bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2026–09–20
58 papers selected by
Gavin McStay, Liverpool John Moores University
  1. Herpes simplex virus 1 subverts the mitochondrial network to support the infection: A lesson on mitochondrial versatility.
  2. Inhibition of mitochondrial dynamics in Dictyostelium discoideum through the overexpression of FszA and FszB proteins.
  3. Mitophagy-pyroptosis-macrophage polarization crosstalk in cardiovascular diseases: mechanistic insights and therapeutic potential.
  4. Diabetic kidney disease: emerging mechanistic and nutritional perspectives from the Mediterranean diet-mitochondria axis. A narrative review.
  5. Doxorubicin and 4-Hydroperoxycyclophosphamide Alter Mitochondrial Dynamics and miR-34 Expression in Spermatogonia and Spermatocytes In Vitro.
  6. Mitophagy as an active regulator of cardiac metabolic reprogramming.
  7. Mitochondrial remodeling by extracellular vesicles co-delivering functional mitochondria and a mitophagy inducer for neuropathic pain relief.
  8. Homocysteine and mitophagy in diabetic retinopathy: unraveling the underlying molecular crosstalk.
  9. Species-dependent activities of the PINK1-parkin axis.
  10. Regulatory mechanisms and interactions of mitophagy and ketone body metabolism in cardiac metabolism.
  11. Nitric oxide signaling and mitophagy in Parkinson's disease: implications for aerobic exercise-related neuroprotection.
  12. Piezo1 as a Key Mechanosensitive Ion Channel Linking Mechanical Overload to Mitochondrial Dysfunction, Mitophagy, and Immunometabolic Dysregulation in Osteoarthritis.
  13. Modified Hu-lu-ba-wan and its active component trigonelline ameliorate diabetic renal tubular injury via enhancing PACS2-regulated mitochondria-endoplasmic reticulum contacts and mitophagy.
  14. Estradiol Ameliorates Postmenopausal Bladder Dysfunction by Restoring Mitophagy via the miRNA-200/KLF4/mTOR Signaling Pathway.
  15. Spire1 and active INF2 promote ER-mitochondria contacts to enhance mitochondrial fission factor-mediated mitochondrial fission.
  16. Neuroglobin positively regulates YTHDF3 to restore mitophagy and suppress ferroptosis in sevoflurane-induced developmental neurotoxicity.
  17. Catalpol extends lifespan through sod-3-mediated mitophagy in Caenorhabditis elegans.
  18. Huangqi Guizhi Wuwu decoction suppresses experimental autoimmune encephalomyelitis by promoting PINK1/Parkin-mediated mitophagy and inhibiting microglial pyroptosis.
  19. Adaptation strategies and resilience mechanisms of the kidney in min pigs under long-term cold stimulation.
  20. AMPKα1 activation enhances mitophagy to counteract hypoxia-induced neuronal apoptosis in cervical spondylotic myelopathy and facilitates functional recovery mediated by rosmarinic acid.
  21. The mitophagy targeted nano-assemblies with high Salvianolic acid B -loading sufficiently enhances osteoarthritis therapy.
  22. Can diet determine glucocorticoid efficacy? Metabolic control of mitochondrial homeostasis in dystrophic muscle.
  23. Stanniocalcin-1 Overexpression Protects Porcine Intestinal Epithelial Cells Against TBHP-Induced Oxidative Stress by Preserving Mitochondrial Homeostasis.
  24. 1,8-Cineole improves hepatic fibrosis by inhibiting HIF-1α/BNIP3/PINK1/Parkin-dependent mitophagy signaling and inducing apoptosis in activated hepatic stellate cells.
  25. Mitochondria-Lysosome Quality Flux in Aging Mesenchymal Stem/Stromal Cells: Quality-Control Bottlenecks and Therapeutic Opportunities for Regenerative Decline.
  26. Spatial control of mitochondrial ubiquitination by the AMBRA1-RMC1-HUWE1 axis.
  27. Outer membrane vesicles secreted by avian pathogenic Escherichia coli promote intracellular survival in macrophages and systemic infection by regulating mitophagy through the MSTRG.11745.1/gga-miR-15b-5p/TNFAIP3 axis.
  28. Organelle-centered ISG15 biology: distinguishing covalent ISGylation from interferon-associated responses.
  29. Tunneling nanotubes regulate mitochondrial homeostasis between glioblastoma and astrocytes, and between tumor cells in vivo.
  30. Multiscale interactions in cardiovascular homeostasis and remodeling: from molecular coupling to organelle and multicellular networks.
  31. Chrysin preserves renal structure and mitochondrial quality control in D-galactose-induced kidney aging: enhanced efficacy via nano-encapsulation.
  32. ARMC10 (S43) phosphorylation mediates trimethyltin chloride-induced cognitive impairment through mitochondrial dynamics disruption.
  33. PPARGC1A Modulation Attenuates Ferroptosis-Related Injury and Promotes Functional Recovery After Spinal Cord Injury: Potential Involvement of PPARγ Signaling.
  34. Isoquercitrin ameliorates chondrocyte dysfunction in osteoarthritis by targeting AKT1-mediated mitochondrial dynamics regulation.
  35. Acoustoelectric nanoregulator for modulating the endoplasmic reticulum and mitochondria in cell fate regulation.
  36. A biomimetic chondrocyte membrane-camouflaged tFNA nanoplatform for reprogramming the cartilage-synovium axis in osteoarthritis.
  37. Breaking the Lipid Bottleneck: A Mitophagy-Driven Nanoregulator Amplifies Ferroptosis for Colorectal Cancer Immunotherapy.
  38. PEX11β controls early neural progenitor fate through regulation of peroxisomal fission and lipid metabolism.
  39. KLF5-driven G6PD protects lung squamous cell carcinoma from ferroptosis by sustaining mitochondrial homeostasis and SLC7A11-dependent cystine uptake.
  40. Interplay between mitophagy, ferroptosis, and pyroptosis in acute pancreatitis: Regulatory mechanisms and therapeutic implications.
  41. Maternal hyperhomocysteinemia promotes adverse pregnancy outcomes via mtDNA-cGAS-STING signaling-mediated trophoblast mitophagy.
  42. Limosilactobacillus reuteri orchestrates IAA-mediated mitochondrial homeostasis and stem cell renewal against intestinal oxidative injury in aged hens.
  43. Cardiac-specific Lmpt knockdown induces heart dysfunction via mitochondrial quality decline and metabolic disturbance in Drosophila.
  44. Transcriptomic analysis reveals that neural stem cell-derived exosomes regulate the HMGB1/TLR2 signaling axis to promote astrocytic differentiation and mitochondrial biogenesis in the repair of radiation-induced blood-brain barrier damage.
  45. Photobiomodulation with 808 nm Laser Light Repairs Mitochondrial Integrity and Normalizes ROS, ATP, and Membrane Depolarization in Aβ-Exposed Primary Neurons in Alzheimer's Disease Model.
  46. Autophagy-Ferroptosis Crosstalk in Dry Eye Disease: Context-Dependent Regulation of Ocular Surface Homeostasis.
  47. Mitokines as bioenergetic stress signals in cardiovascular disease: mitochondrial communication, endocrine adaptation, and translational implications.
  48. Metabolic Reprogramming of Cancer Stem Cells: Targeting Lipid Flux and Mitochondrial Plasticity to Overcome Therapeutic Resistance.
  49. Non-canonical modulation of mitochondrial ROS and dynamics by Netrin-3 drives inflammasome activation in cardiomyocytes.
  50. Multilayered interplay between the cGAS-STING pathway and autophagy.
  51. Magneto-Sono-Enhanced Nanozyme Catalysis Drives ROS-Mediated Pathogen Killing and Mitophagy-Linked Inflammation Control in Bacterial Pneumonia.
  52. SIRT1/PGC-1α-regulated mitochondrial biogenesis is involved in T-2 toxin-induced chondrocyte injury.
  53. Fucose ameliorates aging and inflammatory injury by promoting mitophagy.
  54. CRISPR/Cpf1-mediated editing of DNM1L in induced pluripotent stem cells.
  55. Nicotine modulates α7nAChR associated ceramide-mitochondrial stress responses in Parkinsonian models.
  56. Functional impact of Nth like DNA glycosylase 1 on mitochondrial dynamics.
  57. SIRT3-mediated DRP1 acetylation changes are associated with the restoration of mitochondrial function and alleviation of anterior cruciate ligament injury-induced osteoarthritis.
  58. Liraglutide Attenuates Multiorgan Oxidative, Astroglial, and Mitochondrial Stress Responses in Thioacetamide-Induced Hepatic Encephalopathy.
  1. bioRxiv. 2026 Sep 02. pii: 2026.09.02.748825. [Epub ahead of print]
    Herpes simplex virus 1 subverts the mitochondrial network to support the infection: A lesson on mitochondrial versatility.
    Rabina Saud, Kimberly Foster-Lemieur, Brett Duguay, Russell Swerdlow, Maria Kalamvoki.
      Herpes simplex virus 1 (HSV-1) infects approximately 67% of the population worldwide. It establishes lifelong reservoirs in sensory neurons and has been linked to several diseases including neuronal dysfunction. Disruption of mitochondrial homeostasis is a hallmark of HSV-1 infection, however a molecular understanding of these changes and their significance is not yet well defined. HSV-1 infection causes a UL12.5-dependent inhibition of mitochondrial biogenesis through the loss of mitochondrial DNA and mitochondrial transcription factors, PGC-1α (peroxisome proliferator-activated receptor-gamma co-activator) and TFAM (mitochondrial transcription factor). Conversely, UL12.5-independent mechanisms inhibit mitochondrial fusion by activating the OMA1 metallopeptidase that cleaves the inner mitochondrial membrane fusion protein OPA1 (optic atrophy protein 1) and by down-modulating the outer mitochondrial membrane fusion protein MFN2 (mitofusin 2). This inhibition of fusion results in a smaller mitochondrial network that clusters to perinuclear regions, likely supplying energy for viral replication and envelopment. The inner mitochondrial membrane protein TIM23 is also down-modulated during infection in a UL12.5-independent mechanism. Failure of the virus to promote these changes negatively impacts the infection. Despite these changes, mitochondria are protected from mitophagy due to the viral-induced degradation of several mitophagy adaptor proteins, whereby damaged mitochondrial components, including mitochondrial DNA, are extruded via extracellular vesicles. These mitochondrial changes still support functions necessary for HSV-1 infection. Basal cell respiration is preserved, while spare respiratory capacity and extracellular acidification rates increase, indicating glycolytic activity. Mitochondrial membrane potential is also preserved. Overall, our studies provide mechanistic insight into how HSV-1 impacts mitochondria, which could contribute to viral pathogenesis.
    Importance: Mitochondria are often referred to as the "powerhouse" of the cell because they are the main energy producers. Disruption of mitochondrial homeostasis is associated with multiple diseases and occurs after infection with pathogens such as HSV-1. By investigating the mechanism(s) by which HSV-1 disrupts mitochondrial homeostasis, we can better understand how HSV-1 causes pathogenesis. HSV-1 infection impacts mitochondrial homeostasis through disruption of four key processes, including: 1) inhibition of mitochondrial biogenesis and the generation of new mitochondria; 2) inhibition of mitochondrial fusion, which rescues reversibly damaged mitochondria; 3) sustaining mitochondrial fission, which removes damaged content; and 4) preventing mitophagy, which clears damaged mitochondria. UL12.5-dependent and UL12.5- independent events during HSV-1 infection disrupt mitochondrial homeostasis, redirecting mitochondrial resources towards progeny virus production. These changes cause irreversible damage to host cells, ultimately driving pathogenesis.
    DOI:  https://doi.org/10.64898/2026.09.02.748825
  2. Front Cell Dev Biol. 2026 ;14 1903771
    Inhibition of mitochondrial dynamics in Dictyostelium discoideum through the overexpression of FszA and FszB proteins.
    Ashley Ryan, Kari Naylor.
      Mitochondria play a central role in cells through energy production, calcium regulation, and cell death regulation. Dysfunction of mitochondria can impair energy production causing cellular damage which could be detrimental to an organism. Mitochondrial dynamics such as fission, fusion, and motility determine the organelle's structure and can indicate the overall health of the cell. Dictyostelium discoideum, a well-established model for mitochondrial dynamics, contains two GTPase proteins that are predicted to mediate mitochondrial dynamics, FszA and FszB. In this study, we overexpressed GFP tagged FszA and FszB proteins to gain insight into their role in the mitochondrial dynamics of D. discoideum. Through live imaging, we quantified mitochondrial fission and fusion events, localization of the proteins with respect to fission and fusion events, and mitochondrial velocity. Results show that the overexpression of FszA-GFP, FszB-GFP, and GFP-FszB significantly decreased mitochondrial fission and fusion, and overexpressed GFP-FszA significantly decreased mitochondrial fusion compared to the control AX4 strain. Images of GFP-FszA and FszA-GFP strains showed little co-localization with the mitochondria during fission and fusion events, but GFP-FszB and FszB-GFP were localized to the mitochondria during fission events. Overexpression of FszB-GFP and GFP-FszB also significantly decreased mitochondrial velocity. The results of this study give insight into the underlying mechanism behind mitochondrial dynamics and could advance future studies in D. discoideum neurodegeneration models.
    Keywords:  Dictyostelium discoideum; FszA; FszB; FtsZ proteins; fission; fusion; mitochondrial dynamics
    DOI:  https://doi.org/10.3389/fcell.2026.1903771
  3. Front Cardiovasc Med. 2026 ;13 1886093
    Mitophagy-pyroptosis-macrophage polarization crosstalk in cardiovascular diseases: mechanistic insights and therapeutic potential.
    Jieying Yuan, Tingru Ji, Ruquan Chen, Yuesong Yuan, Lin Ji.
      Cardiovascular disease (CVD) is one of the leading causes of global morbidity and mortality. Its development and progression are closely associated with mitochondrial dysfunction, sterile inflammation, and immunometabolic dysregulation. Mitophagy, a key mechanism of mitochondrial quality control, maintains mitochondrial homeostasis by selectively removing damaged mitochondria. However, either insufficient or excessive mitophagy may disrupt cellular metabolism, promote ROS production and mitochondrial DNA (mtDNA) release, and activate inflammatory signaling pathways, thereby aggravating cardiovascular injury. Increasing evidence indicates that mitophagy is closely linked to pyroptosis and macrophage polarization. Impaired mitophagy can enhance inflammasome activation and gasdermin-mediated pyroptosis. In turn, inflammatory mediators released during pyroptosis may further impair mitochondrial quality control, forming a self-amplifying inflammatory loop. Meanwhile, mitophagy regulates macrophage metabolic reprogramming and phenotypic switching, thereby influencing the balance between pro-inflammatory M1-like responses and reparative M2-like functions. This review summarizes the molecular mechanisms underlying the crosstalk among mitophagy, pyroptosis, and macrophage polarization in CVD, with particular emphasis on myocardial infarction (MI) and myocardial ischemia-reperfusion injury. Current evidence suggests that restoring appropriate mitophagic flux, inhibiting aberrant pyroptosis, and reshaping macrophage phenotypes may help alleviate inflammatory injury and adverse cardiac remodeling. This review aims to provide a mechanistic framework for immunometabolic regulation in CVD and to support the development of precision therapeutic strategies targeting mitochondrial quality control and inflammatory cell responses.
    Keywords:  cardiovascular disease; immunometabolic regulation; macrophage polarization; mitochondrial quality control; mitophagy; pyroptosis
    DOI:  https://doi.org/10.3389/fcvm.2026.1886093
  4. J Nutr Health Aging. 2026 Sep 15. pii: S1279-7707(26)00220-4. [Epub ahead of print]30(11): 100987
    Diabetic kidney disease: emerging mechanistic and nutritional perspectives from the Mediterranean diet-mitochondria axis. A narrative review.
    Giovanna Mercurio, Antonia Giacco, Nicla Scopigno, Michela Vigliotti, Giuseppe Petito, Maria Moreno, Federica Cioffi, Elena Silvestri.
       OBJECTIVES: To examine mitochondrial dysfunction as a key driver of diabetic kidney disease (DKD) and to evaluate the Mediterranean diet (MD) as a potential nutritional modulator of renal mitochondrial health.
    METHODS: Clinical, epidemiological, and preclinical studies addressing mitochondrial alterations in podocytes and proximal tubular cells were critically reviewed, with particular attention to MD adherence and MD-derived bioactive compounds.
