bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2025–11–02
67 papers selected by
Gavin McStay, Liverpool John Moores University
  1. Mitochondrial homeostasis: A key regulator in endometrial physiology and pathology.
  2. Longevity-promoting mitochondrial unfolded protein response activation requires elements of the PeBoW complex.
  3. XIAP-ULK1-Mediated mitophagy modulates carnitine metabolism to mitigate diabetic kidney disease.
  4. CircAASS alleviates renal injury and fibrosis by regulating mitochondrial homeostasis in tubular epithelial cells.
  5. Advances in Mitochondrial Dysfunction and Its Role in Cardiovascular Diseases.
  6. Mesenchymal stem cells inhibit mitochondrial fission by upregulating armadillo repeat containing 1, ameliorating oxidative stress in renal fibrosis.
  7. TERT translocation to mitochondria: Exploring its role in mitochondrial homeostasis.
  8. VPS35 mutation inhibits PINK1/parkin-mediated mitophagy via increased LRRK2 kinase activity.
  9. Allicin attenuates necrotizing enterocolitis via PINK1/Parkin-mediated mitophagy to suppress pyroptosis.
  10. FGF21 confers neuroprotection in Parkinson's disease by activating the FGFR1-sirt1 pathway.
  11. Prognostic genes related to mitochondrial dynamics and mitophagy in diffuse large B-cell lymphoma are identified and validated using an integrated analysis of bulk and single-cell RNA sequencing.
  12. The Role of ER/ERK/CREB Pathway Mediated Mitophagy in Bisphenol F-Induced Cognitive Function Changes in Young Female Rats.
  13. Chemerin-CMKLR1 differentially mediated OGD/R-induced mitochondrial dysfunction, oxidative stress, and autophagy in microglia and neurons.
  14. HNF1α-Q125ter-mediated mitochondrial dysfunction and impaired mitophagy in β-cells.
  15. Mitochondria-enriched nanovesicles: A novel approach for treating radiation-induced skin injury.
  16. FGF21-FGFR1 signaling protects against cardiac hypertrophy by regulating PINK1-mediated mitophagy pathway.
  17. Miro1 protects against brain injury after CPR in rats by enhancing the effect of BMSCs on mitochondrial homeostasis.
  18. Mitochondrial Dynamics in Blood Cancer Development and Progression.
  19. Mitophagy alleviates neuronal damage after subarachnoid hemorrhage: Role of autophagy-targeting chimera 4.
  20. Parkin-Mediated Ubiquitination of DCUN1D1: Implications for CXCL10 Regulation in Vitiligo.
  21. The Caenorhabditis elegans sdhb-1(R244H) Model Shows Characteristics of Human PPGL Tumor Cells.
  22. Lactate-HIF-1a axis promotes PINK1-dependent mitophagy to protect porcine granulosa cells against hypoxic stress.
  23. Mitophagy in Alzheimer's disease and its potential as a therapeutic target.
  24. Mitochondrial Protease ClpP: Cancer Marker and Drug Target.
  25. METTL3-driven m6A modification orchestrates mitophagy-dependent ferroptosis in PM2.5-induced lung injury.
  26. Multi-omics insights into the role of mitophagy receptor-related genes in glioma prognosis and immune microenvironment remodeling.
  27. Mitochondrial autophagy mechanism and berberine therapeutic target discovery in hepatocellular carcinoma based on single-cell and transcriptome analysis.
  28. Ultrastructural evaluation of lithium-induced autophagic and mitochondrial stress in 3D endometrial and neuroblastoma spheroids.
  29. Marf- and Opa1-Dependent Formation of Mitochondrial Network Structure Is Required for Cell Growth and Subsequent Meiosis in Drosophila Males.
  30. Porcine deltacoronavirus infection triggers mitophagy to dampen the interferon response and promote viral replication.
  31. TFAP2A induces cisplatin resistance via BNIP3-mediated mitophagy in non-small cell lung cancer.
  32. Empagliflozin-pretreated BMSC exosomes attenuate myocardial ischemia-reperfusion injury by enhancing atad3a/pink1-dependent mitophagy.
  33. Role of mitophagy in ischemia-reperfusion renal injury: new insights from bioinformatics analysis.
  34. Altered Expression of Calpastatin by Hypoxia Regulates Trophoblast Cell Function through Mitochondria Associated Endoplasmic Reticulum Membranes.
  35. KIF23 silencing suppresses papillary thyroid carcinoma metastasis by regulating mitophagy via Wnt/β-catenin pathway.
  36. Electroacupuncture Prevents Depression via PINK1/Parkin-Driven Suppression of NLRP3 Activation.
  37. Metabolic rewiring prevents neurodegeneration caused by chronic mitochondrial dysfunction.
  38. Substrate recognition by the human mitochondrial processing peptidase and its processing of PINK1.
  39. Edwardsiella piscicida induces largemouth bass PINK1/Parkin-mediated mitophagy for its survival and virulence.
  40. A special latch in yeast mitofusin guarantees mitochondrial fusion by stabilizing self-assembly.
  41. Jiao-tai-wan and its component coptisine attenuate PCOS by regulating mitochondrial cholesterol import through suppression of SIRT1 ubiquitination.
  42. Rutin Suppresses EMT and Induces Mitochondrial Biogenesis via ER Stress-linked AMPK/SIRT1 Signaling in Prostate Cancer Cells.
  43. Effect of the mitophagy inducer urolithin A on age-related immune decline: a randomized, placebo-controlled trial.
  44. Mitochondrial Dysfunction in Aging, HIV, and Long COVID: Mechanisms and Therapeutic Opportunities.
  45. SIRT1/PGC-1α/Mfn2 pathway regulates mitochondrial homeostasis in VSMC to attenuate aging-related vascular calcification.
  46. Urolithin A promotes peripheral nerve regeneration via TFEB-mediated mitophagy and NLRP3 inflammasome suppression.
  47. Superoxide Anion-Dependent Mitochondrial Fission Contributes to Hippocampal Synaptic Dysfunction in Stress-Susceptible Mice.
  48. D-mannose alleviates neurological deficits and inhibits NLRP3 inflammasome activation via the AMPK-mitophagy signaling pathway after traumatic brain injury.
  49. Intrauterine oxygen milieu governs placental sphingolipid metabolism.
  50. Light-evoked activity and BDNF regulate mitochondrial dynamics and mitochondrial localized translation in CNS axons.
  51. Synthesis of mitochondria-targeted caffeic acid-coumarin fluorescent conjugates to ameliorate inflammation in acute lung injury by protecting mitochondria.
  52. In silico analysis of a MicroRNA regulatory network Influencing mitochondrial fission in hepatocellular carcinoma.
  53. Verbascoside Suppresses Epithelial-Mesenchymal Transition and Mitochondrial Biogenesis by Targeting Anti-senescence Signaling in Castration-resistant Prostate Cancer.
  54. Sirt3-Bnip3 signaling axis alleviates myocardial ischemia/reperfusion-induced cardiac injury via regulating GSDME.
  55. [Salvianolic acid B promotes mitochondrial homeostasis and improves cardiac function in mice with ischemia-reperfusion injury by inhibiting Sirt1 protein degradation].
  56. Hotspot mutant p53-R273H enhances mitochondrial biogenesis and cell migration in primary colorectal cancer in response to oxaliplatin.
  57. L-Glutamate enables the EGFR-MEK-ERK-mTFB2 axis to enhance mitochondrial biogenesis in intestinal stem cells.
  58. Hyperuricemia exacerbates acetaminophen hepatotoxicity via JNK activation and mitophagy reduction.
  59. Dynamic Coupling between Tom22 Motions and Tom40 Pore Dynamics Modulates Ion Transport in the Mitochondrial TOM Complex.
  60. Mechanisms of Mitochondrial Impairment by SARS-CoV-2 Proteins: A Nexus of Pathogenesis with Significant Biochemical and Clinical Implications.
  61. microRNA-22 Inhibition Stimulates Mitochondrial Homeostasis and Intracellular Degradation Pathways to Prevent Muscle Wasting.
  62. Quercetin-derived microbial metabolite DOPAC potentiates CD8+ T cell anti-tumor immunity via NRF2-mediated mitophagy.
  63. V8, a lysosomotropic wogonin derivative, alleviates hepatic steatosis by modulating GDF15-dependent mitochondrial homeostasis.
  64. Fufang Danshen Pill improves mitochondrial homeostasis by regulating the S100a9/TLR4 axis to alleviate myocardial ischemia-reperfusion injury.
  65. Correction: Zhang et al. An Integrated Approach Utilizing Single-Cell and Bulk RNA-Sequencing for the Identification of a Mitophagy-Associated Genes Signature: Implications for Prognostication and Therapeutic Stratification in Prostate Cancer. Biomedicines 2025, 13, 311.
  66. Cancer suppresses mitochondrial chaperone activity in macrophages to drive immune evasion.
  67. VDAC1 inhibitor DIDS uncouples respiration in isolated tissue mitochondria and induces mitochondrial hyperfusion in mammalian cells.
  1. Drug Discov Today. 2025 Oct 28. pii: S1359-6446(25)00232-6. [Epub ahead of print] 104519
    Mitochondrial homeostasis: A key regulator in endometrial physiology and pathology.
    Keke Zhang, Enfeng Zhang, Kun Wu, Wenxiu Cheng, Shaobin Wei.
      Endometrial cyclic remodeling and decidualization are critical physiological processes for female reproductive function and are profoundly influenced by mitochondrial homeostasis. Mitochondrial homeostasis is maintained through the mitochondrial quality control system, which precisely regulates mitochondrial energy metabolism via peroxisome proliferator-activated receptor-gamma (PPARγ) coactivator-1 alpha (PGC-1α)-nuclear respiratory factor (NRF)1/2-mediated biogenesis, mitofusin (MFN)1/2-optic atrophy (OPA1)-dependent fusion, dynamin-related protein (DRP)1-regulated fission, and PTEN-induced putative kinase 1 (PINK1)-Parkin-executed mitophagy. Dysregulation of this system caused by infection, endocrine disruption, or iatrogenic injury can alter or reprogram endometrial energy metabolism, disrupt immune balance, and promote fibrosis and abnormal proliferation, leading to various endometrial diseases and impaired fertility. This review systematically summarizes recent research advances on mitochondrial homeostasis in endometrial physiology and pathology, and its emerging role as a therapeutic target, aiming to provide insights and references for therapeutic strategies against endometrial diseases.
    Keywords:  endometrial pathology; endometrial physiology; mitochondrial homeostasis; therapeutic target
    DOI:  https://doi.org/10.1016/j.drudis.2025.104519
  2. Genes Dev. 2025 Oct 29.
    Longevity-promoting mitochondrial unfolded protein response activation requires elements of the PeBoW complex.
    Adebanjo Adedoja, Niclole Stuhr, Yifei Zhou, Yuyao Zhang, Armen Yerevanian, Alexander A Soukas.
      Mitochondria play a crucial role in cellular energy metabolism and homeostasis and are strongly implicated in aging and age-related diseases. The outer mitochondrial membrane protein voltage-dependent anion channel (VDAC) plays multiple roles in mitochondrial homeostasis, including transport of metabolites, ATP, and Ca2+ Dysregulation of VDAC levels has been associated with cancer, neurodegeneration, metabolic disorders, and aging. Previously, we demonstrated that elevated VDAC-1 levels in Caenorhabditis elegans lead to increased mitochondrial permeability and reduced life span. Here we demonstrate that reduced VDAC-1 function extends life span through the activation of the mitochondrial unfolded protein response (UPRmt), a conserved stress response that maintains mitochondrial proteostasis and is linked to life span extension in multiple species. Leveraging unbiased genomic discovery, we identified genes encoding several proteins in the PeBoW complex as a critical mediator of UPRmt activation following VDAC-1 loss. More broadly, we demonstrated a universal requirement for several PeBoW component genes across diverse mitochondrial stressors in order to fully animate the UPRmt Our findings reveal a heretofore unappreciated role for PeBoW components in UPRmt induction and life span extension in response to mitochondrial stress, highlighting its essential function in mitochondrial quality control and longevity pathways.
    Keywords:  PeBoW; mito-stress; mitoUPR; mitochondria
    DOI:  https://doi.org/10.1101/gad.352979.125
  3. Autophagy. 2025 Oct 25.
    XIAP-ULK1-Mediated mitophagy modulates carnitine metabolism to mitigate diabetic kidney disease.
    Hongtu Hu, Rui Ji, Yiqun Hao, Zikang Liu, Jian Yang, Yun Cao, Qian Yang.
      Diabetic kidney disease (DKD) is a major complication of diabetes, characterized by progressive renal dysfunction and mitochondrial impairment. Mitophagy, a selective form of macroautophagy/autophagy that maintains mitochondrial quality, is essential for kidney homeostasis. However, the molecular mechanisms by which mitophagy links these pathways to DKD remain poorly understood. This study investigated the role of XIAP-ULK1-mediated mitophagy in regulating carnitine metabolism and its therapeutic potential in alleviating DKD. Through a combination of renal biopsy analysis from DKD patients, diabetic mouse models, high-glucose-treated tubular epithelial cells, and molecular docking, we determined that XIAP upregulation led to ULK1 degradation via K48-linked polyubiquitination, impairing mitophagy and disrupting carnitine metabolism. Restoring ULK1 expression through the ULK1 agonist echinacoside and L-carnitine supplementation improved mitophagy and carnitine homeostasis, reducing kidney injury and enhancing mitochondrial function in diabetic mouse models. These findings suggested that targeting the XIAP-ULK1 axis to restore mitophagy and stabilize carnitine metabolism hold significant promise as a therapeutic strategy for DKD, highlighting the importance of metabolic regulation in kidney disease management.
    Keywords:  XIAP-ULK1 signaling; carnitine metabolism; diabetic kidney disease; mitochondrial dysfunction; mitophagy; therapeutic strategies
    DOI:  https://doi.org/10.1080/15548627.2025.2581214
  4. Autophagy. 2025 Oct 29.
    CircAASS alleviates renal injury and fibrosis by regulating mitochondrial homeostasis in tubular epithelial cells.
    Tongtong Ma, Yanmei Yu, Huasheng Luo, Ziqi Zhang, Miaotao Wei, Chunjie Tian, Xianmou Fan, Zhenyi Yan, Shaowu Zhang, Junfeng Hao, Peng Wang.
      Acute kidney injury (AKI) is characterized by the dysfunction of renal tubular epithelial cells (TECs), often leading to renal fibrosis. Mitochondrial impairment is a common hallmark across various types of AKI. However, the potential role of circular RNAs (circRNAs) in modulating mitochondrial homeostasis during AKI and subsequent renal fibrosis remains underexplored. Our findings reveal a significant reduction of circAass levels in the renal cortex across all three AKI models. Mechanistically, circAASS mitigates TEC apoptosis and inflammatory responses by promoting mitochondrial homeostasis, thereby attenuating AKI. Specifically, cytoplasmic circAASS acts as a competing endogenous RNA (ceRNA) by sequestering MIR324-3p, which in turn enhances the expression of PINK1, a critical regulator of mitophagy. Additionally, nuclear circAASS directly interacts with the PPARGC1A/PGC-1α protein, inhibiting its ubiquitin-mediated degradation and thereby promoting mitochondrial biogenesis. Furthermore, we demonstrated that the RNA-binding protein IGF2BP2 suppresses circAASS biogenesis by binding to intronic sequences in the AASS pre-mRNA. Restoring circAass in AKI mouse models improves both mitochondrial biogenesis and mitophagy, ameliorating pro-inflammatory responses of TECs and thus mitigating renal fibrosis. Decreased circAASS expression and its association with impaired mitochondrial function in TECs, followed by more severe renal fibrosis, are observed in AKI patients. Collectively, our results suggest that circAASS protects against AKI by regulating mitochondrial homeostasis, highlighting its potential as a therapeutic target for kidney injury.
    Keywords:  acute kidney injury; autophagy; chronic kidney disease; circular RNA; mitochondrial dysfunction; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2025.2581212
  5. Cells. 2025 Oct 17. pii: 1621. [Epub ahead of print]14(20):
    Advances in Mitochondrial Dysfunction and Its Role in Cardiovascular Diseases.
    Yan Qiu, Shuo Chang, Ye Zeng, Xiaoqi Wang.
      Cardiovascular diseases (CVDs) remain the leading cause of morbidity and mortality worldwide and is attributed to complex pathophysiological mechanisms that surpass the traditional risk factors. Emerging evidence indicates that mitochondrial dysfunction plays a central role in CVD progression, linking impaired bioenergetics, oxidative stress imbalance, and defective mitochondrial quality control to endothelial dysfunction, myocardial injury, and adverse cardiac remodeling. However, the mechanistic interplay between mitochondrial dysfunction and CVD pathogenesis remains unclear. This review provides a comprehensive synthesis of recent knowledge, focusing on the dysregulation of mitochondrial energy metabolism, alterations in mitochondrial membrane potential, and disruptions in mitochondrial dynamics, including the balance of fusion and fission, mitophagy, and biogenesis. Furthermore, we critically evaluated emerging mitochondria-targeted therapeutic strategies, including pharmacological agents, gene therapies, and regenerative approaches. By bridging fundamental mitochondrial biology with clinical cardiology, this review underscores the critical translational challenges and opportunities in developing mitochondria-focused interventions. A deeper understanding of the mitochondrial mechanisms in CVD pathophysiology will offer novel diagnostic biomarkers and precision-targeted therapeutics, thereby transforming CVD management.
    Keywords:  cardiovascular disease; mitochondria dynamics; mitochondrial dysfunction; mitophagy; oxidative stress; targeted therapy
    DOI:  https://doi.org/10.3390/cells14201621
  6. Stem Cell Res Ther. 2025 Oct 28. 16(1): 584
    Mesenchymal stem cells inhibit mitochondrial fission by upregulating armadillo repeat containing 1, ameliorating oxidative stress in renal fibrosis.
    Tao Li, Chuan Guo, Qing Liu, Fengting Jing, Min Zhao, Hemin Xiong, Chang Li, Wei Zhang, Bo Chen.
       BACKGROUND: Oxidative stress damage is the important mechanism that promotes the process of fibrosis. Whether mesenchymal stem cells (MSCs) regulate mitochondrial dynamics and oxidative stress via armadillo repeat containing 1 (ARMC1) in renal fibrosis?
    METHODS: Using proteomics analysis, compare the significant differences in renal tissue proteins before and after MSCs intervention in adenine-induced nephropathy. Using a lentiviral vector to overexpress the ARMC1 gene in HK-2 cells, with the empty vector as a control. MSCs conditioned media (MSCs-CM) was applied to TGF-β1 treated cells, and MSCs were used in a cisplatin-induced nephropathy mouse model to assess mitochondrial dynamics, ROS generation, antioxidant stress, and fibrosis indicators, with Mdivi-1 (a Drp1 inhibitor) and Apocynin (a selective NADPH oxidase inhibitor) as positive controls.
