, BNIP3 knockdown partially abolished the anti-senescent effects of FOXO3, supporting BNIP3-mediated mitophagy as a key downstream mechanism. In vivo, adeno-associated virus-mediated FOXO3 overexpression attenuated puncture-induced disc degeneration, reduced p16 and MMP13 expression, and restored aggrecan and collagen II levels. Collectively, these findings identify FOXO3 as a critical regulator of mitochondrial quality control and NP cell senescence, and suggest that targeting the FOXO3-BNIP3-mitophagy axis may represent a promising therapeutic strategy for IVDD.
    Keywords:  Cellular Senescence; FOXO3; Intervertebral Disc Degeneration; Mitophagy; Oxidative Stress
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.08.011
  29. J Mater Chem B. 2026 Aug 05.
    A 3-n-butylphthalide-based nanoagent modulates PINK1/Parkin-associated mitophagy signaling in ischemia-reperfusion brain injury.
    Dingyang Li, Fukai Zhu, Zhongxiong Fan, Shujie Yu, Yuan Liao, Lele Kou, Ruifang Zheng, Zhijian Li.
      Cerebral ischemia and reperfusion induce profound mitochondrial dysfunction in neurons, characterized by excessive mitochondrial fragmentation and persistent accumulation of damaged organelles, which in turn sustain and amplify oxidative stress and inflammatory signaling. Therefore, restoring mitochondrial quality control by enhancing mitophagy to selectively eliminate dysfunctional mitochondria and maintain energy homeostasis represents a promising strategy for alleviating secondary neuronal injury. Here, we develop a phosphatidylcholine (PC)-based supramolecular self-assembly scaffold co-loaded with curcumin (Cur) and 3-n-butylphthalide (NBP) as therapeutic cargos. Hydrophobic interactions and π-π stacking drove the co-incorporation of both drugs into the PC scaffold, resulting in the formation of a stable supramolecular nanoagent (CNP). In neurons subjected to oxygen-glucose deprivation followed by reoxygenation (OGD/R), CNP significantly enhanced intracellular delivery, reduced reactive oxygen species levels, preserved mitochondrial membrane potential, and restored ATP production. Moreover, CNP modulated PINK1/Parkin-associated mitophagy signaling, reduced the accumulation of TOM20 and p62, and suppressed the production of IL-6 and TNF-α. In a transient middle cerebral artery occlusion and reperfusion mouse model (tMCAO/R), intravenous administration of CNP enhanced brain accumulation, reduced infarct volume, and improved neurological scores. These effects were accompanied by reduced CD86-positive pro-inflammatory microglia and increased CD31-positive vascular structures and TUJ1-positive neuronal signals. Overall, CNP represents a promising dual-drug nanoagent strategy for neuroprotection after ischemia/reperfusion by coupling mitochondrial functional preservation with mitophagy reactivation.
    DOI:  https://doi.org/10.1039/d6tb01047d
  30. Autophagy. 2026 Aug 02. 1-21
    African swine fever virus pMGF360-3 L suppresses innate immunity by facilitating CMA-dependent SKP1 degradation to promote BNIP3-mediated mitophagy.
    Sizhan Lin, Jingtao Liang, Jiafang Ye, Minping Chen, Mingyu Zhang, Zhao Huang, Qi Gao, Yingnan Liu, Hongjun Chen, Guihong Zhang, Lang Gong.
      African swine fever (ASF) is an acute, hemorrhagic, and highly contagious disease caused by African swine fever virus (ASFV), which causes severe economic losses in the swine industry. ASFV has evolved multiple strategies to evade host antiviral immune responses. Here, we report that ASFV pMGF360-3 L promotes host mitophagy by manipulating chaperone-mediated autophagy (CMA), thereby inhibiting the production of type I interferon (IFNB/IFN-β). Mechanistically, pMGF360-3 L targets the SKP1 protein via its N-terminal ankyrin (ANK) repeat domain, promoting the degradation of SKP1 through the CMA pathway, which inhibits the proteasomal degradation of BNIP3 to increase its expression level in mitochondria. Subsequently, BNIP3 binds to MAP1LC3B/LC3B to induce mitophagy, a process that leads to the degradation of mitochondria. Notably, the CMA-mediated degradation of SKP1 depends on its K94 site, and the SKP1-BNIP3 axis is critical for pMGF360-3 L-mediated IFNB inhibition. In summary, our study reveals a mechanism through which ASFV pMGF360-3 L facilities CMA-dependent degradation of the E3 complex component SKP1. This stabilizes mitochondrial BNIP3 to initiate mitophagy and block IFNB production. This deepens our understanding of the immune evasion strategies of ASFV and provides potential drug targets for controlling viral infection.Abbreviations: 3-MA: 3-methyladenine; ASFV: African swine fever virus; BafA1: bafilomycin A1; BNIP3: BCL2 interacting protein 3; CMA: chaperone-mediated autophagy; co-IP: co-immunoprecipitation; CQ: chloroquine; CHX: cycloheximide; CUL1: cullin 1; DAPI: 4', 6-diamidino-2'-phenylindole; EV: emptor vector; FBXL4: F-box and leucine rich repeat protein 4; hpi: hours post-infection; IFNB: interferon beta; ISGs: IFN-stimulated genes; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MG132: cbz-leu-leu-leucinal; MAVS: mitochondrial antiviral signaling protein; MOI: multiplicity of infection; PAMs: porcine alveolar macrophages; PPTC7: protein phosphatase targeting COQ7; RBX1: ring-box 1; RT-PCR: real-time polymerase chain reaction; siRNA: small interfering RNA; SKP1: S-phase kinase associated protein 1; TCID50: 50% tissue culture infectious doses; Ub: ubiquitin; WCL: whole-cell lysate; WT: wild-type.
    Keywords:  African swine fever virus; BNIP3; chaperone-mediated autophagy; innate immunity; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2026.2707892
  31. Int J Biol Macromol. 2026 Aug 05. pii: S0141-8130(26)03862-6. [Epub ahead of print] 153916
    Triphenylphosphonium-functionalized ferric-tannic acid nanometallic framework delivers optic atrophy 1 protein to restore mitochondrial homeostasis in diabetic erectile dysfunction.
    Ming Zhang, Xiaolin Zhang, Xiaoqi Wu, Bo Wang, Xinda Chen, Yiliang Peng, Weimin Liu, Mujun Lu, Tao Qi.
