bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2026–05–10
sixty-four papers selected by
Gavin McStay, Liverpool John Moores University
  1. Cardioprotective effects of 3-N-Butylphthalide in diabetic cardiomyopathy: focus on balanced mitochondrial dynamics and pyroptosis pathways.
  2. NLRX1 alleviates sepsis-induced acute lung injury by activating mitophagy and suppressing NLRP3 inflammasome activation.
  3. The protective effects of selenium on mitochondrial quality under exogenous and endogenous stressors.
  4. ETS1 targets the SENP2/HSPA8/FUNDC1 axis to ameliorate bronchopulmonary dysplasia by inhibiting mitochondrial damage-induced autophagy.
  5. SIRT1-mediated deacetylation of DRP1 suppresses excessive mitophagy and ameliorates pediatric functional dyspepsia.
  6. Lycopene Attenuates Hexavalent Chromium-Induced Kidney Injury By Modulating PINK1/Parkin-Mediated Mitophagy.
  7. Fluid Restriction Enhances Mitochondrial Stress in Peripheral Blood Mononuclear Cells Following High-Volume Resistance Exercise in Health Young Males.
  8. Significance of mitophagy in reactive oxygen species-dependent neuronal apoptosis triggered by pyrrolidinophenones.
  9. Drp1 regulates mitochondrial health and controls skeletal muscle mass through the Erk1/2-Nur77 pathway.
  10. HIF1-α induces mitochondrial fission in trophoblastic cells during early pregnancy and in preeclampsia.
  11. TREM1 inhibition via LP17 alleviates secondary spinal cord injury by activating AMPKα-PINK1-parkin-dependent microglial mitophagy.
  12. Correction to "Monoamine Oxidase-A Is a Novel Driver of Stress-Induced Premature Senescence Through Inhibition of Parkin-Mediated Mitophagy".
  13. A rule-based simulation model illuminates the role of asymmetric mitochondrial fission on beta-cell health.
  14. Yoda1-activated Piezo1 enhances mitophagy in human gingival fibroblasts to promote maxillofacial wound repair.
  15. Mitochondrial Network Dynamics in Aging: Cellular Mechanisms, Intercellular Communication, and Their Impact on Tissue Adaptability.
  16. The mechanism and therapeutic prospect of HIF-1 α/BNIP3 pathway in regulating mitophagy in tubulointerstitial fibrosis.
  17. ROS-driven mitophagy arrest mediates the anti-glioblastoma activity of Molephantin.
  18. Comment on "Bergapten ameliorates osteoarthritis progression by inhibiting the PI3K/AKT/mTOR pathway to activate mitophagy and suppress pyroptosis".
  19. FTO-mediated m6A demethylation regulates PGC-1α-dependent mitochondrial biogenesis to attenuate aluminum-induced neuronal senescence.
  20. Targeting P2X purinergic receptors with suramin alleviates rotenone-induced Parkinson's-like pathology via modulation of mitophagy and NLRP3-pyroptosis: Comparison with metformin.
  21. The Effect of mascRNA on the Phenotype Transition and Mitophagy in Vascular Smooth Muscle Cells Exposed to Hypoxia.
  22. YOD1 Regulates Neuronal Mitochondrial Unfolded Protein Response Activation by Deubiquitinating DNAJA1 After Subarachnoid Hemorrhage.
  23. Erythropoietin signaling regulated by Rab26 attenuates sepsis-associated lung injury by suppressing macrophage ferroptosis via enhanced mitophagy.
  24. Hepatoprotective Mechanisms of Lactiplantibacillus plantarum SCS7 Cell-Free Extract Against Aflatoxin B1 Toxicity.
  25. Hypoxia-inducible factor-1α: Dual roles in maintaining neuronal homeostasis and neuronal degeneration via regulation of oxidative stress, mitochondrial dynamics, and bioenergetics.
  26. Mitochondrial dynamics and oxidative metabolism: an emerging role for Septin7 in skeletal muscle.
  27. Activation of tripartite motif-containing protein 16 improves cardiac function in aging mice by regulating Mfn2-dependent mitochondrial fusion through Sirt6.
  28. Chiral Covalent Organic Frameworks Trigger Tumor-Specific Mitophagy via Notch/Mitogen-Activated Protein Kinase Pathways and Enantiomer-Dependent Photodynamic Therapy.
  29. Astragaloside IV Enhances Mitophagy to Alleviate Renal Ischemia/Reperfusion Injury via PINK1/Parkin Pathway.
  30. Spatial, temporal and sex specific mitochondrial dynamic changes in severe controlled cortical impact mouse model of traumatic brain injury.
  31. Targeting the OPA1 pathway in autosomal dominant optic atrophy (ADOA): 25 years from gene discovery to therapeutic strategy.
  32. Paeonol mitigates age-related osteoporosis via mitophagy-mediated NLRP3 inflammasome inhibition.
  33. Dynamic proximity networks of myosin-19 (Myo19) and its mitochondrial receptors Miro2 and metaxin-3.
  34. Senp1 knockdown alleviates neuronal pyroptosis after subarachnoid hemorrhage by enhancing PINK1-mediated mitophagy.
  35. Paeoniflorin modulates DL-glyceraldehyde metabolism to promote mitochondrial dynamics homeostasis and ameliorate knee osteoarthritis cartilage degeneration.
  36. Mitophagy and Immune Infiltration in Primary Sjögren's Disease: Insights from Bioinformatics Analysis.
  37. Mitochondrial Regulation of Periodontal Ligament Stem Cell Fate and Function.
  38. Advancements in Understanding the Interplay between Mitophagy and Acute Pancreatitis: A Comprehensive Research Overview.
  39. The Role of Phospho-ubiquitin in Mitochondrial Health and Diseases.
  40. Combining multi-omics analysis methods to identify biomarkers for mitophagy involved in immune checkpoint inhibitors-related myocarditis.
  41. Harnessing mitohormesis: A thiazole-based mitochondrial respiration inhibitor restores metabolic homeostasis in type 2 diabetes.
  42. A Straw-Reinforced-Clay-Inspired Composite Hydrogel Promotes Diabetic Bone Regeneration via Driving the Immune-Osteogenic Cascade to Remodel Mitochondrial Homeostasis.
  43. The BTN3A3-TOMM22 axis preserves mitochondrial homeostasis to facilitate HCC stemness and drug resistance.
  44. Mitochondrial fission factor regulates mitochondrial Ca2+ homeostasis and neuronal activity in AgRP neurons.
  45. An integrated anti-aging framework targeting NAD+ homeostasis, mitochondrial quality control, and redox stability: Roles of NMN/NR, PQQ, and EGT.
  46. A Standardized Onion Peel-Derived Bioactive Ingredient Attenuates Palmitate-Induced Steatosis and Oxidative Stress by Modulating Mitochondrial Dynamics and Autophagy in HepG2 Cells.
  47. Metformin attenuates lens epithelial cell senescence by suppressing cGAS-STING via SIRT1-PGC-1α-mediated mitochondrial fission.
  48. Physalin A Restores Redox and Mitochondrial Homeostasis to Protect against Diabetic Retinopathy.
  49. Oleocanthal Induces Mitochondrial Dysfunction in Breast Cancer Cell Lines Depending on c-MET Expression.
  50. The c-Abl-RIPK3 Axis Drives Mitochondrial Dysfunction and Impaired Mitophagy in Gaucher Disease Models.
  51. Mitochondrial dysfunction-ferroptosis crosstalk drives renal fibrosis in chronic kidney disease.
  52. Vitamin E alleviates energy stress-induced injury in yak granulosa cells by blocking the AMPK/mTOR-mitophagy-ferroptosis axis.
  53. Leveraging mitochondrial dynamics-related risk signatures to predict the prognosis and tumor microenvironment of lung adenocarcinoma.
  54. Juyuanjian attenuates sarcopenia through dual regulation of the Akt/FoxO1 and SIRT1/PGC-1α pathways.
  55. Time-resolved tmFRET reveals GTP-coupled conformational changes in Mfn1.
  56. Mitochondrial dynamics in skin health and disease: energy, aging, and therapeutic perspectives.
  57. Targeting the PI3K/Akt/mTOR and Nrf2 signaling axis with berberine: a novel strategy for attenuating diabetic cardiomyopathy.
  58. Cuproptosis and Mitophagy Mediated by the THUMPD1/IGF2R-Dependent Suppression of AKT and Activation of AMPK Signaling Suppress Lung Adenocarcinoma Progression.
  59. STREMI: a dual-function upstream ORF-encoded regulator of mitochondrial cristae architecture.
  60. Triose phosphate isomerase 1 remodels mitochondrial cristae ultrastructure to rewire microglial immunometabolism against ischemic stroke.
  61. Morin hydrate mitigates renal ischemia-reperfusion injury in association with modulation of TXNIP/NLRP3 inflammasome signaling and FOXO1/PGC-1α-mediated mitochondrial regulation.
  62. Synphilin-1 Is Essential for Cytoskeletal Integrity of Brain Ventricular Cilia and Mitochondrial Proteostasis.
  63. The trypanosomatid dynamin-like protein associates with glycosomes.
  64. Cynandione A improves white adipose tissue homeostasis in high-fat diet-fed mice.
  1. Korean J Physiol Pharmacol. 2026 May 06.
    Cardioprotective effects of 3-N-Butylphthalide in diabetic cardiomyopathy: focus on balanced mitochondrial dynamics and pyroptosis pathways.
    Huaning Xie, Shaik Althaf Hussain, Narendra Maddu, Jing An.
      Diabetic cardiomyopathy (DCM) is a severe complication of diabetes, marked by myocardial dysfunction due to mitochondrial dysfunction and pyroptosis. 3-N-Butylphthalide (NBP), known for cardioprotective effects, remains unstudied in DCM. We evaluated NBP's therapeutic potential in a rat model of type 2 DCM, focusing on mitochondrial dynamics, mitophagy, and pyroptosis. Male Sprague-Dawley rats with DCM, induced by a high-fat diet and streptozotocin, were divided into five groups: control, DCM, DCM + NBP (100 mg/kg/day for 14 days' post-diabetes), DCM + Mdivi-1 (1.2 mg/kg/day), and DCM + NBP + Mdivi-1. Cardiac function was assessed by echocardiography; myocardial injury, histopathology, inflammasome-pyroptosis activation, mitophagy, mitochondrial dynamics, and function were analyzed via ELISA, hematoxylin and eosin staining, transmission electron microscopy, Western blot, and biochemical assays. DCM rats showed reduced ejection fraction and fractional shortening, increased left ventricular end-diastolic and systolic diameters, elevated cTnI and BNP, and histopathological damage. Inflammasome and pyroptosis markers (NLRP3, cleaved-caspase-1, ASC, GSDMD-N, IL-1β, LDH) increased, mitophagy (PINK1, Parkin) decreased, and mitochondrial function (ROS up, ATP down) worsened in DCM group. NBP improved cardiac function, reduced injury markers, and histopathology by suppressing inflammasome-pyroptosis, enhancing mitophagy, and restoring mitochondrial function and dynamics (Mfn2 up, Drp1 modulated). Co-treatment with Mdivi-1 attenuated these effects, indicating reliance on balanced mitochondrial dynamics. NBP mitigates DCM by enhancing mitochondrial homeostasis and inhibiting pyroptosis, but its efficacy diminishes with excessive fission inhibition. These findings suggest NBP's potential as a DCM therapy, meriting further clinical exploration.
    Keywords:  3-N-Butylphthalide; Diabetic cardiomyopathy; Mitochondrial dynamics; Mitophagy; Pyroptosis
    DOI:  https://doi.org/10.4196/kjpp.25.294
  2. Front Pharmacol. 2026 ;17 1797066
    NLRX1 alleviates sepsis-induced acute lung injury by activating mitophagy and suppressing NLRP3 inflammasome activation.
    Zilong Hu, Jing Ding, Meng Huo, Yuqing Lu, Rui Wang, Liyuan Zhang, Dawei Li.
       Background: Sepsis-induced acute lung injury (ALI) is a life-threatening condition with limited therapeutic options. The mitochondrial protein NOD-like receptor X1 (NLRX1) has emerged as a potential immunometabolic modulator, but its functional role and mechanism in septic ALI remain poorly defined.
    Methods: Bioinformatic analysis was performed on the GSE4607 sepsis dataset. A murine model of sepsis-induced ALI was established using cecal ligation and puncture (CLP), with NLRX1 overexpression achieved through adeno-associated virus serotype 9 (AAV9)-mediated gene delivery. Histopathological evaluation, TUNEL staining, and transmission electron microscopy, ELISA were employed to assess lung injury. Mouse lung epithelial cells (MLE-12) were stimulated with lipopolysaccharide (LPS), combined with NLRX1 overexpression and Mdivi-1-mediated mitophagy inhibition to explore the key mechanism by which NLRX1 improves ALI.
    Results: NLRX1 was significantly downregulated in septic patients and mouse lungs, correlating with mitochondrial damage and NOD-like receptor protein 3 (NLRP3) inflammasome activation. NLRX1 overexpression in CLP mice attenuated pulmonary injury, edema, inflammation, and systemic cytokine release by enhancing mitophagy and suppressing apoptosis. Mechanistically, NLRX1 directly interacted with LC3B to promote mitophagy, thereby preserving mitochondrial membrane potential, reducing superoxide production and mtDNA release, and maintaining ATP levels. By improving mitochondrial homeostasis, NLRX1 overexpression indirectly suppressed NLRP3 inflammasome activation and pyroptosis. Crucially, the mitochondrial fission and mitophagy inhibitor Mdivi-1 abolished all beneficial effects of NLRX1, underscoring the essential role of comprehensive mitochondrial quality control.
    Conclusion: Our findings identify NLRX1 as a critical protective regulator of mitochondrial integrity that alleviates septic ALI by orchestrating mitophagy and mitochondrial quality control to restrain NLRP3-driven inflammation, presenting a promising therapeutic target.
    Keywords:  NLRP3; NLRX1; acute lung injury; mitochondrial autophagy; sepsis
    DOI:  https://doi.org/10.3389/fphar.2026.1797066
  3. Chem Biol Interact. 2026 May 05. pii: S0009-2797(26)00244-9. [Epub ahead of print] 112136
    The protective effects of selenium on mitochondrial quality under exogenous and endogenous stressors.
    Anatoly V Skalny, Michael Aschner, Abel Santamaria, Fernando Barbosa, Joao B T Rocha, Feng Zhang, Xiong Guo, Tatiana V Korobeinikova, Alexey A Tinkov.
      Selenium (Se) and selenoproteins play a significant role in preventing mitochondrial damage. Se regulates mitochondrial dynamics, biogenesis, and mitophagy, but the mechanisms by which it controls mitochondrial quality remain to be fully characterized. Thus, the objective of this review is to address the underlying mechanisms of Se in regulation of mitochondrial quality control upon exposure to endogenous and exogenous stressors. Contemporary data show that Se deficiency is associated with a shift from mitochondrial fusion to fission, inhibition of mitochondrial biogenesis via down-regulation of sirtuin 1 (SIRT1)/peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α)/nuclear respiratory factor 1 and 2 (NRF1/2)/mitochondrial transcription factor A (TFAM) signaling, and alterations in PTEN-induced kinase 1 (PINK1)/Parkin-mediated mitophagy in vitro and in vivo. The role of Se in regulating mitochondrial quality control is mediated by specific selenoproteins, as evidenced from experimental selenoprotein knockout and overexpression models. Correspondingly, treatment with various forms of Se attenuates inhibitory effect of endogenous stressors (oxidative stress, ischemia, etc.), as well as exogenous agents like heavy metals, ammonia, fluoride, mycotoxins, and paraquat, on mitochondrial fusion/fission balance and biogenesis. Administration of Se mitigates the adverse effects of these stressors on mitophagy by recovering impaired mitophagy or by inhibiting mitophagy overactivation. Therefore, Se treatment might be considered a therapeutic approach to mitigate the adverse effects of various stressors on mitochondrial quality control and functioning, leading to prevention of liver, kidney, brain, and intestinal damage. However, the specific mechanisms, as well as dose-response and species-specific effects have yet to be investigated.
    Keywords:  fission; fusion; mitochondrial dysfunction; mitophagy; selenium
    DOI:  https://doi.org/10.1016/j.cbi.2026.112136
  4. Arch Biochem Biophys. 2026 Apr 30. pii: S0003-9861(26)00110-4. [Epub ahead of print] 110839
    ETS1 targets the SENP2/HSPA8/FUNDC1 axis to ameliorate bronchopulmonary dysplasia by inhibiting mitochondrial damage-induced autophagy.
    Min Yang, Qinglan Yang, Yanni Meng, Jiyan Zhang, Shuangjie Li.
      Mitochondrial damage and subsequent aberrant mitophagy are critical drivers of alveolar simplification in bronchopulmonary dysplasia (BPD). E26 transformation specific-1 (ETS1) is a transcription factor whose role in BPD and its regulation of mitophagy have not been fully investigated. This study aims to explore the role of ETS1 in mitophagy in BPD and its underlying molecular mechanisms. Using hyperoxia-induced BPD models in cells and mice, we found that ETS1 overexpression simplified alveolar structure, reduced alveolar number, inhibited mitophagy, improved cell viability and mitochondrial damage. Mechanistically, EST1 promoted the transcription of SENP2. After SENP2 removed the SUMO1 modification from FUNDC1, the binding site of HSPA8 was exposed, thereby promoting the degradation of FUNDC1. In BPD mice, ETS1 overexpression alleviated lung injury and inhibited mitophagy, while SENP2 knockdown reversed these effects. In conclusion, ETS1, as a novel transcriptional hub, maintained mitochondrial homeostasis by coordinating the deSUMOylation-coupled FUNDC1 degradation pathway. ETS1 blocked mitochondrial damage-induced mitophagy by targeting the SENP2/HSPA8/FUNDC1 axis, providing a promising strategy for the treatment of BPD.