    RESULTS: Renal proteomics showed that MSCs increased ARMC1 protein in the renal tissue of adenine nephropathy (3.521 times). In vitro, MSCs-CM increased ARMC1, reduced DRP1, and enhanced OPA1 and MFN2, lowering ROS, boosting mitochondrial bioactivity, and increasing antioxidant proteins NRF2, SOD1, SOD2, and CAT while decreasing fibrosis markers α-SMA, FN, COL-I, and KIM-1, and raising E-cadherin. The indicator variations in ARMC1-OE cells and OE-Con cells were similar between subgroups; Notably, under identical treatment conditions, the shifts in indicators within ARMC1-OE cells were more significant than those observed in OE-Con cells. In cisplatin-induced nephropathy mice, MSCs, Apocynin, and Mdivi-1 improved renal function and reduced interstitial collagen deposition, inhibited mitochondrial fission, enhanced antioxidant capacity, and reduced fibrosis. However, individual interventions were found to be less effective than their combined counterparts, with the synergistic impact of MSCs and Mdivi-1 achieving the most remarkable outcomes.
    CONCLUSION: MSCs have the potential to improve renal fibrosis by influencing mitochondrial dynamics and oxidative stress through the upregulation of ARMC1 expression. ARMC1 may be an effective target for anti-fibrosis.
    Keywords:  ARMC1; MSCs; Mitochondrial dynamics; Oxidative stress; Renal fibrosis
    DOI:  https://doi.org/10.1186/s13287-025-04706-7
  7. PLoS Genet. 2025 Oct 27. 21(10): e1011923
    TERT translocation to mitochondria: Exploring its role in mitochondrial homeostasis.
    Jessica Marinaccio, Erica Rossi, Emanuela Micheli, Ion Udroiu, Nicolò Baranzini, Gaia Marcolli, Antonella Sgura.
      Telomerase Reverse Transcriptase (TERT), in addition to its well-known role in telomere lengthening, also has non-canonical functions, including gene regulation and protection against apoptosis. Beyond its nuclear functions, it is now recognized for its presence inside mitochondria. However, the biological role of TERT in mitochondrial physiological activity, with its specific mechanism of action, still needs to be clarified. This work clearly demonstrates the presence of TERT inside the mitochondrion under physiological conditions, in different cellular contexts, both with endogenous and ectopic TERT expression, and regardless of the presence of telomerase RNA counterpart TERC. TERT was shown to bind mitochondrial DNA, influencing mitochondrial replication and transcription. Furthermore, electron microscopy analysis of morphology revealed TERT-induced fragmentation of the mitochondrial network. Collectively, our findings suggest that TERT may play a role in regulating mitochondrial biogenesis and dynamics, and influencing processes such as fission and mitophagy, essential for maintaining mitochondrial homeostasis and closely connected to cellular states.
    DOI:  https://doi.org/10.1371/journal.pgen.1011923
  8. Brain. 2025 Oct 30. pii: awaf414. [Epub ahead of print]
    VPS35 mutation inhibits PINK1/parkin-mediated mitophagy via increased LRRK2 kinase activity.
    Liselot Manders, Thibaut Heyninck, Dorien Imberechts, Bjørn Holst, Rejko Krüger, Wim Vandenberghe.
      The p.D620N mutation in VPS35 causes an autosomal dominant form of Parkinson's disease via mechanisms that are poorly understood. PINK1 and parkin, two proteins whose loss of function underlies autosomal recessive Parkinson's disease, cooperate to mediate mitophagy, a quality control pathway for selective elimination of damaged mitochondria. PINK1/parkin-mediated mitophagy is disrupted by LRRK2 mutations, which are the most prevalent cause of autosomal dominant Parkinson's disease. Here, we investigated whether the p.D620N VPS35 mutation has an effect on PINK1/parkin-mediated mitophagy. We identified a novel family with autosomal dominant Parkinson's disease caused by a p.D620N VPS35 mutation. We cultured skin fibroblasts and iPSC-derived dopaminergic neurons from the proband and from a second, unrelated Parkinson's disease patient with the p.D620N VPS35 mutation, and compared them with isogenic and non-isogenic control cells. PINK1/parkin-mediated mitophagy was severely impaired in VPS35 mutant fibroblasts and neurons, while non-selective, starvation-induced autophagy and lysosomal degradative capacity were preserved. siRNA-mediated VPS35 knockdown rescued the mitophagy defect in VPS35 mutant cells, whereas overexpression of wild-type VPS35 did not, suggesting a gain-of-function mechanism of the mutation. The VPS35 mutation did not interfere with activation of PINK1 or parkin after mitochondrial depolarization, but impaired mitochondrial recruitment of the autophagy receptor optineurin. LRRK2 kinase activity was increased in the VPS35 mutant cells, as shown by enhanced levels of the T73-phosphorylated form of the LRRK2 substrate RAB10. The enhanced level of phosphorylated RAB10 in VPS35 mutant cells was decreased by treatment with LRRK2 kinase inhibitors and by VPS35 knockdown. Importantly, the mitophagy defect of VPS35 mutant fibroblasts and neurons was fully rescued by LRRK2 kinase inhibitors as well as by overexpression of PPM1H, a phosphatase that dephosphorylates multiple RAB substrates of LRRK2. Finally, in situ proximity ligation experiments revealed that endogenous VPS35 and LRRK2 are proximity partners in human dopaminergic neurons and that this proximity relationship is enhanced by the VPS35 mutation. In conclusion, the VPS35 mutation impairs PINK1/parkin-mediated mitophagy via a gain-of-function mechanism that involves stimulation of LRRK2 kinase activity. Thus, a VPS35/LRRK2 axis linked to dominant Parkinson's disease intersects with a pathway mediated by proteins encoded by the recessive Parkinson's disease genes.
    Keywords:  Parkinson’s disease; RAB; autophagy; induced pluripotent stem cell; lysosome; mitochondrion
    DOI:  https://doi.org/10.1093/brain/awaf414
  9. Int Immunopharmacol. 2025 Oct 30. pii: S1567-5769(25)01737-0. [Epub ahead of print]167 115749
    Allicin attenuates necrotizing enterocolitis via PINK1/Parkin-mediated mitophagy to suppress pyroptosis.
    Fan Zhang, Hui Xu, Tianqi Li, Qiuhong Wang, Yiqian Ding, Zhanhu Zhang.
      Necrotizing enterocolitis (NEC) is a common and severe gastrointestinal disease in neonates, with unclear pathogenesis and limited therapeutic options. This study explores the intestinal protective effects of allicin in NEC and its potential molecular mechanisms. In lipopolysaccharide (LPS)-induced in vitro NEC model using IEC-6 cells, allicin significantly improved cell viability, reduced cytotoxicity, inhibited apoptosis, promoted proliferation, and suppressed ROS overproduction and inflammatory responses (IL-1β, IL-6, IL-18, TNF-α). Expanding to a physiologically relevant 3D intestinal organoid model mimicking NEC pathology, allicin enhanced organoid budding efficiency and proliferative capacity while restoring epithelial barrier integrity through E-cadherin upregulation, highlighting its ability to repair multicellular structural damage. In a neonatal rat NEC model, allicin treatment reduces mortality in NEC rats, alleviates intestinal pathological damage, and restores intestinal barrier integrity while suppressing intestinal inflammation and pyroptosis, as evidenced by downregulated NLRP3, Cleaved-Caspase-1, and N-terminal-GSDMD expression. Notably, the therapeutic benefits of allicin were largely abolished by the mitophagy inhibitor 3-MA at both cellular and animal levels, underscoring the necessity of mitophagy for its protective effects. Mechanistic studies indicate that allicin activates the PINK1/Parkin-dependent mitophagy pathway, effectively reducing mitochondrial ROS levels and inhibiting pyroptosis. Furthermore, genetic knockdown of PINK1 or Parkin partially reversed allicin-mediated cytoprotection, ROS reduction, and anti-pyroptotic effects, definitively establishing PINK1/Parkin-dependent mitophagy as the crucial pathway. Our findings provide substantial theoretical and scientific support for the potential of allicin as a therapeutic agent for NEC.
    Keywords:  Allicin; Intestinal organoids; Mitophagy; Necrotizing enterocolitis; Pyroptosis,
    DOI:  https://doi.org/10.1016/j.intimp.2025.115749
  10. Cell Mol Biol Lett. 2025 Oct 28. 30(1): 127
    FGF21 confers neuroprotection in Parkinson's disease by activating the FGFR1-sirt1 pathway.
    Tingting Liu, Jianshe Wei.
       BACKGROUND: Parkinson's disease (PD) lacks disease-modifying therapies. Fibroblast growth factor 21 (FGF21) is implicated in PD, but its neuroprotective mechanisms via fibroblast growth factor receptor 1 (FGFR1)-sirtuin 1 (Sirt1) remain unclear.
    METHODS: Using 1-methyl-4-phenyl-1,2,3,6-te-trahydropyridine (MPTP)-induced PD mice and lipopolysaccharides (LPS)-stimulated BV2 microglia, this study employed recombinant adeno-associated virus (rAAV)-mediated FGF21 overexpression (OE). Multi-dimensional analyses (behavior, immunofluorescence, molecular docking, Western blot, PCR, transmission electron microscopy (TEM)) assessed FGF21's effects and mechanisms.
    RESULTS: FGF21OE significantly improved motor deficits (gait, rotarod) and non-motor symptoms (depression/anxiety) in PD mice. It repaired the blood-brain barrier (BBB) by upregulating tight junction proteins (claudin, zonula occludens (ZO-1), occludin) and reducing astrocyte activation (glail fibrillary acidicprotein, GFAP). Mechanistically, FGF21 binding to FGFR1 activated Sirt1, enhancing mitochondrial fusion (optic atrophy 1 (OPA1), mitofusin 1 (Mfn1)) and inhibiting fission (dynamin-related protein 1 (Drp1), Fission 1 (Fis1)), improving membrane potential and ultrastructure. FGF21 also activated the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway, boosting PINK1/Parkin-mediated mitophagy and inhibiting Casp3/Bax-dependent apoptosis. Furthermore, FGF21 reduced neuroinflammation by suppressing nuclear factor kappa-B (NF-κB)/NOD-like receptor thermal protein domain associated protein 3 (NLRP3) and shifting microglia from pro-inflammatory M1 to anti-inflammatory M2. Molecular docking and co-IP confirmed FGF21 enhances direct FGFR1-Sirt1 interaction, synergistically regulating these pathways.
    CONCLUSION: FGF21 exerts multi-faceted protection in PD via the FGFR1-Sirt1 axis, including BBB repair, mitochondrial homeostasis restoration, microglial polarization towards M2, balancing autophagy and apoptosis, and promoting neuronal survival.
    Keywords:  Blood–brain barrier; FGF21; Microglia; Mitochondrial dysfunction; Parkinson’s disease; Sirt1
    DOI:  https://doi.org/10.1186/s11658-025-00807-6
  11. Front Immunol. 2025 ;16 1686948
    Prognostic genes related to mitochondrial dynamics and mitophagy in diffuse large B-cell lymphoma are identified and validated using an integrated analysis of bulk and single-cell RNA sequencing.
    Qingjiao Chen, Mingui Chen, Jizhen Wang, Jinfeng Dong, Apeng Yang, Xiaolin Zhu, Qiaoxian Lin, Jinlong Huang, Guilan Lai, Meihong Zheng, Zhiyong Zeng, Junmin Chen, Junfang Lin, Xiaoqiang Zheng.
       Background: While the link between mitochondrial homeostasis, specifically dynamics and mitophagy, and the progression of diffuse large B-cell lymphoma (DLBCL) has been suggested, their prognostic significance and functional networks remain unclear. This study aimed to investigate the role of mitochondrial dynamics-related genes (MDRGs) in DLBCL patient outcomes.
    Methods: Candidate MDGRs were identified via Weighted Gene Co-expression Network Analysis (WGCNA) and differential expression analysis using public RNA-seq data. A prognostic signature was established via LASSO-Cox regression, followed by proportional hazards assumption validation. Functional pathways, regulatory networks (including miR-1252-5p/NEAT1), and a risk-scoring model were analyzed. Model assessment included nomograms, immune cell infiltration, m6A regulator, and pharmacogenomics. Single-cell mapping was employed to characterize B-cell differentiation and spatial gene expression. Finally, the findings were validated using RT-qPCR on clinical samples.
    Results: Six lysosomal-enriched genes (TCF7, CEBPA, BBC3, GALR3, BMP8B, and BAALC) were identified as independent prognostic indicators. A composite model integrating our risk score and clinical parameters showed superior predictive accuracy (AUC > 0.8). High-risk DLBCL was characterized by altered M0 macrophage infiltration, YTHDC1-mediated m6A dysregulation, and dihydrotestosterone sensitivity. Single-cell analysis revealed an association between stage-specific B-cell differentiation and gene expression gradients. RT-qPCR confirmed the upregulation of CEBPA, BBC3, GALR3, BMP8B, and BAALC in DLBCL clinical samples.
    Conclusion: TCF7, CEBPA, BBC3, GALR3, BMP8B, and BAALC were identified as novel lysosomal pathway-enriched prognostic genes in DLBCL. Our validated composite model demonstrated strong predictive power. These findings establish an association between high-risk disease and specific tumor microenvironment alterations (M0 macrophages), epitranscriptomic dysregulation (m6A), and therapeutic vulnerabilities, providing valuable insights for refining prognosis and advancing targeted therapies for DLBCL.
    Keywords:  diffuse large B-cell lymphoma; mitochondrial dynamics; mitochondrial homeostasis signature; mitophagy; single-cell prognostic stratification
    DOI:  https://doi.org/10.3389/fimmu.2025.1686948
  12. Neurotoxicology. 2025 Oct 28. pii: S0161-813X(25)00146-9. [Epub ahead of print] 103340
    The Role of ER/ERK/CREB Pathway Mediated Mitophagy in Bisphenol F-Induced Cognitive Function Changes in Young Female Rats.
    Wenhe Wang, Zeqin Peng, Xinyi Feng, Zixuan Chen, Jie Zhang, Tianwenjing Huang, Qin Zhang, Dan Wu, Qin Liu.
      Bisphenol F (BPF) is a widespread industrial chemical and suspected neurotoxicant, yet its effects on cognitive function and the underlying mechanisms remain unclear. This study aimed to investigate whether BPF exposure induced cognitive function changes in young female rats were associated with ER/ERK/CREB pathway and subsequent mitophagy. 4-week-old Sprague-Dawley female rats received BPF via oral gavage (25 or 250μg/kg bw/d) for 4 weeks. Cognitive function was evaluated using the Morris water maze and novel object recognition test during the last week of exposure. Hippocampal tissue was analysed for histomorphology, ER/ERK/CREB pathway changes, mitophagy and apoptosis. In this study, spatial learning in rats was transiently impaired, whereas long-term spatial memory remained unchanged in rats following BPF exposure. The recognition capability was improved as the dose increased. At the molecular level, the protein related to ER/ERK/CREB pathway, mitophagy and apoptosis were downregulated. Moreover, the mitophagy was downregulated in hippocampal CA1 region. These findings suggested that BPF exposure affected cognitive functions in young female rats, which was associated with the alterations of mitophagy mediated by ER/ERK/CREB pathway.
    Keywords:  ER/ERK/CREB pathway; apoptosis; bisphenol F; cognitive functions; mitophagy
    DOI:  https://doi.org/10.1016/j.neuro.2025.103340
  13. Biomed Pharmacother. 2025 Oct 27. pii: S0753-3322(25)00896-0. [Epub ahead of print]192 118702
    Chemerin-CMKLR1 differentially mediated OGD/R-induced mitochondrial dysfunction, oxidative stress, and autophagy in microglia and neurons.
    Pei-Yan Long, Zhi Tang, Na Cai, Zhi-Qin Yan, Xiao Gao, Zheng-Wei Wang, Zhi-Zhong Guan, Xiao-Lan Qi, Ruiqing Ni, Yan Xiao.
      Ischemia-reperfusion (I/R) injury exacerbates tissue damage upon reperfusion after ischemia. The effects of chemerin and its receptor, chemokine-like receptor 1 (CMKLR1), on I/R injury remain poorly understood. We hypothesized that the chemerin-CMKLR1 axis differentially regulates signaling in microglia and neuronal cells during oxygen-glucose deprivation/reoxygenation (OGD/R), influencing mitochondrial function, oxidative stress, and autophagy. Using BV2 microglia and Neuro-2a (N2a) neuronal cells, we examined OGD/R-induced changes in the expression of the autophagy-associated proteins chemerin and CMKLR1. We investigated the functional consequences of CMKLR1 overexpression and chemerin treatment on oxidative stress, apoptosis, autophagy, and mitochondrial dynamics in BV2 microglia and N2a neuronal cells. Following OGD/R, CMKLR1 expression was downregulated, whereas autophagy was upregulated in both cell types. In contrast, chemerin expression decreased in BV2 microglia but increased in N2a cells. Treatment with chemerin dose-dependently reduced oxidative stress and apoptosis while enhancing mitochondrial fusion, suppressing fission, and promoting autophagy and mitochondrial function in both cell types under OGD/R conditions. CMKLR1 overexpression exacerbated mitochondrial respiratory dysfunction, mitochondrial fusion, fission, and increased autophagy (LC3II/LC3I and Pink1 levels), with cell type-specific differences observed in Parkin and P62 regulation. Our study revealed cell type-specific regulation of chemerin-CMKLR1 signaling in I/R injury and distinct mitophagy activation mechanisms in microglia and neurons. These findings suggest that the cell type-specific modulation of chemerin-CMKLR1 is a potential therapeutic target for preserving mitochondrial homeostasis; modulating autophagy and mitophagy; and reducing oxidative stress and apoptosis in both microglia and neurons to mitigate I/R injury.
    Keywords:  CMKLR1; Chemerin; Ischemic stroke; Microglia; Mitochondria; Neuron; Oxidative stress; Oxygen and glucose deprivation/reoxygenation (OGD/R)
    DOI:  https://doi.org/10.1016/j.biopha.2025.118702
  14. J Mol Endocrinol. 2025 Oct 27. pii: JME-25-0033. [Epub ahead of print]
    HNF1α-Q125ter-mediated mitochondrial dysfunction and impaired mitophagy in β-cells.
    Fei Jiang, Jie Huang, Xinyan Chen, Xiao-Xi Zhang, Yinling Chen.