      Diabetic erectile dysfunction (DMED) is a prevalent complication of diabetes mellitus, with mitochondrial dysfunction playing a central pathogenic role. Current treatments inadequately address these subcellular pathological mechanisms. This study aimed to develop a mitochondria-targeted nanotherapeutic platform for efficient optic atrophy 1 (OPA1) protein delivery to restore mitochondrial homeostasis in cavernous tissue. A triphenylphosphonium (TPP)-functionalized Fe3O4-ferric tannic acid (FeTA) nanocarrier was synthesized and loaded with recombinant human OPA1 to form Fe3O4-FeTA-TPP-OPA1 (OFFT). OFFT nanoparticles exhibited a spherical morphology, a hydrodynamic diameter of 285.00 ± 6.36 nm, and an OPA1 loading content of 0.69%. OFFT showed pH-responsive OPA1 release, with cumulative release reaching 71.27 ± 3.42% at pH 5.5 versus 60.64 ± 0.20% at pH 7.4 within 72 h, and retained intrinsic superoxide dismutase/catalase-like activities. In high glucose-treated mouse Schwann cells, OFFT efficiently targeted mitochondria, restored cell viability from 52.87 ± 1.48% to 87.46 ± 1.60%, reduced apoptosis from 68.73 ± 1.94% to 51.25 ± 0.95%, suppressed reactive oxygen species, increased the JC-1 red/green fluorescence ratio from 25.20 ± 0.96 to 80.09 ± 2.53, and normalized mitochondrial fusion-fission balance. In DMED rats, OFFT treatment (15 mg/kg every 48 h for 8 weeks) increased the intracavernosal pressure/mean arterial pressure (ICP/MAP) ratio from 0.24 ± 0.05 to 0.45 ± 0.05, alleviated cavernosal fibrosis, enhanced local antioxidant capacity, and normalized mitochondrial dynamics-related protein expression. Collectively, the OFFT nanoplatform enables mitochondria-targeted OPA1 delivery, effectively restores mitochondrial homeostasis, and ameliorates DMED. This work presents a promising organelle-targeted protein delivery strategy for treating diabetic complications.
    Keywords:  Diabetic complications; Erectile dysfunction; Metal-organic framework; Mitochondrial dynamics; OPA1 protein delivery; Targeted nanotherapy
    DOI:  https://doi.org/10.1016/j.ijbiomac.2026.153916
  32. Brain Res Bull. 2026 Aug 03. pii: S0361-9230(26)00356-4. [Epub ahead of print] 112069
    Urolithin B Ameliorates Depressive-like Behavior and Hippocampal Neuronal Damage in Depressed Rats via regulation of the SLP2/PINK1/Parkin Signaling Pathway.
    Feifei Chen, Lingkai Tang, Ling Yuan, Jiali Xiong, Rong Kuang, Wen Qian, Yufang Kong, Yina Yin.
       BACKGROUND: Depression is a highly prevalent mental disorder, with current medications often limited by delayed onset and insufficient efficacy, underscoring the urgent need to explore novel therapeutic strategies. Urolithin B (UB), a natural ellagitannin-derived metabolite, exhibits anti-inflammatory and antioxidant activities in neuroinflammation, yet its role in depression remains unclear.
    OBJECTIVE: The present research aimed to uncover possible effects of UB on depressive-like behavior and hippocampal neuronal damage in a rat model of depression and to preliminarily elucidate its underlying molecular mechanisms.
    METHODS: A rat model of depression was created using the chronic unpredictable mild stress (CUMS) paradigm, after which UB intervention was applied. To evaluate depressive-like behaviors, several behavioral tests were conducted, including sucrose preference test, forced swim test, tail suspension test, and open field test. Hippocampal pathological changes and related factor expression were evaluated using histopathology, immunofluorescence, and ELISA. Potential targets were screened via single-cell RNA sequencing (scRNA-seq) data obtained from the GEO database. Subsequently, the function of the identified target gene was validated through in vitro knockdown/overexpression experiments and an in vivo rescue experiment.
    RESULTS: UB significantly ameliorated depressive-like behaviors in CUMS rats and alleviated hippocampal neuronal damage, synaptic loss, and neuroinflammation. scRNA-seq analysis revealed a significant upregulation of SLP2 expression in hippocampal neurons (HNs) from the treated group, along with the enrichment of mitophagy-related pathways. Functional experiments confirmed that SLP2 regulates the PINK1/Parkin pathway, promotes mitophagy, and maintains neuronal energy homeostasis. Conversely, knockdown of SLP2 reversed the antidepressant and neuroprotective effects of UB.
    CONCLUSION: UB alleviates CUMS-induced depressive-like behavior and hippocampal neuronal damage by upregulating SLP2 and regulating the PINK1/Parkin-mediated mitophagy pathway. This study presents a new potential target and theoretical basis for developing natural compound-based therapies for depression.
    Keywords:  Chronic Unpredictable Mild Stress; Depression; Hippocampal Neurons; Mitophagy; PINK1/Parkin Pathway; SLP2; Urolithin B
    DOI:  https://doi.org/10.1016/j.brainresbull.2026.112069
  33. MedComm (2020). 2026 Aug;7(8): e70895
    Type 2 Diabetes Mellitus: Molecular Pathogenesis and Therapeutic Interventions.
    Shinuan Fei, Xiyue Xiong, Lu Zhang, Jian Zhang, Lawrence W C Chan, Hong Jiang, Qingqing Xiong, Changtao Hu, Jie Chen, Sijun Yang.
      Type 2 diabetes mellitus (T2D) is a pervasive metabolic disorder driven by insulin resistance and progressive pancreatic β-cell failure, with a rapidly growing global prevalence. Its pathogenesis now extends beyond hyperglycemia to encompass intricate immunometabolic dysregulation, mitochondrial dysfunction, and organelle stress. However, a cohesive synthesis that integrates these disparate molecular mechanisms with contemporary therapeutic advancements remains missing. This review systematically investigates the immunometabolic axis, highlighting macrophage polarization and exosomes, as well as nanotube-mediated crosstalk with β-cells, and describes how mitochondrial dynamics disorder and impaired mitophagy become the core driving factors for β-cell failure. Lipotoxicity mediated by ceramides, diacylglycerols, and cholesterol imbalance is critically analyzed alongside proteotoxicity from islet amyloid polypeptide aggregation. We then chart the therapeutic evolution from glucocentric strategies to modern complication-centric paradigms, emphasizing SGLT2 inhibitors and GLP-1 receptor agonists that confer proven cardio-renal protection. Personalized treatment, multiomics integration, next-generation precision therapies, and holistic art-based interventions that promote sustainable lifestyle changes are further discussed. By connecting molecular insights to clinical application, this review provides a comprehensive resource for researchers and clinicians, aiming to advance T2D management and improve global patient outcomes.