    RESULTS: Evidence indicates that early, cell-specific mitochondrial dysfunction contributes to DKD progression through impaired bioenergetics, oxidative stress, altered mitochondrial dynamics, defective mitophagy, and reduced biogenesis. Clinical and epidemiological studies consistently associate higher MD adherence with preserved renal function and lower DKD risk, while experimental studies suggest that MD-derived bioactives modulate mitochondrial quality control pathways in renal cells.
    CONCLUSION: The MD-mitochondria axis represents a biologically plausible framework linking nutrition and mitochondrial homeostasis in DKD. Mediterranean diet adherence may therefore contribute to renal resilience and complement current strategies aimed at preventing DKD progression.
    Keywords:  Cell type–specific mitochondrial dysfunction; Dietary polyphenols; Mitochondrial quality control; Nutritional nephroprotection
    DOI:  https://doi.org/10.1016/j.jnha.2026.100987
  5. Basic Clin Pharmacol Toxicol. 2026 Oct;139(4): e70304
    Doxorubicin and 4-Hydroperoxycyclophosphamide Alter Mitochondrial Dynamics and miR-34 Expression in Spermatogonia and Spermatocytes In Vitro.
    Hülya Öztatlıcı, Mahmut Kemal Özbilgin, Rukiye Betül Çolaksel, Suna Karadeniz Saygılı, Mustafa Öztatlıcı.
      Doxorubicin (DOX) and cyclophosphamide (CP) are widely used chemotherapeutic agents with known gonadotoxic effects. Since miRNAs play a key role in the transcriptional regulation of spermatogenesis, they are suggested as biomarkers for male infertility. This study aimed to investigate changes in vitro the expression of proteins related to mitochondrial dynamics, apoptotic cell profiles and cell cycle distribution after treating mouse spermatogonia and spermatocytes with DOX and 4-hydroperoxycyclophosphamide (4-HC). Additionally, we also aimed to evaluate the correlation between mitochondrial function-related miR-34 family expression and mitochondrial dynamics in both cells. Mitochondrial fusion, fission, mitophagy and apoptosis markers were analysed by immunocytochemistry and qPCR. miR-34 family expressions were assessed by qPCR. Apoptosis profiles and cell cycle distributions were determined using flow cytometry. We found that DOX and 4-HC increased the percentage of cells in S and G2/M phases and apoptosis levels. Mitochondrial fusion and mitophagy gene expressions decreased, whereas fission gene expression increased. Moreover, miR-34a expression rose, whereas miR-34b and miR-34c expressions significantly decreased after treatment. These miR-34 family expression changes correlated with mitochondrial dynamics-related gene expressions, suggesting a potential role of the miR-34 family in mitochondrial dysfunction.
    Keywords:  chemotherapy; miR‐34; mitochondrial dynamics; spermatagonium; spermatocyte
    DOI:  https://doi.org/10.1111/bcpt.70304
  6. Front Cardiovasc Med. 2026 ;13 1884607
    Mitophagy as an active regulator of cardiac metabolic reprogramming.
    Li Gai, Yan Li, Chen Yang, Mengya Wang.
      Mitophagy is increasingly recognized as a context-dependent regulator of cardiac metabolic adaptation rather than solely as a disposal pathway for damaged mitochondria. By coupling mitochondrial turnover to substrate selection, redox control, and inflammatory signaling, mitophagy can influence fatty acid oxidation (FAO), glycolysis, and oxidative phosphorylation (OXPHOS) in cardiomyocytes, vascular endothelial cells, and immune cells. In this review, the term Mitophagy-Metabolic Rewiring Axis (MMRA) is used as an integrative conceptual framework-not as a newly discovered pathway or theory-to organize evidence for bidirectional interactions between mitophagy and metabolic remodeling. The framework comprises stress inputs, mitophagy machinery and flux, metabolic outputs, and cell- or disease-level consequences, while emphasizing that the biological effect of mitophagy depends on cell type, disease stage, and duration of activation. We critically assess the AMP-activated protein kinase (AMPK)-UNC-51-like kinase 1 (ULK1), sirtuin 3 (SIRT3)-peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), PTEN-induced kinase 1 (PINK1)-Parkin E3 ubiquitin ligase, and hypoxia-inducible factor 1-alpha (HIF-1α)-BCL2-interacting protein 3 (BNIP3)/FUN14 domain-containing 1 (FUNDC1) modules in atherosclerosis, heart failure, and ischemia/reperfusion injury. Pharmacological, substrate-based, and exercise interventions are evaluated with particular attention to the predominantly preclinical evidence base, methodological limitations in measuring mitophagy flux, and the need for validated human biomarkers. Multi-omics and spatial approaches may improve mechanistic resolution, but clinical translation will require prospective studies that link target engagement to metabolic and cardiovascular outcomes.
    Keywords:  AMPK–ULK1; FUNDC1; SIRT3–PGC-1α; cardiovascular disease; metabolic reprogramming; mitochondrial quality control; mitophagy
    DOI:  https://doi.org/10.3389/fcvm.2026.1884607
  7. Mater Today Bio. 2026 Oct;40 103636
    Mitochondrial remodeling by extracellular vesicles co-delivering functional mitochondria and a mitophagy inducer for neuropathic pain relief.
    Xianquan An, Li Zhang, Xin Zhang, Meidan Fang, Cong Wang, Yu Han, Zheng Wang, Jinfeng Wang, Shuting Zuo.
      Neuropathic pain remains a major clinical challenge due to limited efficacy and tolerability of current treatments. Mitochondrial dysfunction in dorsal root ganglion (DRG) cells is recognized as a key pathogenic mechanism, but effective strategies to restore mitochondrial homeostasis are lacking. Here, we first identified profound deficits in mitochondrial quantity and quality in DRG neurons and satellite glial cells (SGCs) from a chemotherapy-induced peripheral neuropathy (CIPN) model. To address this, we developed an extracellular vesicle-based nanoplatform (EVs@Mi/UR) loaded with a mitophagy inducer, which integrates exogenous mitochondrial transplantation with mitophagy induction. EVs@Mi/UR not only increased mitochondrial mass in DRG neurons and SGCs through efficient mitochondrial transplantation, but also improved mitochondrial quality by eliminating damaged organelles, thereby enhancing mitochondrial respiration and metabolic function. In both CIPN and spared nerve injury (SNI) mouse models, EVs@Mi/UR significantly alleviated mechanical allodynia, thermal hyperalgesia, and cold hypersensitivity with superior efficacy. Notably, even in SNI models that did not exhibit baseline mitochondrial deficits, EVs@Mi/UR still produced analgesic effects by improving mitochondrial quality. This work establishes mitochondrial remodeling as a promising strategy for neuropathic pain and provides a translatable EV-based nanoplatform for dual-modality mitochondrial intervention.
    Keywords:  Dorsal root ganglion; Extracellular vesicles; Mitochondrial transplantation; Mitophagy; Neuropathic pain
    DOI:  https://doi.org/10.1016/j.mtbio.2026.103636
  8. Endocrine. 2026 09 16. pii: 297. [Epub ahead of print]91(1):
    Homocysteine and mitophagy in diabetic retinopathy: unraveling the underlying molecular crosstalk.
    Nian Tan, Yanru Chen, Min Li, Wei Liu, Xiaoyun Li, Pengyuan Li, Xunwen Lei.
       PURPOSE: Diabetic retinopathy (DR), the leading cause of blindness among microvascular complications of diabetes, remains poorly understood regarding its pathogenesis, with effective clinical interventions remaining limited. Emerging evidence indicates that hyperhomocysteinemia (HHcy) and mitochondrial autophagy dysfunction act synergistically as key pathogenic drivers in DR progression, where their interactive cascade serves as a central mechanism disrupting retinal homeostasis.
    METHODS: This review systematically examines the complex mechanisms through which HHcy induces oxidative stress, inflammation, and endothelial dysfunction contributing to retinal injury, while elucidating the stage-specific regulatory dynamics of mitochondrial autophagy during DR pathogenesis.
    RESULTS: We specifically investigate the molecular mechanism by which HHcy triggers mitochondrial autophagy dysfunction through oxidative stress-mediated regulation of the AMPK/mTOR signaling axis, thereby establishing a pathogenic positive feedback loop that accelerates DR progression.
    CONCLUSIONS: Given the current lack of direct causal evidence, absence of retina-specific in vivo models, and incomplete understanding of their dynamic interactions, comprehensive analysis of core molecular nodes within the "HHcy-mitochondrial autophagy" regulatory axis is expected to refine the theoretical framework of DR pathogenesis while providing experimental foundations for developing targeted therapeutic strategies against DR-induced retinal damage.
    Keywords:  Diabetic retinopathy; Homocysteine; Hyperhomocysteinemia; Mitophagy; Signal transduction
    DOI:  https://doi.org/10.1007/s12020-026-04787-1
  9. Transl Neurodegener. 2026 Sep 18. pii: 48. [Epub ahead of print]15(1):
    Species-dependent activities of the PINK1-parkin axis.
    Wei Huang, Kecheng Chen, Jiayi Wen, Tong Zhang, Shihua Li, Xiao-Jiang Li, Weili Yang.
      In vitro studies have established that PTEN-induced putative kinase 1 (PINK1) and parkin are central regulators of mitophagy, and loss-of-function mutations in either gene can cause early-onset Parkinson's disease (PD). Although various animal models, including mice and pigs with PINK1 or PRKN knockout, have largely failed to recapitulate the neurodegeneration seen in PD patients, effective knockdown of PINK1 or PRKN in non-human primates, when achieving substantial protein depletion, does induce dopaminergic neuron loss in the substantia nigra and α‑synuclein pathology, suggesting that both the degree of protein loss and the species-dependent PINK1-parkin axis activity contribute to PD pathogenesis. This review compares pathological and behavioral outcomes of PINK1- and parkin-deficient animal models across species, illustrates diverse functions of the PINK1-parkin axis beyond mitophagy, discusses mechanisms underlying the species-dependent differences, and highlights the therapeutic potential of targeting this pathway. The review also underscores the necessity of considering species-specific mechanisms when investigating the PINK1/parkin pathway.
    Keywords:  Animal models; Non-human primate; PINK1; Parkinson’s disease; Species specificity; parkin
    DOI:  https://doi.org/10.1186/s40035-026-00586-w
  10. Front Cardiovasc Med. 2026 ;13 1925684
    Regulatory mechanisms and interactions of mitophagy and ketone body metabolism in cardiac metabolism.
    Shujun Ding, Yuna Hu, Qin Zhang, Xinyi Liu, Xuan Zhao, Yajing Zhao, Wen Zhang.
      Cardiac function depends on tightly regulated energy metabolism, with mitochondria serving as key sites of cellular energy production. Mitophagy, a selective form of autophagy that maintains mitochondrial quality, has received growing attention for its role in cardiomyocyte metabolism. Under specific physiological and pathological conditions, the myocardium increases its use of ketone bodies as energy substrates, and ketone body metabolism is closely linked to mitochondrial function. However, the relationship between mitophagy and ketone body metabolism is incompletely understood, particularly in cardiovascular disease. This review summarizes their roles and regulatory mechanisms in the myocardium and evaluates evidence for a potential bidirectional relationship. Mitophagy may preserve the mitochondrial capacity required for ketone body oxidation, whereas ketone body metabolism and β-hydroxybutyrate-mediated signaling may regulate mitophagy and mitochondrial stress resilience. By integrating these interactions across cardiovascular disease phenotypes, this review highlights their potential therapeutic relevance and identifies priorities for mechanism-based intervention and clinical translation.
    Keywords:  ketone body; metabolic flexibility; mitochondria; mitophagy; myocardial metabolism
    DOI:  https://doi.org/10.3389/fcvm.2026.1925684
  11. Med Gas Res. 2027 Jan 01. 17(1): 129-138
    Nitric oxide signaling and mitophagy in Parkinson's disease: implications for aerobic exercise-related neuroprotection.
    Yang Zhou, Yongliang Wu.
      Parkinson's disease is strongly associated with mitochondrial dysfunction and impaired mitochondrial quality control, including defective mitophagy. Aerobic exercise is increasingly recognized as a safe and accessible intervention that can improve motor and non-motor outcomes in Parkinson's disease and may also engage mechanisms relevant to disease modification. In this review, we propose a context-dependent framework in which aerobic exercise reshapes nitric oxide signaling toward a more adaptive profile, characterized by relatively moderate, transient, and spatially restricted nitric oxide bioactivity, and we discuss how this shift may influence mitochondrial biogenesis, mitophagy initiation, and autophagic flux regulation. Rather than treating nitric oxide as uniformly protective or deleterious, we argue that its biological effects in Parkinson's disease depend on source, concentration, duration, subcellular localization, cellular target, and surrounding redox milieu. However, direct evidence that exercise-derived nitric oxide activates these pathways in Parkinson's disease-relevant neural tissue is still limited. We further highlight major translational gaps, including cell-type and brain-region heterogeneity, incomplete definition of exercise dose-response relationships, and the lack of validated in vivo biomarkers of neuronal mitophagy and nitric oxide dynamics in patients with Parkinson's disease. Overall, aerobic exercise is a plausible modulator of mitophagy-related pathways in Parkinson's disease, and nitric oxide is a credible contributor to this effect; however, the current evidence supports a multi-node, context-dependent model rather than a simple linear mechanism.
    Keywords:  PINK1/Parkin pathway; Parkinson’s disease; S-nitrosylation; aerobic exercise; mitochondrial dysfunction; mitochondrial quality control; mitophagy; neuroprotection; nitric oxide; oxidative stress
    DOI:  https://doi.org/10.4103/mgr.MEDGASRES-D-26-00008
  12. Cells. 2026 Aug 22. pii: 1511. [Epub ahead of print]15(17):
    Piezo1 as a Key Mechanosensitive Ion Channel Linking Mechanical Overload to Mitochondrial Dysfunction, Mitophagy, and Immunometabolic Dysregulation in Osteoarthritis.
    Hechmi Toumi, Ahmad Almhdie-Imjabbar, Eric Lespessailles.
      Osteoarthritis (OA) is increasingly recognized as a mechanically driven whole-joint disease in which abnormal mechanotransduction initiates a cascade of mitochondrial dysfunction, chronic inflammation, and progressive cartilage degeneration. Among the mechanosensitive molecules identified to date, Piezo1 has emerged as a key mechanosensitive regulator linking pathological mechanical loading to intracellular calcium signaling and downstream cellular responses. Growing evidence indicates that persistent Piezo1 activation promotes mitochondrial calcium overload, excessive reactive oxygen species production, ATP depletion, mitochondrial membrane depolarization, and impaired mitophagy, ultimately amplifying chondrocyte dysfunction and extracellular matrix degradation. In parallel, mitochondrial damage triggers immunometabolic reprogramming through activation of the cGAS-STING pathway and the NLRP3 inflammasome. It also promotes pro-inflammatory cytokines, including interleukin-1β, tumor necrosis factor-α, and interleukin-6. Together, these responses may contribute to a self-perpetuating cycle of inflammation and tissue destruction. This review provides a comprehensive synthesis of recent advances regarding the role of Piezo1 in OA, focusing on the mechanistic links between mechanotransduction, mitochondrial dysfunction, mitophagy, and immunometabolic dysregulation. We further discuss the contribution of mitochondrial quality-control pathways, including PINK1/Parkin-, BNIP3-, and FUNDC1-mediated mitophagy, as well as alterations in mitochondrial dynamics involving DRP1, MFN1, MFN2, and OPA1. Emerging experimental models are discussed as valuable tools for accelerating therapeutic discovery. Finally, we critically evaluate current therapeutic strategies targeting the Piezo1-mitochondria axis, including mechanosensitive channel modulation, mitochondrial protection, mitophagy enhancement, gene therapy, biomaterial-assisted delivery, and nanomedicine. Collectively, current evidence supports the Piezo1-mitochondria-immune axis as an important mechanistic framework contributing to OA pathogenesis and as a potential therapeutic target. Integrating mechanobiology, mitochondrial medicine, and precision-engineered experimental models may facilitate the development of next-generation disease-modifying therapies capable of slowing or preventing osteoarthritis progression.
    Keywords:  Piezo1; calcium signaling; immunometabolism; mechanotransduction; mitochondria; mitochondrial dysfunction; mitophagy; osteoarthritis; precision medicine
    DOI:  https://doi.org/10.3390/cells15171511
  13. Fitoterapia. 2026 Sep 18. pii: S0367-326X(26)00379-5. [Epub ahead of print] 107460
    Modified Hu-lu-ba-wan and its active component trigonelline ameliorate diabetic renal tubular injury via enhancing PACS2-regulated mitochondria-endoplasmic reticulum contacts and mitophagy.
