bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2026–03–08
forty-six papers selected by
Gavin McStay, Liverpool John Moores University
  1. Mfi2: an outer mitochondrial membrane mitofissin required for mitophagy.
  2. Targeting mitochondrial quality control: Ginsenoside Rg1 as a therapeutic candidate for neuromuscular diseases.
  3. ROCK signaling at the crossroads of redox stress, mitochondrial dynamics, and metabolic disease.
  4. Aeromonas hydrophila induces mitophagy for intracellular survival through its secreted effectors in the splenic macrophages of grass carp (Ctenopharyngodon idella).
  5. Early mitophagy activation by Urolithin A prevents, but late activation does not reverse, age-related cognitive impairment.
  6. The Interaction Between Mitophagy Dysregulation and the Diabetic Bladder Microenvironment.
  7. 1,25D3 reprograms mitochondrial quality control via sirtuin and sensitizes glioblastoma to chemotherapy.
  8. Mitophagy Enhancement Delays Mouse Mesenchymal Stem Cell Senescence by Attenuating the Senescence-Associated Secretory Phenotype.
  9. Cyclic tensile loading regulates nucleus pulposus cell autophagy through mitochondrial dynamics: molecular mechanisms and implications.
  10. YAP in synovial macrophages mitigates mechanically-induced osteoarthritis by preserving mitochondrial fusion.
  11. Autocrine SFRP2 (secreted frizzled related protein 2) enhances lung myofibroblast fibrogenic activity by suppressing PINK1-mediated mitophagy initiation.
  12. Mitophagy-driven prognosis in pediatric acute myeloid leukemia: a new frontier.
  13. Celastrol triggers CAV-1-mediated mitochondrion cholesterol metabolism and mitophagy to suppress liver cancer.
  14. Mitochondrial dynamics in neurodevelopment and neurodevelopmental disorders.
  15. HSP70 preserves brain microvascular endothelial integrity under heat stress associated with suppressed JNK-mediated apoptosis and mitophagy.
  16. Aconitine outperforms mesaconitine and hypaconitine in triggering excessive mitophagy via lysosomal two-pore channels disruption in SH-SY5Y cells and zebrafish.
  17. Ginsenoside Rg1 ameliorates the senescence and neurite injury of retinal ganglion cells in DR via targeting VDR and promoting mitochondrial biogenesis.
  18. The protective effects of melatonin postconditioning in cerebral ischemia may be mediated through the modulation of FUNDC1 and Bnip3 levels.
  19. Gas-sensing neurons prime mitochondrial fitness to offset metabolic stress.
  20. Functions of J-domain proteins in mitochondrial protein biogenesis.
  21. USP30 alleviates intestinal ischemia-reperfusion injury by deubiquitinating MFN2 mediating the mitochondrial endoplasmic reticulum pathway.
  22. Miro1 in Parkinson's Disease: A Key Regulator of Mitochondrial Homeostasis and Neurodegeneration.
  23. Single-cell and multi-omics analysis identifies mitophagy-related biomarkers and therapeutic targets in ischemic stroke.
  24. Crosstalk between mitophagy and breast cancer: mechanisms of action and clinical applications.
  25. Oxaloacetate Restores HIF-1α-Mediated Mitochondrial Homeostasis to Counter Tubulointerstitial Injury in Diabetic Kidney Disease.
  26. Nicotine-induced mitophagy in bronchial epithelial cells and MYST1 downregulation in cigarette smoke-exposed lungs: potential mechanisms of COPD progression.
  27. Dendrobine ameliorates non-alcoholic fatty liver disease by inhibiting mitochondrial fission through modulation of the Wnt5a/p-CaMKII/p-Drp1 signaling axis.
  28. Ajugoside Promotes the Repair of Osteoporotic Bone by Inducing Osteogenic Differentiation of Bone Marrow Mesenchymal Stem Cells.
  29. Rg1-R1 attenuates cardiac ischemia/reperfusion-induced endothelial cell injury through activating the ULK1/PGAM5-FUNDC1-mitophagy pathway.
  30. Shikonin alleviates high-fat diet-induced vascular aging and dysfunction by inhibiting oxidative stress and mitochondrial damage.
  31. Discovery of Genes Related to Cuproptosis and Mitophagy to Improve Myocardial Infarction Diagnosis and Treatment.
  32. Characterization of pathogenic missense mutations in nuclear encoded mitochondrial dynamin -1 like protein.
  33. Uncovering mitochondrial dynamics-related genes as potential diagnostic biomarkers for acute myocardial infarction.
  34. Dimethyl fumarate and mitochondrial physiology: implications for neurological disorders.
  35. Gentiana szechenyii Kanitz Compounds Regulate Lipopolysaccharide-Induced Inflammation and Mitochondrial Autophagy Via the Toll-Like Receptor 4-Nuclear Factor Kappa B Pathway.
  36. Resveratrol alleviates neuropathic pain associated with restoration of mitochondrial fission-fusion balance in CCI mice.
  37. MITOCHONDRIA IN MUSCLE STEM CELL BIOLOGY: GATEKEEPERS OF FATE, FUNCTION, AND REGENERATION.
  38. Mitochondrial-Derived Vesicles: An Emerging Whisperer in Neurological Disorders.
  39. Structural remodeling of the mitochondrial protein biogenesis machinery under proteostatic stress.
  40. Correction: Bavachin ameliorates cisplatin-induced nephrotoxicity by enhancing mitochondrial β-oxidation and lipid metabolism through MFN2.
  41. Extracellular Vesicle-Mediated Precision Delivery of Paclitaxel Activates Mitophagy to Promote Repair after Spinal Cord Injury.
  42. Tofacitinib repairs inflammation and mitochondrial dysregulation in GM-CSF-reprogrammed RA macrophages.
  43. Transgenerational effects of environmentally relevant concentrations of ibuprofen on Daphnia magna.
  44. Polystyrene Nanoplastics and Cadmium Co-Exposure Accelerates Mitochondrial Autophagy Mediated by HSP60-SIRT3-SOD2 Signaling Pathway in Primary Duck Embryo Hepatocytes.
  45. Lactate supplementation modulates molecular and functional responses during chronic neuromuscular electrical stimulation in male rats.
  46. Reno-protective mechanisms of curcumin in diabetic nephropathy.
  1. Autophagy Rep. 2026 ;5(1): 2635914
    Mfi2: an outer mitochondrial membrane mitofissin required for mitophagy.
    Kentaro Furukawa, Tatsuro Maruyama, Yuji Sakai, Nobuo N Noda, Tomotake Kanki.
      Mitophagy selectively eliminates damaged or excess mitochondria to maintain mitochondrial homeostasis. During this process, mitochondria need to be fragmented to allow their sequestration within autophagosomes. However, the well-known dynamin-related fission factors, Dnm1 in yeasts and DNM1L/DRP1 in mammals, are dispensable for mitophagy, leaving the underlying mechanism unresolved. In the yeast Saccharomyces cerevisiae, the identification of the mitochondrial intermembrane space protein Atg44 (autophagy-related 44) uncovered the existence of a new class of proteins, mitofissin, involved in mitochondrial fission during mitophagy. Whether Atg44 alone is sufficient for mitophagy-associated fission remained unclear. Our recent study identified Mfi2 (mitofissin 2) as a mitochondrial outer membrane-resident mitofissin that is required for efficient mitophagy and acts independently of Dnm1. Our findings indicate that mitophagy-associated mitochondrial fission is driven by mitofissins acting from both the inner and outer mitochondrial membranes. Here, we discuss remaining issues, including how mitofissin activities are regulated and how their function is modulated by mitochondrial lipids such as cardiolipin.
    Keywords:  Atg44; Dnm1; Mfi2; mitochondrial fission; mitofissin; mitophagy
    DOI:  https://doi.org/10.1080/27694127.2026.2635914
  2. J Ginseng Res. 2026 Mar;50(2): 100930
    Targeting mitochondrial quality control: Ginsenoside Rg1 as a therapeutic candidate for neuromuscular diseases.
    Xiaoqing Cai, Haixia Lan, Yingying Jiao, Yaoqi Wu, Peidan Yang, Tongkai Chen, Yafang Song.
      Neuromuscular diseases (NMDs) are complex disorders caused by the dysfunction of motor neurons and skeletal muscles. They lead to progressive muscle weakness and atrophy and impose a significant economic burden on patients and society at large. The dysregulation of mitochondrial quality control (MQC), a key cellular process, contributes to the pathogenesis of several NMDs. Interestingly, accumulating evidence demonstrates that ginsenoside Rg1 can regulate MQC by modulating mitochondrial dynamics, mitophagy, mitochondrial biogenesis, and mitocytosis, thus aiding with the management of several diseases. This review comprehensively summarizes the current understanding of ginsenoside Rg1's effects on mitochondrial function. Furthermore, it proposes that Rg1 may target MQC mechanisms, emerging as an effective active agent for the treatment of NMDs. This review aims to bridge existing knowledge gaps and establish a theoretical foundation for the clinical application of ginsenoside Rg1 in the treatment of NMDs characterized by MQC dysfunction.
    Keywords:  Ginsenoside Rg1; Mitochondrial dynamics; Mitochondrial quality control; Mitophagy; Neuromuscular diseases
    DOI:  https://doi.org/10.1016/j.jgr.2025.12.003
  3. Redox Biol. 2026 Mar 03. pii: S2213-2317(26)00107-2. [Epub ahead of print]92 104109
    ROCK signaling at the crossroads of redox stress, mitochondrial dynamics, and metabolic disease.
    Yosuke Nagai, Keiichiro Matoba, Rimei Nishimura.
      Rho-associated coiled-coil-containing kinases (ROCK1 and ROCK2) serve as central molecular switches that couple cytoskeletal dynamics with redox regulation and mitochondrial quality control. Dysregulated ROCK signaling promotes mitochondrial fragmentation, oxidative stress, and metabolic inflexibility, thereby linking nutrient overload to multi-organ dysfunction in diabetes, obesity, and cardiometabolic disease. Recent advances have identified ROCK1 as a key regulator of mitochondrial dynamics and bioenergetics: ROCK1 directly phosphorylates the fission protein Drp1 and suppresses the AMPK-PGC-1α pathway, resulting in impaired fatty acid oxidation, decreased mitochondrial biogenesis, and enhanced oxidative injury. Pharmacological or genetic inhibition of ROCK restores mitochondrial structure, energy metabolism, and redox balance across the heart, kidney, and liver, underscoring its therapeutic relevance. In contrast, ROCK2 plays more complementary roles in immune regulation and fibrotic remodeling, as evidenced by the clinical success of selective ROCK2 inhibition. In addition, metabolic drugs such as statins and GLP-1 receptor agonists can indirectly attenuate ROCK activity, suggesting feasible translational strategies for cardiometabolic disease. Despite these advances, isoform-specific mechanisms remain incompletely defined, and selective ROCK1 inhibitors have not yet been developed. Future studies should focus on clarifying ROCK1-specific signaling in mitochondrial homeostasis, developing tissue-targeted inhibitors, and combining ROCK modulation with metabolic or antioxidant therapies. A further understanding of the ROCK-mitochondria axis will enable the design of precise interventions to restore redox equilibrium and prevent progression of metabolic and cardiovascular disorders.
    Keywords:  Cardiometabolic diseases; Metabolic remodeling; Mitochondrial dynamics; ROCK1; Redox signaling
    DOI:  https://doi.org/10.1016/j.redox.2026.104109
  4. Fish Shellfish Immunol. 2026 Mar 03. pii: S1050-4648(26)00152-X. [Epub ahead of print] 111248
    Aeromonas hydrophila induces mitophagy for intracellular survival through its secreted effectors in the splenic macrophages of grass carp (Ctenopharyngodon idella).