    Keywords:  Bronchopulmonary dysplasia; Chaperone-mediated autophagy; Mitophagy; SUMOylation
    DOI:  https://doi.org/10.1016/j.abb.2026.110839
  5. BMC Immunol. 2026 May 08.
    SIRT1-mediated deacetylation of DRP1 suppresses excessive mitophagy and ameliorates pediatric functional dyspepsia.
    Shuan Yin, Dongdong Dai, Gaoyan Wang, Shaomei Zhou.
      Functional dyspepsia (FD) is a prevalent gastrointestinal disorder in children, but its underlying molecular mechanisms remain poorly understood. Mitochondrial dysfunction and excessive mitophagy have been implicated in FD, but the underlying mechanisms remain poorly understood. This study aimed to investigate the role of SIRT1 in mitochondrial quality control and its potential therapeutic value in pediatric FD. Serum samples from pediatric FD patients and healthy controls were analyzed for SIRT1 expression and inflammatory cytokines. Human gastric smooth muscle cells (HGSMCs) were treated with carbonyl cyanide m-chlorophenyl hydrazone (CCCP) to induce mitochondrial stress. Mitochondrial function, mitophagy, oxidative stress, and protein interactions were assessed using qPCR, Western blot, co-immunopcipitation, and functional assays including ATP levels, mitochondrial membrane potential, ROS, MDA, SOD, and GSH-Px. The results showed that SIRT1 was significantly downregulated in both pediatric FD patient sera and CCCP-stimulated HGSMCs, accompanied by elevated pro-inflammatory cytokines including IL-6, TNF-α, and IL-1β. Overexpression of SIRT1 improved cell viability, ATP production, mitochondrial membrane potential, and suppressed excessive mitophagy and oxidative stress. Conversely, DRP1 knockdown phenocopied the protective effects of SIRT1, reducing mitophagy and oxidative stress in CCCP-stimulated cells. SIRT1 directly interacted with DRP1 and promoted its deacetylation at lysine 283, leading to accelerated DRP1 degradation. Rescue experiments confirmed that DRP1 overexpression reversed the protective effects of SIRT1 on mitochondrial function and redox homeostasis. In conclusion, SIRT1 exerts protective effects in pediatric FD by deacetylating DRP1 at K283, thereby inhibiting excessive mitophagy and ameliorating mitochondrial dysfunction and oxidative stress. These findings identify the SIRT1-DRP1 axis as a potential therapeutic target for pediatric FD.
    Keywords:  DRP1; Deacetylation; Functional dyspepsia; Mitophagy; SIRT1
    DOI:  https://doi.org/10.1186/s12865-026-00842-8
  6. Biol Trace Elem Res. 2026 May 06.
    Lycopene Attenuates Hexavalent Chromium-Induced Kidney Injury By Modulating PINK1/Parkin-Mediated Mitophagy.
    Quan-Mei Zhang, Xia Zhang, Lun-Bin Xia, Kai Ge, De-Yong She, Shao-Shuai Bi.
      Hexavalent chromium [Cr(VI)] is a well-established environmental nephrotoxicant that induces renal injury. Lycopene (LYC), one of the most potent naturally occurring antioxidants found in plants, has demonstrated protective effects against various forms of oxidative damage; however, its therapeutic role and underlying mechanisms in Cr(VI)-induced nephrotoxicity remain unclear. In this study, eighty female SPF-grade ICR mice were randomly assigned to four groups: control (Con), LYC, Cr(VI), and LYC + Cr(VI), and treated for 28 days. The results demonstrated that LYC significantly alleviated Cr(VI)-induced renal dysfunction and structural damage. Cr(VI) exposure markedly increased malondialdehyde (MDA) and hydrogen peroxide (H₂O₂) levels while suppressing antioxidant enzyme activities, including catalase (CAT), glutathione peroxidase (GSH-Px), and total superoxide dismutase (T-SOD). In contrast, LYC supplementation effectively restored antioxidant capacity and activated the Nuclear factor-erythroid 2-related factor 2(Nrf2) signaling pathway. Moreover, LYC mitigated Cr(VI)-induced mitochondrial dysfunction by suppressing excessive activation of mitochondrial fission-related proteins (Fis1, Drp1, and MFF) and PINK1/Parkin-mediated mitophagy. Notably, LYC co-treatment enhanced the expression of key mitochondrial biogenesis regulators, including Sirt1 and PGC-1α, in renal tissue. Collectively, these findings indicate that LYC protects against Cr(VI)-induced kidney injury, at least in part, by regulating mitochondrial biogenesis, mitochondrial dynamics, mitophagy, and the Nrf2 antioxidant signaling pathway.
    Keywords:  Hexavalent chromium; Lycopene; Mitochondrial dysfunction; Nephrotoxicity; Nrf2 signaling pathway
    DOI:  https://doi.org/10.1007/s12011-026-05139-w
  7. Am J Physiol Cell Physiol. 2026 May 06.
    Fluid Restriction Enhances Mitochondrial Stress in Peripheral Blood Mononuclear Cells Following High-Volume Resistance Exercise in Health Young Males.
    Hui-Ying Luk, Casey R Appell, Nigel C Jiwan, Heather L Vellers, Yasuki Sekiguchi, Danielle E Levitt.
      Exercising under dehydrated conditions is common among physically active individuals, yet its impact on immune cell mitochondrial quality control, oxidative stress and inflammatory signaling, and systemic inflammatory mediators remains poorly defined. This study investigated mitochondrial quality control and systemic inflammatory responses to high-volume resistance exercise (HVRE) under hydrated (HYD) and dehydrated (DEH) conditions in ten young men (21±1 years, 175±6 cm, 76.9±10.5 kg, 18.5±6.3% fat). Participants completed two identical HVRE sessions following either normal hydration or 24h fluid restriction. Peripheral blood mononuclear cells (PBMCS) collected before (PRE) and at 1h and 3h post-HVRE were analyzed for proteins related to mitochondrial quality control (PINK1, Parkin, DRP1, p-DRP1S616, MFN2), oxidative stress and inflammatory signaling (p-NF-κBS536, NF-κB, SOD2, H2O2), autophagy machinery and degradation (LC3-I, LC3-II, p62, cathepsin-L), and blood samples for systemic inflammatory mediators (IL-6, TNF-α, CRP, H2O2). Significant time × condition interaction effects revealed that LC3-II/I was greater in DEH than HYD at PRE and 3h. In DEH, LC3-II/I returned to PRE levels at 3h, whereas in HYD, it was greatest at 3h. PINK1 was greater at 1h and 3h and pDRP1S616 was greater at 3h in DEH than HYD. Also, PINK1 and pDRP1S616 were greatest at 3h post-HVRE in DEH. Lastly, significant condition main effects revealed greater MFN2, p62, LC3-II, H2O2 in PBMCs and greater IL-6, and CRP in serum in DEH than HYD. These results provide novel evidence that 24 hours of fluid restriction before metabolically demanding resistance exercise activates mitochondrial quality control in PBMCs and elevates systemic inflammatory mediators.
    Keywords:  Hypohydration; IL-6; Mitochondrial Dynamics; Mitophagy; ROS
    DOI:  https://doi.org/10.1152/ajpcell.00859.2025
  8. Chem Biol Interact. 2026 May 05. pii: S0009-2797(26)00231-0. [Epub ahead of print] 112123
    Significance of mitophagy in reactive oxygen species-dependent neuronal apoptosis triggered by pyrrolidinophenones.
    Yuji Sakai, Yoshifumi Morikawa, Shunsuke Jimbo, Koichi Suenami, Emiko Yanase, Akira Ikari, Toshiyuki Matsunaga.
      Pyrrolidinophenones (PPs), a class of synthetic cathinones, have emerged as hazardous new psychoactive substances due to their high lipophilicity and potent neurotoxicity. However, the mechanisms underlying PPs-induced neuronal damage, particularly the roles of mitochondrial reactive oxygen species (ROS) and mitophagy, remain unclear. In this study, we investigated the interplay among ROS overproduction, mitochondrial dysfunction, mitophagy, and apoptosis in human neuronal cells exposed to representative PPs. Treatment with PPs induced neuronal cell toxicity in a manner dependent on the elongation of the alkyl chain, with α-pyrrolidinooctanophenone (POP) exhibiting the strongest effects. The treatment also facilitated the production of intracellular and mitochondrial ROS, including superoxide, hydrogen peroxide, and hydroxyl radical. Furthermore, the cytotoxicity was remarkably attenuated by pretreating with antioxidant, N-acetyl-L-cysteine, indicating a critical role of ROS in PPs-induced cytotoxicity. Subcellular fractionation analysis revealed an accumulation of highly lipophilic PPs such as α-pyrrolidinoheptanophenone (PHPP) and POP in mitochondria, and the treatment with PHPP or POP resulted in an increase in Bax/Bcl2 ratio, caspase-9 activation, and mitochondrial lipid peroxidation, presumably due to an activation of mitochondria-dependent apoptotic signaling. Notably, POP induced mitophagy via activation of the PINK1/Parkin pathway. Additionally, pharmacological inhibition of autophagy or mitophagy exacerbated both ROS production and cytotoxicity, suggesting a protective role of mitophagy through the removal of damaged mitochondria. Collectively, these findings demonstrate that mitochondrial accumulation of PPs promotes ROS-dependent apoptosis, while mitophagy functions as an adaptive cytoprotective mechanism. This study provides new insights into mitochondrial quality control in PPs-induced neurotoxicity and highlights mitophagy as a potential therapeutic target.
    Keywords:  Apoptosis; Mitophagy; Neuronal SK-N-SH cell; Pyrrolidinophenones; Reactive oxygen species
    DOI:  https://doi.org/10.1016/j.cbi.2026.112123
  9. Sci Adv. 2026 May 08. 12(19): eaec0795
    Drp1 regulates mitochondrial health and controls skeletal muscle mass through the Erk1/2-Nur77 pathway.
    Alice M Ma, Peter H Tran, Nicole L Yang, Jennifer Ngo, Hirotaka Iwasaki, Wenjuan Ren, Simone Livit, Linsey Stiles, Sarah Wang, Trinity Ho, Emma Y Yim, Noelle Morrow, Morgan M Johnson, Caroline Cleary, Kai Zou, Rachelle H Crosbie, Yuwei Jiang, Orian S Shirihai, Jonathan Wanagat, Sushil Mahata, James A Wohlschlegel, Andrea L Hevener, Zhenqi Zhou.
      The maintenance of skeletal muscle mass relies on mitochondrial quality control, including balanced dynamics and mitophagy. Dynamin-related protein 1 (Drp1), a central mediator of mitochondrial fission, is essential for these processes, yet its role in muscle mass regulation remains incompletely defined. Here, we show that acute Drp1 deletion in the skeletal muscle increases Parkin-mediated mitochondrial degradation, reduces mitochondrial DNA (mtDNA) content, and leads to severe muscle atrophy. Although dual deletion of Drp1 and Parkin restores mtDNA content, muscle loss persists. Mechanistically, Drp1 loss impairs mitochondrial respiratory chain activity, suppressing extracellular signal-regulated kinase 1/2 (Erk1/2) signaling and down-regulating the nuclear receptor subfamily 4 group A member 1 (Nur77). Pharmacologic β2-adrenergic receptor activation with clenbuterol reactivated Erk1/2, restored Nur77 expression, and rescued muscle atrophy. These findings define a Drp1-Erk1/2-Nur77 signaling axis linking mitochondrial integrity to skeletal muscle mass and identify a potential therapeutic target for muscle degeneration in mitochondrial and metabolic diseases.
    DOI:  https://doi.org/10.1126/sciadv.aec0795
  10. iScience. 2026 May 15. 29(5): 115674
    HIF1-α induces mitochondrial fission in trophoblastic cells during early pregnancy and in preeclampsia.
    Léa Poinsignon, Audrey Chissey, Juliette Colombel, Bertrand Lefrère, Charlotte Izabelle, Lucie Bernard, Jean-Louis Beaudeux, Thierry Fournier, Ioana Ferecatu, Isabelle Hernandez, Amal Zerrad-Saadi.
      The placenta undergoes a major oxygen transition between 7 and 9 gestation weeks (GW) and 12-14 GW. Inadequate adaptation to these environmental changes leads to oxidative stress and the release of syncytial knots, a hallmark of preeclampsia (PE). As mitochondria play a central role in redox regulation, we investigated mitochondrial network dynamics and the role of hypoxia-inducible factor 1-alpha (HIF1-α) in trophoblasts during early pregnancy and in PE. HIF1-α is stabilized in placenta before 9 GW, associated with mitochondrial hypertubulation and increased mitofusin (MFN) 1 expression. Experimental stabilization of HIF1-α using cobalt chloride induces mitochondrial fission through downregulation of MFN1 and MFN2, and upregulation of dynamin-related protein 1 (DRP1). In pre-eclamptic placentas, significantly elevated mitochondrial fission 1 protein (FIS1) levels suggest enhanced mitochondrial fission, supporting FIS1 as a potential biomarker of PE-associated placental alterations.
    Keywords:  cell biology; developmental biology
    DOI:  https://doi.org/10.1016/j.isci.2026.115674
  11. Neuropeptides. 2026 Apr 27. pii: S0143-4179(26)00035-1. [Epub ahead of print]118 102619
    TREM1 inhibition via LP17 alleviates secondary spinal cord injury by activating AMPKα-PINK1-parkin-dependent microglial mitophagy.
    Bin Xia, Yuanfang Sun, Jin Liu, Jiezhao Lin.
      Spinal cord injury (SCI) is characterized by primary mechanical trauma and subsequent secondary pathogenic cascades, with chronic neuroinflammation impeding neurological functional recovery. Microglial activation, mitochondrial dysfunction, and mitophagy are key pathological players, while the role of triggering receptor expressed on myeloid cells 1 (TREM1) in SCI remains incompletely elucidated. This study explored TREM1 targeting and the regulation of microglial mitophagy in SCI using 8-week-old female C57BL/6 J mice and BV2 microglial cells. Mice were administered the TREM1 inhibitor LP17 or physiological saline. Assessments included behavioral evaluations, Nissl staining, immunofluorescence staining, Western blot analysis, and transmission electron microscopy. We found that TREM1 expression peaked at 3 days post-SCI and was specifically localized to microglia. LP17 inhibited TREM1 expression, improved 4-week post-injury Basso Mouse Scale scores and footprint parameters, reduced Nissl body loss, and downregulated proinflammatory mediators in the spinal cord and lipopolysaccharide (LPS)-stimulated BV2 cells. LP17 enhanced LPS-induced mitophagy in BV2 cells and activated the AMPKα-PINK1-Parkin signaling pathway. Small interfering RNA-mediated AMPKα knockdown (si-AMPKα) blocked LP17-induced mitophagy and its anti-inflammatory effects. In conclusion, LP17 inhibits TREM1 to alleviate secondary SCI via the AMPKα-PINK1-Parkin-dependent microglial mitophagy pathway, making TREM1 a potential therapeutic target for SCI.
    Keywords:  Inflammation; Microglial; Mitophagy; Spinal cord injury; TREM1
    DOI:  https://doi.org/10.1016/j.npep.2026.102619
  12. Aging Cell. 2026 May;25(5): e70531
    Correction to "Monoamine Oxidase-A Is a Novel Driver of Stress-Induced Premature Senescence Through Inhibition of Parkin-Mediated Mitophagy".
      
    DOI:  https://doi.org/10.1111/acel.70531
  13. NPJ Syst Biol Appl. 2026 May 05. pii: 64. [Epub ahead of print]12(1):
    A rule-based simulation model illuminates the role of asymmetric mitochondrial fission on beta-cell health.
    Philipp Henning, Julia Schultz, Simone Baltrusch, Adelinde M Uhrmacher.
      Mitochondrial dynamics play a critical role in the development of aging-related diseases such as type 2 diabetes mellitus. To investigate how mitochondrial dynamics influence cellular behavior in pancreatic beta-cells, we developed a rule-based, multi-level simulation model of insulin secretion. The pancreatic beta-cell model encompasses metabolic pathways (glycolysis and oxidative phosphorylation), compartmental processes (mitochondrial fusion and fission), and cellular processes (insulin secretion), allowing for the investigation of their interplay. The rule-based simulation model captures the high plasticity of these organelles and integrates and builds upon insights from various experimental studies and previous simulation models. Its rule-based specification facilitates the exploration of new hypotheses, the integration of new knowledge and data, and the successive extension of the model. The results of our simulation experiments underscore the importance of peripheral, sorted mitochondrial fission in maintaining mitochondrial health. Downregulation of the fission-associated anchor proteins Fis1 and MFF impacts mitochondrial structure and function differently, highlighting their distinct roles in maintaining mitochondrial health and cellular biogenesis, respectively. With respect to insulin secretion, Drp1 suppression shows that beta-cells become unresponsive to glucose, whereas Fis1 downregulation only attenuates the cellular response. The simulation model and simulation results corroborate experimental findings and contribute to a deeper understanding of the mechanisms involved in mitochondrial dynamics of pancreatic beta-cells and their relation to metabolic dysregulation in type 2 diabetes mellitus.
    DOI:  https://doi.org/10.1038/s41540-026-00732-0
  14. Front Pharmacol. 2026 ;17 1803022
    Yoda1-activated Piezo1 enhances mitophagy in human gingival fibroblasts to promote maxillofacial wound repair.