      Maturity-onset diabetes of the young (MODY) is a form of monogenic diabetes caused by single-gene mutations. MODY3, the most common subtype, results from mutations in the hepatocyte nuclear factor 1-alpha (HNF1α) gene. HNF1α is a transcription factor essential for pancreatic β-cell function and insulin production. Clinically, β-cells in MODY3 patients generally retain intact sulfonylurea receptor function, making sulfonylureas the preferred treatment. However, a novel loss-of-function variant, HNF1α-Q125ter, has been shown to induce sulfonylurea insensitivity in MODY3 patients. This study aimed to investigate the role and mechanism of HNF1α-Q125ter-mediated mitochondrial dysfunction and impaired mitophagy in new variant-induced β-cell dysfunction. Mitophagy-related protein and transcription levels were analysed by western blotting and reverse transcription-quantitative PCR (RT-qPCR). Mitochondrial morphology was examined by transmission electron microscope (TEM). Ins-1 cells were transfected with overexpression constructs for HNF1α-Q125ter or short hairpin RNA targeting HNF1a (shHNF1α) to assess its effects on mitochondrial function and mitophagy. Ins-1 cells expressing HNF1α-Q125ter showed decreased mitochondrial number, oxygen consumption, and energy metabolism. Correspondingly, mitochondrial morphology was damaged in an hnf1a+/- zebrafish model. HNF1α-Q125ter also inhibited mitophagy by suppressing the mRNA expression of PTEN-induced kinase 1 (PINK1), pyruvate dehydrogenase E1 subunit α1 (PDHA1), and Parkin RBR E3 ubiquitin-protein ligase (Parkin). Mechanistically, HNF1α-Q125ter impaired autophagy by downregulating phosphorylated mammalian target of rapamycin (p-mTOR) (Ser2448) and phosphorylated-70 kDa ribosomal protein S6 kinase (p-p70S6K) (Thr389). In conclusion, our findings suggest that HNF1α-Q125ter induces mitophagy dysfunction by suppressing the p-mTOR(ser2448)/ p-p70S6K(Thr389) signalling pathway, providing novel insights into the mechanisms underlying sulfonylurea insensitivity in patients with this variant.
    Keywords:  HNF1α-Q125ter; mTOR/p70S6K pathway; mitochondrial function; mitophagy
    DOI:  https://doi.org/10.1530/JME-25-0033
  15. Mater Today Bio. 2025 Dec;35 102377
    Mitochondria-enriched nanovesicles: A novel approach for treating radiation-induced skin injury.
    Mengru Zhu, Junhao Xia, Jia Liu, Wei Zou, Xin Guan, Lizhi Wang, Yichen Wang, Bing Wang, Fengya Wang, Qingwen Zhang, Keman He, Lukuan Liu, Jing Liu.
      Radiation-induced skin injury (RSI) is characterized by persistent mitochondrial dysfunction and compromised DNA repair mechanisms, posing significant challenges for clinical management. To address this, we engineered mitochondria-enriched nanovesicles (NVs) derived from human umbilical cord mesenchymal stem cells (hUMSCs), designed to deliver bioactive mitochondrial components to irradiated skin tissues. Using established in vitro and in vivo models of X-ray-induced RSI, we demonstrated efficient NV internalization into epidermal and dermal cells, leading to restoration of mitochondrial ultrastructure and metabolic function, attenuation of reactive oxygen species (ROS), and facilitation of DNA damage repair. Data-independent acquisition (DIA) proteomic profiling further indicated that NVs significantly upregulated key DNA repair proteins (including POLD3, POLE4, RFC1, and ERCC6), which were downregulated after irradiation, and activated the PINK1-Parkin mitophagy pathway. Additionally, NVs restored mitochondrial dynamics by suppressing DRP1-mediated fission and enhancing MFN1/2-dependent fusion, collectively promoting cellular homeostasis. These findings support the development of a cell-free, mitochondria-based nanotherapeutic strategy that concurrently targets DNA repair and mitochondrial quality control, presenting a scalable and promising treatment for RSI and potentially other radiation-induced disorders.
    Keywords:  DNA repair; Mitochondrial dysfunction; Mitochondrial homeostasis; Mitophagy; Nanovesicles; Radiation-induced skin injury
    DOI:  https://doi.org/10.1016/j.mtbio.2025.102377
  16. J Adv Res. 2025 Oct 29. pii: S2090-1232(25)00848-3. [Epub ahead of print]
    FGF21-FGFR1 signaling protects against cardiac hypertrophy by regulating PINK1-mediated mitophagy pathway.
    Lei Chen, Lingxin Zheng, Yuan Qin, Bilin Liu, Yejing Zheng, Xiaojian Tong, Mengting Dai, Guohua Gong.
       INTRODUCTION: Cardiac hypertrophy is an independent risk factor and the primary predictor of heart failure (HF). Mitochondria are crucial for the shift from hypertrophy to heart failure. The expression of fibroblast growth factor 21 (FGF21), a cardioprotective factor, is increased in patients with cardiac hypertrophy but fails to prevent heart failure. Additionally, the molecular mechanism through which FGF21 exerts its beneficial effects on hypertrophic myocardial mitochondria remains unclear.
    OBJECTIVES: Our study investigated the effect of FGF21 on cardiac hypertrophy, elucidating its mechanism of action through the enhancement of mitophagy-mediated cardioprotection.
    METHODS: A transverse aortic constriction (TAC) model and a phenylephrine (PE) model were applied to explore the effect and mechanism of FGF21. P62-mediated mitophagy inducer (PMI) and rapamycin (Rapa) were used to confirm that FGF21-regulated mitophagy under overload pressure conditions.
    RESULTS: FGF21 knockout markedly exacerbated TAC-induced cardiac function damage, mitochondrial damage, and mitophagy impairment. In vitro, FGF21 knockdown aggravated PE-induced cardiomyocyte hypertrophy and mitophagy dysfunction. FGF21 treatment promoted mitophagy in the TAC and PE models, but this effect was abolished in the absence of PTEN-induced putative kinase 1 (PINK1). The increase in PINK1 expression induced by Rapa can rescue impaired cardiac function and mitophagy impairment in FGF21-deficient TAC mice. Similarly, PMI enhances mitophagy, which inhibits damage to cardiac functions. A further study revealed that the expression of fibroblast growth factor receptor 1 (FGFR1) and FGF21 was opposite in heart failure. Knockdown of FGFR1 inhibited FGF21-mediated mitophagy.
    CONCLUSION: FGF21 promotes PINK1-mediated mitophagy to attenuate cardiac hypertrophy, and mismatched FGFR1 expression may hamper the beneficial effect of FGF21 on cardiac hypertrophy.
    Keywords:  Cardiac hypertrophy; FGF21; FGFR1; Mitophagy; PINK1
    DOI:  https://doi.org/10.1016/j.jare.2025.10.053
  17. Stem Cell Res Ther. 2025 Oct 28. 16(1): 585
    Miro1 protects against brain injury after CPR in rats by enhancing the effect of BMSCs on mitochondrial homeostasis.
    Xuyuan Ma, Maozheng Shen, JiaYu Hu, Jie Zhu, Zhen Wang, Qian Zhou, MingYue Zeng, Mengda Xu, YanLiang Qu, Xiang Zhou.
       BACKGROUND: Mitochondrial dyshomeostasis plays an important role in neuronal damage after cerebral ischemia-reperfusion, and Miro1 is a core protein that regulates mitochondrial homeostasis. In this study, we aimed to investigate the neuroprotective effects of bone marrow-derived mesenchymal stem cells (BMSCs) via mitochondrial homeostasis in rats after cardiac arrest (CA), and to clarify the role that the protein Miro1 plays in this protective efficacy.
    METHODS: The study compared the effects of BMSCs in which Miro1 was overexpressed BMSCs (BMSCs-mirohi), knocked down (BMSCs-mirolo), and unmodified BMSCs on mitochondrial homeostasis in hippocampal neurons to evaluate their neuroprotective effects of these cells in a rat model of global cerebral ischemia-reperfusion injury. Rats underwent CA modeling for 5 min and received cardiopulmonary resuscitation (CPR). Two hours after the restoration of spontaneous circulation, 1 mL of PBS or 1 mL containing 1 × 106 BMSCs (normal, mirohi, or mirolo) were injected via the femoral vein. The neurological function of rats was assessed based on Neurological Disability Score (NDS) values. Brain histopathological examination was conducted to evaluate brain injury by measuring oxidative stress levels and the apoptosis rate of hippocampal neurons. Immunoblotting and transmission electron microscopy were applied to detect the expression of mitophagy-related proteins in hippocampal neurons. Immunofluorescence was used to track the mitochondria in BMSCs and observe mitochondrial transfer. Additionally, the membrane potential level, oxidative stress level, and ATP content of mitochondria in hippocampal neurons were measured to assess the impact of transplanted BMSCs on mitochondrial quality in these hippocampal neurons.
    RESULTS: Immunofluorescence staining revealed the presence of mitochondria from MitoTracker-labeled BMSCs in rat hippocampal neurons post-CPR. Additionally, the fluorescence intensity of TOMM20 was notably increased following the transplantation of BMSCs. Through immunoblotting experiments, we identified that BMSCs amplified the post-CPR protein expression of LC3, p62, PINK1 and parkin in hippocampal neurons. The number of autophagosomes significantly increased in hippocampal neurons following BMSC transplantation, as observed through transmission electron microscopy. Flow cytometry, Hematoxylin and Eosin (HE) staining, and NDS scoring indicated that BMSCs effectively reduced reactive oxygen species accumulation in hippocampal neurons and mitochondria after CPR. Furthermore, they restored mitochondrial membrane potential and ATP levels in the hippocampus while decreasing apoptosis, ultimately contributing to the restoration of neurological function. Additionally, unlike BMSCs-mirolo, BMSCs-mirohi were able to significantly enhance the efficiency of BMSC-mediated mitochondrial transfer and enhance mitophagy. This amplification, in turn, was found to bolster the protective impact of BMSCs on hippocampal neurons during CPR, thereby contributing to the restoration of rat neurological function.
    CONCLUSIONS: These analyses revealed that BMSC transplantation has a dual protective effect by facilitating healthy mitochondrial transfer and promoting the autophagic degradation of damaged mitochondria, effectively enhancing hippocampal neuronal mitochondrial function following CA while reducing neuronal apoptosis, restoring neuronal function, and alleviating neuropathological damage. Moreover, Miro1 can enhance the efficiency of mitochondrial transfer and promote BMSC-mediated mitophagy induction, thereby optimizing the therapeutic effect of BMSCs.
    Keywords:  Bone marrow-derived mesenchymal stem cells; Cardiopulmonary resuscitation; Miro1; Mitochondria
    DOI:  https://doi.org/10.1186/s13287-025-04724-5
  18. Curr Pharmacol Rep. 2025 ;11(1): 53
    Mitochondrial Dynamics in Blood Cancer Development and Progression.
    Saurav Doshi, Christina Glytsou.
       Purpose of Review: This article outlines the role of mitochondrial dynamics in healthy cells and elaborates on how blood cancer cells hijack these processes to support uncontrolled proliferation, stemness, and drug resistance. A comprehensive understanding of the mechanistic details of mitochondrial behavior in malignant hematopoiesis will provide new therapeutic avenues and improve the prediction of therapy responses.
    Recent Findings: Mitochondrial dynamics, governed by the complementary events of fusion and fission, is a key cellular process for maintaining metabolic flexibility, organelle integrity, and cellular homeostasis. Impairment of the dynamic fusion-fission balance can lead to various chronic pathologies. Recent research has highlighted how blood cancer cells exploit mitochondrial remodeling to maintain metabolic efficiency and adjust organellar quality control mechanisms to sustain survival pathways and enable cancer progression. Furthermore, leukemia and lymphoma cells use mitochondrial plasticity to adapt under stress conditions and to evade cell death induced by various clinically used or tested therapeutic regimens. Investigations using blood cancer cell lines, patient-derived samples, and xenograft models have begun to uncover the specific roles and regulatory mechanisms of mitochondrial dynamics proteins in different subtypes of hematologic malignancies, as well as in therapy resistance. Additionally, preclinical studies suggest that targeting these regulators may present novel therapeutic opportunities and serve as predictive biomarkers in blood cancers.
    Summary: This review highlights the therapeutic potential of modulating mitochondrial dynamics, underscoring the need for further integrative studies to fully harness this vulnerability in hematologic malignancies.
    Keywords:  Blood cancer; Fission; Fusion; Leukemia; Mitochondria
    DOI:  https://doi.org/10.1007/s40495-025-00431-0
  19. Neural Regen Res. 2025 Oct 30.
    Mitophagy alleviates neuronal damage after subarachnoid hemorrhage: Role of autophagy-targeting chimera 4.
    Yongzhi Zhang, Jianqiao Li, Qi Sun, Peichun Zhou, Pei Wu, Zhiyong Ji, Yuchen Li, Huaizhang Shi.
       ABSTRACT: This study investigated the role of autophagy-targeting chimera 4, a novel activator of autophagy that targets mitochondria, in a subarachnoid hemorrhage model. The data demonstrated that in an in vitro mitochondrial damage model, autophagy-targeting chimera 4 reversed carbonyl cyanide 3-chlorophenylhydrazone-induced mitochondrial membrane potential collapse and activated mitophagy. In the in vitro subarachnoid hemorrhage model, autophagy-targeting chimera 4 improved neuronal proliferation and migration during the acute phase and reduced neuronal apoptosis after subarachnoid hemorrhage. In the in vivo subarachnoid hemorrhage model, autophagy-targeting chimera 4 also decreased neuronal apoptosis during the acute phase, improved neurological function, and ultimately reduced long-term neuronal loss. Additionally, increased ring finger protein 144B expression after subarachnoid hemorrhage was associated with poor prognosis, and autophagy-targeting chimera 4 significantly inhibited ring finger protein 144B expression, thereby activating mitophagy and reducing neuronal apoptosis. The results also showed that the mitophagic marker parkin did not exert protective effects during the acute phase after subarachnoid hemorrhage and might be inhibited by ring finger protein 144B. Moreover, parkin inhibition did not interfere with the mitophagic or apoptotic effects of autophagy-targeting chimera 4. These findings not only confirm that autophagy-targeting chimera 4 exerts neuroprotective effects by targeting mitophagy after subarachnoid hemorrhage, but also demonstrate competitive inhibition between ring finger protein 144B and parkin, leading to poor prognosis in the acute phase after subarachnoid hemorrhage.
    Keywords:  apoptosis; autophagy; brain injury; mitochondrial membrane potential; mitochondrion; mitophagy; neurons; stroke; subarachnoid hemorrhage; ubiquitin
    DOI:  https://doi.org/10.4103/NRR.NRR-D-25-00705
  20. FASEB J. 2025 Nov 15. 39(21): e71169
    Parkin-Mediated Ubiquitination of DCUN1D1: Implications for CXCL10 Regulation in Vitiligo.
    Shiyu Jin, Tingru Dong, Yujie Li, Fenglan Yang, Renxue Xiong, Xiuzu Song, Cuiping Guan.
      Vitiligo is a skin disorder marked by the loss of pigmentation due to melanocyte destruction. Our previous study demonstrated that DCUN1D1 is a novel regulator of CXCL10 and is associated with mitochondrial dysfunction. RNA-seq data revealed that the expression of Parkin, a mitophagy-related molecule, is decreased in vitiligo patients. Parkin functions as an E3 ubiquitin ligase. Based on these findings, we hypothesize that Parkin ubiquitinates DCUN1D1, thereby influencing the level of CXCL10 during the progression of vitiligo. Parkin and DCUN1D1 expression levels were assessed in both vitiligo patients and mice. To examine interactions, HaCaT cells were transfected with Flag-DCUN1D1, Myc-PRKN, or HA-Ub, followed by coimmunoprecipitation (co-IP) and Western blotting analysis. Mitochondrial activity and mitophagy were evaluated following various treatments, including the use of CCCP. HaCaT cells were transfected with DCUN1D1 or different concentrations of Parkin to assess CXCL10 levels. The supernatant from HaCaT cells was collected and incubated with melanocytes for 48 h, after which the apoptosis level was examined. DCUN1D1 was found to be upregulated, whereas Parkin was downregulated in both vitiligo patients and mice. Parkin interacts with DCUN1D1 and ubiquitinates it at lysine 27 (K27). Increased levels of Parkin counteract the reductions in mitochondrial activity and mitophagy induced by DCUN1D1, significantly downregulate CXCL10 levels, and reduce melanocyte apoptosis. This study provides evidence that Parkin-mediated ubiquitination of DCUN1D1 regulates CXCL10 levels in vitiligo, thereby offering a new experimental foundation for understanding the pathogenesis of vitiligo.
    Keywords:  CXCL10; DCUN1D1; Parkin; ubiquitination; vitiligo
    DOI:  https://doi.org/10.1096/fj.202501349R
  21. Int J Mol Sci. 2025 Oct 20. pii: 10185. [Epub ahead of print]26(20):
    The Caenorhabditis elegans sdhb-1(R244H) Model Shows Characteristics of Human PPGL Tumor Cells.
    Fanni Ősz, Mahmood Akbar, Balázs Zoltán Zsidó, Csaba Hetényi, Tamás I Orbán, Ábel Fóthi, Gábor M Kovács, Alexandra Pintye, Attila Boda, Aamir Nazir, Zsolt Farkas, Krisztina Takács-Vellai.
      Pheochromocytomas and paragangliomas (PPGL) are classified as rare cancers but can be highly metastatic, particularly in individuals with inherited succinate dehydrogenase B (SDHB) mutations. As current therapies and the availability of SDHB-deficient animal models are both limited, we have previously constructed a nematode PPGL model, a transgenic worm carrying the R244H missense mutation equivalent to human R230H in the sdhb-1 gene. In this study, we show that R244H mutants display characteristics of PPGL tumors, such as pseudohypoxia activation and the accumulation of reactive oxygen species. The latter can be the result of compromised antioxidant machinery, as R244H mutants have reduced levels of cytosolic and mitochondrial superoxide dismutase enzymes. In addition, the expression of mitophagy markers pink-1 (PTEN-induced putative kinase) and pdr-1 (E3 ubiquitin-protein ligase parkin) were downregulated in R244H mutants, suggesting impaired mitophagy and reflecting the crucial role of mitochondrial health in PPGL pathology. Treatments by the SDH inhibitor fluopyram revealed that the SDH complex carrying the R244H mutation in subunit B displayed residual SDH activity, which was also confirmed by our structural analyses. We also observed a link between dopaminergic neuronal health and SDHB-1.
    Keywords:  ROS; SDH inhibitor; SDHB; dopaminergic neuronal damage; fluopyram; fungicide; hypoxia; mitophagy; succinate dehydrogenase B
    DOI:  https://doi.org/10.3390/ijms262010185
  22. Int J Biol Macromol. 2025 Oct 23. pii: S0141-8130(25)09060-9. [Epub ahead of print] 148503
    Lactate-HIF-1a axis promotes PINK1-dependent mitophagy to protect porcine granulosa cells against hypoxic stress.
    Jiaqi Zhou, Mingke Guo, Quzhen Danzeng, Qinghong Gu, Mijiu Zhaxi, Xiumei Lu, Junzhuo Deng, Linjie Zhu, Honglin Liu.