    Xiaoyu Ma, Rong Ye, Wansong Li, Zhenhong Ou, Hong Zhou.
      Aeromonas hydrophila, a Gram-negative bacterium ubiquitously distributes in aquatic environments, represents a prevalent pathogenic threat to aquatic animals. The present study investigated how A. hydrophila induced mitophagy to promote its own survival in the splenic macrophages of grass carp (Ctenopharyngodon idella). Our results revealed that A. hydrophila impaired mitochondrial integrity by reducing mitochondrial membrane potential and ATP levels, as well as increasing mitochondrial ROS (mtROS) production. Meanwhile, this bacterium decreased the expression of the TOM20, a mitochondrial outer membrane protein, accompanied by an increased colocalization of the autophagy marker LC3 with TOM20, as well as an enhanced fusion of mitochondria with lysosomes. These effects were reversed by the mitophagy inhibitor Mdivi-1, confirming the occurrence of A. hydrophila-induced mitophagy. Subsequently, we found that both live bacteria and their culture supernatants but not heat-inactivated supernatants triggered the mitophagy responses. Mechanistical evidence of A. hydrophila-induced mitophagy by the PINK1-Parkin pathway included the upregulation of PINK1/Parkin expression and the blockade of TOM20-LC3 colocalization by Oroxylin A, which specifically dampens the PINK1-Parkin pathway. Furthermore, the physiological significance of A. hydrophila-induced mitophagy was emphasized in the splenic macrophages where pretreatment with Mdivi-1 was found to significantly reduce the intracellular load of A. hydrophila. In contrast, the mitophagy inducer m-chlorophenylhydrazone (CCCP) enhanced bacterial survival, indicating that A. hydrophila triggered mitophagy to maintain its intracellular survival. Collectively, A. hydrophila induced PINK1/Parkin-mediated mitophagy via its secreted effectors, thereby mitigating antimicrobial pressure and facilitating its own survival. This provided a novel perspective for understanding the intracellular survival mechanisms of extracellular pathogens.
    Keywords:  Aeromonas hydrophila; Effector; Mitophagy; PINK1-Parkin pathway; Splenic macrophage; Teleost
    DOI:  https://doi.org/10.1016/j.fsi.2026.111248
  5. NPJ Aging. 2026 Mar 05.
    Early mitophagy activation by Urolithin A prevents, but late activation does not reverse, age-related cognitive impairment.
    Claudia Jara, Leslye Venegas-Zamora, Han S Park-Kang, Matías Lira, Micaela Ricca, Sebastian Valenzuela, Cheril Tapia-Rojas.
      The hippocampus is crucial to learning and memory, functions that decline with age due to impaired mitochondrial bioenergetics and reduced mitophagy, resulting in the accumulation of dysfunctional mitochondria and increased susceptibility to neurodegeneration. Urolithin A (UA), a natural mitophagy activator derived from polyphenols, has demonstrated benefits in Alzheimer's disease models; however, its role in normal aging remains unclear. Here, we investigated whether UA can prevent or reverse hippocampal dysfunction by enhancing mitophagy and mitochondrial function. Two mouse models were used: 18-month-old C57BL/6 mice with established mitochondrial and cognitive deficits, and 5-month-old SAMP8 mice, an accelerated aging with cognitive decline starting from 6 months of age. UA was administered for 8 weeks, followed by assessments of ATP production, mitochondrial dynamics, mitophagy markers, synaptic proteins, and memory. In C57BL/6 mice, UA increased ATP, boosted proteins associated with fusion, antioxidant defense, and biogenesis, and reduced phosphorylated tau; however, these changes did not restore memory. In contrast, SAMP8 mice showed stronger effects: ATP rose sharply, mitochondrial stress and aberrant proteins decreased, and cognitive performance improved. These findings highlight UA effects as a preventive therapeutic agent, but are insufficient to reverse established cognitive decline, suggesting early mitophagy activation is critical to mitigate brain aging and neurodegeneration.
    DOI:  https://doi.org/10.1038/s41514-026-00351-3
  6. J Diabetes. 2026 Mar;18(3): e70199
    The Interaction Between Mitophagy Dysregulation and the Diabetic Bladder Microenvironment.
    Shi Li, Zongyao Fan, Zheng Duan, Jun Xue, Zhongqing Wei.
      Diabetic bladder dysfunction (DBD) is a prevalent and multifactorial urological complication of diabetes, with pathogenesis driven by complex interactions between hyperglycemia-induced oxidative stress, mitochondrial dysfunction, and bladder microenvironment dysregulation. Mitophagy, a selective autophagic process critical for mitochondrial quality control, has been linked to various metabolic diseases, but its precise role and the bidirectional interactions with the diabetic bladder microenvironment remain underexplored. This review outlines a novel, self-reinforcing feedback loop central to DBD progression. In this cycle, hyperglycemia impairs both the PINK1/Parkin-mediated mitophagy pathway and ubiquitin-independent pathways like FUNDC1 under hypoxic conditions, leading to the accumulation of damaged mitochondria. Mitochondrial dysfunction then exacerbates microenvironmental damage through excessive mitochondrial reactive oxygen species (mtROS) production, release of damage-associated molecular patterns (DAMPs), and activation of the NLRP3 inflammasome, which further drives inflammation, fibrosis, and extracellular matrix (ECM) remodeling. This aggravated microenvironment inhibits mitophagy, thereby accelerating the pathogenic cycle. Beyond elucidating this loop, this review suggests that targeting it offers a promising therapeutic strategy. A breakthrough in DBD treatment may necessitate a combined approach that both restores mitophagy and modulates the microenvironment. Additionally, this study critically reviews several promising, yet underexplored, interventions, including pharmacological mitophagy activation with urolithin A, NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome inhibition via MCC950, and advanced techniques like nanoparticle-mediated PINK1 mRNA delivery and CRISPR/Cas9-based Parkin gene editing. Future research should incorporate spatial transcriptomics to resolve cellular heterogeneity, develop targeted nanodelivery systems, and establish mechanism-driven, highly specific combination therapies to enable precision medicine for DBD.
    Keywords:  DBD; PINK1/Parkin pathway; bladder microenvironment; mitophagy dysregulation; oxidative stress
    DOI:  https://doi.org/10.1111/1753-0407.70199
  7. Mol Ther. 2026 Mar 05. pii: S1525-0016(26)00191-7. [Epub ahead of print]
    1,25D3 reprograms mitochondrial quality control via sirtuin and sensitizes glioblastoma to chemotherapy.
    Karrie M Kiang, Yixiong Shen, Yogesh K H Wong, Bo Chen, Junbo Liao, Anza Mnahal, Wanjun Tang, Zhiyuan Zhu, Shuhan Cao, Carmen S C Lo, Sang Jin Lee, Hongbo Guo, Liyang Zhang, Gilberto Ka-Kit Leung.
      Tumor cells adapt to therapeutic stress by preserving mitochondrial integrity through mitophagy, but excessive mitophagy can overwhelm this adaptative mechanism and precipitate mitochondrial collapse. Here, we demonstrate that 1,25-dihydroxyvitamin D3 (1,25D3) reduces glioblastoma resistance to the standard chemotherapeutics temozolomide by driving mitophagic overload and mitochondrial dysfunction. We identified mitochondrial sirtuin SIRT4 as a key downstream effector of mitochondrial metabolism and quality control triggered by 1,25D3-induced mitochondrial stress. Pharmacological levels of 1,25D3 activate mitophagy by transcriptionally upregulating SIRT4 through vitamin D receptor (VDR) signaling. SIRT4, which is frequently downregulated in glioblastoma, suppresses glioblastoma glutamine metabolism by inhibiting glutamate dehydrogenase activity and limiting α-ketoglutarate availability, thereby integrating metabolic stress with enhanced mitophagy. This VDR-SIRT4 axis shifts mitophagy from a cytoprotective process to a lethal pathway, selectively sensitizing tumor cells while sparing normal astrocytes and brain tissue. By exploiting mitochondrial quality control as a metabolic vulnerability, 1,25D3 enhances chemotherapeutic efficacy and provides a translational rationale for repurposing 1,25D3 in resistant glioblastoma.
    DOI:  https://doi.org/10.1016/j.ymthe.2026.03.006
  8. Mol Biol Cell. 2026 Mar 04. mbcE25110560
    Mitophagy Enhancement Delays Mouse Mesenchymal Stem Cell Senescence by Attenuating the Senescence-Associated Secretory Phenotype.
    Yingying Sun, Xudong Fu, Yi Li, Mengfan Peng, Lei Yang.
      Aging is a complex biological process that heightens susceptibility to age-related diseases, often driven by declining mitochondrial function. Mitophagy, the selective removal of damaged mitochondria, is a key quality-control mechanism essential for maintaining cellular health, and its decline has been closely linked to aging. However, the specific role of mitophagy in cellular senescence, a hallmark of aging, remains insufficiently understood, largely due to the lack of methods to manipulate mitophagy. In this study, we employed UMI-77, a new potent mitophagy activator, to evaluate its effects on senescence in mouse mesenchymal stem cells (MSCs). Our results show that UMI-77 preserves mitochondrial integrity and effectively delays cellular senescence through mitophagy. Mechanistically, UMI-77 markedly suppressed the senescence-associated secretory phenotype (SASP). Together, our findings reveal a new anti-aging therapeutic application for UMI-77 by targeting senescence-associated chronic inflammation through mitophagy induction and SASP reduction.
    DOI:  https://doi.org/10.1091/mbc.E25-11-0560
  9. J Transl Med. 2026 Mar 02.
    Cyclic tensile loading regulates nucleus pulposus cell autophagy through mitochondrial dynamics: molecular mechanisms and implications.
    Shaodong Xue, Hamed Soleimani Samarkhazan.
      
    Keywords:  Autophagy regulation; Cyclic tensile loading; Intervertebral disc degeneration; Mechanotransduction; Mitochondrial dynamics
    DOI:  https://doi.org/10.1186/s12967-026-07932-6
  10. Cell Signal. 2026 Feb 26. pii: S0898-6568(26)00080-X. [Epub ahead of print]143 112430
    YAP in synovial macrophages mitigates mechanically-induced osteoarthritis by preserving mitochondrial fusion.
    Yi Cheng, Zhi-Liang Guo, Yi-Fei Gu, Wen-Lei Li, Wei-Bing Zhang.
       BACKGROUND: Osteoarthritis (OA) is a prevalent and progressive degenerative joint disease resulting from abnormal loading; however, the mechanisms by which load induces OA remain incompletely understood. The Hippo/YAP signaling pathway is crucial for cellular mechanosensation, yet its effects on synovial macrophages-key players in joint inflammation-have not been documented. This study aims to investigate whether YAP regulates mitochondrial homeostasis to influence macrophage function in the context of mechanically induced OA.
    METHODS: We generated anterior cruciate ligament transection (ACLT) mice to induce OA and administered bone marrow-derived macrophages (BMDMs) subjected to cyclic tensile strain (CTS). We employed micro-computed tomography (micro-CT), histological analysis, immunofluorescence, and Western blotting to assess joint damage and molecular alterations. DCFH-DA and JC-1 staining were conducted to investigate mitochondrial function, followed by transmission electron microscopy for further analysis. Functional enhancement and deficiency studies were performed using Yap1 overexpression and small interfering RNAs (siRNAs), with rescue experiments conducted using AAV5-YAP1 in macrophages.
    RESULTS: ACLT induced joint instability, activated the Hippo pathway, and inhibited YAP in synovial macrophages, which is associated with OA progression. Pathological mechanical stress (12% CTS) directly inhibited YAP's nuclear localization and promoted M1 polarization in BMDMs. Mechanistically, YAP maintained mitochondrial homeostasis through TEAD1-dependent transcriptional regulation of Mfn1, a crucial mitochondrial fusion protein. Inhibition of YAP disrupted mitochondrial dynamics, leading to a decrease in mitochondrial membrane potential, an increase in mitochondrial ROS, and a reduction in ATP content. Overexpression of YAP1 rescued mitochondrial dysfunction, suppressed M1 polarization, and protected chondrocytes from catabolic effects. In vivo, specific macrophage overexpression of YAP1 significantly alleviated OA progression by restoring the YAP-MFN1 axis.