    Xinyue Jiang, Ping Ma, Huiyan Duan, Fuer Lu, Lishan Zhou, Hui Dong, Yang Gao, Minmin Gong.
       BACKGROUND: Mitochondrial dysfunction and impaired mitophagy in proximal tubule epithelial cells are central to the pathogenesis of Diabetic Kidney Disease (DKD). The mechanisms of Modified Hu-lu-ba-wan (MHLBW), a clinically validated herbal formula for DKD patients, remain to be explored.
    PURPOSE: This study aimed to investigate the renal protective effects of MHLBW against DKD, identify its bioactive component and elucidate the underlying mechanisms.
    METHODS: The efficacy of MHLBW was evaluated in DKD mice. Transcriptomics, chemical profiling analysis, and serum metabolomics were employed to uncover the mechanisms of MHLBW and to identify its active components. Molecular docking (MD) and dynamics simulations were conducted to predict the binding affinity between the identified component, trigonelline (TRL), and its putative target, Phosphofurin Acidic Cluster Sorting Protein 2 (PACS2). Gene silence in vitro experiments were further performed for mechanism verification.
    RESULTS: MHLBW treatment significantly ameliorated hyperglycemia and renal injury in db/db mice. MHLBW restored mitochondrial morphology and function, enhanced mitochondria-endoplasmic reticulum contacts (MERCs), and activated Pink1/Parkin-mediated mitophagy in renal tubules, an effect associated with increased PACS2 expression. Chemical profiling analysis and serum metabolomics identified TRL as a key component of MHLBW. TRL replicated the benefits of MHLBW in HK-2 cells. MD and dynamics simulations demonstrated stable binding between TRL and PACS2. Crucially, knockdown of PACS2 abolished the protective effects of TRL on MERCs and mitophagy.
    CONCLUSION: MHLBW and TRL can alleviate diabetic renal proximal tubular damage by targeting PACS2 to enhance MERCs and promote Pink1/Parkin-mediated mitophagy, indicating that MHLBW represents a promising therapeutic formula for DKD.
    Keywords:  Diabetic kidney disease; MHLBW; Mitochondria-ER contacts; Mitophagy; PACS2; Trigonelline
    DOI:  https://doi.org/10.1016/j.fitote.2026.107460
  14. Int J Mol Sci. 2026 Aug 22. pii: 7529. [Epub ahead of print]27(17):
    Estradiol Ameliorates Postmenopausal Bladder Dysfunction by Restoring Mitophagy via the miRNA-200/KLF4/mTOR Signaling Pathway.
    Kuang-Shun Chueh, Jian-He Lu, Jing-Wen Mao, Bin-Nan Wu, Cheng-Yu Long, Zhi-Feng Miao, Tai-Jui Juan, Rong-Jyh Lin, Shu-Mien Chuang, Mei-Chen Shen, Ting-Wei Sun, Mei-Chin Lu, Yung-Shun Juan.
      Postmenopausal ovarian hormone deficiency (OHD) contributes to overactive bladder (OAB) through oxidative stress, mitochondrial dysfunction, and dysregulated estrogen receptor (ER) signaling. This study investigated whether estradiol (E2) alleviates dysfunction by modulating the ER/Smad/miRNA-200/KLF4/mTOR signaling pathway to restore mitochondrial quality control. Thirty female Sprague-Dawley rats were initially allocated to Sham, Ovariectomy (OVX) and OVX + E2 group; after attrition during the 12-month protocol, six surviving animals per group were included in the principal analyses. The OVX + E2 group received daily intramuscular E2 (IM, 30 μg/kg/day) for one month. Bladder function was assessed via micturition volume and frequency by metabolic cages, cystometrograms, and contractility assays. Mechanisms were analyzed using immunofluorescence, Western blotting, transmission electron microscopy (TEM), and miRNA sequencing. OVX rats exhibited significant overactivity and compromised contractility, accompanied by upregulated ERα and downregulated ERβ/GPER. Molecularly, OHD was associated with the upregulation of the miRNA-200 family (miRNA-200a-3p, miRNA-200b-3p and miRNA-200b-5p), which was accompanied by reduced levels of KLF4 and autophagy proteins (ATG7, ATG12 and Beclin-1), as well as elevated p-mTOR expression. TEM revealed the accumulation of damaged mitochondria with ultrastructural features associated with impaired mitophagy. However, E2 treatment ameliorated these abnormalities. These improvements were associated with the restoration of TGF-β/Smad signaling, downregulation of selected miRNA-200 family members, recovery of KLF4 level, and increased expression of autophagy-related markers, accompanied by improved mitochondrial ultrastructural integrity. This cellular restoration might be correlated with improved urodynamic parameters. E2 might exert therapeutic effects by improving mitochondrial quality, potentially via the ER/Smad/miRNA-200/KLF4 signaling pathway. These findings provided mechanistic insights into estrogen-mediated protection and highlight this proposed signaling pathway as a therapeutic target for postmenopausal OAB.
    Keywords:  Krüppel-like factor 4; estradiol; miRNA-200; mitophagy; ovarian hormone deficiency; overactive bladder
    DOI:  https://doi.org/10.3390/ijms27177529
  15. FEBS J. 2026 Sep 15.
    Spire1 and active INF2 promote ER-mitochondria contacts to enhance mitochondrial fission factor-mediated mitochondrial fission.
    Yuxuan Zheng, Chunchun An, Yutong Ye, Zewei Luo, Tongsheng Chen.
      How interactions between the endoplasmic reticulum and mitochondria (ER-Mito) regulate mitochondrial fission remains a controversial topic. This study focuses on the molecular mechanism by which Spire type actin nucleation factor 1 (Spire1), mutant activator INF2 A149D (active INF2), and mitochondrial fission factor (MFF) regulate ER-Mito interactions to enhance mitochondrial fission. Our results show MFF-knockout severely inhibited mitochondrial fragmentation irrespective of Spire1 and active INF2 expression, demonstrating that MFF functions downstream of Spire1 and active INF2. Furthermore, we show a correlation between Spire1 and INF2 A149D expression and mitochondrial fission, confirming that an increase in ER-Mito contacts and mitochondrial fission events but a decrease in the duration of mitochondrial fission in the context of Spire1 and INF2 A149D overexpression. In addition, live-cell quantitative fluorescence resonance energy transfer (FRET) analysis found that the donor-centric FRET efficiency (ED)-concentration ratio of total acceptor-to-donor (RC) plots was lowered in the shSpire1 or shINF2 cells, indicating that Spire1 and INF2 may enhance the tightening of MFF oligomers to promote mitochondrial fission. Together our results show that Spire1 and active INF2 promote ER-mitochondria contacts to enhance MFF-mediated mitochondrial fission in MCF-7 cells.
    Keywords:  ER‐mitochondria contacts; MFF; Spire1; active INF2; mitochondrial fission
    DOI:  https://doi.org/10.1111/febs.70723
  16. Chem Biol Interact. 2026 Sep 12. pii: S0009-2797(26)00435-7. [Epub ahead of print]439 112327
    Neuroglobin positively regulates YTHDF3 to restore mitophagy and suppress ferroptosis in sevoflurane-induced developmental neurotoxicity.
    Jiaxin Yang, Rongli Guan, Jinyan Liu, Xinyi Li, Sheng Yang, Hai Zhao, Fan Yang.
      Sevoflurane-induced developmental neurotoxicity is characterized by impaired mitophagy and excessive ferroptosis. Neuroglobin (NGB) exerts broad neuroprotective effects, yet its exact epitranscriptomic regulatory mechanism against sevoflurane injury remains elusive. Two complementary experimental systems with identical total sevoflurane exposure length were adopted for in vitro mechanistic exploration and in vivo physiological verification, respectively. HT22 hippocampal neurons underwent uninterrupted 6 h sevoflurane incubation, while neonatal rats received 2 h intermittent inhalation each day for three consecutive days. We constructed lentiviral systems to overexpress or knockdown NGB/YTHDF3, then detected cell viability, mitochondrial function, reactive oxygen species (ROS), iron levels and pathway biomarkers. Co-immunoprecipitation verified endogenous protein interaction between NGB and m6A reader YTHDF3, and in vivo experiments further detected hippocampal mitophagy, ferroptosis indicators and mitochondrial ultrastructure. In vitro assays demonstrated that NGB alleviates sevoflurane-triggered mitochondrial damage and neuronal death via two separate cascades: NGB restores mitophagy and suppresses ferroptosis by interacting with and positively regulating the protein expression of YTHDF3, whereas its intrinsic antioxidant activity improves cell viability and eliminates ROS in a YTHDF3-independent manner. Collectively, this study describes a NGB-YTHDF3 epitranscriptomic regulatory mechanism that mitigates sevoflurane-triggered developmental neurotoxicity and offers therapeutic insights for pediatric brain protection.
    Keywords:  Ferroptosis; Mitophagy; Neuroglobin; Neurotoxicity; Sevoflurane; YTHDF3; m(6)A methylation
    DOI:  https://doi.org/10.1016/j.cbi.2026.112327
  17. Arch Gerontol Geriatr. 2026 Sep 09. pii: S0167-4943(26)00274-8. [Epub ahead of print]151 106405
    Catalpol extends lifespan through sod-3-mediated mitophagy in Caenorhabditis elegans.
    Songtao Bie, Xiang Li, Hui Shang, Pingxuan Fan, Nana Chen, Saopu Li.
      Autophagy is an essential process that helps cells maintain balance by breaking down and reusing damaged organelles and abnormal proteins. The decline in its function is widely acknowledged as a significant contributor to aging. Catalpol (CAT), the main active ingredient in Rehmannia root, shows promise for treating age-related diseases by influencing autophagy. However, its specific mechanisms for anti-aging effects are not well understood. This study used Caenorhabditis elegans (C. elegans) as a model organism to explore the role of CAT in mitophagy and to uncover its potential anti-aging mechanisms. Our findings reveal that CAT treatment significantly extends both median and maximum lifespan, maintains muscle mass and viable cell content, improves survival, and attenuates age‑related decline in aging C. elegans. Further analysis indicates that CAT enhances mitochondrial function in these C. elegans through mitophagy, thereby improving their resistance to oxidative stress. Additionally, RNA sequencing and bioinformatics analysis identified SOD-3 as a key target of CAT. Using SOD-3KO strains, we confirmed that CAT improves mitochondrial function and boosts resistance to oxidative stress through SOD-3 dependent mitophagy. In conclusion, our study shows that CAT has anti-aging effects in C. elegans by promoting mitophagy mediated by SOD-3.
    Keywords:  Anti-aging; Antioxidant stress; Autophagy; Bioinformatics analysis; Caenorhabditis elegans; SOD-3
    DOI:  https://doi.org/10.1016/j.archger.2026.106405
  18. Fitoterapia. 2026 Sep 15. pii: S0367-326X(26)00389-8. [Epub ahead of print]194 107470
    Huangqi Guizhi Wuwu decoction suppresses experimental autoimmune encephalomyelitis by promoting PINK1/Parkin-mediated mitophagy and inhibiting microglial pyroptosis.
    Wenying Li, Shuangshuang Wang, Shuhao Fang, Wendi Ma, Mengmeng Dou, Tongyin Yan, Xiaoyu Zhao, Nan Liu, Chong Liu, Lin Zhu, Yaojuan Chu.
      Multiple sclerosis (MS) is a chronic autoimmune disorder of the central nervous system. Huangqi Guizhi Wuwu Decoction (HGWD), a classic traditional Chinese medicine formula, exerts protective effects against MS, yet the underlying mechanism involving mitophagy and microglial pyroptosis remains poorly elucidated. This study investigated the ameliorative effects of HGWD on experimental autoimmune encephalomyelitis (EAE) and its molecular mechanism. HGWD components were identified via UHPLC-Q-Orbitrap HRMS, and potential anti-MS targets were predicted by network pharmacology and molecular docking. EAE mice and LPS-stimulated microglia were treated with HGWD, with mitophagy inhibitor 3-MA and PINK1 siRNA used for mechanism validation. Assessments included clinical scoring, histopathology, Western blotting, immunofluorescence, ELISA, transmission electron microscopy and mitochondrial function assays. A total of 59 constituents were identified; network pharmacology revealed core pyroptosis-related targets (IL-1β, IL-18, NLRP3, CASP1) in MS, and molecular docking confirmed strong binding affinities between key active components and these proteins. HGWD significantly alleviated EAE clinical severity and reduced demyelination by enhancing PINK1/Parkin-mediated mitophagy, improving mitochondrial function, and inhibiting microglial pyroptosis, which was validated in vitro. Notably, both 3-MA and PINK1 silencing abolished HGWD's protective effects. This study first confirms that HGWD treats EAE via the PINK1/Parkin mitophagy-pyroptosis axis, providing theoretical evidence for its clinical translation and quality control.
    Keywords:  Huangqi Guizhi Wuwu decoction; Microglia; Mitophagy; Multiple sclerosis; PINK1/Parkin; Pyroptosis
    DOI:  https://doi.org/10.1016/j.fitote.2026.107470
  19. J Therm Biol. 2026 Sep 10. pii: S0306-4565(26)00201-9. [Epub ahead of print]141 104568
    Adaptation strategies and resilience mechanisms of the kidney in min pigs under long-term cold stimulation.
    Guodong Sun, Chaoyue Zhao, Ze Wang, Zhongyu Li, Teng Teng, Baoming Shi.
      The Min pig, a unique local breed in northeastern China, exhibits exceptional cold resistance. However, the renal adaptive mechanisms underlying this trait under long-term cold stimulation remain unclear. This study investigated the effects of long-term cold stimulation on renal structure, antioxidant function, purine metabolism, programmed cell death, and mitochondrial dynamics in Min pigs. The results showed that long-term cold stimulation led to mild morphological changes in the kidneys of Min pigs, as evidenced by pathological sections and ultrastructural analysis. Concurrently, long-term cold stimulation inhibited GSH-Px activity in the kidney and partially impaired the antioxidant capacity. Intriguingly, long-term cold stimulation did not significantly alter the protein levels of major inflammatory factors in the kidney, while IL-2 mRNA expression was increased. Notably, long-term cold stimulation suppressed mRNA expression of CNT1 and ENT2 and promoted mRNA expression of URAT1 in the kidney. At the same time, uricase levels were markedly increased and 5'-NT levels were significantly decreased in the kidney, which may have contributed to the downward trend of UA levels in Min pigs. Surprisingly, long-term cold stimulation does not activate pyroptosis, apoptosis and mitophagy pathways in the kidney of Min pigs. Moreover, long-term cold stimulation increased the expression of OPA1 mRNA in the kidney. In summary, long-term cold stimulation induced mild morphological changes in the kidneys of Min pigs. Simultaneously, the kidney cold adaptation mechanism is triggered, renal purine metabolism is readjusted, and mitochondrial fusion is facilitated. This contributes to mitigating the negative effects of long-term cold stimulation on Min pigs.
    Keywords:  Kidney; Long-term cold stimulation; Min pigs; Mitochondrial fusion; Purine metabolism
    DOI:  https://doi.org/10.1016/j.jtherbio.2026.104568
  20. Phytomedicine. 2026 Sep 07. pii: S0944-7113(26)01011-1. [Epub ahead of print]161 158781
    AMPKα1 activation enhances mitophagy to counteract hypoxia-induced neuronal apoptosis in cervical spondylotic myelopathy and facilitates functional recovery mediated by rosmarinic acid.
    Pei-Min Pu, Yu-Xiang Dai, Shi-Pian Li, Ya-Yun Zhang, Yue-Li Sun, Yong-Jun Wang, Xue-Jun Cui, Min Yao.
       BACKGROUND: Cervical spondylotic myelopathy (CSM) involves progressive neurological dysfunction often linked to mitochondrial impairment. Mitophagy, a selective autophagic process, is crucial for neuronal homeostasis; however, its role in CSM and the specific involvement of AMPK subunits in TFEB-mediated mitophagy remain unclear. Rosmarinic acid (RA) is known for neuroprotection and mitophagy activation, but its exact mechanism in CSM has not yet been clarified.
    METHODS: We investigated the neuroprotective efficacy of RA using a rat model of chronic spinal cord compression, alongside oxygen-glucose deprivation (OGD)-challenged primary neurons and PC12 cells. To dissect the roles of AMPK subunits, PC12 lines with individual (a1-KO, a2-KO) or combined (a1/a2-DKO) deficiencies were employed. Mitophagy, lysosomal integrity, and signaling pathways were assessed via RNA-seq, immunofluorescence (IF), transmission electron microscopy, and Western blot.