      Ovarian follicular development occurs under chronic hypoxia, imposing significant stress on granulosa cells (GCs) and leading to hypoxia-induced apoptosis, a key factor in follicular atresia and impaired fertility. However, the intrinsic mechanisms enabling GCs to resist hypoxic apoptosis remain unclear. Emerging evidence suggests lactate, beyond its traditional role as a glycolytic byproduct, functions as a critical mediator of cellular stress adaptation. Here, we investigated whether lactate confers protection to porcine granulosa cells (pGCs) by activating mitophagy under hypoxic conditions and elucidated the underlying molecular pathways. Using pGCs subjected to normoxia and hypoxia, combined with pharmacological inhibitors, RNA interference targeting LDHA, HIF-1α, and PINK1, mitochondrial membrane potential assays, apoptosis detection, Western blotting, and mitochondrial-lysosomal co-localization imaging, we demonstrated that lactate depletion exacerbates mitochondrial dysfunction and apoptosis under hypoxia. Conversely, exogenous lactate supplementation attenuated these effects by stabilizing HIF-1α and enhancing PINK1-Parkin-mediated mitophagy. Inhibition of mitophagy via 3-MA or PINK1 knockdown abolished lactate's protective effects, highlighting mitophagy as essential for lactate-mediated cell survival. Cross-species validation in murine granulosa cells (mGCs) in vitro and in vivo confirmed the conservation of lactate's protective mechanisms, where lactate depletion impaired mitochondrial function and increased follicular apoptosis, while lactate supplementation restored mitochondrial integrity and granulosa cell viability. Our findings reveal a novel lactate-HIF-1α-PINK1 signaling axis critical for pGCs resilience to hypoxic stress, offering new therapeutic targets for ovarian disorders such as polycystic ovary syndrome and ovarian aging.
    Keywords:  Apoptosis; HIF-1α; Lactate; Mitophagy; PINK1; Parkin; Porcine granulosa cell
    DOI:  https://doi.org/10.1016/j.ijbiomac.2025.148503
  23. Neurobiol Dis. 2025 Oct 28. pii: S0969-9961(25)00379-1. [Epub ahead of print] 107162
    Mitophagy in Alzheimer's disease and its potential as a therapeutic target.
    Jiahua Wei, Tiegang Xiao, Jialu Lyu, Yueshuang Zhao, Yang Zhang, Xiangyu Du, Ying He, Mengqing Zhao, Xiaoyi Yang, Yutong Yao, Jun Ruan, Kaili Liu, Li Zhang, Jiangbo Zhao, Jun Xu, Bing Wang.
      Accumulation of damaged mitochondria is a well-established hallmark of age-related neurodegenerative disorders, including Alzheimer's disease (AD). Increasing evidence suggests that mitophagy, a selective autophagic degradation of damaged mitochondria, plays an important role in AD progression. The interaction between mitophagy deficits and amyloid-β (Aβ) or Tau pathology may establish a vicious cycle that ultimately results in neuronal damage and death. Mitochondrial dysfunction exacerbates AD pathogenesis by activating the NLRP3 inflammasome, whereas modulation of mitophagy may confer neuroprotection by attenuating inflammation in neurons and microglia. Pathological ferroptosis has emerged as a potential key driver of AD, with mitophagy intriguingly demonstrating a dual role in this process. In this review, we elucidate the molecular mechanisms underlying mitophagy and its involvement in AD, thereby providing insights into its pathogenesis. We further highlight the therapeutic potential of targeting mitophagy as a promising strategy for AD intervention.
    Keywords:  Alzheimer's disease; Ferroptosis; Mitochondrial dysfunction; Mitophagy; Neuroinflammation
    DOI:  https://doi.org/10.1016/j.nbd.2025.107162
  24. Pharmaceuticals (Basel). 2025 Sep 25. pii: 1443. [Epub ahead of print]18(10):
    Mitochondrial Protease ClpP: Cancer Marker and Drug Target.
    Domenico Armenise, Olga Maria Baldelli, Anselma Liturri, Gianfranco Cavallaro, Cosimo Gianluca Fortuna, Savina Ferorelli, Morena Miciaccia, Maria Grazia Perrone, Antonio Scilimati.
      Background: The human mitochondrial ClpP is a serine protease located in the mitochondrial matrix responsible for degrading short lived regulatory proteins as well as misfolded or damaged proteins, thereby maintaining cellular homeostasis. Proteastasis dysregulation is linked to tumor progression. Methods: We conducted a literature review (2020-2025) using PubMed and Scopus, focusing on studies addressing ClpP structure, function, activity modulation, and cancer relevance. Keywords included "ClpP", "ClpP activators", "ClpP inhibitors", and "mitochondrial protease". Results: ClpP is upregulated in many tumors compared to normal tissues. Cancer cells depend on ClpP for mitochondrial proteostasis, metabolic adaptation, and survival. ClpP proteolytic activity modulation-via activators or inhibitors-disrupts these processes showing efficacy even in clinical setting. Conclusions: ClpP is emerging as a key player in cancer pathophysiology and holds potential as a therapeutic target. Its selective overexpression in tumors, along with its involvement in mitochondrial homeostasis, makes it a compelling candidate for precision oncology.
    Keywords:  ClpP activators/inhibitors; ClpP overexpression; cancer; human ClpP protease; mitochondrial proteostasis; quality control system
    DOI:  https://doi.org/10.3390/ph18101443
  25. Front Immunol. 2025 ;16 1683819
    METTL3-driven m6A modification orchestrates mitophagy-dependent ferroptosis in PM2.5-induced lung injury.
    Qin Ran, Jie Gao, Guoping Li, Junyi Wang, Xiaolan Li, Anying Xiong, Yi Zhang, Ying Xiong, Xiang He.
      Air pollution, particularly from fine particulate matter (PM2.5), poses a significant threat to respiratory health, yet the molecular mechanisms underlying PM2.5-induced lung injury remain incompletely understood. This study investigated the role of N 6-methyladenosine (m6A) methyltransferase METTL3 in regulating mitophagy-dependent ferroptosis in bronchial epithelial cells exposed to PM2.5. Using in vitro and in vivo models, we demonstrated that PM2.5 exposure induced histological alterations in mouse lung tissues, including inflammatory cell infiltration, goblet cell hyperplasia, and mucus hypersecretion, concurrent with enhanced ferroptosis and mitophagy in bronchial epithelial cells. Gain-of-function and loss-of-function experiments showed that METTL3 overexpression exacerbated mitophagy and ferroptosis, while METTL3 silencing attenuated these processes, rescuing cell viability and reducing pulmonary inflammation. In vivo, intratracheal administration of METTL3 recombinant protein recapitulated these effects, confirming its role in amplifying PM2.5-induced lung injury. Mechanistically, PM2.5 upregulated METTL3 expression, which promoted PINK1 mRNA stability through m6A modification, activating the PINK1-dependent mitophagy pathway. This led to the excessive clearance of damaged mitochondria, culminating in iron-dependent lipid peroxidation, dysregulation of ferroptosis-related proteins (ACSL4 and xCT), and ferroptotic cell death. Critically, the inhibition of mitophagy with Mdivi-1 protected against histological damage and ferroptosis in mice, underscoring the therapeutic potential of targeting this pathway. Collectively, our findings established a hierarchical regulatory axis where m6A-mitophagy-ferroptosis drove lung injury. This study uncovered a novel link between epigenetic modification, mitophagy, and ferroptosis, identifying METTL3-mediated m6A modification and mitophagy as potential targets for preventing PM2.5-related respiratory diseases.
    Keywords:  METTL3; PM2.5; ferroptosis; lung injury; mitophagy
    DOI:  https://doi.org/10.3389/fimmu.2025.1683819
  26. Front Immunol. 2025 ;16 1672678
    Multi-omics insights into the role of mitophagy receptor-related genes in glioma prognosis and immune microenvironment remodeling.
    Yuheng Xu, Wanqi Weng, Yuanyi Xiong, Jintao Hu, Chunmei Chen, Zhiqiang Peng, Zhaotao Wang.
       Background: Mitophagy receptor-related genes (MRRGs) orchestrate mitochondrial quality control and may shape glioma progression and immune tolerance, yet their integrated prognostic and immunobiological significance remains unclear.
    Methods: We combined WGCNA, single-cell AUCell scoring, and LASSO/Cox modeling across public glioma cohorts to derive and externally validate a 17-gene MRRG risk signature. Multi-omics comparisons (transcriptome, pathway enrichment, mutation, and GWAS association), immune infiltration, and therapy response prediction were performed. Core driver(s) were interrogated by in vitro functional assays and in vivo xenograft validation.
    Results: The MRRG signature robustly stratified overall survival across independent datasets and remained an independent prognostic factor after multivariable adjustment. High-risk tumors exhibited activation of P53 signaling and MAPK signaling pathway, coupled with immunosuppressive remodeling characterized by increased M2-like macrophage infiltration and T cell dysfunction. Integrative analyses highlighted IFNAR2 as a central node; its silencing impaired glioma cell proliferation, invasion, and metastatic potential, while in vivo suppression attenuated tumor growth. The model correlated with differential predicted sensitivity to immunotherapy and targeted agents, suggesting potential for precision stratification.
    Conclusion: We present and validate a 17-MRRG prognostic model that links mitophagy receptors to glioma immunosuppression and clinical outcome, and identify IFNAR2 as a functional driver. These findings provide a rationale for incorporating MRRG profiling into prognostic assessment and therapeutic decision-making in glioma.
    Keywords:  IFNAR2; glioma; immune infiltration; mitophagy receptors; prognosis
    DOI:  https://doi.org/10.3389/fimmu.2025.1672678
  27. Naunyn Schmiedebergs Arch Pharmacol. 2025 Oct 30.
    Mitochondrial autophagy mechanism and berberine therapeutic target discovery in hepatocellular carcinoma based on single-cell and transcriptome analysis.
    Shumin Wen, Xiaofeng Cheng, Zhangrong Zhu, Tao Liu, Min Chen.
      Hepatocellular carcinoma (HCC) is a highly prevalent malignant tumor worldwide, and its progression is closely related to mitochondrial damage, but its mechanism is not yet clear. The natural compound berberine has multi-target anti-tumor potential, but further exploration is needed to determine whether it regulates mitochondrial autophagy. This study aims to explore the molecular mechanisms of HCC and evaluate the possibility of berberine intervention, providing new research directions and a theoretical basis for its treatment. This study integrated GEO data, single-cell sequencing, and in vitro cell experiments to systematically analyze the differential gene expression characteristics and pathway regulatory networks of HCC by screening core targets through the intersection with autophagy genes and combining single-cell data to reveal the interaction between malignant cells and immune cells. In addition, potential therapeutic targets of berberine were validated through in vitro experiments, and its mechanism of action was analyzed through bioinformatics. This study screened 5700 differentially expressed genes and 4515 modular genes through GEO database analysis. After intersecting with the autophagy dataset, 132 HCC autophagy-related genes were obtained. Further identification of 20 hub genes, which are mainly involved in the regulation of autophagy and the formation of autophagosomes, was performed. Enrichment analysis showed that pathways such as Autophagy other, Mitophagy animal, and HIF-1 signaling pathway were significantly activated in HCC. The single-cell immune microenvironment reveals a significant increase in macrophage and neutrophil infiltration in tumor tissues, while NK cell function may be inhibited. In addition, berberine reverses the malignant phenotype of HCC cells by targeting genes such as BECN1, HSP90AA1, ATG5, PINK1, HIF1A, and GSK3B, regulating the Autophagy other, Mitophagy animal, and HIF-1 signaling pathways. This study reveals the core mechanism of mitochondrial autophagy in HCC and proposes a new strategy for berberine targeted therapy, laying a theoretical foundation for molecular typing and combination therapy development of hepatocellular carcinoma.
    Keywords:  Autophagy; Berberine; Hepatocellular carcinoma; Single-cell technology; Transcriptomics
    DOI:  https://doi.org/10.1007/s00210-025-04772-x
  28. Sci Rep. 2025 Oct 28. 15(1): 37652
    Ultrastructural evaluation of lithium-induced autophagic and mitochondrial stress in 3D endometrial and neuroblastoma spheroids.
    Berna Yıldırım, Agnes Ansa Archibong-Omon, Ayhan Bilir.
      Lithium chloride (LiCl), a widely used mood stabilizer, has been reported to modulate selective autophagy pathways, including mitophagy. However, its ultrastructural effects in three-dimensional (3D) tumor models remain incompletely characterized. In this study, we examined the subcellular alterations induced by LiCl in 3D spheroid cultures derived from Ishikawa endometrial cancer and SH-SY5Y neuroblastoma cells. Spheroids were treated with 1, 10, or 50 mM LiCl and analyzed using transmission electron microscopy (TEM). The analysis revealed double-membrane-bound vesicles surrounding degenerating mitochondria, along with cytoplasmic vacuolization and membrane remodeling. These morphological features are suggestive of mitophagic activity, accompanied by stress-related ultrastructural remodeling. Although molecular validation (e.g., LC3B or PINK1/Parkin Western blotting) was not performed, the observed ultrastructural profiles are consistent with organelle-selective autophagy. These findings underscore the dose-dependent cellular responses to LiCl and support the value of 3D cancer spheroids as models to explore non-canonical autophagy-related stress pathways. Future studies incorporating molecular markers such as LC3B, PINK1, Parkin, and Lamin B1 will be essential to confirm these observations.
    Keywords:  3D cancer spheroids; Endometrial cancer; Lithium chloride; Mitophagy; Transmission electron microscopy
    DOI:  https://doi.org/10.1038/s41598-025-21569-3
  29. Int J Mol Sci. 2025 Oct 14. pii: 9991. [Epub ahead of print]26(20):
    Marf- and Opa1-Dependent Formation of Mitochondrial Network Structure Is Required for Cell Growth and Subsequent Meiosis in Drosophila Males.
    Tatsuru Matsuo, Mitsuki Yamanaka, Yoshihiro H Inoue.
      Mitochondria are dynamic organelles that undergo repeated fusion and fission. We studied how the distribution and shape of mitochondria change during Drosophila spermatogenesis and whether factors that regulate their dynamics are necessary for these changes. Unlike the shortened mitochondria seen in mitosis, an interconnected network of elongated mitochondria forms before meiosis and is maintained during meiotic divisions. Mitochondria are evenly divided into daughter cells, relying on microtubules and F-actin. To explore the role of mitochondrial network structure in cell growth and meiosis, we depleted the mitochondrial fusion factors Opa1 and Marf and the morphology proteins Letm1 and EndoB in spermatocytes. This knockdown led to inhibited cell growth and failed meiosis. As a result, the spermatocytes differentiated into spermatids without completing meiosis. The knockdown also inhibited the cytoplasmic and nuclear accumulation of Cyclin B before meiosis, and Cdk1 was not fully activated at the onset of meiosis. Notably, ectopic overexpression of Cyclin B partially rescued the failure of meiosis. Many spermatids from the spermatocytes subjected to the knockdowns contained multiple smaller nuclei and abnormally shaped Nebenkerns. These findings suggest that mitochondrial network structure, maintained by fusion and morphology factors, is essential for meiosis progression and Nebenkern formation in Drosophila spermatogenesis.
    Keywords:  Cyclin B; Drosophila; meiosis; mitochondrial dynamics; nebenkern; spermatogenesis
    DOI:  https://doi.org/10.3390/ijms26209991
  30. Front Immunol. 2025 ;16 1684178
    Porcine deltacoronavirus infection triggers mitophagy to dampen the interferon response and promote viral replication.
    Yue Chen, Yuan Zhao, Qingqing Song, Shijing Zhang, Zhenbang Zhu, Wenqiang Wang, Wei Wen, Xiangdong Li.
      Porcine deltacoronavirus (PDCoV) is a newly emerging enteric pathogenic that causes severe diarrhea in neonatal piglets worldwide and presents a significant public health threat due to its potential for cross-species transmission. MAVS (Mitochondrial Antiviral Signaling Protein), serves as a crucial immune hub that connects virus recognition (RIG-I/MDA5) and interferon response. In this study, we found that PDCoV infection damage mitochondrial structure and function, as shown by mitochondrial membrane potential depolarization and reduction in mitochondrial numbers. In addition, PDCoV infection triggered mitophagy to eliminate the impaired mitochondria and degradation of MAVS, which resulted in a suppression of Interferon type I (IFN-I) production, thereby promoting viral replication. In conclusion, the data of this study indicate that PDCoV can degrade MAVS through mitophagy to weak the production of IFN-I, thereby promoting virus replication.
    Keywords:  MAVS; interferons production inhibition; mitochondrial damage; mitophagy; porcine deltacoronavirus (PDCoV)
    DOI:  https://doi.org/10.3389/fimmu.2025.1684178
  31. Transl Cancer Res. 2025 Sep 30. 14(9): 5353-5369
    TFAP2A induces cisplatin resistance via BNIP3-mediated mitophagy in non-small cell lung cancer.
    Li-Li Guo, Xiao-Hua Yang, Hai-Zhen Jin, Ling Tian.
       Background: Cisplatin resistance in non-small cell lung cancer (NSCLC) significantly limits treatment efficacy. Mitophagy has been shown to play a protective role in cisplatin resistance. This study aims to further investigate the mechanisms underlying this process, with a particular focus on identifying transcription factor AP-2 (activating enhancer binding protein 2) alpha (TFAP2A) as a novel regulatory factor in NSCLC.
    Methods: The correlation between TFAP2A and NSCLC was analysed by The Cancer Genome Atlas (TCGA) database and Kaplan-Meier Plotter database, and validated in clinical samples and cisplatin-resistant NSCLC cells (A549-Re and PC9-Re cells). The changes of mitophagy, apoptosis, and proliferation in cisplatin-resistant NSCLC cells were examined by silencing TFAP2A. The regulatory relationship between TFAP2A and BCL2/adenovirus ElB 19kDa interacting protein 3 (BNIP3) was determined by constructing BNIP3 mutations in vitro. Cisplatin-resistant NSCLC cells with different treatments were ectopically grown with rapamycin (RAPA) interventions, and the tumor growth rate was examined in vivo.
    Results: Our results suggested that TFAP2A might induce cisplatin resistance via BNIP3-mediated mitophagy in NSCLC. The cell counting kit-8 (CCK-8) assay and colony formation showed that silencing TFAP2A dramatically inhibited proliferation and migration of cisplatin-resistant NSCLC cells. The propidium iodide (PI) staining and MitoSOX staining experiments revealed that silencing TFAP2A significantly improved the apoptosis and mitochondrial reactive oxygen species (ROS) levels in cisplatin-resistant NSCLC cells. Subsequently, western blot, reverse transcription quantitative polymerase chain reaction (RT-qPCR) and immunofluorescence experiments revealed that TFAP2A silencing induced cell apoptosis and heightened mitochondrial ROS levels through inhibition of mitophagy via inhibiting BNIP3 pathways. Additionally, western blot, colony formation and immunofluorescence experiments demonstrated that TFAP2A silencing reversed RAPA interventions in cisplatin-resistant NSCLC cells. Finally, we confirmed that TFAP2A silencing can inhibit tumor growth in vivo through experiments on xenograft tumor model of nude mice.