    Keywords:  Type 2 diabetes; mitochondrial dynamics; molecular pathogenesis; therapeutic interventions; β‐cell dysfunction
    DOI:  https://doi.org/10.1002/mco2.70895
  34. Zhongguo Zhong Yao Za Zhi. 2026 Jul;51(14): 4122-4132
    [Costunolide improves sorafenib-induced cardiomyocyte injury by inhibiting mitophagy].
    Dan-Dan Niu, Cheng Wang, Chang-En Duan.
      This study focused on the protective effect of costunolide(COS) against sorafenib(SOR)-induced cardiomyocyte injury and its association with mitophagy. Cell viability was assessed using the CCK-8 assay. H9c2 cells were divided into six groups: control(ctrl) group, SOR group, SOR + low-dose COS(SOR+low-COS) group, SOR + high-dose COS(SOR+high-COS) group, SOR + high-COS + rapamycin group, and SOR + high-COS + adenosine monophosphate-activated protein kinase(AMPK) activator(AICAR) group, with each group receiving the respective treatments for 24 hours. Concurrently, male C57BL/6J mice were randomly assigned to six groups(10 per group): ctrl group, SOR group, SOR + low-COS group, SOR + high-COS group, SOR + high-COS + rapamycin group, and SOR + high-COS + AICAR group. Following the respective interventions, cardiac function and myocardial pathological changes were evaluated. The autophagosome formation labelled by microtubule-associated protein 1A/1B light chain 3(LC3) and the overall autophagic status, as well as the expression levels of proteins related to the AMPK/UNC-51-like autophagy activating kinase 1(ULK1)/FUN14 domain containing 1(FUNDC1) signaling pathway, were examined in both cellular and murine samples. The results demonstrated that 0-20 μmol·L~(-1) SOR significantly reduced H9c2 cell viability in a dose-dependent manner(P&lt;0.05). Conversely, 2.5-10 μmol·L~(-1) COS dose-dependently and significantly increased the viability of SOR-treated H9c2 cells(P&lt;0.05). Compared with the ctrl group, the SOR group exhibited notable changes in multiple indicators, including a significant increase in lactate dehydrogenase(LDH) leakage rate, LC3-related indices, and the expression levels of various autophagy-related proteins, as well as a significant decrease in mitochondrial membrane potential and p62 protein(p62) expression(P&lt;0.05). Following COS administration, these indices were significantly reversed in the SOR+low-COS and SOR+high-COS groups(P&lt;0.05). Further addition of rapamycin and AICAR resulted in changes opposite to those observed in the SOR+high-COS groups(P&lt;0.05). Animal experiments exhibited a similar trend: the SOR group showed significant differences in multiple cardiac functional parameters and protein expression levels compared with the ctrl group, which were ameliorated by COS treatment. Upon further addition of rapamycin and AICAR, both cardiac functional indices and protein expression levels displayed trends opposite to those in the SOR+high-COS group(P&lt;0.05). In conclusion, COS inhibits excessive mitophagy in cardiomyocytes and exerts a protective effect against SOR-induced cardiomyocyte injury, a mechanism potentially mediated through suppression of the AMPK/ULK1/FUNDC1 signaling pathway.
    Keywords:  AMPK; FUNDC1; ULK1; costunolide; mitophagy; myocardial cell; sorafenib
    DOI:  https://doi.org/10.19540/j.cnki.cjcmm.20260406.801
  35. Cell Signal. 2026 Aug 01. pii: S0898-6568(26)00441-9. [Epub ahead of print] 112783
    Targeting the AMPK signalling pathway: Honokiol modulated energy metabolism to mitigate pulmonary injury induced by airborne microplastics through regulating autophagy and mitophagy.
    Yajing Ma, Ruisi Zhu, Songyuan Xia, Qingfeng Huang, Huixin Song, Yuzhi Luo, Lingyi Liu, Heping Fan, Yarong Zhang, Leilei Su, Zhenxing Shen, Jian Sun, Weifeng Li, Xiaofeng Niu.
      Microplastics (MPs) pollution represents a pressing global environmental challenge, with studies increasingly highlighting their associated health risks. Although MPs have been detected in human lung tissues, the majority of existing research has concentrated on their physicochemical characteristics, environmental distribution and pulmonary health risks. Consequently, our understanding of the specific biological targets and effective intervention strategies against these risks remains limited. To identify therapeutic targets, we screened for pulmonary differential metabolites between normal mice and mice exposed to airborne MPs, derived from dust fall of 10 cities in China. Proteomics results showed adenosine 5'-monophosphate-activated protein kinase (AMPK) signalling pathway was one of critical targets. Through molecular docking and molecular dynamics stimulation, honokiol (HNK) was selected as therapeutic drug to regulate AMPK. In vitro results demonstrated that HNK significantly ameliorated autophagy inhibition in RAW264.7 cell, and alleviated mitochondrial dysfunction in BEAS-2B cell. Drug mechanism research revealed that HNK activated autophagy via the AMPK/mammalian target of rapamycin (AMPK/mTOR) pathway, and promoted mitophagy through the AMPK/E3 ubiquitin protein ligase parkin (AMPK/Parkin) pathway, thereby restoring mitochondrial function. Further targeted energy metabolomics analysis illustrated that HNK regulated the guanosine triphosphate to guanosine diphosphate (GTP/GDP) ratio, adenosine triphosphate ‌(ATP) production, and nucleotide metabolism. These functions accelerated the restoration of autophagic flux, mitophagy reactivation and DNA repair. In conclusion, HNK effectively alleviates airborne MPs-induced autophagy inhibition, mitochondrial dysfunction and energy metabolism disorder via AMPK signalling, providing a promising intervention strategy for pulmonary injury caused by airborne MPs.
    Keywords:  AMPK; Airborne microplastics; Autophagy and mitophagy; Energy metabolism; Honokiol; Pulmonary injury
    DOI:  https://doi.org/10.1016/j.cellsig.2026.112783
  36. Adv Sci (Weinh). 2026 Aug 05. e76824
    Miro1 Protects Against Acute Kidney Injury Through Modulating Mitochondrial Homeostasis via Interaction With Sirt6.
    Lin Wu, Qing Li, Yiyang Xu, Zitao Wang, Hua Shu, Yangfan Wu, Fang Lu, Zhimin Huang, Bo Zhang, Hongwei Liang, Changying Xing, Huijuan Mao, Yanggang Yuan.