    CONCLUSION: This study identifies YAP as a mechanosensitive regulator of synovial macrophages that modulates mitochondrial homeostasis to inhibit inflammatory polarization. The YAP-MFN1 axis emerges as a novel therapeutic target for mechanical stress-induced osteoarthritis and elucidates the interplay between cellular mechanosensing and joint inflammation.
    Keywords:  Hippo/YAP pathway; Macrophage polarization; Mechanical stress; Mitochondrial dynamics; Osteoarthritis; Synovial inflammation
    DOI:  https://doi.org/10.1016/j.cellsig.2026.112430
  11. Autophagy. 2026 Mar 06.
    Autocrine SFRP2 (secreted frizzled related protein 2) enhances lung myofibroblast fibrogenic activity by suppressing PINK1-mediated mitophagy initiation.
    Yingying Lin, Tianxiang Lei, Yifan Jia, Meiling Yao, Xiaofeng Wang, Shaojie Huang, Zhongxing Wang, Xiaofan Lai.
      Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease driven by persistent activation of pulmonary myofibroblasts, but the regulatory mechanisms sustaining this pathological state remain incompletely understood. Using single-cell RNA sequencing (scRNA-seq), we identified SFRP2 (secreted frizzled related protein 2) as a critical mediator of profibrotic myofibroblasts in IPF lungs. Functional studies revealed that SFRP2 acted in an autocrine manner to promote myofibroblast activation and extracellular matrix (ECM) production. Mechanistically, SFRP2 activated FZD5-mediated non-canonical WNT-Ca2 + signaling, leading to PPP3/calcineurin-dependent translocation of PINK1 from the outer to the inner mitochondrial membrane (IMM), where it was degraded, thereby inhibiting PINK1-mediated mitophagy. Furthermore, therapeutic intervention with AAV6-shSfrp2, SFRP2-neutralizing antibody, or the autophagy inducer rapamycin significantly ameliorated lung fibrosis in bleomycin (BLM)-induced mouse models. Our results define a novel autocrine SFRP2-mitophagy regulatory axis that perpetuates myofibroblast activation and represents a promising therapeutic target for pulmonary fibrosis.
    Keywords:  Extracellular matrix; PINK1-mediated mitophagy; WNT-Ca2 + signaling; idiopathic pulmonary fibrosis; mitochondrial reactive oxygen species; myofibroblast fibrogenic activity
    DOI:  https://doi.org/10.1080/15548627.2026.2642341
  12. Sci Rep. 2026 Mar 03.
    Mitophagy-driven prognosis in pediatric acute myeloid leukemia: a new frontier.
    Rajiv Ranjan Kumar, Uttam Sharma, Akshi Shree, Shilpi Chaudhary, Shuvadeep Ganguly, Radhika Bakhshi, Archna Singh, Jayanth Kumar Palanichamy, Ranjit Kumar Sahoo, Atul Batra, Surender K Sharawat, Deepam Pushpam, Anita Chopra, Archana Sasi, Sameer Bakhshi.
      Mitophagy is a selective form of autophagy that plays a crucial role in mitochondrial quality control. Mediators of the mitophagy pathway have been reported to contribute to tumor progression in multiple solid tumors. Limited data suggests that the overexpression of certain pathway components may predict for adverse survival outcomes in adult AML. However, the role of these mediators in pediatric AML has not been studied previously. We identified nine mitophagy-related genes (PINK1, PARKIN, SQSTM1, NDP52, OPTN, ULK1, MAP1LC3B, FUNDC1, and BNIP3) using the Reactome pathway database and Ensembl genome browser. Gene expression for each of the nine genes was quantified using quantitative reverse transcription polymerase chain reaction on bone marrow mononuclear cells in a retrospective cohort of 90 children (aged ≤ 18 years) with AML and 30 controls. Differential expression of these genes between patients and controls and across different molecular subtypes was assessed using nonparametric statistical tests. For external validation, transcriptomic data from children and young adults (aged ≤ 39 years) with AML and control samples from the Beat AML cohort were also analyzed. Survival analyses were performed using Kaplan-Meier estimates, and log-rank tests were used to evaluate associations between gene expression (upper versus lower quartiles) and relapse-free and overall survival in our patient cohort. A total of 90 children with AML patients and 30 controls were included. All nine mitophagy-related genes were significantly overexpressed in AML compared with controls, which was independently confirmed in the Beat AML cohort. Upregulation of all nine genes was consistent across most subgroups examined. Among these genes, only FUNDC1 overexpression was significantly associated with inferior relapse-free survival (HR = 2.039, p = 0.044). Mitophagy-related genes are upregulated across pediatric AML subtypes. FUNDC1 expression overexpression is associated with inferior relapse-free survival (RFS). Identifying vulnerabilities in mitophagy pathways may open avenues for therapeutic targeting in pediatric AML.
    Keywords:  AML; Acute myeloid leukemia; Autophagy; Cancer; Mitophagy; Mitophagy-related genes
    DOI:  https://doi.org/10.1038/s41598-026-42399-x
  13. Phytomedicine. 2026 Feb 21. pii: S0944-7113(26)00226-6. [Epub ahead of print]153 157989
    Celastrol triggers CAV-1-mediated mitochondrion cholesterol metabolism and mitophagy to suppress liver cancer.
    Hong-Fang Li, Chan-Juan Zhang, Ya-Ning Shi, Neng Zhu, Qiong Yang, Jun-Peng Long, Yan-Tian Liang, Li Qin.
       BACKGROUND: Celastrol (CeT), a bioactive natural compound derived from Tripterygium wilfordii Hook. f., exhibits potent anti-cancer properties, partially mediated through modulating lipid metabolism. However, its effects on the intricate lipid landscape of liver cancer and the precise underlying molecular mechanisms remain to be fully elucidated.
    PURPOSE: This study aimed to investigate the mechanism by which CeT induces mitophagy through regulating mitochondrial cholesterol metabolism in liver cancer.
    METHODS: Filipin staining and enzymatic assays were applied to evaluate CeT-mediated alterations in mitochondrial cholesterol metabolism. RNA sequencing, combined with RT-qPCR, Western blotting, and co-immunoprecipitation, was used to investigate the effect of CeT on the caveolin-1 (CAV-1)/sterol carrier protein-2 (SCP2) axis and its regulatory role in mitochondrial cholesterol metabolism in liver cancer cells. In vivo, xenograft models of liver cancer established in CAV-1 knockout mice were utilized to validate that CeT induces mitophagy via CAV-1 inhibition and subsequent modulation of mitochondrial cholesterol.
    RESULTS: CeT triggers significant intracellular cholesterol redistribution, culminating in pronounced cholesterol accumulation within mitochondria. This mitochondrial cholesterol overload activates mitophagy and suppresses liver cancer progression. Mechanistically, CeT disrupts the interaction between CAV-1 and SCP2, thereby impairing intracellular cholesterol trafficking and leading to cholesterol enrichment specifically within mitochondria. This resultant mitochondrial cholesterol accumulation substantially elevates reactive oxygen species (ROS) levels, dissipates mitochondrial membrane potential, and initiates mitophagy, collectively inhibiting liver cancer growth. Notably, CeT effectively attenuated tumor development in both nude mice and CAV-1 knockout mice xenograft models.
    CONCLUSION: Our study demonstrates that CeT reprograms mitochondrial cholesterol homeostasis by inhibiting the CAV-1/SCP2 axis, thereby triggering mitophagy. These findings not only provide a mechanistic foundation for the development of CeT as a promising therapeutic agent against liver cancer but also underscore the potential of targeting organelle-specific cholesterol metabolism as a novel and compelling strategy in oncology.
    Keywords:  Caveolin-1; Celastrol; Cholesterol metabolism; Liver cancer; Mitophagy
    DOI:  https://doi.org/10.1016/j.phymed.2026.157989
  14. Nat Rev Neurosci. 2026 Mar 04.
    Mitochondrial dynamics in neurodevelopment and neurodevelopmental disorders.
    Carissa L Sirois, Jiyoun Lee, Audrey L Chambers, Xinyu Zhao.
      Mitochondrial deficits have been found in individuals with neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD). However, how mitochondria are regulated during brain development and how their dysregulation contributes to NDDs remains unclear. Mitochondria are continuously generated and degraded, dynamically remodelled through fusion and fission and actively transported to specific cellular compartments. Altered mitochondrial dynamics have been linked to several human diseases, and there is rising interest in their roles in neurodevelopment. However, most studies of mitochondrial contributions to NDDs have focused on the metabolic consequences of their dysfunction. This Review focuses on the mitochondrion itself, with particular emphasis on mitochondrial dynamics. We summarize recent advances in understanding the mechanisms that regulate mitochondrial dynamics during brain development and discuss how genetic and epigenetic alterations that affect mitochondrial dynamics contribute to NDDs. Finally, we consider mitochondrial dynamics as a potential therapeutic target for treatment of NDDs.
    DOI:  https://doi.org/10.1038/s41583-026-01031-7
  15. Int J Biol Macromol. 2026 Mar 04. pii: S0141-8130(26)01165-7. [Epub ahead of print] 151239
    HSP70 preserves brain microvascular endothelial integrity under heat stress associated with suppressed JNK-mediated apoptosis and mitophagy.
    Menglin Zhou, Haisheng Li, Meilin Wan, Zeping Ji, Zhihao Liu, Zhongling Wan, Jiawei Cai, Jiachen Shi, Xinjun Qiu, Xiaohui Zhang.
      Heat stress profoundly disrupts blood-brain barrier (BBB) integrity and brain homeostasis in both livestock and humans; yet, the underlying molecular mechanisms remain poorly understood. In this study, we used in vivo models (chickens and mice) and an in vitro brain microvascular endothelial cell model (bEnd.3 cells) to elucidate the mechanisms underlying heat stress-induced endothelial injury. Our results demonstrated that heat stress produced pronounced perivascular edema and endothelial oxidative injury, downregulated tight junction proteins, and impaired barrier function. Heat stress also induced severe mitochondrial structural damage, promoted mitochondrial fission, and triggered sustained activation of c-Jun N-terminal kinase (JNK) signaling, with consequent caspase-dependent apoptosis and enhanced PTEN-induced putative kinase 1 (PINK1)/Parkin RBR E3 ubiquitin protein ligase (Parkin)-mediated mitophagy. Pharmacological intervention with 3-methyladenine and mdivi-1 indicated that heat stress-induced autophagy and mitophagy contributed to endothelial cell injury rather than providing cytoprotection. In addition, heat stress markedly increased heat shock protein 70 (HSP70) expression in both brain tissue and endothelial cells. Functional studies with HSP70 overexpression and knockdown, together with chemical activation and inhibition of JNK, revealed that HSP70 alleviated heat stress-induced endothelial oxidative damage, mitochondrial apoptosis, and mitophagy by suppressing JNK activation, thereby preserving BBB integrity. Finally, Co-immunoprecipitation and immunofluorescence analyses confirmed interaction between HSP70 and JNK. Collectively, this study advances our knowledge of heat stress-induced BBB dysfunction and identifies HSP70-mediated regulation of JNK as a potential therapeutic intervention, with important implications for reducing heat stress-induced mortality in poultry and mitigating central nervous system injury in humans with heatstroke.