    Conclusions: TFAP2A overexpresses significantly in NSCLC, and promotes cisplatin resistance through BNIP3-mediated mitophagy.
    Keywords:  BCL2/adenovirus ElB 19kDa interacting protein 3 (BNIP3); Non-small cell lung cancer (NSCLC); cisplatin resistance; mitophagy; transcription factor AP-2 (activating enhancer binding protein 2) alpha (TFAP2A)
    DOI:  https://doi.org/10.21037/tcr-2025-646
  32. Stem Cell Res Ther. 2025 Oct 29. 16(1): 595
    Empagliflozin-pretreated BMSC exosomes attenuate myocardial ischemia-reperfusion injury by enhancing atad3a/pink1-dependent mitophagy.
    Yuling Jing, Ying Cai, Qiuting Li, Zaiyong Zheng, Haiqiong Yang, Yang Yu, Chunxiang Zhang.
       BACKGROUND AND OBJECTIVES: Mounting evidence demonstrates that exosomes derived from mesenchymal stem cells (MSCs) can mitigate myocardial ischemia-reperfusion injury (MIRI). However, the therapeutic potential of untreated MSC-derived exosomes remains limited. Here, we investigate whether exosomes derived from sodium-glucose co-transporter 2 inhibitor (SGLT2i)-pretreated MSCs exhibit enhanced cardioprotective effects against MIRI and elucidate the underlying mechanisms.
    METHODS AND RESULTS: Mouse bone marrow-derived MSCs (BMSCs) were pretreated with the SGLT2 inhibitor empagliflozin (EMPA), and the secreted exosomes (EMPA-EXO) were isolated. Primary neonatal cardiomyocytes were co-cultured with EMPA-EXO or untreated exosomes (EXO) for 24 h before hypoxia-reoxygenation (H/R) injury. In the MIRI mice, EXO or EMPA-EXO were delivered via intramyocardial injection. EMPA pretreatment significantly augmented exosome secretion from BMSCs by modulating the expression of Alix, nsmase2, and RAB27a. In vitro, both EXO and EMPA-EXO enhanced cardiomyocyte viability, attenuated cellular damage, and suppressed apoptosis following H/R injury. In vivo, EMPA-EXO and EXO administration improved cardiac function, reduced myocardial apoptosis, and diminished infarct size in MIRI mice mice. Mechanistically, Western blot and transmission electron microscopy (TEM) revealed that both exosome types upregulated ATAD3A expression, thereby activating PINK1/PARKIN-mediated mitophagy and ameliorating cardiomyocyte injury.
    CONCLUSION: Our findings demonstrated that EMPA enhanced exosome secretion from BMSCs. Both EMPA-EXO and EXO attenuated MIRI by upregulating ATAD3A, which promoted PINK1/PARKIN-dependent mitophagy. Notably, EMPA-EXO exhibitd superior therapeutic efficacy compared to EXO, suggesting a promising strategy for optimizing MSC-derived exosome therapy in ischemic heart disease.
    Keywords:  Empagliflozin; Exosomes; Mitophagy; Myocardial ischemia-reperfusion injury
    DOI:  https://doi.org/10.1186/s13287-025-04715-6
  33. Nephron. 2025 Oct 30. 1-27
    Role of mitophagy in ischemia-reperfusion renal injury: new insights from bioinformatics analysis.
    Huanjie Zhou, Qionghui Huang, Aoran Huang, Jingying Feng, Sihua Chen, Peixing Li, Lang-Jing Zhu.
       INTRODUCTION: Mitophagy is central to acute kidney injury (AKI) pathogenesis. Elucidating its molecular interplay with AKI is crucial for novel therapeutics.
    METHODS: This study is based on transcriptome sequencing combined with single-cell sequencing, and applies bioinformatics analysis. Finally, it is verified by in vitro, in vivo and clinical specimen experiments.
    RESULTS: In transcriptome analysis, combining protein-protein interaction mapping with machine intelligence algorithms, we screened out two mitophagy-related differentially expressed genes (MitoDEGs), Solute Carrier Family 3 Member 2 (SLC3A2) and Thioredoxin (TXN). The immunological analysis revealed a notable rise in monocyte infiltration in the immune microenvironment of ischemia-reperfusion renal injury (IRI)-AKI. Spearman analysis indicated hub MitoDEGs were positively correlated with pro-inflammatory immune cell infiltration, and negatively correlated with anti-inflammatory or regulatory immune cell infiltration. Based on the highest binding score, 506-26-3 CTD (Gamma-linolenic acid, GLA) was determined to be the top promising therapeutic candidate. At the single-cell level, hub MitoDEGs were mainly expressed in proximal tubular. In cell experiments, mitophagy was inhibited after hypoxia-reoxygenation, SLC3A2 matched earlier results, while TXN was contrary to the previous analysis results. In the IRI-AKI rat experiments, the findings regarding hub MitoDEGs aligned with our prior analysis, revealing a decrease in the expression of genes associated with mitophagy. Consequently, we directed our attention to the expression levels of SLC3A2 in clinical cases of AKI, where we observed a notable increase.
    CONCLUSION: Our research indicates that SLC3A2 could be a crucial target for enhancing IRI-AKI through the modulation of the mitophagy pathway.
    DOI:  https://doi.org/10.1159/000548962
  34. Reprod Sci. 2025 Oct 29.
    Altered Expression of Calpastatin by Hypoxia Regulates Trophoblast Cell Function through Mitochondria Associated Endoplasmic Reticulum Membranes.
    Cui Zhang, Jingjing Jiang, Hongfang Kong, Xuyuan Ma, Haiyan Li, Hong Xin.
      Preeclampsia (PE), a severe pregnancy complication, arises from placental hypoxia-induced mitochondrial and endoplasmic reticulum (ER) oxidative stress, contributing to inadequate spiral artery remodeling and endothelial dysfunction. Calpastatin, a mitochondrial protective protein, mitigates oxidative stress-related pathologies, but its role in PE remains unclear. This study investigated the effects of Calpastatin on trophoblast cellular proliferation, migration, invasion, apoptosis, and the expression of autophagy protein (PINK1), mitochondrial dynamics protein (Mfn2), ER stress protein (GRP78), ATP, Ca2+, and mitochondrial membrane potential under hypoxia using transfected HTR8-SVneo cells. Calpastatin overexpression significantly enhanced proliferation, migration, and invasion while reducing apoptosis (P < 0.05); knockdown inversely affected these parameters under normoxic conditions. Under hypoxia, overexpression further amplified proliferation and migration (P < 0.01), whereas knockdown reduced migration at 48 h (P = 0.04) but not proliferation. Invasion decreased and apoptosis increased in both groups (P < 0.05). Calpastatin overexpression upregulated PINK1, downregulated Mfn2/GRP78, increased ATP and mitochondrial membrane potential, and reduced Ca2+. Conversely, knockdown suppressed Pink1/Parkin, elevated Mfn2/Drp1/GRP78, decreased ATP, and increased Ca2+ and mitochondrial depolarization (P < 0.05). These findings demonstrate calpastatin promotes trophoblast function by maintaining mitochondrial-ER contact sites stability and ATP production, Ca2+ homeostasis, and mitophagy mechanism, suggesting its critical role in PE pathogenesis.
    Keywords:  Endoplasmic reticulum; Mitochondria; Oxidative stress; Preeclampsia; Trophoblasts
    DOI:  https://doi.org/10.1007/s43032-025-01995-4
  35. Endocr Connect. 2025 Oct 01. pii: e250090. [Epub ahead of print]14(10):
    KIF23 silencing suppresses papillary thyroid carcinoma metastasis by regulating mitophagy via Wnt/β-catenin pathway.
    Ying Liu, Junping Zhang, Yuhang Chen, Mengya Zhu, Wen Chen, Zejin Hao, Yuanyuan Deng, Xiudan Han, Jixiong Xu.
       Background: Kinesin family member 23 (KIF23) plays a critical role in the regulation of cell division. This study aims to explore the function of KIF23 and its underlying regulatory mechanisms in the progression of papillary thyroid carcinoma (PTC).
    Methods: KIF23 expression was analyzed in PTC and adjacent tissues using RNA sequencing (RNA-Seq) data in The Cancer Genome Atlas (TCGA). Immunohistochemistry (IHC) and quantitative reverse transcription PCR (qRT-PCR) were performed to assess KIF23 expression in PTC tissues and cell lines. A KIF23 knockdown cell line was established to evaluate its effects on cell proliferation and migration via cell counting kit-8 (CCK-8), colony formation, Transwell migration, and wound-healing assays. Western blotting (WB) was used to analyze Wnt/β-catenin signaling and mitophagy markers.
    Results: KIF23 transcript levels were significantly elevated in PTC tissues compared to adjacent normal tissues, correlating with poor progression-free interval. IHC staining confirmed the upregulation of KIF23 in PTC tissues, while qRT-PCR analysis verified the increased mRNA expression of KIF23 in cell lines. KIF23 knockdown reduced cell proliferation, migration, and invasion and decreased levels of Wnt/β-catenin signaling proteins β-catenin (CTNNB1) and c-Myc (MYC) while increasing mitophagy markers Parkin (PRKN), PTEN-induced kinase 1 (PINK1), and LC3B (MAP1LC3B). Wnt agonist treatment reversed these effects, and both the Wnt agonist and the mitophagy inhibitor Mdivi-1 were able to rescue the migratory inhibition caused by KIF23 knockdown.
    Conclusions: KIF23 regulates mitophagy via the Wnt/β-catenin pathway, influencing PTC cell proliferation and migration, suggesting its potential as a therapeutic target for PTC.
    Keywords:   KIF23 ; Wnt/β-catenin; mitophagy; papillary thyroid carcinoma
    DOI:  https://doi.org/10.1530/EC-25-0090
  36. Brain Res Bull. 2025 Oct 28. pii: S0361-9230(25)00421-6. [Epub ahead of print] 111609
    Electroacupuncture Prevents Depression via PINK1/Parkin-Driven Suppression of NLRP3 Activation.
    Zhenhan Li, Jinmoni Huang, Jingyu Zhang, Bowen Tian, Yu Guo, Xi Zhou, Xiang Mao, Zhuxing Wang, Fengwei Tian, Chunyan Gou, Qiujie Mou.
      Although several hypotheses have been proposed to elucidate the etiology of depression, its pathogenesis and effective treatment remain elusive. electroacupuncture (EA), a non-pharmacological therapy, exerts antidepressant effects through promoting the inhibition of immune pathways activation and the release of cytokines. Still, the underlying mechanisms of EA have yet to be fully explored. When it comes to the pathogenesis of depression, various previous studies have demonstrated that neuroinflammation and mitochondrial autophagy hold critical roles. The current study found that EA greatly attenuated the generation of inflammatory factors caused by chronic restraint stress (CRS), such as IL-1β, IL-6, and TNF-α. Notably, EA diminished the levels of the Nod-like receptor (NLR) protein family, pyrin domain containing three (NLRP3) inflammasome and pyroptosis-related proteins, which includes NLRP3, apoptosis-associated speck protein‌ (ASC), and active caspase-1. Further studies showed that an association could be made between this anti-inflammatory effect of EA and the regulation of mitochondrial autophagy. Actually, EA can promote autophagy via the PINK1/Parkin mitochondrial autophagy pathway to enhance the clearance of damaged mitochondria and attenuate NLRP3 inflammasome activation. Our data suggest that EA ameliorates depressive behavior in CRS model rats and inhibits NLRP3 inflammasome activation by promoting mitochondrial autophagy, thereby exerting neuroprotective and antidepressant effects.
    Keywords:  Depression; Electroacupuncture; Mitophagy; Neuroinflammation
    DOI:  https://doi.org/10.1016/j.brainresbull.2025.111609
  37. Curr Biol. 2025 Oct 27. pii: S0960-9822(25)01263-1. [Epub ahead of print]
    Metabolic rewiring prevents neurodegeneration caused by chronic mitochondrial dysfunction.
    Shlesha Richhariya, Daniel Shin, Matthias Schlichting, Michael Rosbash.
      The mitochondrial fission-fusion cycle is often disrupted in neurodegenerative diseases, but this important, dynamic process is not well characterized in healthy long-lived neurons of animals. We used an efficient cell-type-specific CRISPR strategy to knock out key fission and fusion genes in specific Drosophila neurons. Neither process is essential for neuronal survival and function, but the fusion knockouts had a larger impact than that of fission, especially in older animals. Mutations in the human mitochondrial inner membrane fusion gene Opa1 often cause the disease optic atrophy. Importantly, knockout of Opa1 in neurons causes a dramatic age-dependent transcriptomic response. This response resembles those of cancer cells and includes the upregulation of glycolytic genes, including Lactate dehydrogenase (Ldh). A novel double knockout strategy indicates that Ldh enhances the reduced ATP levels of the fusion mutants and is essential to prevent age-dependent neurodegeneration. This neuroprotective upregulation of Ldh is largely mediated by the transcription factor ATF4. The identified relationship-dysfunctional mitochondrial fusion alters metabolism-is reminiscent of Warburg's original cancer hypothesis, albeit in neurons. These data underscore the similarity of the two molecular programs, which promote growth in cancer and viability in the case of neurodegeneration.
    Keywords:  ATF4; CRISPR; Drosophila; Warburg effect; mitochondrial dynamics; neurodegeneration
    DOI:  https://doi.org/10.1016/j.cub.2025.09.063
  38. J Biol Chem. 2025 Oct 27. pii: S0021-9258(25)02712-7. [Epub ahead of print] 110860
    Substrate recognition by the human mitochondrial processing peptidase and its processing of PINK1.
    Andrew N Bayne, Danielle M Simons, Naoto Soya, Karl Grenier, Gergely L Lukacs, Edward A Fon, Jean-François Trempe.
      Nuclear-encoded mitochondrial proteins rely on N-terminal targeting sequences (N-MTS) for their import. Most N-MTSs are cleaved in the matrix by the mitochondrial processing peptidase (MPP), a heterodimeric metalloprotease composed of (α) and catalytic (β) subunits, essential for the maturation of imported proteins. Import and processing of PINK1, a kinase implicated in Parkinson's disease, govern its ability to sense mitochondrial damage. The current paradigm suggests PINK1 undergoes two sequential processing steps: first, MPP removes the PINK1 N-MTS in the matrix; second, the inner mitochondrial membrane protease PARL cleaves the PINK1 transmembrane domain, leading to PINK1 degradation. Upon depolarization, PINK1 escapes proteolysis and accumulates on mitochondria to initiate mitophagy. However, the MPP cleavage site on PINK1, the role of MPP in PINK1 signalling, and the mechanisms of substrate recognition by human MPP remain unclear. Here, we define the MPP cleavage site on PINK1 between Ala28-Tyr29 and show it is inefficiently processed compared to canonical N-MTSs. In cells, MPP cleavage is dispensable for both PARL processing and PINK1 function, decoupling PINK1 import and damage sensing from its N-MTS removal. However, in vitro, the PINK1 N-MTS binds potently to MPP, inhibits the cleavage of other substrates, and traps MPP in a slowly processing complex. Exploiting PINK1 as a mechanistic probe, we use hydrogen-deuterium exchange mass spectrometry to map the PINK1 binding site on MPPα. We identify a two-step mechanism involving MPPα lid rearrangement followed by active site engagement, providing key insight into PINK1's unique import pathway and fundamental MPP processing mechanisms.
    Keywords:  PTEN-induced putative kinase 1 (PINK1); Parkinson disease; hydrogen-deuterium exchange; mitochondria; mitochondrial processing peptidase (MPP); protein import; protein processing
    DOI:  https://doi.org/10.1016/j.jbc.2025.110860
  39. J Immunol. 2025 Oct 29. pii: vkaf277. [Epub ahead of print]
    Edwardsiella piscicida induces largemouth bass PINK1/Parkin-mediated mitophagy for its survival and virulence.
    Xiangyu Pi, Mingzhu Pan, Xuan Wei, Qihuan Zhang, Zhitao Qi.
      PTEN-induced kinase 1 (PINK1)-mediated mitophagy, a classic mechanism underlying the elimination of damaged mitochondria, plays a crucial role in the immune evasion of bacteria. In the present study, we found that Edwardsiella piscicida, an intracellular pathogenic bacterium that infects fish, could induce PINK1-mediated mitophagy to enhance its survival and virulence in largemouth bass (Micropterus salmoides). E. piscicida infection damaged mitochondria in the liver or hepatocytes of largemouth bass and induced PINK1-mediated mitophagy, as confirmed by knockdown of PINK1, transmission electron microscopy, and qPCR analysis. Knockdown of PINK1 decreased the intracellular growth of E. piscicida and lowered the mortality rate of fish infected with E. piscicida. Additionally, qPCR revealed that knockdown of PINK1 increased the production of reactive oxygen species (ROS) and the expression levels of several immune-related genes, including piscidin-1, piscidin-3, TNF-α, TGF-β, and IL-10. Our results suggest that the PINK1-mediated pathway induced by E. piscicida may facilitate the survival of E. piscicida by inhibiting the production of ROS and regulating the expression of immune-related host genes. Our study provides new insights into the mechanism of immune escape of E. piscicida in largemouth bass.
    Keywords:   Edwardsiella piscicida ; PINK1; immune evasion, Micropterus salmoides; mitophagy
    DOI:  https://doi.org/10.1093/jimmun/vkaf277
  40. Nat Commun. 2025 Oct 31. 16(1): 9644
    A special latch in yeast mitofusin guarantees mitochondrial fusion by stabilizing self-assembly.
    Shu-Jing Huang, Dong-Fei Ma, Caiting Yu, Jing Li, Xinyu Tu, Zi Huang, Yuanbo Qi, Jun-Ying Ou, Jian-Xiong Feng, Bing Yu, Yu-Lu Cao, Jia-Xing Yue, Junjie Hu, Ming Li, Ying Lu, Liming Yan, Song Gao.