    PURPOSE: To investigate the role of the AMPKα1-TFEB signaling axis in regulating mitophagy in CSM and to identify RA as a potent neuroprotective agent.
    RESULTS: Our findings indicate that while chronic hypoxia induces severe neuronal apoptosis, transient hypoxia enhances mitophagy and preserves lysosomal integrity via the AMPK-TFEB signaling pathway. Notably, Prkaa1 knockout or a1/a2 double-knockout PC12 cells exhibited exacerbated apoptosis and impaired mitophagy/lysosomal function under hypoxic challenge, whereas no significant differences were observed in Prkaa2 knockout cells. Furthermore, RA was found to restore impaired spinal cord function by activating the AMPK-TFEB axis.
    CONCLUSION: AMPKα1 is a pivotal regulator of the AMPK-TFEB/mitophagy axis. Targeting AMPKα1 or utilizing RA represents a promising therapeutic strategy for CSM, although further well-designed randomized controlled trials are required to evaluate clinical efficacy.
    Keywords:  AMPK; Cervical spondylotic myelopathy; Mitophagy; Neuronal apoptosis; Rosmarinic acid
    DOI:  https://doi.org/10.1016/j.phymed.2026.158781
  21. Mater Today Bio. 2026 Oct;40 103601
    The mitophagy targeted nano-assemblies with high Salvianolic acid B -loading sufficiently enhances osteoarthritis therapy.
    Yulin Jiang, Mingzhu Wang, Hanshuang Liang, Xuejie Hu, Liuwei Chu, Ranran Yang, Kang Wang, Ruhong Fang, Cailiang Shen, Xinming Wang, Wei Wei, Qingtong Wang.
      Osteoarthritis (OA) is characterized by chondrocyte degeneration and associated intracellular organelle dysfunction. Restoring impaired mitophagy represents a critical strategy for ameliorating OA-induced chondrocyte dysfunction and promoting cartilage repair, yet a significant therapeutic gap persists due to the lack of highly potent agents that can effectively restore mitophagy in OA chondrocyte. In this work, we identified Salvianolic acid B (SaB), a novel small-molecule agent, which binds to PINK1/Parkin proteins to stabilize them, promote their expression, and activate mitophagy. SaB nano-assemblies (SaB NAs) were fabricated via hydrogen bonding and π-π stacking between SaB and triphenylphosphine, achieving exceptional drug loading (74.4%) and mitochondrial-targeted synergistic therapeutic effects. In vitro and in vivo assessments confirmed that SaB NAs significantly outperformed free SaB in restoring mitochondrial function, facilitating chondrocyte recovery, prolonging therapeutic residence time and alleviating OA progression. The intra-articular delivery of SaB NAs represents a promising approach for treating OA and other joint inflammatory diseases.
    Keywords:  Chondrocyte; Mitophagy; Nano-assemblies; Osteoarthritis; PINK1; Salvianolic acid B
    DOI:  https://doi.org/10.1016/j.mtbio.2026.103601
  22. J Physiol. 2026 Sep 14.
    Can diet determine glucocorticoid efficacy? Metabolic control of mitochondrial homeostasis in dystrophic muscle.
    Anusha Liaqat, Salman Ahmad.
      
    Keywords:  Duchenne muscular dystrophy; glucocorticoid; high‐fat; high‐sucrose diet; mdx mice; mitochondria
    DOI:  https://doi.org/10.1113/JP292108
  23. Animals (Basel). 2026 Aug 25. pii: 2668. [Epub ahead of print]16(17):
    Stanniocalcin-1 Overexpression Protects Porcine Intestinal Epithelial Cells Against TBHP-Induced Oxidative Stress by Preserving Mitochondrial Homeostasis.
    Liming Wu, Yan Bin, Yubei Wei, Zihan Cui, Jiayi Du, Jinluo Lv, Xiaoliang Xiang.
      Stanniocalcin-1 (STC-1) is a multifunctional glycoprotein; however, its role in protecting intestinal epithelial cells against oxidative injury has not been completely elucidated. This study investigated the cytoprotective effects and underlying molecular mechanisms of STC-1 overexpression in porcine intestinal epithelial (IPEC-J2) cells subjected to tert-butyl hydroperoxide (TBHP)-induced oxidative stress. IPEC-J2 cells were transfected with pcDNA3.1/STC-1 prior to TBHP challenge. STC-1 overexpression markedly rescued cells from TBHP-induced cytotoxicity and cell death, and was associated with a reduced Bax/Bcl-2 ratio. Concurrently, elevated STC-1 expression dramatically suppressed intracellular reactive oxygen species and mitochondrial superoxide accumulation while preserving the mitochondrial membrane potential. These physiological improvements were accompanied by enhanced total antioxidant capacity and activities of key antioxidant enzymes. Mechanistically, STC-1 overexpression enhanced autophagic flux and promoted Pink1/Parkin-mediated mitophagy to eliminate dysfunctional mitochondria. Furthermore, STC-1 upregulation potentiated the AMPK-Nrf2/Sirt1 signaling axis and the subsequent transcriptional upregulation of mitochondrial quality control markers, including FoxO1, PGC-1α, and TFAM, under stress conditions. Collectively, these findings demonstrate that STC-1 safeguards porcine intestinal cells against oxidative injury by orchestrating a cooperative defense network encompassing ROS scavenging, mitochondrial homeostasis, and antioxidant defense amplification via the AMPK-Nrf2/Sirt1 pathway, highlighting a potential therapeutic target for preventing stress-associated intestinal disorders in piglets.
    Keywords:  AMPK/Nrf2/Sirt1 pathway; IPEC-J2 cells; mitophagy; oxidative stress; stanniocalcin-1
    DOI:  https://doi.org/10.3390/ani16172668
  24. Front Pharmacol. 2026 ;17 1873519
    1,8-Cineole improves hepatic fibrosis by inhibiting HIF-1α/BNIP3/PINK1/Parkin-dependent mitophagy signaling and inducing apoptosis in activated hepatic stellate cells.
    Lifeng Qin, Jiawu Tan, Chan He, Maoyin He, Jiqiao Zhang.
       Aim: The HIF-1α/BNIP3/mitophagy signaling pathway might be closely associated with hepatic fibrosis. Although 1,8-cineole (CIN) has been shown to improve fibrosis in several organs, direct evidence for its anti-hepatic fibrotic effects remains lacking. The objective of this study was to confirm the role of mitophagy in hepatic stellate cells (HSCs) and the role of the HIF-1α/BNIP3 signaling pathway in the pathogenesis of hepatic fibrosis. Additionally, in vivo and in vitro experiments were conducted to explore the effect of CIN on hepatic fibrosis.
    Methods: In a CCl4-induced hepatic fibrosis rat model and in CoCl2-treated HSCs, expression level of HIF-1α, BNIP3, α-SMA, collagen 1, PINK1, Parkin, p62 and LC3-II/LC3-I were examined, and the ubiquitinated Parkin level was detected following immunoprecipitation. In addition, the proliferation and apoptosis of HSCs were detected.
    Results: Our findings indicated that CIN significantly mitigated CCl4-induced hepatic fibrosis. The alleviation of hepatic fibrosis after CIN treatment was associated with a markedly decrease in HIF-1α, BNIP3, α-SMA, collagen 1, PINK1, Parkin and LC3-II/LC-I, as well as a signally increase in P62. Moreover, CIN, Mdivi-1 (mitophagy inhibitor) and Bafilomycin A1 (lysosomal inhibitors) significantly inhibited the proliferation of HSCs. The ubiquitinated Parkin level was significantly more prominent in the CoCl2 group, while the ubiquitinated Parkin level was observably decreased after CIN treatment. Additionally, CIN exhibited efficacy comparable to that of TRAIL (apoptosis-inducing agent) in significantly promoting apoptosis in hepatic stellate cells.
    Conclusion: CIN improves hepatic fibrosis by inhibiting HIF-1α/BNIP3/PINK1/Parkin-dependent mitophagy signaling and inducing apoptosis in activated HSCs.
    Keywords:  1,8-cineole; HIF-1α/BNIP3; Pink1/Parkin; hepatic fibrosis; mitophagy
    DOI:  https://doi.org/10.3389/fphar.2026.1873519
  25. Cells. 2026 Aug 27. pii: 1548. [Epub ahead of print]15(17):
    Mitochondria-Lysosome Quality Flux in Aging Mesenchymal Stem/Stromal Cells: Quality-Control Bottlenecks and Therapeutic Opportunities for Regenerative Decline.
    Lingling Cheng, Gaojie Song.
      Aging mesenchymal stem/stromal cells (MSCs) lose regenerative capacity as redox imbalance, mitochondrial damage, defective organelle quality control and chronic inflammation converge. Yet these processes are commonly considered in isolation, obscuring whether damaged mitochondrial cargo reaches lysosomes and is ultimately degraded. Here, we define mitochondria-lysosome quality flux (MLQF) as an author-proposed, evidence-graded framework that tracks mitochondrial damage from recognition and sorting through lysosomal delivery to terminal lysosomal degradation in aging MSCs. The framework explicitly separates delivery to an acidic compartment from completed degradation and distinguishes direct MSC evidence from cross-model mechanisms and candidate pathways. MSC studies most strongly support macroautophagy-dependent mitophagy, particularly when assessed using dynamic flux reporters. By contrast, mitochondria-derived vesicles and microautophagy-like or piecemeal routes remain incompletely validated in MSCs. Studies in non-MSC systems further show that mitochondria-lysosome contact sites can support lysosomal acidification, although their contribution to natural MSC aging remains unresolved. By locating rate-limiting defects across this continuum, MLQF provides a testable basis for linking incomplete mitochondrial clearance to inflammatory signaling, lineage drift and regenerative decline, and for selecting bottleneck-matched interventions.
    Keywords:  cellular senescence; mesenchymal stem/stromal cells; mitochondrial quality control; mitochondria–lysosome quality flux; mitophagy
    DOI:  https://doi.org/10.3390/cells15171548
  26. Autophagy. 2026 Sep 16.
    Spatial control of mitochondrial ubiquitination by the AMBRA1-RMC1-HUWE1 axis.
    Jiamin Yi, Xin Yong, Da Jia.
      Mitochondrial ubiquitination is a central component of mitochondrial quality control. The PINK1 (PTEN induced kinase 1)-PRKN (parkin RBR E3 ubiquitin protein ligase) pathway established how loss of mitochondrial membrane potential can trigger a phospho-ubiquitin feed-forward cascade on the outer mitochondrial membrane (OMM). It remains less clear how mitochondrial ubiquitination is achieved when PRKN is absent or inactivated. In our recent work, we identify a recruitment platform organized by AMBRA1 (autophagy and beclin 1 regulator 1), in which RMC1 (regulator of MON1-CCZ1) positions HUWE1 (HECT, UBA and WWE domain containing E3 ubiquitin protein ligase 1) at mitochondria. This spatial arrangement promotes HUWE1-dependent ubiquitination and turnover of OMM proteins, including MFN2 (mitofusin 2), VDAC1 (voltage-dependent anion channel 1), and VDAC2 (voltage-dependent anion channel 2). Our findings raise the question of how cells select among distinct mitochondrial ubiquitination pathways and whether these pathways function independently, sequentially, or cooperatively.
    Keywords:  AMBRA1; HUWE1; PINK1-PRKN; RMC1; mitochondrial quality control; ubiquitination
    DOI:  https://doi.org/10.1080/15548627.2026.2735210
  27. Poult Sci. 2026 Sep 13. pii: S0032-5791(26)01387-8. [Epub ahead of print]105(12): 107755
    Outer membrane vesicles secreted by avian pathogenic Escherichia coli promote intracellular survival in macrophages and systemic infection by regulating mitophagy through the MSTRG.11745.1/gga-miR-15b-5p/TNFAIP3 axis.
    Jiayin Gao, Zhe Li, Tongtong Cui, Ying Shao, Jiumeng Sun, Zhenyu Wang, Xiangjun Song, Zhengyang Cheng, Jian Tu.
      Avian pathogenic Escherichia coli (APEC) is a major extraintestinal pathogen responsible for severe systemic infections in poultry. It evades the immune system and establishes persistent infection by hijacking macrophages as its primary site of intracellular survival. During the pathogenic process, outer membrane vesicles (OMVs) secreted by APEC serve as key carriers for the delivery of virulence factors to host cells. However, the specific mechanisms by which OMVs disrupt macrophage defence mechanisms and promote the intracellular survival of APEC have not yet been fully elucidated. We demonstrated that APEC OMVs disrupt the mitochondrial structure of chicken macrophages (HD11) and lead to the collapse of the mitochondrial membrane potential. This injury-induced mitophagy contributes to a reduction in stress-related ROS levels, thereby promoting the intracellular survival of APEC and systemic infection. Furthermore, intervention with a mitophagy inhibitor significantly reduced the extent of intracellular survival resulting from mitophagy (P < 0.01) as well as the bacterial load in chick tissues (trachea: P < 0.001; lung: P < 0.001; liver: P < 0.001; spleen: P < 0.01). Furthermore, We identified a novel lncRNA-MSTRG.11745.1-associated with mitophagy through transcriptomic screening, and upregulated MSTRG.11745.1 acts as a competitive endogenous RNA (ceRNA), binding to gga-miR-15b-5p to regulate the TNFAIP3 expression, thereby promoting mitophagy and the intracellular survival of APEC. In summary, APEC-derived OMVs induce severe mitochondrial damage in host macrophages. They also activate the MSTRG.11745.1/gga-miR-15b-5p/TNFAIP3 ceRNA axis and promote mitophagy. This process contributes to APEC immune evasion and systemic infection. This study provides new insights into the core mechanisms by which OMVs enable APEC to evade innate immune surveillance by macrophages.
    Keywords:  Immune evasion; Mitochondrial damage; Mitophagy; Outer membrane vesicles of avian pathogenic Escherichia coli; ceRNA
    DOI:  https://doi.org/10.1016/j.psj.2026.107755
  28. Front Immunol. 2026 ;17 1960492
    Organelle-centered ISG15 biology: distinguishing covalent ISGylation from interferon-associated responses.
    Zhuoer Li, Chunli Wang, Jinrong Zhang, Zhiqiang Guo.
      ISGylation is an interferon-inducible ubiquitin-like post-translational modification mediated by the interferon-stimulated gene 15 conjugation system. Initially characterized as an antiviral effector pathway, ISGylation is now increasingly recognized as a regulator of organelle homeostasis and cellular stress responses. This review summarizes emerging evidence linking ISG15-related mechanisms and covalent ISGylation to major organelle systems, including mitochondria, the endoplasmic reticulum-Golgi axis, endolysosomal compartments, ribosome-associated translation, and lipid droplets. We distinguish covalent ISGylation from free ISG15 signaling and ubiquitin specific protease 18-mediated interferon regulation, and further classify existing findings into evidence-based levels ranging from substrate-validated modification to correlative interferon signatures. At the mitochondrial level, direct and pathway-level evidence implicates ISG15 biology in DRP1-mediated fission, MFN1/2-associated mitophagy, oxidative metabolism, and redox regulation; direct effects of MFN1/2 ISGylation on mitochondrial fusion remain unproven. Along the ER-Golgi axis, ISG15-related pathways intersect with unfolded protein response signaling, endoplasmic reticulum-associated degradation, and stimulator of interferon genes-mediated innate immune activation. In the endolysosomal system, ISGylation and ISG15-associated pathways modulate autophagic flux, multivesicular body fate, and exosome secretion in a context-dependent manner. Ribosome-associated co-translational ISGylation links nascent protein surveillance with antiviral defense, whereas lipid droplet-associated ISG15/ISGylation pathways are linked to lipid metabolism and immune signaling. Current evidence supports an organelle-centered view of ISG15 biology but indicates that validated covalent mechanisms remain confined to selected substrates and contexts. Clinical translation will require organelle-resolved ISGylome mapping, substrate-level validation, and standardized biomarker assays before context-selective targeting can be considered.
    Keywords:  ISG15; ISGylation; autophagy; biomarkers; endoplasmic reticulum stress; mitochondrial dynamics; organelle homeostasis
    DOI:  https://doi.org/10.3389/fimmu.2026.1960492
  29. Nat Commun. 2026 09 15. pii: 9788. [Epub ahead of print]17(1):
    Tunneling nanotubes regulate mitochondrial homeostasis between glioblastoma and astrocytes, and between tumor cells in vivo.