    Keywords:  Apoptosis; Blood–brain barrier; Heat shock protein; Heat stress; Mitophagy
    DOI:  https://doi.org/10.1016/j.ijbiomac.2026.151239
  16. Toxicol Res (Camb). 2026 Feb;15(1): tfag008
    Aconitine outperforms mesaconitine and hypaconitine in triggering excessive mitophagy via lysosomal two-pore channels disruption in SH-SY5Y cells and zebrafish.
    Han Feng, Qiaoxing Mou, Xiaoyu Yan, Zijian Zhang, Tianyu Liang, Fu Peng, Tingting Zhang, Mengfan Yan, Jie Liang, Weiying Liu, Huayang Tang, Cheng Peng, Xiaoqi Pan.
      The genus Aconitum L. is widely used in the treatment of rheumatoid arthritis, tumors, and cardiovascular diseases due to its prominent pharmacological properties. However, increasing scientific attention has been directed toward its neurotoxicity. Diester-diterpenoid alkaloids (DDAs), such as aconitine (AC), mesaconitine (MA), and hypaconitine (HA), have been identified as the principal toxic constituents of Aconitum. Although disruption of calcium homeostasis has been demonstrated to mediate DDAs-induced neurotoxicity, the key neurotoxic components and their underlying molecular mechanisms remain unclear. Our study employed both in vivo and in vitro to compare the neurotoxic effects of structurally similar DDAs (AC, MA, and HA) to screen for the key effector substance for further investigation. Experiments conducted in both zebrafish and SH-SY5Y cells revealed that AC exerted more significant regulatory effects on mitophagy, calcium homeostasis, and two-pore channels (TPCs) than MA and HA. Consequently, subsequent mechanistic studies focused on the role of the TPCs-Ca2+-mitophagy axis in AC-induced neurotoxicity. Treatment with the TPCs inhibitor Ned-19 suppressed mitochondrial-lysosomal fusion and reversed the AC-induced upregulation of LC3B-II/I and Parkin, thereby attenuating the overactivation of mitophagy markers in SH-SY5Y cells. Similarly, the calcium chelator BAPTA-AM diminished mitochondrial-lysosomal colocalization and LC3B-II/I protein levels. In summary, AC disrupts lysosomal TPCs-mediated calcium homeostasis, leading to excessive mitophagy more pronounced than that of MA and HA. These findings not only deepen our understanding of the intrinsic mechanisms underlying AC-induced neurotoxicity, but also provide new experimental evidence supporting the identification of AC as the primary neurotoxic component in the genus Aconitum L.
    Keywords:  aconitine; calcium homeostasis; diester-diterpenoid alkaloids; lysosomal TPCs; mitophagy; neurotoxicity
    DOI:  https://doi.org/10.1093/toxres/tfag008
  17. J Ginseng Res. 2026 Mar;50(2): 100878
    Ginsenoside Rg1 ameliorates the senescence and neurite injury of retinal ganglion cells in DR via targeting VDR and promoting mitochondrial biogenesis.
    Kai Tang, Congcong Huang, Zhengjie Huang, Zhilei Lin, Zhen Wang, Ninghua Tan.
       Background: Injury of retinal ganglion cells (RGCs) is one of the earliest signs of diabetic retinopathy (DR), preceding retinal microvascular abnormalities. Driven by metabolic and biochemical cascades, diabetes-dependent senescence in the retinal neural cells is responsible for neurodegeneration and subsequent permanent visual loss. This study investigated the involvement of ginsenoside Rg1 (Rg1) in neuropathy associated with DR to identify a possible therapeutic target.
    Methods: The anti-aging and synaptogenesis effects, and neuroprotective mechanism of Rg1 were investigated in high glucose-induced RGCs and STZ-induced DR mice.
    Results: Rg1 effectively reduced the β-galactosidase activity, promoted the neurite outgrowth, and reversed the expression of senescence and synaptic development-related proteins. Mechanistically, the compromised mitochondrial biogenesis induced by hyperglycaemia manifested as a critical driver of functional and structural impairments in RGCs. Meanwhile, Rg1 interacts with VDR to potentiate transcription of PGC-1α via the VDR/cAMP/PKA/CREB pathway. Activation of PGC-1α by Rg1 revitalized hyperglycaemia-hampered mitochondrial biogenesis, and resultantly alleviated senescence and neurite outgrowth inhibition of RGCs both in vitro and in vivo models.
    Conclusion: Rg1 ameliorates neuropathy of DR by activating VDR non-genomic pathway and facilitating mitochondrial biogenesis. These results suggest a therapeutic approach for mitigating neurodegeneration in early DR, and provide insights into the potential clinical application of VDR agonism with Rg1 in regulating mitochondrial quality control.
    Keywords:  Diabetic retinopathy; Ginsenoside Rg1; Mitochondrial biogenesis; VDR/cAMP/PKA/CREB pathway; Vitamin D receptor
    DOI:  https://doi.org/10.1016/j.jgr.2025.05.006
  18. Brain Inj. 2026 Mar 06. 1-11
    The protective effects of melatonin postconditioning in cerebral ischemia may be mediated through the modulation of FUNDC1 and Bnip3 levels.
    Gulnur Aslan, Ozgur Bulmus, Mehmet Tuzcu, Ebru Gokdere, Kezban Can Sahna, Kazim Sahin, Engin Sahna.
       OBJECTIVE: The regulation of mitochondrial bioenergetics - as one of the endogenous defense mechanisms against ischemia-reperfusion (IR) injury - has been considered promising. This study aimed to determine which mitophagy-related signaling pathways (parkin, Bnip3, or FUNDC1) mediate the protective effects of postconditioning (PostC) and melatonin, both of which enhance the intrinsic defense capacity of cerebral tissue. In addition, microRNA-137 and microRNA-145, as well as serum asprosin, a novel glucogenic adipokine, levels were analyzed in cerebral IR injury.
    METHOD: Rats were divided into four groups: control (sham), IR, IR+PostC and IR+Mel(n:10). After 90 minutes of occlusion, PostC was performed at the onset of reperfusion in three cycles of 30-sec reperfusion, followed by 10-sec ischemia. Results: All parameters involved in mitophagy pathways increased with IR in cerebral cortex, and serum asprosin level decreased. Parkin and PINK1 levels did not change due to the treatments, while the FUNDC1 and Bnip3 levels decreased and serum asprosin levels increased significantly compared to IR. MicroRNA-137 and microRNA-145 decreased, although treatment partially restored the levels of these microRNAs.
    CONCLUSION: Increased expressions of parkin/PINK1, FUNDC1 and Bnip3 may suggest that all mitophagy pathways are activated by cerebral IR. Melatonin PostC may protect the cerebral tissue by inhibiting BNİP3- and FUNDC1-mediated mitophagy.
    Keywords:  Bnip3; FUNDC1; Ischemic postconditioning; asprosin; melatonin; microRNA-137 and -145
    DOI:  https://doi.org/10.1080/02699052.2026.2638954
  19. Proc Natl Acad Sci U S A. 2026 Mar 10. 123(10): e2525619123
    Gas-sensing neurons prime mitochondrial fitness to offset metabolic stress.
    Rebecca Cornell, Ava Handley, Roger Pocock.
      The mitochondrial unfolded protein response (UPRmt) is triggered by cells to alleviate proteotoxicity in response to metabolic stress. The ability to anticipate and prime cells against mitochondrial stress, by sensing potentially toxic changes in the external or internal environment, would provide a survival advantage. Yet, whether and how animals anticipate mitochondrial stress remains unclear. Here, we show that the Caenorhabditis elegans receptor guanylyl cyclase GCY-9 regulates neuropeptide signaling from carbon dioxide-sensing neurons to govern a noncanonical mitochondrial stress response in the intestine. This noncell autonomous stress response induces atypical mitochondrial chaperone transcription, confers mitochondrial stress resistance, and increases mitochondrial membrane potential and respiration. We show that starvation decreases GCY-9 expression and propose that the resultant cytoprotective program is launched to offset metabolic and proteotoxic risks. Thus, environmental sensing by peripheral neurons can preemptively enhance systemic mitochondrial function in response to metabolic uncertainty.
    Keywords:  Caenorhabditis elegans; gas-sensing; mitochondrial stress; neuropeptide
    DOI:  https://doi.org/10.1073/pnas.2525619123
  20. Protein Sci. 2026 Apr;35(4): e70516
    Functions of J-domain proteins in mitochondrial protein biogenesis.
    Vitasta Tiku, Georg Bossenz, Janine Kirstein, Thomas Becker.
      Mitochondrial biogenesis and functions depend on the import and assembly of more than 1000 proteins that are made as precursors on cytosolic ribosomes. The majority of these precursor proteins are transported from the ribosome to the translocase of the outer membrane (TOM complex), which constitutes the main entry site for mitochondrial precursors. The transient localization of mitochondrial precursor proteins in the cytosol represents a major burden for cellular proteostasis since these proteins can aggregate and accumulate in different cellular compartments, causing proteotoxic stress. Inside mitochondria, protein translocases sort the precursor proteins into the mitochondrial subcompartments-outer and inner membrane, the intermembrane space and matrix. The imported proteins have to be folded and efficiently assembled into functional protein complexes. Molecular chaperones such as Hsp70 monitor these processes to minimize proteotoxic stress. J-domain proteins stimulate the ATPase activity of Hsp70 and recruit the chaperones to their clients in the biogenesis of mitochondrial proteins. They ensure protein targeting to mitochondria, drive protein import into mitochondria, as well as folding and assembly of mitochondrial proteins. Here, we summarize the emerging view of how J-domain proteins guide mitochondrial precursor proteins from their synthesis in the cytosol until their folding into a mature protein and assembly into protein complexes in mitochondria.
    Keywords:  ER‐SURF; Hsp70; J‐domain protein; TOM complex; mitochondria; protein targeting
    DOI:  https://doi.org/10.1002/pro.70516
  21. Biochem Pharmacol. 2026 Feb 27. pii: S0006-2952(26)00181-4. [Epub ahead of print]248 117850
    USP30 alleviates intestinal ischemia-reperfusion injury by deubiquitinating MFN2 mediating the mitochondrial endoplasmic reticulum pathway.
    Ziyi Weng, Tulanisa Kadier, Ruili Ding, Yu Shi, Jingyuan Xie, Rong Chen, Qingtao Meng.
      Intestinal ischemia-reperfusion (IIR) injury can cause intestinal barrier damage, systemic inflammatory response, and high mortality. The key mechanism is the disorder of the mitochondrial-endoplasmic reticulum network. Ubiquitin-specific peptidase 30 (USP30), located on the outer mitochondrial membrane, can reverse the partial ubiquitination of Parkin substrates or completely remove the ubiquitin chain to maintain mitochondrial function. Mitofusin 2 (MFN2) is a mitochondrial outer membrane fusion protein that mediates mitophagy and endoplasmic reticulum stress and participates in the formation of mitochondria-associated endoplasmic reticulum (MAMs). Our research showed that IIR reduces the protein expression of USP30 and MFN2, and overexpression of USP30 can increase the stability of MFN2 through deubiquitination and alleviate the damage caused by IIR. After overexpression of MFN2, mitochondrial dysfunction and endoplasmic reticulum stress caused by IIR are restored, while knockdown of MFN2 weakens the protective effect of USP30 on the MAMs. USP30 alleviates endoplasmic reticulum stress and mitochondrial dysfunction caused by intestinal ischemia-reperfusion injury by reducing the ubiquitination level of MFN2. The regulation of USP30 may be a promising strategy for alleviating intestinal ischemia-reperfusion injury.
    Keywords:  Endoplasmic reticulum stress; Intestinal ischemia-reperfusion; MAMs; MFN2; Mitochondrial dysfunction; USP30
    DOI:  https://doi.org/10.1016/j.bcp.2026.117850
  22. Neuromolecular Med. 2026 Mar 07. pii: 15. [Epub ahead of print]28(1):
    Miro1 in Parkinson's Disease: A Key Regulator of Mitochondrial Homeostasis and Neurodegeneration.
