bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2026–07–19
68 papers selected by
Gavin McStay, Liverpool John Moores University
  1. Mitochondrial Dynamics as Determinants of Cancer Drug Resistance: A Systematic Review.
  2. A biomimetic mesenchymal stem cell membrane-coated nanodelivery system attenuates cardiac fibrosis by restoring mitochondrial homeostasis.
  3. Retraction: HSP72 interacts with PRDX6 to deubiquitinate mitochondrial PINK1, activating mitophagy to treat MASLD.
  4. Redox-dependent mitochondrial dynamics: PLK1 couples glutathione metabolism to ROS-driven JNK and DUSP6 pathways in colorectal cancer.
  5. Microglial mitophagy as an immunometabolic checkpoint in alzheimer's disease: linking mitochondrial quality control to neuroinflammation.
  6. RNF10 deficiency in cardiomyocytes impairs mitophagy and drives pathological hypertrophy.
  7. Involvement of Mitophagy in Endothelin-1 Mediated Neurodegeneration in Rodent Models of Glaucoma.
  8. Mitochondrial dynamics imbalance in hepatocellular carcinoma: from molecular mechanisms to new strategies for targeted therapy.
  9. Mitochondrial dynamics and metabolic regulation in cellular inflammation: From mechanisms to precision therapeutics.
  10. Astragaloside IV Attenuates Atherosclerosis By Regulating Endothelial Mitophagy And Oxidative Stress Via The Nrf2/PINK1/Parkin Pathway.
  11. Interpretable single-cell machine learning identifies PINK1-centred mitophagy as a determinant of metabolic fitness in type 2 diabetes.
  12. Polydatin improves mitochondrial dynamics dysrhythmia by regulating BMAL1 to prevent and treat metabolic dysfunction-associated fatty liver disease.
  13. cPKCγ facilitates the apoptosis of mouse GC-1 spg cells by regulating the mitophagy via inhibiting the UCHL1/HIF‑1α axis.
  14. Single-cell mitophagy patterns dictate intercellular crosstalk in the tumor microenvironment to promote osteosarcoma progression.
  15. Stress Induced Mitochondrial Hyperfusion (SIMH): A Concise Review on SIMH in Neurodegenerative Disorders and Other Diseases.
  16. Fenofibrate attenuates cisplatin-induced nephrotoxicity in rats by restoring mitochondrial dynamics and improving fatty acid oxidation.
  17. Impaired Renal Mitochondria and Bioenergetics During Obesity-Associated NAFLD.
  18. Docosahexaenoic acid attenuates cisplatin nephrotoxicity by restoring mitophagy.
  19. Mitochondrial calcium uniporter-mediated mitochondrial dynamics imbalance contributes to contrast medium-induced renal tubular cell injury.
  20. Asprosin Protects H9C2 Cells From Ferroptosis Following Hypoxia/Reoxygenation by Promoting Mitophagy.
  21. Dual-faced metabolic reprogramming powers proliferation: FGF21 drives lung squamous carcinoma progression via CaMKII-DRP1-mediated mitochondrial fission.
  22. Therapeutic intervention with sinomenine and irisin to preserve cardiac function after ischaemia-reperfusion injury.
  23. Biallelic hexose-6-phosphate dehydrogenase variants cause mitochondrial dysfunction underlying Parkinson's disease.
  24. Reactivation of DRP1 plays a functional role in resistance to MEK inhibition in pancreatic cancer cells.
  25. Spatial Transcriptomic Atlas Reveals That Forkhead Box O3-Mediated Mitochondrial Dynamics Imbalance Drives Premature Ovarian Insufficiency in Mice.
  26. LPS‑induced impairment of neuroregeneration is alleviated by fluoxetine in Dugesia japonica.
  27. Network Destabilization in Aging: Mitochondrial Dysfunction, Nutrient Sensing, and Chronic Inflammation as Interconnected Drivers.
  28. Grx attenuates diabetes cataract by activating AMPK/BNIP3/BNIP3L-mediated mitophagy in lens epithelial cells.
  29. [Effect of eye acupuncture on mitophagy in neurons of ischemic cortical brain tissue in rats with cerebral ischemia reperfusion injury based on AMPK/ULK1/FUNDC1 signaling axis].
  30. Guizhi Wuling Decoction alleviates myocardial fibrosis by restoring mitochondrial homeostasis: Evidence from network pharmacology, molecular docking, and multi-omics integration.
  31. Rewiring Lipid Metabolism: PINK1 as a Central Regulator of Mitochondrial Homeostasis in Parkinson's Disease.
  32. Metformin triggers ATF4-mediated UPRmt and COX-2 inflammation in adipocytes.
  33. The mtROS-Mitophagy Axis: A Decisive Redox Hub Governing Cell Fate in Myocardial Ischemia-Reperfusion Injury.
  34. Kaempferide in Alpinia officinarum Hance Exerts Anti-Hepatocellular Carcinoma Activity by Inhibiting Mitophagy Through Downregulation of BNIP3L.
  35. Mitophagy deficiency and calcium dyshomeostasis underlying the pathogenesis and progression of Alzheimer's disease.
  36. TBX20 promotes doxorubicin resistance in breast cancer cells through enhanced ABCC1 expression and inhibition of mitophagy.
  37. Pathogenic DRP1 variants reveal a role for biomolecular condensation in mitochondrial fission.
  38. Tissue-specific consequences of impaired RNA surveillance converge on mitochondrial homeostasis.
  39. Urolithin A enhances mitochondrial biogenesis-related markers and maximal respiratory capacity during C2C12 differentiation.
  40. Corrigendum to"Downregulation of Nrf2 deteriorates cognitive impairment in APP/PS1 mice by inhibiting mitochondrial biogenesis through the PPARγ/PGC1α signaling pathway" [Behavioural Brain Res. 495 (2025) 115805].
  41. Layered double hydroxide nanocarriers loaded with butylphthalide attenuate the AKI-CKD transition by regulating mitophagy.
  42. Exendin-4 improves high glucose-induced mitochondrial dysfunction of pancreatic β-cells via PKA/Drp1 signaling.
  43. LKB1/ AMPK deficiency aggravates mitochondrial DNA leakage via mTOR-dependent mitophagy damage in liver injury sensitized by trichloroethylene.
  44. Coffee as a polypharmacological modulator of mitochondrial health: from molecular mechanisms to translational implications.
  45. Regulation of mitochondrial biogenesis by the 5-HT1F receptor and its agonist in inferior spinal cords after spinal cord injury.
  46. Molecular Mechanisms of Photobiomodulation in Retinal Diseases: Cytochrome c Oxidase, Mitochondrial Bioenergetics and Cytoprotective Signalling.
  47. A Multitarget Nanosystem Loaded with Donepezil for Alzheimer's Disease Treatment by Activating Mitophagy and Reshaping the Inflammatory Microenvironment.
  48. Mitochondrial Immunometabolism in Sepsis: From Oxidative Stress and mtDAMP Signaling to Biomarker-Guided Therapy.
  49. Salvianolic Acid A Inhibits Ferroptosis in Endothelial Cells and the Progression of Atherosclerosis by Augmenting the Mitochondrial Homeostasis Pathway Associated With Adiponectin Receptor 1.
  50. Targeting Mitochondrial Dynamics in VEGFR-TKI Hypertension and Cardiotoxicity.
  51. Discovery of a mitochondria-targeted propranolol conjugate PL37 that induces mitophagy for potent anti-hemangioma activity.
  52. Dracocephalum moldavica L. Flavonoids Alleviate Doxorubicin-Induced Cardiotoxicity by Activating the AMPK/PGC1αPathway to Preserve Mitochondrial Homeostasis.
  53. METTL5-mediated rRNA modification controls prostate cancer progression through the IRF7/DNA2 axis and mitophagy regulation.
  54. Time-dependent effects of hypoxia on mitochondrial dynamics, dysfunction and apoptosis in C8-D1A astrocytes.
  55. Mitochondria Clearance Enables Macrophage-Driven Maturation of iPSC-Derived Cardiomyocyte Metabolism.
  56. [Retracted] Resveratrol attenuates type 2 diabetes mellitus by mediating mitochondrial biogenesis and lipid metabolism via Sirtuin type 1.
  57. Orchestrating the gut microbiota-mitochondrial-immune axis in gynecological diseases: mechanisms and dual-targeting therapeutic strategies.
  58. LRG1 Drives Pathological Angiogenesis by Disrupting Neutrophil Mitochondrial Homeostasis in Bladder Cancer.
  59. Itgb1-Mediated Stabilization of Vimentin Alleviates Excessive Mechanical Stress-Induced Nucleus Pulposus Cell Pyroptosis and Intervertebral Disc Degeneration via PINK1-Parkin-Dependent Mitophagy.
  60. Grape Seed Proanthocyanidin Extract (GSPE) Mitigates Preterm White Matter Injury in Mice Via Improving Mitochondrial Homeostasis and Activity of IMMP2L-Related Signaling Pathway.
  61. ROS-mitochondrial nexus in stem cell growth and differentiation and implications in cancer and degenerative diseases.
  62. Autophagy Stress Responses in Localized Prostate Cancer: A Flux-Aware Framework for Disease-Relevant Interpretation.
  63. Allosteric modulation of Drp1 by natural compounds for cardiac therapeutics: a molecular docking and dynamics study.
  64. Spinosin mitigates bone loss in ovariectomy rats by activating the Nrf2/HO-1 pathway, which reduces oxidative stress and improves mitochondrial function.
  65. Enavogliflozin alleviates motor deficits in rotenone-induced Parkinson's disease mice via attenuation of oxidative stress and neuroinflammation as well as activation of the SIRT1/PINK1/Parkin pathway.
  66. Resensitizing drug-resistant cancers by co-targeting apoptosis and mitochondrial stress pathway.
  67. Testosterone propionate maintains autophagic flux and mitochondrial integrity via regulation of the LC3B/p62/Beclin-1/mTOR axis in induced liver fibrosis.
  68. Intermittent time-restricted feeding improves physical performance and modulates mitochondrial morphology in a muscle fiber type dependent manner in middle-aged mice.
  1. Curr Cancer Drug Targets. 2026 Jul 07.
    Mitochondrial Dynamics as Determinants of Cancer Drug Resistance: A Systematic Review.
    Swaroop Kumar Pandey, Ayush Kulshreshtha, Anuja Mishra.
       INTRODUCTION: Mitochondria continuously undergo fission and fusion processes, and this dynamic balance is essential for maintaining proper cellular function. Disruption of this balance can lead to cellular dysfunction, making cancer cells more resistant, increasing their metastatic potential, and promoting tumor growth. In this review, we examine how dysregulation of proteins involved in mitochondrial dynamics contributes to drug resistance. We also discuss emerging therapeutic strategies aimed at correcting mitochondrial dysfunction to enhance the effectiveness of cancer therapies.
    METHODS: This review synthesizes recent research on mitochondrial dynamics in cancer. It focuses on key proteins DRP1, MFN1, MFN2, and OPA1 and their roles in mitochondrial fission, fusion, and clearance. The review also integrates current understanding of these processes at the cellular level with emerging findings from studies on drug-resistant cancers.
    RESULTS: When proteins such as DRP1, MFN1, MFN2, and OPA1 are dysregulated, cancer cells develop mechanisms to survive treatments. These cells alter mitochondrial function, affecting energy production, reactive oxygen species management, and susceptibility to apoptosis. In drug-resistant tumors, mitochondria undergo dynamic remodeling, fusing or dividing depending on cellular requirements. Additionally, mitophagy removes damaged mitochondria while preserving functional ones, further enhancing the survival and resilience of these cells.
    DISCUSSION: When mitochondria undergo such adaptations, cancer cells can survive hostile environments and evade conventional therapies. Targeting these processes offers therapeutic opportunities: inhibitors of DRP1 can prevent abnormal mitochondrial fission, while modulation of OPA1 or other fusion proteins can restore healthy mitochondrial structure and promote apoptosis. By focusing on mitochondrial dynamics, new strategies emerge to overcome drug resistance by disrupting cancer cell metabolism and organelle homeostasis.
    CONCLUSION: This review underscores the potential of mitochondrial dynamics as a promising new target in cancer therapy. Examining the regulation of mitochondrial fission and fusion, the clearance of damaged mitochondria, and the dysregulation of key proteins reveals potential therapeutic opportunities. Furthermore, recent drugs that modulate these processes offer strategies to enhance the durability of cancer treatments and overcome drug resistance.
    Keywords:  Mitochondria; ROS.; apoptosis; cancer drugs; fission; fusion
    DOI:  https://doi.org/10.2174/0115680096460139260618104458
  2. Int J Pharm. 2026 Jul 16. pii: S0378-5173(26)00645-9. [Epub ahead of print] 127197
    A biomimetic mesenchymal stem cell membrane-coated nanodelivery system attenuates cardiac fibrosis by restoring mitochondrial homeostasis.
    Yagang Ding, Bangde Xue, Sibin Guan, Mingkui Gao, Xinxin Sun, Qinchuan Li, Jun Liu.
      Myocardial fibrosis is a critical pathological endpoint in heart failure, yet effective targeted therapies remain lacking. Dysregulation of mitochondrial dynamics, particularly Drp1-mediated excessive fission, drives cardiomyocyte dysfunction and pro-fibrotic signaling. Mdivi-1 is a selective Drp1 inhibitor, but suffers from poor solubility, lack of cardiac targeting, and potential systemic toxicity. To address these limitations, we developed a mesenchymal stem cell membrane-coated biomimetic nanodelivery system (MM@NPs/Mdivi-1) with high drug loading capacity and pH-responsive release properties. In vitro, MM@NPs/Mdivi-1 enhanced cellular uptake in injured cardiomyocytes, restored mitochondrial network integrity and membrane potential, and suppressed Drp1 phosphorylation. In an isoproterenol-induced murine cardiac fibrosis model, the system achieved cardiac-specific enrichment, improved cardiac function, reduced collagen deposition, and restored mitochondrial ultrastructure. Mechanistically, transcriptomics combined with functional rescue experiments revealed that its anti-fibrotic effects were dependent on FUNDC1-mediated mitophagy activation. Collectively, MM@NPs/Mdivi-1 effectively attenuates myocardial fibrosis by restoring mitochondrial homeostasis, offering a promising targeted nanotherapeutic strategy for heart failure.
    Keywords:  Biomimetic nanodelivery; Drp1 inhibition; Mesenchymal stem cell membrane; Mitochondrial homeostasis; Myocardial fibrosis
    DOI:  https://doi.org/10.1016/j.ijpharm.2026.127197
  3. Hepatology. 2026 Aug 01. 84(2): E52
    Retraction: HSP72 interacts with PRDX6 to deubiquitinate mitochondrial PINK1, activating mitophagy to treat MASLD.
    Yong Rao, Rui Su, Wen-Jie Cao, Yue Chen, Shu-Heng Huang, Jun-Jie Wu, Darren C Henstridge, Lin-Sheng Huang, Jin Liu, Fei-Fei Liu, Zhong-Ping Jiang, Cong-Jun Xu, Zhi-Shu Huang, Ji-Ming Ye, Ling Huang.
      
    DOI:  https://doi.org/10.1097/HEP.0000000000001810
  4. Free Radic Biol Med. 2026 Jul 14. pii: S0891-5849(26)00944-5. [Epub ahead of print]255 124-144
    Redox-dependent mitochondrial dynamics: PLK1 couples glutathione metabolism to ROS-driven JNK and DUSP6 pathways in colorectal cancer.
    Yan Li, Lili Zhao, Zhiyun Xu, Wencan Wang, Songmei Lu, Jingyu Du, Shuhao Chen, Jie Chen, Fangdong Zou.
      Polo-like protein kinase 1 (PLK1) is aberrantly overexpressed in colorectal cancer (CRC) and promotes malignant progression. However, whether PLK1 contributes to redox adaptation remains unclear. Here, we identify PLK1 as a critical hub that integrates glutathione (GSH) metabolism with mitochondrial dynamics to sustain redox homeostasis in CRC cells. Mechanistically, PLK1 drives STAT3-dependent SLC1A1 transcription to fuel GSH synthesis, thereby keeping reactive oxygen species (ROS) at a non-toxic level. When PLK1 is inhibited, GSH depletion triggers a burst of ROS, which acts as a signaling switch to disrupt mitochondrial homeostasis. Accumulated ROS drive two parallel pathways: (i) ROS promote proteasomal degradation of DUSP6, leading to sustained DRP1-Ser616 phosphorylation and excessive mitochondrial fission; (ii) ROS activate JNK, which translocates to mitochondria, binds MFN2, and promotes its ubiquitin-dependent degradation, thereby blocking mitochondrial fusion. This ROS-dependent collapse of mitochondrial dynamics results in cytochrome c release and intrinsic apoptosis. Our findings reveal that PLK1 sustains CRC survival by coupling GSH metabolism with redox-sensitive control of mitochondrial dynamics. These findings identify the ROS-mediated metabolic-mitochondrial axis as a potential therapeutic vulnerability in CRC.
    Keywords:  Apoptosis; Colorectal cancer; GSH; Mitochondrial dynamics; PLK1; ROS
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.07.017
  5. J Neuroinflammation. 2026 Jul 13.
    Microglial mitophagy as an immunometabolic checkpoint in alzheimer's disease: linking mitochondrial quality control to neuroinflammation.
    Mingyue Zou, Tengyu Zhao, Weidong Wu, Jian Zhang, Pengyu Pan, Jingdong Yan, Quan Li, Yanyan Zhou.
      AD is a complex neurodegenerative disorder characterized by chronic neuroinflammation. Microglia, the brain's resident immune cells, centrally regulate AD pathophysiology. Recent studies have highlighted microglial mitophagy as an important interface linking mitochondrial quality control to innate immune responses.Intact mitophagy facilitates the timely clearance of damaged mitochondria, thereby limiting the release of mitochondrial DAMPs (e.g., mtDNA and mtROS) and helping restrain aberrant activation of the cGAS-STING pathway and the NLRP3 inflammasome.In the AD pathological milieu, however, factors including Aβ deposition, tau pathology, and genetic risk variants such as TREM2 and APOE4 disrupt mitophagy at multiple levels-from initiation and recognition to lysosomal degradation. This review systematically summarizes the molecular regulatory network of microglial mitophagy, with a particular focus on the mechanisms by which AD-associated pathological factors impair this process. We further discuss potential mechanisms through which mitophagic dysfunction may contribute to the amplification of neuroinflammation, including the release of mitochondrial DAMPs, the reprogramming of TBK1 signaling, and intercellular interactions. Finally, we outline current therapeutic strategies aimed at restoring mitophagy and discuss their potential to modulate neuroinflammatory responses and AD-related pathological processes, while highlighting the challenges and future directions in this emerging field.
    Keywords:  Alzheimer's disease; CGAS-STING; Immunometabolism; Microglia; Mitophagy; NLRP3 inflammasome; Neuroinflammation
    DOI:  https://doi.org/10.1186/s12974-026-03946-5
  6. Acta Pharmacol Sin. 2026 Jul 15.
    RNF10 deficiency in cardiomyocytes impairs mitophagy and drives pathological hypertrophy.
    Jia-Ni Song, Tong-Tong Qiu, Lei Zhang, Jin-Can Huang, Yu-Jie Zhang, Yin-Liang Zhang, Yong-Sheng Chang.