      Acute kidney injury (AKI) is highly prevalent worldwide but lacks specific treatments. Mitochondrial dysfunction plays a central role in its pathogenesis, making mitochondrial protection a promising therapeutic strategy. Miro1 is a key regulator of mitochondrial dynamics, yet its involvement in AKI remains unexplored. In this study, we found that Miro1 expression was significantly downregulated in renal tubular cells from AKI patients and in multiple murine AKI models. Functional studies demonstrated that Miro1 loss aggravated tubular cell injury and mitochondrial dysfunction, whereas Miro1 overexpression exerted protective effects. Mechanistically, we identified Sirt6 as a novel interacting partner of Miro1. Sirt6 directly deacetylated Miro1 at lysine residue K182, which inhibited its ubiquitin-proteasome degradation and maintained Miro1 protein stability. Disruption of Sirt6 activity led to enhanced Miro1 downregulation and increased tubular cell apoptosis, while Sirt6 activation reversed these detrimental effects in a deacetylase-dependent manner. Reciprocal rescue experiments further confirmed that Miro1 serves as a critical downstream effector of Sirt6. Collectively, our findings uncover the Sirt6-Miro1 axis as a previously unrecognized protective mechanism in AKI, wherein Sirt6 stabilizes Miro1 via deacetylation to preserve mitochondrial homeostasis and alleviate kidney injury. This axis may represent a novel therapeutic target for AKI intervention.
    Keywords:  Miro1; Sirt6; acute kidney injury; mitochondrial movement
    DOI:  https://doi.org/10.1002/advs.76824
  37. Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2026 Jun;48(3): 432-443
    Dusquetide Regulates SQSTM1/p62-Mediated Mitophagy to Alleviate PM2.5-Aggravated Airway Inflammation in Asthma.
    Jie Gao, Ji-Liu Liu, Man-Ling Jiang, Guo-Ping Li, Xiang He.
      Objective To investigate the pathological mechanism by which fine particulate matter (PM2.5) exacerbates asthma,with a focus on SQSTM1/p62-mediated mitophagy,and to evaluate the regulatory and therapeutic potential of dusquetide in this process. Methods A house dust mite (HDM)-induced asthma model was established with 6- to 8-week-old female C57BL/6 mice,which were then exposed to PM2.5.Control,HDM,HDM+PM2.5 (HP),and intervention (HP+Mdivi-1 and HP+dusquetide) groups were established.Airway hyperresponsiveness was assessed through whole-body plethysmography,and airway inflammation and mucus secretion were evaluated by HE and PAS staining.Immunofluorescence assay was employed to detect the co-localization of TOMM20 and LC3B.Key factors were screened and validated by LC-MS/MS-based mitochondrial proteomics. Results PM2.5 exposure enhanced airway hyperresponsiveness (P<0.01),exacerbated inflammation and mucus secretion (P<0.01),and increased TOMM20 and LC3B co-localization signals (P<0.01) in HDM-sensitized mice.Mdivi-1 inhibition of mitophagy reduced inflammation (P<0.01).Mitochondrial proteomics identified SQSTM1/p62 as a core regulatory factor,whose expression was up-regulated after PM2.5 exposure (P<0.01).Dusquetide intervention inhibited SQSTM1/p62 function and mitophagy (P<0.01),reduced airway hyperresponsiveness in mice of the HP group (P<0.01),and alleviated inflammatory manifestations (P<0.01). Conclusion PM2.5 exacerbates HDM-induced asthma pathology by activating SQSTM1/p62-mediated mitophagy,while dusquetide effectively alleviates this process,demonstrating the potential as a therapeutic target for PM2.5-related asthma.
    Keywords:  Dusquetide; PM2.5; SQSTM1/p62; asthma; mitophagy
    DOI:  https://doi.org/10.3881/j.issn.1000-503X.16948
  38. Adv Sci (Weinh). 2026 Aug 05. e76941
    Ion-Driven Regulation of Ca2 + Flow by Ti/Zn Composite Activates ERK/MAPK Signaling and Maintains Mitochondrial Homeostasis to Promote Macrophage-Mediated Bone Regeneration.
    Wanyi Huang, Qiyue Zhang, Yueyang Qiu, Haocheng Suo, Zengqian Liu, Bing Bai, Qiang Wang, Qing Zhou.
      The field of tissue engineering is transitioning from bioinert to bioactive materials that actively regulate host biology. Here, we developed a 3D-printed porous Ti scaffold infiltrated with molten Zn to form an interpenetrating Ti/Zn composite with immunomodulatory and osteogenic bioactivity. Corrosion characterization revealed sustained and stable Zn2+ release. In vivo evaluation using a rat rib implantation model confirmed enhanced peri-implant bone regeneration, accompanied by localized Ca/P deposition at Zn degradation sites, indicating biofunctionally favorable degradation. In vitro, Ti/Zn extract induced a shift toward an anti-inflammatory M2 macrophage phenotype. Mechanistically, Zn2+ altered intracellular Ca2+ dynamics, elevating cytoplasmic Ca2+ while preventing mitochondrial Ca2+ overload, thereby preserving mitochondrial membrane potential and inner membrane protein complex stability. This Ca2+ redistribution selectively activated ERK/MAPK signaling, linking ionic cues to mitochondrial homeostasis, reduced ROS generation, and suppression of cytochrome c-mediated intrinsic apoptosis. The immunoregulatory secretome from Ti/Zn-reprogrammed macrophages further promoted osteoblast proliferation, ALP activity, and osteogenic gene/protein expression. In vivo immunohistochemistry and immunofluorescence validated a remodeled immune microenvironment with attenuated oxidative stress and active new bone synthesis. Overall, the Ti/Zn composite integrates bone-mimetic architecture with ion-driven immunometabolic regulation, highlighting its potential as a next-generation bioactive bone implant.
    Keywords:  biomaterials; macrophage polarization; mitochondrial homeostasis; osteogenesis; zinc
    DOI:  https://doi.org/10.1002/advs.76941
  39. J Cardiovasc Transl Res. 2026 Aug 04. pii: 97. [Epub ahead of print]19(1):
    Beyond the Pump: Unravelling Immunometabolic Crosstalk and Organelle Dynamics in Sepsis-Induced Cardiomyopathy.
    Guangfu Liu, Liya Hao, Junfeng Zhang, Yidan Guo, Guangyue Lv, Jiuyuan Liu, Cheng Cheng, Han Yi, Jingjing Zhou, Zhenzhu Liu.
      Sepsis-induced cardiomyopathy (SICM) has traditionally been viewed as pump-centered contractile failure, but this paradigm fails to explain the clinical spectrum and recovery patterns. This review presents an integrative framework where immunometabolic crosstalk and organelle dysfunction drive disease, including metabolic routing defects, mitochondrial fission, ER stress, and epigenetic regulation via m6A modification and lactylation. Clinically, it proposes a four-phenotype taxonomy (hyperdynamic, hypodynamic, right ventricular-predominant, Takotsubo-like) and advocates for strain imaging and MRI over ejection fraction. Diagnostic innovation includes liquid biopsy for mitochondrial DNA, extracellular vesicles, and metabolomics. Therapeutically, metabolic resuscitation and phenotype-guided vasopressors offer disease modification. The authors call for adaptive trials, biobanking, and organelle-targeted interventions, positioning SICM as a model for precision immunometabolic medicine.