    Gaurav Singh, Simranpreet Kaur, Khadga Raj Aran.
      Parkinson's disease (PD), is slowly advancing disease condition of the nervous system, which leads to interruption of normal motor function, resulting in symptoms such as tremor, muscle rigidity, bradykinesia, and postural instability. PD is commonly also accompanied by motor impairment, associated with broad non-motor symptoms, of which sensory prob 21qwlems are including behavioural and sleeping disorders and autonomic dysfunctions. The disease is characterised by slow degeneration of the dopaminergic neurons in the substantia nigra pars compacta (SNpc), and pathological misfolded α-synuclein (α-syn) deposition protein. Mitochondrial Rho GTPase (Miro1) is one of the major regulators of neuronal energy transport, mitochondrial motility, and communication in the central nervous system (CNS). It also regulates the quality of mitochondria in their interaction with regulatory proteins, PTEN-induced kinase 1 (PINK1), Parkin, and Leucine-rich repeat kinase2 (LRRK2). Studies stated that there are a few PD-related genes that are correlated with Miro1, which influences its activity. The dysregulation or genetic mutations of Miro1 disrupt the mitochondrial activities, including the transport, mitophagy, and calcium (Ca2+) homeostasis, particularly among dopaminergic neurons. These imbalances augment oxidative stress, mitochondrial dysfunction, and α-syn aggregation, which eventually regulate neuron exposure and are a risk factor in the development of PD. This review highlights the role of Miro1 in the development and pathophysiology of PD, with particular emphasis on recent experimental and clinical findings. It also focuses on the therapeutic prospect of Miro1-targeted approaches as new emerging interventions to reduce the development of the disease.
    Keywords:  Calcium homeostasis; Miro1; Mitochondrial dysfunction; Neurodegeneration; Neuroinflammation; Parkinson’s disease
    DOI:  https://doi.org/10.1007/s12017-026-08917-w
  23. Sci Rep. 2026 Mar 06.
    Single-cell and multi-omics analysis identifies mitophagy-related biomarkers and therapeutic targets in ischemic stroke.
    Zhan Cao, Yingluan Wang, Mingjian Sun, Runyi Du, Xu Feng, Lin Wang, Ziyi Zhao, Wei Sun.
      Ischemic stroke (IS) remains a leading cause of death and disability, with limited effective treatments in the acute phase. Mitophagy, the selective degradation of damaged mitochondria, plays a crucial role in cellular homeostasis and survival during IS. However, its exact mechanisms in stroke pathophysiology remain unclear. This study utilized a multi-omics approach, integrating gene expression data from bulk and single-cell RNA sequencing, to investigate the role of mitophagy-related genes (MRGs) in IS. We identified differentially expressed MRGs (DE-MRGs) in IS using bioinformatics techniques, including weighted gene co-expression network analysis (WGCNA) and machine learning models, which led to the identification of five core biomarkers: SRPRB, ATP5J, LSM7, DEGS1, and TGDS. Validation via qPCR and analysis of immune cell infiltration further supported their relevance. Single-cell analysis revealed significant differences in mitophagy activity in microglial subpopulations, with ATP5J showing dynamic expression patterns linked to stroke-induced mitochondrial dysfunction. Additionally, pseudo-time analysis suggested a progressive shift from homeostatic to disease-associated microglial states. Our findings highlight the complexity of mitophagy regulation in IS and suggest that targeting mitophagy-related pathways, such as ATP5J, could provide novel therapeutic strategies for IS management.
    Keywords:  Biomarkers; Ischemic stroke; Microglia; Mitophagy; Translational medicine
    DOI:  https://doi.org/10.1038/s41598-026-43377-z
  24. J Cancer Res Clin Oncol. 2026 Feb 28. pii: 55. [Epub ahead of print]152(2):
    Crosstalk between mitophagy and breast cancer: mechanisms of action and clinical applications.
    Kun Rui, Jingjing Qiu, Minghao Li, Jianjun Huang, Tao Wang, Kai Yin.
      Mitophagy, a key mechanism of selective autophagy, maintains cellular homeostasis by removing dysfunctional mitochondria, and its dysregulation is closely associated with tumor initiation and progression. As breast cancer remains one of the most prevalent malignancies among women worldwide, its heterogeneity and therapeutic resistance have prompted growing interest in identifying novel molecular targets. Emerging evidence indicates that mitophagy plays a dual role in breast cancer development, metastasis, and treatment resistance by regulating energy metabolism, oxidative stress, and cell-fate decisions. This review systematically summarizes the molecular mechanisms of mitophagy and its dynamic regulatory networks in breast cancer. Further, it discusses emerging mitophagy-targeted therapeutic strategies, aiming to provide a theoretical foundation for the precision treatment of breast cancer.
    DOI:  https://doi.org/10.1007/s00432-026-06434-8
  25. Diabetes Obes Metab. 2026 Mar 03.
    Oxaloacetate Restores HIF-1α-Mediated Mitochondrial Homeostasis to Counter Tubulointerstitial Injury in Diabetic Kidney Disease.
    Yao Zhang, Jia-Ling Ji, Dan-Dan Yao, Yan Zhou, Cong-Cong Liu, Zhen-Lin Tang, Jia-Le Xue, Bi-Cheng Liu, Zuo-Lin Li, Rui-Xia Ma.
       BACKGROUND: Renal tubular injury, one of the most critical events in diabetic kidney disease (DKD), plays a pivotal role in the progression of the disease. Metabolic reprogramming of renal tubular cells emerges as a prominent pathological feature, yet its underlying molecular mechanisms remain incompletely understood.
    METHODS: We established a streptozotocin-induced mouse model of diabetes. Metabolomic analysis was then used to characterise DKD-specific metabolic alterations. To test the functional consequence of a metabolic intervention, DKD mice received intraperitoneal injections of oxaloacetate (OAA). Furthermore, molecular docking and cellular thermal shift assays were used to elucidate the molecular mechanisms underlying OAA's effects on renal tubular injury, which were further validated in HK-2 cells exposed to high glucose. Finally, a specific pharmacological inhibitor was applied to study the relevant signalling pathway.
    RESULTS: Metabolomic profiling identified a marked decrease in OAA, a key tricarboxylic acid (TCA) cycle intermediate, in injured renal tubular cells. OAA supplementation significantly attenuated tubulointerstitial injury, as evidenced by reduced tubular cell damage, fibrosis, and macrophage infiltration. Moreover, restored mitochondrial homeostasis was observed in DKD mice after OAA treatment. Mechanistically, we found that OAA inhibited prolyl hydroxylase domain 2 (PHD2), an essential regulator of hypoxia-inducible factor-1α (HIF-1α), thereby stabilising mitochondrial homeostasis. Furthermore, pharmacological inhibition of HIF-1α abolished the protective effects of OAA, confirming the involvement of the PHD2/HIF-1α axis.
    CONCLUSIONS: OAA ameliorates renal tubulointerstitial injury in DKD by restoring mitochondrial homeostasis through the PHD2/HIF-1α axis.
    Keywords:  HIF‐1α; diabetic kidney disease; mitochondrial homeostasis; oxaloacetate; tubulointerstitial injury
    DOI:  https://doi.org/10.1111/dom.70612
  26. Mol Biol Rep. 2026 Mar 04. pii: 462. [Epub ahead of print]53(1):
    Nicotine-induced mitophagy in bronchial epithelial cells and MYST1 downregulation in cigarette smoke-exposed lungs: potential mechanisms of COPD progression.
    Kai Liu, Dongchuan Xu, Jie Zhao, Rubing Mo, Mei Lin, Chanyi He, Qi Lin, Tian Xie, Quanni Li, Yipeng Ding.
      
    Keywords:  COPD; H4K16 Acetylation; MYST1; Mitophagy; Nicotine
    DOI:  https://doi.org/10.1007/s11033-026-11574-8
  27. J Ethnopharmacol. 2026 Feb 26. pii: S0378-8741(26)00296-5. [Epub ahead of print] 121445
    Dendrobine ameliorates non-alcoholic fatty liver disease by inhibiting mitochondrial fission through modulation of the Wnt5a/p-CaMKII/p-Drp1 signaling axis.
    Xiaolong Fu, Shiyi Gou, Leiqin Shi, Ling Tan, Yingtong Xian, Naiyu Fan, Lizhen Hu, Songjie Liao, Jianxiang Huang, Qin Wu, Shaoyu Zhou.
       ETHNOPHARMACOLOGICAL RELEVANCE: Dendrobium nobile Lindl. (DNL) is a precious traditional Chinese herbal medicine with a variety of bioactive substances, which is recorded in the Chinese Pharmacopoeia (2025 edition). Contemporary pharmacological research has demonstrated that DNL possesses the functions of enhancing immune function, regulating the gastrointestinal tract, resisting liver injury and lowering blood sugar levels. Recently, dendrobine (DDB), the principal bioactive component of DNL, has been identified to exhibit hepatoprotective effects. However, the therapeutic effects and mechanisms of DDB in the context of non-alcoholic fatty liver disease (NAFLD) remain largely unexplored.
    AIM OF THE STUDY: The aim of this study was to investigate the role of mitochondrial fission in the model of high-fat diet (HFD) and palmitic acid (PA)-induced NAFLD and determine whether DDB protects against NAFLD by inhibiting dynamin-related protein 1 (Drp1)-mediated mitochondrial fission.
    MATERIALS AND METHODS: In this study, NAFLD models in vivo and in vitro were established in C57BL/6J mice and AML12 cells through HFD and PA, respectively. Animal ultrasound, hepatic histopathological examination and serum biochemical analysis were employed to evaluate liver fat accumulation and damage. RNA-sequencing was conducted to explore the changes in gene expression in NAFLD. Transmission electron microscope, ATP and JC-1 were applied to assess mitochondrial function. Western blotting and immunofluorescence were utilized to elucidate the regulatory effect of DDB on Wnt5a/p-CaMKII pathway and mitochondrial fission. Molecular docking, PoseView and cellular thermal shift assay were employed to further validate the molecular mechanism of DDB binding to Wnt5a.
    RESULTS: DDB administration significantly inhibited body/liver weight gain and hepatic fat accumulation in NAFLD mice, reducing TG and TC levels in serum, and improving mitochondrial function. RNA-sequencing highlighted energy metabolism regulation and noncanonical Wnt signaling pathways as key roles of DDB played in the treatment of NAFLD. The in vivo experimental results showed that DDB inhibited the Wnt5a/p-CaMKII pathway and p-Drp1 mediated mitochondrial fission. Further in vitro experiments demonstrated that inhibition of Drp1 and Wnt5a was essential for DDB-mediated liver protection, thereby suppressing mitochondrial fission and alleviating lipid accumulation in AML12 cells. Role of Wnt5a/p-CaMKII/p-Drp1 signaling in mitochondrial fission was further characterized using Drp1 and Wnt5a inhibitors, namely Mdivi-1 and Box5, both of which exhibited a similar hepatoprotective mechanism as DDB. Additional studies unraveled that DDB binding to Wnt5a led to a reduction in the thermal stability of Wnt5a protein and acted as its antagonist to block the noncanonical Wnt pathway mediated by Wnt5a.
    CONCLUSIONS: This study reveals that DDB mitigates mitochondrial fission mediated by p-Drp1 through the inhibition of the Wnt5a/p-CaMKII signaling pathway, thereby improving lipid metabolism and alleviating NAFLD.
    Keywords:  Dendrobine; Mitochondrial fission; Non-alcoholic fatty liver disease; Wnt5a/CaMKII signaling; p-Drp1
    DOI:  https://doi.org/10.1016/j.jep.2026.121445
  28. Clin Exp Pharmacol Physiol. 2026 Mar;53(3): e70114
    Ajugoside Promotes the Repair of Osteoporotic Bone by Inducing Osteogenic Differentiation of Bone Marrow Mesenchymal Stem Cells.