    Yuhan Qi, Que Feng, Yan Wu, Jing Xu, Xin Zhang, Lipeng Jiang, Wenjing Liu, Jing Cao, Zhenbao Zhang, Yanfeng Li.
       Background: Delayed healing of maxillofacial soft tissue wounds is closely associated with inffammatory injury and mitochondrial dysfunction in fibroblasts, while effective therapeutic strategies remain limited. This study investigated whether activation of the mechanosensitive ion channel Piezo1 by Yoda1 could promote wound healing.
    Methods: An LPS-induced inflammatory model was established in human gingival fibroblasts (HGFs) and treated with Yoda1. Intracellular calcium influx, cell viability, oxidative stress, mitochondrial membrane potential, apoptosis, migration, wound closure, and type I collagen expression were assessed. The involvement of the PINK1/Parkin-mediated mitophagy pathway was analyzed. An in vivo inflammatory wound model was used to evaluate therapeutic efficacy.
    Results: Yoda1 significantly increased intracellular calcium influx, improved cell viability, reduced oxidative stress, restored mitochondrial membrane potential, and inhibited apoptosis in LPS-treated HGFs. It also enhanced HGFs migration, wound closure, and type I collagen expression in vitro. Mechanistically, these effects were associated with activation of the PINK1/Parkin-mediated mitophagy pathway. In vivo, Yoda1 accelerated wound closure, accompanied by increased collagen deposition and improved tissue regeneration.
    Conclusion: Activation of Piezo1 by Yoda1 can alleviate its inflammatory damage by restoring mitochondrial homeostasis and regulating the cellular functions of HGFs. Piezo1 may be a promising therapeutic target for promoting maxillofacial wound repair.
    Keywords:  Piezo1; Yoda1; lipopolysaccharide; mitochondrial autophagy; wound healing
    DOI:  https://doi.org/10.3389/fphar.2026.1803022
  15. Int J Mol Sci. 2026 Apr 16. pii: 3557. [Epub ahead of print]27(8):
    Mitochondrial Network Dynamics in Aging: Cellular Mechanisms, Intercellular Communication, and Their Impact on Tissue Adaptability.
    Luminita Labusca, Teodor Stefan Gheorghevici, Bogdan Puha.
      Beyond their classical role as "cellular powerhouses", mitochondria are increasingly recognized as dynamic and interconnected networks whose architecture, quality control, and intercellular communication influence cellular and organismal homeostasis. Mitochondrial dynamics-including fusion-fission balance, mitophagy-biogenesis coupling, intracellular organization, and intercellular transfer via tunneling nanotubes, extracellular vesicles, or transient cell fusion-contribute to tissue adaptation and functional decline during aging. Focusing on cardiac muscle, skeletal muscle, and the nervous system, this narrative review synthesizes current evidence describing how aging disrupts mitochondrial network integrity through altered dynamics, impaired organelle positioning and transport, reduced mitophagy, mtDNA instability, and compromised metabolic coupling between cells. These alterations propagate across tissues, limiting energetic flexibility, stress resilience, and regenerative capacity. Building on these mechanisms, we discuss a systems-level perspective in which aging is associated with progressive loss of mitochondrial network coherence rather than solely cumulative molecular damage. Within this framework, mitochondrial connectivity functions as an integrative descriptor of cellular resilience: well-organized networks counteract metabolic perturbations, whereas functionally decoupled networks amplify stress and promote maladaptive aging trajectories. Emerging evidence indicates that physiological and pharmacological interventions, including endurance exercise, caloric restriction or mimetics, fusion-supporting pathways, and mitophagy-enhancing strategies, can partially restore network organization even later in life. Molecular, cellular, and tissue-level insights are integrated to highlight mitochondrial network dynamics as both a mechanistic contributor to aging and a potentially modifiable target for future preventive and therapeutic interventions.
    Keywords:  aging; intercellular mitochondrial communication; mitochondria; mitophagy; myocardial aging; neurodegeneration; skeletal muscle aging
    DOI:  https://doi.org/10.3390/ijms27083557
  16. Ren Fail. 2026 Dec;48(1): 2667684
    The mechanism and therapeutic prospect of HIF-1 α/BNIP3 pathway in regulating mitophagy in tubulointerstitial fibrosis.
    Xinru Wang, Zhaoan Guo.
      Tubulointerstitial fibrosis (TIF) is a key pathological hallmark and a major determinant of end-stage renal disease (ESRD). The mechanisms of TIF remain unclear, and there are currently no specific drugs to slow or reverse its progression. Notably, due to the kidney's unique structure, the course of renal dysfunction is intimately connected with hypoxia. The signaling pathway formed by hypoxia-inducible factor 1α (HIF-1α) and its downstream target gene, B-cell lymphoma-2/adenovirus E1B 19-kDa interacting protein (BNIP3), exerts a pivotal effect during renal hypoxia. This pathway mediates mitophagy, inhibits apoptosis and inflammatory responses, maintains cellular energy balance, and thus profoundly influences the progression of TIF. This article focuses on the molecular mechanism by which the HIF-1α/BNIP3 pathway regulates mitophagy and affects TIF, and delves into its mechanisms in pyroptosis, oxidative stress, and ischemia-reperfusion injury, This work endeavors to establish a theoretical foundation and potential intervention targets for developing novel treatment strategies for TIF.
    Keywords:  BNIP3; HIF-1α; Tubulointerstitial fibrosis; mitophagy; pyroptosis
    DOI:  https://doi.org/10.1080/0886022X.2026.2667684
  17. Autophagy. 2026 May 06. 1-3
    ROS-driven mitophagy arrest mediates the anti-glioblastoma activity of Molephantin.
    Zhipeng Ling, Junliang Li, Guocai Wang, Yubo Zhang, Jun-Ping Pan.
      Mitophagy, the selective autophagic degradation of mitochondria, often acts as a pro-survival mechanism in tumor cells, including Glioblastoma (GBM), by clearing damaged mitochondria and mitigating oxidative stress. GBM is a highly aggressive brain tumor characterized by profound resistance to conventional therapies. Our recent study identified Molephantin (EM-5), a natural small molecule capable of crossing the blood-brain barrier, as a potent anti-GBM agent. Mechanistically, EM-5 triggers severe mitochondrial dysfunction and massive reactive oxygen species (ROS) production in GBM. Crucially, we discovered that EM-5 acts as a novel late-stage mitophagy inhibitor. It specifically blocks the fusion of mitophagosomes with lysosomes without affecting early autophagosome formation or lysosomal acidification. This ROS-driven fusion defect leads to the toxic accumulation of damaged mitochondria, thereby amplifying oxidative stress and driving GBM cells into apoptosis. Collectively, our work establishes that targeting late-stage mitophagy flux via ROS modulation is a valuable paradigm for the discovery and development of therapeutic agents against GBM.
    Keywords:  Autophagosome-lysosome fusion; Molephantin; glioblastoma; mitophagy; reactive oxygen species
    DOI:  https://doi.org/10.1080/15548627.2026.2668084
  18. Int Immunopharmacol. 2026 May 05. pii: S1567-5769(26)00555-2. [Epub ahead of print]181 116709
    Comment on "Bergapten ameliorates osteoarthritis progression by inhibiting the PI3K/AKT/mTOR pathway to activate mitophagy and suppress pyroptosis".
    Manyi Cui, Fapeng Gao, YuKe Zhu.
      
    DOI:  https://doi.org/10.1016/j.intimp.2026.116709
  19. Sci Rep. 2026 May 07.
    FTO-mediated m6A demethylation regulates PGC-1α-dependent mitochondrial biogenesis to attenuate aluminum-induced neuronal senescence.
    Zhaoya Jin, Shuai Li, Jinzhu Yin, Xiaoyu He, Ru Wang, Yang Liu, Huifang Zhang.
      Aluminum (Al) exposure is increasingly recognized as a risk factor for neurodegenerative disorders; however, the epitranscriptomic mechanisms linking environmental Al toxicity to neuronal senescence and mitochondrial alterations remain poorly understood. We hypothesized that impairs mitochondrial biogenesis and may disrupt mitochondrial homeostasis through dysregulation of N6-methyladenosine (m6A) RNA modification mediated by the m6A demethylase fat mass and obesity-associated protein (FTO). HT22 mouse hippocampal neurons were exposed to aluminum maltolate (60-240 µmol/L). An FTO-overexpression model was established. MeRIP-seq and RNA-seq were performed to assess m6A and transcriptomic changes. Mitochondrial status, particularly mitochondrial biogenesis-related indicators, was evaluated via ATP and mtDNA levels. SA-β-Gal staining assessed senescence. The expression of senescence-associated markers (e.g., p16, p21, HMGA1) and mitochondrial regulatory factors (e.g., FTO, PGC-1α, NRF-1, NRF-2, TFAM) was examined by qPCR and Western blotting. Aluminum exposure globally increased m6A methylation (7,068 peaks upregulated), affecting pathways linked to senescence and neurodegeneration. PGC-1α showed increased m6A and decreased expression. Aging markers (P16, P21, HMGA1) were upregulated, while mitochondrial biogenesis-related indicators (ATP levels, mtDNA copy number, and the PGC-1α axis) were reduced, indicating impaired mitochondrial biogenesis. FTO expression was suppressed by aluminum but overexpression of FTO reversed these effects, reducing m6A levels, restoring PGC-1α expression, partially restoring mitochondrial biogenesis-related parameters, and attenuating senescence. Our findings suggest that aluminum induces neuronal senescence by inhibiting FTO, increasing m6A methylation, and downregulating PGC-1α-mediated mitochondrial biogenesis. The FTO-m6A-PGC-1α axis plays a critical role in aluminum neurotoxicity.
    Keywords:  Aluminum; FTO; Mitochondrial biogenesis; PGC-1α; Senescence; m6A methylation
    DOI:  https://doi.org/10.1038/s41598-026-51674-w
  20. Life Sci. 2026 May 01. pii: S0024-3205(26)00229-8. [Epub ahead of print]397 124420
    Targeting P2X purinergic receptors with suramin alleviates rotenone-induced Parkinson's-like pathology via modulation of mitophagy and NLRP3-pyroptosis: Comparison with metformin.
    Mohamed S Attia, Nancy N Shahin, Ahmed S Kamel, Mohamed A Khattab, Marwa I Shabayek, Hebatallah A Darwish, Maha M El-Sawalhi.
      Purinergic P2X receptor overactivation, impaired mitophagy, and NLRP3 inflammasome-driven neuroinflammation have been increasingly implicated in Parkinson's disease (PD) pathogenesis. Suramin, a purinergic receptor antagonist, has recently attracted attention for its neuroprotective effects in several neurological disorders. However, its potential to modulate the P2X/mitophagy/NLRP3 axis in PD remains unexplored. This study evaluated the neuroprotective effects of suramin in comparison with metformin, a reported mitophagy and inflammasome modulator, in a rotenone-induced PD rat model. Rotenone (1.5 mg/kg, s.c.) was administered on alternate days for three weeks. Suramin (100 mg/kg, I.V.) was administered on days 11 and 18, while metformin (200 mg/kg, p.o.) was given from days 11 to 21. Behavioral outcomes were evaluated using the open-field, footprint, grip strength, and rotarod tests. Expression levels of selected target signals were quantified using qPCR, ELISA, Western blot, and immunohistochemistry. Suramin and metformin significantly improved motor and behavioral performance, preserved dopaminergic integrity, improved tyrosine hydroxylase expression, and diminished α-synuclein accumulation, with suramin demonstrating greater efficacy. At the molecular level, suramin more effectively downregulated striatal P2X7R, P2X4R, and ROS levels and increased p-AMPK/t-AMPK ratio. Both treatments promoted mitophagy, as evidenced by increased PINK1, Parkin, and BNIP3 levels along with reduced LC3-II/I ratio. They also suppressed NLRP3 inflammasome activation and pyroptosis, with suramin showing more potent anti-inflammatory effects. Altogether, suramin's neuroprotective effects could be mediated via suppressing P2X7/P2X4 receptors, enhancing mitophagy and counteracting NLRP3-driven pyroptosis in the striatum, with its relatively stronger profile attributable to more robust P2X7/P2X4 signaling inhibition, underscoring its potential as a therapeutic candidate for PD.
    Keywords:  Metformin; NLRP3-driven pyroptosis; PINK1/Parkin-Mediated Mitophagy; Parkinson's disease; Purinergic receptors (P2X); Suramin
    DOI:  https://doi.org/10.1016/j.lfs.2026.124420
  21. Curr Mol Med. 2026 May 05.
    The Effect of mascRNA on the Phenotype Transition and Mitophagy in Vascular Smooth Muscle Cells Exposed to Hypoxia.
    Jingyuan Hou, Ruiqiang Weng, Xia Li, Xiaodong Gu, Junli Zhao, Sudong Liu.
       INTRODUCTIONS: A primary complication of atherosclerosis(AS) is characterized by chronic inflammatory and mitochondrial dysfunction, both of which play critical roles in the disease's progression. This study aims to investigate the regulatory role of mascRNA in mediating the hypoxia-induced phenotypic transition of vascular smooth muscle cells (VSMCs).
    METHODS: An AS model was established, and the aortic plaque area was assessed by Oil Red O staining. Human VSMCs were divided into five groups: normoxia, hypoxiainduced, negative control (pGV-NC), mascRNA overexpression (pGV-mascRNA), and inhibitor-treated. Quantitative PCR (qPCR) was utilized to detect the expression of mascRNA, vWF, and MMP2. Western blotting was performed to detect the expression of phenotypic transformation-related proteins.
    RESULTS AND DISCUSSION: In high-fat diet (HFD)-fed mice, the expression of mascRNA was significantly decreased in the aortas (P < 0.05). Hypoxia led to a reduction in mascRNA levels, an upregulation of synthetic markers, and increased reactive oxygen species (ROS) in VSMCs. Overexpression of mascRNA suppressed VSMC migration and proliferation, enhanced mitophagy, and inhibited the PI3K-AKT pathway. Our study has been the first to demonstrate mascRNA play a crucial role in VSMC phenotypic transformation and functions via regulation of mitophagy. These findings highlight mascRNA's role in AS development and provide a theoretical basis for its clinical applications, but in vivo experiments are called for to validate its anti-AS effect.
    CONCLUSION: MascRNA suppressed hypoxia-induced phenotypic transformation of VSMCs, potentially through the modulation of the PI3K-AKT signaling pathway and the enhancement of mitochondrial autophagy. These findings indicate a prospective therapeutic application of mascRNA in AS.
    Keywords:  Hypoxia; Vascular smooth muscle cells; atherosclerosis; mascRNA; mitophagy; phenotypic transformation
    DOI:  https://doi.org/10.2174/0115665240427492251210155520
  22. Free Radic Biol Med. 2026 May 06. pii: S0891-5849(26)00742-2. [Epub ahead of print]
    YOD1 Regulates Neuronal Mitochondrial Unfolded Protein Response Activation by Deubiquitinating DNAJA1 After Subarachnoid Hemorrhage.
    Xi Liu, Bixi Gao, Lei Bai, Dengfeng Lu, Zhaoming Song, Zongqi Wang, Di Li, Chao Ma, Haiying Li, Zhong Wang.
       BACKGROUND: Mitochondrial dysfunction plays a critical role in early brain injury (EBI) following subarachnoid hemorrhage (SAH) and represents a promising therapeutic target.The mitochondrial unfolded protein response (UPRmt) maintains mitochondrial homeostasis and enables neurons to cope with oxidative stress. In this study, we explored UPRmt activation mediated by OTU-deubiquitinating enzyme 1 (YOD1) / DnaJ homolog subfamily A member 1 (DNAJA1) and its role in SAH.
    METHODS: We isolated UPRmt positive (UPRmt+) and UPRmt negative (UPRmt-) primary neurons by flow cytometry and validated their differential tolerance to oxidative stress following SAH. We then explored the underlying causes of differential levels of UPRmt activation. By combining molecular docking, co-immunoprecipitation, and protein stability assays, we established that YOD1 regulates the deubiquitination of DNAJA1. In addition, we assessed the neuroprotective role of YOD1 after SAH in vivo and in vitro models.
    RESULTS: UPRmt+ neurons exhibited reduced oxyhemoglobin (OxyHb)-induced apoptosis and mitochondrial damage compared with UPRmt- neurons. DNAJA1 was upregulated and binding to HSP70 led to a strong activation of UPRmt. DNAJA1 stability was regulated by the ubiquitin-proteasome system, and YOD1 stabilized DNAJA1 via deubiquitination. Neuron-specific YOD1 overexpression preserved mitochondrial function, reduced neuronal apoptosis in vitro and in vivo, and improved neurological outcomes in SAH.
    CONCLUSION: YOD1 stabilizes DNAJA1 through deubiquitination, promoting UPRmt activation to mitigate mitochondrial dysfunction and neuronal death during EBI following SAH.
    Keywords:  DNAJA1; Deubiquitination; Mitochondrial dysfunction; Oxidative stress; Subarachnoid hemorrhage; UPR(mt); YOD1
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.05.278
  23. Free Radic Biol Med. 2026 May 03. pii: S0891-5849(26)00466-1. [Epub ahead of print]252 69-81
    Erythropoietin signaling regulated by Rab26 attenuates sepsis-associated lung injury by suppressing macrophage ferroptosis via enhanced mitophagy.
    Daohui Gong, Zhihao Zhu, Heng Qin, Mingzhou Zhang, Wen Zhang, Qing Xiang, Hang Qian, Binfeng He, Rong Zhang, Guansong Wang.