    Keywords:  Immunometabolism; Metabolic resuscitation; Mitochondrial dynamics; Organelle crosstalk; Sepsis-induced cardiomyopathy
    DOI:  https://doi.org/10.1007/s12265-026-10826-z
  40. Acta Pharmacol Sin. 2026 Aug 04.
    Targeting FOSL1-KCa3.1 inhibits ferroptosis and cartilage destruction by suppressing mitochondrial hyperfusion.
    Ren-Peng Zhou, Shu-Fang Li, Ke Wang, Xing-Yu Liu, Hao-Yu Liu, Peng Yu, Yu-Fan Zhang, Wei-Rong Hu, Yu-Cai Xu, Jie Ding, Cheng Sun, Ying-Jie Zhao, Feng Yao, Wei Wei, Chao Lu, Wei Hu.
      Dysregulated chondrocyte death contributes substantially to cartilage destruction in rheumatoid arthritis (RA), yet the underlying mechanisms remain incompletely understood. Here, we identify the calcium-activated potassium channel KCa3.1 as a critical mediator of chondrocyte ferroptosis and cartilage destruction in RA. We demonstrate that both genetic ablation and pharmacological inhibition of KCa3.1 alleviate lipid peroxidation, pathological mitochondrial hyperfusion and ROS accumulation, thereby inhibiting iron deposition, ultimately protecting against chondrocyte ferroptosis and cartilage destruction. In addition, inhibiting mitochondrial fusion can suppress KCa3.1-mediated-ferroptosis in chondrocytes. Mechanistically, we establish that the transcription factor FOSL1 directly binds to the KCa3.1 promoter, upregulating its expression and triggering calcium overload, pathological mitochondrial hyperfusion and ferroptotic cell death. Crucially, FOSL1 gene silencing and pharmacological inhibition can down-regulate the pathological high expression of KCa3.1, restore mitochondrial homeostasis, and reduces ferroptosis, alleviate disease progression and cartilage damage. Collectively, our findings unveil the FOSL1-KCa3.1 axis as a promising target for the treatment of RA and other ferroptosis-related pathologies.
    Keywords:  FOSL1; KCa3.1; cartilage destruction; ferroptosis; mitochondrial fusion
    DOI:  https://doi.org/10.1038/s41401-026-01897-4
  41. Mol Biol Cell. 2026 Aug 05. mbcE25010022
    The identification of drp1 patient mutations that limit interactions with mff.
    Yuli Buckley, Anelise N Hutson, Brianna L Bauer, Isaiah M Waiters, Jasmine C Liu, Dayanlee De León Cordero, Maria S K Stoll, Jason A Mears.
      Patient mutations within Drp1, the master regulator of mitochondrial fission, lead to severe neurological defects and poor patient outcomes. Many of these mutations have been characterized as causing functional or assembly defects in Drp1, but our study highlights three mutations (G362S, E379K, E410K) that do not have an apparent defect in core Drp1 functions. We investigated the possibility that these mutations impact interactions with Mff, a pro-fission partner protein of Drp1. Negative stain electron microscopy and mass photometry were used to visualize and quantify assembly properties, while GTPase assays assessed the enzymatic activities of distinct proteins and protein complexes. In parallel, confocal microscopy highlighted the effects of overexpressing each mutation on mitochondrial morphology in cells. We discovered that G362S and E410K Drp1 mutations limit interactions with Mff, as co-assembly into larger filaments and the associated stimulation of GTPase activity was inhibited. Conversely, the E379K mutation is able to form functional complexes with Mff, and no apparent defect was observed, warranting additional studies focused on unique mitochondrial fission attributes. Overall, our data highlight the complex nature of disease-associated mutations in Drp1 and emphasize the importance of Drp1-Mff interactions in sustaining mitochondrial and cellular health.
    DOI:  https://doi.org/10.1091/mbc.E25-01-0022
  42. Front Neurosci. 2026 ;20 1910621
    Identification and validation of mitophagy and astrocyte-related molecular signature in the pathogenesis of Alzheimer's disease: evidence from ensemble learning-driven multi-omics and clinical validation.
    Jiacheng Liu, Wei Chen.
       Background: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with limited diagnostic tools and therapeutic options. Dysregulated mitophagy in astrocytes plays a pivotal role in AD pathogenesis. This study aims to identify a mitophagy and astrocyte (MA)-associated molecular signature for AD diagnosis and therapeutic targeting.
    Methods: Limma, WGCNA, xCell, PPI network and integrated machine learning pipeline coupled with SHAP were deployed on AD patient hippocampal bulk profiles (GSE28146, GSE36980, GSE29378, GSE48350) for identification of MA-associated predictive model and hub gene. Next, astrocyte patten and MA-associated hub gene molecular performance were estimated in hippocampal single-cell profile of AD patients (GSE163577) via advanced analytical frameworks. In addition, active learning framework and molecular docking was deployed in GSE29378 for identification of therapeutic candidate for AD patients by targeting MA-associated hub gene. Furthermore, AD hippocampal tissues were collected, and then MA-associated hub gene expression was estimated.
    Results: A core 8-gene MA signature (ITSN1, VLDLR, CYP7A1, SREBF2, RASL12, TPMT, CYP4X1, ARHGEF) was identified, which can guide the molecular subgroup identification and predictive model construction for AD patients. ITSN1 can be considered as the MA-associated hub gene in AD pathogenesis, which was up-regulated and predominantly expressed in astrocytes. Drug repositioning identified BRD-K10008415 as the potential compound predicted to reverse the AD signature by targeting ITSN1.
    Conclusions: This study identified ITSN1 as a MA-associated critical hub potential connecting mitophagy dysregulation and astrocyte dysfunction in AD. We also identified MA-associated molecular signatures that can potentially elaborate predictive effects on AD pathogenesis. BRD-K10008415 can be considered as potential candidate for AD treatment by targeting ITSN1.
    Keywords:  Alzheimer's disease; ITSN1; astrocyte; clinical validation; mitophagy; multi-omics
    DOI:  https://doi.org/10.3389/fnins.2026.1910621
  43. Phytomedicine. 2026 Jul 28. pii: S0944-7113(26)00889-5. [Epub ahead of print]160 158658
    Integrating UHPLC-HRMS with SSA-BP neural network identifies optimal components of Astragali Radix‑Salviae Miltiorrhizae combination for mitigating cerebral ischemia-reperfusion injury via mitophagy and ferroptosis pathways.