    Ines Saenz-de-Santa-Maria, Anna Pepe, Jean-Yves Tinevez, Christel Brou, Yakov Vitrenko, Thomas Cokelaer, Elizabeth Cohen-Jonathan Moyal, Roberto Weigert, Chiara Zurzolo.
      Tumor progression is driven by cancer cells' ability to establish a cellular network through tunneling nanotube-like connections (TNTs), which enable mitochondrial exchange both within the tumor cells and with the tumor microenvironment (TME). However, the functional consequences of mitochondrial transfer between tumor and non-tumor cells, and its occurrence in vivo, remain poorly understood. Here we show bidirectional mitochondrial transfer between Glioblastoma (GBM) cells and non-tumoral astrocytes (AS). We report that transfer of damaged mitochondria from GBM cells to AS is associated with activation of mitophagy in recipient cells, while astrocyte-derived mitochondria to GBM cells correlates with changes in mitochondrial activity and metabolic readouts. Furthermore, intravital subcellular microscopy (ISMic) in a live animal model allows the visualization of TNT connections with characteristics similar to those observed in vitro and supported TNT-mediated mitochondrial transfer in vivo. These findings reveal a potential mechanism of tumor adaptation and highlight TNTs as promising therapeutic targets.
    DOI:  https://doi.org/10.1038/s41467-026-76619-9
  30. J Physiol Sci. 2026 Sep 14. pii: S1880-6546(26)00048-X. [Epub ahead of print]76(3): 100102
    Multiscale interactions in cardiovascular homeostasis and remodeling: from molecular coupling to organelle and multicellular networks.
    Motohiro Nishida.
      Cardiovascular homeostasis is increasingly understood not as the output of isolated pathways, but as an emergent and history-dependent property of interactions across biological scales. Cutting-edge technologies have revealed coupling between transcription and metabolism, signaling within molecular microdomains, organelle networks, communication between cardiomyocytes and non-myocytes, neurovascular regulation, and interorgan interactions. This special issue brings together five perspectives that examine how such interactions preserve physiological function and, under stress, redirect the cardiovascular system toward adaptation or disease. As a representative multiscale example, this Editorial highlights hierarchical mitochondrial quality control. Biogenesis, fusion-fission dynamics, proteostasis, mitochondria-derived vesicles, organelle contacts, and mitophagy form a graded defense network that matches the response to the burden and location of damage. The same network connects mitochondrial dysfunction to innate immunity and tissue remodeling. Defining directionality, spatial context, temporal order, and flux within these interactions will be essential for converting descriptive interaction maps into causal physiology and selective therapies.
    Keywords:  Cardiovascular homeostasis; Cellular circuits; Functional interaction; Heart failure; Microdomains; Mitochondrial quality control
    DOI:  https://doi.org/10.1016/j.jphyss.2026.100102
  31. J Pharm Pharmacol. 2026 Sep 01. pii: rgag104. [Epub ahead of print]78(9):
    Chrysin preserves renal structure and mitochondrial quality control in D-galactose-induced kidney aging: enhanced efficacy via nano-encapsulation.
    Ekramy M Elmorsy, Ayat B Al-Ghafari, Huda A Al Doghaither, Syed Sajid Hussain Shah, Asmara Syed, Neven A Ebrahim, Muhammad Jan, Hamada S Salem.
       OBJECTIVES: Aging-associated renal dysfunction is driven by mitochondrial impairment, oxidative stress, inflammation, and apoptosis. This study investigated the renoprotective effects of chrysin (Chry) and nano-encapsulated chrysin (Chry-Cas-NPs) in a D-galactose-induced rat model of kidney aging, with emphasis on mitochondrial quality control mechanisms.
    METHODS: Sixty male Wistar rats were assigned to control, D-galactose, Chry, and Chry-Cas-NPs groups and treated for 10 weeks. Renal function indices, mitochondrial respiratory chain activities, ATP levels, mitophagy-related proteins (PINK1/Parkin), mitochondrial gene expression, oxidative stress markers, inflammatory mediators, apoptotic proteins, and renal histopathology were evaluated.
    KEY FINDINGS: D-galactose induced marked renal dysfunction, tubular and glomerular degeneration, and mitochondrial structural damage. These changes were associated with impaired respiratory chain activity, reduced ATP production, altered PINK1/Parkin expression, downregulation of mitochondrial genes, increased oxidative stress (reactive oxygen species, malondialdehyde), depletion of antioxidant defenses, increased MAPK and NF-κB/TLR4 signaling, elevated pro-inflammatory cytokines, and enhanced apoptosis. Chry partially improved these alterations. Notably, Chry-Cas-NPs significantly restored mitochondrial function and structure, modulated PINK1/Parkin-related protein expression, attenuated oxidative and inflammatory responses, reduced apoptosis, and preserved renal architecture more effectively than free Chry.
    CONCLUSIONS: Chry-Cas-NPs provided greater renoprotective effects than free Chry, associated with preservation of mitochondrial function and modulation of PINK1/Parkin-related proteins, oxidative stress, inflammation, and apoptosis in experimental renal aging.
    Keywords:  MAPK signaling; NF-κB pathway; apoptotic signaling; chrysin; mitochondrial quality control; mitophagy; nano-encapsulation; oxidative stress; renal aging; renal ultrastructure
    DOI:  https://doi.org/10.1093/jpp/rgag104
  32. J Hazard Mater. 2026 Sep 15. pii: S0304-3894(26)02628-2. [Epub ahead of print]517 143647
    ARMC10 (S43) phosphorylation mediates trimethyltin chloride-induced cognitive impairment through mitochondrial dynamics disruption.
    Mingke Qin, Fan Zhang, Liting Wang, Rui Tian, Ping Deng, Huihui Hong, Sicheng Liu, Lingling Yang, Peng Gao, Min Li, Jingdian Li, Sheng Jie, Yuchen Qu, Rongrong Hao, Lei Zhang, Chunhai Chen, Mindi He, Qinlong Ma, Weijia Qing, Yan Luo, Mengyan Chen, Li Tian, Jia Xie, Zhengping Yu, Zhou Zhou, Huifeng Pi.
      Trimethyltin chloride (TMT) is a well-established environmental neurotoxin known to induce hippocampal damage and cognitive impairment. Abnormal mitochondrial dynamics are involved in TMT-induced neurotoxicity, but the underlying molecular mechanisms remain unclear. Here, our study revealed that TMT-induced mitochondrial fragmentation led to mitochondrial dysfunction, nerve cell death and cognitive deficit. We assessed the expression of mitochondrial dynamics‑related proteins (OPA1, MFN1/2, DRP1, and FIS1). Using phosphoproteomics, we further identified Ser43 (S43) as a phosphorylation site in ARMC10, a protein implicated in mitochondrial dynamics. TMT exposure elevated the phosphorylation level of ARMC10S43, validated by the anti-ARMC10S43 phospho-specific antibody and parallel reaction monitoring (PRM). The overexpression of nonphosphorylatable ARMC10S43A, but not phosphomimic ARMC10S43D, remarkably antagonized TMT-induced mitochondrial fragmentation and dysfunction in vitro and in vivo. Immunoprecipitation-coupled mass spectrometry (IP-MS), followed by co-localization analysis and proximity ligation assay (PLA), verified that phosphorylated ARMC1S43 targets MTFP1 and BNIP3, contributing to TMT-induced neurotoxicity. We identified the natural product derivative 1-(3,5-dimethylbenzenesulfonyl)-8',9'-dimethyl-5'H-spiro[piperidine-4,4'-pyrrolo[1,2-a]quinoxaline] from over 160,000 natural product-derived compounds library as a potential inhibitor of ARMC10 phosphorylation at S43, which antagonizes TMT-induced mitochondrial fragmentation and dysfunction. This study provides a better understanding of how post-translational modifications regulate mitochondrial dynamics in TMT-induced memory disorders, and offers guidance for a comprehensive assessment of the ecological and health risks associated with neurodegenerative diseases.
    Keywords:  ARMC10; Cognitive impairment; Mitochondrial dynamics; Trimethyltin chloride
    DOI:  https://doi.org/10.1016/j.jhazmat.2026.143647
  33. Eur J Neurosci. 2026 Sep;64(6): e70672
    PPARGC1A Modulation Attenuates Ferroptosis-Related Injury and Promotes Functional Recovery After Spinal Cord Injury: Potential Involvement of PPARγ Signaling.
    Deli Wang, Bing Wu, Chuanpeng Liu, Yafeng Wu, Xinyu Meng, Xijing He.
      Spinal cord injury (SCI) is a devastating neurological condition with limited therapeutic options. Emerging evidence implicates ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, in secondary injury cascades following SCI. However, the molecular regulators linking mitochondrial quality control to ferroptosis in the injured spinal cord remain incompletely characterized. Here, through integrated bioinformatics analysis of the GEO dataset GSE155610 combined with ferroptosis gene screening and weighted gene co-expression network analysis (WGCNA), we identified PPARGC1A (PGC-1a) as a hub gene at the intersection of ferroptosis and mitochondrial dysfunction. Clinical validation in a retrospective cohort of 186 acute SCI patients demonstrated that serum ferritin, PPARGC1A, and PPARg expression levels in spinal cord tissue were significantly associated with neurological prognosis. In vitro, PPARGC1A overexpression in oxygen-glucose deprivation/reoxygenation (OGD/R)-treated SH-SY5Y cells attenuated ferroptosis by reducing intracellular ferrous iron (Fe2+), lipid reactive oxygen species, and malondialdehyde while restoring glutathione levels and GPX4 expression. Mechanistically, PPARGC1A promoted PPARg nuclear translocation and upregulated CD36 and CPT1A transcription, while enhancing PINK1/Parkin-mediated mitophagy. These protective effects were abolished by PPARGC1A knockdown and partially reversed by PPARg agonism. In a rat contusion SCI model, AAV-mediated PPARGC1A overexpression improved BBB locomotor scores, preserved spinal cord tissue architecture, and restored PPARg/GPX4 expression and mitophagy markers in vivo. Collectively, these findings reveal that the PPARGC1A/PPARg axis orchestrates a lipid metabolism mitochondrial quality-control network that protects against ferroptosis in SCI, positioning this pathway as a potential therapeutic target.
    Keywords:  PPARGC1A; PPARγ; ferroptosis; mitophagy; spinal cord injury
    DOI:  https://doi.org/10.1111/ejn.70672
  34. PLoS One. 2026 ;21(9): e0357989
    Isoquercitrin ameliorates chondrocyte dysfunction in osteoarthritis by targeting AKT1-mediated mitochondrial dynamics regulation.
    Yuan Ding, Xiang Wang, Shihua Zong, Qiong Wen, Luyang Zhang.
      Osteoarthritis (OA), a prevalent degenerative joint disorder, is driven by chondrocyte anabolic-catabolic imbalance, aberrant inflammation, and mitochondrial dysfunction. Disease-modifying therapies targeting these pathological processes remain scarce, limiting effective clinical intervention. Herein, we demonstrate an isoquercitrin (IQ)-based chondroprotective strategy that rectifies osteoarthritis-related chondrocyte impairment by targeting AKT1. IQ first reverses IL-1β-induced chondrocyte proliferation arrest, shifts metabolic homeostasis toward anabolism, and mitigates pro-inflammatory responses. It simultaneously restores mitochondrial homeostasis by normalizing dynamic balance. Mechanistically, IQ binds to AKT1 with high affinity, and AKT1 overexpression abolishes its protective effects-confirming AKT1 as a key mediator. This approach re-establishes chondrocyte functional homeostasis by coupling anti-inflammatory, metabolic-regulatory, and mitochondrial-stabilizing activities. This work highlights IQ as a promising candidate for osteoarthritis intervention and provides a mechanistic framework linking AKT1 targeting to chondroprotection.
    DOI:  https://doi.org/10.1371/journal.pone.0357989
  35. Bioact Mater. 2027 Feb;68 522-538
    Acoustoelectric nanoregulator for modulating the endoplasmic reticulum and mitochondria in cell fate regulation.
    Guoqing Feng, Guoxin Han, Yang Bai, Bowen Li, Feiyu Zhao, Run Yang, Xuheng Chen, Renwang Liu, Niansong Qian, Bin Zheng, Shanlong Zhang.
      The endoplasmic reticulum (ER) and mitochondria are critical organelles in maintaining cellular homeostasis and regulating cell fate. However, current biological and chemical approaches for modulating ER and mitochondrial functions often lack specificity and spatiotemporal controllability, potentially leading to off-target or systemic effects that limit their clinical applications. Here, by synthesizing a physical stimulus-based acoustoelectric nanoregulator, barium zirconate titanate (BZT) nanoparticles (NPs) with enhanced piezoelectric properties, we aimed to modulate ER and mitochondrial functions by regulating intracellular concentrations of calcium ions (Ca2+) and hydrogen ions (H+), thereby enabling spatiotemporally controllable modulation of cell fate. BZT NPs significantly modulated calcium ion dynamics and pH in tumor cells under ultrasound stimulation, accompanied by perturbations in ER and mitochondrial homeostasis, induction of ER stress and mitophagy, and ultimately alterations in cell fate. In the tumor-bearing mouse model, the acoustoelectric nanoregulator spatiotemporally modulates the intracellular environment through electrical signaling and ionic dynamic modulation under ultrasound stimulation, expanding the application prospects of physical stimulation-based strategies for abnormal cell function regulation. Our findings provide fresh perspectives for understanding cellular stress responses and cell fate determination processes, and lay the foundation for developing novel interventions in precision therapy and cell engineering applications.
    Keywords:  Acoustoelectric nanoregulator; Endoplasmic reticulum stress; Mitophagy; Piezoelectric nanomaterials
    DOI:  https://doi.org/10.1016/j.bioactmat.2026.09.001
  36. Mater Today Bio. 2026 Oct;40 103609
    A biomimetic chondrocyte membrane-camouflaged tFNA nanoplatform for reprogramming the cartilage-synovium axis in osteoarthritis.
    Zhen Zhang, Yifan Li, Meihan Ye, Hanqing Liu, Qianshuo Huang, Xuanwei Wang, Miaoda Shen, Sanzhong Xu, Jiafeng Li.
      Osteoarthritis (OA) is a whole-joint disorder characterized by progressive cartilage degeneration and synovial remodeling, yet effective disease-modifying therapies remain unavailable. Mitochondrial dysfunction-driven chondrocyte senescence is increasingly recognized as a key driver of cartilage degeneration and pathological cartilage-synovium crosstalk. Here, we engineered a biomimetic, programmable nanoplatform, termed CM@THC, by loading hesperidin, a natural flavonoid with potent antioxidant activity, into tetrahedral framework nucleic acids (tFNAs) and subsequently cloaking the nanocomplex with chondrocyte membranes (CMs). This hierarchical design combines the programmable drug-delivery capacity of tFNAs with the homologous targeting and biointerfacial properties of membrane camouflage, thereby improving nanocomplex stability, cellular internalization, and intra-articular retention. Functionally, CM@THC restored redox homeostasis and PINK1/Parkin-associated mitophagy in IL-1β-stimulated chondrocytes, attenuating cellular senescence and extracellular matrix imbalance while limiting the secondary profibrotic activation of fibroblast-like synoviocytes (FLSs). Collectively, these findings establish a membrane-camouflaged tFNA strategy for natural-product delivery and identify CM@THC as a biomimetic, mitochondria-protective nanotherapeutic that disrupts the pathological cartilage-synovium axis in OA.
    Keywords:  Biomimetic nanoplatform; Cartilage–synovium crosstalk; Chondrocyte membrane; Chondrocyte senescence; Mitophagy; Osteoarthritis
    DOI:  https://doi.org/10.1016/j.mtbio.2026.103609
  37. Small. 2026 Sep 16. e75825
    Breaking the Lipid Bottleneck: A Mitophagy-Driven Nanoregulator Amplifies Ferroptosis for Colorectal Cancer Immunotherapy.
    Shaopeng Zhang, Guoqiang Pan, Qing Xu, Hengchang Liu, Shiqi Bai, Donghao Qu, Shaokang Yang, Mingqi Li, Hao Zhang, Peng Han.