      Macrophage ferroptosis contributes to sepsis-associated acute lung injury (ALI); however, its upstream regulatory mechanisms remain poorly understood. Here, using a cecal ligation and puncture (CLP) murine sepsis model, we observed that macrophages from septic mice and bone marrow-derived macrophages (BMDMs) exposed to septic bronchoalveolar lavage fluid (BALF) exhibited concurrent suppression of EPOR expression and induction of ferroptosis. EPOR deficiency selectively reduced basal GPX4 expression and amplified ferroptotic cell death upon challenge with RSL3 or septic BALF. EPORM-/- mice showed exacerbated sepsis-induced lung injury and mortality, which were rescued by the ferroptosis inhibitor ferrostatin-1 (Fer-1). Mechanistically, EPOR deficiency downregulated PPARγ, which promotes GPX4 expression. EPOR deficiency also impaired PINK1-mediated mitophagy by reducing PINK1 but not PARKIN levels, while mitophagy induction attenuated ferroptosis in EPOR-deficient cells. rhEPO stimulation enhanced the EPOR/PPARγ axis and suppressed lipid peroxidation, whereas PPARγ antagonism inhibited PINK1 expression. We further identified Rab26 as a critical stabilizer of EPOR. Specifically, Rab26 deficiency upregulated the expression of BTRC, an E3 ligase that interacts with EPOR to promote its degradation. Consequently, Rab26 deficiency decreased EPOR levels, subsequently suppressing PPARγ and PINK1, thereby reducing GPX4 expression and blunting rhEPO-induced PINK1 upregulation. Collectively, EPOR signaling protects macrophages from ferroptosis by activating PINK1-mediated mitophagy in a Rab26-dependent manner. The Rab26-EPOR-PPARγ axis represents a promising therapeutic target for sepsis-induced lung injury.
    Keywords:  EPOR; Ferroptosis; Macrophage; Rab26; Sepsis
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.05.002
  24. Probiotics Antimicrob Proteins. 2026 May 02.
    Hepatoprotective Mechanisms of Lactiplantibacillus plantarum SCS7 Cell-Free Extract Against Aflatoxin B1 Toxicity.
    Yuxi Wang, Wei Pu, Ying Zhang, Qiuyan Liu, Xiao Meng, Lishi Jiang.
      Aflatoxin B1 (AFB1) is a widespread contaminant of food and feed that poses significant risks to both human and animal health. Developing safe and effective strategies to mitigate its toxicity remains a major public health priority. In this study, we investigated the protective effects of Lactiplantibacillus plantarum SCS7 cell-free extract (CFE) against AFB1-induced liver injury using integrated in vivo (mouse) and in vitro (AML12 hepatocyte) models. CFE treatment markedly alleviated AFB1-induced hepatic damage, mitochondrial dysfunction, and gut microbiota dysbiosis. Mechanistic analyses indicate that the protective effects of CFE are associated with the alleviation of excessive mitophagy and concomitant restoration of the PINK1/Parkin signaling axis, while systemic protection is conferred through modulation of the gut-liver axis. Importantly, unlike live probiotics, CFE circumvents concern related to intestinal colonization and biosafety while maintaining multi-pathway efficacy. Notably, this study identifies a previously unrecognized role for probiotic-derived metabolites in organelle quality control, demonstrating that CFE mitigates liver injury by inhibiting pathological mitophagy. Furthermore, CFE reshaped the intestinal microbiota and promoted the production of beneficial microbial metabolites, changes that were closely associated with improved hepatic homeostasis. Collectively, these findings suggest a coordinated interplay among the gut microbiota, microbial metabolites, and restoration of the PINK1/Parkin pathway, thereby providing a theoretical foundation for the development of stable, cell-free probiotic therapeutics with potential applications in food safety and public health.
    Keywords:   Lactiplantibacillus plantarum SCS7; AFB1; Cell-free extract; Hepatotoxicity; Intestinal flora; Mitochondrial autophagy
    DOI:  https://doi.org/10.1007/s12602-026-11034-6
  25. J Physiol Biochem. 2026 May 07. pii: 47. [Epub ahead of print]82(1):
    Hypoxia-inducible factor-1α: Dual roles in maintaining neuronal homeostasis and neuronal degeneration via regulation of oxidative stress, mitochondrial dynamics, and bioenergetics.
    Saipriya Parol Puthusseri, Sruthy Ravivarma, Merin Johny, Ajith Vengellur.
      Hypoxia-inducible factor-1α (HIF-1α) is an oxygen-sensitive transcription factor with an inherently paradoxical biology: under mild-to-moderate hypoxic stress, it functions as a pro-survival regulator, yet under severe or prolonged hypoxia, the same signalling axis promotes apoptotic and autophagic cell death. This duality carries particular significance in neurons, where HIF-1α serves as a critical nexus among neuronal survival, metabolic adaptation, and mitochondrial integrity, and where the consequences of its dysregulation are most profound given their exceptional metabolic demands and limited regenerative capacity. This review examines the molecular determinants governing this protective-to-detrimental switch, integrating key interconnected dimensions: the context-dependent regulation of oxidative stress, the control of mitochondrial bioenergetics, dynamics, mitophagy, and axonal transport; the dual role of HIF-1α in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and cerebral ischemia; and the therapeutic implications of precision-targeted HIF-1α modulation. Across all these contexts, a consistent pattern emerges: early or acute HIF-1α activation is broadly neuroprotective, while chronic or severe hypoxic stress converts the same pathway into a driver of neurodegeneration. Understanding the determinants of this switch, including hypoxia duration, severity, and cell-type specificity, provides a framework for designing temporally precise therapeutic interventions for hypoxia-related neurological disorders.
    Keywords:  HIF-1α; Hypoxia; Mitochondria; Neuronal stress; Neuroprotection; Oxidative stress
    DOI:  https://doi.org/10.1007/s13105-026-01187-x
  26. J Physiol. 2026 May 07.
    Mitochondrial dynamics and oxidative metabolism: an emerging role for Septin7 in skeletal muscle.
    Márcio Augusto Campos-Ribeiro, Rudá Prestes E Albuquerque, Thiago N Menezes, Vanessa Morais Lima.
      
    Keywords:  cytoskeleton; mitochondrial dynamics; mitochondrial function; skeletal muscle metabolism
    DOI:  https://doi.org/10.1113/JP291379
  27. Cell Signal. 2026 May 03. pii: S0898-6568(26)00226-3. [Epub ahead of print] 112573
    Activation of tripartite motif-containing protein 16 improves cardiac function in aging mice by regulating Mfn2-dependent mitochondrial fusion through Sirt6.
    Yawu Chen, Hong Guo, Xiaochen Ding, Linhe Lu, Ping Jin.
      Aging increases susceptibility to various diseases, including cardiac injury. Which leads to cardiac dysfunction by increasing myocardial fibrosis and mitochondrial dynamics disorder. However, the molecular mechanisms in the aging heart have not been elucidated. The E3 ligase TRIM16 (tripartite motif-containing protein 16) functions as a regulator to alleviate cardiac injury. Sirt6 has been shown to play a cardioprotective role by maintaining mitochondrial dynamics. Our study aimed to elucidate the molecular mechanisms of the TRIM16-Sirt6-Mfn2 signaling pathway in the aging heart. We used aged mice and performed intracardiac injections of AAV-TRIM16/Sirt6. The results demonstrated that TRIM16 improved cardiac function by increasing Sirt6 expression in the aging heart. Further in vitro studies were conducted using D-galactose-cultured h9c2 cells to explore the relationship between TRIM16/Sirt6 and mitochondrial dynamics. The findings showed that TRIM16/Sirt6 protected D-galactose-cultured h9c2 cells by promoting Mfn2-dependent mitochondrial fusion and enhancing mitochondrial respiratory capacity. In conclusion, our results confirm that TRIM16 activation improves cardiac function via the Sirt6/Mfn2 signaling pathway in the aging heart. This study provides evidence that TRIM16/Sirt6/Mfn2 signaling plays a novel protective role in the aging heart and offers a promising therapeutic strategy for age-related heart failure.
    Keywords:  Aging; Mfn2; Mitochondrial; Sirt6; TRIM16
    DOI:  https://doi.org/10.1016/j.cellsig.2026.112573
  28. ACS Nano. 2026 May 07.
    Chiral Covalent Organic Frameworks Trigger Tumor-Specific Mitophagy via Notch/Mitogen-Activated Protein Kinase Pathways and Enantiomer-Dependent Photodynamic Therapy.
    Wen-Xiu Ren, Jie Feng, Ya-Nan Zhai, Zhi-Lin Dong, Jian-Yu Zhao, Jing-Lan Kan, Yu-Bin Dong.
      Chirality enlightens promising antitumor strategies. However, the limited understanding of chirality-associated cellular metabolism regulation and cell death mechanisms impede the rational design of chirality-dependent functional nanoplatforms for safe and effective antitumor therapy. In this work, we engineered a propargylamine-linked chiral covalent organic framework (CCOF) and conducted a comprehensive examination of its interactions with living organisms and its cytotoxicity. Our findings demonstrate that CCOF enters tumor cells in a chirality-dependent manner, induces mitochondrial autophagy, and thereby promotes cell death. Furthermore, the efficiency of autophagy activation is influenced by chirality, with (S)-DTzP-COF being more potent than (R)-DTzP-COF. Subsequent high-throughput transcriptomics analysis unveiled the mechanisms underlying CCOF's efficacy against tumors. Additionally, CCOF demonstrates enantiomer-dependent performance in the photocatalytic oxidation of oxygen under laser irradiation, both in vitro and in vivo. Under laser irradiation, the proposed CCOF nanoplatform achieves the desired antitumor effect in three different subcutaneous tumor models. This study represents an application of CCOFs in oncology, uncovering a chirality-dependent mechanism of mitochondrial autophagy induction, with (S)-DTzP-COF engaging the Notch signaling pathway in addition to both (R)-DTzP-COF and (S)-DTzP-COF being involved in the Mitogen-Activated Protein Kinase (MAPK) signaling pathway. These discoveries lay a robust foundation for the advancement of chiral nanomaterials in biomedical application.
    Keywords:  chiral covalent organic frameworks; enantioselective; mitophagy; photodynamic therapy; tumor
    DOI:  https://doi.org/10.1021/acsnano.6c00511
  29. Phytother Res. 2026 May 05.
    Astragaloside IV Enhances Mitophagy to Alleviate Renal Ischemia/Reperfusion Injury via PINK1/Parkin Pathway.
    Lin Liu, Zonghui Xu, Shujing Wu, Man Li, Ruoan Wei, Mpofu Uphakeme Inobubele Sitholumusa, Junqiu Liu, Guoyin Kai.
      Astragaloside IV (AS-IV), a primary bioactive component of Astragalus membranaceus (AM). It is very effective in regulating renal diseases. However, the possible underlying mechanism of AS-IV on renoprotection remains unclear. The aim of this study is to find out the regulation mechanism of AS-IV on ischemia/reperfusion injury-induced Acute kidney injury (IRI-AKI). At first, AS-IV was confirmed to significantly alleviate renal dysfunction, inflammation, and renal tubular epithelial cell apoptosis in IRI-AKI mice. Then, it was found that AS-IV alleviated mitochondrial dysfunction and renal tubular epithelial cell injury induced by IRI. Growing evidence has suggested that PINK1/Parkin-mediated mitophagy plays a critical protective role in IRI. Based on this, we hypothesized that AS-IV might exert renoprotective effects through activating the PINK1/Parkin mitophagy pathway. After 3-MA inhibition of autophagy, AS-IV no longer showed its protective effect on HK-2 cells in a hypoxic environment. Through further molecular docking, cell thermal migration, and gene targeted silencing experiments, we confirmed that AS-IV activates the PINK1/Parkin mitophagy pathway and ultimately alleviates IRI-AKI. In summary, all these comprehensive experimental findings indicated that AS-IV can be used as a functional food for the prevention of renal ischemia/reperfusion injury.
    Keywords:  Astragaloside IV; PINK1/Parkin; ischemia–reperfusion injury; mitophagy
    DOI:  https://doi.org/10.1002/ptr.70369
  30. bioRxiv. 2026 Apr 23. pii: 2026.04.20.719702. [Epub ahead of print]
    Spatial, temporal and sex specific mitochondrial dynamic changes in severe controlled cortical impact mouse model of traumatic brain injury.
    Hemendra J Vekaria, Chirayu D Pandya, Paresh Prajapati, Elika Z Moallem, Gopal V Velmurugan, W Brad Hubbard, Adam D Bachstetter, Patrick G Sullivan.
      Traumatic brain injury (TBI) triggers complex and evolving secondary cascades that disrupt mitochondrial homeostasis and contribute to progressive neurodegeneration. Although mitochondrial impairment is a well-recognized driver of post-traumatic pathology, the spatial and temporal progression of mitochondrial dysfunction, particularly in regions distal to the injury site, remains poorly defined, and potential sex-specific responses remain understudied. Here, we performed a comprehensive mitochondrial-focused analysis in a mouse model of controlled cortical impact (CCI), quantifying mtDNA copy number (mtDNA-CN), mitochondrial gene expression, and protein markers regulating biogenesis, transcription, electron transport chain integrity, and mitophagy. Mitochondrial profiles were assessed across four brain regions (cortex at 2, 4, and 6 mm from the injury epicenter, and hippocampus) at four time points (6h, 12h, 24h, and 48h) in both female and male C57BL/6J mice. While mtDNA content exhibited only modest and region-restricted reduction, particularly near the injury core, transcriptional and protein-level changes were far more pronounced and sex-divergent. Females displayed extensive early cortical gene activation followed by widespread hippocampal suppression at 48 h across mitochondrial dynamics, OXPHOS, transcriptional regulation, and biogenesis pathways, accompanied by 48h in PGC-1α, TFAM, and NDUFS1. In contrast, males showed minimal transcriptional disruption but demonstrated delayed compensatory increases in TFAM, NDUFS1, and p62 protein levels, suggesting activation of mitochondrial maintenance and recovery programs. These spatially and temporally distinct responses reveal fundamental sex-specific vulnerabilities in mitochondrial regulation after TBI. Together, our findings provide a direction to an integrated mitochondrial landscape of early post-injury events and identifies critical windows and pathways that may support sex-specific therapeutic targeting to restore mitochondrial function after TBI.
    DOI:  https://doi.org/10.64898/2026.04.20.719702
  31. Expert Opin Ther Targets. 2026 May 08.
    Targeting the OPA1 pathway in autosomal dominant optic atrophy (ADOA): 25 years from gene discovery to therapeutic strategy.
    Marcel V Alavi.
       INTRODUCTION: Autosomal Dominant Optic Atrophy (ADOA) is a rare hereditary optic neuropathy primarily caused by OPA1 mutations. Retinal ganglion cell (RGC) loss results in variable visual impairments, occasionally accompanied by extra-ocular manifestations. ADOA also involves a developmental component consistent with OPA1's essential role in mitochondrial fusion, cristae organization, and quality control. As such, ADOA serves as a paradigm for studying mitochondrial contributions to neurodegeneration.
    AREAS COVERED: This article provides a comprehensive overview of ADOA, covering genetic and clinical aspects while distinguishing between degenerative and developmental features of the pathology. The author examines OPA1 function and assesses emerging therapeutic strategies - ranging from gene augmentation and small-molecule therapeutics to alternative targets - before appraising translational challenges.
    EXPERT OPINION: Antisense therapies targeting OPA1 haploinsufficiency are among the more advanced ADOA treatments currently under human safety evaluation, with other modalities following closely in development. However, the field still lacks robust clinical endpoints for the highly variable and slowly progressive phenotype. Furthermore, developmental RGC loss may limit therapeutic efficacy of late-stage interventions - a challenge compounded by the difficulty of early diagnosis. Nevertheless, the FDA's recent shift toward Bayesian statistical frameworks and the emergence of neuroprotective alternative targets are expected to streamline the clinical development for ADOA.
    Keywords:  Antisense oligonucleotides; Haploinsufficiency; OMA1; OPA1; autosomal dominant optic atrophy (ADOA); gene therapies; mitochondrial dynamics; neuroprotection; retinal ganglion cells (RGCs); small molecules
    DOI:  https://doi.org/10.1080/14728222.2026.2671678
  32. Int Immunopharmacol. 2026 May 06. pii: S1567-5769(26)00633-8. [Epub ahead of print]182 116787
    Paeonol mitigates age-related osteoporosis via mitophagy-mediated NLRP3 inflammasome inhibition.
    Jingliang Gu, Min Ma, Laiya Lu, Zhangyi Pan, Junfeng Cai, Yanglin Wu, Shulin Luo.
      Age-related osteoporosis, a progressive skeletal disorder inherent to aging, is pathologically defined by diminished bone mass and deteriorated bone microarchitecture, resulting in heightened skeletal fragility. Despite extensive research, effective therapeutic interventions for age-associated bone loss remain limited. Accumulating evidence indicates that aging-induced immune dysregulation contributes significantly to chronic low-grade inflammation, thereby exacerbating osteoporotic progression. In this study, we identify Paeonol (PAE) as a potent mitigator of senile osteoporosis, acting through the modulation of the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome/mitophagy axis. We demonstrate that PAE ameliorates aging-induced bone loss in the NLRP3 inflammasome-dependent manner by enhancing mitophagic flux. Specifically, PAE facilitates the clearance of dysfunctional mitochondria, thereby suppressing NLRP3 inflammasome activation and subsequent inflammatory responses. Notably, pharmacological or genetic inhibition of mitophagy abrogates the protective effects of PAE, as evidenced by the attenuated suppression of NLRP3 inflammasome activation and the diminished preservation of bone mass in aged murine models. These findings highlight the critical interplay between mitophagy and NLRP3 inflammasome in age-related bone loss and suggest that PAE-mediated enhancement of mitochondrial quality control represents a promising therapeutic strategy for osteoporosis management.