      Mitophagy-mediated mitochondrial quality control is essential for normal cardiac physiology. In this study, we observed that cardiac RNF10 expression was induced by multiple chronic stressors, including aging, angiotensin II (Ang II) exposure, and obesity. Cardiac-specific RNF10 knockout (RNF10-CKO) mice developed cardiac hypertrophy with aging, characterized by cardiomyocyte enlargement, exacerbated myocardial fibrosis, and impaired cardiac function. Aged RNF10-CKO mice exhibited elevated reactive oxygen species (ROS) levels and reduced mitochondrial membrane potential in cardiomyocytes. Transmission electron microscopy revealed mitochondrial rounding, matrix expansion, and cristae disorganization. Similarly, compared with control mice, Ang II-exposed RNF10-CKO mice exhibited cardiomyocyte hypertrophy, increased fibrosis, and cardiac dysfunction, accompanied by mitochondrial membrane potential depolarization, ROS accumulation, and mitochondrial morphological abnormalities equivalent to those in aged RNF10-CKO mice. Mechanistically, chronic stressors upregulated RNF10 expression, which subsequently mediated the K63-linked polyubiquitination of the mitochondrial outer membrane protein mitofusin 2 (MFN2). This modification stabilized MFN2 on mitochondria and facilitated Parkin recruitment. The accumulated Parkin in mitochondria further promoted the robust recruitment of the autophagy adaptor sequestosome 1 (SQSTM1/p62), leading to increased LC3-II lipidation and the initiation of mitophagy. Notably, this RNF10-mediated mitophagy is dependent on MFN2. However, the effects of RNF10 are independent of those of PINK1. This study identifies RNF10 as a critical regulator of cardiac mitophagy, suggesting that targeting cardiac RNF10 may represent a therapeutic strategy for treating cardiac pathologies.
    Keywords:  MFN2; Parkin; RNF10; cardiac hypertrophy; mitophagy; ubiquitination
    DOI:  https://doi.org/10.1038/s41401-026-01838-1
  7. bioRxiv. 2026 Jul 08. pii: 2026.07.02.735939. [Epub ahead of print]
    Involvement of Mitophagy in Endothelin-1 Mediated Neurodegeneration in Rodent Models of Glaucoma.
    Calvin D Brooks, Bindu Kodati, Sanjna Prasad, Jacob Cunningham, Poojan Patel, Michael Mangan, Stacy Curry, Drayanna K FoxRun, Aysha Ehsan, Ojasvi Arya, Hayden Flume, Kishor Kunwar, August E Woerner, Denise M Inman, Dorota L Stankowska, Raghu R Krishnamoorthy.
      The ultimate cause of blindness in glaucoma is the death of retinal ganglion cells, and understanding the mechanism behind retinal ganglion cell loss during glaucoma could lead to the development of novel treatments for glaucoma. Endothelin-1 has been shown to mediate retinal ganglion cell death during glaucoma through impairment of mitochondrial function. Retinal ganglion cells are highly metabolically active, and susceptible to oxidative damage and decreased respiratory capacity. Mitophagy is the process whereby damaged mitochondria are degraded to prevent further propagation of oxidative damage. The current study evaluates the effect of endothelin-1 on mitophagy in retinal ganglion cells. Electron microscopy revealed endothelin-1 administration lead to a decrease in healthy mitochondria in the optic nerve. The MitoQC mouse was used to evalute mitophagy in response to endothelin-1, along with immunohistochemical analysis of mitophagy proteins. Mitophagy follows different trends in the optic nerve and retinal ganglion cell bodies following endothelin-1 administration, mitophagy was increased in the optic nerve but decreased in the retina following endothelin administration. With elevation of intraocular pressure, mitophagy was increased in the retina but decreased in the optic nerve. In retinal ganglion cells, parkin expression and activation was unchanged 24 hours after endothelin-1 administration, but was decreased 72 hours following endothelin-1 administration. Taken together, these results suggest that endothelin-1 impacts mitophagy through parkin-independent mechanisms in retinal ganglion cell bodies, and the ganglion cell bodies and optic nerve appear to have different responses to endothelin-1.
    DOI:  https://doi.org/10.64898/2026.07.02.735939
  8. Transl Cancer Res. 2026 Jun 30. 15(6): 507
    Mitochondrial dynamics imbalance in hepatocellular carcinoma: from molecular mechanisms to new strategies for targeted therapy.
    Fuxiang Chen, Chunyang Ma, Xitong Bo, Yilong Zhou, Suqing Zhang.
      Hepatocellular carcinoma (HCC), a malignancy with high global mortality, exhibits a close association with mitochondrial dynamic imbalance. Mitochondria maintain cellular homeostasis through a dynamic equilibrium of fission and fusion, and dysregulation of this process can trigger metabolic reprogramming, oxidative stress, and dysregulation of multiple modes of cell death, ultimately driving HCC progression. This review systematically elucidates the molecular mechanisms and therapeutic targets associated with mitochondrial dynamic imbalance in HCC. It begins by analyzing the structure and functional characteristics of mitochondria, outlining the universal impact of their fission-fusion regulatory network on cancer biology. Subsequently, it focuses on HCC-specific pathological mechanisms, revealing how mitochondrial dynamic imbalance reshapes the tumor microenvironment via the Warburg effect, lipotoxicity, and reactive oxygen species (ROS) burst. A key emphasis is placed on the role of mitochondrial dysfunction in regulating multiple modes of cell death, including apoptosis, ferroptosis, pyroptosis, autophagy, and the emerging mechanism of cuproptosis. The link between cuproptosis and mitochondrial copper accumulation, lipoylated protein aggregation, and metabolic collapse provides a novel perspective for HCC therapy. Finally, the review critically evaluates therapeutic strategies targeting mitochondrial dynamics, discussing the translational potential of DRP1 inhibitors (e.g., Mdivi-1), mitophagy activators (e.g., rapamycin), and copper chelators (e.g., tetrathiomolybdate). Future directions, such as mitochondrial-targeted nanodelivery systems and multi-target combination therapies, are also explored. This comprehensive review aims to provide a theoretical foundation and innovative insights for understanding the pathogenesis and advancing precision therapy in HCC.
    Keywords:  Mitochondrial dynamics; hepatocellular carcinoma (HCC); molecular mechanisms; multimodal cell death; targeted therapeutic strategies
    DOI:  https://doi.org/10.21037/tcr-2026-0591
  9. Pharmacol Ther. 2026 Jul 16. pii: S0163-7258(26)00113-0. [Epub ahead of print] 109086
    Mitochondrial dynamics and metabolic regulation in cellular inflammation: From mechanisms to precision therapeutics.
    Woo Hyun Park.
      Beyond their canonical role in bioenergetics, mitochondria are now recognized as critical signaling platforms that orchestrate innate immune responses. Central to this function is mitochondrial dynamics-the controlled equilibrium between fission and fusion-which serves as a critical structural and thermodynamic checkpoint for cellular fate and immunological status. A substantial body of evidence indicates that pathological mitochondrial fission, frequently driven by Dynamin-related protein 1 (Drp1), is a hallmark of numerous inflammatory conditions. Mechanistically, fragmented mitochondria release damage-associated molecular patterns (DAMPs) and induce acute ATP suppression, metabolically "licensing" NLRP3 activation by collapsing the ATP hydrolysis potential (ΔGATP). Recent breakthroughs have redefined this axis, distinguishing between physical damage and metabolic triggers, such as pyrimidine imbalance via the YME1L-SLC25A33 axis. Furthermore, the immunogenicity of DAMPs is strictly context-dependent; oxidized or "fragile" mtDNA containing ribonucleotides act as hyper-immunogenic ligands for cytosolic sensors like cGAS-STING. Emerging evidence further highlights that endosomal-mitochondrial crosstalk, intercellular mitochondrial transfer, and lipid-driven metabolic rewiring profoundly govern macrophage polarization and tissue homeostasis. Conversely, promoting mitochondrial fusion and robust quality control preserves organellar integrity and attenuates inflammatory cascades. This review critically synthesizes current literature, deconstructing the molecular linkages between organelle structure and metabolic signaling. By exploring the consequences in sepsis, neuroinflammation, osteoarthritis, and cancer, this treatise evaluates the pharmacological potential of modulating mitochondrial dynamics-ranging from direct Drp1 inhibitors and unfractionated heparin to metabolic stabilizers (e.g., GLP-1 receptor agonists), multi-pronged disruptors (e.g., Antimycin A), targeted nanomedicine, and communication-driven mitochondrial transplantation-positioning this axis as a promising frontier for precision pharmacology.
    Keywords:  Drp1; Intercellular mitochondrial transfer; Macrophage polarization; Mitochondrial dynamics; Mitoimmunity; NLRP3 inflammasome; Pharmacological intervention; cGAS-STING
    DOI:  https://doi.org/10.1016/j.pharmthera.2026.109086
  10. Eur J Pharmacol. 2026 Jul 17. pii: S0014-2999(26)00632-1. [Epub ahead of print] 179150
    Astragaloside IV Attenuates Atherosclerosis By Regulating Endothelial Mitophagy And Oxidative Stress Via The Nrf2/PINK1/Parkin Pathway.
    Chang Chai, Dandan Liu, Yanjie Li, Yang Gao, Yiting Zhao, Hewei Qin.
      Astragaloside IV (AS-IV) exhibits cardiovascular protective effects, but its role in mitochondrial quality control during atherosclerosis remains unclear. This study evaluated whether AS-IV attenuates atherosclerosis by regulating the nuclear factor erythroid 2-related factor 2 (Nrf2)-PTEN-induced putative kinase 1 (PINK1)/Parkin pathway. High-fat diet-fed apolipoprotein E-deficient (ApoE-/-) mice and oxidized low-density lipoprotein (ox-LDL)-treated human umbilical vein endothelial cells (HUVECs) were used as in vivo and in vitro models. AS-IV reduced aortic plaque burden and alleviated endothelial injury in ApoE-/- mice. In HUVECs, AS-IV decreased oxidative stress and improved mitochondrial function, accompanied by enhanced mitophagy. Mechanistically, AS-IV promoted Nrf2 nuclear translocation and upregulated the PINK1/Parkin axis. Silencing Nrf2 or PINK1, or pharmacological inhibition of Nrf2 with ML385, abolished the cytoprotective effects of AS-IV and suppressed mitophagy. Molecular docking and molecular dynamics simulations provided supportive structural context for a plausible AS-IV pose within the Kelch-like ECH-associated protein 1 (Keap1) pocket in the simulated system. Mechanistically, AS-IV appears to mitigate atherosclerotic progression by promoting Nrf2-driven, PINK1/Parkin-dependent mitophagy.
    Keywords:  Astragaloside IV; Atherosclerosis; Mitophagy; Nrf2; Oxidative stress; PINK1; Parkin
    DOI:  https://doi.org/10.1016/j.ejphar.2026.179150
  11. Acta Diabetol. 2026 Jul 13.
    Interpretable single-cell machine learning identifies PINK1-centred mitophagy as a determinant of metabolic fitness in type 2 diabetes.
    Bingjun Zeng, Da Qin, Xiaowei Xu, Dayun Tao, Ying Jiang, Hao Zhou, Yanli Wang.
       BACKGROUND: Progressive pancreatic β-cell dysfunction constitutes a hallmark of type 2 diabetes (T2D), yet the molecular programmes governing metabolic fitness deterioration remain incompletely characterised at single-cell resolution.
    METHODS: Single-cell transcriptomic data (GSE221156) encompassing pancreatic islet cells from 48 donors (non-diabetic [ND], n = 17; pre-diabetic [PD], n = 14; T2D, n = 17) were analysed using an interpretable machine learning framework that integrated sparse rule-based classification, pathway-constrained modelling, and mitochondrial fitness indexing.
    RESULTS: Five transcriptionally distinct β-cell subtypes (β1-β5) were resolved. The β1 subtype exhibited peak proportional representation in PD donors (35.0%) compared with ND (16.7%) and T2D (21.1%), consistent with stress-induced adaptive expansion. Mitochondrial biogenesis and ER stress emerged as the top-ranked programmes discriminating T2D from ND β-cells (importance scores = 0.329 and 0.329). Within the mitophagy gene set, MFN2 exhibited the highest feature importance (|logFC| = 0.472), followed by PINK1 (|logFC| = 0.199). PINK1 expression progressively declined across β1→β5 subtypes. A mitochondrial fitness index integrating mitophagy, proteostasis, biogenesis, and oxidative phosphorylation achieved R² = 0.65 against module-based quality scores. Hypergeometric enrichment analysis of differentially expressed genes between the adaptive β1 subtype and dysfunctional β2-β5 subtypes revealed significant enrichment of insulin secretion (p = 0.0019), endoplasmic reticulum stress (p = 0.0013), and oxidative phosphorylation (p = 0.045) pathways.
    CONCLUSIONS: PINK1-centred mitophagy represents a critical determinant of β-cell metabolic fitness in T2D, with implications for therapeutic strategies aimed at preserving islet function during disease progression.
    Keywords:  Interpretable machine learning; Mitophagy; PINK1; Single-cell transcriptomics; Type 2 diabetes; β-cell heterogeneity
    DOI:  https://doi.org/10.1007/s00592-026-02743-z
  12. J Ethnopharmacol. 2026 Jul 17. pii: S0378-8741(26)01049-4. [Epub ahead of print] 122195
    Polydatin improves mitochondrial dynamics dysrhythmia by regulating BMAL1 to prevent and treat metabolic dysfunction-associated fatty liver disease.
    Shujun Wang, Haichao Wang, Guoliang Yin, Xuehuan Liu, Na Xie, Xin Zhang, Wenfei Yu, Haiyi Zhang, Yuqing Sun, Hongshuai Liu, Linya Wang, Muxi Qi, Huagui Feng, Fengxia Zhang.
       ETHNOPHARMACOLOGICAL RELEVANCE: Polygonum cuspidatum, a traditional Chinese medicine indicated for "blood stasis" and "damp-heat" disorders (e.g., arthralgia, jaundice, amenorrhea), has modern relevance as these conditions correlate with dyslipidemia, inflammation, and microcirculatory issues. Its main constituent, polydatin (PD), exhibits multiple bioactivities, yet its role in metabolic dysfunction-associated fatty liver disease (MAFLD) remains unclear.
    AIM OF THE STUDY: To elucidate the mechanisms by which PD alleviates MAFLD through BMAL1-mediated mitochondrial dynamics.
    MATERIALS AND METHODS: FFA-induced HepG2 cells and HFD-induced MAFLD rats were used to evaluate the effects of PD on hepatic lipid accumulation, mitochondrial function, and oxidative stress immune imbalance via histological staining and biochemical assays. Additionally, molecular docking, molecular dynamics simulations, and BMAL1 knockdown experiments were conducted to identify potential upstream regulators.
    RESULTS: PD significantly suppressed lipid accumulation, reduced levels of ROS, MDA, NLRP3, TNF-α, and IL-1β, while enhancing SOD activity, thereby alleviating oxidative stress-immune imbalance. PD increased mitochondrial membrane potential (MMP), ATP content, and mtDNA copy number, reversing mitochondrial dysfunction. Notably, PD improved expression rhythms of BMAL1 and mitochondrial dynamics-related genes (DRP1, OPA1, MFN1, MFN2, FIS1), normalizing their amplitude and phase. Concurrently, PD activated the mitochondrial autophagy pathway by upregulating PINK1 and PARKIN expression, thereby facilitating timely clearance of impaired mitochondria. Most importantly, all the aforementioned therapeutic benefits of PD were abolished upon BMAL1 knockdown, establishing BMAL1 as an essential target for PD's action.
    CONCLUSION: This is the first study to demonstrate that PD alleviates MAFLD by mediating BMAL1-regulated circadian rhythms of mitochondrial dynamics, positioning PD as a potential therapeutic candidate for MAFLD.
    Keywords:  BMAL1; MAFLD; Polydatin; mitochondrial dynamics
    DOI:  https://doi.org/10.1016/j.jep.2026.122195
  13. Syst Biol Reprod Med. 2026 Dec;72(1): 282-298
    cPKCγ facilitates the apoptosis of mouse GC-1 spg cells by regulating the mitophagy via inhibiting the UCHL1/HIF‑1α axis.
    Huajun Yang, You Tian, Shaoguang Feng, Jing Shen, Xianming Yao, Feng Lin.
      Cryptorchidism, among the most frequent congenital urogenital anomalies in male infants, has a global prevalence ranging from 1% to 9%. Characterized by failure of testicular descent into the scrotum, such a condition exposes the testes to elevated temperature, oxidative stress, and impaired spermatogenesis, significantly increasing risks of infertility and testicular cancer. Although orchiopexy is the standard treatment, long-term spermatogenic defects often persist, highlighting the need to elucidate underlying molecular mechanisms. Although the main mechanistic experiments were performed in GC-1 spg cells through genetic manipulation of cPKCγ, an additional heat-stress experiment was included to simulate the high-temperature condition associated with cryptorchidism. In the present study, the role of conventional protein kinase C gamma (cPKCγ) in regulating mitophagy and apoptosis was investigated using mouse spermatogonial GC-1 cells. Through siRNA-mediated knockdown and adenovirus-induced overexpression, cPKCγ upregulation was demonstrated to significantly induce cellular apoptosis and disrupt mitochondrial function, indicated by elevated malondialdehyde (MDA) levels, reduced superoxide dismutase (SOD) activity, decreased ATP production, increased 8-hydroxy-2'-deoxyguanosine (8-OHdG) accumulation, increased mitochondrial reactive oxygen species (ROS), and loss of mitochondrial membrane potential. Mechanistically, cPKCγ was found to inhibit the UCHL1/HIF-1α signaling pathway, suppressing mitophagy, as evidenced by a reduced LC3-II/LC3-I ratio and decreased PINK1 and Parkin expression. Importantly, adverse effects induced by cPKCγ overexpression were substantially rescued through UCHL1 or HIF-1α overexpression, or rapamycin treatment. Conversely, knockdown of UCHL1 or HIF-1α partially counteracted the protective effects of cPKCγ silencing on cell viability, oxidative stress, and mitophagy activation. Furthermore, heat stress upregulated endogenous cPKCγ and suppressed UCHL1/HIF-1α signaling and mitophagy-related proteins in GC-1 spg cells. Collectively, cPKCγ exacerbates spermatogonial apoptosis by repressing UCHL1/HIF-1α-dependent mitophagy, suggesting a potential molecular mechanism for spermatogonial vulnerability under cryptorchidism-related heat stress.
    Keywords:  UCHL1/HIF-1α; apoptosis; cPKCγ; mitophagy; spermatogonia
    DOI:  https://doi.org/10.1080/19396368.2026.2700977
  14. Transl Cancer Res. 2026 Jun 30. 15(6): 499
    Single-cell mitophagy patterns dictate intercellular crosstalk in the tumor microenvironment to promote osteosarcoma progression.
    Wei Shi, Lei Zhang, Liying Mei, Chengqi Zhang, Lei Liu, Nan Zhao, Qingyu Liu.
       Background: Osteosarcoma (OS) is a highly aggressive primary bone malignancy in adolescents, with poor prognosis due to limited diagnostic and therapeutic strategies. Mitochondrial dysfunction is a hallmark of cancer, and mitophagy, the selective clearance of damaged mitochondria, critically maintains cellular homeostasis. However, the specific role of mitophagy in shaping the OS tumor microenvironment (TME) at single-cell resolution remains poorly understood. This study aims to systematically characterize mitophagy patterns within the OS TME and investigate their impact on intercellular communication, tumor progression, and patient prognosis.