      The mitochondrion is a highly dynamic organelle, constantly undergoing fusion and fission, which are critical processes for the health of cells. Fusion of the outer mitochondrial membrane (OMM) is mediated by the mitofusins belonging to the dynamin superfamily of GTPases. Most eukaryotic organisms possess two cooperatively functioning mitofusins, but yeast has only one mitofusin (Fzo1). How Fzo1 solely catalyzes OMM fusion is unclear. Here, we present crystal structures of truncated Fzo1 (Fzo1IM) in different nucleotide-loading states and report a special mechanistic feature of Fzo1 through systematic functional studies. Differing from mammalian mitofusins, Fzo1 contains an extra latch bulge (LB) that is essential for the viability of yeast. Upon GTP loading, Fzo1IM dimerizes via the GTPase domain and prefers the closed conformation. This state is then locked by the subsequent trans interaction mediated by the LB of each protomer, so that Fzo1IM remains dimerized in the closed conformation even after GTP hydrolysis. This special mechanistic feature may be relevant to the previous observation that degradation of Fzo1 by the ubiquitin-proteasome system is required for mitochondrial fusion. Our study reveals how mitochondrial fusion in yeast is efficiently ensured with limited GTP consumption, which broadens current understanding of this fundamental biological process.
    DOI:  https://doi.org/10.1038/s41467-025-64646-x
  41. Phytomedicine. 2025 Oct 21. pii: S0944-7113(25)01083-9. [Epub ahead of print]148 157446
    Jiao-tai-wan and its component coptisine attenuate PCOS by regulating mitochondrial cholesterol import through suppression of SIRT1 ubiquitination.
    Hongzhan Wang, Yang Gao, Ping Ma, Xinyue Jiang, Zhi Wang, Yueheng Tang, Hao Su, Xiaohu Xu, Hui Dong.
       BACKGROUND: Polycystic ovary syndrome (PCOS) has emerged as a common endocrine disorder that impacts female reproductive health. The traditional herbal formulation, Jiao-tai-wan (JTW), exhibits multiple biological activities, including improving insulin resistance, reducing oxidative stress, and mitigating inflammation. The clinical efficacy of JTW against PCOS has been reported, however, mechanistic studies remain absent.
    PURPOSE: To clarify the mechanisms behind the therapeutic efficacy of JTW in PCOS.
    METHODS: The PCOS rat model was established by injection of DHEA. The in vivo study consisted of two parts: Part 1 included control, PCOS, low-dose JTW, high-dose JTW, and metformin (Glucophage) groups; Part 2 included control, PCOS, and coptisine groups. The in vitro study utilized primary theca cells. The effects of JTW on ameliorating PCOS phenotypes were assessed. Key pathways were identified via RNA sequencing, and the primary constituents of JTW were identified using UPLC fingerprinting. Further mechanistic investigations were conducted using techniques including network pharmacology, cell transfection, transmission electron microscopy imaging, confocal imaging, co-immunoprecipitation, CETSA, and SPR.
    RESULTS: JTW attenuated abnormal ovulation, sex hormone imbalance, ​​glycolipid metabolism disorders​, and oxidative stress in PCOS rats. RNA sequencing revealed that JTW regulated the ovarian steroidogenesis pathway. Furthermore, JTW regulated mitochondrial dynamics and inhibited ​​StAR localization to the outer mitochondrial membrane in the ovarian theca cells. SIRT1 was identified as the key target of JTW. Coptisine, a component of JTW, reversed abnormal mitochondrial dynamics in theca cells by upregulating SIRT1 expression, which in turn suppressed mitochondrial cholesterol import, thereby alleviating LH-induced aberrant steroidogenesis. Coptisine intervention produced effects similar to SIRT1 overexpression, but SIRT1 knockdown blocked these effects. Notably, coptisine did not alter SIRT1 mRNA levels but enhanced SIRT1 protein expression by suppressing ubiquitination-mediated degradation. Coptisine weakened the interaction between the E3 ubiquitin ligase SMURF2 and SIRT1. Additionally, coptisine exhibited high affinity for SIRT1 (KD = 5.71 μM). Finally, coptisine demonstrated therapeutic effects in PCOS rats.
    CONCLUSION: JTW and its component, coptisine, modulate mitochondrial dynamics by inhibiting SIRT1 ubiquitination to restrict StAR-mediated mitochondrial cholesterol import, thereby normalizing abnormal ovarian steroidogenesis and attenuating PCOS. Furthermore, this study provides novel evidence that coptisine functions as a natural stabilizer of SIRT1 protein.
    Keywords:  Coptisine; Jiao-tai-wan; Ovarian steroidogenesis; Polycystic ovary syndrome; SIRT1; Theca cells
    DOI:  https://doi.org/10.1016/j.phymed.2025.157446
  42. Cancer Genomics Proteomics. 2025 Nov-Dec;22(6):22(6): 971-990
    Rutin Suppresses EMT and Induces Mitochondrial Biogenesis via ER Stress-linked AMPK/SIRT1 Signaling in Prostate Cancer Cells.
    Sih-Han Chen, Richard C Wu, Wei-Lun Huang, Chun-Hsien Wu, Hsing-Chia Mai, Yu-Lin Yang, Pei-Fang Hsieh, Victor C Lin, Chien-Hui Ou.
       BACKGROUND/AIM: Prostate cancer is the second most commonly diagnosed malignancy and a leading cause of cancer-related mortality among men worldwide. While early-stage disease can often be managed effectively, advanced and treatment-resistant forms such as castration-resistant prostate cancer (CRPC) remain a major therapeutic challenge. Novel therapeutic strategies targeting alternative pathways are therefore urgently needed. Rutin, a natural flavonoid abundant in fruits and vegetables, has demonstrated antioxidant and anticancer properties. This study aimed to investigate the anticancer effects of Rutin in prostate cancer cells, focusing on epithelial-mesenchymal transition (EMT), mitochondrial biogenesis, and endoplasmic reticulum (ER) stress-linked signaling.
    MATERIALS AND METHODS: Four prostate cancer cell lines (PC-3, DU-145, LNCaP, and LNCaP-Enz) were treated with rutin. Cell proliferation was assessed, and EMT markers [E-cadherin, α-smooth muscle actin (α-SMA), Snail, Slug], mitochondrial biogenesis-related proteins (AMPK, SIRT1, PGC-1α, NRF1, TFAM), and ER stress markers (BiP, IRE1, PERK, ATF6) were analyzed by standard molecular and cellular assays. Co-treatment with the ER stress inhibitor TUDCA and the eIF2α phosphorylation modulator Salubrinal was performed to determine pathway involvement.
    RESULTS: Rutin significantly suppressed cell proliferation and EMT in all tested prostate cancer cell lines, as indicated by increased E-cadherin expression and decreased α-SMA, Snail, and Slug. It also promoted mitochondrial biogenesis through the up-regulation of AMPK, SIRT1, PGC-1α, NRF1, and TFAM. In parallel, rutin reduced ER stress marker expression, and these effects were reversed by co-treatment with TUDCA or Salubrinal.
    CONCLUSION: Rutin inhibits prostate cancer progression by suppressing EMT, inducing mitochondrial biogenesis, and acting via ER stress-linked AMPK/SIRT1 signaling. These findings suggest that Rutin may serve as a potential therapeutic candidate for advanced prostate cancer.
    Keywords:  AMPK; EMT; ER stress; Rutin; mitochondrial biogenesis; prostate cancer
    DOI:  https://doi.org/10.21873/cgp.20550
  43. Nat Aging. 2025 Oct 31.
    Effect of the mitophagy inducer urolithin A on age-related immune decline: a randomized, placebo-controlled trial.
    Dominic Denk, Anurag Singh, Herbert G Kasler, Davide D'Amico, Julia Rey, Lucía Alcober-Boquet, Johanna M Gorol, Christoph Steup, Ritesh Tiwari, Ryan Kwok, Rafael J Argüello, Julie Faitg, Kathrin Sprinzl, Stefan Zeuzem, Valentina Nekljudova, Sibylle Loibl, Eric Verdin, Chris Rinsch, Florian R Greten.
      Mitochondrial dysfunction and stem cell exhaustion contribute to age-related immune decline, yet clinical interventions targeting immune aging are lacking. Recently, we demonstrated that urolithin A (UA), a mitophagy inducer, expands T memory stem cells (TSCM) and naive T cells in mice. In this randomized, double-blind, placebo-controlled trial, 50 healthy middle-aged adults received oral UA (1,000 mg day-1) or placebo for 4 weeks; time points of analysis were baseline and day 28. Primary outcomes were phenotypical changes in peripheral CD3+ T cell subsets and immune metabolic remodeling. UA expanded peripheral naive-like, less terminally exhausted CD8+ cells (treatment difference 0.50 percentage points; 95% CI = 0.16 to 0.83; P = 0.0437) while also increasing CD8+ fatty acid oxidation capacity (treatment difference = 14.72 percentage points; 95% confidence interval (CI) = 6.46 to 22.99; P = 0.0061). Secondary outcomes included changes in plasma cytokine levels (IL-6, TNF, IL-1β, IL-10), immune populations assessed via flow cytometry, immune cell function, and mitochondrial content. Analysis revealed augmented mitochondrial biogenesis in CD8+ cells, increased peripheral CD56dimCD16bright NK cells, and nonclassical CD14loCD16hi monocytes in UA-treated participants, as well as improved activation-elicited TNF secretion in T cells and bacterial uptake by monocytes. Exploratory single-cell RNA sequencing demonstrated UA-driven transcriptional shifts across immune populations, modulating pathways linked to inflammation and metabolism. These findings indicate that short-term UA supplementation modulates human immune cell composition and function, supporting its potential to counteract age-related immune decline and inflammaging. ClinicalTrials.gov registration number: NCT05735886 .
    DOI:  https://doi.org/10.1038/s43587-025-00996-x
  44. Pathogens. 2025 Oct 16. pii: 1045. [Epub ahead of print]14(10):
    Mitochondrial Dysfunction in Aging, HIV, and Long COVID: Mechanisms and Therapeutic Opportunities.
    María Victoria Delpino, Jorge Quarleri.
      We hypothesize that a unified mitochondrial perspective on aging, HIV, and long COVID reveals shared pathogenic mechanisms and specific therapeutic vulnerabilities that are overlooked when these conditions are treated independently. Mitochondrial dysfunction is increasingly recognized as a common factor driving aging, HIV, and long COVID. Shared mechanisms-including oxidative stress, impaired mitophagy and dynamics, mtDNA damage, and metabolic reprogramming-contribute to ongoing energy failure and chronic inflammation. Recent advancements highlight new therapeutic strategies such as mitochondrial transfer, transplantation, and genome-level correction of mtDNA variants, with early preclinical and clinical studies providing proof-of-concept. This review summarizes current evidence on mitochondrial changes across aging and post-viral syndromes, examines emerging organelle-based therapies, and discusses key challenges related to safety, durability, and translation.
    Keywords:  HIV; SARS-CoV-2; mitochondria
    DOI:  https://doi.org/10.3390/pathogens14101045
  45. Sci Rep. 2025 Oct 30. 15(1): 38045
    SIRT1/PGC-1α/Mfn2 pathway regulates mitochondrial homeostasis in VSMC to attenuate aging-related vascular calcification.
    Chao Wu, Zufei Wu, Long Hu, Long Tang, Xuejun Hu, Cunming Fang.
      Aging-related vascular calcification is closely associated with the development and progression of arterial diseases in elderly patients. Studies have shown that mitochondrial fusion/fission imbalance plays a crucial role in the formation of aging-related vascular calcification, and upregulation of silent information regulator 1 (SIRT1) blocks mitochondrial damage thereby protecting vascular smooth muscle cells (VSMCs). Our study aimed to explore whether SIRT1 can inhibit the vascular calcification and its potential molecular mechanism. VSMCs were used to establish the vascular aging model, and confirmed by β-galactosidase staining. The overexpressed SIRT1 and si-PGC-1α were transfected into VSMCs and verified by RT-qPCR or Western Blot. Proteins relevant to vascular calcification were detected by ELISA, while the level of calcified nodules was stained by Alizarin Red S. The molecules relevant to mitochondrial fusion were detected by RT-qPCR and immunofluorescence. Mito Tracker staining was used to evaluate the mitochondrial membrane potential and morphology. The level of ROS and ATP in VSMCs and its supernatant were detected by reagent kits combined flow cytometry. The levels of β-galactosidase and calcification were higher in the senescent VSMCs compared to normal VSMCs, while mitochondrial membrane potential and fusion and the expression of the SIRT1/PGC-1α/Mfn2 pathway were reduced. Overexpression of SIRT1 promoted its downstream targets PGC-1α and Mfn2 expression and reversed these aging characteristics, inhibited VSMC apoptosis and ROS level while increasing the ATP secretion compared to senescence VSMCs. Knocking down PGC-1α inhibit the function of SIRT1 overexpression on senescence VSMCs. This study presents a novel mechanism to the mitochondria-mediated age-related vascular calcification, and provides the potential molecular targets for the prevention and treatment of arterial diseases in elderly patients.
    Keywords:  Aging; Mitochondrial homeostasis; SIRT1/PGC-1α-ERRα/Mfn2 signaling; Vascular calcification; Vascular smooth muscle cells
    DOI:  https://doi.org/10.1038/s41598-025-21905-7
  46. Int Immunopharmacol. 2025 Oct 30. pii: S1567-5769(25)01711-4. [Epub ahead of print]167 115723
    Urolithin A promotes peripheral nerve regeneration via TFEB-mediated mitophagy and NLRP3 inflammasome suppression.
    Zhe Zhang, Shanying Xiao, Dongbu Tian, Tao Lin, Kongmei Luo, Dong Peng, Yixin Bo, Anhao Guo, Yujie Hu, Long Wu, Hede Yan.
       BACKGROUND: Peripheral nerve injury (PNI) often results in incomplete recovery due to persistent neuroinflammation and mitochondrial dysfunction. Here, we investigated the therapeutic potential of Urolithin A (UA), a gut microbiota-derived metabolite, in promoting nerve regeneration by modulating mitophagy and inflammasome activation.
    OBJECTIVE: To evaluate whether UA enhances peripheral nerve regeneration by activating TFEB-mediated mitophagy and inhibiting NLRP3 inflammasome activation.
    METHODS: In a rat sciatic nerve crush injury model and Schwann cell cultures, UA effects were evaluated using behavioral tests, histological analysis, transmission electron microscopy, immunofluorescence, Western blotting, and molecular docking.
    RESULTS: UA administration significantly improved sciatic functional index, reduced muscle atrophy, and enhanced axonal regeneration and remyelination. Mechanistically, UA promoted transcription factor EB (TFEB) nuclear translocation, upregulated autophagy-lysosomal genes, and facilitated clearance of damaged mitochondria, leading to reduced ROS levels and suppression of NLRP3 inflammasome activation. These effects were abolished by TFEB knockdown or autophagy inhibition, indicating a TFEB-dependent mechanism. Molecular docking suggested direct binding between UA and TFEB.
    CONCLUSION: UA facilitates peripheral nerve repair by coupling TFEB-mediated mitophagy with NLRP3 inflammasome inhibition. This dual action provides a promising non-invasive therapeutic strategy for PNI and warrants further translational research.
    Keywords:  Mitophagy; NLRP3 inflammasome; Peripheral nerve regeneration; Urolithin A
    DOI:  https://doi.org/10.1016/j.intimp.2025.115723
  47. JACS Au. 2025 Oct 27. 5(10): 4695-4705
    Superoxide Anion-Dependent Mitochondrial Fission Contributes to Hippocampal Synaptic Dysfunction in Stress-Susceptible Mice.
    Xiwei Li, Xue Xue, Simiao Zhang, Tony D James, Ping Li, Xin Wang, Bo Tang.
      Reduced synaptic plasticity of hippocampal neurons is a core aspect of depression. Mitochondrial dysfunction affects the synaptic plasticity of neurons. However, the characteristics and molecular mechanisms of mitochondrial dysfunction in hippocampal neurons remain unclear. Oxidative stress observed in depression suggests that excess superoxide anion radical (O2 •-), the first ROS generated in mitochondria, may play crucial roles in mediating mitochondrial damage associated with depression. Unfortunately, current small-molecule fluorescent probes may suffer from diffusion after reacting with O2 •-, thereby limiting the accuracy of studying O2 •-'s biological roles in subcellular structures. Thus, we exploited a fluorescence sensing and labeling strategy for accurately acquiring spatiotemporal information on O2 •-. The fluorescent probe (RB-FM) could react with O2 •-, triggering the generation of a covalent fluorescent label that binds to nearby biological nucleophiles. This action facilitates high-precision in situ imaging of O2 •- during mitochondrial dysfunction. The imaging results demonstrated a reduction in dendritic spine density in hippocampal neurons of stress-susceptible mice, accompanied by a significant increase in mitochondrial O2 •- (mtO2 •-)-dependent mitochondrial peripheral fission. Notably, we found an intriguing form of mitochondrial damage: mitochondrial peripheral fission increased, while total mitochondrial fission and mitophagy were unaffected. We further identified a depression-associated pathological cascade beginning with elevated Ca2+ levels in hippocampal neurons, which triggers mtO2 •--dependent reductions in Coq4 and elevations in Parkin, driving mitochondrial peripheral fission and reducing synaptic plasticity. This work provides a mechanistic framework for O2 •- control of mitochondrial peripheral fission and demonstrates how redox signaling relates to synaptic plasticity in depression.
    Keywords:  depression; fluorescence imaging; mitochondrial fission; superoxide anion
    DOI:  https://doi.org/10.1021/jacsau.5c00493
  48. Brain Res. 2025 Oct 28. pii: S0006-8993(25)00578-5. [Epub ahead of print] 150015
    D-mannose alleviates neurological deficits and inhibits NLRP3 inflammasome activation via the AMPK-mitophagy signaling pathway after traumatic brain injury.
    Haoran Jia, Han Zheng, Xiao Li, Xin Chen, Xilei Liu, Yiyao Cao, Shu Zhang, Jianning Zhang.
      Traumatic brain injury (TBI) represents one of the most common and severe central nervous system (CNS) disorders, contributing significantly to the global health burden However, effective clinical strategies to mitigate TBI-induced secondary damage remain limited. The NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasome plays a pivotal role in secondary neuroinflammation following the primary insult of TBI. D-mannose, a C-2 epimer of glucose and a major monosaccharide component of N-glycans, has recently been reported as a potential therapeutic agent for neurological disorders. Nevertheless, its protective effects against neuroinflammation and neurological deficits after TBI have not been fully elucidated. In this study, we investigated whether D-mannose attenuates secondary injury by suppressing NLRP3 inflammasome activation. Our findings demonstrated that D-mannose treatment significantly reduced neuronal apoptosis and blood-brain barrier (BBB) disruption, while promoting motor function recovery. Furthermore, D-mannose suppressed the activation of pro-inflammatory microglia and neurotoxic astrocytes. Mechanistically, we propose that D-mannose exerts neuroprotection by activating AMP-activated protein kinase (AMPK), thereby promoting mitophagy and suppressing NLRP3 inflammasome activation. D-mannose markedly increased AMPK phosphorylation, enhanced mitophagy, and reduced the expression of NLRP3-related proteins in the peritraumatic cortex. Notably, pharmacological inhibition of AMPK abolished these effects. Collectively, these findings highlight AMPK-mitophagy signaling as a critical pathway through which D-mannose confers neuroprotection after TBI.