    Chao Guo, Dong Xu, Zhongying Ma, Kai Gao, Wei Zhang, Yang Du, Meina Zhao, Xingru Tao, Yi Ding, Jingwen Wang.
       BACKGROUND: Astragali Radix (Huangqi) and Salvia miltiorrhiza (Danshen) represent a frequently paired herbal combination in traditional Chinese medicine for tonifying Qi and promoting blood circulation. Previous pharmacological investigations have shown that phytochemicals derived from these herbs exhibit neuroprotective properties against cerebral ischemia-reperfusion (CI/R) injury. Nevertheless, the underlying principles governing the combined application of Huangqi and Danshen (QD) and the molecular pathways involved in their therapeutic efficacy remain unexplored in ischemic stroke management.
    PURPOSE: This study sought to systematically investigate the bioactive components in the QD formulation and elucidate their mechanisms of action against cerebral ischemic injury.
    MATERIALS AND METHODS: The therapeutic effects of QD were evaluated in a mouse model of middle cerebral artery occlusion (MCAO). UHPLCHRMS was used to identify QD-derived components in blood and brain tissues. An SSA-BP neural network was constructed to predict the optimal combination of active ingredients. 4D label-free proteomics, coupled with GO and KEGG enrichment analyses, was performed to identify key pathways. Molecular docking and molecular dynamics simulations were used to validate candidate targets. Mitochondrial function and iron homeostasis were assessed by measuring ROS, mitochondrial membrane potential (ΔΨm), ATP, complex I activity, Fe2+, and the GSH/GSSG ratio. Western blotting and immunofluorescence were used to detect FUNDC1, Nrf2, SLC7A11, NCOA4, p62, FTH1, UQCRC2, and GPX4. The autophagy inhibitor 3-MA was used for mechanistic validation. For cellular studies, HT22 cells were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R), and QD was added during reoxygenation. Cell viability and cytotoxicity were assessed using CCK-8 and LDH assays, respectively. ROS, ΔΨm, Fe2+, and GSH were measured using commercial kits. Western blotting was used to analyze FUNDC1, UQCRC2, LC3-II/I, p62, GPX4, SLC7A11, NCOA4, Nrf2, and FTH1. siFUNDC1 was transfected 48 h before OGD/R to assess FUNDC1 dependency.
    RESULTS: Among the tested ratios (1:1, 2:1, 3:1, 3:2, and 2:3), the 3:2 QD combination was the most effective, significantly improving neurological function, reducing infarct size, and alleviating neuronal damage in MCAO mice. UHPLCHRMS identified 21 compounds absorbed into the bloodstream, seven of which were detected in brain tissue. Astragaloside IV, astragaloside II, lithospermic acid, tanshinone IIA, and calycosin were identified as key active components. Their combination, predicted by the SSA-BP neural network, exerted significant neuroprotection in vivo. Proteomics revealed 124 differentially expressed proteins, with GO and KEGG enrichment analyses identifying mitophagy and ferroptosis as the primary therapeutic pathways. Molecular docking and dynamics analyses revealed high-affinity binding interactions between QD constituents and key targets, including FUNDC1, UQCRC2, GPX4, and SLC7A11. QD upregulated FUNDC1, UQCRC2, GPX4, SLC7A11, Nrf2, and FTH1 and downregulated p62 and NCOA4; these effects were partially reversed by 3-MA. In HT22 cells, QD improved cell viability, reduced LDH release, restored ΔΨm and GSH levels, and attenuated ROS and Fe²⁺ accumulation following OGD/R. The protein expression changes were consistent with those observed in vivo. Knockdown of FUNDC1 largely blocked the protective effects of QD, confirming that FUNDC1 is essential for QD-mediated neuroprotection.
    CONCLUSION: QD ameliorates MCAO-induced cerebral ischemic injury via mitophagy and ferroptosis pathways, offering a novel therapeutic perspective for treating ischemic stroke with traditional Chinese medicine that tonifies Qi and promotes blood circulation.
    Keywords:  Active ingredients; Ferroptosis; Huangqi-danshen (QD); Mitophagy; SSA-BP neural network
    DOI:  https://doi.org/10.1016/j.phymed.2026.158658
  44. Front Nutr. 2026 ;13 1907443
    Research progress on the association of maternal high-fat diet with offspring neurodevelopment and susceptibility to Parkinson's disease.
    Qi Li, Zhi Jia, Musi Ji, Bayaer Nashun.
      Maternal high-fat diet (mHFD) is a growing global nutritional concern during pregnancy. It induces maternal systemic low-grade inflammation and oxidative stress, reshaping the intrauterine milieu via the placenta and causing selective developmental impairments in offspring midbrain dopaminergic (DA) neurons-including aberrant precursor proliferation/differentiation, simplified synapses, and nigrostriatal circuit deficits-which may increase adulthood Parkinson's disease (PD) susceptibility. Mechanistically, mHFD acts through two synergistic pathways: persistent activation of the insulin resistant-NF-κB inflammatory axis and suppression of PINK1/Parkin-mediated mitophagy, mutually reinforcing and compromising DA neuron resilience. This article reviews the pathological process of mHFD-mediated remodeling of the intrauterine microenvironment to increase the susceptibility of offspring PD and its two core mechanism pathways: the continuous activation of the IR-NF-κB inflammatory pathway and the functional inhibition of the PINK1/Parkin-mediated mitophagy pathway. On this basis, multi-dimensional early warning markers based on inflammatory factors, mitophagy-related molecules, epigenetic markers and nutritional exposure indicators, as well as potential intervention strategies such as nutritional supplementation, anti-inflammatory and pro-mitophagy targeting the above pathways were summarized, in order to provide a theoretical reference for the primary prevention of PD.
    Keywords:  NF-κB; Parkinson's disease susceptibility; Pink1/Parkin; clinical translation; maternal high-fat diet; offspring neurodevelopment; the marker of early-warning
    DOI:  https://doi.org/10.3389/fnut.2026.1907443
  45. Aging Cell. 2026 Aug;25(8): e70646
    HNRNPC Succinylation Influences the Neurodegeneration of Alzheimer's Disease Through YME1L1-Mediated Mitochondrial Metabolism.
    Xuewei Li, Fan Yang, Yuyan Jiang, Fei Zhao, Fan Liu.