    Methods: We analyzed single-cell RNA sequencing data from OS samples using non-negative matrix factorization to cluster cells based on mitophagy-related genes. We characterized distinct mitophagy-associated subtypes of TME cells. Pseudotime trajectory, cell-cell communication), gene regulatory network, and functional enrichment analyses were performed. Prognostic significance was evaluated using GSVA and Cox regression in bulk RNA-seq cohort. Immunotherapy response was predicted using the TIDE algorithm.
    Results: We identified diverse mitophagy-activated cellular subtypes within the TME. Mitophagy-active CAFs and macrophages exhibited enhanced angiogenic signaling to endothelial cells. Mitophagy-associated CD8+ T cells displayed marked exhaustion features, while macrophages showed metabolic reprogramming. Clinically, higher infiltration of these mitophagy-related subtypes was consistently associated with poorer overall survival. TIDE analysis indicated that mitophagy patterns potentially correlate with immune checkpoint blockade response.
    Conclusions: Our findings reveal that mitophagy drives complex intercellular crosstalk in the OS TME, promoting angiogenesis and immunosuppression. Mitophagy-related signatures serve as robust prognostic biomarkers. These insights suggest that targeted inhibition of mitophagy, rather than activation, represents a promising therapeutic strategy, providing a novel framework for improving OS patient outcomes.
    Keywords:  Mitophagy; osteosarcoma (OS); prognosis; single-cell RNA sequencing (scRNA-seq); tumor microenvironment (TME)
    DOI:  https://doi.org/10.21037/tcr-2026-0735
  15. Organelle. 2025 ;3
    Stress Induced Mitochondrial Hyperfusion (SIMH): A Concise Review on SIMH in Neurodegenerative Disorders and Other Diseases.
    Jeffrey D Brown, Mei-Zhen Cui, Xuemin Xu.
      Mitochondria are critical for cell health, and damaged or dysfunctional mitochondria have been strongly linked to various human diseases, particularly neurodegenerative disorders. Mitochondrial function is regulated by several mechanisms, including the regulation of mitochondrial shape, size, number, and morphology. Mitochondria constantly fuse together and separate; this fusion and fission process is known as mitochondrial dynamics. These mitochondrial dynamics are modulated in response to various stimuli, and recent reports have demonstrated that mitochondria undergo hyperfusion under mild to moderate stress conditions, resulting in the formation of elongated filaments. This phenomenon is referred to as stress induced mitochondrial hyperfusion (SIMH). SIMH is associated with enhanced protection of mitochondria and improved cell viability under stress conditions. The induction of hyperfusion can be triggered by diverse stressors, each with distinct and unique mechanisms. This mini review will focus on these stressors and their corresponding mechanisms, as well as the subsequent effects on mitochondrial and cell health. Additionally, disease models which demonstrate a correlation between specific disease-related stress conditions and mitochondrial hyperfusion are discussed.
    Keywords:  Drp1; ER Stress; MAM; Mfn; Mitochondrial dynamics; Neurodegenerative disorders; OPA1; SIMH; UPR
    DOI:  https://doi.org/10.61747/0ifp.202503002
  16. Tissue Cell. 2026 Jul 13. pii: S0040-8166(26)00478-7. [Epub ahead of print]104(Pt 1): 103784
    Fenofibrate attenuates cisplatin-induced nephrotoxicity in rats by restoring mitochondrial dynamics and improving fatty acid oxidation.
    Mingkang Zhang, Abudula Jumai, Xiang Wang, Yan Zhou, Yanrong Ma, Xin'an Wu.
      Cisplatin is a standard chemotherapeutic agent widely used for the treatment of common solid tumors; however, its dose-dependent nephrotoxicity severely limits its clinical application. Currently, effective and specific strategies for preventing or reversing cisplatin-induced nephrotoxicity remain limited. Fenofibrate, a clinically used selective PPARα agonist, has shown renoprotective effects in multiple kidney injury models. This study investigated whether fenofibrate attenuates cisplatin-induced nephrotoxicity in rats and explored the underlying mechanisms. Our results showed that cisplatin significantly induces renal injury, along with renal oxidative stress, apoptosis, mitochondrial dynamics imbalance, as well as impaired fatty acid oxidation. However, fenofibrate treatment significantly reduced cisplatin-induced elevations in serum BUN and SCr levels, decreased NGAL and Kim1 expression, and ameliorated renal histopathological damage. Mechanistically, fenofibrate restored mitochondrial homeostasis in the kidney by downregulating Drp1 and upregulating Mfn1, Mfn2, and OPA1. It also alleviated renal oxidative stress, as evidenced by increased GSH and SOD levels and decreased MDA levels, and inhibited renal apoptosis by reducing the expression of Bax and Cleaved Caspase3 while increasing Bcl2 expression. Furthermore, fenofibrate activated the AMPK/PGC-1α/PPARα pathway, suppressed the aberrant upregulation of the fatty acid transporters CD36 and FATP4, and restored the expression of key fatty acid oxidation-related enzymes, including CPT1A, CPT2, and ACOX1. Taken together, these findings suggest that fenofibrate protects against cisplatin-induced nephrotoxicity by restoring mitochondrial dynamics and improving renal fatty acid oxidation.
    Keywords:  Cisplatin; Fatty acid oxidation; Fenofibrate; Mitochondrial dynamics; Nephrotoxicity
    DOI:  https://doi.org/10.1016/j.tice.2026.103784
  17. Nutrients. 2026 Jun 24. pii: 2061. [Epub ahead of print]18(13):
    Impaired Renal Mitochondria and Bioenergetics During Obesity-Associated NAFLD.
    Amod Sharma, Reza Hakkak, Shannon Rose, Neriman Gokden, Nirmala Parajuli.
      Background/Objectives: Obesity-associated non-alcoholic fatty liver disease (NAFLD) drives systemic metabolic stress and accelerates chronic kidney disease, yet the mechanistic links remain unclear. Mitochondrial dysfunction has emerged as a central mediator of obesity-induced organ injury. Here, we investigated renal mitochondrial remodeling in a rat model of obesity-associated NAFLD (Ob-NAFLD) and examined the effects of metformin. Methods: Female Zucker rats (obese fa/fa and lean Fa/Fa) were fed an AIN-93G diet for eight weeks, followed by 10 weeks of metformin treatment in designated groups. Kidney tissues were analyzed using biochemical assays, immunoblotting, blue native PAGE, in-gel activity assays, and histological evaluation. Results: In Ob-NAFLD rats, renal ATP levels were elevated despite reduced electron transport chain (ETC) Complex III and increased Complex V expression, reflecting compensatory ATP synthase hyperactivity uncoupled from efficient oxidative phosphorylation. Mitochondrial dynamics were disrupted such that inhibitory phosphorylation of DRP1 was reduced, promoting fission, and total OPA1 expression was decreased with a shift in short-to-long isoform balance, indicating impaired fusion and cristae remodeling. Notably, ATPase inhibitory factor 1 (IF1), a checkpoint that limits ATP synthase overdrive, remained stably expressed, suggesting an adaptive ceiling or failed protective control under chronic metabolic stress. Metformin partially alleviated bioenergetic stress by lowering ATP and modestly restoring Complex III, yet ETC imbalance and structural remodeling persisted, revealing the limitations of metabolic modulation alone. Conclusions: These findings position entrenched mitochondrial dysregulation as a mechanistic bridge linking obesity-driven liver disease to kidney injury. Therapeutic strategies combining metabolic interventions with targeted restoration of ETC coordination, mitochondrial dynamics, and regulatory checkpoints such as IF1 may be required to fully restore renal mitochondrial health and prevent the progression of metabolic kidney disease.
    Keywords:  ATP; kidney injury; metformin; mitochondrial dynamics; obesity–NAFLD
    DOI:  https://doi.org/10.3390/nu18132061
  18. Sci Rep. 2026 Jul 17.
    Docosahexaenoic acid attenuates cisplatin nephrotoxicity by restoring mitophagy.
    Yuxian Zhuang, Zhenying Zuo, Chen Yang, Shangmei Li, Huafeng Liu, Kaipeng Jing.
      Cisplatin exhibits potent antitumor efficacy but also causes dose-dependent nephrotoxicity mediated through apoptosis of renal tubular epithelial cells, which limits its clinical application. Cisplatin induces significant mitophagy in these cells; however, the mechanisms underlying its effects on apoptotic processes remain incompletely elucidated. This study investigated the mechanism by which the polyunsaturated fatty acid docosahexaenoic acid (DHA) modulates mitophagy to alleviate cisplatin nephrotoxicity. A cisplatin-induced (15 mg/kg, intraperitoneal) acute kidney injury model was established in C57BL/6J mice, with the intervention group receiving albumin-conjugated DHA (4 mg/kg). Systematic analyses revealed that cisplatin perturbed lysosomal degradation, which led to accumulation of dysfunctional mitochondria and increased apoptosis due to impaired mitophagic flux. DHA ameliorated lysosomal dysfunction, enhanced clearance of dysfunctional mitochondria, and suppressed apoptosis. Our findings suggest that blockade of mitophagic flux is a pivotal mechanism underlying cisplatin nephrotoxicity and that DHA-mediated restoration of mitophagy is a promising therapeutic strategy.
    Keywords:  Acute kidney injury (AKI); Apoptosis; Cisplatin; Docosahexaenoic acid (DHA); Mitophagic flux
    DOI:  https://doi.org/10.1038/s41598-026-62168-0
  19. Front Mol Biosci. 2026 ;13 1848361
    Mitochondrial calcium uniporter-mediated mitochondrial dynamics imbalance contributes to contrast medium-induced renal tubular cell injury.
    Yangyang Chen, Manyu Zhang, Sha Chen, Meiling Lv, Shuo Huang, Dingwei Yang.
       Background: Cellular and intramitochondrial calcium (Ca2+) overload, along with mitochondrial dysfunction, play a critical role in contrast-induced renal tubular epithelial cell injury. This study aims to clarify the role and mechanism of the Mitochondrial Calcium Uniporter (MCU) and mitochondrial dynamics in this process.
    Methods: Part 1: An in vitro CI-AKI model was established using human renal proximal tubular epithelial (HK-2) cells. The experimental design comprised a normal control group and iohexol-treated groups (100 mg I/mL) incubated for 4, 8, and 12 h, respectively. Part 2: To investigate the role of MCU, HK-2 cells were assigned to four conditions: normal control, iohexol alone, MCU inhibitor + iohexol group, and MCU agonist + iohexol group. We evaluated tubular cell injury and mitochondrial impairment, focusing on MCU expression, mitochondrial dynamics and Ca2+ loading, to clarify the molecular mechanisms.
    Results: Iohexol induced time-dependent cellular injury and apoptosis, accompanied by MCU upregulation, elevated intramitochondrial Ca2+ and mitochondrial dynamic imbalance. It also triggered mitochondrial membrane potential (ΔΨm) loss and mitochondrial reactive oxygen species (mtROS) accumulation. MCU inhibition with Ru360 enhanced cell viability, reduced apoptosis, improved mitochondrial function, suppressed Dynamin-related protein 1 (DRP1), reduced mitochondrial Ca2+, preserved ΔΨm and decreased mtROS. Conversely, MCU activation with spermine exacerbated the injury.
    Conclusion: Contrast-induced upregulation of MCU exacerbates intramitochondrial Ca2+ overload, preferentially promotes mitochondrial fission, resulting in the dissipation of ΔΨm and aggravated oxidative stress, which ultimately leads to cellular injury and apoptosis. Critically, inhibition of MCU conferred a protective effect against contrast-induced injury.
    Keywords:  MCU; apoptosis; contrast medium; mitochondrial dynamics; mitochondrial dysfunction
    DOI:  https://doi.org/10.3389/fmolb.2026.1848361
  20. Cardiovasc Ther. 2026 ;2026(1): e8401037
    Asprosin Protects H9C2 Cells From Ferroptosis Following Hypoxia/Reoxygenation by Promoting Mitophagy.
    Xiangkun Wang, Xiaoyu Zhang, Huaiguang Tang, Xiaojuan Su, Shutong Ding, Xuelian Li, Bingong Li.
       BACKGROUND: Acute myocardial infarction is a leading cause of death globally. Percutaneous coronary intervention is the primary treatment to restore blood flow to the affected myocardium, but reperfusion can cause myocardial injury, affecting the prognosis of patients with acute myocardial infarction. Asprosin (ASP) is a newly discovered adipokine whose role in myocardial protection requires further research.
    METHODS: The GSE240847 dataset was downloaded from the GEO database, and 511 ferroptosis-related genes were collected from the FerrDb database. Gene coexpression network analysis (WGCNA) was performed to identify coexpression modules associated with Fibrillin 1 (FBN1), followed by enrichment analysis. H9C2 cells were subjected to hypoxia/reoxygenation (H/R) and pretreated with ASP at different concentrations. The effects of ASP were determined by measuring cellular reactive oxygen species (ROS), Cell Counting Kit-8 (CCK-8), and lactate dehydrogenase (LDH) levels and assessing the expression of ferroptosis-related proteins, intracellular iron content, mitophagy-related proteins, and mitochondrial membrane potential.
    RESULTS: Enrichment analysis showed Gene Ontology (GO) terms linked to GTPase signaling, chromosome behavior, and cell stability. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis highlighted mitophagy and MAPK pathways in the FBN1 module. ASP cut ROS, boosted cell viability, and raised glutathione peroxidase 4 (GPX4)/solute carrier family 7 member 11 (SLC7A11) expression, upregulating glutathione and lowering iron particles dose dependently post H/R. It also increased PINK1 and stabilized mitochondria. A mitophagy inhibitor reduced these effects.
    CONCLUSIONS: This study confirms the protective effects of ASP on myocardial cells after H/R injury and demonstrates that ASP can inhibit ferroptosis and promote mitophagy in myocardial cells during ischemia-reperfusion injury. The potential mechanism may involve ASP promoting PINK1-associated mitophagy in myocardial cells after H/R injury to inhibit ferroptosis.
    Keywords:  asprosin; cardiomyocyte protection; ferroptosis; hypoxia/reoxygenation injury; mitophagy
    DOI:  https://doi.org/10.1155/cdr/8401037
  21. Cell Death Dis. 2026 Jul 16.
    Dual-faced metabolic reprogramming powers proliferation: FGF21 drives lung squamous carcinoma progression via CaMKII-DRP1-mediated mitochondrial fission.
    Xiao-Xin Pu, Yan Zhang, Bao-Yi Liu, Xiao-Jie Song, Yu-Wen Xue.
      Fibroblast growth factor 21 (FGF21) is upregulated in lung squamous cell carcinoma (LUSC) tissues, cell lines, and tumor-conditioned media. Functional studies using LUSC cell lines (H1703, H520) demonstrate that FGF21 promotes cancer cell proliferation, migration, invasion, and tumor sphere formation in vitro. This pro-tumorigenic effect was validated in vivo through xenograft models, where intra-tumoral FGF21 administration accelerated tumor growth. Mechanistically, FGF21 activates calcium/calmodulin-dependent protein kinase II (CaMKII), which phosphorylates dynamin-related protein 1 (DRP1, encoded by DNM1L) at Ser616. Phosphorylated DRP1 translocates to mitochondria, inducing mitochondrial fission. Metabolic analyses revealed that FGF21 remodels cellular energetics in a cell type-specific manner, enhancing glycolysis in H520 cells and oxidative phosphorylation (OXPHOS) in H1703 cells, consistent with their inherent predominant metabolic states. Knockdown of DRP1 or pharmacological inhibition of CaMKII (KN93) abolished FGF21-driven mitochondrial fission, metabolic reprogramming, and tumor-promoting effects. Collectively, FGF21 acts as a tumor-promoting factor in LUSC by activating the CaMKII/DRP1-Ser616 axis to induce pathological mitochondrial fission and metabolic reprogramming, identifying this pathway as a potential therapeutic target.
    DOI:  https://doi.org/10.1038/s41419-026-09084-3
  22. Exp Physiol. 2026 Jul 14.
    Therapeutic intervention with sinomenine and irisin to preserve cardiac function after ischaemia-reperfusion injury.
    Lianjun Wu, Sining Bi, Amany Belal, Zhuzhu Liu.
      Despite advancements in reperfusion therapy, myocardial ischaemia-reperfusion (IR) injury remains a major clinical challenge. This study investigated whether a novel dual-target pre-conditioning strategy using sinomenine and irisin could enhance myocardial resistance against IR injury. Ninety male Sprague-Dawley rats were utilized. Protocol 1 evaluated cardioprotection by assigning rats to Sham, IR, sinomenine, irisin or a combination of both agents, with pharmacological pre-treatments administered for 7 days prior to surgery. To model IR injury in vivo, animals underwent 30 min surgical ligation of the left anterior descending coronary artery followed by 24 h reperfusion. Combined pre-treatment exerted superior protection, significantly reducing infarct size (P = 0.0187) and serum cardiotroponin-I (P = 0.0028), while preserving myocardial architecture. Echocardiography and haemodynamic monitoring confirmed significantly enhanced ejection fraction (P < 0.0001), fractional shortening (P = 0.0002), developed pressure (P = 0.0001), +dP/dt (P < 0.0001), and -dP/dt (P = 0.0003), alongside reduced left ventricular internal diameter at end-systole (P < 0.0001) and end-diastole (P = 0.0004), as well as decreased end-diastolic pressure (P = 0.0128) in the combination group. Protocol 2 investigated mechanisms using mitochondrial division inhibitor 1 (Mdivi-1). Combined pre-treatment mitigated oxidative stress, suppressed pro-inflammatory cytokines and inhibited the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome, evidenced by significant reductions in NLRP3, apoptosis-associated speck-like protein containing a CARD, and cleaved Gasdermin D. Conversely, it significantly upregulated PTEN-induced putative kinase 1 (PINK1) and Parkin. Notably, Mdivi-1 abrogated these benefits, confirming that the enhanced protection is mediated through the activation of the PINK1/Parkin-dependent mitophagy pathway. These results suggest that pharmacological pre-conditioning with sinomenine and irisin offers a potent strategy against IR injury by modulating the mitophagy-pyroptosis axis.
    Keywords:  Irisin; mitophagy; myocardial ischaemia–reperfusion injury; pyroptosis; sinomenine
    DOI:  https://doi.org/10.1113/EP093586
  23. Sci Bull (Beijing). 2026 Jul 13. pii: S2095-9273(26)00791-7. [Epub ahead of print]
    Biallelic hexose-6-phosphate dehydrogenase variants cause mitochondrial dysfunction underlying Parkinson's disease.
    Miao Zhao, Yuwen Zhao, Juan Huang, Yu Guo, Wenjun Yu, Haiyan Hou, Yilin Huang, Xinying Du, Yu Zhang, Mujun Xie, Zuowen Ren, Haoyu Guan, Hongxu Pan, Wenwen Xu, Qiying Sun, Qian Xu, Lingling Lv, Chunyu Wang, Lifang Lei, Heng Wu, Lu Shen, Hong Jiang, Xinxiang Yan, Jinchen Li, Pengli Zheng, Jifeng Guo, Beisha Tang, Jieqiong Tan, Zhenhua Liu.