    Keywords:  Age-related osteoporosis; Mitophagy; NLRP3 inflammasome; Paeonol
    DOI:  https://doi.org/10.1016/j.intimp.2026.116787
  33. Mol Cell Proteomics. 2026 May 06. pii: S1535-9476(26)00078-2. [Epub ahead of print] 101582
    Dynamic proximity networks of myosin-19 (Myo19) and its mitochondrial receptors Miro2 and metaxin-3.
    Aya Attia, Jürgen Eirich, Ulrike Honnert, Petra Nikolaus, Birgit Lohmann, Iris Finkemeier, Martin Bähler.
      Myosin-19 (Myo19) plays a crucial role in mitochondrial dynamics, cristae organization and ER-mitochondria contact sites (ERMCS). It regulates cytokinesis and inheritance of mitochondria to daughter cells. To better understand the dynamic molecular network of Myo19 during the cell cycle, we determined the in vivo proximity protein interaction networks of Myo19 in interphase and prometaphase using proximity-based TurboID biotinylation followed by mass spectrometry. We further determined the proximity networks of its known mitochondrial binding partners Miro2 and metaxin-3. The outer mitochondrial membrane protein Miro2 not only binds but also stabilizes Myo19. This interaction depends on the nucleotide state of the N-terminal GTPase domain of Miro2. Therefore, we analysed both the proximity networks of Miro2 and its GTP-binding mutant Miro2 T18N. We were able to show a differential association of Myo19 during the cell cycle with functional protein clusters and a participation of Myo19 in mitochondrial trafficking, ERMCS and mitochondria intermembrane space bridging complex / cristae organizing system (MIB/MICOS). The proximity network of Myo19 showed more overlap with Miro2 than metaxin-3. Abolishing GTP-binding to the N-terminal GTPase domain of Miro2 reduced the number of proteins in proximity of Miro2 considerably. In conclusion, we discovered a comprehensive dynamic in vivo protein proximity network of Myo19 and its mitochondrial receptors Miro2 and metaxin-3.
    Keywords:  ERMCS; MIB/MICOS; MTX3; Miro2; Mitochondrial dynamics; Myo19; OMM; TurboID Proximity Labelling; actin; mitochondria; myosin
    DOI:  https://doi.org/10.1016/j.mcpro.2026.101582
  34. Free Radic Biol Med. 2026 May 02. pii: S0891-5849(26)00465-X. [Epub ahead of print]252 40-54
    Senp1 knockdown alleviates neuronal pyroptosis after subarachnoid hemorrhage by enhancing PINK1-mediated mitophagy.
    Yinrui Ma, Haibo Long, Han Xiong, Shizhen Cui, Yimin Zhuang, Haotian Wei, Zhaohui He, Jiahe Tan.
       BACKGROUNDS: Subarachnoid hemorrhage (SAH) is a critical condition in neurosurgery, and the severity of early brain injury (EBI) plays a pivotal role in determining patient outcomes. Recent studies have demonstrated that neuronal pyroptosis occurs following SAH, aggravating neuroinflammatory damage and severely affecting prognosis. Small ubiquitin-like modifier (SUMO)-specific protease 1 (Senp1), a member of the SUMO protease family, is known to be involved in the regulation of neuroinflammation. However, whether Senp1 also modulates neuronal pyroptosis to influence neuroinflammation after SAH remains unclear.
    METHODS: A total of 284 male C57BL/6J mice were used to establish the SAH model via endovascular perforation. Fourteen days prior to modeling, an adeno-associated virus carrying Senp1 shRNA was injected into the lateral ventricles of the mice for gene knockdown. Additionally, primary neurons were treated with oxyhemoglobin to simulate the in vitro SAH environment. CCCP and PINK1 siRNA were applied to enhance and inhibit mitophagy, respectively.
    RESULTS: Senp1 primarily localized in cortical neurons, with its expression being significantly upregulated following SAH and peaking at 24 h. Its knockdown markedly alleviated brain edema and improved neurological function 24 h after SAH. Moreover, its downregulation reduced the neuronal expression of NLRP3 and cleaved GSDMD, as well as the production of IL-1β and IL-18, thereby attenuating neuroinflammation. Mechanistically, Senp1 knockdown enhanced PINK1-mediated mitophagy, reducing reactive oxygen species accumulation.
    CONCLUSIONS: Our findings suggest that Senp1 knockdown enhances mitophagy, thereby inhibiting NLRP3 inflammasome-mediated neuronal pyroptosis following SAH and improving EBI and neurological prognosis.
    Keywords:  Mitophagy; Neuroinflammation; Neuron; Pyroptosis; Subarachnoid hemorrhage
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.05.001
  35. Phytomedicine. 2026 Apr 16. pii: S0944-7113(26)00445-9. [Epub ahead of print]156 158211
    Paeoniflorin modulates DL-glyceraldehyde metabolism to promote mitochondrial dynamics homeostasis and ameliorate knee osteoarthritis cartilage degeneration.
    Zugui Wu, Yue Zhu, Rong Yuan, Yuanlong Li, Jiao Li, Bo Qiao, Zhiwei Wu, Yanfei Xu, Yu Zhang, Wei Dong, Ying Guo, Xuemeng Xu.
       BACKGROUND: Knee osteoarthritis (KOA) is a common chronic degenerative joint disease, and its primary pathological feature of articular cartilage is degeneration. Paeniflorin, a bioactive terpene glycoside isolated from Paeonia lactiflora, has demonstrated a protective effect on chondrocytes, but its specific mechanism are not well understood.
    PURPOSE: The study aimed to clarify the molecular mechanism by which paeoniflorin enhances cartilage repair and metabolic functions.
    METHODS: The effects of paeoniflorin on chondrocyte were evaluated using cell staining (toluidine blue and Alcian blue), flow cytometry, PCR, Western blotting, and immunofluorescence. A destabilization of the medial meniscus (DMM) -induced rat model with KOA was established. Micro-Computed Tomography, histopathological staining, and immunohistochemistry were used to assess cartilage repair and metabolic changes. Additionally, transcriptomic and metabolomic analyses were conducted to evaluate the effects of paeoniflorin on mitochondrial dynamics-related genes and their differential metabolites. Molecular docking experiments were used to verify these targets.
    RESULTS: The in vitro experiments demonstrated that paeoniflorin markedly enhanced the proliferative activity of chondrocytes, and reduced the apoptosis rate. in vivo experiments, paeoniflorin intervention significantly improved bone volume and structural parameters of the subchondral bone in rats with KOA and facilitated the repair of cartilage damage. Combined transcriptomic and metabolomic analyses revealed that paeoniflorin promoted mitochondrial homeostasis by regulating DL-glyceraldehyde (DLG), thereby improving chondrocyte energy metabolism. Molecular docking, molecular dynamics simulations, and downstream mechanistic study indicated that paeoniflorin regulated the expression of mitochondrial dynamics-related genes by modulating DLG levels, promoting mitochondrial fusion, and inhibiting excessive fission.
    CONCLUSION: Paeoniflorin effectively ameliorated cartilage degeneration in KOA by modulating the downstream metabolite DLG to promote mitochondrial dynamic homeostasis.
    Keywords:  Cartilage degeneration; Knee osteoarthritis; Metabolomics; Mitochondrial dynamics; Paeoniflorin; Transcriptomics
    DOI:  https://doi.org/10.1016/j.phymed.2026.158211
  36. Int J Mol Sci. 2026 Apr 09. pii: 3365. [Epub ahead of print]27(8):
    Mitophagy and Immune Infiltration in Primary Sjögren's Disease: Insights from Bioinformatics Analysis.
    Liqiong Hou, Gaxue Jiang, Yanfei Chen.
      Primary Sjögren's disease (SjD) is characterized by lymphocyte infiltration into exocrine glands. Mitochondrial dysfunction is a critical pathological mechanism underlying SjD, and mitophagy plays a vital role in clearing damaged mitochondria. This study used bioinformatic analysis to explore the potential roles of mitophagy-related genes in SjD pathogenesis and immune infiltration. Bioinformatic analysis was performed on the SjD microarray datasets to identify differentially expressed genes (DEGs). Mitophagy-related DEGs were selected and analyzed using functional enrichment, protein-protein interaction (PPI) networks, and machine learning (Least Absolute Shrinkage and Selection Operator [LASSO] and Random Forest) to identify hub genes. Their diagnostic value was assessed by receiver operating characteristic (ROC) curves. Immune infiltration and its correlation with hub genes were also evaluated. Hub gene expression in the salivary glands of patients was validated using qRT-PCR. Regulatory networks were also predicted. Three hub genes (GABARAPL1, PINK1, and SQSTM1) were identified. They showed high diagnostic specificity and were downregulated in SjD salivary glands. Immune infiltration analysis revealed increased levels of activated natural killer (NK) cells, memory B cells, plasma cells, CD8+ T cells, Tfh cells, and M1 macrophages, but decreased levels of Tregs and M2 macrophages. Hub gene expression was correlated with specific immune cell subsets. Regulatory network predictions highlighted potential upstream regulators and therapeutic compounds. This study identified three mitophagy-related hub genes linked to immune dysregulation in SjD, providing novel insights into disease mechanisms and potential therapeutic targets.
    Keywords:  LASSO; bioinformatics analysis; biomarkers; immune infiltration; mitophagy; primary Sjögren’s disease; random forest
    DOI:  https://doi.org/10.3390/ijms27083365
  37. Stem Cell Rev Rep. 2026 May 05.
    Mitochondrial Regulation of Periodontal Ligament Stem Cell Fate and Function.
    Zixuan Zhao, Sijia Liu, Na Liu, Qing Liu.
      Periodontal ligament stem cells (PDLSCs) are regarded as among the most promising seed cells for periodontal tissue regeneration because of their strong self-renewal ability, multipotent differentiation potential, and accessibility. However, their biological behaviors vary significantly under different microenvironments and stimuli, and the underlying regulatory mechanisms remain unclear. Recent advances have identified mitochondria as central signaling hubs that regulate cell fate. This review summarizes current progress in understanding the role of mitochondria in modulating the biological behaviors of PDLSCs, focusing on mitochondrial reactive oxygen species and oxidative stress, mitochondrial dynamics, mitophagy, glucose metabolic reprogramming, and tricarboxylic acid cycle metabolites. We integrate evidence linking mitochondrial function with key biological processes in PDLSCs, including osteogenic differentiation, senescence, inflammation, apoptosis, and regenerative capacity. Furthermore, we highlight major unresolved issues and challenges in current research and emphasize the significant "dual effects" of mitochondria-related signaling in diverse physiological and pathological conditions. A deeper understanding of mitochondrial regulatory networks in PDLSCs may provide a theoretical foundation for mitochondria-targeted precision therapies and reveal novel therapeutic strategies for periodontal tissue regeneration and related diseases.
    Keywords:  Metabolic reprogramming; Mitochondrial dynamics; Mitophagy; Periodontal ligament stem cells; Periodontal regeneration; Reactive oxygen species
    DOI:  https://doi.org/10.1007/s12015-026-11148-y
  38. Pancreas. 2026 May 08.
    Advancements in Understanding the Interplay between Mitophagy and Acute Pancreatitis: A Comprehensive Research Overview.
    Xin Liu, Zhenzhen Huang, Peiwu Li.
      Acute pancreatitis (AP) is characterized by the abnormal activation of pancreatic enzymes within the pancreas, triggering inflammatory responses such as auto-digestion and necrosis of tissue. As a prevalent clinical condition, AP manifests with symptoms including abdominal pain, nausea, and fever, and in severe cases can be fatal. Despite its prevalence, the etiology of AP is complex, with an unknown cause and a scarcity of effective treatments. Possible triggers for AP include bile duct obstruction from gallstones, prolonged and excessive alcohol consumption, pancreatic vascular embolism, infection, and dysfunction. A noteworthy contributor to AP is the dysfunction of pancreatic cells induced by mitochondrial autophagy, an increasingly prominent focus of research in this field. Inflammatory vesicles, reactive oxygen radicals, endoplasmic reticulum stress, calcium overload, and iron-induced death are intricately linked to both mitochondrial autophagy and AP. This review consolidates insights into the pathogenesis of mitochondrial autophagy and AP, offering novel perspectives and avenues for the diagnosis and treatment of AP.
    Keywords:  acute pancreatitis; endoplasmic reticulum stress; inflammatory corpuscles; mitophagy; reactive oxygen species
    DOI:  https://doi.org/10.1097/MPA.0000000000002664
  39. J Biol Chem. 2026 May 06. pii: S0021-9258(26)02000-4. [Epub ahead of print] 113128
    The Role of Phospho-ubiquitin in Mitochondrial Health and Diseases.
    Kumar Suresh, Christopher Rainvillee, David E Sterner, Matthew S Goldberg, Tauseef R Butt.
      Mitochondria play a major role in cellular health, yet their contribution to chronic diseases has been underestimated. Mitochondria are essential for all tissues, and a major source of ATP in high-energy-demand organs such as brain and heart being vulnerable to mitochondrial dysfunction. Failure to repair or remove damaged mitochondria contributes to aging and chronic diseases. Cells have evolved quality control mechanisms, including mitophagy to eliminate damaged mitochondria and mitobiogenesis to replenish them. The ubiquitin-proteasome system (UPS) is responsible for removing misfolded proteins, a process that is highly ATP dependent and therefore reliant on mitochondrial function. In turn, damaged mitochondria are eliminated through coordinated actions of the UPS and lysosomal degradation through mitophagy. Many neurodegenerative diseases are characterized by the presence of disease-specific protein aggregates, such as α-synuclein aggregates in Parkinson's disease and tau neurofibrillary tangles in Alzheimer's disease. These aggregates impair mitochondrial function, while dysfunctional mitochondria generate reactive oxygen species that further exacerbate proteotoxic stress, creating a pathogenic cycle. This highlights the functional interplay between mitochondria and the UPS. Recent studies have uncovered phosphorylation of ubiquitin at Serine 65 by the mitochondrial kinase PINK1 as a key signal of mitochondrial dysfunction. Phospho-Ser65-Ubiquitin (pUb) has emerged as an indicator of mitochondrial health and a potential biomarker for aging and neurodegenerative disease. However, due largely to a lack of tools, little is known about the role of pUb in cellular physiology. Here we review the current landscape of pUb biology, the phospho-ubiquitome, and its role as biomarker for mitochondrial health, and neurodegeneration.
    Keywords:  (10): mitochondria; PINK1; Parkin; aging; autophagy; biomarker; mitophagy; neurodegeneration; phospho-ubiquitin; proteasome
    DOI:  https://doi.org/10.1016/j.jbc.2026.113128
  40. Front Immunol. 2026 ;17 1691848
    Combining multi-omics analysis methods to identify biomarkers for mitophagy involved in immune checkpoint inhibitors-related myocarditis.
    Jian Yu, Jiangtao Wang, Xinya Liu, Jing Shi, Yang Zhang, Cancan Wang, Li Wu, Yuanming Zhang.
       Background: Immune checkpoint inhibitors (ICIs) are prone to induce cardiovascular adverse reactions during the immunotherapy of cancer patients, among which ICIs-related myocarditis is the most severe. Mitophagy dysregulation is associated with various heart diseases, but its role in ICIs-related myocarditis remains unclear.
    Materials and methods: Mitophagy key genes in ICIs-related myocarditis were screened based on the single-cell RNA sequencing and bulk RNA sequencing data, and their expression levels and diagnostic value were verified. Meanwhile, the key genes, trajectory analysis and cell interaction were validated at the single-cell level. Finally, the myocardial injury markers, cardiac function indicators, histopathological analysis and mitophagy key genes were verified by constructing a mouse model of ICIs-related myocarditis.
    Results: A total of 4 mitophagy key genes in ICIs-related myocarditis were identified by combining multiple bioinformatics analysis methods: AW112010, Igfbp7, Tmsb4x, Ost4. The expression levels of mitophagy key genes in the ICIs-related myocarditis group were significantly higher than those in the normal group (P < 0.05 or P < 0.01), and both had high diagnostic value. Trajectory analysis and cell interaction results showed the interaction intensity and relative expression patterns among these 4 key genes. The ICIs-related myocarditis mouse model showed elevated myocardial injury markers (BNP, CK-MB, cTnT) and decreased cardiac function indicators (LVEDV, LVEF, LVIDd, LVIDs) compared to the normal group (P < 0.05 or P < 0.01). The pathological sections revealed obvious inflammation and damage in the myocardium of myocarditis group mice. Additionally, the qRT-PCR results indicated that the expression levels of AW112010, Igfbp7, Tmsb4x and Ost4 were significantly higher than those in the normal group (P < 0.05 or P < 0.01).
    Conclusion: Mitophagy is involved in the pathogenesis of ICIs-related myocarditis, and AW112010, Igfbp7, Tmsb4x and Ost4 may become potential biomarkers for future clinical practice.
    Keywords:  ICIs-related myocarditis; biomarkers; immune checkpoint inhibitors; mitophagy; single-cell RNA sequencing
    DOI:  https://doi.org/10.3389/fimmu.2026.1691848
  41. Bioorg Chem. 2026 Apr 26. pii: S0045-2068(26)00461-X. [Epub ahead of print]177 109925
    Harnessing mitohormesis: A thiazole-based mitochondrial respiration inhibitor restores metabolic homeostasis in type 2 diabetes.
    Yang Zhang, Jie Guo, Jie Jin, Ci-An Cheng, Yixin Hu, Shihao Chen, Chen Wang, Xinwei Meng, Binglu Jiang, Zhihao Jia, Yixue Qiao, Jinxin Gu, David A Tyvoll, James P Collman, Lei Fu.