      Mitochondrial dysfunction and abnormal energy metabolism are important pathological features of Alzheimer's disease (AD). This study investigates how mitochondrial protease YME1L1 affects mitochondrial function and its upstream regulation in the pathogenesis of AD. The AD model was established by using APP/PS1 transgenic mice, primary neurons treated with Aβ1-42, and HT22 cells. The silencing of YME1L1 was achieved to evaluate its effects on mitochondrial function and OPA1 protein hydrolysis. RIP-qPCR and RNA pull-down test were used to evaluate the interaction between HNRNPC and YME1L1 mRNA. The protein succinylation level was detected by proteomic analysis of succinylation, and co-immunoprecipitation (Co-IP) was used to verify the succinylation of HNRNPC. Cognitive ability was tested by behavioral tests, including the Morris water maze, Y-maze, object recognition test, and olfactory test. Finally, the therapeutic potential of SIRT5 was studied by an overexpression experiment in an AD model. YME1L1 was significantly upregulated in the AD model, which promoted mitochondrial dysfunction and neuronal damage through OPA1 hydrolysis. HNRNPC enhances the stability of YME1L1 mRNA through an m6A-dependent mechanism, while its own K50 succinylation enhances the stability of HNRNPC by competitively inhibiting TRIM25-mediated ubiquitination, further amplifying the expression of YME1L1. SIRT5 downregulation in AD elevated HNRNPC succinylation levels. SIRT5 overexpression promoted HNRNPC desuccinylation, reduced YME1L1 expression, restored mitochondrial function, and ameliorated Aβ deposition and cognitive deficits in AD mice. The SIRT5-HNRNPC-YME1L1 axis contributes to AD pathogenesis by disrupting OPA1 proteolysis and mitochondrial dynamics. Targeting HNRNPC succinylation represents a promising therapeutic strategy for AD.
    Keywords:  Alzheimer's disease; HNRNPC; SIRT5; YME1L1; mitochondrial metabolism
    DOI:  https://doi.org/10.1111/acel.70646
  46. Cell Rep. 2026 Aug 03. pii: S2211-1247(26)00828-4. [Epub ahead of print]45(8): 117750
    Mechanistic basis for calmodulin‑dependent allosteric activation of the neuropathy-associated formin INF2.
    Bohan Zhang, Meng Zhang, Ke Liu, Chenhui Zhao, Jianwen Zhang, Zhijun Liu, Ying Fan, Ruo-Xu Gu, Lin Lin, Chuanhai Fu, Jinwei Zhu.
      Calcium signaling regulates the atypical formin INF2 to drive actin assembly in diverse cellular processes, yet the underlying molecular mechanism remains elusive. Here, we uncover a direct, nanomolar-affinity interaction between calcium-bound calmodulin (Ca2+-CaM) and the diaphanous inhibitory domain (DID) of INF2. The high-resolution crystal structure of the Ca2+-CaM-INF2 DID complex reveals a unique allosteric activation mechanism distinct from canonical Rho GTPase-mediated formin regulation. Ca2+-CaM binding induces conformational changes that disrupt the autoinhibitory DID-DAD interaction, triggering its actin assembly activity. We show that Ca2+-CaM activates ER-bound INF2, thereby promoting mitochondrial fission. We further demonstrate that a Charcot-Marie-Tooth neuropathy-associated INF2 mutation enhances Ca2+-CaM binding through optimized interfacial dynamics, revealing a gain-of-function disease mechanism. Our findings provide a mechanistic framework for Ca2+-CaM-dependent activation of INF2, establishing the CaM-INF2 axis as a direct activator of actin-dependent organelle dynamics, with implications for INF2-linked pathologies.
    Keywords:  CP: molecular biology; INF2; actin filament; allosteric regulation; autoinhibition; calcium signaling; calmodulin; formin; mitochondrial fission; neuroscience
    DOI:  https://doi.org/10.1016/j.celrep.2026.117750
  47. Front Microbiol. 2026 ;17 1874222
    The Microbiome-Mitochondria Axis in aging: a self-reinforcing vicious cycle linking metabolic dysregulation, mitochondrial quality control failure, and inflammaging.
    Enshuo Liu, Jianbo Jia, Qi Liu, Chunyan Li, Shanhui Li, Tao Cai.
      Aging is a progressive degenerative process of cellular and systemic homeostasis in organisms, with mitochondrial dysfunction and altered intercellular communication as core hallmarks of this process. During aging, the gut microbiome and mitochondria exhibit a highly synchronized degenerative trajectory: this is characterized by decreased microbial diversity, reduced abundance of beneficial short-chain fatty acid (SCFA)-producing bacteria, and expansion of pro-inflammatory pathobionts in the gut, alongside impaired oxidative phosphorylation efficiency, excessive reactive oxygen species (ROS) production, and compromised quality control in mitochondria. Built on the evolutionary cornerstone of endosymbiotic theory, this review establishes a theoretical framework for the Microbiome-Mitochondria Axis (MMA) and proposes that the ancient molecular homology between mitochondria and modern gut bacteria has preserved a sensitive cross-species signal crosstalk mechanism. This review systematically dissects the bidirectional communication mechanisms of the MMA. First, microbial metabolites-including SCFAs, tryptophan-derived indole metabolites, and secondary bile acids-regulate mitochondrial energy metabolism, oxidative stress responses, and dynamic homeostasis via key signaling pathways such as AMPK-PGC-1α, AhR-Nrf2, and FXR/TGR5. Conversely, dysfunctional mitochondria actively reshape the gut microenvironment and propagate sterile inflammation through multiple pathways: mitochondrial ROS (mtROS)-mediated intestinal barrier disruption, metabolic reprogramming of immune cells toward a pro-inflammatory phenotype, and activation of the cGAS-STING innate immune pathway triggered by mitochondrial DNA (mtDNA) release. Here, we propose a unified theoretical framework centered on the MMA as a self-reinforcing pathological loop. In this model, gut dysbiosis drives depletion of beneficial microbial metabolites, which triggers mitochondrial quality control failure, mtDNA leakage, and inflammaging; in turn, inflammaging exacerbates gut dysbiosis by remodeling the intestinal microenvironment, thus forming a closed, self-amplifying vicious cycle. The MMA links multiple hallmarks of aging, including epigenetic alterations, immunosenescence, and stem cell exhaustion, providing a unifying pathological basis for age-related disorders such as neurodegenerative diseases, cardiovascular diseases, sarcopenia, and osteoarthritis. It also offers a systematic entry point for anti-aging interventions targeting the bidirectional metabolic-immune crosstalk between the microbiome and mitochondria.
    Keywords:  Microbiome-Mitochondria Axis; aging; inflammaging; metabolic dysregulation; mitochondrial quality control; mitophagy
    DOI:  https://doi.org/10.3389/fmicb.2026.1874222
  48. Zhongguo Zhong Yao Za Zhi. 2026 Jun;51(11): 3231-3242
    [Huangqi Guizhi Wuwu Detection regulates mitochondrial quality control and autophagy-lysosome flux to ameliorate skeletal muscle pathology in rheumatoid arthritis-associated sarcopenia].