      Parkinson's disease (PD) is a progressive neurodegenerative disorder influenced by complex genetic and environmental factors. We report that biallelic variants in hexose-6-phosphate dehydrogenase (H6PD), which encodes a key enzyme in the endoplasmic reticulum (ER) pentose phosphate pathway, contribute to PD and investigate its role in maintaining mitochondrial homeostasis. Through whole-exome sequencing of 2223 patients with PD and 1229 controls, together with whole-genome sequencing of 4010 patients and 6072 controls, we found 13 biallelic H6PD variants in eight probands, including two homozygous and six compound heterozygous cases (six early-onset PD, two late-onset PD). Functional studies were conducted using cultured cells, Drosophila, and AAV-shRNA-mediated H6PD knockdown mice. Mitochondrial function and redox status were assessed using confocal imaging, flow cytometry, and Seahorse metabolic flux analysis. ER-mitochondria contacts, Ca2⁺ dynamics, and mitophagy were evaluated using SPLICS sensors, calcium imaging, and PINK1-Parkin pathway assays. Our study revealed that H6PD depletion impaired NADPH generation, disrupted ER-mitochondria coupling, caused abnormal Ca2+ release, mitochondrial fragmentation, reduced respiratory capacity, and suppressed PINK1-Parkin-dependent mitophagy. PD-related H6PD variants lost the ability to maintain NADPH/redox balance and mitochondrial protective function. In Drosophila, H6PD loss induced dopaminergic neurodegeneration, locomotor deficits, and shortened lifespan, all partially rescued by human H6PD. Similarly, H6PD knockdown in mice aggravated MPTP-induced neuronal loss and mitochondrial abnormalities. In conclusion, our study identifies biallelic variants in H6PD as a novel cause of PD. H6PD maintains ER NADPH/redox homeostasis, stabilizes ER-mitochondria communication, and preserves mitochondrial function and mitophagy, thereby supporting dopaminergic neuron survival.
    Keywords:  Biallelic variants; Endoplasmic reticulum-mitochondria coupling; H6PD; Mitochondrial dysfunction; Mitophagy; Parkinson’s disease
    DOI:  https://doi.org/10.1016/j.scib.2026.07.038
  24. Br J Cancer. 2026 Jul 14.
    Reactivation of DRP1 plays a functional role in resistance to MEK inhibition in pancreatic cancer cells.
    Salma Sharmin, Jennifer A Kashatus, Sara J Adair, Emma Bakall Loewgren, Mohammad Fallahi-Sichani, Todd W Bauer, David F Kashatus.
       BACKGROUND: In RAS-mutant tumours, ERK phosphorylates the mitochondrial fission GTPase DRP1 to promote mitochondrial fission. DRP1 activity is tumour-promoting in pancreatic and other RAS-driven cancers, but its role in therapeutic resistance is unknown.
    METHODS: We developed a panel of patient-derived pancreatic cancer cell lines resistant to the MEK inhibitor trametinib. We used immunofluorescence imaging, in vitro growth assays and orthotopic xenografts to determine the role of DRP1 in trametinib resistance.
    RESULTS: We find that trametinib-resistant cells exhibit increased expression and phosphorylation of DRP1 compared to sensitive counterparts. Quantitative analysis of mitochondrial structure reveals that mitochondria in resistant cells are morphologically distinct and relatively smaller than sensitive cells treated with trametinib. Genetic and pharmacological inhibition of both c-Myc and CDK6 are sufficient to block DRP1 phosphorylation in resistant cells, suggesting that activation of a c-Myc-CDK6 signalling axis drives reactivation of mitochondrial fission in the absence of MAPK signalling. Importantly, deletion of DRP1 leads to either growth inhibition or re-sensitisation to trametinib in resistant lines.
    CONCLUSION: These findings suggest DRP1 contributes to drug resistance, and that inhibition of mitochondrial fission might be a promising therapeutic strategy to combat resistance to MAPK and RAS inhibitors.
    DOI:  https://doi.org/10.1038/s41416-026-03542-7
  25. Aging Cell. 2026 Jul;25(7): e70623
    Spatial Transcriptomic Atlas Reveals That Forkhead Box O3-Mediated Mitochondrial Dynamics Imbalance Drives Premature Ovarian Insufficiency in Mice.
    Ziwei Song, Yaoli Yin, Meilin Chen, Xiaolu Jin, Zemin Li, Hongxiao Li, Meihong Shen.
      Premature ovarian insufficiency (POI) is a major driver of female reproductive aging, but its mechanisms and the spatial and structural patterns of reproductive aging remain poorly understood. This study, therefore, constructed a spatial transcriptomic atlas of POI mouse models to define the spatial and molecular features of granulosa senescence during disease progression. Spatial analysis revealed disrupted follicular structure and distinct granulosa subpopulations exhibiting blocked differentiation and senescence-associated gene signatures. Integrating multiple gene sets identified structural and functional mitochondrial impairment, excess fission, reduced fusion, mitochondrial membrane potential loss, insufficient ATP production, and reactive oxygen species accumulation as central features of granulosa senescence in POI. KEGG pathway enrichment implicated FOXO signaling in regulating mitochondrial dysfunction, and FOXO3 phosphorylation was significantly reduced in POI. In a triptolide-induced KGN cell POI model, pharmacological inhibition of aberrant FOXO3 activation partially restored mitochondrial morphology and function, whereas suppressing FOXO3 phosphorylation in normal KGN cells induced mitochondrial dysfunction. AAV-mediated FOXO3 overexpression in mouse granulosa cells recapitulated the senescent phenotype and mitochondrial dynamic imbalance, activating PINK1/PARKIN-mediated mitophagy signaling. Physiologically aged 10-month-old mouse ovaries showed identical hallmarks-reduced p-FOXO3, upregulated senescence markers, and disrupted mitochondrial dynamics-suggesting a conserved feature of ovarian functional decline. Together, these findings demonstrate that aberrant FOXO3 pathway activation disrupts mitochondrial dynamic homeostasis, driving granulosa senescence and ovarian failure in POI. By integrating spatial transcriptomics with functional and mechanistic analyzes, this study establishes a spatially resolved framework for understanding ovarian aging and identifies FOXO3-regulated mitochondrial pathways as potential diagnostic and therapeutic targets for POI.
    Keywords:  FOXO3; granulosa cells; mitochondria; premature ovarian insufficiency; spatial transcriptomics
    DOI:  https://doi.org/10.1111/acel.70623
  26. Behav Brain Res. 2026 Jul 16. pii: S0166-4328(26)00361-X. [Epub ahead of print]514 116385
    LPS‑induced impairment of neuroregeneration is alleviated by fluoxetine in Dugesia japonica.
    Zuoqing Yuan, Jinying Huang, Qi Chen, Jingyi Sun, Rui Cao, Huidan Shi, Ran Li, Jianyong Zhang.
      Freshwater planarians (Dugesia japonica) are excellent models for neural regeneration due to their neoblast-dependent regenerative capacity. This study explored the regulatory effects of fluoxetine (FLX) on lipopolysaccharide (LPS)-triggered neuroinflammation as well as cyclosporin A (CsA)-mediated mitophagy inhibition during the regeneration of Dugesia japonica. Planarians were exposed to LPS, FLX, and CsA alone or in combination for 10 days, with assessments of regeneration, locomotion, antioxidant function, DNA damage, neoblast proliferation, apoptosis, and PINK1/Parkin pathway activity. Results showed LPS (10 μg/mL) and CsA (0.5 μg/mL) significantly impaired eyespot regeneration and locomotion, disrupted antioxidant enzyme (SOD, CAT, GST, GR) activity/expression, induced DNA damage, suppressed neoblast proliferation, disturbed neurotransmitter-related gene expression, and reduced the level of LC3B, a key protein in the PINK1/Parkin pathway. FLX (2 μg/mL) alleviated these adverse effects by restoring antioxidant balance, mitigating DNA damage, promoting proliferation, potentially associated with the activation of PINK1/Parkin-related mitophagy, and normalizing neurotransmitter synthesis-related genes. Notably, CsA reversed FLX's neuroprotective effects, implying FLX-mediated protection against LPS toxicity may be linked to the PINK1/Parkin-associated mitophagy pathway. This study validates FLX's neuroprotective potential, reinforces D. japonica as a model for mitophagy-related neuroregeneration, and provides preliminary insights for FLX's application in neurological disorders with impaired mitophagy and neuroregeneration.
    Keywords:  Dugesia japonica; Fluoxetine; Mitophagy; Neural regeneration; Neuroprotection
    DOI:  https://doi.org/10.1016/j.bbr.2026.116385
  27. Molecules. 2026 Jul 01. pii: 2317. [Epub ahead of print]31(13):
    Network Destabilization in Aging: Mitochondrial Dysfunction, Nutrient Sensing, and Chronic Inflammation as Interconnected Drivers.
    Wojciech Rzeski.
      Aging is the dominant risk factor for most chronic diseases, yet the mechanisms driving this relationship remain poorly integrated across biological scales. Existing frameworks have catalogued key hallmarks of aging but do not explain how these processes converge to produce organism-level decline and multimorbidity. A systems-level framework is introduced in which aging is conceptualized as progressive destabilization of interacting regulatory networks. Mitochondrial quality control, nutrient-sensing pathways, and chronic inflammatory signaling form a putative high-centrality network core: mitochondria coordinate redox balance, bioenergetics, and transcriptional adaptation, while NAD+-dependent signaling and NLRP3 inflammasome activation propagate perturbations across regulatory layers. This architecture provides a mechanistic basis for the convergence of neurodegenerative, cardiovascular, metabolic, and oncological phenotypes as emergent consequences of shared network instability. Reframing the hallmarks as coupled network nodes shifts the explanatory focus from isolated mechanisms to system-level resilience and non-linear dynamics. This narrative and conceptual review integrates evidence across mitochondrial biology, metabolic signaling, and inflammatory pathways to develop these arguments, with explicit acknowledgment that the proposed framework is hypothesis-generating rather than formally validated. Interventions targeting high-centrality nodes, including mTOR modulation, NAD+ restoration, mitophagy activation, and anti-inflammatory strategies, may exert system-wide effects by reconfiguring network dynamics rather than correcting individual pathways. This perspective suggests that biomarker-stratified, network-calibrated interventions may offer a broader systems-level therapeutic rationale than single-pathway approaches.
    Keywords:  NAD+ metabolism; aging; chronic inflammation; integrative biology; mitochondria; mitophagy; multimorbidity; network medicine
    DOI:  https://doi.org/10.3390/molecules31132317
  28. Int Immunopharmacol. 2026 Jul 14. pii: S1567-5769(26)00967-7. [Epub ahead of print]186 117121
    Grx attenuates diabetes cataract by activating AMPK/BNIP3/BNIP3L-mediated mitophagy in lens epithelial cells.
    Jie Zhang, Chenjun Guo, Chao Liang, Xiaona Ning.
      Glutaredoxin (Grx) plays an important antioxidant role in the pathogenesis of cataracts. Our previous research found that Grx knockout accelerated the occurrence of aging-related cataract (ARC) and was closely related to lens opacity, but the regulatory mechanism of Grx in diabetes cataract (DC) is still unclear. Here, we found that AMPK activity was significantly decreased in the anterior lens capsule of DC patients and high-glucose (HG) treated human lens epithelial cells HLEC-B3, and Grx protein expression and activity were compensatory increased. Moreover, Grx protected HLEC-B3 cells from HG-induced oxidative stress injury and apoptosis, and induced mitophagy. Both AMPK inhibitor (Compound C) and BNIP3 knockdown attenuated these effects. In vivo, Grx alleviated DC by inhibiting oxidative damage, whereas Compound C reversed the protective effect of Grx. In summary, our findings suggest that Grx alleviates DC in rats by activating AMPK to induce BNIP3/BNIP3L-mediated mitophagy. This study provides new experimental evidence and potential targets for the future treatment of DC.
    Keywords:  AMPK/BNIP3/BNIP3L signaling pathway; Diabetes cataract; Grx; Mitophagy; Oxidative damage
    DOI:  https://doi.org/10.1016/j.intimp.2026.117121
  29. Zhongguo Zhen Jiu. 2026 Jul 12. 46(7): 1108-1114
    [Effect of eye acupuncture on mitophagy in neurons of ischemic cortical brain tissue in rats with cerebral ischemia reperfusion injury based on AMPK/ULK1/FUNDC1 signaling axis].
    Yanpeng Pu, Jingyan Cheng, Zhen Wang, Haoran Chu.
       Objective: To observe the effects of eye acupuncture on neurological deficits and mitophagy in neurons of ischemic cortical brain tissue in rats with cerebral ischemia reperfusion injury (CIRI), and to explore the possible mechanism of eye acupuncture in improving CIRI.
    Methods: Forty-eight SD rats were randomly divided into a sham operation group, a model group, an eye acupuncture group, and an inhibitor group, with 12 rats in each group. The modified middle cerebral artery occlusion method was used to establish CIRI model in the model group, eye acupuncture group, and inhibitor group. Before modeling, the rats in the sham operation group, model group, and eye acupuncture group were intraperitoneally injected with phosphate-buffered solution, while the rats in the inhibitor group were intraperitoneally injected with Compound C solution (adenosine monophosphate-activated protein kinase [AMPK] inhibitor). After successful modeling, the rats in the eye acupuncture group and inhibitor group received eye acupuncture intervention. Bilateral Shangjiao, Xiajiao, Gan (CO12) and Shen (CO10) were selected, with needles retained for 30 min without manipulation, once every 12 h, for a total of 7 interventions. Longa and Bederson scores were used to evaluate neurological deficits in rats. TTC staining was used to observe cerebral infarction. Nissl staining was used to observe the number of Nissl bodies in cortical brain tissue in the ischemic penumbra area. Transmission electron microscopy was used to observe the ultrastructure of neuronal mitochondria in cortical brain tissue in the ischemic penumbra area. Western blot was used to detect the protein expressions of AMPK, phosphorylated adenosine monophosphate-activated protein kinase (p-AMPK), unc-51-like autophagy activating kinase 1 (ULK1), phosphorylated unc-51-like autophagy activating kinase 1 (p-ULK1), FUN14 domain containing 1 (FUNDC1), phosphorylated FUN14 domain containing 1 (p-FUNDC1), and microtubule-associated protein light chain 3βⅡ (LC3-Ⅱ).
    Results: Compared with the sham operation group, Longa and Bederson scores in the model group were increased (P<0.05), cerebral infarct volume was increased (P<0.05), the number of Nissl bodies in cortical brain tissue in the ischemic penumbra area was reduced (P<0.05), autophagosomes appeared, and the ratios of p-AMPK/AMPK, p-ULK1/ULK1, p-FUNDC1/FUNDC1, as well as LC3-Ⅱ protein expression in cortical brain tissue in the ischemic penumbra area were increased (P<0.05). Compared with the model group and inhibitor group, Longa and Bederson scores in the eye acupuncture group were reduced (P<0.05), cerebral infarct volume was reduced (P<0.05), the number of Nissl bodies in cortical brain tissue in the ischemic penumbra area was increased (P<0.05), a small number of autophagosomes were observed, and the ratios of p-AMPK/AMPK, p-ULK1/ULK1, p-FUNDC1/FUNDC1, as well as LC3-Ⅱ protein expression in cortical brain tissue in the ischemic penumbra area were increased (P<0.05).
    Conclusion: The eye acupuncture may improve CIRI by upregulating the AMPK/ULK1/FUNDC1 signaling axis, promoting mitophagy, and alleviating neuronal injury.
    Keywords:  AMPK/ULK1/FUNDC1 signaling axis; cerebral ischemia reperfusion injury (CIRI); eye acupuncture; mitophagy
    DOI:  https://doi.org/10.13703/j.0255-2930.20250322-k0002
  30. J Ethnopharmacol. 2026 Jul 16. pii: S0378-8741(26)01051-2. [Epub ahead of print]372 122197
    Guizhi Wuling Decoction alleviates myocardial fibrosis by restoring mitochondrial homeostasis: Evidence from network pharmacology, molecular docking, and multi-omics integration.
    Lipeng Shi, Jie Wang, Ruogu Yang, Bingxin Qian, Yixuan Li, Xuqin Du, Yi Ren.
       ETHNOPHARMACOLOGICAL RELEVANCE: Guizhi Wuling Decoction (GWD), a combined prescription consisting of the classical formulas Wuling San and Guizhi Fuling Wan without modification, has been clinically applied for cardiovascular diseases. Previous studies have reported its cardioprotective and anti-fibrotic effects; however, the underlying molecular mechanisms remain incompletely understood.
    AIM OF THE STUDY: To investigate whether restoration of mitochondrial homeostasis contributes to the anti-fibrotic effects of GWD and to explore the involvement of AMPK/PGC-1α signaling.
    MATERIALS AND METHODS: Myocardial fibrosis (MF) was induced in C57BL/6 J mice by isoproterenol (ISO) administration. Cardiac function, myocardial fibrosis, mitochondrial ultrastructure, mitochondrial membrane potential, ATP production, and NAD+/NADH ratio were evaluated. Absorbed constituents in GWD-containing serum were characterized using UHPLC-MS/MS. Integrated transcriptomic-proteomic analysis highlighted AMPK signaling as one of the important pathways associated with GWD treatment. Molecular docking and molecular dynamics simulations were conducted to evaluate the interactions between representative absorbed compounds and candidate targets. The involvement of AMPK signaling was further validated by pharmacological inhibition using Compound C.
    RESULTS: GWD significantly improved cardiac function, attenuated myocardial fibrosis, and restored mitochondrial homeostasis, as evidenced by improved mitochondrial ultrastructure, increased mitochondrial membrane potential, ATP production, and NAD+/NADH ratio. Integrated transcriptomic and proteomic analyses identified AMPK signaling as an important pathway associated with the protective effects of GWD. Mechanistically, GWD activated the AMPK/PGC-1α signaling pathway and upregulated mitochondrial biogenesis- and quality control-related proteins, including NRF1, TFAM, and MFN2. Pharmacological inhibition of AMPK by Compound C significantly attenuated GWD-associated improvement of mitochondrial homeostasis and anti-fibrotic effects.
    CONCLUSION: GWD alleviates ISO-induced MF, at least in part, by restoring mitochondrial homeostasis. Integrated multi-omics analyses and pharmacological validation suggest that AMPK/PGC-1α signaling may contribute to the anti-fibrotic effects of GWD. These findings provide experimental evidence suggesting the involvement of mitochondrial homeostasis in MF and offer new insights into the anti-fibrotic effects of GWD.
    Keywords:  AMPK/PGC-1α signaling pathway; Guizhi wuling decoction; Mitochondrial homeostasis; Myocardial fibrosis; Proteomics; Transcriptomics
    DOI:  https://doi.org/10.1016/j.jep.2026.122197
  31. Int J Mol Sci. 2026 Jul 07. pii: 6073. [Epub ahead of print]27(13):
    Rewiring Lipid Metabolism: PINK1 as a Central Regulator of Mitochondrial Homeostasis in Parkinson's Disease.
    Ana Beatriz Ramos, Vanessa Alexandra Morais.