    Ruifeng Yang, Chong Wang, Panpan Xie, Jifei Ye, Shuming Huang.
      Bone marrow mesenchymal stem cells (BMSCs) are multipotent cells that play a critical role in bone formation and are vulnerable to oxidative stress-induced dysfunction in osteoporosis (OP). This study investigates the pro-osteogenic potential of ajugoside, a naturally occurring iridoid monoterpene from Ajuga reptans, through a two-phase experimental design involving both in vitro and in vivo models. In the in vitro phase, an oxidative stress model was established in BMSCs using H2O2, followed by ajugoside treatment or lentiviral overexpression of solute carrier family 5 member 1 (Slc5a1). Cell viability, osteogenic differentiation, oxidative stress, and mitophagy were assessed. In the in vivo phase, an ovariectomy-induced OP mouse model was utilized to examine the therapeutic effects of ajugoside, resveratrol (a positive control), or adeno-associated virus-mediated Slc5a1 overexpression. Ajugoside inhibited Slc5a1 expression and activated AMPK signalling, leading to enhanced mitophagy and reduced oxidative stress. Ajugoside demonstrated a significant capacity to alleviate H2O2-induced injury in BMSCs, exhibiting a comparable mitigating effect on oxidative stress and mitophagy impairment in OP mice. However, the reactivation of Slc5a1 led to the reversal of these effects. Collectively, these findings demonstrate that ajugoside promotes osteogenic differentiation by suppressing Slc5a1 and activating AMPK-mediated mitophagy, offering a promising therapeutic strategy for OP.
    Keywords:  ajugoside; bone marrow mesenchymal stem cells; mitophagy; osteoporosis; oxidative stress
    DOI:  https://doi.org/10.1111/1440-1681.70114
  29. J Ginseng Res. 2026 Mar;50(2): 100973
    Rg1-R1 attenuates cardiac ischemia/reperfusion-induced endothelial cell injury through activating the ULK1/PGAM5-FUNDC1-mitophagy pathway.
    Xiayinan Song, Jinlan Deng, Danyang Wang, Zhenzhen Zheng, Chao Li, Jie Li.
       Background: Mitochondrial dysfunction has been recognized as a pivotal pathological mechanism underlying myocardial ischemia/reperfusion injury (MIRI).Ginsenoside Rg1 and notoginsenoside R1 exhibits cardioprotective effects against MIRI. However, their molecular mechanisms remain unclear. This study aims to investigate the therapeutic potential of Rg1 and R1 in ameliorating cardiomyocyte injury through mitophagy regulation, with a focus on elucidating the molecular crosstalk between these compounds and key mitophagy-related signaling pathways.
    Methods: Cardiac injury in mice was induced by subjecting the heart to 45 min of ischemia followed by 6 h of reperfusion. Post-injury, the mice were treated with intraperitoneal injections of Rg1-R1. The effects of Rg1-R1 on MIRI were assessed through electrocardiography, echocardiography, HE/Masson staining, and Transmission Electron Microscope. The impact of Rg1-R1 on biochemical markers of myocardial injury was also analyzed. Cardiac microvascular endothelial cells (CMECs) were pretreated with Rg1-R1 prior to being exposed to hypoxia/reoxygenation (H/R). Subsequently, cellular function and mitochondrial function were evaluated.
    Results: Our results indicated that in vivo, Rg1-R1 improved MIRI-induced cardiac dysfunction; in vitro, exposure of CMECs to Rg1-R1 reduced H/R injury severity and protected mitochondria. Further studies illustrated the protective effect of Rg1-R1 achieved via the regulation of FUNDC1-mediated mitophagy. In addition, we found that Rg1-R1 exerted these protective effects by activating FUNDC1-dependent mitophagy through the ULK1/PGAM5 pathway.
    Conclusions: Our results indicated that Rg1-R1 attenuates MIRI-induced endothelial cell injury through activating the ULK1/PGAM5-FUNDC1-mitophagy pathway, and may represent a novel therapeutic target in the context of MIRI.
    Keywords:  CMEC; FUNDC1; MIRI; Mitophagy; Rg1-R1
    DOI:  https://doi.org/10.1016/j.jgr.2025.100973
  30. Mol Biol Rep. 2026 Mar 04. pii: 461. [Epub ahead of print]53(1):
    Shikonin alleviates high-fat diet-induced vascular aging and dysfunction by inhibiting oxidative stress and mitochondrial damage.
    Guang-Qiu Ren, Hui-Jun Liu, Ya-Qi Guo, Mei-Ling He, Jiao Li, Zhan-Xia Li, Chen-Hui Jia, Tong Liu, Jing Yang.
      
    Keywords:  High-fat diet; Mitochondrial dynamics; Shikonin; Vascular aging; Vascular dysfunction
    DOI:  https://doi.org/10.1007/s11033-026-11626-z
  31. Curr Gene Ther. 2026 Feb 26.
    Discovery of Genes Related to Cuproptosis and Mitophagy to Improve Myocardial Infarction Diagnosis and Treatment.
    Fenlong Xue, Yuhui Zhang, Chao Chang, Qingliang Chen.
       INTRODUCTION: Emerging evidence links cuproptosis and mitophagy to the progression of myocardial infarction (MI). This study explored cuproptosis- and mitophagy-related gene modules in MI, aiming to identify potential biomarkers to improve MI management.
    METHODS: The GSE66360 dataset, containing 50 control and 49 MI samples, was obtained from GEO. Differentially expressed genes (DEGs) were identified using the "limma" 3.42.2 package, and pathway differences were analyzed via gene set enrichment analysis (GSEA). After clustering gene modules related to cuproptosis and mitophagy using weighted gene co-expression network analysis (WGCNA), core modular genes were selected. LASSO regression and random forest were employed for feature selection. Immune microenvironment profiling was conducted using singlesample GSEA (ssGSEA) and CIBERSORT algorithms. Finally, potential therapeutic targets were identified using DSigDB and molecular docking.
    RESULTS: We identified the DEGs between MI and control samples. GSEA analysis showed that these genes were associated with the cell cycle, glycolysis, and the inflammatory signaling pathway. The dark green module identified by WGCNA was correlated with both cuproptosis and mitophagy and enriched in oxidative phosphorylation and immune processes. By combining the core modular genes and DEGs, six hub genes were selected using LASSO and random forests. A 3-gene diagnostic model established based on GPCPD1, S100A8, and CD55 achieved an Area under the Curve (AUC) of 0.959. The three genes were upregulated in MI and correlated with immune infiltration. Molecular docking showed Corbadrine and Dicyclomine were potential therapeutic agents targeting CD55.
    DISCUSSION: This study highlights the broader implications of linking cuproptosis and mitophagy in MI, proposing a novel perspective on mitochondrial dysfunction as a central hub connecting metabolic stress, immune dysregulation, and cell death. The identified core genes-S100A8, CD55, and GPCPD1-not only serve as potential diagnostic markers but may represent functional nodes at the intersection of copper-dependent cell death and mitochondrial quality control. Their strong association with inflammatory cell infiltration suggests that these genes could influence the post-MI immune microenvironment, potentially affecting both injury progression and repair. Moreover, the feasibility of targeting CD55, as indicated by molecular docking, opens new avenues for therapeutic interventions to modulate complement activation and inflammation. While the findings are computationally derived, they generate testable hypotheses about crosstalk between emerging cell death pathways and immune-metabolic pathways in MI, underscoring the need for future experimental studies to validate these interactions and explore their translational potential in cardiovascular disease.
    CONCLUSION: The core genes (GPCPD1, S100A8, and CD55) identified in this study not only served as potential diagnostic markers but were also functional nodes in copper-dependent cell death, contributing to MI treatment.
    Keywords:  Myocardial infarction; cuproptosis; immune infiltration; mitophagy; molecular docking.
    DOI:  https://doi.org/10.2174/0115665232440699251209120654
  32. Mutat Res. 2026 Feb 19. pii: S1386-1964(26)00001-1. [Epub ahead of print]832 111928
    Characterization of pathogenic missense mutations in nuclear encoded mitochondrial dynamin -1 like protein.
    Kaniha Sivakumar, Nihala Sidhic, Usha Subbiah, Sudhan Mookkandi.
       BACKGROUND: The DNM1L gene encodes the dynamin-related protein, Drp1, essential for mitochondrial fission. Impaired mitochondrial division contributes to cardiovascular, neurodegenerative, and metabolic disorders. This study aimed to identify and analyse deleterious nonsynonymous single nucleotide polymorphisms (nsSNPs) in DNM1L that may impair protein function.
    METHODS: An integrated in silico strategy combining multiple predictive tools (SIFT, PolyPhen-2, PhD-SNP, PANTHER, Meta-SNP, FATHMM, I-Mutant 2.0, INPS-MD, Medusa, MutPred2, DynaMut2, ConSurf, NetSurfP-2.0, STRING, GeneMANIA) was used to identify deleterious nonsynonymous SNPs (nsSNPs) in DNM1L and evaluate their structural and functional effects.
    RESULTS: Eleven nsSNPs (A395D, V417G, R60W, etc.) were consistently predicted to be pathogenic. These variants occurred at conserved residues and induced significant changes in protein stability, flexibility, and interaction potential. Functional annotations suggested possible alterations in metal binding, secondary structure, and post-translational modifications.
    CONCLUSION: The identified DNM1L variants may compromise Drp1 function and contribute to mitochondrial dysfunction underlying disease mechanisms. This study provides a computational basis for future experimental validation and clinical exploration of DNM1L-associated disorders. These variants may underlie mitochondrial dysfunction contributing to neurodegenerative and metabolic disorders.
    Keywords:  Analysis; DNM1L; Drp1; Mitochondrial fission; NsSNPs; Pathogenic variant prediction; Protein stability
    DOI:  https://doi.org/10.1016/j.mrfmmm.2026.111928
  33. Front Cardiovasc Med. 2026 ;13 1755024
    Uncovering mitochondrial dynamics-related genes as potential diagnostic biomarkers for acute myocardial infarction.
    Xiaolin Yue, Jinlei Wu, Xueyun Shi, Youshun Xu, Xiaowei Han, Ruijian Li.
       Introduction: Mitochondrial dynamics play a vital role in maintaining cardiac energy balance and cellular homeostasis. Increasing evidence suggests that dysregulated mitochondrial dynamics contribute to the development of acute myocardial infarction (AMI). However, the underlying molecular mechanisms and related biomarkers remain largely unclear.
    Methods: In this study, transcriptomic profiling of AMI and control samples was used to identify mitochondrial dynamics-associated genes (MD-RGs) linked to AMI progression. Based on the expression of 50 curated MD-RGs, AMI samples were classified into molecular subgroups using single-sample gene set enrichment analysis (ssGSEA). Differentially expressed genes were integrated into multiple machine learning models to identify potential diagnostic biomarkers. Expression validation and receiver operating characteristic (ROC) analyses were performed to assess diagnostic accuracy. Functional enrichment, immune infiltration, and N6-methyladenosine (m6A) regulator correlation analyses were conducted to explore biological mechanisms. Key cell types were identified through single-cell RNA sequencing (scRNA-seq) analysis, and biomarker expression was validated by reverse transcription quantitative PCR (RT-qPCR) in patient-derived samples.
    Results: Two genes, COX7B and SNORD54, were identified as novel biomarkers associated with mitochondrial dynamics in AMI. ROC and nomogram analyses confirmed their strong diagnostic performance. Enrichment analysis revealed shared pathways including oxidative phosphorylation and Notch signaling, while six m6A regulators (HNRNPC, KIAA1429, METTL3, WTAP, YTHDC1, and YTHDC2) were markedly downregulated, suggesting possible epigenetic involvement. RT-qPCR confirmed reduced expression of COX7B and SNORD54 in AMI tissues. Single-cell analysis further identified monocytes and natural killer (NK) cells as key cell types linked to these biomarkers.