      Colorectal cancer (CRC) therapy is severely constrained by the immunosuppressive tumor microenvironment (TME). This study presents a TME-responsive nanometabolic regulator, ZnO2@Fe@HA (ZFH), designed to bridge mitochondrial dysfunction, lipid reprogramming, and ferroptosis to enhance anti-tumor immunity. ZFH specifically dissociates in the acidic TME, releasing Zn2 +, Fe2 +, and H2O2. Crucially, ZFH leverages Zn2 + to trigger mitochondrial oxidative stress and mitophagy, which subsequently disrupts the mitochondrial fatty acid β-oxidation pathway. This mitochondria-driven metabolic reprogramming causes a substantial accumulation of intracellular free fatty acids, effectively providing abundant lipid substrates to fuel iron-catalyzed lipid peroxidation. This cascade successfully overcomes the lipid deficiency bottleneck of conventional ferroptosis. The resulting intense ferroptosis induces potent immunogenic cell death (ICD), facilitating dendritic cell maturation and effector T cell infiltration. In vitro and in vivo results demonstrate that ZFH effectively suppresses CRC growth via this mitochondria-lipid-ferroptosis axis. This mechanism-guided strategy offers a promising paradigm for treating refractory CRC.
    Keywords:  colorectal cancer; ferroptosis; metabolic reprograming; mitophagy; tumor immunotherapy
    DOI:  https://doi.org/10.1002/smll.75825
  38. Stem Cell Reports. 2026 Sep 17. pii: S2213-6711(26)00291-2. [Epub ahead of print] 103080
    PEX11β controls early neural progenitor fate through regulation of peroxisomal fission and lipid metabolism.
    C Bodnya, R P Theart, M E Colley, J M Spraggins, V Gama.
      Peroxisomes are metabolic organelles that undergo fission to maintain peroxisome number for lipid homeostasis and cellular function. The peroxisomal fission machinery is shared with mitochondria, and although mitochondrial fission regulates neural cell fate decisions during human neurogenesis, it remains unclear whether peroxisomal fission independently influences human neural development. PEX11β selectively regulates peroxisomal fission by promoting membrane deformation, elongation, and downstream fission factor recruitment. To uncouple mitochondrial and peroxisomal fission in early human neurogenesis, we generated PEX11β knockout iPSCs and tracked differentiation into neural progenitors and neural rosettes. At the cellular level, perturbing PEX11β selectively impaired peroxisomal lipid metabolism, characterized by reduced ether-linked phospholipids. At the tissue level, PEX11β deficiency altered neural rosette architecture, resulting in enlarged central lumens and expanded neural progenitor populations. This human neural model uncouples mitochondrial and peroxisomal fission and positions PEX11β as a distinct regulator of lipid metabolism and neural progenitor fate during human neurogenesis.
    Keywords:  DRP1; PEX11β; fission; induced pluripotent stem cells; neural progenitor cells; neurogenesis; peroxisomes
    DOI:  https://doi.org/10.1016/j.stemcr.2026.103080
  39. Int Immunopharmacol. 2026 Sep 16. pii: S1567-5769(26)01270-1. [Epub ahead of print]189 117423
    KLF5-driven G6PD protects lung squamous cell carcinoma from ferroptosis by sustaining mitochondrial homeostasis and SLC7A11-dependent cystine uptake.
    Nanding Yu, Yingxiao Wu, Mengling Li, Yang Liu, Weidong Wu, Xiangqi Chen.
       AIMS: Lung squamous cell carcinoma (LUSC) is a highly aggressive malignancy with limited therapeutic options. Ferroptosis has emerged as a promising antitumor strategy. However, the metabolic determinants governing ferroptotic vulnerability in LUSC remain incompletely understood. We investigated glucose-6-phosphate dehydrogenase (G6PD) in this context.
    MATERIALS AND METHODS: In vitro models using small interfering RNA (siRNA)-mediated G6PD depletion, together with pharmacological studies using 6-aminonicotinamide (6-AN) and LUSC xenograft models, were employed to investigate the underlying mechanisms.
    KEY FINDINGS: G6PD was markedly upregulated in LUSC, and analysis of the Cancer Genome Atlas lung squamous cell carcinoma (TCGA-LUSC) cohort showed that elevated G6PD expression was associated with advanced clinicopathological features and poorer overall survival. While ferroptosis inducers (erastin and RSL3) did not alter G6PD mRNA, they robustly increased G6PD protein during ferroptotic stress. Genetic or pharmacological inhibition of G6PD significantly sensitized LUSC cells to RSL3-induced ferroptosis, evidenced by enhanced lipid peroxidation, glutathione depletion, and ferrostatin-1-reversible cell death. Mechanistically, G6PD inhibition led to mitochondrial ferrous iron accumulation, elevated reactive oxygen species, impaired respiration, and activation of PINK1/Parkin-dependent mitophagy, which further exacerbated ferroptotic injury. In vivo, combined treatment with 6-aminonicotinamide and RSL3 markedly suppressed LUSC xenograft growth and enhanced biochemical markers of ferroptotic stress. Furthermore, G6PD protects cells by positively regulating the cystine/glutamate antiporter SLC7A11 to maintain redox homeostasis. Upstream, the oncogenic factor Krüppel-like factor 5 (KLF5) directly activates G6PD transcription.
    SIGNIFICANCE: Our findings identify a KLF5-G6PD-SLC7A11 axis as a critical metabolic safeguard against ferroptosis in LUSC. Targeting G6PD disrupts mitochondrial homeostasis, enhances mitophagy-dependent oxidative stress, and sensitizes tumors to ferroptotic therapy, highlighting a promising therapeutic strategy for LUSC.
    Keywords:  Ferroptosis; G6PD; KLF5; Lung squamous cell carcinoma
    DOI:  https://doi.org/10.1016/j.intimp.2026.117423
  40. Tissue Cell. 2026 Sep 17. pii: S0040-8166(26)00666-X. [Epub ahead of print]104(Pt 2): 103971
    Interplay between mitophagy, ferroptosis, and pyroptosis in acute pancreatitis: Regulatory mechanisms and therapeutic implications.
    Jialei Li, Shanqing Gao, Li Gao, Xiaohao Xu, Yongxing Xu.
       BACKGROUND: With a very high death rate, acute pancreatitis (AP) is a frequent acute abdominal illness of the digestive system. It is challenging for the conventional notion of "trypsin self digestion" to adequately explain the molecular underpinnings of local inflammation that spreads across the body and the heterogeneity of acinar cell death. The science of programmed cell death has advanced significantly in recent years, and it has been demonstrated that oxidative stress, mitophagy, ferroptosis, and pyroptosis are important factors in AP tissue damage and inflammation amplification. Nevertheless, there hasn't been a methodical integration of the spatiotemporal dynamic interaction and cross-regulatory network among the four.
    METHODS: In order to find material on AP and reactive oxygen species (ROS) formation, PINK1/Parkin mediated mitophagy, GPX4 dependent lipid peroxidation defense, and NLRP3/caspase-1/GSDMD mediated pyroptosis, the system searched the Web of Science, PubMed, and Google Scholar databases. The cross-talk linkages between various cell death pathways were compiled and examined, with an emphasis on mechanistic studies and evidence of in vitro and in vivo treatments.
    RESULTS: Ca2 + excess, mitochondrial respiratory chain malfunction, and NOX2 activation work together to cause an explosive build-up of ROS in the early stages of AP, creating a shared ignition event for downstream programmed death. In this network, mitophagy exhibits a typical "double-edged sword" effect: moderate autophagy with intact flux can remove damaged mitochondria and prevent ROS and mitochondrial DNA release, thereby suppressing ferroptosis and pyroptosis at the same time; insufficient autophagy, impaired lysosomal clearance, or abnormally enhanced autophagy can result in mitochondrial accumulation, which exacerbates oxidative stress. Excessive ROS depletes glutathione and suppresses GPX4 activity at the level of cell death execution process, causing membrane lipid peroxidation and ferroptosis; conversely, activation of the NLRP3 inflammasome via TXNIP dissociation causes pro-inflammatory pyroptosis mediated by caspase-1/GSDMD. It is noteworthy that GPX4 may act as a shared molecular interface that limits both forms of death; its deactivation not only promotes ferroptosis directly but may also facilitate GSDMD pore formation through lipid peroxidation, suggesting a potential functional connection between ferroptosis and pyroptosis. More importantly, available evidence suggests that a positive feedback loop involving mitochondrial injury, antioxidant depletion, ferroptotic and pyroptotic signaling, and inflammatory amplification may contribute to the progression of AP from local pancreatic injury to SAP and distant organ damage. DAMPs such as HMGB1 and ATP released during ferroptotic injury, together with IL-1β, IL-18, and other inflammatory mediators released during pyroptosis, may further amplify oxidative stress and impair GPX4-dependent antioxidant defense.
    CONCLUSION: Current evidence suggests that ferroptosis and pyroptosis may be functionally interconnected in AP through shared mediators such as ROS, DAMPs, and alterations in membrane lipid oxidation. Such interactions may contribute to the progression of AP from localized pancreatic injury to systemic inflammation and severe disease. However, the causal relationships among these pathways have not yet been fully established within a unified AP-specific experimental system. These findings suggest that a multi-level cooperative strategy integrating mitochondrial homeostasis restoration, GPX4 preservation, and NLRP3/GSDMD suppression may offer advantages over isolated blockade of a single death pathway. The optimal timing of intervention may vary across different stages of AP, although this stage-dependent therapeutic concept remains hypothesis-generating and requires direct experimental validation. This integrated perspective may provide new insights into therapeutic strategies for SAP.
    Keywords:  Acute pancreatitis; Ferroptosis; Mitophagy; Oxidative stress; Pyroptosis; Signal crosstalk
    DOI:  https://doi.org/10.1016/j.tice.2026.103971
  41. Redox Biol. 2026 Sep 12. pii: S2213-2317(26)00396-4. [Epub ahead of print]97 104397
    Maternal hyperhomocysteinemia promotes adverse pregnancy outcomes via mtDNA-cGAS-STING signaling-mediated trophoblast mitophagy.
    Chaoqun Liu, Zhuoqiao Gao, Jianyin Chen, Yunyan Yang, Qiaolin Xiao, Shaohui Deng, Yumei Zhang, Wenen Su, Tao Liu.
       OBJECTIVES: Hyperhomocysteinemia (HHcy) is a recognized risk factor for adverse pregnancy outcomes. However, the underlying mechanisms precipitating placental dysfunction, particularly the potential involvement of mitochondrial DNA (mtDNA), remain largely elusive. This study aims to investigate the association between maternal HHcy and adverse pregnancy outcomes mediated by reduced placental mtDNA copy number (mtDNAcn), and to elucidate the underlying molecular mechanisms driving HHcy-induced placental dysfunction.
    METHODS: We prospectively investigated the associations between maternal HHcy, placental mtDNA copy number (mtDNAcn), and adverse pregnancy outcomes using data from the PEOH (Prenatal Environments and Offspring Health) birth cohort. To elucidate the underlying mechanisms, human placental tissues, maternal HHcy rat placentae, and HTR-8/SVneo trophoblast cells were utilized to assess HHcy-induced mitochondrial damage, PINK1/Parkin-mediated mitophagy, and downstream inflammatory signaling.
    RESULTS: Epidemiological analysis revealed that maternal HHcy was significantly associated with increased risks of preterm birth and low birth weight, with reduced placental mtDNAcn serving as a critical mediator. Mechanistically, HHcy exposure induced severe mitochondrial dysfunction and excessive PINK1/Parkin-dependent mitophagy across human placentae, maternal HHcy rat placentae, and HTR-8/SVneo cells. This unrestrained mitophagic flux precipitated the leakage of mtDNA into the cytosol, which directly engaged and activated the cGAS-STING pathway, leading to placental sterile inflammation and subsequent placental dysfunction via upregulating COX-2 and pro-inflammatory cytokines.
    CONCLUSION: Maternal HHcy exposure contributes to adverse pregnancy outcomes by reducing placental mtDNAcn and triggering a cascade of PINK1/Parkin-mediated mitophagic disruption, cytosolic mtDNA release, and subsequent cGAS-STING-driven sterile inflammation and placental dysfunction, underscoring the need for clinical Hcy monitoring and early intervention.
    Keywords:  Adverse pregnancy outcomes; Homocysteine; Mitochondrial DNA copy number; Mitochondrial damage
    DOI:  https://doi.org/10.1016/j.redox.2026.104397
  42. J Anim Sci Biotechnol. 2026 Sep 14. pii: 184. [Epub ahead of print]17(1):
    Limosilactobacillus reuteri orchestrates IAA-mediated mitochondrial homeostasis and stem cell renewal against intestinal oxidative injury in aged hens.
    Shenao Zhan, Ziyu Wang, Yujie Lv, Weichen Huang, Chaoyue Ge, Lianchi Wu, Dongyou Yu, Bing Liu.
       BACKGROUND: Intestinal oxidative stress compromises gut health and production performance in laying hens. Although Limosilactobacillus reuteri (L. reuteri) has been shown to mitigate oxidative stress, the underlying mechanisms remain incompletely understood. This study therefore investigated the protective effects and mechanisms of L. reuteri against diquat-induced intestinal oxidative injury in aged hens.
    METHODS: A total of 270 70-week-old Jinbai hens were divided into control (CON), diquat (DQ), and L. reuteri + diquat (LRD) groups with 6 replicates each. Birds in CON and DQ groups received a basal diet, while those in LRD group received basal diet supplemented with L. reuteri. After a 10-week pretreatment, DQ and LRD hens were intraperitoneally injected with diquat, while CON hens were injected intraperitoneally with an equivalent amount of saline solution.
    RESULTS: Diquat challenge significantly compromised intestinal barrier integrity, as evidenced the downregulated mRNA and protein expression of MUC2, ZO-1 and Occludin (P < 0.05). Notably, these adverse impacts were markedly reversed by L. reuteri pretreatment. Moreover, L. reuteri reshaped the gut microbiota by increasing the abundance of Lactobacillus (P < 0.05). Metabolomic analysis revealed significant enrichment of tryptophan metabolism, with a notable upregulation of indole-3-acetic acid (IAA). At the mitochondrial level, L. reuteri reduced mitochondrial ROS production, restored ATP content (P < 0.05), and downregulated mitochondrial biogenesis-related genes expression of PGC-1α and NRF1 and balanced mitochondrial dynamics genes expression of MFN1 and DRP1 (P < 0.05). Furthermore, L. reuteri elevated GSH-Px and T-AOC activities via activation of the Nrf2 pathway, and reduced IL-1β and IL-6 levels by suppression of NF-κB signaling (P < 0.05). In vitro organoid culture further demonstrated IAA significantly reduced mitochondrial ROS production and restored ATP levels (P < 0.05) and stimulated stem cell proliferation. These changes inhibited apoptosis and promoted intestinal proliferation, thereby alleviating intestinal oxidative injury.
    CONCLUSION: L. reuteri alleviates intestinal oxidative damage via modulation of the gut microbiota-IAA axis, which coordinates mitochondrial homeostasis and stem cell renewal, thereby mitigating oxidative stress and enhancing barrier function. These findings highlight its potential as a probiotic therapeutic agent for mitigating oxidative stress and preserving gut health in aging poultry.
    Keywords:   Limosilactobacillus reuteri ; Intestinal barrier; Laying hens; Mitochondria; Oxidative stress
    DOI:  https://doi.org/10.1186/s40104-026-01499-4
  43. Biochem Biophys Res Commun. 2026 Sep 17. pii: S0006-291X(26)01338-0. [Epub ahead of print]837 154574
    Cardiac-specific Lmpt knockdown induces heart dysfunction via mitochondrial quality decline and metabolic disturbance in Drosophila.
    Tingting Jiang, Peiyun Xie, Min Tang, Wang Jing, Qun Zeng.
      Lmpt (Limpet, CG42679) is a Drosophila LIM domain protein homologous to human FHL2. Our prior work demonstrated it represses Wnt signaling during embryonic cardiac development. However, its role in adult cardiac homeostasis remains unclear. Here, we generated Hand-gal4-driven Lmpt knockdown flies (predominantly targeting adult cardiomyocytes) using the Hand-gal4/UAS-RNAi system and examined its function in adult flies. Lmpt knockdown significantly reduced climbing ability and triggered intrinsic cardiac contractile dysfunction, manifested as bradycardia, impaired fractional shortening and prolonged diastolic intervals in 3-week-old flies. These flies also exhibited systemic metabolic disorders and ATP depletion, decreased lipid accumulation in multiple tissues, and elevated ROS levels in the heart and gut. Meanwhile, Lmpt knockdown led to disorganized and fractured myocardial fibers and progressive age-dependent mitochondrial quality decline. qPCR analysis revealed abnormal expression of genes related to mitochondrial dynamics, respiratory chain, and quality control. In conclusion, Lmpt maintains adult cardiac function by preserving mitochondrial quality, energy metabolism, and myocardial structural integrity. This study provides new insights into the mitochondrial and metabolic mechanisms maintaining adult cardiac homeostasis, with potential implications for FHL2-related cardiomyopathies.