      Increasing evidence highlights a tight interplay between lipid metabolism and mitochondrial homeostasis in neurons, with disruptions in either pathway amplifying cellular vulnerability. PTEN-induced kinase 1 (PINK1), a familial Parkinson's disease (PD)-related gene and a key regulator of mitochondrial quality control and homeostasis, emerges at the intersections of lipid metabolic pathways, influencing membrane composition, fatty acid utilization, and neuronal energy balance. Within this review, we discuss the role of mitochondria as hubs for lipid metabolism, the mechanisms and functional consequences of neuronal lipid handling, and the complex bidirectional relationship between lipid dysregulation and PD pathology. Special focus is given to lipid-mitochondria crosstalk and how PINK1 orchestrates this interface to maintain neuronal homeostasis. Finally, we consider therapeutic perspectives that target lipid and mitochondrial pathways, highlighting strategies to restore cellular function and PD pathology.
    Keywords:  PINK1; Parkinson’s disease; lipids; metabolism; mitochondria
    DOI:  https://doi.org/10.3390/ijms27136073
  32. Biochim Biophys Acta Mol Cell Res. 2026 Jul 16. pii: S0167-4889(26)00090-X. [Epub ahead of print] 120191
    Metformin triggers ATF4-mediated UPRmt and COX-2 inflammation in adipocytes.
    Juthakorn Poothong, Chutipong Chiamkunakorn, Wichit Suthammarak, Teva Phanaksri, Prasert Auewarakul, Jing Yong, Randal J Kaufman.
      Metformin is the most common drug for type 2 diabetes due to its action to improve insulin sensitivity and enhance glucose uptake in tissues, including adipose tissue. As a mitochondrial complex I inhibitor, treatment with metformin may cause deleterious effects. Here, we demonstrated that treatment of adipocytes 3 T3-L1 cells with a high concentration of metformin (10 mM) led to increased reactive oxygen species (ROS) accumulation and triggered the mitochondrial unfolded protein response (UPRmt), as revealed by increased mRNA expression of UPRmt markers (mtHSP70, Lonp1, and FGF21). High-concentration metformin also induced COX-2 inflammation, as indicated by increased NF-κB phosphorylation and cyclooxygenase-2 (COX-2) expression. By contrast, a lower concentration (1.25 mM) showed no effects. We found that ATF4 was selectively upregulated and was required for UPRmt and COX-2 inflammation induced by metformin. Interestingly, we showed that the integrated stress response inhibitor (ISRIB) effectively inhibited ATF4, mitigated metformin-induced UPRmt, and reduced NF-κB/COX-2 expression. Taken together, our findings point to the undesirable effect of the high-concentration metformin in adipocytes.
    Keywords:  ATF4; COX-2; ISRIB; Metformin; ROS; UPR(mt)
    DOI:  https://doi.org/10.1016/j.bbamcr.2026.120191
  33. Cardiovasc Toxicol. 2026 Jul 11. pii: 79. [Epub ahead of print]26(7):
    The mtROS-Mitophagy Axis: A Decisive Redox Hub Governing Cell Fate in Myocardial Ischemia-Reperfusion Injury.
    Wei Wang, Zhihao Xu, Wei Liu, Yaolu Kang, Fan Zhang, Qing Yu, Ronglin Cai.
      The progression of myocardial ischemia-reperfusion injury (MIRI) is orchestrated by a decisive, bidirectional dialogue between mitochondrial reactive oxygen species (mtROS) and mitophagy. This review advances the concept of a dynamic "mtROS-mitophagy axis" as the central redox hub determining cardiomyocyte fate. We systematically dissect how moderate mtROS initiates protective mitophagy via key pathways (e.g., PINK1/Parkin, FUNDC1) and reinforces endogenous defenses through the Sirt3-FoxO3a integrator. Conversely, an mtROS burst disrupts this axis, triggering a vicious cycle of oxidative damage, impaired autophagic flux, and Drp1-mediated pathological fission. Critically, we emphasize the double-edged and temporally governed nature of this axis, arguing that its precise spatiotemporal modulation represents the next frontier in cardioprotection. Beyond mechanism, this synthesis provides a unified framework for developing novel therapies and for evaluating the cardiac safety of pharmacological agents, directly aligning with the core pursuits of cardiovascular redox biology and toxicology.
    Keywords:  Antioxidant defense; Mitochondrial reactive oxygen species; Mitophagy; Myocardial ischemia-reperfusion injury; Oxidative stress; Redox signaling; Sirt3
    DOI:  https://doi.org/10.1007/s12012-026-10137-4
  34. J Cell Mol Med. 2026 Jul;30(13): e71249
    Kaempferide in Alpinia officinarum Hance Exerts Anti-Hepatocellular Carcinoma Activity by Inhibiting Mitophagy Through Downregulation of BNIP3L.
    Lu Lu, Changxian Li, Cunzhen Jiang, Yuan Zhao, Yinghong Zhong, Jicheng Hu, Zhe Wang, Mingyan Zhou, Jian Xu, Xiangcheng Li.
      Hepatocellular carcinoma (HCC), the most common primary malignant tumour of the liver, is notorious for its high mortality rate.Alpinia officinarum Hance (A. officinarum) is a perennial medicinal herb used for the management of abdominal pain, vomiting, and gastrointestinal tumours, and is widely applied as a dietary intervention by the Li ethnic group in Hainan, China. Kaempferide, a bioactive flavonoid isolated from this herb, exhibits promising antitumor properties; however, its precise mechanism against HCC remains incompletely understood. In this study, we demonstrated that kaempferide could inhibit proliferation and migration of HCC cells, induce G0/G1 phase cell arrest and promote the accumulation of ROS, while suppressing xenograft tumour growth in nude mice. Further investigations revealed that kaempferide targeted BNIP3L and suppressed mitophagy, evidenced by elevated P62 levels and reduced LC3-II levels. In summary, kaempferide exerts anti-HCC effects by inhibiting mitophagy via the downregulation of BNIP3L, suggesting its potential role as a therapeutic candidate for HCC.
    Keywords:  Alpinia officinarum Hance; BNIP3L; hepatocellular carcinoma; kaempferide; mitophagy
    DOI:  https://doi.org/10.1111/jcmm.71249
  35. J Alzheimers Dis. 2026 Jul 11. 13872877261465779
    Mitophagy deficiency and calcium dyshomeostasis underlying the pathogenesis and progression of Alzheimer's disease.
    Guangrong Meng, Liang Cai, Zhongcheng Mo, Shaoying An, Wenhui Sun, Ping Shen, Yuanjie Xie.
      Alzheimer's disease (AD) is a neurodegenerative disorder defined by three pathological hallmarks: amyloid-β (Aβ) deposition, tau hyperphosphorylation leading to neurofibrillary tangles formation, and neuronal loss. Mounting evidence over the past decade has underscored that mitophagy deficiency and calcium dyshomeostasis play pivotal regulatory roles in AD pathological progression, with these two abnormalities persisting throughout the entire course of disease onset and development. Mitophagy impairment can result in the accumulation of dysfunctional mitochondria, thereby further exacerbating calcium dyshomeostasis which can suppress autophagic flux in turn. This reciprocal interaction establishes a vicious cycle that can synergistically accelerate Aβ plaque and neurofibrillary tangle formation, impair synaptic structure and function, and ultimately elicit neuronal programmed cell death and cognitive decline. This review systematically summarizes the biological basis of mitophagy and calcium homeostasis, as well as their mutual regulatory networks. It places particular emphasis on deciphering the pathological mechanisms through which concurrent impairments of these two pathways synergistically drive AD pathogenesis and progression. Furthermore, we propose intervention strategies targeting to modulate mitophagy deficiency and calcium dyshomeostasis, which hold great promise for providing novel insights and potential therapeutic targets for the clinical management of AD.
    Keywords:  Alzheimer's disease; calcium dyshomeostasis; mitophagy deficiency; neuronal programmed cell death
    DOI:  https://doi.org/10.1177/13872877261465779
  36. PLoS One. 2026 ;21(7): e0353376
    TBX20 promotes doxorubicin resistance in breast cancer cells through enhanced ABCC1 expression and inhibition of mitophagy.
    Shuai Nie, Dejian Liu, Jun Hu, Yu Gan, Liangliang Mi.
      This study aimed to investigate the role and mechanism of T-box transcription factor 20 (TBX20) in doxorubicin resistance in breast cancer cells. RNA-seq data from breast cancer samples in the TCGA database were analyzed. Lentiviral vectors were used to establish TBX20 overexpression and silencing models in MCF-7 and MDA-MB-231 cells. Gene and protein expression were detected by qPCR and Western blot, respectively. Cell viability and the half-maximal inhibitory concentration of doxorubicin were measured using the CCK-8 assay. Apoptosis, migration, and invasion were analyzed by flow cytometry, wound healing assay, and Transwell assay. Mitophagy levels were assessed via immunofluorescence staining and western blotting. ChIP and dual-luciferase reporter assays were performed to validate the transcriptional regulation of ABCC1 by TBX20. Results showed that TCGA data analysis revealed a high expression of TBX20 in breast cancer tissues, which was positively correlated with ABCC1 expression. In MCF-7 and MDA-MB-231 cells, TBX20 overexpression significantly enhanced cell proliferation, migration, invasion, and resistance to doxorubicin, while suppressing the expression of mitophagy-related proteins LC3-II/LC3-I, PINK1, and BNIP3. ChIP and dual-luciferase reporter assays confirmed that TBX20 directly binds to and activates the ABCC1 promoter. Silencing of ABCC1 or restoration of mitophagy by CCCP reversed TBX20 overexpression‑induced doxorubicin resistance. TBX20 enhances the resistance of breast cancer cells to doxorubicin by transcriptionally upregulating ABCC1 and is correlated with the suppression of mitophagy.
    DOI:  https://doi.org/10.1371/journal.pone.0353376
  37. bioRxiv. 2026 Jul 08. pii: 2026.07.06.735726. [Epub ahead of print]
    Pathogenic DRP1 variants reveal a role for biomolecular condensation in mitochondrial fission.
    Kyle A Ross, Amanda M Travis, Megan C Harwig, Micaela S Young, Erica H Rodas Montejo, Michael J Donohue, Robert W Taylor, Monika Oláhová, R Blake Hill.
      Fission is essential for proper mitochondrial function and for cellular homeostasis. Dysfunction in mitochondrial fission is associated with several neurological disorders, including the rare and lethal encephalopathy EMPF1, which is caused by de novo heterozygous DNM1L variants. DNM1L encodes the mitochondrial fission mechanoenzyme DRP1, which can intrinsically self-assemble and induce membrane scission. Wild-type DRP1 puncta that appear throughout the cytoplasm are thought to be pre-scission complexes of well-ordered oligomeric assemblies. Immunofluorescence imaging of patient-derived EMPF1 fibroblasts carrying assembly-deficient DNM1L variants reveals elongated mitochondrial networks consistent with impaired fission. Despite this loss-of-function phenotype, these cells retain essentially wild-type numbers of DRP1 puncta. We confirmed the previously reported inability of purified pathogenic DRP1 variants p.Gly363Asp and p.Gly401Ser to assemble under conditions in which WT DRP1 forms helical polymers. Under macromolecular crowding conditions, however, both wild-type and mutant DRP1 access condensed states whose formation depends on protein concentration and solution conditions. Acute treatment of EMPF1 fibroblasts with 1,6-hexanediol preferentially alters DRP1 puncta fluorescence intensity and distribution in mutant cells relative to wild type, indicating genotype-dependent differences in puncta material properties. Together, these findings support a model in which DRP1 puncta occupy a continuum of condensed states, only a subset of which mature into fission-competent assemblies, revealing biomolecular condensation as a previously unrecognized layer of DRP1 regulation. Biasing DRP1 along this continuum may provide a mechanistic basis for impaired fission in EMPF1 and suggest opportunities to restore productive assembly in select pathogenic contexts.
    Significance Statement: DRP1 puncta associated with mitochondrial fission are thought to be well-ordered oligomeric assemblies that precede membrane scission. Yet their dynamic behavior within cells has remained difficult to reconcile as well-ordered assembly. Under prevailing models, cells bearing pathogenic DNM1L variants impaired in assembly would be expected to lack puncta, but we show these cells retain wild-type puncta levels. We demonstrate that both wild-type and pathogenic mutant DRP1 populate multiple condensed states in vitro , and that disease variants are biased toward more fluid, chemically sensitive assemblies. These findings identify biomolecular condensation as a regulatory layer of DRP1 organization and suggest that shifting DRP1 along this assembly continuum may restore productive fission in select pathogenic contexts.
    DOI:  https://doi.org/10.64898/2026.07.06.735726
  38. bioRxiv. 2026 Jul 09. pii: 2026.07.08.737379. [Epub ahead of print]
    Tissue-specific consequences of impaired RNA surveillance converge on mitochondrial homeostasis.
    Lauryn A Higginson, Xingjun Wang, Derrick J Morton.
      RNA surveillance pathways maintain transcriptome integrity by eliminating aberrant, excess, and non-functional RNAs, yet it remains unclear whether distinct tissues exhibit equivalent requirements for RNA quality control. Here, we investigated the tissue-specific consequences of impaired RNA surveillance using a Drosophila allelic series of the RNA exosome subunit Rrp40. Comparative transcriptomic analyses revealed that neuronal-enriched head tissue and muscle-enriched thorax tissue exhibit largely distinct molecular programs following reduced RNA exosome activity despite disruption of the same RNA surveillance machinery. Antisense RNAs emerged as particularly sensitive targets of RNA exosome dysfunction, accumulating preferentially in neuronal tissue and largely independent of changes in overlapping sense host transcripts, indicating enhanced requirements for RNA-level quality control within the nervous system. Although tissue-specific transcriptomic alterations diverged substantially, multiple analyses converged on mitochondrial homeostasis as a shared vulnerability. Reduced RNA exosome activity was associated with widespread dysregulation of nuclear-encoded mitochondrial genes, mitochondrial dynamics pathways, and mitochondrial RNA regulatory programs, accompanied by progressive defects in mitochondrial organization, membrane potential, and ATP production. Mitochondrial dysfunction was further associated with activation of proteostatic stress pathways, including p62 accumulation and increased ubiquitination. Together, these findings demonstrate that tissue context shapes the molecular consequences of impaired RNA surveillance while revealing mitochondrial homeostasis as a convergent vulnerability arising from transcriptome instability. More broadly, our findings suggest that distinct tissue-specific defects in RNA regulation converge on common cellular vulnerabilities that ultimately govern tissue homeostasis.
    DOI:  https://doi.org/10.64898/2026.07.08.737379
  39. Front Cell Dev Biol. 2026 ;14 1854844
    Urolithin A enhances mitochondrial biogenesis-related markers and maximal respiratory capacity during C2C12 differentiation.
    Ronald Vargas-Foitzick, Diego Irribarra-Tapia, Mayalen Valero-Breton, Elisa Balboa.
       Introduction: Skeletal muscle differentiation in the C2C12 myoblast model requires extensive mitochondrial remodeling to meet rising bioenergetic demands through coordinated changes in biogenesis, dynamics, and respiratory adaptation. Urolithin A (UA), a gut microbiota-derived metabolite of ellagitannins, improves mitochondrial health, but its role in late-stage myogenic differentiation remains unclear.
    Methods: C2C12 myotubes were treated with UA (2 μM) for 72 h during late-stage differentiation (days 3-6). Mitochondrial signaling, respiratory capacity, myogenic morphology, and ultrastructure were assessed by Western blot, high-resolution respirometry, hematoxylin-eosin staining, and transmission electron microscopy.
    Results: UA was non-cytotoxic and increased AMPKα phosphorylation and PGC-1α expression, whereas TOM20, MFN2, and OPA1 were unchanged. Mitophagy/autophagy-related markers (p-ULK1, p62, BNIP3L/NIX, LC3-II/I) were not altered, indicating no detectable changes in steady-state autophagy under the conditions tested. UA selectively increased OXPHOS Complex I and II abundance and enhanced maximal uncoupled respiration, and was associated with increased myotube diameter and myogenic marker abundance. No overt ultrastructural differences were observed by electron microscopy.
    Discussion: These findings suggest that UA promotes mitochondrial functional adaptation during myogenic differentiation, with accompanying changes in myogenic phenotype, without clear evidence of altered steady-state mitophagy/autophagy markers or mitochondrial morphology.
    Keywords:  C2C12 myotubes; maximal respiration; myogenic differentiation; oxphos; urolithin A
    DOI:  https://doi.org/10.3389/fcell.2026.1854844
  40. Behav Brain Res. 2026 Jul 15. pii: S0166-4328(26)00353-0. [Epub ahead of print] 116377
    Corrigendum to"Downregulation of Nrf2 deteriorates cognitive impairment in APP/PS1 mice by inhibiting mitochondrial biogenesis through the PPARγ/PGC1α signaling pathway" [Behavioural Brain Res. 495 (2025) 115805].
    Weigang Luo, Wei Bu, Guisong Zhang, Yujuan Dong, Yuling Wang, Jinyang Wang, Cuicui Liu, Xiaokai Hu, Yanan Jia, Huiling Ren.
      
    DOI:  https://doi.org/10.1016/j.bbr.2026.116377
  41. Mater Today Bio. 2026 Aug;39 103393
    Layered double hydroxide nanocarriers loaded with butylphthalide attenuate the AKI-CKD transition by regulating mitophagy.
    Ke Wang, Xing-Chun Zhu, Yi Xia, Yan Yan, Jun-Jie Ma, Jing-Yi Xia, Yuan Xu, Meng-Han He, Feng-le Guo, Wen-Rui Wang, Li Ren, Cong-Li Zhang.
      Acute kidney injury (AKI) caused by ischemia-reperfusion (IR) is an independent risk factor for the progression of chronic kidney disease (CKD), yet there is a lack of effective clinical interventions. Although butylphthalide (NBP) has been proven to have multi-organ protective potential, its rapid in vivo metabolism and low bioavailability limit its clinical application. To overcome these limitations, we rationally designed and synthesized a layered double hydroxide (LDHs)-based nanocarrier system for NBP delivery (LDHs@NBP) via hydrothermal co-precipitation. Comprehensive characterization confirmed successful nanocomplex formation. Critically, LDHs@NBP exhibited accelerated NBP release under mildly acidic conditions, matching the pathological acidosis of injured and fibrotic renal tubules-thereby achieving pH-responsive drug release. Using both an in vivo rat model of unilateral renal ischemia-reperfusion injury (uIRI) and an in vitro TGF-β1-stimulated HK-2 cell model, we demonstrated that LDHs@NBP significantly attenuated renal dysfunction, suppressed interstitial fibrosis, and improved mitochondrial function. Importantly, all protective effects were abolished upon co-treatment with Mdivi-1, confirming mitophagy as the central mechanistic axis. Collectively, this study successfully constructed LDHs@NBP nanocomplexes with pH-responsive drug release properties. This system enhances mitophagy by activating the PINK1-Parkin pathway, thereby effectively blocking AKI-CKD transition. It provides a new strategy with good translational prospects for clinical intervention in kidney diseases.
    Keywords:  AKI; Butylphthalide; CKD; Layered double hydroxide; Mitophagy
    DOI:  https://doi.org/10.1016/j.mtbio.2026.103393
  42. J Endocrinol. 2026 Jul 14. pii: JOE-26-0023. [Epub ahead of print]
    Exendin-4 improves high glucose-induced mitochondrial dysfunction of pancreatic β-cells via PKA/Drp1 signaling.
    Jiahao Zhao, Xin Ling, Siwen Fan, Zhenyu Sun, Xingyu Huang, Hao Fu, Haiyan Liu, Yuanyuan Xing, Xia Zhu.