    Discussion: Collectively, this study identifies COX7B and SNORD54 as mitochondrial dynamics-related biomarkers and highlights the role of monocytes and NK cells in AMI, offering new insight into mitochondrial dysfunction-driven cardiac injury and potential targets for precision diagnosis and therapy.
    Keywords:  acute myocardial infarction; biomarkers; machine learning; mitochondrial dynamics; regulatory network; single-cell RNA sequencing
    DOI:  https://doi.org/10.3389/fcvm.2026.1755024
  34. Front Pharmacol. 2026 ;17 1748360
    Dimethyl fumarate and mitochondrial physiology: implications for neurological disorders.
    Marcos Roberto de Oliveira.
      Dimethyl fumarate (DMF; C6H8O4) is an ester of fumaric acid widely used in clinical practice for the treatment of relapsing forms of multiple sclerosis and plaque psoriasis. Beyond its established immunomodulatory actions, DMF is increasingly recognized as a small molecule capable of reshaping cellular redox homeostasis and mitochondrial physiology. Mitochondria are double-membrane organelles that integrate energy metabolism, calcium buffering, and apoptosis regulation, while also generating reactive oxygen species that function as signaling mediators. Given their central role in neuronal survival and function, mitochondrial integrity is a critical determinant of neuroprotection. The aim of this review is to discuss the mechanistic aspects by which DMF influences mitochondrial physiology in central nervous system (CNS) cells, based on evidence from experimental models and patient-derived samples. Data consistently show that DMF activates the Nrf2 pathway, leading to increased expression of antioxidant enzymes (e.g., NQO-1, HO-1) and induction of mitochondrial biogenesis markers (e.g., PGC-1α, NRF1, TFAM). In neurons and oligodendrocytes, DMF enhances respiratory function and limits apoptosis by modulating BCL-2 family proteins and suppressing cytochrome c release. Disease-relevant studies further demonstrate frataxin upregulation in Friedreich's ataxia and reduction of mitochondrial reactive oxygen species in C9orf72-related models. Conversely, in microglia, T cells, and vascular cells, DMF may impair mitochondrial respiration or increase apoptosis, particularly under inflammatory stress, suggesting a context-dependent effect. In conclusion, DMF exerts multifaceted and cell type-specific actions on mitochondria. Understanding these mechanisms may guide optimized therapeutic strategies and the identification of biomarkers for precision use in neurological disorders.
    Keywords:  dimethyl fumarate; mitochondria; mitochondrial biogenesis; mitochondrial function; mitophagy
    DOI:  https://doi.org/10.3389/fphar.2026.1748360
  35. Chem Biodivers. 2026 Mar;23(3): e03838
    Gentiana szechenyii Kanitz Compounds Regulate Lipopolysaccharide-Induced Inflammation and Mitochondrial Autophagy Via the Toll-Like Receptor 4-Nuclear Factor Kappa B Pathway.
    Haihua Zhang, Zonghao Zhang, Jingwen Hu, Yongfang Li, Xingmei Nan, Fang Yang.
      Inflammation plays a key role in the progression and prognosis of most diseases. Mitochondrial autophagy has been demonstrated to correlate with inflammatory processes. The anti-inflammatory Tibetan medicinal herb Gentiana szechenyii Kanitz (GS) exhibits mechanisms of action in inflammation and mitochondrial autophagy that remain incompletely elucidated. This study aims to elucidate the effects of GS on inflammatory cytokines, oxidative stress, and the TLR4/NF-κB signaling pathway, whilst revealing its potential targeted action in ameliorating inflammatory responses through regulation of the mitochondrial autophagy pathway. The effects of GS on the TLR4/NF-κB pathway were evaluated via enzyme-linked immunosorbent assay (ELISA), flow cytometry, western blotting (WB), and proteomics, whilst investigating the role of mitochondrial autophagy in inflammatory mechanisms. GS significantly reduced cell apoptosis, decreased the release of proinflammatory cytokines and ROS, inhibited the TLR4/NF-κB signaling pathway, and suppressed mitochondrial autophagy, indicating that GS compounds can prevent LPS-induced pathological mitochondrial autophagy. GS exhibits significant anti-inflammatory and antioxidant effects in vitro, with its mechanism of action involving regulation of the TLR4/NF-κB pathway and mitochondrial autophagy markers, thereby alleviating inflammation in RAW264.7 cells. This study provides valuable insights into the potential therapeutic mechanisms of GS in inflammatory diseases.
    Keywords:  Gentiana szechenyii Kanitz; RAW264.7 cells; inflammation; mitochondrial autophagy
    DOI:  https://doi.org/10.1002/cbdv.202503838
  36. Sci Rep. 2026 Mar 04.
    Resveratrol alleviates neuropathic pain associated with restoration of mitochondrial fission-fusion balance in CCI mice.
    Liu Xie, Yiran Xu, Qingqing Yang, Wanting Chang, Linna Song, Yanyan Sun.
      
    Keywords:  DRG; Fission and fusion; Mitochondrial; Neuropathic pain; Oxidative stress; Resveratrol
    DOI:  https://doi.org/10.1038/s41598-026-41965-7
  37. Am J Physiol Cell Physiol. 2026 Mar 04.
    MITOCHONDRIA IN MUSCLE STEM CELL BIOLOGY: GATEKEEPERS OF FATE, FUNCTION, AND REGENERATION.
    Mireille Khacho, Yan Burelle.
      Muscle stem cells (MuSCs) are essential for muscle regeneration, but their function declines with aging 1-4, neuromuscular disorders5-8 , and non-genetic muscle-wasting conditions9 . Their regenerative capacity is also influenced by environmental factors, including dietary changes such as high-fat diets and diabetes 10-12, impacting their ability to restore muscle integrity. Understanding the mechanisms that regulate MuSC function is thus crucial for developing strategies to preserve muscle health and improve regenerative potential in both physiological and pathological contexts. Recent advances have unveiled a crucial role for mitochondria in controlling MuSC quiescence, fate decisions, and differentiation into myofibers. Several studies have now shown that disruption of mitochondrial function, through genetic or pharmacological means, leads to dysregulation of MuSC functions and impaired myogenic lineage progression. Mitochondrial abnormalities in MuSCs have also been shown to contribute to the loss of regenerative capacity observed in conditions such as aging, sepsis, in myopathies. Together, this evidence and others have sparked great interest for understanding how these organelles regulate MuSC behavior and exploring the therapeutic potential of mitochondria targeted therapies to improve or maintain muscle regeneration. This review aims to provide a comprehensive overview of the role of mitochondria in regulating MuSC quiescence, fate decisions and myogenesis under both normal and diseased conditions. It summarizes current knowledge, highlights existing gaps, and explores emerging areas related to bioenergetic properties and metabolic signaling, mitochondrial network dynamics, quality control, and inter-organelle cross-talk across different MuSC states. It also discusses potential therapeutic strategies targeting mitochondrial function to enhance MuSC regenerative capacity and counteract muscle degeneration.
    Keywords:  Muscle stem cells; metabolism; mitochondrial dynamics; mitophagy; stem cell fate
    DOI:  https://doi.org/10.1152/ajpcell.00027.2026
  38. Eur J Neurosci. 2026 Mar;63(5): e70449
    Mitochondrial-Derived Vesicles: An Emerging Whisperer in Neurological Disorders.
    Nermeen Z Abuelezz, Fayza Eid Nasr, Amira Emad Abd El Aziz, Mariam K Ahmed, Nesrine S El Sayed.
      Mitochondrial dysfunction is a pivotal feature in the pathogenesis of various neurological and neurodegenerative disorders. The brain, with its high metabolic demands, is particularly vulnerable to impaired mitochondrial function, leading to oxidative stress, disturbed calcium homeostasis, and hyperactivated microglial responses. Mitochondrial disturbances majorly contribute to neuronal damage, synaptic dysfunction, and cognitive decline, making mitochondria a crucial target for therapeutic intervention in brain disorders. In this context, mitochondrial-derived vesicles (MDVs) are increasingly emerging as a novel aspect of mitochondrial biology with significant implications for brain health and disease. Prior to mitophagy, MDVs are released from stressed mitochondria, incorporating either healthy or damaged mitochondrial components as an earlier defense mechanism to maintain mitochondrial integrity and homeostasis. Furthermore, MDVs contribute to intercellular communication and extracellular neuroinflammation signaling, potentially influencing the progression of neurological disorders. This review provides a thorough overview of MDVs' subpopulations, highlighting the most recently reported MDVs roles across multiple neurological disorders and exploring their potential in diagnostic and therapeutic settings. Additionally, we further analyze the current limitations that hinder broader clinical applications of MDVs and present future perspectives and key recommendations to overcome these obstacles, aiming to enhance their effectiveness in diagnosis, therapy, and brain-targeted drug delivery.
    Keywords:  mitochondrial communication; mitochondrial dysfunction; mitophagy; neurodegenerative disorders; vesicles
    DOI:  https://doi.org/10.1111/ejn.70449
  39. Sci Adv. 2026 Mar 06. 12(10): eaed3579
    Structural remodeling of the mitochondrial protein biogenesis machinery under proteostatic stress.
    Kenneth Ehses, Jorge P López-Alonso, Odetta Antico, Yannik Lang, Till Rudack, Abdussalam Azem, Miratul M K Muqit, Iban Ubarretxena-Belandia, Rubén Fernández-Busnadiego.
      Cells have evolved organelle-specific responses to maintain protein homeostasis (proteostasis). During proteostatic stress, mitochondria down-regulate translation and enhance protein folding, yet the underlying mechanisms remain poorly defined. Here, we used cryo-electron tomography to observe the structural consequences of mitochondrial proteostatic stress within human cells. We detected protein aggregates within the mitochondrial matrix, accompanied by a marked remodeling of cristae architecture. Concomitantly, the number of mitochondrial ribosome complexes was significantly reduced. Mitochondrial Hsp60 (mHsp60), a key protein folding machine, underwent major conformational changes to favor complexes with its co-chaperone mHsp10. We visualized the interactions of mHsp60 with native substrate proteins and determined in vitro mHsp60 cryo-electron microscopy structures enabling nucleotide state assignment of the in situ structures. These data converge on a model of the mHsp60 functional cycle and its essential role in mitochondrial proteostasis. More broadly, our findings reveal structural mechanisms governing mitochondrial protein biosynthesis and their remodeling under proteostatic stress.
    DOI:  https://doi.org/10.1126/sciadv.aed3579
  40. Mol Med. 2026 Feb 28. pii: 32. [Epub ahead of print]32(1):
    Correction: Bavachin ameliorates cisplatin-induced nephrotoxicity by enhancing mitochondrial β-oxidation and lipid metabolism through MFN2.
    Shilu Luo, Ming Yang, Na Jiang, Chenrui Li, Yan Liu, Lin Sun.
      
    DOI:  https://doi.org/10.1186/s10020-026-01443-2
  41. ACS Nano. 2026 Mar 03.
    Extracellular Vesicle-Mediated Precision Delivery of Paclitaxel Activates Mitophagy to Promote Repair after Spinal Cord Injury.
    Shuxian Zhao, Liqun Duan, Zuogang Lv, Zhiqiang Han, Wenbin Xu, Kaikai Zhang, Wei Liu, Jiaxiang Bai, Weihua Cai, Wenzhi Zhang, Yufeng Gao, Yuluo Rong.