    Keywords:  Cardiac function; Drosophila; Lmpt; Metabolic homeostasis; Mitochondrial quality; Oxidative stress
    DOI:  https://doi.org/10.1016/j.bbrc.2026.154574
  44. Cell Death Discov. 2026 Jul 25. pii: 373. [Epub ahead of print]12(1):
    Transcriptomic analysis reveals that neural stem cell-derived exosomes regulate the HMGB1/TLR2 signaling axis to promote astrocytic differentiation and mitochondrial biogenesis in the repair of radiation-induced blood-brain barrier damage.
    Fanrui Zeng, Yalei Zhang, Yun Zhou, Zichen Ma, Chenghao Li, Guohua Yao, Rong Li.
      Radiation-induced brain injury (RBI) is frequently associated with blood-brain barrier (BBB) disruption, which contributes to poor prognosis. Neural stem cell-derived exosomes (NSC-Exo) have recently attracted attention as mediators of intercellular communication with potential roles in tissue repair. However, how NSC-Exo promote BBB recovery after RBI remains unclear. This study explored whether NSC-Exo restore BBB function by regulating the HMGB1/TLR signaling pathway, thereby promoting endogenous NSC differentiation toward astrocytes and enhancing mitochondrial biogenesis. A rat RBI model was established and treated with NSC-Exo. Molecular marker analysis, transcriptomic profiling, and BBB functional assessment were performed to clarify the underlying mechanisms. The results showed that NSC-Exo enhanced NSC stemness and astrocytic differentiation, improved mitochondrial function, and reduced ROS accumulation. NSC-Exo also suppressed HMGB1/TLR2 pathway activation and promoted BBB repair. Functional experiments further indicated that HMGB1 overexpression weakened the protective effects of NSC-Exo, whereas TLR2 knockdown reversed this effect. In conclusion, NSC-Exo facilitate endogenous NSC remodeling and BBB restoration after RBI, at least partly through regulation of the HMGB1/TLR2 axis, providing a potential strategy for RBI treatment. Schematic illustration of the molecular mechanism by which NSC-Exo ameliorates RBI through inhibition of the HMGB1/TLR2 signaling pathway.
    DOI:  https://doi.org/10.1038/s41420-026-03250-4
  45. Int J Mol Sci. 2026 Sep 01. pii: 7834. [Epub ahead of print]27(17):
    Photobiomodulation with 808 nm Laser Light Repairs Mitochondrial Integrity and Normalizes ROS, ATP, and Membrane Depolarization in Aβ-Exposed Primary Neurons in Alzheimer's Disease Model.
    Iuliia Golovynska, Binjun Li, Qinglin Chen, Sergii Golovynskyi, Hao Xu, Yurii V Stepanov, Liudmyla I Stepanova, Fangrui Lin, Junle Qu, Tymish Y Ohulchanskyy.
      Alzheimer's disease (AD) is increasingly recognized as a disorder involving profound mitochondrial dysfunction. Although photobiomodulation (PBM) has shown neuroprotective efficacy in experimental AD models, whether restoration of mitochondrial architecture is mechanistically required for these effects remains unknown. Here, we investigated the role of mitochondrial network remodeling in PBM-mediated neuroprotection in primary mouse hippocampal neurons exposed to amyloid-β (Aβ). Neurons were treated for 24 h with oligomeric Aβ1-42 and irradiated with 808 nm PBM (100 mW/cm2, 30 J/cm2). Mitochondrial morphology was quantified using three-dimensional confocal microscopy and computational network analysis. Aβ exposure induced severe mitochondrial fragmentation and swelling, reflected by increased mitochondrial count and sphericity together with reduced mitochondrial volume, surface area, branch length, and network connectivity. These structural alterations were accompanied by elevated reactive oxygen species production, adenosine triphosphate depletion, membrane depolarization, and reduced neuronal viability. PBM significantly reversed these abnormalities, restoring mitochondrial network integrity and partially normalizing cellular bioenergetics and redox homeostasis. To determine whether mitochondrial dynamics contributes to PBM-induced effects, neurons in another experiment were pre-treated with the dynamin-related protein-1 (DRP-1) mitochondrial division inhibitor-1 (Mdivi-1). The physiological and morphological profiles of the Aβ + PBM + Mdivi-1 and Aβ + Mdivi-1 groups were found to be largely indistinguishable in this case, revealing that PBM failed to restore mitochondrial connectivity, cellular bioenergetics, or viability of neurons in the partially blocked fission-fusion machinery. These findings demonstrate that mitochondrial dynamics is essential for PBM-mediated neuroprotection and identify restoration of mitochondrial network integrity as a crucial mechanism linking PBM to improved neuronal bioenergetics, redox balance, and survival in AD.
    Keywords:  Alzheimer’s disease; amyloid-β; mitochondrial network morphology; neurons; photobiomodulation
    DOI:  https://doi.org/10.3390/ijms27177834
  46. Cells. 2026 Aug 26. pii: 1542. [Epub ahead of print]15(17):
    Autophagy-Ferroptosis Crosstalk in Dry Eye Disease: Context-Dependent Regulation of Ocular Surface Homeostasis.
    Yuan Zhong, Jun Peng, Qinghua Peng.
      Dry eye disease (DED) exposes the ocular surface to persistent hyperosmolar, oxidative, metabolic, and inflammatory stress that may increase susceptibility to ferroptosis. Whether autophagy promotes or limits ferroptotic injury in DED remains unresolved. This review critically evaluates evidence from corneal and conjunctival epithelia, lacrimal glands, and meibomian glands, using non-ocular models only to interpret mechanisms not yet resolved in ocular tissues. We propose a threshold-balance framework in which autophagy has context-dependent effects. Ferritinophagy, lipophagy, and impaired autophagic flux can expand the labile iron pool, mobilize peroxidizable lipids, and promote lipid peroxidation. Conversely, intact autophagic-lysosomal flux and mitophagy can remove damaged cargo, limit mitochondrial oxidative stress, and preserve membrane antioxidant defenses. The balance between these processes may determine whether stressed ocular-surface cells adapt or progress toward ferroptotic injury, with consequences for epithelial barrier integrity, tear-film homeostasis, glandular secretion, and inflammation. Studies combining autophagy-related pathway perturbation with ferroptosis-related outcomes are concentrated in ocular-surface epithelial models, whereas this relationship has been less directly examined in lacrimal and meibomian tissues. Establishing causality will require flux-aware measurements, targeted pathway perturbation, tissue-resolved models, and functional validation in human samples. Such studies should clarify when and where autophagy-ferroptosis crosstalk is therapeutically actionable in DED.
    Keywords:  autophagic flux; autophagy; dry eye disease; ferritinophagy; ferroptosis; lipophagy; mitophagy; ocular surface; oxidative stress
    DOI:  https://doi.org/10.3390/cells15171542
  47. J Bioenerg Biomembr. 2026 Sep 14. pii: 52. [Epub ahead of print]58(1):
    Mitokines as bioenergetic stress signals in cardiovascular disease: mitochondrial communication, endocrine adaptation, and translational implications.
    Gino A Kurian.
      Cardiovascular disease is strongly influenced by mitochondrial dysfunction, yet how mitochondrial stress is communicated beyond the affected cell to coordinate systemic responses remains incompletely understood. Mitokines are stress-responsive signaling factors that link mitochondrial perturbation to cellular and interorgan adaptation. These include nuclear-encoded proteins such as fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15), as well as mitochondrial-derived peptides including Humanin and MOTS-c. This review critically examines mitokine regulation and signaling in the context of cardiovascular stress, with emphasis on mitochondrial unfolded protein response and integrated stress response pathways, receptor and downstream signaling mechanisms, and the functional divergence among major mitokines. Transient mitokine responses during physiological or metabolic challenge may support metabolic flexibility, cytoprotection, and stress adaptation, whereas persistent elevations of FGF21 and GDF15 in cardiovascular and cardiometabolic disease frequently accompany unresolved mitochondrial stress and adverse clinical phenotypes. Importantly, such associations do not establish that sustained mitokine signaling is itself maladaptive, and major mechanistic uncertainties remain, particularly for mitochondrial-derived peptides. We integrate these observations within a proposed "mitokine code" framework in which mitokine identity, relative patterns, temporal dynamics, and disease context may collectively provide information about mitochondrial stress and systemic adaptation. We further evaluate the potential and current limitations of mitokines as cardiovascular biomarkers and therapeutic targets. This framework positions mitokine signaling at the interface between mitochondrial dysfunction, systemic stress adaptation, and cardiovascular disease while identifying mechanistic and translational questions requiring prospective validation.
    Keywords:  Cardiovascular disease; Integrated stress response; Mitochondrial stress signaling; Mitochondrial unfolded protein response; Mitochondrial-derived peptides; Mitokines
    DOI:  https://doi.org/10.1007/s10863-026-10136-8
  48. Cancer Med. 2026 Sep;15(9): e72275
    Metabolic Reprogramming of Cancer Stem Cells: Targeting Lipid Flux and Mitochondrial Plasticity to Overcome Therapeutic Resistance.
    Daniel Ejim Uti, Esther Ugo Alum, Josephine E Egbung, Zuhair M Mohammedsaleh, Manpreet Kaur, Kranti Kiran Reddy Ealla.
      Cancer stem cells (CSCs) are increasingly recognized as metabolically plastic subpopulations within malignant tissues that drive tumor initiation, metastatic dissemination, and relapse after therapy. Although traditional models of cancer metabolism have emphasized aerobic glycolysis, CSCs rarely exhibit a single, clearly defined bioenergetic phenotype. Rather, they dynamically remodel glucose utilization, oxidative phosphorylation, redox regulation, de novo fatty acid synthesis, lipid uptake, lipid sequestration, and fatty acid oxidation in response to hypoxic conditions, nutrient restriction, stromal interactions, and therapeutic perturbations. This review focuses on two interconnected aspects of metabolic flexibility: lipid flux and mitochondrial plasticity. We examine how de novo lipogenesis, CD36-mediated fatty acid uptake, fatty acid-binding protein trafficking, cholesterol biosynthesis, and lipid-droplet turnover contribute to stemness, membrane remodeling, metastatic potential, and resistance to cytotoxic agents. We also examine how mitochondrial dynamics, including fusion, fission, mitophagy, and biogenesis, together with reactive oxygen species buffering and shifts in oxidative phosphorylation, facilitate CSC survival during chemotherapy, radiotherapy, targeted therapy, and immune-mediated cytotoxicity. Particular emphasis is placed on the integration of fatty acid oxidation to respiratory metabolism, on the epigenetic consequences associated with the acetyl-CoA availability, and the metabolic crosstalk linking CSCs to adipocytes, fibroblasts, mesenchymal cells, and immune cell populations in the tumor microenvironment. Finally, we evaluate therapeutic strategies involving inhibitors of fatty acid synthase (FASN), acetyl-CoA carboxylase (ACC), stearoyl-CoA desaturase-1 (SCD1), carnitine palmitoyltransferase-1 (CPT1), and OXPHOS. We also discuss combination therapies, nanotechnology-based drug delivery, and emerging artificial intelligence (AI)-guided approaches. Taken together, current evidence identifies the lipid-mitochondrial axis as a critical systems-level driver of therapeutic resistance and a promising target for improving long-term cancer control.
    Keywords:  cancer stem cells; lipid metabolism; metabolic plasticity; mitochondrial dynamics; therapeutic resistance
    DOI:  https://doi.org/10.1002/cam4.72275
  49. Int Immunopharmacol. 2026 Sep 12. pii: S1567-5769(26)01207-5. [Epub ahead of print]189 117360
    Non-canonical modulation of mitochondrial ROS and dynamics by Netrin-3 drives inflammasome activation in cardiomyocytes.
    Biao Li, Haoyang Ge, Xiwei Chen, Fang Zeng, Jianjia Chen, Qiang Zhao.
       BACKGROUND: Heart failure is driven by pathological remodeling in which inflammation and mitochondrial dysfunction reinforce each other, yet the molecules that coordinate this interplay remain poorly defined. Netrin-3 is a guidance cue with no known function in the heart. We asked whether Netrin-3 acts in cardiomyocytes to affect mitochondrial integrity under inflammatory stress.
    METHODS: We used neonatal rat cardiomyocytes treated with nigericin to activate the NLRP3 inflammasome. Netrin-3 was overexpressed via adenovirus or knocked down by siRNA. Its subcellular distribution was tracked by fractionation and by immunofluorescence. Mitochondrial morphology, Drp1 Ser616 phosphorylation, Mfn2 protein levels, and ROS production were quantified. Inflammasome activation was evaluated through caspase-1 cleavage, ASC speck formation, and IL-1β release. In mice with transverse aortic constriction, we delivered AAV9-shNetrin-3 or a neutralizing antibody and assessed cardiac function, tissue histology, and molecular markers.
    RESULTS: NLRP3 activation increased Netrin-3 expression and its mitochondrial fraction content, a pattern supported by immunofluorescence colocalization with TOM20. Netrin-3 overexpression was associated with greater mitochondrial fragmentation, higher Drp1 phosphorylation, lower Mfn2, and increased mitochondrial ROS. Netrin-3 knockdown had the opposite effects on these parameters. ROS scavenging with N-acetylcysteine or MitoTEMPO attenuated the Netrin-3-associated increases in caspase-1 cleavage and IL-1β secretion. In pressure-overloaded hearts, Netrin-3 was upregulated; its genetic or pharmacological inhibition correlated with improved ejection fraction and reduced hypertrophy, fibrosis, and macrophage infiltration.
    CONCLUSION: These observations support a model in which Netrin-3 participates in coupling inflammasome signaling to mitochondrial alterations through a ROS-dependent route. Whether Netrin-3 inhibition has therapeutic value in heart failure warrants further investigation.
    Keywords:  Heart failure; Mitochondrial dysfunction; NLRP3 inflammasome; Netrin-3; Oxidative stress
    DOI:  https://doi.org/10.1016/j.intimp.2026.117360
  50. Autophagy Rep. 2026 ;5(1): 2728537
    Multilayered interplay between the cGAS-STING pathway and autophagy.
    Ze-Bo Huang, Xiang-Zheng Gao, Jin-Yi Lin, Du Feng, Guang Lu.
      The cGAS-STING pathway detects cytosolic dsDNA to initiate innate immune responses, serving as a critical surveillance system against infection and cellular stress. Autophagy is an evolutionarily conserved catabolic process that maintains homeostasis by degrading cytoplasmic components. Although these two systems operate through distinct mechanisms, recent studies have uncovered a complex bidirectional regulatory network that intimately links them. On the one hand, STING has an evolutionarily conserved capacity to induce TBK1-independent noncanonical autophagy, and recent studies further link this activity to TFEB-dependent lysosome biogenesis, expanding its functional repertoire beyond classical interferon induction. On the other hand, autophagy restricts cGAS-STING signaling by clearing cytosolic DNA and selectively degrading pathway components, thereby preventing excessive inflammation. Furthermore, mitophagy curtails the release of mitochondrial DNA, a potent cGAS agonist, and recent studies further implicate lysosomes as active signaling platforms associated with mtDNA release, LRRK2 activation, and STING-dependent NF-κB responses. In this review, we discuss recent advances in understanding how the cGAS-STING pathway and autophagy mutually regulate each other at the cellular level, focusing on the molecular mechanisms of this interplay, both canonical and noncanonical, and highlighting how their crosstalk shapes cellular homeostasis and stress adaptation.
    Keywords:  cGAS-STING pathway; innate immunity; lysosome; mitophagy; mtDNA; non-canonical autophagy
    DOI:  https://doi.org/10.1080/27694127.2026.2728537
  51. Adv Sci (Weinh). 2026 Sep 16. e77785
    Magneto-Sono-Enhanced Nanozyme Catalysis Drives ROS-Mediated Pathogen Killing and Mitophagy-Linked Inflammation Control in Bacterial Pneumonia.
    Xiaofeng Luo, Yundi Wu, Shuai Zhang, Huanran Qu, Shiyang Shao, Jianqiang Chen, Xilong Wu.