      The development of type 2 diabetes mellitus is closely associated with mitochondrial dysfunction of pancreatic β-cells, but the mechanisms by which glucagon-like peptide-1 receptor activation preserves mitochondrial homeostasis under glucotoxic conditions remain incompletely understood. Herein, we investigated whether Exendin-4 protects β-cells against chronic high glucose (HG)-induced mitochondrial injury by regulating the cAMP/PKA/Drp1 signaling pathway. INS-1 β-cells, pancreatic tissues from db/db mice, and isolated primary islets were used to assess oxidative stress, apoptosis, mitochondrial function and morphology, insulin secretion, and cAMP/PKA/Drp1 signaling. Prolonged HG exposure increased oxidative stress and apoptosis, impaired mitochondrial membrane potential, elevated mitochondrial ROS accumulation, reduced ATP content, and promoted mitochondrial fragmentation in INS-1 β-cells. These changes were accompanied by increased Drp1 expression, reduced cAMP levels and PKA activity, decreased inhibitory phosphorylation of Drp1 at Ser637, and increased Ser616 phosphorylation. Exendin-4 attenuated HG-induced oxidative stress and apoptosis, restored mitochondrial function, improved mitochondrial morphology, and partially restored Drp1 Ser637 phosphorylation, whereas it did not significantly affect HG-induced Ser616 phosphorylation. In db/db mice, Exendin-4 improved metabolic parameters and alleviated β-cell apoptosis, with partial recovery of Drp1 Ser637 phosphorylation in pancreatic islets. Furthermore, glucose-stimulated insulin secretion assays in isolated primary islets showed that Exendin-4 improved β-cell secretory function in islets isolated from db/db mice. Pharmacological inhibition of PKA with H89 attenuated Exendin-4-induced Drp1 Ser637 phosphorylation and mitochondrial protection. Collectively, these results suggest that Exendin-4 protects pancreatic β-cells against HG-induced mitochondrial dysfunction and β-cell injury by restoring PKA-associated inhibitory phosphorylation of Drp1 at Ser637 and improving mitochondrial dynamics.
    Keywords:  Drp1; Exendin-4; PKA; pancreatic β-cells
    DOI:  https://doi.org/10.1530/JOE-26-0023
  43. Chem Biol Interact. 2026 Jul 16. pii: S0009-2797(26)00369-8. [Epub ahead of print] 112261
    LKB1/ AMPK deficiency aggravates mitochondrial DNA leakage via mTOR-dependent mitophagy damage in liver injury sensitized by trichloroethylene.
    Lifu Zhu, Chenghuan Wan, Zijun Li, Xuan Fan, Dongsheng Liu, Xueqian Jia, Hui Li, Jiaxiang Zhang.
      Occupational medication-like dermatitis induced by trichloroethylene (OMDT) is a severe systemic allergic disease, often accompanied by acute liver injury. However, the underlying mechanisms linking metabolic disorders and immune damage remain unclear. In a TCE-sensitized mouse model, we demonstrated that TCE sensitization inhibited LKB1/AMPK/mTOR signaling pathway (LKB1 overexpression, AICAR, rapamycin) or autophagy (3-MA) in hepatocytes, resulting in defective mitophagy. This mitochondrial dysfunction leads to leakage of mitochondrial DNA (mtDNA) into the cytoplasm, where mtDNA acts as a damage-associated molecular pattern (DAMP) to activate the cGAS-STING pathway, driving the production of proinflammatory cytokines (IL-1β, IL-6, TNF-α), and exacerbating liver inflammation. Restoration of LKB1/AMPK signaling or inhibition of mTOR rescued mitophagi, reduced mitochondrial DNA leakage, inhibited cGAS-STING activation, and alleviated liver pathology, while inhibition of autophagy alone recapitulated the TCE-induced phenotype. Taken together, our findings demonstrate that failure of TCE via LKB1/AMPK/mTOR mediated mitophagy destroys hepatocyte homeostasis, leading to mtDNA-driven cGAS-STING activation and immune-mediated liver injury in the pathogenesis of OMDT, thus providing a potential therapeutic target for OMDT-related liver injury.
    Keywords:  LKB1/AMPK/mTOR; Mitophagy; OMDT; TCE; mtDNA
    DOI:  https://doi.org/10.1016/j.cbi.2026.112261
  44. J Transl Med. 2026 Jul 17.
    Coffee as a polypharmacological modulator of mitochondrial health: from molecular mechanisms to translational implications.
    Zhaochang Jiang, Yu Ding.
       BACKGROUND: Coffee is one of the most widely consumed beverages worldwide, yet its biological effects have often been attributed primarily to caffeine. Emerging evidence suggests that coffee contains a complex array of bioactive compounds, including chlorogenic acids, trigonelline, diterpenes, and melanoidins that collectively exert pleiotropic effects on cellular metabolism. However, a comprehensive framework linking the full spectrum of coffee-derived bioactives to mitochondrial health and chronic disease prevention is still lacking.
    MAIN BODY: This review proposes an integrated perspective on coffee as a systemic "mitochondrial network optimizer." We present this model as an integrative framework and hypothesis rather than an established causal model. We synthesize molecular, pre-clinical, and clinical evidence suggesting that coffee bioactives converge on key regulatory nodes, namely the AMPK/SIRT1/PGC-1α axis, Nrf2/ARE antioxidant pathway, PINK1/Parkin-mediated mitophagy, and mitochondrial calcium signaling to coordinately enhance mitochondrial biogenesis, quality control, redox defense, and metabolic efficiency. These multi-targeted mechanisms provide a plausible biological basis for the consistent epidemiological associations between moderate coffee consumption and reduced risk of metabolic diseases (type 2 diabetes, non-alcoholic fatty liver disease), neurodegenerative disorders (Parkinson's, Alzheimer's), and cardiovascular conditions. Furthermore, we critically examine key determinants of response heterogeneity, including non-linear hormetic dose-response relationships, inter-individual variability (CYP1A2 genotype, gut microbiota, sex), and the impact of coffee processing and brewing methods on bioactive composition.
    CONCLUSIONS: Collectively, these findings support the hypothesis that coffee may serve as a paradigm of polypharmacological dietary intervention that targets fundamental pathways of mitochondrial resilience. Moving beyond reductionist views centered on single compounds, we propose that the holistic effects of coffee are best understood through systems-level modulation of mitochondrial homeostasis. Future research should prioritize precision nutrition approaches stratified by genotype, microbiome, and metabolic phenotype, to translate these mechanistic insights into personalized dietary recommendations and the development of mitochondria-targeted nutraceuticals. We caution that this integrative framework requires direct validation in human causal studies.
    Keywords:  Coffee; Hormesis; Mitochondrial biogenesis; Oxidative stress; Precision nutrition
    DOI:  https://doi.org/10.1186/s12967-026-08662-5
  45. Neurosci Lett. 2026 Jul 15. pii: S0304-3940(26)00185-0. [Epub ahead of print] 138685
    Regulation of mitochondrial biogenesis by the 5-HT1F receptor and its agonist in inferior spinal cords after spinal cord injury.
    Chao Zhang, Liqun Ren, Yanfang Fan.
       BACKGROUND: Muscle spasticity is among the common secondary complications in patients with spinal cord injury (SCI). On the basis of our previous findings, the present study focuses on mitochondrial biogenesis (MB) to further explore the relationship between the regulation of 5-HT1F receptor (5-HT1FR) activity and muscle spasticity following SCI.
    METHODS: A stable spasticity model was established in male Wistar rats, which were randomly assigned to low-, medium-, and high-dose lasmiditan (a 5-HT1FR agonist; designated SLL, SLM, and SLH, respectively) and control groups. Spasticity scores were assessed over time in all groups. The expression levels of proteins associated with the PGC-1α signalling pathway were measured, and mitochondrial ultrastructural morphology was examined and compared among the groups.
    RESULTS: SCI significantly increased spasticity scores, which peaked on Day 60. Compared with the SCI group, the SLH group exhibited significantly lower spasticity scores on Days 67 and 74 (both P < 0.05), whereas the SLM group showed significant improvement only on Day 74 (P = 0.003). SCI markedly downregulated the mRNA and protein expression of PGC-1α, Nrf1, p-AMPKα, ATP Synβ, and TFAM (all P < 0.05). Lasmiditan restored the expression of these molecules. Notably, the SLH group and SLM group had significantly upregulated ATP Synβ and TFAM expression at both the mRNA and protein levels (P < 0.05). Furthermore, the 5-HT1FR agonist lasmiditan effectively alleviated mitochondrial ultrastructural damage following SCI.
    CONCLUSION: Activation of the 5-HT1FR promotes MB in spinal cord tissue below the injury level after SCI. This mechanism may contribute to its therapeutic potential for secondary spasticity.
    Keywords:  5-HT1FReceptor; Lasmiditan; Mitochondrial biogenesis; Spasticity; Spinal cord injury
    DOI:  https://doi.org/10.1016/j.neulet.2026.138685
  46. Int J Mol Sci. 2026 Jun 24. pii: 5683. [Epub ahead of print]27(13):
    Molecular Mechanisms of Photobiomodulation in Retinal Diseases: Cytochrome c Oxidase, Mitochondrial Bioenergetics and Cytoprotective Signalling.
    Rubens Camargo Siqueira.
      Photobiomodulation (PBM) is a non-invasive therapeutic strategy that uses red and near-infrared (NIR) light in the 590-950 nm range to modulate the cellular and molecular pathways involved in retinal homeostasis. At the molecular level, PBM acts primarily through photon absorption by cytochrome c oxidase (CcO, complex IV of the mitochondrial electron transport chain), whose four metal centres-two copper (CuA and CuB) and two heme groups (heme a and heme a3)-absorb light across approximately 600-1000 nm. Photon capture promotes photodissociation of inhibitory nitric oxide (NO) from the binuclear CuB-heme a3 centre, accelerates electron transfer, restores the proton-motive force and increases ATP synthesis. These primary events trigger a coordinated molecular programme that includes (i) transient mitochondrial reactive oxygen species (ROS) bursts that activate the Nrf2/Keap1/ARE axis and upregulate phase II antioxidant enzymes (HO-1, NQO1, GCLC, SOD2, catalase, GPx); (ii) calcium- and cAMP-dependent secondary signalling that converges on PI3K/Akt, MAPK/ERK, AMPK and mTOR pathways; (iii) suppression of NF-κB-driven cytokine production (TNF-α, IL-1β, IL-6) and of NLRP3 inflammasome activation; (iv) downregulation of the HIF-1α/VEGF axis, particularly at 590 nm; (v) anti-apoptotic remodelling of the Bcl-2/Bax ratio with reduced cytochrome c release and caspase-3/9 activation; and (vi) PGC-1α/TFAM/NRF1-driven mitochondrial biogenesis, alongside restoration of fission/fusion homeostasis (Drp1, Mfn1/2, Opa1) and PINK1/Parkin-mediated mitophagy. Wavelength specificity has a defined molecular basis: 590 nm modulates VEGF signalling and RPE pump activity, 660 nm interacts with the CuB centre and enhances O2 binding at CcO, and 850 nm is absorbed by CuA and supports electron entry into complex IV. A second molecular axis is the bidirectional crosstalk between PBM and the circadian system: mitochondrial respiration, ATP turnover and CcO activity oscillate over the 24 h cycle under the control of the BMAL1/CLOCK and PER/CRY core machinery, the NAD+/SIRT1-SIRT3 axis and REV-ERBα. Preliminary preclinical and human observations suggest that NIR-induced bioenergetic and functional gains may be coupled to this rhythm, with greater benefit reported when light is delivered in the morning window (≈08:00-11:00); this time dependence should be regarded as an emerging hypothesis rather than an established clinical principle. The clinical evidence is unevenly developed across indications. It is most robust for non-exudative age-related macular degeneration, where multiwavelength PBM (590/660/850 nm; Valeda Light Delivery System) has shown disease-modifying potential in randomized controlled trials (LIGHTSITE I-III and the LIGHTSITE IIIB extension), with sustained BCVA gains and reduced incidence of geographic atrophy over 24 months and beyond. Evidence for retinitis pigmentosa, central serous chorioretinopathy and, with red-light monotherapy, childhood myopia is at present limited to small or short-term studies and remains preliminary. This narrative review synthesizes the molecular machinery engaged by PBM, integrates clinical findings across retinal diseases and discusses how chronotherapeutic delivery of light, aligned with the molecular clock, may further optimize therapeutic efficacy.
    Keywords:  BMAL1; NF-κB; Nrf2; PGC-1α; age-related macular degeneration; central serous chorioretinopathy; circadian rhythm; cytochrome c oxidase; mitochondria; mitochondrial biogenesis; mitophagy; myopia; near-infrared light; photobiomodulation; retinitis pigmentosa
    DOI:  https://doi.org/10.3390/ijms27135683
  47. ACS Appl Mater Interfaces. 2026 Jul 13.
    A Multitarget Nanosystem Loaded with Donepezil for Alzheimer's Disease Treatment by Activating Mitophagy and Reshaping the Inflammatory Microenvironment.
    Liqiang Wang, Qianyu Cai, Yonglan Yang, Yuezhao Zhou, Yujia Liu, Peiyao Wu, Jie Liu, Yanan Liu.
      A paradigm shift from single-target interventions toward multitarget synergistic actions is increasingly recognized as a promising therapeutic approach for Alzheimer's disease (AD). Given this, an oxidative stress-responsive nanocomposite, RuO2-TPP/Don@BSA (RDB), was developed to enable effective AD therapy via a "cocktail strategy". Utilizing bovine serum albumin (BSA), the system crosses the blood-brain barrier (BBB) through gp60 receptor-mediated endocytosis. Within the AD brain microenvironment, RDB undergoes disulfide bond cleavage in response to elevated H2O2 levels, thereby releasing donepezil (Don) and RuO2-TPP in a stimuli-responsive manner. Meanwhile, RuO2-TPP escapes from lysosomes, targets mitochondria, and interrupts the oxidative stress cascade, further repairing mitochondrial dysfunction and activating mitophagy. Moreover, RDB promotes the polarization of microglia from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype, thereby reshaping the inflammatory microenvironment of AD. Finally, RDB demonstrated significant efficacy in APP/PS1 transgenic AD mice, markedly reducing hippocampal expression of GFAP and Iba-1, concomitant with a notable improvement in cognitive dysfunction. In summary, these findings establish RDB as a multitarget synergistic therapeutic system that offers a promising strategy for the treatment of AD.
    Keywords:  Alzheimer’s disease; mitophagy; nanozyme; oxidative stress; remodel the inflammatory microenvironment
    DOI:  https://doi.org/10.1021/acsami.6c05393
  48. Int J Mol Sci. 2026 Jun 30. pii: 5918. [Epub ahead of print]27(13):
    Mitochondrial Immunometabolism in Sepsis: From Oxidative Stress and mtDAMP Signaling to Biomarker-Guided Therapy.
    Minsoo Kim, Phyu Phyu Khin, Hyeran Jung, Chang Woo Chae, Byeong Hwa Jeon, Cuk-Seong Kim.
      Sepsis is a life-threatening syndrome characterized by a dysregulated host response to infection and progressive organ dysfunction. Although early antimicrobial therapy, source control, hemodynamic resuscitation, and organ support remain the foundations of care, these approaches do not directly reverse the cellular mechanisms that connect systemic inflammation to multi-organ failure. Mitochondrial dysfunction has emerged as a central mechanism linking impaired oxygen utilization, oxidative and nitrosative stress, immune-cell metabolic reprogramming, inflammatory amplification, and organ injury. During sepsis, inflammatory mediators, nitric oxide, microcirculatory abnormalities, calcium dysregulation, and metabolic stress converge on mitochondria, impairing oxidative phosphorylation and promoting mitochondrial reactive oxygen species/reactive nitrogen species (ROS/RNS) generation. When mitochondrial quality-control programs, including fission, fusion, mitophagy, and mitochondrial biogenesis, fail to restore network integrity, damaged mitochondria accumulate and become persistent sources of oxidative stress and danger signals. Mitochondrial damage-associated molecular patterns, particularly mitochondrial DNA, oxidized mitochondrial DNA, cardiolipin, ATP, and N-formyl peptides, activate innate immune pathways such as TLR9-MyD88-NF-kappaB, the NLRP3 inflammasome, and cGAS-STING signaling. In parallel, mitochondrial metabolism shapes macrophage activation, neutrophil function, T-cell competence, pyruvate-lactate handling through the pyruvate dehydrogenase complex, and the transition between hyperinflammation and immunosuppression. Clinical translation remains challenging because sepsis is biologically heterogeneous and mitochondrial dysfunction is dynamic, tissue-specific, and influenced by disease stage. This review synthesizes current knowledge on mitochondrial dysfunction in sepsis, emphasizing oxidative and nitrosative stress, mitochondrial quality control, mitochondrial damage-associated molecular pattern (DAMP) signaling, immunometabolism, organ-specific injury, candidate biomarkers, clinical translational strategies for mitochondria-targeted therapy, and future approaches based on multi-omics and artificial intelligence-assisted patient stratification. We argue that future therapeutic development should move beyond nonspecific antioxidant supplementation toward time-sensitive, phenotype-informed, and biomarker-guided mitochondrial medicine.
    Keywords:  biomarkers; immunometabolism; mitochondria; mitochondria-targeted therapy; mitochondrial DNA; mitophagy; organ dysfunction; oxidative stress; sepsis
    DOI:  https://doi.org/10.3390/ijms27135918
  49. Phytother Res. 2026 Jul 17.
    Salvianolic Acid A Inhibits Ferroptosis in Endothelial Cells and the Progression of Atherosclerosis by Augmenting the Mitochondrial Homeostasis Pathway Associated With Adiponectin Receptor 1.
    Ji Zhu, Jianan Guo, Jing Liu, Cheng Chen, Hang Chen, Cui Wang, Aini Yuan, Dezhao Lu, Yifei Le.
      Endothelial cell ferroptosis drives atherosclerosis. Salvianolic acid A (SAA), a polyphenol from Salvia species, was tested for its ability to inhibit ferroptosis and attenuate atherosclerosis, and its molecular mechanism was investigated. Screening of 124 natural compounds identified SAA as the most potent inhibitor of RSL3-induced ferroptosis in human umbilical vein endothelial cells (HUVECs). Cellular/mitochondrial lipid peroxidation, Fe2+ content, ROS, and mitochondrial function were assessed with or without SAA. AMPK signaling was probed using pharmacological inhibitors. The AdipoR1 axis was examined via siRNA knockdown. In vivo, ApoE-/- mice on a Western diet were treated with SAA to evaluate atherosclerosis and ferroptotic damage. SAA was identified as the most potent inhibitor of (1S,3R)-RSL3-induced ferroptosis in HUVECs among the screened natural compounds. SAA inhibited the ferroptotic response by restoring GPX4-dependent antioxidant capacity and preventing lipid peroxidation at both the cellular and mitochondrial levels. It improved mitochondrial function by restoring homeostasis of the mitochondrial quality control system, inhibiting mitochondrial reactive oxygen species generation, reducing ferrous iron accumulation, limiting mitochondrial lipid peroxidation, and preserving mitochondrial ultrastructure. The protective effects of SAA against ferroptosis were abolished by AMPK inhibitors, which disrupted cellular lipid metabolism and mitochondrial function regulation. The deleterious effects of AMPK inhibition were reversed by co-treatment with the mitochondrial reactive oxygen species inhibitor MitoTempol. Knockdown of AdipoR1 and experiments with the AMPK agonist AICAR confirmed that salvianolic acid A restores mitochondrial homeostasis and inhibits ferroptosis specifically through activation of the AdipoR1-AMPK signaling pathway. In vivo, treatment with SAA significantly ameliorated Western diet-induced atherosclerosis and ferroptosis-like cell damage in ApoE-/- mice. SAA has strong therapeutic potential against endothelial ferroptosis and atherosclerosis by restoring mitochondrial homeostasis through AdipoR1-AMPK pathway activation. These findings support further clinical investigation of SAA for treating atherosclerosis and other endothelium-related cardiovascular diseases.