    Keywords:  AMPK signaling pathway; D-mannose; Mitophagy; NLRP3 inflammasome; Traumatic brain injury
    DOI:  https://doi.org/10.1016/j.brainres.2025.150015
  49. J Lipid Res. 2025 Oct 28. pii: S0022-2275(25)00193-2. [Epub ahead of print] 100930
    Intrauterine oxygen milieu governs placental sphingolipid metabolism.
    Julien Sallais, Martin Post, Isabella Caniggia.
      Early placentation relies on temporal changes in intrauterine oxygen tension that regulate trophoblast differentiation events. Studies have highlighted the contribution of bioactive sphingolipids to the pathogenesis of placental disorders, characterized by hypoxia. However, it is unknown whether placental sphingolipid metabolism changes during the switch from a hypoxic to an oxygenated environment in the first trimester of gestation and if sustained hypoxia is causative of sphingolipid alterations seen in preeclampsia. Herein, we performed sphingolipid analysis of first-trimester human placentae as well as placentae from conditional (placenta-specific) Phd2 knockout mice (Phd2-/- cKO) that exhibit preeclampsia-like features, including placental hypoxia. Analysis revealed elevated long chain ceramide (Cer16:0, Cer18:0, Cer20:0 and Cer22:0) and reduced sphingosine-1-phosphate (So-1-P) content in Phd2-/- cKO placentae. Expression of key regulatory sphingolipid enzymes, acid ceramidase (ASAH1) and sphingosine kinase 1 (SPHK1), was reduced in Phd2-/- cKO placentae, while that of alkaline ceramidase ACER2 remained unchanged. Human placentae from 5-9 weeks of gestation, when intrauterine oxygen tension is low, exhibited heightened long chain ceramide (Cer14:0, Cer16:0, Cer18:0, Cer 18:1) and sphingosine content and reduced ASAH1and SPHK1 expression, highlighting the relevance of low oxygen in regulating sphingolipid metabolism under physiological (placental development) and pathological (Phd2-/- cKO induced preeclampsia) conditions. Ultrastructural analyses of early (5-9 weeks) human and murine Phd2-/- cKO placentae revealed that increased trophoblast mitochondrial fission events accompanied elevated ceramide. Together, the data support the concept that a chronic low-oxygen environment leads to placental ceramide buildup, which may alter mitochondrial homeostasis and potentially contribute to cell death events characteristic of preeclampsia.
    Keywords:  Placenta; mitochondrial dynamics; oxygen; sphingolipids; trophoblast
    DOI:  https://doi.org/10.1016/j.jlr.2025.100930
  50. iScience. 2025 Oct 17. 28(10): 113563
    Light-evoked activity and BDNF regulate mitochondrial dynamics and mitochondrial localized translation in CNS axons.
    Alexander Kreymerman, Jessica E Weinstein, Nirmal Vadgama, Sahil H Shah, Michael M Nahmou, Kinsley C Belle, Marco H Ji, Xin Xia, Anne Faust, Yolandi Van Der Merwe, David N Buickians, In-Jae Cho, Star K Huynh, Sonya Verma, Kristina Russano, Xiao-Lu Jin, Ioannis Karakikes, Michael B Steketee, Jeffrey L Goldberg.
      Mitochondria coordinate well-described maintenance functions within neuronal axons and dendrites. However, less is known about how mitochondria are regulated during axon development and maturation. Here, we demonstrate that within the developing visual system, retinal ganglion cell (RGC) axons in the retina and optic nerve exhibit increases in mitochondria size, number, and total area in vivo. Our findings indicate that these developmental changes in mitochondria are driven by neuronal activity associated with eye opening and by brain-derived neurotrophic factor (BDNF). These events occur in concert with downstream gene and protein expression changes consistent with mitochondrial biogenesis and energetics pathways. We further demonstrate that activity- and BDNF-regulated transcripts are localized and translated at mitochondria within RGC axons in vivo, concomitant with the regulation of mitochondrial dynamics. These data highlight the previously undescribed regulation of mitochondrial dynamics in axonal maturation, dependent on mechanisms involving neuronal activity and neurotrophic factor signaling, coordinated with mitochondrial-localized translation.
    Keywords:  Biological sciences; Natural sciences; Neuroscience; Systems neuroscience
    DOI:  https://doi.org/10.1016/j.isci.2025.113563
  51. Eur J Med Chem. 2025 Oct 22. pii: S0223-5234(25)01046-3. [Epub ahead of print]302(Pt 1): 118281
    Synthesis of mitochondria-targeted caffeic acid-coumarin fluorescent conjugates to ameliorate inflammation in acute lung injury by protecting mitochondria.
    Yichuan Ran, Yongfu Wang, Chunwei Lv, Yue Zhao, Lifang Zheng.
      Antioxidant supplementation demonstrates significant efficacy in alleviating lung inflammation. Herein, the mitochondria-targeted caffeic acid derivatives were designed and synthesized, aimed to improve the symptoms of acute lung injury. By conjugating phenylacrylic acid skeleton with the fluorophore carrier of coumarin-3-carboxamide using ethylenediamine link, fifteen target compounds were obtained. The structure-activity relationships and calculations of Mulliken charges revealed that the installment of electron-withdrawing groups in the α-position of olefinic bond enhanced anti-inflammatory activity. The potential compound 5d containing a catechol fragment and CF3 group on olefinic bond displayed the highest activities in suppressing the levels of inflammatory factors (NO, TNF-α, IL-6) and attenuating the carrageenan-induced paw edema in rats. Moreover, it localized in mitochondria and protected mitochondria from oxidative and inflammatory insults, including suppressing reactive oxygen species (ROS) level, inhibiting mitochondrial membrane potential collapsing and mitochondrial fragmentation, even enhancing mitophagy and inhibiting NLRP3 inflammasome activation. In vivo, it significantly attenuated lipopolysaccharide-induced acute lung injury. Our study provides evidence that protection mitochondria by phenolic antioxidant will be a promising approach to relieve inflammation response in the lung.
    Keywords:  Acute lung injury; Caffeic acid; Mitochondria-targeted antioxidant; Mitophagy; NLRP3 inflammasome
    DOI:  https://doi.org/10.1016/j.ejmech.2025.118281
  52. Mitochondrion. 2025 Oct 28. pii: S1567-7249(25)00089-3. [Epub ahead of print]86 102092
    In silico analysis of a MicroRNA regulatory network Influencing mitochondrial fission in hepatocellular carcinoma.
    Ali Jawad Akki, Shankargouda V Patil, Nilima Dongre, Prachi Parvatikar.
      MicroRNAs (miRNAs), small non-coding RNA molecules known for their gene regulatory functions, are increasingly recognized to target genes critical for mitochondrial function in hepatocellular carcinoma (HCC). By employing in silico analysis this research investigates the underexplored involvement of a network of microRNAs in regulating mitochondrial fission within the context of HCC. We constructed a novel regulatory network, identifying hsa-miR-138-5p as a central regulator targeting key mitochondrial genes. Furthermore, we identified druggable binding pockets on the transcription factors WDR5 and HNF4, which regulate hsa-miR-138-5p. Molecular docking studies demonstrated favorable binding affinities of FDA-approved HCC drugs (sorafenib, lenvatinib, and regorafenib) to these binding pockets, suggesting an off-target mechanism by which these drugs might influence mitochondrial function through the hsa-miR-138-5p pathway. These findings contribute to the growing understanding of miRNA-mediated regulation in HCC and offer a foundation for developing novel microRNA-targeting drugs to modulate mitochondrial dynamics to manage HCC progression.
    Keywords:  Hepatocellular carcinoma; Mitochondrial dynamics; RNA targeting drugs; microRNA
    DOI:  https://doi.org/10.1016/j.mito.2025.102092
  53. Cancer Genomics Proteomics. 2025 Nov-Dec;22(6):22(6): 1044-1060
    Verbascoside Suppresses Epithelial-Mesenchymal Transition and Mitochondrial Biogenesis by Targeting Anti-senescence Signaling in Castration-resistant Prostate Cancer.
    Hsing-Chia Mai, Pei-Fang Hsieh, Chun-Hsien Wu, Richard C Wu, Sih-Han Chen, Wei-Lun Huang, Mu-Chiao Tung, Yu-Lin Yang, Victor C Lin, Chiang-Ting Wang.
       BACKGROUND/AIM: Verbascoside, a natural phenylethanoid glycoside, has demonstrated significant therapeutic potential in castration-resistant prostate cancer (CRPC). This study aimed to elucidate the mechanistic pathways through which verbascoside exerts its antisenescence and anti-metastatic effects, focusing on epithelial-mesenchymal transition (EMT), oxidative stress response, and mitochondrial biogenesis regulation in CRPC cells.
    MATERIALS AND METHODS: CRPC cell models were treated under various concentrations of verbascoside. EMT markers, oxidative stress-related proteins, mitochondrial biogenesis regulators, and proinflammatory cytokines were assessed using Western blotting and ELISA. Cellular senescence and proliferation were evaluated through analysis of p38 MAPK activation and key cell cycle regulators (p16, p21, p27, and retinoblastoma protein (Rb).
    RESULTS: Verbascoside treatment inhibited EMT, reduced oxidative stress markers, and enhanced mitochondrial biogenesis, supporting cellular energy homeostasis. It also suppressed the secretion of proinflammatory cytokines, including interleukin (IL)-6, IL-8, and IL-1, associated with the senescence-associated secretory phenotype. Downstream signaling analysis revealed that verbascoside decreased p38 MAPK activation and down-regulated p16, p21, p27, and Rb, thereby attenuating prosenescence signaling and proliferation control.
    CONCLUSION: Verbascoside attenuates CRPC progression by modulating EMT, alleviating oxidative damage, enhancing mitochondrial function, and inhibiting prosenescence signaling pathways. These findings highlight its therapeutic potential for targeting senescence-related mechanisms in aggressive prostate cancer and provide a basis for future CRPC management strategies.
    Keywords:  Verbascoside; anti-senescence; castration-resistant prostate cancer; epithelial–mesenchymal transition; mitochondrial biogenesis
    DOI:  https://doi.org/10.21873/cgp.20554
  54. Cell Signal. 2025 Oct 29. pii: S0898-6568(25)00617-5. [Epub ahead of print] 112202
    Sirt3-Bnip3 signaling axis alleviates myocardial ischemia/reperfusion-induced cardiac injury via regulating GSDME.
    Zhiqiang Yin, Xiong Jia, Bin Zhang, Yumei Gong, Qijun Zheng, Linhe Lu.
      Myocardial ischemia/reperfusion (MI/R) injury is a serious complication of myocardial infarction, resulting in acute cardiac dysfunction, arrhythmias, and potentially sudden death. However, the exact mechanisms of MI/R remain unclear. Mitochondrial dysfunction, mediated by mitophagy imbalance, is an important molecular mechanism leading to cardiac dysfunction post-MI/R. The study aims to investigate the roles of the Sirt3-Bnip3 axis and GSDME during MI/R injury. We established MI/R and simulated ischemia/reperfusion (SIR) injury models using male C57BL/6 J mice and H9c2 cells respectively. To regulate the expression of Sirt3, Bnip3 and GSDME, we used adenovirus, activators, inhibitors and small interfering RNA (siRNA). Echocardiography was utilized to assess cardiac function. Western blot was used to determine the levels of protein expression. Our data revealed that Sirt3 and Bnip3 were down regulated after MI/R injury stress. Increasing Sirt3 and Bnip3 expression levels resulted in a reduction of myocardial infarct, apoptosis rate, reactive oxygen species (ROS) production, serum lactate dehydrogenase (LDH), and malondialdehyde (MDA) levels. Further studies revealed that the Sirt3-Bnip3 signaling axis mitigates MI/R injury by inhibiting the activity of the key pyroptosis signal molecule GSDME. The discovery offers a promising target for the treatment of MI/R injury.
    Keywords:  Bnip3; GSDME; Myocardial ischemia/reperfusion (MI/R); Pyroptosis; Sirt3
    DOI:  https://doi.org/10.1016/j.cellsig.2025.112202
  55. Nan Fang Yi Ke Da Xue Xue Bao. 2025 Oct 20. pii: 1673-4254(2025)10-2062-09. [Epub ahead of print]45(10): 2062-2070
    [Salvianolic acid B promotes mitochondrial homeostasis and improves cardiac function in mice with ischemia-reperfusion injury by inhibiting Sirt1 protein degradation].
    Simeng Li, Jianning Chen, Siman Shen, Wanglong Liu, Lili Yu, Liangqing Zhang.
       OBJECTIVES: To investigate the molecular mechanism by which salvianolic acid B (Sal-B) modulates mitochondrial functional homeostasis and alleviates myocardial ischemia-reperfusion (I/R) injury in mice.
    METHODS: Mouse cardiomyocyte HL-1 cells were pretreated with 5 μmol/L Sal-B with or without sh-Sirt1 transfection before exposure to hypoxia-reoxygenation (HR), and the changes in ATP production, mitochondrial superoxide activity, substrate oxidation level were evaluated. In the animal experiment, 36 C57BL/6J mice were randomized into 3 groups (n=12) for sham operation or ligation of the left anterior coronary artery to induce myocardial I/R injury with or without intravenous injection of Sal-B+I/R (50 mg/kg). In the rescue experiment, 60 adult C57BL/6J mice were randomized into 5 groups (n=12): sham-operated group, myocardial I/R group, Sal-B+I/R group, I/R+Sal-B+Sirt1fl/fl group, and I/R+Sal-B+cKO-Sirt1 group. Myocardial injury was evaluated with HE staining, and cardiac function was assessed by measurement of the ejection fraction and fractional shortening using echocardiography.
    RESULTS: In HL-1 cells with HR injury, Sal-B pretreatment significantly increased cellular ATP production, reduced mitochondrial superoxide anion levels, and enhanced oxygen consumption level. In the mouse models of myocardial I/R injury, Sal-B pretreatment markedly ameliorated I/R-induced structural disarray of the cardiac myocytes and improved cardiac ejection. Cycloheximide chase with Western blotting and ubiquitination assays after Sirt1-IP showed that Sal-B significantly inhibited Sirt1 degradation in HL-1 cells. Sirt1 knock-down reversed Sal-B-induced increases in ATP production, reduction in superoxide, and elevation of OCR in HL-1 cells. Cardiomyocyte-specific Sirt1 knockout obviously reversed Sal-B-mediated improvement in cardiac ejection function and myocardial structure damage in mice with myocardial I/R injury.
    CONCLUSIONS: Sal-B promotes mitochondrial functional homeostasis in cardiomyocytes with HR injury and improves cardiac function in mice after myocardial I/R by inhibiting Sirt1 protein degradation.
    Keywords:  Sirt1; heart; mitochondrial homeostasis; myocardial ischemia-reperfusion injury; salvianolic acid B
    DOI:  https://doi.org/10.12122/j.issn.1673-4254.2025.10.02
  56. Biochim Biophys Acta Mol Cell Res. 2025 Oct 27. pii: S0167-4889(25)00178-8. [Epub ahead of print] 120073
    Hotspot mutant p53-R273H enhances mitochondrial biogenesis and cell migration in primary colorectal cancer in response to oxaliplatin.
    Toni Martinez-Bernabe, Pere Miquel Morla-Barcelo, Alessandra Fiore, Massimo Donadelli, Pilar Roca, Jordi Oliver, Jorge Sastre-Serra, Daniel G Pons.
      Oxaliplatin is commonly known as a successful chemotherapy for advanced colorectal cancer, improving patient survival and eradicating micro-metastases, but its use in early stages remains controversial. Mitochondria fuel energy-intensive programs such as cell migration, yet how oxaliplatin regulates the mitochondrial network in CRC - and how TP53 context shapes this - remains unclear. We investigated a matched pair of CRC cell lines from the same patient - SW480 (primary) and SW620 (lymph-node metastasis) - both harboring TP53-R273H mutation, to define differential responses in mitochondrial biogenesis, dynamics and respiration and the mechanisms underlying them. The results indicate that primary-derived colorectal cancer cell line increased cell migration, mitochondrial biogenesis, and mitochondrial respiration capacity in response to oxaliplatin through a new and firstly described gain-of-function (GOF) of p53-R273H. Additionally, in the primary-derived CRC line, oxaliplatin elicited fate heterogeneity - coexisting apoptotic and senescent fractions alongside an R273H-driven, bioenergetically primed migratory subpopulation - together with increased mitochondrial biogenesis and respiratory capacity; by contrast, the metastatic-derived line was more sensitive and displayed structural mitochondrial injury with reduced maximal respiration. More broadly, this work underscores the importance of p53 gain-of-function mutations in CRC: the same GOF (TP53-R273H) amplifies cell migration by coupling an enhanced mitochondrial biogenesis/OXPHOS program to motility. Oxaliplatin further accentuates this energetically primed, pre-metastatic state, arguing for mitochondrial-targeted combination strategies in early-stage CRC.
    Keywords:  Cell migration; Colorectal cancer; Metabolic shift; Oxaliplatin; p53-R273H
    DOI:  https://doi.org/10.1016/j.bbamcr.2025.120073
  57. Stem Cell Res Ther. 2025 Oct 31. 16(1): 599
    L-Glutamate enables the EGFR-MEK-ERK-mTFB2 axis to enhance mitochondrial biogenesis in intestinal stem cells.
    Cai-Xia Dou, Hao-Zhan Qu, Ying-Chao Qin, Xiao-Fan Wang, Jia-Yi Zhou, Xiu-Qi Wang, Hui-Chao Yan.
       BACKGROUND: Intestinal stem cells (ISCs) sustain epithelial homeostasis through rapid mitochondrial metabolism, however, how they sense nutrient signals to regulate mitochondrial function remains unclear.
    METHODS: We examined the role of L-glutamate (Glu) in regulating cell mitochondrial biosynthesis using in vivo piglets, ex vivo porcine intestinal organoids (IOs), and in vitro IPEC-J2 cells.
    RESULTS: Glu enhanced jejunal development in weaned piglets. Isobaric tags for relative and absolute quantitation (iTRAQ) analysis revealed the significant enrichment of mitochondrial functions and activation of EGFR-MEK-ERK-mTFB2 signaling pathway in the jejunum. In vitro, 5 mM Glu promotes mitochondrial biosynthesis and potentiates the EGFR-MEK-ERK-mTFB2 axis. Whereas inhibition of EGFR with Osimertinib and silencing EGFR abolished these effects in IOs and IPEC-J2 cells. Colocalization and biochemical studies demonstrated interaction between Glu and EGFR in IOs.
    CONCLUSIONS: Glu promotes mitochondrial biogenesis and ISC expansion by activating the EGFR-MEK-ERK-mTFB2 axis, highlighting a nutrient-sensing mechanism that couples energy availability to ISC function.