      Mitohormesis, an adaptive cellular response to moderate mitochondrial stress, represents a promising therapeutic paradigm. To pharmacologically harness this phenomenon, we developed mitochondrial respiration inhibitors by conjugating a thiazole-based pharmacophore to a triphenylphosphonium (TPP) cation. Here, we report three TPP-thiazole conjugates which are distinguished by their hydrolytically labile linkers, comprising an ester (Compound 1), a more labile thioester (Compound 2), and a more stable amide (Compound 3). In vitro evaluation demonstrated that the hydrolytic stability of the linkers correlated inversely with inhibitory potency, where Compound 2 exhibited the strongest inhibition, followed by Compound 1. In contrast, Compound 3 showed negligible activity, lacking a clear dose-response relationship. As therapeutic mitohormesis requires a mild stress induction within a beneficial hormetic window, Compound 1 was selected for further investigation based on its intermediate inhibition and pronounced biphasic effects. Compound 1 activated the mitochondrial unfolded protein response (UPRmt) in Caenorhabditis elegans (C. elegans) and stimulated transcription of mitokines in both C. elegans and mice. In a murine model of diet-induced type 2 diabetes, Compound 1 significantly improved systemic metabolism, ameliorating glucose intolerance, insulin resistance, and hepatic steatosis. Furthermore, it outperformed metformin at an equivalent dose without observed toxicity. Collectively, these findings establish the rationally tuned inhibition of mitochondria as a viable small-molecule strategy for the treatment of metabolic disorders through mitohormesis.
    Keywords:  Metabolic disorders; Mitochondria; Mitohormesis; TPP-thiazole; UPR(mt)
    DOI:  https://doi.org/10.1016/j.bioorg.2026.109925
  42. ACS Nano. 2026 May 08.
    A Straw-Reinforced-Clay-Inspired Composite Hydrogel Promotes Diabetic Bone Regeneration via Driving the Immune-Osteogenic Cascade to Remodel Mitochondrial Homeostasis.
    Yuanyang Li, Zhuoya Cui, Hanrui Liao, Xiaoxuan Han, Kehong Guo, Zitong Xia, Rui Cai, Dan Zhao, Gang Tao.
      Diabetes mellitus (DM) is a chronic metabolic disorder. Bone defect repair in this condition faces significant challenges due to hyperglycemia-induced oxidative stress, chronic inflammation, and dysregulation of the immuno-osteogenic cascade. Macrophage-mediated immuno-osteogenic cascade dysfunction compromises mitochondrial homeostasis in bone marrow mesenchymal stem cells (BMSCs), disrupting the balance of bone regeneration. Therefore, modulating the immune microenvironment to restore BMSCs' mitochondrial homeostasis and osteogenic potential is crucial. This study constructed a reactive oxygen species (ROS)-responsive hydrogel matrix (AP) based on boronic ester bonds. Inspired by the "straw-reinforced clay" structure, mineralized silk fibroin short fibers doped with strontium hydroxyapatite (mSF) were introduced. These fibers were designed to enhance both the mechanical properties and the pro-angiogenic and osteogenic performance of the hydrogel. Finally, EGCG-Met nanoparticles (EM NPs) were loaded to obtain the EM@mSF-AP hydrogel. In a high-ROS microenvironment, this hydrogel intelligently releases EM NPs, scavenges ROS, and promotes macrophage polarization toward the M2 phenotype. This subsequently drives immuno-osteogenic cascade regulation, systemically restoring mitochondrial homeostasis in BMSCs: it activates the Sod2-Cat axis to enhance endogenous antioxidant capacity, restores mitochondrial membrane potential and dynamics stability, upregulates the key ATP-synthesizing enzyme COX IV, and re-establishes efficient energy metabolism. Meanwhile, mSF within the hydrogel further synergistically promotes angiogenesis and osteogenic differentiation. In animal experiments, this hydrogel improved the immune microenvironment, enhanced energy metabolism, and stimulated angiogenesis in a diabetic rat calvarial defect model, significantly accelerating new bone formation. In summary, inspired by the "straw-reinforced clay" structure, this study developed a ROS-responsive EM@mSF-AP hydrogel, elucidating a cascade therapeutic strategy centered on "immunomodulation-mitochondrial homeostasis restoration-osteogenic coupling", offering an alternative strategy for diabetic bone regeneration.
    Keywords:  diabetic bone regeneration; immuno-osteogenic cascade; mineralized short fibers; mitochondrial homeostasis; reactive oxygen species (ROS)-responsive hydrogel
    DOI:  https://doi.org/10.1021/acsnano.6c02616
  43. Cancer Lett. 2026 Apr 30. pii: S0304-3835(26)00320-4. [Epub ahead of print] 218557
    The BTN3A3-TOMM22 axis preserves mitochondrial homeostasis to facilitate HCC stemness and drug resistance.
    Xiaofeng Kang, Guanglin Lei, Xiaobo Hou, Yimeng Du, Minghao Xu, Chunyuan Xue, Donghui Liu, Songhao Jia, Jingbo Shan, Chuanhao Tang, Xiaojie Xu, An Xu.
      Cancer stemness drives malignant progression and drug resistance in hepatocellular carcinoma (HCC). Although mitochondrial dynamics are known to influence HCC development, the precise mechanisms linking mitochondrial function to stemness remain largely elusive. Integrating bulk and single-cell transcriptomics, we identified Butyrophilin Subfamily 3 Member A3 (BTN3A3) as a novel oncogene driving HCC stemness. BTN3A3 depletion markedly reduced sphere formation, stemness-related gene expression, and the percentage of CD90+/EpCAM+ cancer stem cells. Rescue experiments confirmed that BTN3A3 promotes HCC cell proliferation, migration, and invasion. Furthermore, BTN3A3 depletion sensitized HCC cells to sorafenib by inducing ROS accumulation and apoptosis. Mechanistically, mass spectrometry and Co-IP identified TOMM22 as a key mitochondrial interactor of BTN3A3. Crucially, sorafenib stress actively promotes BTN3A3 mitochondrial translocation, where it shields TOMM22 from ubiquitin-proteasome-dependent degradation. BTN3A3 deficiency led to TOMM22 depletion, mitochondrial fragmentation, and impaired oxidative phosphorylation (OXPHOS) and ATP production. Importantly, silencing TOMM22 reversed BTN3A3-mediated stemness and sorafenib resistance. In vivo orthotopic xenograft models and patient-derived organoids (PDOs) further validated that BTN3A3 correlates with stemness and malignant tumor growth. Utilizing 5E08, a pan-BTN3 monoclonal antibody, markedly suppressed tumor growth and concurrently downregulated TOMM22 expression in vivo. In conclusion, our study unveils a previously unrecognized non-immunological role for BTN3A3 in mitochondrial reprogramming. We demonstrate that BTN3A3 drives HCC stemness and drug resistance by preventing TOMM22 ubiquitination to maintain mitochondrial homeostasis. These findings position BTN3A3 as a promising therapeutic target, with the pan-BTN3 monoclonal antibody 5E08 offering a potential strategy to overcome stemness-driven malignancy and resistance in HCC patients.
    Keywords:  BTN3A3; Cancer stemness; Hepatocellular carcinoma; Sorafenib resistance; TOMM22
    DOI:  https://doi.org/10.1016/j.canlet.2026.218557
  44. Neuron. 2026 May 01. pii: S0896-6273(26)00268-0. [Epub ahead of print]
    Mitochondrial fission factor regulates mitochondrial Ca2+ homeostasis and neuronal activity in AgRP neurons.
    Almudena Del Río-Martín, Gagik Yeghiazaryan, Rui de Oliveira Beleza, Sinika Henschke, Marie H Solheim, Paul N Mirabella, Tamara Sotelo-Hitschfeld, Corinna A Bauder, Hong Jiang, Weiyi Chen, Paul Klemm, Lukas Steuernagel, Alain J de Solís, Philipp Hammerschmidt, Henning Fenselau, F Thomas Wunderlich, Peter Kloppenburg, Jens C Brüning.
      Mitochondria represent central regulators of neuronal function, and their network is dynamically restructured via fission and fusion. The mitochondrial fission factor (MFF) serves as an adaptor protein that recruits and organizes the core fission machinery at the outer mitochondrial membrane. Here, we investigated the role of MFF in Agouti-related peptide (AgRP) neurons of the arcuate nucleus of the hypothalamus (ARC) in their regulation of systemic energy homeostasis. We demonstrated that mice lacking MFF in AgRP neurons exhibited increased mitochondrial size, both in AgRP neuron somata and their axonal compartments. This translated into increased mitochondrial Ca2+ uptake capacity, increased mitochondrial membrane potential, and a shift toward a more reduced mitochondrial NAD(P)H redox state. Ultimately, these changes resulted in increased neuronal excitability and neurotransmitter release to functionally enhance dynamic food intake during energy state transitions. Collectively, MFF-dependent mitochondrial fission links cell-type-specific neuronal mitochondrial dynamics via mitochondrial Ca2+ handling to control systemic metabolism.
    Keywords:  AgRP; MFF; calcium; metabolism; mitochondria; neuronal activity
    DOI:  https://doi.org/10.1016/j.neuron.2026.03.038
  45. Redox Biol. 2026 Apr 24. pii: S2213-2317(26)00189-8. [Epub ahead of print]93 104191
    An integrated anti-aging framework targeting NAD+ homeostasis, mitochondrial quality control, and redox stability: Roles of NMN/NR, PQQ, and EGT.
    Yidan Sun, June-Chiew Han, Kenneth Tran, Toan Pham, Qiang Zhou, Jun Lu.
      As the global population ages rapidly, delaying and preventing age-related diseases have become urgent priorities in public health and biomedical research. During aging, mitochondrial dysfunction is a core molecular hallmark and a common pathogenic mechanism underlying multiple age-related disorders. Age-related mitochondrial dysfunction typically manifests as diminished metabolic capacity, impaired organelle renewal, and disrupted redox homeostasis. These factors interact to form a feedback loop constraining mitochondrial adaptability. Specifically, the interdependent decline in NAD+ availability, impaired mitochondrial biogenesis, and excessive oxidative stress render single-pathway interventions ineffective in mitigating systemic functional impairments triggered by aging. To address this complex mechanism, this review presents a novel tri-axis anti-aging model encompassing three key compounds: nicotinamide mononucleotide/nicotinamide riboside (NMN/NR), pyrroloquinoline quinone (PQQ), and l-ergothioneine (EGT). Within this framework, NMN/NR serves as a broad NAD+-dependent regulator of mitochondrial homeostasis, with its most immediate effects on metabolic activation, while PQQ and EGT may further strengthen mitochondrial remodeling and redox resilience, respectively. While each compound has distinct functional emphases, they are highly mechanistically coupled, collectively forming a closed-loop network regulating mitochondrial number, function, and homeostasis. This review synthesizes preclinical and emerging clinical evidence supporting the standalone or combined use of NMN/NR, PQQ, and EGT across various diseases. Collectively, by conceptualizing mitochondrial aging as a systemic imbalance rather than isolated molecular defects, this paper highlights a three-axis model of NMN/NR, PQQ, and EGT. This framework offers a theoretical foundation for mitochondrial-targeted anti-aging interventions while laying the groundwork for future clinical research, nutritional interventions, and the development of multi-target combination strategies.
    Keywords:  Anti-aging; Ergothioneine; Mitochondria; NMN; NR; PQQ
    DOI:  https://doi.org/10.1016/j.redox.2026.104191
  46. Antioxidants (Basel). 2026 Apr 21. pii: 513. [Epub ahead of print]15(4):
    A Standardized Onion Peel-Derived Bioactive Ingredient Attenuates Palmitate-Induced Steatosis and Oxidative Stress by Modulating Mitochondrial Dynamics and Autophagy in HepG2 Cells.
    Ilaria Di Gregorio, Vincenzo Migliaccio, Maria D'Elia, Rita Celano, Valentina Santoro, Anna Lisa Piccinelli, Mariateresa Russo, Luca Rastrelli, Lillà Lionetti.
      Onion peel represents a valuable food by-product rich in bioactive phenolic compounds. Building on previous phytochemical investigations, an onion peel extract from the Rossadi Tropea variety was developed as a standardized bioactive ingredient (OPI-T), defined by flavonol (quercetin and its glycosylated and oxidized derivatives) and anthocyanin (cyanidin derivatives) markers, ensuring batch-to-batch consistency, and evaluated for its potential against hepatic steatosis. The present study aimed to assess the protective effects of OPI-T against palmitate-induced steatosis and oxidative stress in HepG2 cells, a widely used in vitro model of hepatic lipid accumulation. An onion peel extract derived from the Ramata di Montoro variety was included as a natural negative reference to account for varietal variability. HepG2 cells were co-treated with palmitate (500 µM) and OPI-T (25 or 50 µg/mL). Lipid accumulation was evaluated by Oil Red O and BODIPY staining, while oxidative stress was assessed by the DCF assay. Mitochondrial dynamics and autophagy were investigated through the analysis of key protein markers, including MFN2, DRP1, SQSTM1/p62 and LC3 II/I. OPI-T significantly attenuated palmitate-induced lipid accumulation (-18%) and reduced intracellular ROS production (-75%), while modulating mitochondrial dynamics toward a reduced fission phenotype with a marked increase in the MFN2/DRP1 ratio (1.66) and improving autophagy flux. In contrast, the Ramata di Montoro variety showed weaker or inconsistent effects under the same experimental conditions. Overall, these findings support the functional validation of a standardized onion peel-derived ingredient, highlighting its potential application as a bioactive component for functional food or nutraceutical development targeting hepatic steatosis and oxidative stress.
    Keywords:  HepG2 cells; autophagy; mitochondrial dynamics; onion peel bioactive ingredient; oxidative stress; palmitate-induced steatosis
    DOI:  https://doi.org/10.3390/antiox15040513
  47. Exp Gerontol. 2026 Apr 30. pii: S0531-5565(26)00136-1. [Epub ahead of print]219 113157
    Metformin attenuates lens epithelial cell senescence by suppressing cGAS-STING via SIRT1-PGC-1α-mediated mitochondrial fission.
    Jialin Luo, Chaoqun Wei, Liyao Sun, Huirui Liu, Yu Mi, Qi An, Chen Yang, Xiaohan Yu, Zijian Yu, Hongyan Ge.
      UVB-induced lens epithelial cell (LEC) senescence is among the important factors involved in the pathogenesis of age-related cataract (ARC). This study aimed to investigate the anti-aging effect of metformin (Met) and to elucidate the molecular mechanisms underlying this effect. RNA sequencing, nontargeted metabolomics analysis and network pharmacology were conducted. The expression of senescence indicators (P53 and P21Cip1) and senescence-associated β-galactosidase (SA-β-gal) activity were assessed. Mitochondrial function and dynamics were evaluated by measuring the mitochondrial membrane potential (MMP), transmission electron microscope (TEM), and Western blotting. Cytosolic mtDNA was visualized by fluorescence staining, and the activation of the SIRT1-PGC-1α pathway and the cGAS-STING pathway were analysed by Western blotting. Our findings indicated that cellular senescence was predominantly responsible for UVB-induced cataract. Met attenuated UVB-induced cataract by inhibiting the senescence phenotype. Mechanistically, Met activated the SIRT1-PGC-1α pathway to inhibit mitochondrial fragmentation. This attenuation of mitochondrial fragmentation reduced mtDNA release into the cytosol, thereby inhibiting the activation of the cGAS-STING-mediated LEC senescence. Our findings on the efficacy of Met pave the way for the development of new pharmacological strategies to prevent cataract development.
    Keywords:  Age-related cataract; Metformin; Mitochondrial fission; SIRT1-PGC-1α; cGAS-STING
    DOI:  https://doi.org/10.1016/j.exger.2026.113157
  48. Antioxid Redox Signal. 2026 May 09. 15230864261442217
    Physalin A Restores Redox and Mitochondrial Homeostasis to Protect against Diabetic Retinopathy.
    Yan-Ru Xiao, Yow-Wen Hsieh, Wei-Yong Lin, Yu-Sheng Hsieh, Wei-Cheng Jiang, Pei-Ying Pai, Yueh-Hsiung Kuo, Dah-Yuu Lu, Yu-Jung Lin, Wen-Tsong Hsieh.
       AIMS: To determine whether physalin A (PA) safeguards the outer blood-retinal barrier under diabetic stress by engaging nuclear factor erythroid 2-related factor 2 (Nrf2) to restore redox balance and restrain ferroptosis in human retinal pigment epithelial (hRPE) cells and C57BLKS/J Iar -+Leprdb/+Leprdb mice.
    RESULTS: In high-glucose challenged hRPE cells, PA dose-dependently preserved viability, maintained claudin-1/occludin/zonula occludens-1 abundance and membrane localization, and reversed ferroptosis hallmarks (restored solute carrier family 7 member 11 [SLC7A11], SLC3A2, and glutathione peroxidase 4; reduced ferrous iron [Fe2+] overload and lipid peroxidation). PA restored glutathione levels, reduced malondialdehyde (MDA), and enhanced the antioxidant defense pathway mediated by Nrf2, including upregulation of heme oxygenase 1, NAD(P)H quinone dehydrogenase 1, and superoxide dismutase 2. Silencing Nrf2 abolished the effects of PA on barrier integrity and ferroptosis suppression, with rebounds in reactive oxygen species, MDA, Fe2+, and tight junction loss. In db/db mice treated systemically for 20 weeks, PA reduced Evans Blue leakage, increased retinal thickness, restored RPE tight junction proteins, and normalized mitochondrial architecture by transmission electron microscopy. PA rebalanced mitochondrial dynamics (dynamin 1-like, optic atrophy 1, fission 1, mitofusin 1, FUN14 domain containing 1), increased retinal mitochondrial DNA copy number, and partially stabilized glycemia and weight.