    Keywords:  AdipoR1; atherosclerosis; endothelial cells; ferroptosis; mitochondria; salvianolic acid A
    DOI:  https://doi.org/10.1002/ptr.70419
  50. Hypertension. 2026 Aug;83(8): e27340
    Targeting Mitochondrial Dynamics in VEGFR-TKI Hypertension and Cardiotoxicity.
    Stanislovas S Jankauskas, Urna Kansakar, Pasquale Mone, Shivangi Pande, Fahimeh Varzideh, Gaetano Santulli.
      
    Keywords:  cardiotoxicity; endothelial cells; nitric oxide; oxidative stress; protein kinase inhibitors; reactive oxygen species; vascular endothelial growth factor A
    DOI:  https://doi.org/10.1161/HYPERTENSIONAHA.126.27340
  51. Bioorg Med Chem. 2026 Jul 09. pii: S0968-0896(26)00206-3. [Epub ahead of print]141 118750
    Discovery of a mitochondria-targeted propranolol conjugate PL37 that induces mitophagy for potent anti-hemangioma activity.
    Mengge Zhang, Jian Chen, Liying Meng, Xuemeng Liu, Guanzhao Wu, Zhongjun Yang.
      Propranolol is the first-line therapy for infantile hemangioma (IH), yet its clinical utility is limited by systemic adverse effects, variable patient response, and an incompletely defined mechanism of action. To develop a more effective and mechanism-driven therapeutic strategy, we designed and synthesized a series of propranolol-peptide conjugates incorporating distinct targeting motifs. Among them, the mitochondria-targeted derivative PL37 exhibited markedly enhanced anti-hemangioma activity. PL37 potently inhibited endothelial cell proliferation, migration, invasion, and tube formation, and significantly induced apoptosis in both human umbilical vein endothelial cells and hemangioma-derived endothelial cells. Mechanistic studies demonstrated that PL37 triggers severe mitochondrial dysfunction, including excessive reactive oxygen species generation, mitochondrial membrane potential collapse, and structural disruption. Notably, PL37 activates mitophagy, leading to mitochondrial quality-control dysregulation and apoptosis via a mitochondria-dependent pathway, a mechanism distinct from β-adrenergic receptor blockade. In vivo, PL37 significantly suppressed tumor growth and angiogenesis in a hemangioma xenograft model without observable toxicity. These findings establish mitochondrial targeting as a viable strategy to enhance propranolol efficacy and identify PL37 as a promising lead for the development of next-generation anti-hemangioma agents.
    Keywords:  Infantile hemangioma; Mitochondrial targeting; Mitophagy; Peptide conjugates; Propranolol
    DOI:  https://doi.org/10.1016/j.bmc.2026.118750
  52. Int J Mol Sci. 2026 Jun 23. pii: 5641. [Epub ahead of print]27(13):
    Dracocephalum moldavica L. Flavonoids Alleviate Doxorubicin-Induced Cardiotoxicity by Activating the AMPK/PGC1αPathway to Preserve Mitochondrial Homeostasis.
    Ruifang Zheng, Yanwen Du, Shoubao Wang, Wenling Su, Kaderyea Kader, Lijuan Zhang, Zihan Wang, Diwei Liu, Jianguo Xing, Shifeng Chu, Ming Xu.
      Doxorubicin (DOX) is a potent chemotherapeutic drug, whose clinical application is largely restricted by dose-dependent cardiotoxicity (DIC). Dracocephalum moldavica L. is a classic medicinal and edible plant with obvious cardiovascular protective effects; however, the role of its total flavonoids (TFDM) in DIC remains unclear. This study explored the cardioprotective effect of TFDM on DOX-induced myocardial injury and its mechanism related to mitochondrial quality control. We established in vivo and in vitro DIC models and adopted echocardiography, detection of cardiac injury and oxidative stress indicators, transmission electron microscopy, mitochondrial functional assessment and Western blotting, with AMPK knockdown performed for mechanism verification. Results showed that TFDM effectively improved cardiac function, reduced myocardial oxidative stress and apoptosis, and maintained mitochondrial ultrastructure and energy metabolism. TFDM activated the AMPK/PGC1α signaling axis to facilitate mitochondrial biogenesis, and AMPK silencing eliminated the protective effect of TFDM. In conclusion, AMPK/PGC-1α pathway is a primary key pathway involved in TFDM's protective effects, which provides an experimental basis for the development of Dracocephalum moldavica L. as a functional food and adjuvant agent against DIC.
    Keywords:  AMPK/PGC1α pathway; doxorubicin-induced cardiotoxicity; functional food; mitochondrial damage; total flavonoids of Dracocephalum moldavica L.
    DOI:  https://doi.org/10.3390/ijms27135641
  53. Oncogene. 2026 Jul 13.
    METTL5-mediated rRNA modification controls prostate cancer progression through the IRF7/DNA2 axis and mitophagy regulation.
    Ruifeng Yang, Qintao Ge, Fengyao Wu, Manmei Long, Bingyu Li, Zhe Hong, Wenhao Xu, Miaomiao Guo, Tao Feng, Xi Tian, Wei Zhang, Kun Chang, Fangning Wan, Zhi Shang, Zhongyuan Wang, Ming Zhan, Bin Xu, Dingwei Ye.
      Prostate cancer progression to advanced disease is accompanied by extensive metabolic rewiring, yet the upstream regulatory mechanisms remain incompletely defined. Here, we showed that the rRNA m6A methyltransferase METTL5 was progressively upregulated during prostate cancer progression and was associated with poor patient survival. Mechanistically, METTL5 catalyzed N6-methyladenosine (m6A) modification at A1832 of 18S rRNA, thereby enhancing overall translational output and promoting prostate cancer cell proliferation in vitro and tumor growth in vivo. Integrative transcriptomic and proteomic analyses further revealed that METTL5-dependent rRNA modification preferentially increased translation of mRNAs harboring a GCACGN(2-4)CC motif within their 5' untranslated regions. Among these targets, the transcription factor IRF7 was selectively upregulated and directly induced DNA2 transcription. DNA2, a mitochondrial nuclease required for mitochondrial DNA maintenance, preserves oxidative phosphorylation capacity in prostate cancer cells. Disruption of the METTL5/IRF7/DNA2 axis led to mitochondrial dysfunction, increased reactive oxygen species, and compensatory mitophagy, ultimately suppressing tumor growth. Notably, neither IRF7 nor METTL5 overexpression rescued the growth defects caused by DNA2 depletion, supporting a hierarchical organization of this pathway with DNA2 as an essential downstream effector. Finally, therapeutic inhibition of METTL5 using locked nucleic acids markedly suppressed prostate cancer growth in vivo without evident systemic toxicity, underscoring translational potential. Collectively, our findings uncover an unappreciated mechanism linking rRNA modification to mitochondrial homeostasis through selective translational control, providing new insights into metabolic regulation and revealing actionable vulnerabilities in advanced prostate cancer.
    DOI:  https://doi.org/10.1038/s41388-026-03867-w
  54. Open Life Sci. 2026 Jan;21(1): 20251353
    Time-dependent effects of hypoxia on mitochondrial dynamics, dysfunction and apoptosis in C8-D1A astrocytes.
    Youjuan Chen, Jing Hou, Meiyuan Tian, Erwa Hao, Yaogang Zhang, Dengliang Huang, Tao Zhang, Yanyan Ma.
      This study aimed to investigate the effects of hypoxia on mitochondrial function in C8-D1A astrocytes and to evaluate its association with apoptosis. Mouse C8-D1A astrocytes were allocated to a normoxia group (21 % O2, 5 % CO2, 37 °C) or a hypoxia group (1 % O2, 5 % CO2, 37 °C) and cultured for 24 h, 48 h, or 72 h. Compared with the normoxia group, the hypoxia group demonstrated a significant reduction in mean mitochondrial fluorescence intensity (p < 0.01) and a significant increase in mitochondrial ROS levels. Regarding mitochondrial dynamics-related proteins, Mfn1 expression was significantly decreased, and Mfn2 expression was significantly decreased at 72 h (p < 0.01). Drp1 expression was significantly increased at all time points (p < 0.01), and Fis1 expression was significantly upregulated (p < 0.01). The proportion of cells exhibiting reduced mitochondrial membrane potential was significantly higher in the hypoxia group. The percentage of apoptotic cells was significantly increased. TEM analysis revealed structural abnormalities of mitochondria in cells exposed to hypoxia. Hypoxia may promote apoptosis in C8-D1A astrocytes through disruption of mitochondrial morphology, function, and dynamics. These alterations are associated with decreased mitochondrial content and increased ROS production, which may contribute to mitochondrial dysfunction and apoptosis under hypoxic conditions.
    Keywords:  C8-D1A astrocytes; astrocyte apoptosis; hypoxia; mitochondria; reactive oxygen species (ROS)
    DOI:  https://doi.org/10.1515/biol-2025-1353
  55. Cell Mol Bioeng. 2026 Jun;19(3): 359-373
    Mitochondria Clearance Enables Macrophage-Driven Maturation of iPSC-Derived Cardiomyocyte Metabolism.
    Frank Ketchum, Lara Celebi, Lauren Hawthorne, Pinar Zorlutuna.
       Background: Immaturity of stem cell-derive cardiomyocytes limits their use in tissue engineering applications. Macrophage contributions to the development of cardiomyocytes have not yet been fully established. While some recent studies have added macrophages to stem cell-derived models of the human myocardium, these previous approaches do not replicate the early colonization of the heart. Due to their importance in regulating cardiomyocyte metabolism, we hypothesized that developmentally informed addition of macrophages to cardiomyocytes would improve cardiomyocyte maturity.
    Methods: We generated cardiomyocytes and embryonic-like macrophages from a single cell line. Macrophages were added to developing cardiomyocytes 8, 16, and 19 days after induction of differentiation, based on changes in cardiomyocyte media formulation at these stages. Cardiomyocytes were cultured until 30 days post differentiation, where they were prepared for analysis. Metabolism was measured through Seahorse Mitochondria Stress assays. Corresponding changes in subcellular structures were measured through high-resolution microscopy. Mitophagy in cardiomyocytes was measured through the fluorescent reporter mtKeima.
    Results: Addition of macrophages to cardiomyocytes 8 days after the induction of differentiation results in a significant increase in cardiomyocyte basal and maximal metabolism. Developing cardiomyocytes shed lowly polarized mitochondria, which are taken up by macrophages. As a result, cardiomyocytes adopt an adjusted mitochondria network architecture featuring less interconnected mitochondria. Mitophagy flux measurements show that cardiomyocytes develop more active mitophagy programs while in coculture with macrophages. Pharmacological inhibition of mitophagy reveals that this interaction is dependent on macrophage MerTK-mediated reception of cardiomyocyte-derived mitochondria material.
    Conclusions: These results improve our understanding of the responsibility of macrophages in the development of cardiomyocyte metabolism. We establish interactions between macrophages and developing cardiomyocytes as essential to produce more mature cardiomyocytes and physiologically relevant models of the human myocardium.
    Supplementary Information: The online version contains supplementary material available at 10.1007/s12195-026-00915-z.
    Keywords:  Cardiomyocyte; Macrophages; Maturation; Mitophagy; Stem cells; Tissue engineering
    DOI:  https://doi.org/10.1007/s12195-026-00915-z
  56. Exp Ther Med. 2026 Sep;32(3): 232
    [Retracted] Resveratrol attenuates type 2 diabetes mellitus by mediating mitochondrial biogenesis and lipid metabolism via Sirtuin type 1.
    Ming-Ming Cao, Xi Lu, Guo-Dong Liu, Ying Su, Yan-Bo Li, Jin Zhou.
      [This retracts the article DOI: 10.3892/etm.2017.5400.].
    DOI:  https://doi.org/10.3892/etm.2026.13227
  57. Front Reprod Health. 2026 ;8 1845581
    Orchestrating the gut microbiota-mitochondrial-immune axis in gynecological diseases: mechanisms and dual-targeting therapeutic strategies.
    Haixia Tang, Yiting Zhang, Yanting Wang, Ze Zhou, Rong Sun, Rong Chen, Lijuan Yang, Mengqiu Shao, Jiabao Liao.
      The "gut microbiota-mitochondria axis" has become the core hub connecting the metabolism, immunity, and endocrine regulation of gynecological diseases. In this review, the hierarchical regulation mechanism of this axis is systematically combed: at the upstream level, intestinal short-chain fatty acids (SCFAs), bile acids (BAs), tryptophan derivatives, and other metabolites can activate AMPK/PGC-1α, FXR/TGR5, and AhR-mediated energy sensing and receptor signaling pathways; On the functional level, bacterial lipopolysaccharide-TLR4 signal and cGAS-STING/NLRP3 inflammasome pathway activated by cytoplasmic mitochondrial DNA (mtDNA) can amplify innate immune response; At the effect level, mitochondrial reactive oxygen species (ROS), mitochondrial dynamics, and PINK1/Parkin-mediated mitophagy are the common key nodes to regulate mitochondrial quality and inflammatory response. Combined with the two-way relationship between the estrobolome and steroid production, the above processes together form a self-reinforcing closed loop of "metabolic input-immune amplification-oxidative stress/autophagy-endocrine regulation". Based on this theoretical framework, this paper analyzes the disease-specific correlations among polycystic ovary syndrome, endometriosis, premature ovarian insufficiency, and gynecological malignancies, and puts forward a dual-targeted treatment idea with research value. The intervention plan with microbiota as the core aims to adjust the metabolite spectrum and endotoxin level; Mitochondria-centered interventions focus on restoring cell energy metabolism and apoptosis sensitivity. In addition, this review constructs a hierarchical research framework of "microbiota-metabolomics-mitochondria" to clarify the targeted phenotypes in the pathway, and provide guidance for subsequent clinical trial design and long-term monitoring. With the deep integration of multi-omics technology and targeted interventions, the gut microbiota-mitochondria axis is expected to become an important breakthrough in precision medical treatment of gynecological diseases and build a brand-new bridge between basic mechanism research and clinical transformation.
    Keywords:  NLRP3/cGAS–STING; endometriosis; gynecological malignancies; microbiota–mitochondria axis; mitophagy/PGC-1α; polycystic ovary syndrome; premature ovarian insufficiency; reproductive endocrinology
    DOI:  https://doi.org/10.3389/frph.2026.1845581
  58. Adv Sci (Weinh). 2026 Jul 13. e76604
    LRG1 Drives Pathological Angiogenesis by Disrupting Neutrophil Mitochondrial Homeostasis in Bladder Cancer.
    Dongshan Chen, Cong Zhang, Song Xue, Yuan Zeng, Haochen Cui, Chenfei Wang, Jiayi Feng, Lei Yan, Yuanwei Zang.
      Abnormal tumor vasculature creates a permissive microenvironment that fuels the malignant progression of bladder cancer (BCa). While Leucine-rich alpha-2 glycoprotein 1 (LRG1) is known to regulate angiogenesis, its specific role in remodeling the BCa microenvironment remains poorly defined.We integrated single-cell RNA sequencing (scRNA-seq) with bulk transcriptomic datasets to identify key cellular subclusters. Functional validation was performed using subcutaneous and orthotopic BCa mouse models, neutrophil depletion, DNase I treatment, and clinical specimens. The molecular interactome was mapped via pull-down assays, mass spectrometry, and confocal imaging.LRG1 is significantly upregulated in BCa and correlates with hematogenous metastasis and poor prognosis. Mechanistically, tumor-derived LRG1 binds to Annexin A2 (ANXA2) on neutrophils through its LRR domain, impeding the mitochondrial translocation of Akt and triggering mtROS-dependent release of Neutrophil Extracellular Traps (NETs). These NETs directly cause vascular destabilization by stripping mural cell coverage. Blockade of the LRG1-NETosis axis induces vascular normalization, effectively overcoming microenvironmental barriers to increase drug delivery and T-cell infiltration, thereby profoundly sensitizing BCa to cisplatin and anti-PD-1 therapy.The LRG1-neutrophil-NETosis axis is a critical driver of vascular dysfunction and therapeutic resistance in BCa. Targeting this axis represents a promising translational strategy to improve clinical outcomes.
    Keywords:  LRG1; angiogenesis; bladder cancer; mitochondrial homeostasis; neutrophil
    DOI:  https://doi.org/10.1002/advs.76604
  59. Cell Prolif. 2026 Jul 14. e70256
    Itgb1-Mediated Stabilization of Vimentin Alleviates Excessive Mechanical Stress-Induced Nucleus Pulposus Cell Pyroptosis and Intervertebral Disc Degeneration via PINK1-Parkin-Dependent Mitophagy.
    Xuening Liu, Fengguang Yang, Yanni Duan, Hefang Xiao, Zhenyu Cao, Zhaoheng Wang, Haijun Zhang, Xuewen Kang.
      Excessive mechanical stress is a main cause of intervertebral disc degeneration (IDD). However, the specific mechanism remains unclear. We established in vivo and in vitro models to investigate the role of cytoskeletal proteins in excessive mechanical stress-induced NP cell pyroptosis and IDD. The expression level of Vimentin was decreased in degenerated NP cells induced by excessive mechanical stress. Knockdown of Vimentin promoted NP cell pyroptosis and IDD in rats, whereas Vimentin overexpression significantly alleviated excessive mechanical stress-induced NP cell pyroptosis and degeneration. Further mechanistic studies revealed that Vimentin ameliorated mitochondrial dysfunction triggered by excessive mechanical stress through PINK1-Parkin-dependent mitophagy, thereby attenuating NP cell pyroptosis and degeneration. Co-immunoprecipitation-mass spectrometry analysis suggested an interaction between Itgb1 and Vimentin, which was validated by Co-immunoprecipitation assays. Itgb1 enhanced Vimentin protein stability via the ubiquitin-proteasome pathway and inhibited mechanical stress-mediated Vimentin degradation. Subsequent experiments confirmed that Itgb1 reduced Vimentin ubiquitination and degradation by blocking the binding of MNAT1 to Vimentin. Itgb1 ameliorated excessive mechanical stress-induced NP cell pyroptosis and degeneration via Vimentin. Restoring Vimentin function through gene overexpression effectively inhibited NP cell pyroptosis and delayed the progression of IDD in rats. In summary, this study reveals a mechanotransduction pathway from mechanical stress sensing to cellular functional regulation in IDD, providing novel insights into the pathological mechanisms underlying IDD. Moreover, this study demonstrates that Vimentin exerts a significant protective effect against excessive mechanical stress-induced NP cell pyroptosis and IDD, offering a potential therapeutic target for the clinical management of IDD.
    Keywords:  Itgb1; intervertebral disc degeneration; mitophagy; pyroptosis; vimentin
    DOI:  https://doi.org/10.1111/cpr.70256
  60. Neurochem Res. 2026 Jul 14. pii: 218. [Epub ahead of print]51(4):
    Grape Seed Proanthocyanidin Extract (GSPE) Mitigates Preterm White Matter Injury in Mice Via Improving Mitochondrial Homeostasis and Activity of IMMP2L-Related Signaling Pathway.