      Bacterial pneumonia treatment faces significant challenges due to uncontrolled inflammation and rising antibiotic resistance. Excessive inflammatory cytokine release and mitochondrial dysfunction exacerbate tissue damage, contributing to the disease's progression. Mitophagy, a process that eliminates dysfunctional mitochondria, helps regulate reactive oxygen species (ROS) levels and suppress inflammation. However, efficient bacteria clearance remains critical for effective inflammatory modulation. Traditional antibiotics struggle against resistant bacteria, necessitating alternative approaches. ROS-based nanocatalytic therapies, particularly nanozymes, show potential for overcoming ROS generation limitations through external stimuli like ultrasound and magnetic fields. This study designs a sono-magneto-responsive nanozyme (BN@NF) composed of boron nanosheets (BN) and neodymium-doped iron phosphide (Nd:Fe2P, NF), modified to form a Z-scheme heterostructure. Delivered via nebulization, BN@NF generates ROS under combined internal and external stimuli, enabling efficient bacterial killing and biofilm disruption. It also modulates inflammation by inhibiting the NF-κB pathway and promoting mitophagy, reducing pro-inflammatory cytokine release. Additionally, BN@NF enhances macrophage polarization from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype, aiding tissue repair. This approach provides a promising strategy for treating bacterial pneumonia by combining effective antibacterial action with intelligent anti-inflammatory functions.
    Keywords:  bacterial pneumonia; magnetothermal therapy; mitophagy; nanozyme catalysis; nebulization delivery; sonodynamic therapy
    DOI:  https://doi.org/10.1002/advs.77785
  52. Ecotoxicol Environ Saf. 2026 Sep 18. pii: S0147-6513(26)01152-8. [Epub ahead of print]324 120822
    SIRT1/PGC-1α-regulated mitochondrial biogenesis is involved in T-2 toxin-induced chondrocyte injury.
    Chenxi Wang, Junfeng Zhou, Weichang Zhang, Yue Zhao, Jiaxin Li, Jiayuan Li, Jun Yu, Silu Cui.
      T-2 toxin, a type A trichothecene mycotoxin, has been implicated as an environmental risk factor for Kashin-Beck disease (KBD), an endemic osteoarthropathy characterized by cartilage damage. However, whether T-2 toxin impairs mitochondrial biogenesis in chondrocytes and the underlying regulatory mechanism remain unclear. This study investigates the effects of T-2 toxin on mitochondrial function and biogenesis using in vivo and primary chondrocyte models and evaluated the involvement of the SIRT1/PGC-1α signaling pathway. T-2 toxin induced chondrocyte injury and mitochondrial dysfunction, as evidenced by ultrastructural mitochondrial abnormalities, loss of mitochondrial membrane potential (ΔΨm), and reduced mitochondrial DNA copy number (mtDNAcn). T-2 toxin also decreased Sirtuin 1 (SIRT1) protein expression, increased peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) acetylation, and downregulated proteins involved in mitochondrial biogenesis. Pharmacological activation of SIRT1 with resveratrol partially restored PGC-1α deacetylation and mitochondrial biogenesis and attenuated chondrocyte injury. These findings indicate that suppression of SIRT1/PGC-1α pathway contributes to T-2 toxin-induced impairment of mitochondrial biogenesis and chondrocyte injury. This study provides mechanistic evidence linking T-2 toxin exposure to defective mitochondrial biogenesis in chondrocytes and identifies the SIRT1/PGC-1α axis as a potential target for mitigating T-2 toxin-induced cartilage toxicity.
    Keywords:  Chondrocyte injury; Mitochondrial biogenesis; MtDNA; PGC-1α; SIRT1; T-2 toxin
    DOI:  https://doi.org/10.1016/j.ecoenv.2026.120822
  53. Tissue Cell. 2026 Sep 11. pii: S0040-8166(26)00646-4. [Epub ahead of print]104(Pt 2): 103951
    Fucose ameliorates aging and inflammatory injury by promoting mitophagy.
    Liu Min, Zhan Cheng Er, Zhang Zhao Lin, Lu Qing Qing, Chen Dong Ya, Chen Jian Yong.
      Intestinal senescence and associated ischemic injury are key pathological factors leading to progressive loss of digestive function.Intestinal ischemia-reperfusion (I/R) injury in the elderly frequently leads to severe digestive and absorptive disorders, along with systemic complications, adversely affecting patients' quality of life and prognosis. This study explored the protective effects and mechanisms of fucose, a key monosaccharide in the traditional Chinese medicine Atractylodes macrocephala Koidz, on intestinal cell ischemia/reperfusion (I/R) injury. We developed an in vitro oxygen-glucose deprivation/reoxygenation (OGD/R) injury model using NCM460 intestinal epithelial cells and Cajal interstitial cells, alongside an in vivo murine intestinal I/R model, to comprehensively assess fucose's therapeutic efficacy.The results showed that fucose treatment significantly improved OGD/R-induced viability decline in both cell types, and its pro-proliferative effect was confirmed by the detection of proliferating cell nuclear antigen (Ki67) expression.Fucose significantly mitigated oxidative stress caused by I/R, demonstrated by lower reactive oxygen species (ROS) levels, reduced malondialdehyde (MDA) content, and maintained superoxide dismutase (SOD) and catalase (CAT) activities.Further mechanistic studies revealed that fucose markedly improved mitochondrial membrane potential and maintained mitochondrial morphological integrity.Fucose treatment notably decreased SA-β-gal activity, suppressed the expression of senescence markers, and mitigated intestinal fibrosis. In vivo experiments further validated the protective effect of fucose, and the data demonstrated that fucose decreased the expression of inflammatory factors and oxidative stress markers in intestinal tissues.This study uncovers the protective role of fucose in mitigating intestinal cell aging and I/R injury, offering a new theoretical and experimental basis for developing fucose-based intestinal protection strategies with significant translational medical potential.
    Keywords:  Cellular senescence; Fucose; Intestinal barrier; Intestinal ischemia-reperfusion; Mitophagy; Oxidative stress
    DOI:  https://doi.org/10.1016/j.tice.2026.103951
  54. Stem Cell Res. 2026 Sep 10. pii: S1873-5061(26)00198-4. [Epub ahead of print]96 104102
    CRISPR/Cpf1-mediated editing of DNM1L in induced pluripotent stem cells.
    Roohallah Ghodrat, Haribaskar Ramachandran, Barbara Hildebrandt, Stephanie Binder, Andrea Rossi, Andreas S Reichert.
      The dynamin-1-like protein (DNM1L), also termed DRP1, is essential for mitochondrial fission. Mutations in DNM1L are associated with neurological disorders and cardiac dysfunction. To decipher the role of DNM1L in human induced pluripotent stem cells (hiPSCs) and in their differentiated counterparts, we used CRISPR/Cpf1 and generated a human iPSC line with a mutation by targeting exon 18 of the DNM1L gene. The generated compound heterozygous (biallelic) DNM1L mutant cell line showed normal cell morphology, genomic stability, and expression of classical stem cell markers. Furthermore, the cells can be differentiated efficiently into the three germ layers meso-, endo-, and ectoderm.
    DOI:  https://doi.org/10.1016/j.scr.2026.104102
  55. Free Radic Biol Med. 2026 Sep 15. pii: S0891-5849(26)01161-5. [Epub ahead of print]256 516-530
    Nicotine modulates α7nAChR associated ceramide-mitochondrial stress responses in Parkinsonian models.
    Gaoge Wang, Zhen Ni, Jingzheng Zhang, Qian Li, Yunfu Tan, Hao Yu, Enliang Hong, Chunmei Guang, Shu Wang, Huan Chen, Hongwei Hou.
      Parkinson's disease (PD) is characterized by progressive dopaminergic degeneration accompanied by mitochondrial dysfunction and oxidative stress, yet the metabolic mechanisms underlying these pathological changes remain incompletely understood. Here, we investigated whether nicotine preserves dopaminergic integrity by modulating ceramide homeostasis through α7 nicotinic acetylcholine receptor (α7nAChR) signalling. In an MPTP mouse model, nicotine improved motor and exploratory deficits, preserved striatal tyrosine hydroxyl positive fibres, and selectively reversed ceramide accumulation in the striatum and plasma. Transcriptional analysis further showed that nicotine suppressed the induction of ceramide biosynthetic genes, suggesting regulation of sphingolipid remodelling in vivo. In MPP + challenged SH-SY5Y cells, nicotine restored cell viability, mitochondrial membrane potential, respiratory function, and mitochondrial morphology while reducing reactive oxygen species (ROS) production and apoptosis. Time-resolved analyses revealed that nicotine modulated an evolving stress response, in which early oxidative stress preceded detectable ceramide accumulation, while later ceramide dysregulation was associated with sustained mitochondrial vulnerability. Targeted lipidomics confirmed that nicotine directly restrained ceramide accumulation in stressed neuronal cells. Genetic (siSPTLC1 or siCHRNA7), pharmacological (Myriocin or MLA), and exogenous ceramide supplementation studies further supported a model in which nicotine limits this ceramide associated mitochondrial stress response through α7nAChR associated metabolic regulation. Mechanistically, nicotine restored AKT signalling and the BCL2 to BAX balance while suppressing cleaved caspase-3. Together, these findings identify ceramide dysregulation as a functionally relevant component of Parkinsonian mitochondrial stress responses and support an α7nAChR associated ceramide regulatory mechanism through which nicotine limits neuronal vulnerability.
    Keywords:  Ceramide; Mitochondrial dysfunction; Nicotine; Parkinson's disease; ROS; α7nAChR
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.09.010
  56. Nucleic Acids Res. 2026 Sep 07. pii: gkag876. [Epub ahead of print]54(17):
    Functional impact of Nth like DNA glycosylase 1 on mitochondrial dynamics.
    Lisa Hubers, Alexander Myhr Skjetne, Luisa Luna, Yohan Lefol, Solveig Osnes Lund, Ane Marit Wågbø, Xavier Renaudin, Annikka Polster, Zoe J da Silva, Anders Knoph Berg-Eriksen, Francisco Jose Naranjo-Galindo, Anna Campalans, Torkild Visnes, Hilde Loge Nilsen, Nicola Pietro Montaldo.
      Nth like DNA glycosylase 1 (NTHL1), a key base excision repair enzyme, has long been considered essential for nuclear and mitochondrial genome integrity. Combining in vitro biochemical assays, in cellulo molecular biology, and bioinformatic analyses, we investigated how NTHL1 loss affects mitochondrial DNA (mtDNA) stability and mitochondrial function. Contrary to the conventional view that mtDNA damage is solely detrimental, we find that NTHL1 loss confers a beneficial, mitochondria-initiated phenotype in human cells. Despite accumulating mtDNA lesions, NTHL1 loss unexpectedly increases mtDNA copy number, elevates oxidative phosphorylation protein levels, and enhances mitochondrial respiration. NTHL1-/- cells also show increased mitochondrial mass and higher levels of the biogenesis regulator PGC1α and the fusion protein OPA1, indicating an adaptive response that boosts mitochondrial function and capacity. Consequently, NTHL1-/- cells exhibit resistance to mitochondrial stress, accompanied by increased eIF2α phosphorylation and reduced MYC levels, converging on a broader transcriptional adaptive program. This phenotype depends on mitochondrial NTHL1 and reactive oxygen species (ROS) signaling, since treatment with ROS scavengers or mitochondria-specific reintroduction of NTHL1 rescues it. Together, these findings position NTHL1 as a key modulator of mtDNA stability and mitochondrial function, revealing that loss of this DNA repair enzyme shifts cellular metabolism toward a stress-adaptive state and enhances resilience to oxidative stress.
    DOI:  https://doi.org/10.1093/nar/gkag876
  57. J Mol Histol. 2026 Sep 16. pii: 309. [Epub ahead of print]57(5):
    SIRT3-mediated DRP1 acetylation changes are associated with the restoration of mitochondrial function and alleviation of anterior cruciate ligament injury-induced osteoarthritis.
    Wenchuan Zhao, Li Zhang, Rui Chen, Weirong Li, Xi Wang, Zongyuan Li, Yixin Li, Wei Dong, Hong Chen.
      Mitochondrial dysfunction and endoplasmic reticulum stress (ERS) play critical roles in the development of osteoarthritis (OA). Sirtuin 3 (SIRT3), a mitochondrial deacetylase, has regulatory effects on OA, but whether it can influence OA progression by modulating the crosstalk between mitochondrial dysfunction and ERS remains unclear. Therefore, the aim of this study was to investigate the effects of SIRT3 on mitochondrial dysfunction and ERS in OA. Anterior cruciate ligament transection was performed to establish an OA rat model, and C28/I2 chondrocytes were treated with IL-1β to establish an in vitro OA cell model for experimental investigation. Hematoxylin and eosin (H&E) staining, Safranin O/Fast Green staining, MitoTracker Red staining, and JC-1 staining were used to assess OA progression in rats and C28/I2 cell damage. RT-qPCR and Western blotting were used to measure the expression levels of target genes and proteins. Coimmunoprecipitation was utilized to examine protein interactions and acetylation levels. The result shows that SIRT3 expression was downregulated in OA rats and IL-1β-induced C28/I2 cells. SIRT3 overexpression significantly alleviated pathological damage to rat articular cartilage tissues, reduced chondrocyte loss, improved matrix metabolism in articular cartilage tissues, and ultimately mitigated OA progression in rats. Moreover, SIRT3 overexpression inhibited IL-1β-induced ERS in C28/I2 cells, reduced the activation of the unfolded protein response, and improved mitochondrial function. Additionally, the mitochondrial Ca2+ transport inhibitor Ru360 suppressed mitochondrial Ca2+ overload caused by disrupted endoplasmic reticulum calcium homeostasis and improved both mitochondrial function and ERS. DRP1 was upregulated in OA rats and IL-1β-stimulated cells, and changes in DRP1 acetylation signals together with decreased DRP1 protein abundance were observed following SIRT3 manipulation. Overall, SIRT3 manipulation was associated with acetylation signals of DRP1 and reduced DRP1 protein abundance, indicating that DRP1 is a potential mediator involved in the SIRT3‑linked restoration of mitochondrial function, attenuation of ERS, and alleviation of OA progression.
    Keywords:  Acetylation; DRP1; Endoplasmic reticulum stress; Mitochondrial function; Osteoarthritis; SIRT3
    DOI:  https://doi.org/10.1007/s10735-026-10965-2
  58. Int J Mol Sci. 2026 Aug 23. pii: 7538. [Epub ahead of print]27(17):
    Liraglutide Attenuates Multiorgan Oxidative, Astroglial, and Mitochondrial Stress Responses in Thioacetamide-Induced Hepatic Encephalopathy.
    Yasin Bilgin, Fatih Mehmet Sari, Betul Cicek, Engin Kurt, Mustafa Ozkaraca, Ali Gungor, Nezahat Kurt, Asli Ozbek Bilgin.
      Hepatic encephalopathy (HE) is a complex complication of liver failure involving oxidative stress, astroglial activation, mitochondrial dysfunction, and multiorgan disturbances along the gut-liver-brain axis. This study investigated the therapeutic effects of liraglutide (LIRA) in a thioacetamide (TAA)-induced rat model of HE. Thirty male Sprague-Dawley rats were assigned to control, TAA, and TAA+LIRA 100, 200, or 400 µg/kg groups. HE was induced with TAA (200 mg/kg, intraperitoneally) for three consecutive days, followed by subcutaneous LIRA treatment for 14 days. Serum biochemical parameters, tissue oxidative and inflammatory markers, histopathology, and Nrf2, MFN2, AKT1, mTOR, GFAP, and VEGFA immunoreactivity were evaluated. TAA caused marked hepatic and cerebral structural injury, increased serum and brain glutamine concentrations, disrupted redox homeostasis, elevated MPO activity, and increased cerebral GFAP and multiorgan VEGFA immunoreactivity. LIRA partially improved hepatic and cerebral histopathology, reduced glutamine disturbances, attenuated selected oxidative, nitrosative, and inflammatory alterations, and modulated Nrf2, MFN2, AKT1, mTOR, GFAP, and VEGFA immunoreactivity in a tissue- and dose-specific manner. The 200 µg/kg dose produced the most consistent overall improvement, whereas the 400 µg/kg dose was less favorable for several endpoints. LIRA may therefore alleviate multiorgan stress associated with experimental HE, although further studies are required to confirm functional and mechanistic relevance.
    Keywords:  VEGFA; astroglial activation; brain; hepatic encephalopathy; intestine; liraglutide; liver; mitochondrial homeostasis; oxidative stress; thioacetamide
    DOI:  https://doi.org/10.3390/ijms27177538
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