    DOI:  https://doi.org/10.1186/s13287-025-04718-3
  58. Biochem Pharmacol. 2025 Oct 29. pii: S0006-2952(25)00752-X. [Epub ahead of print] 117487
    Hyperuricemia exacerbates acetaminophen hepatotoxicity via JNK activation and mitophagy reduction.
    Yan Liu, Baizhao Peng, Dexian Li, Jie Chen, Yigui Lai, Yanting You, Zihao Jiang, Xinghong Zhou, Chuanghai Wu, Liqian Chen, Hiu Yee Kwan, Lin Yu, Daming Zuo, Xiaoshan Zhao.
      Acetaminophen (APAP) induced hepatotoxicity represents a classic form of drug-related liver injury and ranks among the most prevalent causes of acute liver failure globally. Underlying diseases can increase the risk factor of liver injury induced by APAP overdose. Hyperuricemia (HUA), a condition defined by an abnormally high serum uric acid (UA) concentration, is a recognized risk factor for various health conditions, such as gout, cardiovascular disease, metabolic syndrome, and chronic kidney disease. Additionally, HUA is also associated with liver disease, such as non-alcoholic fatty liver and hepatocellular carcinoma. However, the safe dosage of APAP for patients with HUA and the role of HUA in APAP-induced hepatotoxicity remain unclear. This study of a cohort derived from the UK Biobank showed that participants with long-term APAP intake had a 1.26(1.02-1.58) higher odds of developing liver failure than the control group. Importantly, people with HUA had a 1.44(1.12-1.84) higher odds, and those with HUA at baseline had a 1.66(1.06-2.61) higher odds of progressing to liver failure than those with normal UA. Furthermore, our data showed that HUA rats showed more severe hepatic necrosis and liver dysfunction than control rats following APAP injection. Mechanistic investigations revealed that HUA activated c-Jun N-terminal kinase (JNK) and reduced mitophagy to aggravate APAP-induced hepatocyte death. Taken together, this study indicates that HUA is a potential risk factor for APAP-induced hepatic injury, exacerbating hepatic cell death through JNK pathway activation and the suppression of mitophagy. These findings offer important insights for guiding APAP administration in patients with HUA.
    Keywords:  Acetaminophen-induced hepatotoxicity; C-Jun N-terminal kinase; Hyperuricemia; Mitophagy; Reactive oxygen species
    DOI:  https://doi.org/10.1016/j.bcp.2025.117487
  59. J Chem Inf Model. 2025 Oct 31.
    Dynamic Coupling between Tom22 Motions and Tom40 Pore Dynamics Modulates Ion Transport in the Mitochondrial TOM Complex.
    Abhishek Acharya, Stephan Nussberger, Shuo Wang, Ulrich Kleinekathöfer.
      Mitochondria rely on the efficient import of proteins to maintain their functions and regenerate. The translocase of the outer mitochondrial membrane (TOM) complex serves as the primary entry point for the import of mitochondrial proteins. Previous studies have established Tom22 as a multifunctional subunit within the complex and reported mechanosensitive gating-like behavior of the TOM complex. In this study, all-atom molecular dynamics simulations of the TOM core complex reveal large motions of the Tom22 helices that are coupled to global structural rearrangements within the complex, particularly with the α2 helix within the Tom40 pore subunit. Microseconds-long simulations with restraints on the Tom22 helices yield an alternative conformation of the α2 helix that is associated with a reduced ion permeability. The outcome corroborates previous experimental results that reported a reduction in calcium ion flux for transiently stalled TOM complexes. These findings provide a molecular view of a mechanism by which Tom22 modulates the pore architecture of Tom40 and regulates permeability, thus linking the receptor dynamics to the functional control of the mitochondrial protein import.
    DOI:  https://doi.org/10.1021/acs.jcim.5c01761
  60. Int J Mol Sci. 2025 Oct 11. pii: 9885. [Epub ahead of print]26(20):
    Mechanisms of Mitochondrial Impairment by SARS-CoV-2 Proteins: A Nexus of Pathogenesis with Significant Biochemical and Clinical Implications.
    Marco Refrigeri, Alessandra Tola, Rosangela Mogavero, Maria Michela Pietracupa, Giulia Gionta, Roberto Scatena.
      Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) closely interacts with host cellular mechanisms, with mitochondria playing a crucial role in this process. As essential organelles that control cellular energy production, apoptosis, reactive oxygen species (ROS) metabolism, and innate immune responses, mitochondria are vital to the development of COVID-19. However, the exact molecular interactions between mitochondria and SARS-CoV-2 remain under active investigation. Gaining a comprehensive understanding of mitochondrial involvement in SARS-CoV-2 infection is therefore essential for uncovering complex disease mechanisms, identifying prognostic biomarkers, and developing effective treatments. Ultimately, exploring these virus-host interactions may provide new insights into the fundamental and complex aspects of mitochondrial physiology and pathophysiology.
    Keywords:  ROS; SARS-CoV-2; biomarkers; diagnosis; inflammasome activation (e.g., NLRP3); interactoma; long COVID; mitochondria; mitochondrial antiviral signaling (MAVS); mitochondrial bioenergetics; mitochondrial damage-associated molecular patterns (mtDAMPs); mitochondrial disease; mitochondrial fission/fusion dynamics; mitophagy; oxidative phosphorylation; oxidative stress; prognosis; viral immune evasion
    DOI:  https://doi.org/10.3390/ijms26209885
  61. Int J Mol Sci. 2025 Oct 11. pii: 9900. [Epub ahead of print]26(20):
    microRNA-22 Inhibition Stimulates Mitochondrial Homeostasis and Intracellular Degradation Pathways to Prevent Muscle Wasting.
    Simone Tomasini, Emanuele Monteleone, Anna Altieri, Francesco Margiotta, Fereshteh Dardmeh, Hiva Alipour, Anja Holm, Sakari Kauppinen, Riccardo Panella.
      MicroRNA-22 (miR-22) is a negative regulator of mitochondrial biogenesis, as well as lipid and glucose metabolism, in metabolically active tissues. Silencing miR-22 holds promise as a potential treatment of obesity and metabolic syndrome, as it restores metabolic capacity-enhancing oxidative metabolism-and reduces ectopic fat accumulation in chronic obesity, a driver of impaired metabolic flexibility and muscle mass loss. Intramuscular adipose accumulation and defective mitochondrial function are features associated with obese-mediated muscle atrophy and hallmarks of neuromuscular disorders such as Duchenne muscular dystrophy. Therefore, miR-22 could represent a compelling molecular target to improve muscle health across various muscle-wasting conditions. This study describes a pharmacological strategy for the inhibition of miR-22 in skeletal muscle by employing a mixmer antisense oligonucleotide (ASO, anti-miR-22). Administration of the ASO in a mouse model of obesity positively modulated myogenesis while protecting dystrophic mice from muscle function decline, enhancing fatigue resistance, and limiting pathological fibrotic remodeling. Mechanistically, we show that anti-miR-22 treatment promotes derepression of genes involved in mitochondrial homeostasis, favoring oxidative fiber content regardless of the disease model, thus promoting a more resilient phenotype. Furthermore, we suggest that miR-22 inhibition increases autophagy by transcriptional activation of multiple negative regulators of mammalian target of rapamycin (mTOR) signaling to decrease immune infiltration and fibrosis. These findings position miR-22 as a promising therapeutic target for muscle atrophy and support its potential to restore muscle health.
    Keywords:  ASO; DMD; antimiRs; autophagy; fibrosis; miR-22; miRNA therapeutics; microRNA; muscle atrophy; oxidative metabolism
    DOI:  https://doi.org/10.3390/ijms26209900
  62. Cell Metab. 2025 Oct 24. pii: S1550-4131(25)00395-X. [Epub ahead of print]
    Quercetin-derived microbial metabolite DOPAC potentiates CD8+ T cell anti-tumor immunity via NRF2-mediated mitophagy.
    Penghu Han, Shuzheng Chu, Jing Shen, Lixiang Li, Yan Zhang, Shiguan Wang, Yatai Chen, Yangchun Ma, Xiaolong Tang, Chao Gao, Xiangyun Zheng, Bowen Xu, Qiong Wang, Detian Yuan, Shiyang Li.
      Quercetin, a dietary flavonol, shows promise in cancer prevention, though its effects on the immune compartment within the tumor microenvironment are not fully understood. Here, we identify 3,4-dihydroxyphenylacetic acid (DOPAC), a microbial metabolite of quercetin, as a critical mediator of its anti-tumor effects in a CD8+ T cell-dependent manner. Mechanistically, DOPAC directly binds to Kelch-like epichlorohydrin-associated protein 1 (KEAP1), disrupting its interaction with nuclear factor erythroid 2-related factor 2 (NRF2) and preventing KEAP1-mediated degradation of NRF2 in CD8+ T cells. Elevated NRF2 transcriptionally enhances the expression of B cell lymphoma 2-interacting protein 3, promoting mitophagy and mitochondrial functionality, which improves CD8+ T cell fitness within the tumor microenvironment. Furthermore, DOPAC synergizes with immune checkpoint blockade to suppress tumor growth. Our findings underscore the role of microbial metabolites of dietary nutrients in modulating anti-tumor immune responses, positioning DOPAC as a promising candidate for cancer immunotherapy.
    Keywords:  BNIP3; CD8(+) T cells; DOPAC; NRF2; anti-tumor immunity; microbiota; mitophgagy; quercetin
    DOI:  https://doi.org/10.1016/j.cmet.2025.09.010
  63. Free Radic Biol Med. 2025 Oct 23. pii: S0891-5849(25)01299-7. [Epub ahead of print]
    V8, a lysosomotropic wogonin derivative, alleviates hepatic steatosis by modulating GDF15-dependent mitochondrial homeostasis.
    Sichan Li, Shunzi Shao, Zhaokun Zhang, Zhuo Wang, Xiaolei Han, Xiaoqian Jia, Hongxin Zhang, Yuan Gao, Xiaobo Zhang.
      Metabolic dysfunction-associated steatotic liver disease (MASLD) has become a global epidemic, leading to an unmet medical need for pharmacological interventions. This study aims to investigate the protective effect and mechanism of a synthetic wogonin derivate V8 against hepatic steatosis. Herein, we report that V8 attenuates lipid accumulation and prevents mitochondrial dysfunction in hepatocytes. Growth differentiation factor 15 (GDF15), a well-known cytokine with powerful metabolic action, mediates the effect of V8 on lipid metabolic disorders. Mechanistically, due to its lysosomotropic property, V8 promotes nuclear translocation of transcription factor EB (TFEB) and subsequent GDF15 gene transcription through activating adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK). Further analysis demonstrates GDF15 mainly improves mitochondrial homeostasis under stressful condition. Consistently, Gdf15 ablation in mice results in aggravated hepatic lipid deposition and liver injury upon high-fat diet feeding. Moreover, V8 alleviates diet-induced hepatic steatosis in a GDF15-dependent manner, and improves toxins-induced hepatic pathological phenotypes accompanying with upregulation of GDF15. Collectively, these data demonstrate the beneficial metabolic effect of V8 and highlight its utility in treating hepatic steatosis and its associated metabolic complications.
    Keywords:  AMPK; GDF15; TFEB; lysosome; steatosis
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.10.274
  64. Phytomedicine. 2025 Oct 21. pii: S0944-7113(25)01070-0. [Epub ahead of print]148 157433
    Fufang Danshen Pill improves mitochondrial homeostasis by regulating the S100a9/TLR4 axis to alleviate myocardial ischemia-reperfusion injury.
    Ruixia Lu, Wenhao Sun, Wenyong Lin, Siyue Zhu, Dongyuan Wang, Qipeng Jin, Dan Wang, Zhenchi Sang, Xiaolong Wang.
       BACKGROUND: S100a9 protein participates in regulating mitochondrial damage during Myocardial ischemia-reperfusion injury(I/R), but its cell type-specific mechanisms remain unclear. Fufang Danshen Pill (FDP), a traditional Chinese medicine for I/R treatment, requires further investigation to elucidate its therapeutic targets.
    PURPOSE: Investigate the macrophage-specific role of S100a9 in I/R pathogenesis, and clarifies the molecular pathways through which FDP improves mitochondrial function by modulating S100a9.
    METHODS: The murine I/R model was established and subjected to determine the optimal therapeutic dosage of FDP. By integrating Single-cell transcriptomics(scRNA-seq)with spatial transcriptomics, we conducted comprehensive analyses of myocardial tissues from sham, I/R, and FDP groups, including cellular subtyping, intercellular communication analysis, and spatial transcriptomic mapping. Mechanistic validation was performed using Adeno-associated virus serotype 2/9(AAV2/9)-mediated macrophage-specific S100a9 overexpression models to confirm key regulatory targets.
    RESULTS: The medium-dose FDP (122.85 mg/kg) exhibited the best efficacy in improving cardiac function. FDP intervention markedly attenuated macrophage-cardiomyocyte cellular crosstalk. In I/R models, cardiomyocytes displayed significant alterations in mitochondrial-associated gene expression, whereas S100a9 emerged as the predominant differentially expressed gene in macrophages. Spatial transcriptomic mapping localized S100a9 predominantly within myocardial injury regions. Functional investigations revealed that AAV2/9-mediated macrophage-specific S100a9 overexpression exacerbated I/R pathological manifestations, including increased infarct size, reduced ejection fraction, elevated serum cardiac troponin levels, TLR4 signaling activation, and mitochondrial dysfunction. Notably, FDP treatment substantially reversed these pathological alterations.
    CONCLUSION: This study demonstrates that macrophage-derived S100a9 mediates mitochondrial damage in cardiomyocytes during I/R injury. FDP effectively maintains mitochondrial functional homeostasis in cardiomyocytes by targeting and inhibiting macrophage S100a9 expression. These findings provide a important scientific basis for developing intervention strategies targeting the S100a9/TLR4 axis.
    Keywords:  Fufang Danshen Pill; I/R injury; Mitochondrial activity; S100a9; Single-cell transcriptomics sequencing; Spatial transcriptomics sequencing
    DOI:  https://doi.org/10.1016/j.phymed.2025.157433
  65. Biomedicines. 2025 Oct 14. pii: 2501. [Epub ahead of print]13(10):
    Correction: Zhang et al. An Integrated Approach Utilizing Single-Cell and Bulk RNA-Sequencing for the Identification of a Mitophagy-Associated Genes Signature: Implications for Prognostication and Therapeutic Stratification in Prostate Cancer. Biomedicines 2025, 13, 311.
    Yuke Zhang, Li Ding, Zhijin Zhang, Liliang Shen, Yadong Guo, Wentao Zhang, Yang Yu, Zhuoran Gu, Ji Liu, Aimaitiaji Kadier, Jiang Geng, Shiyu Mao, Xudong Yao.
      References [...].
    DOI:  https://doi.org/10.3390/biomedicines13102501
  66. Nat Immunol. 2025 Oct 29.
    Cancer suppresses mitochondrial chaperone activity in macrophages to drive immune evasion.
    Haoxin Zhao, Jaeoh Park, Yuzhu Wang, Yi-Ju Chou, Lemin Li, Lydia N Raines, Michael Hsu, Ching-Cheng Lin, Wei Cao, Yuli Ouyang, Heng-Yi Chen, Linghua Zheng, Zihai Li, Alex Y Huang, Ping-Chih Ho, Chan-Wang Jerry Lio, Stanley Ching-Cheng Huang.
      Contrary to tumor-infiltrating T cells with dysfunctional mitochondria, tumor-associated macrophages (TAMs) preserve their mitochondrial activity in the nutrient-limited tumor microenvironment (TME) to sustain immunosuppression. Here we identify TNF receptor-associated protein-1 (TRAP1), a mitochondrial HSP90 chaperone, as a metabolic checkpoint that restrains oxidative respiration and limits macrophage suppressive function. In the TME, TRAP1 is downregulated through TIM4-AMPK signaling, and its loss enhances immunoinhibitory activity, limits proinflammatory capacity and promotes tumor immune escape. Mechanistically, TRAP1 suppression augments electron transport chain activity and elevates the α-ketoglutarate/succinate ratio, remodeling mitochondrial homeostasis. The resulting accumulation of α-ketoglutarate further potentiates JMJD3-mediated histone demethylation, establishing transcriptional programs that reinforce an immunosuppressive state. Restoring TRAP1 by targeting TIM4 and JMJD3 reprograms TAMs, disrupts the immune-evasive TME and bolsters antitumor immunity. These findings establish TRAP1 as a critical regulator integrating metabolic and epigenetic control of suppressive TAM function and position the TRAP1 pathway as a promising target for cancer immunotherapy.
    DOI:  https://doi.org/10.1038/s41590-025-02324-2
  67. BBA Adv. 2025 ;8 100171
    VDAC1 inhibitor DIDS uncouples respiration in isolated tissue mitochondria and induces mitochondrial hyperfusion in mammalian cells.
    Surajit Das, Arpita Dutta, Minakshi Bedi, Arumay Pal, Shubhra Majumder, Alok Ghosh.
      Mitochondrial outer membrane protein, voltage-dependent anion channel 1 (VDAC1), is a gatekeeper of transport, metabolism, and cellular apoptosis. Ablation of VDAC1 or treatment with small molecular VDAC1 inhibitors often causes metabolic reprogramming in cells. However, the mechanism of VDAC1-mediated reprogramming of mitochondrial oxidative phosphorylation (OXPHOS) is still unclear. To address this problem, we tested how the high-affinity VDAC1 inhibitor, 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS), changes cell viability and mitochondrial functions. The IC50 value of DIDS was found 508 µM and 580 µM after 24 h of treatment on human osteosarcoma U2OS and mouse NIH-3T3 fibroblast cells. Moreover, when we inhibited mitochondrial OXPHOS by oligomycin A, 500 µM DIDS was found to uncouple the respiration like the conventional uncoupler CCCP in both the cells. Additionally, we observed that 50-200 µM DIDS, even after 2 h of treatment, depolarizes mitochondrial membrane potential. Also, brief DIDS treatment leads to an increase in cell population with hyperfused mitochondria and attenuation of DRP1 recruitment to mitochondria in U2OS cells. However, no significant alteration in the steady-state level of mitochondrial respiratory chain complex I and complex V subunits was noticed after DIDS treatment. Similar to cell lines, DIDS treatment also showed significant respiratory uncoupling in isolated mitochondria prepared from the normal muscle, liver, and sarcoma tumor tissues of mice. Finally, in silico modeling using AutoDock Vina and AlphaFold3 identified that DIDS binds inside the beta-barrel structure of VDAC1. Together, our findings directly demonstrate that DIDS binds to the VDAC1 inner pocket, uncouples OXPHOS, and promotes mitochondrial hyperfusion.
    Keywords:  DIDS; Mitochondrial dynamics; OXPHOS; Uncoupling; VDAC1; mitochondria
    DOI:  https://doi.org/10.1016/j.bbadva.2025.100171
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