    CONCLUSION: PA restores redox tone, restrains ferroptosis, and preserves junctional integrity to protect the diabetic retina, with Nrf2 being indispensable for these benefits. These findings position PA as a promising adjunctive candidate for early diabetic retinopathy and support Nrf2-centered strategies to reinforce the outer blood-retinal barrier. Antioxid. Redox Signal. 00, 000-000.
    Keywords:  antioxidant; diabetic retinopathy; ferroptosis; nuclear factor erythroid 2-related factor 2; physalin A; tight junction
    DOI:  https://doi.org/10.1177/15230864261442217
  49. Antioxidants (Basel). 2026 Mar 25. pii: 410. [Epub ahead of print]15(4):
    Oleocanthal Induces Mitochondrial Dysfunction in Breast Cancer Cell Lines Depending on c-MET Expression.
    Sergi Quetglas-Llobera, Pere Miquel Morla-Barcelo, Pilar Roca, Jorge Sastre-Serra, Mercedes Nadal-Serrano.
      Oleocanthal (OC), an anti-inflammatory and antioxidant phenolic compound exclusively found in extra virgin olive oil (EVOO), has emerged as a potential anticancer agent through multiple mechanisms of action, yet its impact on key processes such as cellular metabolism remains insufficiently characterized. Here, we investigated the metabolic and mitochondrial responses to OC across different breast cancer molecular subtypes. Triple-negative (MDA-MB-231) and luminal (MCF7, T47D) breast cancer cell lines were treated with OC to evaluate cell viability, cell cycle progression, metabolic enzyme expression, mitochondrial respiration, and mitochondrial network organization. OC responsiveness differed, being highest in MDA-MB-231 and lowest in T47D cells. Lactate dehydrogenase levels decreased in all cell lines, while mitochondrial response varied. MDA-MB-231 mitochondrial function was fully impaired, while MCF7 cells showed increased respiratory activity, with marked mitochondrial fragmentation, and T47D cells largely preserved mitochondrial integrity and function. Notably, the magnitude of OC effects correlated with MET expression, an established target of OC and a prognostic factor associated with reduced relapse-free survival within the triple-negative subtype. Collectively, these findings identify OC as a modulator of cancer cell metabolism and mitochondrial dynamics, with particular relevance in MET-high triple-negative breast cancers.
    Keywords:  breast cancer subtypes; c-MET signaling; cancer metabolism; mitochondrial dynamics; mitochondrial function; oleocanthal
    DOI:  https://doi.org/10.3390/antiox15040410
  50. Antioxidants (Basel). 2026 Apr 09. pii: 465. [Epub ahead of print]15(4):
    The c-Abl-RIPK3 Axis Drives Mitochondrial Dysfunction and Impaired Mitophagy in Gaucher Disease Models.
    Cristian M Lamaizon, Renatta Tironi-Hernández, Nohela B Arévalo, Sebastián D Ahumada, Daniela A Gutiérrez, Laura Brito-Fernández, Andrea Del Campo, Silvana Zanlungo, Alejandra R Álvarez.
      Gaucher disease (GD) is characterized by the accumulation of glucosylceramide within lysosomes due to mutations in the GBA1 gene, which encodes the enzyme glucocerebrosidase. Current treatments are ineffective for patients suffering from severe neuronopathic forms of the disease. In this context, new therapeutic approaches for neuronopathic GD forms are needed. Lysosomal and mitochondrial dysfunction associated with increased oxidative stress and disturbances in the autophagic process have been described in GD. Here, we address c-Abl-RIPK3 signaling and its contribution to the accumulation of dysfunctional mitochondria in GD. Fibroblasts from patients with GBA1 mutations and neurons treated with the glucocerebrosidase inhibitor CBE exhibited alterations in the ΔΨm and mitochondrial morphology, as well as reduced capacity to form autophagosomes. Pharmacological inhibition of c-Abl or RIPK3 restored mitochondrial function and promoted autophagosome formation, along with an increase in autophagic engulfment of mitochondria in both GD models. In conclusion, the c-Abl-RIPK3 signaling pathway contributes to mitochondrial dysfunction and blockade of autophagy components in the mitochondria, both of which are altered in the neuronopathic forms of GD.
    Keywords:  Gaucher disease; RIPK3; autophagy; c-Abl; lysosomal storage disorders; mitochondrial dysfunction; mitophagy; oxidative stress
    DOI:  https://doi.org/10.3390/antiox15040465
  51. Ren Fail. 2026 Dec;48(1): 2659414
    Mitochondrial dysfunction-ferroptosis crosstalk drives renal fibrosis in chronic kidney disease.
    Lianlin Zeng, Lutao Zhu, Hailan Xu, Yangan Li, Kehui Hu.
      Renal fibrosis is a major pathological process in the progression of chronic kidney disease (CKD). It contributes to progressive loss of kidney function and may ultimately lead to end-stage renal disease. Mitochondrial homeostasis plays a central role in cellular energy metabolism and oxidative balance, while mitochondrial dysfunction is closely associated with various kidney diseases. Ferroptosis, an iron-dependent form of regulated cell death, has been increasingly implicated in kidney injury and fibrotic remodeling. This review summarizes molecular mechanisms linking mitochondrial homeostasis and ferroptosis in renal fibrosis. We discuss how disrupted iron metabolism can induce mitochondrial dysfunction and sensitize renal cells to ferroptosis, thereby promoting fibrogenesis. We integrate recent evidence on the interplay among iron homeostasis, mitochondrial dysfunction, oxidative stress, and regulated cell death pathways in renal fibrosis. We also highlight candidate therapeutic targets, including iron chelation and iron-export regulation (e.g., the FPN-hepcidin axis), restoration of the GPX4-System Xc- antioxidant defense, activation of Nrf2 signaling, and modulation of mitochondrial quality control/mitophagy.
    Keywords:  Chronic kidney disease; crosstalk; ferroptosis; mitochondrial homeostasis; therapeutic targets
    DOI:  https://doi.org/10.1080/0886022X.2026.2659414
  52. J Ovarian Res. 2026 May 02.
    Vitamin E alleviates energy stress-induced injury in yak granulosa cells by blocking the AMPK/mTOR-mitophagy-ferroptosis axis.
    Hecheng Zhang, Guorong Ye, Linjiao Bai, Peiyan Du, Mengjiao Wang, Furong Feng, Hongliang Li, Xueli Ma, Jiamei Lu, Jiangfeng Fan.
       BACKGROUND: Energy stress-induced dysfunction of granulosa cells (GCs) is a major etiological factor in diminished female reproductive performance. Although vitamin E affords cytoprotection to GCs, its specific mechanisms of action under energy stress conditions in the yak model remain unclear.
    RESULTS: This study aimed to elucidate the pathways and cell fate decisions through which vitamin E alleviates energy stress-induced damage in yak GCs. Our results indicate that energy stress triggers a signaling cascade initiated by the AMPK-mTOR pathway, which functions as an upstream regulator for downstream events. Activation of this pathway promotes PINK1/Parkin-mediated mitophagy, leading to ferroptosis, characterized by the downregulation of SLC7A11 and GPX4 and the upregulation of ACSL4. This cascade ultimately drives the cells toward apoptosis, as evidenced by an increased Bax/Bcl-2 ratio and elevated levels of Cleaved-caspase-3, along with impaired intercellular communication due to downregulation of Cx43 and Cx37. Vitamin E intervention mitigated apoptosis and rescued the expression of gap junction proteins by intercepting this AMPK-mTOR-mitophagy-ferroptosis axis.
    CONCLUSION: Our study suggests a mechanism by which vitamin E modulates GC fate via this pathway. These findings provide insight into ovarian follicular pathophysiology in yaks and may inform strategies targeted at reproductive disorders associated with energy metabolic dysregulation.
    Keywords:  AMPK/mTOR Signaling Pathway; Energy Stress; Ferroptosis; Granulosa Cells; Mitophagy; Vitamin E
    DOI:  https://doi.org/10.1186/s13048-026-02128-4
  53. Discov Oncol. 2026 May 08.
    Leveraging mitochondrial dynamics-related risk signatures to predict the prognosis and tumor microenvironment of lung adenocarcinoma.
    Li Xu, Danting Zheng, Jisong Zhang, Huihui Hu, Liangliang Dong, Enguo Chen.
       BACKGROUND: Lung adenocarcinoma (LUAD) is a highly heterogeneous disease, bringing daunting challenges in prognosis prediction. Alterations in mitochondrial dynamics (MD) are crucial in tumor generation and progression. Therefore, this study is the first to build a prognostic model based on mitochondrial dynamics-related genes (MDRGs) to predict microenvironment and potential drugs for LUAD.
    METHODS: LUAD transcriptomic data were sourced from the Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO), respectively. First, differentially expressed genes (DEGs) were screened between normal and LUAD samples in the TCGA cohort. The intersection of DEGs and MDRGs yielded differentially expressed MDRGs (DE-MDRGs). Then, a prognostic model was constructed through univariate Cox regression, LASSO Cox regression, and multivariate Cox regression analysis. A nomogram was graphed using clinical factors and the MD-related risk score (MDRS). The predictive performance of the model and the nomogram was evaluated using ROC curves. Finally, analyses on tumor microenvironment (TME), mutation, and predicted in vitro drug response were undertaken.
    RESULTS: A prognostic model based on 8 MDRGs (SLC52A3, HMGA2, CPS1, GLS2, CYP27A1, CFTR, STAR, and DRP2) was established, demonstrating relatively accurate predictive ability. The low-MDRS group had higher levels of immune cell infiltration, such as aDCs, B cells, neutrophils, and tumor-infiltrating lymphocytes. We also discovered that the tumor mutation burden in the high-MDRS group was considerably higher than that in the low-MDRS group. Additionally, the low-MDRS group was more sensitive to AZD8055, ZM447439, ERK-6604, SB505124, Tozasertib, and BMS-754807, while the high-MDRS group was more sensitive to BI-2536 and Venetoclax.
    CONCLUSION: This work set up a prognostic model for LUAD based on 8 MDRGs, pinpointing promising biomarkers and targets for LUAD treatment.
    Keywords:  Lung adenocarcinoma; Mitochondrial dynamics; Prognosis; Risk signature; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s12672-026-05038-5
  54. Phytomedicine. 2026 Apr 24. pii: S0944-7113(26)00422-8. [Epub ahead of print]156 158188
    Juyuanjian attenuates sarcopenia through dual regulation of the Akt/FoxO1 and SIRT1/PGC-1α pathways.
    Yibing Yan, Xihong Liu, Peiyuan Zhao, Xiaowei Zhang, Huifen Ma, Bing Cao, Peiyan Yang, Gai Gao, Zhishen Xie, Zhenqiang Zhang.
       BACKGROUND: Sarcopenia, an age-related degenerative disease, corresponds to "Qi Xu" syndrome in traditional Chinese medicine. Juyuanjian (JYJ), a classical Qi-tonifying formula, has shown potential against muscle atrophy and functional decline, but its molecular mechanisms are not well understood.
    PURPOSE: To investigate whether JYJ protects against sarcopenia and to elucidate its underlying mechanisms.
    STUDY DESIGN: Caenorhabditis elegans (C. elegans) RW1596, C2C12 myotube cells and senescence-accelerated mouse prone 8 (SAMP8) transgenic mice were used to explore the alleviative effect of JYJ on sarcopenia and the molecular mechanism in vivo and in vitro.
    METHODS: This study systematically evaluated the therapeutic effects of JYJ using multiple biological models. Ultra-high performance liquid chromatography-high-resolution mass spectrometry (UPLC-MS) was employed to characterize its chemical constituents, followed by network pharmacology to predict potential targets and pathways. These mechanisms were further validated through molecular biology experiments. Additionally, molecular docking and molecular dynamics (MD) simulations were conducted to elucidate the interactions and binding stability between key bioactive components and target proteins.
    RESULTS: JYJ significantly alleviated muscle fiber damage in C. elegans RW1596 and mitigated the decline in skeletal muscle mass and strength in SAMP8 mice. Furthermore, JYJ inhibited chronic low-grade inflammation by reducing tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) levels, decreasing macrophage infiltration, and suppressing nuclear factor-kappa B (NF-κB) activation. Network pharmacology analysis indicated that mitochondrial biogenesis and proteasome-mediated ubiquitin-dependent processes were the main biological processes, with protein kinase B (Akt), forkhead box O1 (FoxO1), sirtuin 1 (SIRT1), and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) as key targets. Consistent with this, JYJ enhanced the phosphorylation of Akt and FoxO1 both in vitro and in vivo, while downregulating the expression of muscle atrophy-related E3 ubiquitin ligases muscle ring finger 1 (MuRF1) and muscle atrophy F-box (MAFbx); it also upregulated the expression of SIRT1 and PGC-1α, promoting mitochondrial biogenesis and adenosine triphosphate (ATP) production. Molecular docking and 100-nanosecond MD simulations showed stable interactions between the bioactive components of JYJ and Akt/SIRT1, supported by favorable binding free energy and stable conformational dynamics.
    CONCLUSIONS: JYJ exerts anti-sarcopenic effects by dual regulation of protein degradation (Akt/FoxO1) and mitochondrial biogenesis (SIRT1/PGC-1α), providing a phytotherapeutic for sarcopenia.
    Keywords:  Akt/FoxO1 signaling; Juyuanjian; SIRT1/PGC-1α pathway; Sarcopenia; mitochondrial biogenesis
    DOI:  https://doi.org/10.1016/j.phymed.2026.158188
  55. J Cell Biol. 2026 Jul 06. pii: e202511077. [Epub ahead of print]225(7):
    Time-resolved tmFRET reveals GTP-coupled conformational changes in Mfn1.
    Sophie M Hurwitz, William N Zagotta, Sharona E Gordon, Suzanne Hoppins.
      Outer mitochondrial membrane fusion is mediated by the mitofusin paralogs Mfn1 and Mfn2. Nucleotide-driven self-assembly and conformational changes are required for regulated membrane fusion activity, but the allosteric mechanisms remain enigmatic due to incomplete structural information. In this study, we investigate the GTP-coupled conformational dynamics of Mfn1 using time-resolved transition metal ion fluorescence resonance energy transfer (tmFRET). Using the minimal Mfn1 construct with the GTPase domain and helical bundle 1 (HB1) connected by Hinge 2, we engineered FRET pairs by incorporating a fluorescent noncanonical amino acid donor and a metal ion acceptor. For each state of the catalytic cycle, we measured tmFRET with fluorescence lifetimes and determined distance distributions, which can capture complex structural heterogeneity. Our distance measurements for the GDP-bound state matched predictions from the atomic resolution structure, establishing that the same open state, with GTPase and HB1 domains far apart, exists in solution. Our data reveal that the transition state is not a single closed state with HB1 stably contacting the GTPase domain. Rather, the distance distributions indicate that the presence of GDP + Pi results in an equilibrium between the open and closed states. We also captured the GTP-bound and nucleotide-free states of Mfn1. GTP binding favors the open state, and the conformation of the apo state is distinct from any nucleotide-bound state. Together, these findings redefine our understanding of GTP-driven conformational dynamics in Mfn1, demonstrating an unexpected conformational reversal in a single catalytic cycle and a heterogeneous transition state ensemble with implications for the mechanism and regulation of mitochondrial membrane fusion.
    DOI:  https://doi.org/10.1083/jcb.202511077
  56. Burns Trauma. 2026 ;14 tkag008
    Mitochondrial dynamics in skin health and disease: energy, aging, and therapeutic perspectives.
    Rong Zhang, Tianhao Li, Fengzhou Du, Jiuzuo Huang, Nanze Yu, Xiao Long.
      As cellular energy metabolic hubs, mitochondria undergo dynamic fusion-fission cycles and autophagy that enable rapid adaptation to cellular energy demands and stress conditions. In addition to their role in energy metabolism, mitochondria are integral to cellular homeostasis and regulate cell cycle progression, differentiation, and apoptosis pathways. In recent years, the importance of mitochondrial function in skin health and disease has garnered increasing attention. Mitochondrial dysfunction has been implicated in a spectrum of skin disorders, including skin aging, psoriasis, vitiligo, keloids, scleroderma, and skin cancer. The pathogenesis of these conditions is closely linked to mitochondrial deoxyribonucleic acid (mtDNA) damage, excessive reactive oxygen species (ROS) production, and alterations in mitochondrial metabolic pathways. In terms of therapeutic strategies, this review summarizes a range of mitochondrion-targeted interventions. These treatments include the activation of the PGC-1α pathway to increase mitochondrial adenosine triphosphate synthesis, the use of antioxidants to mitigate mitochondrial ROS production, and the application of bioactive compounds and drugs to protect mitochondria or promote mtDNA repair. These approaches not only contribute to improved skin health but also provide novel insights for the treatment of skin diseases. Additionally, mitochondrial transplantation technology has shown considerable promise in skin regeneration and wound healing and is emerging as a new frontier for skin tissue repair.
    Keywords:  Diseases; Dynamics; Energy; Health; Mitochondrial; Skin
    DOI:  https://doi.org/10.1093/burnst/tkag008
  57. Naunyn Schmiedebergs Arch Pharmacol. 2026 May 05.
    Targeting the PI3K/Akt/mTOR and Nrf2 signaling axis with berberine: a novel strategy for attenuating diabetic cardiomyopathy.
    Omnia Ameen, Eman M Sweed, Mona A Kora, Asmaa Abdelkarim Kenawy, Marwa M Khalil, Suzan A Khodir.