    Nina Wang, Zhe Lei, Xinyu Ge, Qingchen Li, Teng Ma, Xuexian He, Hailin Li, Linlong Li, Shangzong Li, Junyan Wang, Yin Wang.
      Grape seed proanthocyanidins extract (GSPE) has demonstrated significant neuroprotective efficacy in various neurodevelopmental disorders, nevertheless its potential beneficial role in preterm white matter injury (PWMI) remains unclear. This study aims to evaluate the therapeutic potential of GSPE against PWMI and the underlying mechanisms. GSPE (20 mg/Kg) was taken orally by the mouse after PWMI modeling. The survival rate, incidence of macroscopic lesions, body weight change were calculated. The myelin damage was evaluated. Mitochondrial homeostasis‌ was detected in PWMI model mice and cultured oligodendrocyte precursor cells (OPCs). Brain tissues from mice groups underwent RNA-seq. A dual-luciferase reporter assay was employed to validate the direct binding interaction between miR-153 and IMMP2L mRNA. The results showed that treatment of GSPE ameliorated cerebral ischemic injury in PWMI mice and improved behaviour ability and cognition deficits. GSPE restored mitochondria homeostasis in both PWMI mice and OPCs. Additionally, IMMP2L was found to be increased, while ROS was diminished by GSPE intervention. KEGG analysis showed that Wnt signaling pathway, the downstream of IMMP2L, changed significantly in PWMI group, while GSPE reversed it. The dual-luciferase reporter assay demonstrated that miR-153-3p directly suppressed IMMP2L expression through these binding sites. In summary, our findings revealed that GSPE treatment alleviated PWMI and restored mitochondrial homeostasis in mice.These beneficial effects are likely be attributed to the improvement of the activity of IMMP2L-related signaling pathways by GSPE.
    Keywords:  Grape seed proanthocyanidin extract; IMMP2L; Mitochondrial homeostasis; Preterm white matter injury
    DOI:  https://doi.org/10.1007/s11064-026-04828-1
  61. Biochim Biophys Acta Rev Cancer. 2026 Jul 16. pii: S0304-419X(26)00135-6. [Epub ahead of print] 189663
    ROS-mitochondrial nexus in stem cell growth and differentiation and implications in cancer and degenerative diseases.
    Mohd Javed Akhtar, Sudhir Panwar.
      Regenerative cells, also known as stem cells, exhibit transitioning between a resting state, crucial for long-term preservation with low metabolic activity, and an activation state defined by active proliferation and differentiation to repair old or damaged cells. Concomitant with stem cell transition, mitochondria also undergo a similar transition to support cell growth by providing energy and growth precursors. High mitochondrial activity during cell growth, however, results in reactive oxygen species (ROS). ROS function as signaling molecules and activate several metabolic pathways by rewiring key enzymes and proteins. During the resting state, often called quiescence, ROS production should be limited to prevent resumption of inappropriate growth and oxidation of essential components like DNA in a cell type whose main function is to divide and pass its genetic material to daughter cells for repair. Most stem cells in a resting state (also known as G0 phase) display reduced mitochondrial activity by suppressing oxidative phosphorylation (OXPHOS) due to active mitophagy maintained by quiescence regulators in cells. Mitogens and injury markers activate resting or quiescent stem cells to reenter the cell cycle and grow, a process that requires mitochondrial activity for the supply of nucleotides, non-essential amino acids, lipids and many more. Mitochondria undergo cell cycle-specific changes during the G1, S, and G2/M phases. This article examines how mitochondria regulate stem cell growth and control cell fate. Stem cell dysfunction leads to regeneration issues, contributing to premature aging and cancer. Understanding mitochondrial function can further enhance therapeutic interventions in cancer and aging, as highlighted at the end of the review.
    Keywords:  Metabolic plasticity; Mitochondrial dynamics; Redox signaling; Stem cell quiescence; cancer stem cells
    DOI:  https://doi.org/10.1016/j.bbcan.2026.189663
  62. Cells. 2026 Jun 23. pii: 1134. [Epub ahead of print]15(13):
    Autophagy Stress Responses in Localized Prostate Cancer: A Flux-Aware Framework for Disease-Relevant Interpretation.
    Zaira Edith Hernández-Ramírez, Enoc Mariano Cortés Malagón, Jonathan Puente-Rivera, Javier Flores-Estrada.
      Autophagy-associated readouts in localized prostate cancer cannot be interpreted based on LC3, p62/SQSTM1, or LC3 puncta alone. In line with the concept of autophagy as a stress-response system, this review proposes a flux-aware, organelle-centered framework for assigning biological meaning to autophagy-related changes under disease-relevant stress. The framework integrates oxidative burden, lysosomal competence, selective autophagy, mitophagy, ferritinophagy, p62/SQSTM1-NRF2 signaling, ferroptosis-aware controls, and disease-stage context to distinguish four interpretive states: homeostatic quality control, adaptive tumor survival, blocked clearance, and stress-overload vulnerability. Flavonoid-associated responses are used as stress-test examples because they expose recurrent limitations in the field, including supraphysiologic exposures, limited metabolite realism, static-marker inflation, and insufficient assessment of lysosomal function. However, the framework is not restricted to dietary compounds; it applies to metabolic, pharmacological, inflammatory, androgen-related, radiation-associated, or therapy-induced perturbations in which autophagy-associated markers are altered without resolution of flux or organelle function. By linking autophagosome formation, cargo turnover, lysosomal acidification, redox buffering, and phenotype-level endpoints, this review defines a practical evidence hierarchy for interpreting autophagy in localized prostate cancer and for prioritizing translational vulnerabilities arising from organelle crosstalk. This contribution is primarily conceptual and is operationalized methodologically through flux-based evaluation criteria and translationally through disease-window-specific study-design recommendations.
    Keywords:  autophagic flux; autophagy; disease models; ferroptosis; localized prostate cancer; lysosomal competence; mitophagy; proteostasis; selective autophagy; stress response
    DOI:  https://doi.org/10.3390/cells15131134
  63. J Biomol Struct Dyn. 2026 Jul 13. 1-23
    Allosteric modulation of Drp1 by natural compounds for cardiac therapeutics: a molecular docking and dynamics study.
    Bhavya Somaplara Gangadharappa, Keerthana Ramji.
      Pathological mitochondrial fission driven by hyperactivation of the Drp1-MiD49 interaction contributes majorly to several cardiovascular diseases. Existing synthetic Drp1 inhibitors often lack selectivity between pathological and physiological mitochondrial fission, leading to poor bioavailability and off-target effects. Allosteric modulation therefore represents a more promising strategy to fine-tune Drp1 activity than complete inhibition and our study investigated whether natural antioxidants could function as selective allosteric modulators of Drp1 by targeting a characterized allosteric site at the dimer interface using molecular docking, long-timescale (1000 ns) molecular dynamics simulations and MMPBSA analysis. Docking analysis demonstrated favourable binding of the selected phytochemicals at the Drp1 allosteric interface, with Astaxanthin exhibiting the highest docking score, while Baicalin, Luteolin, and Resveratrol formed stable interactions with critical interface residues. Molecular dynamics simulations revealed that these compounds remained consistently associated with the allosteric site and promoted compact conformations of Drp1 characterized by reduced RMSD, radius of gyration (Rg) and solvent-accessible surface area (SASA) relative to apo-Drp1. RMSF, secondary structure and principal component analyses further demonstrated ligand-induced conformational transitions in functionally important regions including the G1/P-loop, G3/Switch II, G5/G-cap and the 80-loop and progressive restriction of conformational space for the Baicalin-, Luteolin-, and Resveratrol-bound complexes. MM-PBSA calculations identified Baicalin as the most energetically favourable complex, followed by Resveratrol. Independent replica simulations of the Baicalin-, Resveratrol-, and Mdivi-1-bound complexes further supported the reproducibility of the observed molecular dynamics trends. Collectively, these findings highlight the potential of Baicalin, Resveratrol, and Luteolin as promising Drp1 allosteric modulators, supporting future development of mitochondrial fission-targeted cardiac therapeutics.
    Keywords:  Drp1 (Dynamin-related protein 1); allosteric modulation; computational simulations; conformational dynamics; natural compounds
    DOI:  https://doi.org/10.1080/07391102.2026.2697338
  64. Mol Cell Endocrinol. 2026 Jul 11. pii: S0303-7207(26)00143-7. [Epub ahead of print]621 112866
    Spinosin mitigates bone loss in ovariectomy rats by activating the Nrf2/HO-1 pathway, which reduces oxidative stress and improves mitochondrial function.
    Yitian Bu, Yixun Huang, Jiayi Yang, Yijun Fei, Dandan Cheng, Weikai Chen, Lei Yang.
      Postmenopausal osteoporosis (PMOP) is driven by oxidative stress and impaired osteogenic potential. We investigated the protective effects of Spinosin (SPI) using rat bone marrow mesenchymal stem cells (BMSCs) and an ovariectomized (OVX) rat model. Oxidative stress was induced by H2O2. We measured reactive oxygen species (ROS) levels, mitochondrial ultrastructure via transmission electron microscopy (TEM), and the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway. Results showed that SPI significantly reduced ROS accumulation and preserved mitochondrial integrity and membrane potential. Mechanistically, SPI activated the Nrf2/HO-1 pathway, upregulating osteogenic markers such as RUNX2. In vivo, oral SPI treatment (20 or 40 mg/kg) effectively restored bone volume and microarchitecture in OVX rats. These bone-protective effects were largely abolished by the Nrf2 inhibitor ML385. In conclusion, SPI alleviates oxidative stress-induced BMSC dysfunction and bone loss through Nrf2/HO-1 activation, highlighting its potential as a natural therapeutic agent for PMOP.
    Keywords:  Apoptosis; Mesenchymal stem cells; Mitophagy; Osteoporosis; Oxidative stress; Spinosin
    DOI:  https://doi.org/10.1016/j.mce.2026.112866
  65. Neuropharmacology. 2026 Jul 15. pii: S0028-3908(26)00286-8. [Epub ahead of print]299 111111
    Enavogliflozin alleviates motor deficits in rotenone-induced Parkinson's disease mice via attenuation of oxidative stress and neuroinflammation as well as activation of the SIRT1/PINK1/Parkin pathway.
    Tengfei Liang, Xiaoyan Pang, Qiaoqiao Liu, Siyu Sun, Lixia Wang, Hexin Yan.
      Parkinson's disease is an age-related neurodegenerative disorder characterized by the progressive degeneration of nigrostriatal dopaminergic neurons. Enavogliflozin, a novel sodium-glucose cotransporter 2 (SGLT2) inhibitor, has recently been demonstrated to exert neuroprotective effects. However, whether enavogliflozin can ameliorate motor behavioral deficits in Parkinson's disease currently remains unclear. To this end, this study aimed to investigate the neuroprotective effects of enavogliflozin on Parkinson's disease and explore its underlying molecular mechanisms. We established a Parkinson's disease model using rotenone-induced C57BL/6 mice (1.5 mg/kg/d, 3 weeks, i.p.) to investigate the neuropharmacological modulation effects of enavogliflozin treatment (0.1 and 1 mg/kg/d, 3 weeks, p.o., 2 h after rotenone injection) on Parkinson's disease from the perspectives of motor behavioral evaluation, pathological changes, oxidative stress, neuroinflammation, and SIRT1/PINK1/Parkin signaling pathways in specific brain regions. The results revealed that enavogliflozin alleviated neuropathological alterations of the substantia nigra, upregulated tyrosine hydroxylase and dopamine transporter expression in nigrostriatal dopaminergic neurons, and improved motor behavioral deficits. Administration of enavogliflozin further significantly reduced the levels of inflammatory cytokines (IL-6 and TNF-α), microglial activation, and oxidative damage in rotenone-induced Parkinson's disease mice. Moreover, we found that enavogliflozin activated PINK1/Parkin-mediated mitophagy by SIRT1 signaling pathway. In conclusion, enavogliflozin ameliorates motor dysfunction in rotenone-induced Parkinson's disease mice by attenuating oxidative stress, inhibiting neuroinflammation, and activating SIRT1/PINK1/Parkin pathway. These findings support a neuroprotective and preventive role for enavogliflozin in Parkinson's disease.
    Keywords:  Enavogliflozin; Mitophagy; Motor deficits; Neuroinflammation; Oxidative stress; Parkinson's disease
    DOI:  https://doi.org/10.1016/j.neuropharm.2026.111111
  66. Drug Resist Updat. 2026 Jul 08. pii: S1368-7646(26)00094-4. [Epub ahead of print]88 101443
    Resensitizing drug-resistant cancers by co-targeting apoptosis and mitochondrial stress pathway.
    Gautam Sethi, Ilnaz Rahimmanesh, Akbar Davoodi, Yujiao Chen, Franklin R Tay, Chandra Sekhar Bhol, Pooyan Makvandi, Yi Xu.
      Therapeutic resistance is a major barrier to durable cancer control in contemporary oncology practice. Despite extensive studies on individual cell death pathways and mitochondrial stress responses, a comprehensive framework describing how mitochondrial organization contributes to the coordination of multiple regulated cell death programs and therapeutic resistance remains insufficiently defined. This review examines resistance as malignant cells evade regulated cell death and adapt to mitochondrial stress. Mitochondria are framed as integrative hubs that link bioenergetics, redox regulation, metabolic flexibility, and stress signaling to apoptotic competence. It also describes how apoptosis connects with other death programs through mitochondrial compartmentalization. Signals from the matrix, inner membrane, and cristae, intermembrane space, and outer membrane influence ferroptosis, necroptosis, mitochondrial permeability transition-driven necrosis, and immunogenic cell death. Stress-response pathways are highlighted as interfaces between mitochondrial dysfunction and fate decisions, including the OMA1-DELE1-heme-regulated inhibitor kinase axis that activates the integrated stress response and ATF4-dependent transcription. Translationally, the review proposes a co-targeting framework that pairs apoptosis-directed therapies, especially BH3 mimetics, with interventions that destabilize mitochondrial homeostasis or tune stress signaling. Examples include electron transport chain inhibitors, integrated stress response modulators, and compartment-targeted strategies that alter cristae remodeling, calcium flux, or cardiolipin oxidation.
    Keywords:  BCL-2 family regulation; BH3 mimetics; Integrated stress response (ISR); Mitochondrial stress signaling; Therapeutic resistance
    DOI:  https://doi.org/10.1016/j.drup.2026.101443
  67. J Mol Histol. 2026 Jul 16. pii: 235. [Epub ahead of print]57(4):
    Testosterone propionate maintains autophagic flux and mitochondrial integrity via regulation of the LC3B/p62/Beclin-1/mTOR axis in induced liver fibrosis.
    Shobhit Verma, Somya Vaishnav, Manisha Yadav, Smriti Verma, Kaveri R Washimkar, Akhilesh Kumar, Madhav Nilakhanth Mugale.
      The current study examines the role of testosterone and androgen deprivation in regulating mitochondrial quality control, autophagy, and apoptosis during CCl4-induced chronic liver injury. Male rats were allocated to Sham, CCl4, TP + CCl4 (testosterone-treated), and Cas + CCl4 (castrated) groups for 4, 8, and 12 weeks, validated through in vitro assays. Mitochondrial function (MitoTracker, MFN2), lysosomal integrity (LAMP1), autophagy markers (LC3B, Beclin-1, p62/SQSTM1), apoptosis regulators (Bcl-2, cleaved caspase-3), and mTOR signaling were assessed by qRT-PCR, immunohistochemistry, and immunofluorescence. CCl4 exposure caused progressive increases in cellular stress and fibrotic markers (α-SMA, TGF-β1, and TXNIP), progressive mitochondrial dysfunction, impaired mitochondrial-lysosomal coordination, reduced Beclin-1 and LC3B, p62 accumulation, and a shift toward an anti-apoptotic Bcl-2 imbalance. Testosterone treatment restored mitochondrial membrane potential in vitro, normalized MitoTracker and MFN2 expression, preserved LAMP1 levels, and partially sustained mitochondrial-lysosomal coupling. TP also enhanced Beclin-1 and LC3B, reduced p62 accumulation, and sustained mTOR activity, consistent with improved autophagic flux. Moreover, TP-lowered Bcl-2 was associated with controlled cleaved caspase-3 activation, suggesting selective clearance of damaged hepatocytes rather than widespread apoptosis. In contrast, Cas + CCl4 animals showed exaggerated mitochondrial impairment, persistent p62 accumulation, reduced LC3B and mTOR signaling, and a pro-apoptotic cleaved caspase-3 profile. Together, these findings demonstrate that testosterone supports mitochondrial-lysosomal homeostasis and autophagy during toxic liver injury, whereas androgen deprivation favors defective autophagy and maladaptive apoptosis, underscoring hormone-dependent regulation of hepatocellular stress responses.
    Keywords:  Apoptosis; Autophagy; CCl4-induced liver injury; Mitochondrial quality control; Testosterone
    DOI:  https://doi.org/10.1007/s10735-026-10905-0
  68. Sci Rep. 2026 Jul 17.
    Intermittent time-restricted feeding improves physical performance and modulates mitochondrial morphology in a muscle fiber type dependent manner in middle-aged mice.
    Fernanda Briones-Manríquez, Gonzalo Almarza, Bastián Ramos, María José Silva-Urbina, Luciana Pesce, Valentina Jeria, Javiera Aranda, Amanda Grau-Grass, Francisco Díaz-Castro, Juan Carlos Bórquez, Luis A Videla, Carla Basualto-Alarcón, Franco Tacchi, Marianny Portal-Rodriguez, Rodrigo Troncoso, Claudio Cabello-Verrugio, Andrea Del Campo.
      Sarcopenia, defined as the age-related decline in skeletal muscle mass and function, markedly reduces physical performance, threatens functional independence, and diminishes quality of life in older adults. Although the clinical manifestations of sarcopenia typically emerge later in life, underlying molecular alterations, particularly within the mitochondrial network, occur well before symptom onset. Growing evidence indicates that dietary interventions, including caloric restriction as well as changes in meal timing, composition, and overall intake, play a critical role in attenuating age-associated pathologies. Time-restricted feeding (TRF) is a dietary regimen in which all caloric intake is confined to a defined daily time window and has emerged as a feasible and widely adopted variant of caloric restriction. This study investigates the effects of inactive phase TRF on skeletal muscle health in a middle-aged murine model, with a particular focus on its potential to delay or attenuate the decrease of physical performance only by modifying daily feeding schedules. Our findings demonstrate that inactive phase TRF allows to dissect the impact of mistimed nutrient intake and confers beneficial effects on skeletal muscle, including improved muscle strength and maintenance of basal glycemia during early aging. These effects were accompanied by a tendency to increase succinate dehydrogenase (SDH) expression and significantly reduced lipid droplet accumulation. These effects correlate with muscle type-specific adaptations of the mitochondrial network and sarcoplasmic reticulum-mitochondria interaction in response to TRF. Collectively, these findings support the potential of inactive phase TRF as an easy-to-follow therapeutic intervention during middle age to maintain physical performance in early aging.
    Keywords:  Middle-age; Mitochondrial dynamics; Sarcopenia; Time-restricted feeding
    DOI:  https://doi.org/10.1038/s41598-026-60902-2
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