      Spinal cord injury (SCI) is a debilitating disorder characterized by intricate pathological processes that result in severe motor and sensory deficits. Existing therapeutic approaches remain insufficient to achieve comprehensive functional restoration, indicating the necessity of alternative treatment strategies. In this study, an advanced nanoparticle-based drug delivery system was established using extracellular vesicles (EVs) modified with a matrix metalloproteinase (MMP)-responsive peptide, ACPP, to achieve the targeted delivery of paclitaxel (PTX). The ACPP-EVs@PTX formulation integrates the drug loading capacity of EVs, the lesion-targeting capability conferred by ACPP, and the neuroprotective properties of PTX. Enhanced accumulation of PTX at the SCI lesion site was achieved, accompanied by a reduction in the off-target distribution. Both in vitro and in vivo experiments demonstrated marked therapeutic efficacy of ACPP-EVs@PTX through modulation of the SCI microenvironment, including stimulation of angiogenesis, attenuation of inflammatory responses, alleviation of oxidative stress, and promotion of axonal regeneration. In addition, the activation of PINK1-Parkin-mediated mitophagy was observed, leading to improved mitochondrial function and enhanced neuronal repair. Behavioral evaluations further confirmed significant recovery of neurological function, supporting the translational potential of this multitarget, synergistic therapeutic strategy. Collectively, this work establishes an integrated therapeutic strategy for spinal cord repair and supports its translational potential.
    Keywords:  ACPP-modified system; extracellular vesicles; mitophagy; multitarget drug delivery; paclitaxel; spinal cord injury
    DOI:  https://doi.org/10.1021/acsnano.5c21273
  42. Cell Mol Immunol. 2026 Mar 04.
    Tofacitinib repairs inflammation and mitochondrial dysregulation in GM-CSF-reprogrammed RA macrophages.
    Neha Satoeya, Stephanie R Zack, Osama Al Zoubi, Sadiq Umar, Adel Burgos, Sara Abdulrab, Brian Zanotti, Michael V Volin, Joseph A Karam, Yinglin Xia, Diana C Umali, Shiva Arami, Mina Al-Awqati, Huan T Chang, Luke A J O'Neill, Georg Schett, Nadera Sweiss, Shiva Shahrara.
      Rheumatoid arthritis (RA) exhibits heterogeneous endotypes, complicating treatment strategies. GM-CSF and GM-CSFRα are enriched in RA synovial CD68⁺macrophages (MΦs), and are implicated in acute and chronic disease stages. Since anti-TNFi and anti-IL6R therapies did not effectively suppress GM-CSF/GM-CSFRα expression or the GM-CSF-associated landscape, we explored alternative therapeutic strategies to target GM-CSF function using RA blood, synovial tissues, and preclinical models. We demonstrate that GM-CSF-MΦs reprogrammed in RA blood and synovial tissue share a distinct IL1β⁺S100A⁺HIF1⁺IL10ˡᵒNFIL3/6ˡᵒ expression profile, manifested by mitochondrial oxidative stress and fragmentation. To correct the metabolic imbalance of GM-CSF-MΦs, cells were treated with a complex I inhibitor (i) or a glucose uptake blocker. Complex Ii did not broadly alter the inflammatory or metabolic networks or affect the mitochondrial dynamics remodeled by GM-CSF-MΦs. While the glucose uptake inhibitor (HK2i) reduced glycolysis-derived ATP, it had limited efficacy in restricting the inflammatory signature or restoring TCA enzymes in GM-CSF-MΦs. In contrast, tofacitinib achieved broad-spectrum effects by downregulating GM-CSFRα expression and inhibiting STAT5 signaling. Moreover, tofacitinib redirected RA blood and synovial IL1β⁺S100A⁺HIF1⁺IL10ˡᵒNFIL3/6ˡᵒMΦs into a regulatory phenotype, reversing oxidative stress and mitochondrial fragmentation. In preclinical models, local GM-CSF overexpression induced MΦ-directed joint inflammation and metabolic dysregulation. Consistently, Tofacitinib reversed GM-CSF-differentiated murine IL1β⁺HBEGF⁺HIF1⁺MΦs by impeding STAT5 signaling, correcting metabolic dysregulation, and repairing mitochondrial fragmentation. In conclusion, anti-TNFi, anti-IL6R, and metabolic-targeted therapies were largely ineffective in modifying GM-CSF-MΦ pathology. Conversely, tofacitinib deactivation of STAT5 attenuates GM-CSF-MΦ-triggered inflammation and mitochondrial malfunction by restoring regulatory markers and rebalancing oxidative phosphorylation in RA specimens and/or preclinical models.
    Keywords:  GM-CSF; Macrophages; Mitochondrial fragmentation; NFIL3; Oxidative stress
    DOI:  https://doi.org/10.1038/s41423-026-01395-x
  43. Aquat Toxicol. 2026 Feb 24. pii: S0166-445X(26)00068-8. [Epub ahead of print]293 107771
    Transgenerational effects of environmentally relevant concentrations of ibuprofen on Daphnia magna.
    Yuanyuan Xiao, Weiqi Zhao, Chunni Duan, Weibo Gong, Yufei Zhao, Huiyu Zhang, Xiangping Nie.
      The widespread occurrence of ibuprofen in aquatic environments poses potential risks to aquatic organisms. This investigation employed a multigenerational exposure approach to address the transgenerational toxicity of ibuprofen in Daphnia magna across an environmentally observed to upper end concentration range (0.5-500 μg/L). The experimental design encompassed direct F0 exposure, continuous exposure until F3 (F3C), and cessation-of-exposure in F3 (F3R). Ibuprofen exposure significantly compromised growth and reproductive capacity of Daphnia magna, induced morphological deformities including tail spine curvature and eyes abnormalities, impaired swimming behavior like the decreased speed and distance. In particularly, these adverse effects persisted across generations, manifesting in both F3C and F3R lineages. The investigations revealed that ibuprofen disrupted endocrine signaling pathways critical for molting and reproduction (EcR, CYP314, VTG) through COX inhibition, alongside mitochondrial dynamic imbalance and oxidative stress. Whole-genome bisulfite sequencing demonstrated generation-specific DNA methylation patterns: widespread epigenetic disruption in F0, "adaptive reprogramming" in F3C, and "transgenerational imprinting" in F3R. Differential methylation in key pathways (FOXO signaling, autophagy, actin organization) provided compelling epigenetic evidence for the observed transgenerational toxicity. Overall, the results indicated that measurable adverse effects can occur at environmentally realistic concentrations (0.5-5 μg/L), whereas mechanistic and epigenetic signatures were most evident under upper-end/hotspot scenario exposure (50-500 μg/L), highlighting the value of incorporating multigenerational assessments into ecological risk evaluation frameworks.
    Keywords:  DNA methylation; Daphnia magna; Ibuprofen; Mitochondrial dynamics; Transgenerational toxicity
    DOI:  https://doi.org/10.1016/j.aquatox.2026.107771
  44. J Agric Food Chem. 2026 Mar 05.
    Polystyrene Nanoplastics and Cadmium Co-Exposure Accelerates Mitochondrial Autophagy Mediated by HSP60-SIRT3-SOD2 Signaling Pathway in Primary Duck Embryo Hepatocytes.
    Yan Chen, LuLu Ding, Lin Xiong, Sifan Li, Zehao Wang, Zhili Yu, Yonggang Ma, Xishuai Tong, Haibo Jin, Wei Liu, Hongyan Zhao, Jianhong Gu, Yan Yuan, Jianchun Bian, Zongping Liu, Hui Zou.
      Microplastics (MPs) in the environment frequently act as a medium to adsorb heavy metals and antibiotics. This combined exposure often has a greater effect on animal toxicity than exposure alone. However, there is a paucity of research focusing on the combined toxicity of nanoplastics (NPs) and heavy metals when coexposed to hepatocytes in poultry. In this study, the effects of PS-NPs (0.08 μm, 10 μg/mL) and cadmium chloride (CdCl2) (4 μg/mL) on duck hepatocytes and their mechanisms were observed using primary duck embryo hepatocytes (PDEH) cells as an in vitro model. The results demonstrated that Cd exposure exacerbated the accumulation of PS-NPs in PDEH cells, likely due to the formation of pores on the cell membrane surface. The addition of the antioxidant N-Acetyl-l-cysteine (NAC) significantly reduced the uptake of PS-NPs by PDEH cells. PDEH cells in the coexposed group exhibited significantly abnormal morphology and diminished cell number and survival rate. Furthermore, exposure to PS-NPs exacerbated Cd-mediated oxidative stress and mitochondrial autophagy damage in duck hepatocytes. The restoration of these injuries was observed in response to intervention with the SIRT3 activator (NRCL, 2 ng/mL). Immunoprecipitation experiments demonstrated that the SIRT3 protein interacted with the SOD2 protein. The present study found that co-exposure of PS-NPs+Cd induced mitochondrial autophagy in PDEH cells, which may be mediated by the HSP60/SIRT3/SOD2 signaling axis. It is hoped that these findings will provide new ideas for combating the mechanism of microplastics and Cd-induced hepatotoxicity in poultry.
    Keywords:  SIRT3; cadmium; mitochondrial autophagy; nanoplastics; primary duck embryo hepatocytes
    DOI:  https://doi.org/10.1021/acs.jafc.5c12247
  45. Physiol Rep. 2026 Mar;14(5): e70790
    Lactate supplementation modulates molecular and functional responses during chronic neuromuscular electrical stimulation in male rats.
    Toshinori Yoshihara, Yasushi Koriyama, Sakura Ogawa, Hisashi Naito.
      Lactate is increasingly recognized as a signaling molecule that modulates muscle plasticity. We examined the effects of oral L-sodium lactate supplementation on skeletal muscle adaptation to chronic neuromuscular electrical stimulation (NMES) in rats. Male Wistar rats received oral lactate or water before either a single NMES session (acute) or repeated sessions over 2 weeks (chronic). We assessed muscle weight, strength, myonuclear-associated protein expression (PCM1), protein synthesis (puromycin incorporation), signaling responses (mechanistic target of rapamycin pathway), and mitochondrial-related protein expression (PGC-1α, OXPHOS, and citrate synthase). The oxidative soleus and glycolytic plantaris muscles were analyzed. Lactate supplementation was associated with greater increases in muscle mass and torque during chronic NMES, particularly in the soleus. PCM1 abundance and myofibrillar puromycin incorporation were higher in the lactate-supplemented group, although there were no significant changes in c-Myc or rpS6. PGC-1α expression was elevated in the plantaris muscle, indicating muscle-type-specific mitochondrial modulation. However, the expression levels of the lactate transporters (MCT1 and MCT4) and GPR81 remained largely unchanged in response to oral lactate. Collectively, these findings suggest that oral lactate is associated with distinct molecular signatures and functional outcomes during chronic NMES in a muscle type-dependent manner, warranting further studies using morphological and muscle-specific functional assessments.
    Keywords:  lactate supplementation; mitochondrial biogenesis; myonuclear; neuromuscular electrical stimulation; protein synthesis
    DOI:  https://doi.org/10.14814/phy2.70790
  46. J Asian Nat Prod Res. 2026 Mar 04. 1-17
    Reno-protective mechanisms of curcumin in diabetic nephropathy.
    Qi Wei, Yang Liu, Wen-Hui Wu, Na Hao.
      Curcumin has a pivotal role in diabetic nephropathy (DN), intervening in its progression through molecular, pathological, and clinical levels. This review systematically summarizes how curcumin modulates multiple pathways, ameliorates pathological alterations, and improves the metabolic disorders in DN. However, its clinical efficacy is constrained by low bioavailability. Consequently, this work provides novel perspectives for the multidimensional intervention of DN and offers strategies for optimizing drug delivery systems.
    Keywords:  Curcumin; diabetic nephropathy; endoplasmic reticulum stress; ferroptosis; mitochondrial homeostasis
    DOI:  https://doi.org/10.1080/10286020.2026.2627010
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