      Diabetic cardiomyopathy (DCM) is a major contributor to heart failure in patients with diabetes. Although berberine (BBR) exhibits broad metabolic and cardiovascular benefits, its mechanistic role in DCM remains incompletely defined. Cardiovascular function was assessed using arterial blood pressure (ABP), electrocardiography (ECG), and echocardiography. Biochemical analyses included glycemic indices, lipid profile, oxidative stress markers, inflammatory cytokines, and cardiac injury biomarkers. Cardiac and aortic tissues were evaluated for calcium (Ca2⁺) content, gene expression by RT-PCR, and immunohistochemical changes. DCM rats exhibited significant increases in ABP, left ventricular internal diameter, fasting glucose, HbA1c, cholesterol, triglycerides, LDL-C, malondialdehyde, tumor necrosis factor-α, interleukin-17, cardiac enzymes, Caspase-3 expression, and myocardial and aortic fibrosis, accompanied by marked ECG abnormalities. Conversely, ejection fraction, fractional shortening, serum insulin, HDL-C, superoxide dismutase activity, interleukin-10 levels, cardiac Ca2⁺ content, and expression of phosphoinositide 3-kinase (PI3K), protein kinase B (Akt), mammalian target of rapamycin (mTOR), nuclear factor erythroid 2-related factor 2 (Nrf2), and PTEN-induced putative kinase protein 1 (PINK1) were significantly reduced. Combined insulin and BBR treatment produced greater improvement in cardiac structure, function, and molecular signaling than either treatment alone. Berberine, particularly as an adjunct to insulin therapy, effectively attenuates DCM by reducing hyperglycemia, dyslipidemia, oxidative stress, inflammation, fibrosis, and apoptosis, while enhancing mitophagy and cardiac Ca2⁺ homeostasis. These effects are mediated, at least in part, through the coordinated modulation of the PI3K/Akt/mTOR and Nrf2 signaling pathways.
    Keywords:  Apoptosis; Berberine; Ca+2 ; Diabetic cardiomyopathy; Ejection fraction; Mitophagy
    DOI:  https://doi.org/10.1007/s00210-026-05407-5
  58. Adv Sci (Weinh). 2026 May 04. e21238
    Cuproptosis and Mitophagy Mediated by the THUMPD1/IGF2R-Dependent Suppression of AKT and Activation of AMPK Signaling Suppress Lung Adenocarcinoma Progression.
    Kai Wu, Bo Qin, Zhuoyu Gu, Weizheng Ding, Xiaoming Chen, Kaishang Zhang, Yujin Qiao, Shuang Yuan, Song Zhao, Xiangnan Li, Peng Zhang.
      Lung adenocarcinoma (LUAD) remains a leading cause of cancer-related mortality. N4-acetylcytidine (ac4C) modification regulates mRNA stability and translation, but the role of its associated co-factor, THUMP domain-containing protein 1 (THUMPD1), in cancer is unknown. Clinical LUAD samples and Gene Expression Omnibus (GEO) datasets were analyzed for THUMPD1 expression and prognosis. In vitro and in vivo functional assays were performed to assess the impact of THUMPD1 on LUAD. Multi-omics approaches and mechanistic studies were employed to identify downstream targets and signaling pathways. THUMPD1 was significantly downregulated in advanced-stage LUAD. THUMPD1 acted as a tumor suppressor, inhibiting LUAD cell proliferation, metastasis, and tumor growth in mouse models. Mechanistically, THUMPD1 directly bound to and upregulated the translation of insulin-like growth factor 2 receptor (IGF2R) mRNA in an ac4C-independent manner by facilitating its cytoplasmic localization. The THUMPD1-IGF2R axis inhibited AKT signaling, which in turn led to the activation of AMPK. This resulted in intracellular Cu+ accumulation, triggering cuproptosis and excessive mitophagy, ultimately suppressing tumor growth. Therapeutically, the copper ionophore elesclomol potently inhibited tumor growth in a Thumpd1-knockout mouse model of LUAD.
    Keywords:  IGF2R; THUMPD1; cuproptosis; lung adenocarcinoma; mitophagy
    DOI:  https://doi.org/10.1002/advs.202521238
  59. EMBO Rep. 2026 May 02.
    STREMI: a dual-function upstream ORF-encoded regulator of mitochondrial cristae architecture.
    Ruiyang Guo, Yabo Guo, Runguo Shu, Jiajia Qian, Jiawei Wang, Ruobing Li, Ti Qin, Ziyi Wang, Hongtao Tian, Mengchen Wu, Long Zhou, Xiaogang Guo, Shan Zhang.
      Eukaryotic mRNAs typically encode a single functional polypeptide, a principle challenged by the discovery of widespread non-canonical peptide-coding ORFs within 5'UTRs. However, their functional significance at the protein level remains underexplored. Using a four-layered pipeline, we identify 14 human transcripts predominantly transcribed in polycistronic forms, each encoding two conserved proteins. Focusing on the SLC35A4 transcript, we show that its 5'UTR encodes a mitochondrial inner membrane-localized microprotein that we name STREMI (SLC35A4 stress response regulating MICOS interactor). Sharing topology and motifs with the MICOS core subunit MIC10, STREMI regulates mitochondrial cristae morphogenesis in mice and human cells. Additionally, the STREMI-encoding uORF mediates stress-responsive translation of SLC35A4-a Golgi nucleotide sugar transporter-upregulating its translation during the integrated stress response. Evolutionary analyses indicate that these bicistronic transcripts likely arose through transcriptional readthrough following retroposition. We propose a mechanism of "gene symbiosis" that enables functional partitioning and coordinated translation of protein pairs from bicistronic transcripts.
    DOI:  https://doi.org/10.1038/s44319-026-00783-8
  60. Nat Commun. 2026 May 07.
    Triose phosphate isomerase 1 remodels mitochondrial cristae ultrastructure to rewire microglial immunometabolism against ischemic stroke.
    Xiao-Wen Zhang, Xiao-Ming Ye, Ran Wang, Yong-Dong Guo, Ling Li, Yang Chen, Ting-Ting Liu, Xiao-Qing Zhou, Yu-Qi Wang, Zhong-Yao Li, Zhi-Yuan Lu, Zhi-Yong Du, Wei Zhou, Bo Han, Peng-Fei Tu, Qi-Xin Chen, Chun-Hong Zheng, Ke-Wu Zeng.
      Mitochondrial cristae ultrastructure enables ATP synthase organization for adaptive energy production. This process is critical for regulating microglia mediated neuroinflammation in ischemic stroke pathology. However, therapeutic strategies targeting cristae remodeling remain unexplored. We identified a chemical probe, icariin II (ICS), which restores mitochondrial cristae by targeting triose phosphate isomerase 1 (TPI1). ICS-induced TPI1 conformational switching recruits ATP5MF to drive F1Fo-ATP synthase dimerization, thereby resulting in cardiolipin-mediated membrane curvature generation for cristae morphogenesis. Functionally, TPI1-targeted intervention reprograms microglial immunometabolism by rescuing oxidative phosphorylation, suppressing mtDNA-STING neuroinflammation, and promoting M2 polarization. In vivo, pharmacologically targeting TPI1 inhibits microglial activation to reverse the pathological processes in a middle cerebral artery occlusion rat model (male only). Further, evidence from stroke patients suggests an association between TPI1 and microglial activation. Collectively, our findings reveal that cristae plasticity is a promising therapeutic target for mitochondrial disorders, with TPI1 as a central regulator for ischemic stroke.
    DOI:  https://doi.org/10.1038/s41467-026-72779-w
  61. Chem Biol Interact. 2026 Apr 30. pii: S0009-2797(26)00223-1. [Epub ahead of print]434 112115
    Morin hydrate mitigates renal ischemia-reperfusion injury in association with modulation of TXNIP/NLRP3 inflammasome signaling and FOXO1/PGC-1α-mediated mitochondrial regulation.
    Marwa Mohanad, Sally A El-Awdan, Basma E Aboulhoda, Hend AbdAllah, Maha A E Ahmed.
       BACKGROUND: Kidney ischemia-reperfusion (I/R) injury is a major cause of acute kidney injury. This study assessed the renooprotective effects of morin hydrate (MH) and its association with inflammatory and mitochondrial regulatory pathways in an I/R rat model.
    METHODS: Molecular docking predicted the potential binding of MH with thioredoxin interacting protein (TXNIP)-thioredoxin (TRX) complex. Rats were assigned to four groups: sham, I/R, and I/R + MH (20 or 40 mg/kg). Renal function, oxidative stress markers, inflammatory mediators, apoptosis-related proteins, mitochondrial markers, and histopathology were assessed.
    RESULTS: Docking analysis suggested a potential interaction of MH with the TXNIP-TRX interface (ΔG = -8.0 kcal/mol). In vivo, MH reduced I/R-induced increase in serum creatinine and blood urea nitrogen. MH restored mitochondrial-related parameters, including NADH dehydrogenase, cytochrome c oxidase subunit 2, and ATP levels, and mitigated oxidative stress, as indicated by reduced carbonyl protein levels and restored glutathione content. MH was also associated with reduced TXNIP, NOD-like receptor protein 3 (NLRP3), and proinflammatory cytokine levels. Apoptotic markers, including phosphorylated apoptosis signal-regulating kinase 1, caspase-3, and the Bax/Bcl2 ratio, were reduced. MH was associated with downregulation of Forkhead box protein O1 (FOXO1) and dynamin-related protein-1 and, upregulation of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) and mitofusin-1. Histological findings supported these results.
    CONCLUSION: MH attenuated renal I/R injury and was associated with reduced oxidative stress, inflammation, and apoptosis, along with improved mitochondrial-related parameters. These findings suggest that MH-mediated renoprotection is associated with coordinated changes in TXNIP/NLRP3 signaling and FOXO1/PGC-1α-related mitochondrial responses. Further research is necessary to elucidate the underlying mechanisms.
    Keywords:  Acute kidney injury; FOXO1-PGC-1α; Ischemia-reperfusion; Mitochondrial dynamics; Morin hydrate; TXNIP-NLRP3 inflammasome
    DOI:  https://doi.org/10.1016/j.cbi.2026.112115
  62. Int J Mol Sci. 2026 Apr 14. pii: 3499. [Epub ahead of print]27(8):
    Synphilin-1 Is Essential for Cytoskeletal Integrity of Brain Ventricular Cilia and Mitochondrial Proteostasis.
    Malik Farhoud, Ankit Kumar Shah, Nicole Pavoncello, Haya Hamza, Fatimah Abd Elghani, Vered Shani, Michal Toren-Hershkoviz, Sofia Zaer, Galit Saar, Lihi Shaulov, Zagorka Vitic, Claude Brodski, Inon Maoz, Salman Zubedat, Avi Avital, Hazem Safory, Simone Engelender.
      Parkinson's disease (PD) is a common neurodegenerative disorder marked by progressive loss of dopaminergic neurons in the substantia nigra pars compacta and the accumulation of Lewy bodies, intracellular inclusions enriched in α-synuclein. Synphilin-1 interacts with α-synuclein, localizes to Lewy bodies, and has been implicated in inclusion formation and neuroprotection in cellular and animal models; however, its physiological function in vivo remains poorly defined. Here, we generated and characterized a synphilin-1 knockout (Sph-1 KO) mouse by targeted genetic deletion of the Sph-1 locus and performed a comprehensive phenotyping battery including behavioral testing as well as biochemical, histological, structural, and ultrastructural analyses. Sph-1 KO mice survived to nearly two years of age and showed normal body weight, lifespan, motor performance, learning and memory, anxiety-like behavior, attention, and gross brain morphology. Western blot analyses indicated that levels of α-synuclein and synaptic proteins were largely unchanged. While outer mitochondrial membrane proteins were unaffected, the mitochondrial matrix protein HSP60 was reduced, consistent with altered mitochondrial proteostasis in the absence of synphilin-1. Strikingly, histochemical analyses, magnetic resonance imaging, and electron microscopy revealed early-onset hydrocephalus in Sph-1 KO mice associated with severe loss and disorganization of motile ependymal cilia in the ventricular lining, a cell type that normally expresses high levels of synphilin-1. Ultrastructural and immunohistochemical analyses revealed disrupted ependymal architecture, mislocalization of acetylated α-tubulin to the cytoplasm, cellular swelling, and enlarged, aberrant mitochondria, whereas cortical neurons appeared largely structurally unaffected. Together, these findings identify synphilin-1 as a key regulator of microtubule organization and cytoskeletal/organelle homeostasis in ependymal cells, required to maintain motile ciliogenesis, cerebrospinal fluid flow, and ventricular integrity. This unexpected role for synphilin-1 in ciliated brain epithelia, along with a reduction in the critical mitochondrial chaperone HSP60, broadens our understanding of synphilin-1 biology and provides a new framework for its potential relevance to PD-associated pathology.
    Keywords:  Parkinson’s disease; cilia; hydrocephalus; microtubules; neurodegeneration; synphilin-1
    DOI:  https://doi.org/10.3390/ijms27083499
  63. bioRxiv. 2026 Apr 29. pii: 2026.04.27.721030. [Epub ahead of print]
    The trypanosomatid dynamin-like protein associates with glycosomes.
    Madeline F Malfara, Blyssalyn V Bieber, Rodolpho O O Souza, Thomas Beer, Hsin-Yao Tang, Megan L Povelones.
      Subcellular organelles must undergo periodic fission to be evenly distributed during cell division. These division events are mediated by protein members of the dynamin family, including dynamin-related proteins. Protozoan parasites, including trypanosomatids such as Trypanosoma brucei , have several single-copy organelles, suggesting tightly regulated systems for organelle fission and segregation. However, trypanosomatid genomes typically encode only one dynamin-like protein (DLP), which in T. brucei has multiple roles including endocytosis and mitochondrial fission. How DLPs are recruited to different membranes, and how their fission activity is regulated, are unknown. We used tandem-affinity purification in the related trypanosomatid Crithidia fasciculata to identify interacting partners of DLP. Surprisingly, we found that Cf DLP co-purified with multiple proteins predicted to localize to glycosomes, peroxisome-related glycolytic organelles. Using expansion microscopy, we confirmed the localization of Cf DLP to glycosomes, specifically those that appear to be undergoing division. To see if changes in the levels of DLP could alter glycosome morphology, we conducted RNAi-mediated knockdown and inducible overexpression experiments in T. brucei . Tb DLP knockdown causes subtle changes in glycosome size, while overexpression of Tb DLP1 causes an increase cytoplasmic vesicles and altered permeability of glycosomal membranes. These results suggest that the multifunctional DLP of trypanosomatids plays a role in glycosome maintenance.
    Author Summary: Trypanosomatids are eukaryotic parasites that cause devastating diseases in humans and animals. Like all eukaryotic cells, they must maintain their subcellular compartments through organelle division and other membrane remodeling events. Dynamin-like proteins are enzymes that work with other proteins to apply mechanical force to membranes. The dynamin-like proteins of Trypanosoma brucei , the causative agent of human African trypanosomiasis, have been implicated in endocytosis and mitochondrial division, although how these activities are regulated is not known. We have used a model trypanosomatid, the mosquito parasite Crithidia fasciculata , to look for dynamin-interacting proteins. In addition to proteins of unknown function, we show that dynamin-like protein associates with proteins found on glycosomes, trypanosomatid-specific organelles that contain enzymes required for breakdown of sugars. Knockdown and overexpression of dynamin-like proteins in T. brucei causes changes in glycosomes, supporting a role in organelle maintenance. Dynamin-like proteins likely regulate organelle structure and function, allowing parasites to adapt to different energetic requirements during their life cycle.
    DOI:  https://doi.org/10.64898/2026.04.27.721030
  64. J Pharm Pharmacol. 2026 May 02. pii: rgag038. [Epub ahead of print]78(5):
    Cynandione A improves white adipose tissue homeostasis in high-fat diet-fed mice.
    Atsushi Sawamoto, Misaki Shiba, Satoshi Okuyama, Chan Jae Cho, Jae Hyun Kim, Mitsunari Nakajima.
       OBJECTIVES: Cynandione A (CA), a major bioactive compound isolated from Cynanchum wilfordii Radix, is a crude drug traditionally used in East Asia. We have previously demonstrated that CA induces a beige adipocyte-like phenotype in vitro. This study aimed to investigate the in vivo effects of CA on white adipose tissue (WAT) function.
    METHODS: C57BL/6 J mice were fed a high-fat diet (HFD) and administered CA (5 or 15 mg/kg, intraperitoneally, once daily) for eight weeks. Body weight, glucose tolerance, insulin sensitivity, and serum parameters were evaluated. Histological analyses of WAT and liver were performed, and gene and protein expression related to beige adipocyte features and mitochondrial biogenesis were assessed in inguinal WAT (iWAT).
    KEY FINDINGS: CA treatment did not affect body weight, glucose tolerance, insulin sensitivity, or serum parameters. However, adipocyte size was significantly reduced in inguinal and epididymal WAT in mice treated with CA at 15 mg/kg (43.8% reduction, P < .001; 33.1% reduction, P = .021, respectively). Moreover, CA increased the expression of beige adipocyte-specific genes (Tmem26, 2.8-fold, P < .001; Cd137, 3.8-fold, P < .001) and mitochondrial marker proteins (UCP1, 2.1-fold, P = .007; TOM20, 2.2-fold, P < .001; VDAC, 1.6-fold, P = .019) in iWAT.
    CONCLUSIONS: CA modulates WAT plasticity and improves WAT homeostasis in HFD-fed mice.
    Keywords:  Cynandione A; UCP1; beige adipocyte; metabolic health; mitochondrial biogenesis; white adipose tissue
    DOI:  https://doi.org/10.1093/jpp/rgag038
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