    Ya-Kun Wan, Ping Jiang, Yuan Liu, Xuan-He Tian, Min Guan, Zhi-Hui Bai, Di Zhang.
      This study investigated the mechanisms by which Huangqi Guizhi Wuwu Detection(HQGZWWT) ameliorates skeletal muscle injury, mitochondrial dysfunction, inflammatory responses, and autophagic flux in rheumatoid arthritis(RA)-associated sarcopenia from the perspective of the &quot;mitochondrial quality control and autophagy-lysosome flux&quot;. The collagen-induced arthritis(CIA) rat model was adopted. Rats were divided into a blank group, a model group, and HQGZWWT treatment groups with different doses: low(1.22 g·kg~(-1)), medium(2.44 g·kg~(-1)), and high(4.88 g·kg~(-1)) doses. Intragastric administration was conducted for 5 weeks. Forelimb grip strength of rats in each group was recorded and analyzed. Masson staining and sirius red staining were used to evaluate pathological changes in skeletal muscle. Transmission electron microscopy(TEM) was used to observe autophagosomes and mitochondrial ultrastructure. Immunofluorescence was employed to detect the colocalization of microtubule-associated protein 1 light chain 3β(LC3B)-lysosome-associated membrane protein 1(LAMP1), as well as the expression of translocase of outer mitochondrial membrane 20(TOMM20). Immunohistochemistry was used to detect sequestosome 1(P62)protein expression. Western blot and RT-qPCR were used to analyze the expression levels of autophagic flux-related markers LC3B, P62, LAMP1, as well as mitochondrial function-related markers TOMM20 and mitofusin 2(MFN2)in skeletal muscle. The concentrations of serum inflammatory factors interleukin-1β(IL-1β) and interferon-γ(IFN-γ) were measured by ELISA to explore changes in the inflammatory environment. Compared with those in the blank group, Masson staining and sirius red staining of the gastrocnemius muscle in the model group showed increased collagen deposition and obvious fibrous hyperplasia. TEM revealed numerous autophagosomes in the cytoplasm of muscle cells, mitochondrial swelling, extensive cristae rupture and dissolution, matrix loss, and vacuolization. Immunofluorescence showed that the number of LC3B puncta and the LC3B-LAMP1 colocalization coefficient increased(P&lt;0.01), while TOMM20 fluorescence intensity decreased(P&lt;0.01). Immunohistochemistry showed increased P62 positive expression(P&lt;0.01). Western blot and RT-qPCR results showed that the expression of TOMM20, MFN2, and P62 in the gastrocnemius muscle significantly decreased(P&lt;0.01), while the expression of LC3B and LAMP1 was upregulated(P&lt;0.01). Serum ELISA results showed that IL-1β and IFN-γ were significantly increased(P&lt;0.01). After HQGZWWT intervention, the expression levels of TOMM20, P62, and MFN2 were significantly upregulated(P&lt;0.01), while the expression of LC3B and LAMP1 was significantly downregulated(P&lt;0.01). Electron microscopy showed improved mitochondrial morphology and reduced autophagosomes. The degree of fibrosis was significantly reduced(P&lt;0.01). Inflammatory factors such as IL-1β and IFN-γ were significantly downregulated(P&lt;0.01). In summary, HQGZWWT can ameliorate skeletal muscle injury in RA-associated sarcopenia by regulating mitochondrial quality control, the autophagy-lysosome flux, and inflammatory responses. This study provides new experimental evidence for the treatment of RA-associated sarcopenia with HQGZWWT and offers basic support for its better clinical application.
    Keywords:  Huangqi Guizhi Wuwu Detection; autophagy-lysosome flux; mitochondrial quality control; rheumatoid arthritis; sarcopenia; skeletal muscle pathology
    DOI:  https://doi.org/10.19540/j.cnki.cjcmm.20260211.801
  49. Oxid Med Cell Longev. 2026 ;2026(1): e9805267
    RETRACTION: SIRT5-Related Desuccinylation Modification Contributes to Quercetin-Induced Protection against Heart Failure and High Glucose-Prompted Cardiomyocytes Injured through Regulation of Mitochondrial Quality Surveillance.
    Oxidative Medicine And Cellular Longevity.
      
    DOI:  https://doi.org/10.1155/omcl/9805267
  50. PLoS Genet. 2026 Aug;22(8): e1012268
    Correction: Bendless is essential for PINK1-Park mediated Mitofusin degradation under mitochondrial stress caused by loss of LRPPRC.
    Rajit Narayanan Cheramangalam, Tarana Anand, Priyanka Pandey, Deepa Balasubramanian, Reshmi Varghese, Neha Singhal, Sonal Nagarkar Jaiswal, Manish Jaiswal.
      [This corrects the article DOI: 10.1371/journal.pgen.1010493.].
    DOI:  https://doi.org/10.1371/journal.pgen.1012268
  51. Research (Wash D C). 2026 ;9 1387
    HO-1 Up-regulation and PINK1/Parkin-Mediated Mitophagy Contribute to the Anti-tumor Effects of Metochalcone in Colorectal Cancer.
    Pingting Chen, Junsha An, Mingyu Han, Yuhan Wang, Xue Li, Jianning Yang, Heng Zhang, Huali Fan, Zhaokai Zhou, Hailin Tang, Fu Peng.
      Colorectal cancer (CRC) remains a global health challenge with rising incidence in younger populations and limited efficacy of current chemotherapies. In this study, we investigated the anti-tumor mechanisms of metochalcone (MET), a natural chalcone derivative, in CRC. Using a combination of transcriptomic, proteomic, and targeted in vitro and in vivo assays, we found that MET substantially reduced viability, migration, and invasion and arrested the cell cycle at the G0/G1 phase in HCT-116 CRC cells. Integrative analysis identified heme oxygenase-1 (HO-1) as a key target, and molecular docking and cellular thermal shift assay confirmed that MET directly binds to and stabilizes the HO-1 protein. Mechanistically, MET treatment led to mitochondrial dysfunction, characterized by increased reactive oxygen species and decreased membrane potential, which in turn activated PTEN induced kinase 1 (PINK1)/Parkin-mediated mitophagy. In 2 distinct mouse models of CRC, MET potently suppressed tumor growth. Furthermore, 16S ribosomal RNA gene sequencing revealed that MET treatment was associated with changes in gut microbiota composition in mice, including an increased relative abundance of beneficial Lactobacillus and a decreased abundance of pro-inflammatory Desulfovibrionaceae. Our findings demonstrate that MET exerts multifaceted anti-tumor effects, including direct targeting of HO-1 and activation of PINK1/Parkin-mediated mitophagy, accompanied by alterations in gut microbiota composition.
    DOI:  https://doi.org/10.34133/research.1387
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