bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2026–02–08
67 papers selected by
Gavin McStay, Liverpool John Moores University
  1. Leonurine alleviates DSS-induced colitis in mice by activating the PINK1/Parkin-mediated mitophagy pathway: an integrated network pharmacology and experimental validation study.
  2. Targeting mitochondrial quality control in diabetic kidney disease: emerging therapeutic opportunities.
  3. Anti-tumor effects of Guggulsterone in osteosarcoma: Role of SIRT3-mediated PINK1-Parkin mitophagy activation.
  4. Mitochondrial iron overload is associated with lysosomal dysfunction-mediated mitophagy impairment in the heart of Friedreich's ataxia.
  5. UBA5 deficiency disrupts mitochondrial autophagy via the PINK1-parkin pathway and impairs myoblast proliferation.
  6. A2AR antagonist IDPU facilitates the restoration of mitochondrial dynamics in 6-OHDA-induced primary mid-brain neuronal cells, via regulating p38MAPK/Parkin/DJ-1/DRP1 axis.
  7. Enhancing Mitophagy with PEP-1-CAT Attenuates Vascular Inflammation and Atherogenesis in Mice.
  8. Parkin protects against traumatic brain injury through regulating mitochondrial quality control.
  9. Xanthatin Targets CISD1 to Drive Ferroptosis and Mitophagy as a Dual Anticancer Strategy in Triple-Negative Breast Cancer.
  10. Peripheral alterations of mitochondrial function and mitophagy in Alzheimer's disease: from fundamental research to clinical perspectives.
  11. Thrombospondin 1 aggravates cardiac remodeling in heart failure with preserved ejection fraction by inhibiting mitophagy.
  12. Mitophagy in pancreatic cancer: mechanistic insights and implications for novel therapeutic strategies.
  13. PF protects retinal pigment epithelial cells from oxidative injury by enhancing mitophagy through a CUL3-dependent AMPK/ULK1 pathway.
  14. HUWE1 regulates mitophagy to protect dopaminergic neurons from 6-OHDA- and MPP⁺-induced neurotoxicity.
  15. Mitophagy Inhibition Suppresses Seizures in Status Epilepticus Mice by Decreasing Hippocampal NLRC4 Expression.
  16. Mesenchymal Stem Cell-derived Exosomes Alleviate Oxidative Stress and Brain Injuries Through Promoting OPA1 Mediated Mitochondrial Fusion After Intracerebral Hemorrhage.
  17. Leveraging mitochondrial stress to improve healthy aging.
  18. Proton pump inhibitors accelerate vascular calcification via COX-2-mediated mitophagy inhibition in chronic kidney disease.
  19. ROS-responsive diselenide exosomes restores mitophagy to resolve sterile inflammation in liver IRI.
  20. HIF-1α/BNIP3-mediated mitophagy mitigates cerebral ischemia/reperfusion injury in rats by suppressing NLRP3 inflammasome activation.
  21. Crocin alleviates doxorubicin-mediated cardiotoxicity by activating PINK1-dependent cardiomyocyte mitophagy.
  22. Role of Septin7 in mitochondrial dynamics and oxidative metabolism in C2C12 skeletal muscle cells.
  23. The mitochondrial intermembrane space nuclease Nuc1 (endonuclease G) prevents mitophagy-mediated mtDNA escape in yeast.
  24. Citronellal Alleviates Myocardial Senescence by Enhancing Mitochondrial Autophagy via AMPKα-PINK1/Parkin Pathway.
  25. Scoparone induces mitophagy and apoptosis via ROS accumulation in pancreatic cancer cells.
  26. Human in vitro and rodent in vivo models highlight progressive mitochondrial dysfunction as a starting point of cerebral amyloidosis.
  27. USP34 attenuates cartilage degradation in temporomandibular joint osteoarthritis by ANT1-mediated mitophagy.
  28. Mitochondrial transfer: A novel mechanism and promising therapeutic strategy in ageing kidney.
  29. Far-infrared irradiation restores mitochondrial dynamics to ameliorate ischemic stroke.
  30. Melatonin protects against fluoride-induced developmental neurotoxicity by alleviating abnormal mitophagy and apoptosis via the PINK1/Parkin pathway.
  31. Visualizing PINK1 Activity Dynamics in Single Cells with a Phase Separation-Based Kinase Activity Reporter.
  32. Inhibition of TRPV4 Regulates Mitophagy Through the Sirt1/FoxO1 Signaling Pathway To Alleviate Acute Lung Injury.
  33. (Pro)renin receptor (PRR) exacerbates diabetic cardiomyopathy by suppressing LRRK2-Mediated mitophagy and promoting senescence.
  34. Mitochondrial changes in clear cell renal cell carcinoma: mechanisms and potential targets.
  35. PRKN activation for mitophagy requires an NME3-regulated phosphatidic acid signal that separates mitochondria from endoplasmic reticulum tethering.
  36. Co-exposure to PFOA, PFBA and nanoplastics synergistically exacerbates neurotoxicity by impairing PINK1/Parkin-mediated mitophagy.
  37. Bushen Huoxue decoction alleviates bisphenol a-induced infertility through the PMK-1 mitogen-activated protein kinases signaling pathway and downstream mitochondrial unfolded protein response in Caenorhabditis elegans.
  38. MRPL13 Deficiency Triggers Trophoblast Mitochondrial Unfolded Protein Response in Early-Onset Preeclampsia.
  39. CHCHD2, Rather than FBXO7, Plays an Essential Role in Modulating the MPP+-Induced mtUPR.
  40. SLC7A11-FUNDC1 Axis Drives Cr(VI)-Induced Renal Injury through Mitophagy-Ferroptosis Crosstalk.
  41. Identification of Mitophagy-Related Genes With Diagnostic Value in Atherosclerosis Using Bioinformatics Analysis and Experiment Validation.
  42. Acetate ameliorates glucolipid metabolic dysregulation and neuroinflammation in diabetic cognitive impairment via enhanced mitophagy.
  43. Targeting the GPX4-FUNDC1 Interaction with Magnesium Lithospermate B Attenuates Sepsis-Associated Lung Injury.
  44. A Recombinant Antibody Against Human DRP1 Serine 616 Phosphorylation Enables Detection of BRAF V600E -Associated Mitochondrial Division in Cancer.
  45. Targeted Extracellular Vesicles Deliver Asiaticoside to Inhibit AURKB/DRP1-Mediated Mitochondrial Fission and Attenuate Hypertrophic Scar Formation.
  46. Endothelial versus global METRNL reveals importance of endothelial METRNL against atherosclerosis via mitochondrial homeostasis.
  47. Dapagliflozin attenuates hypothyroidism induced liver and lung dysfunction via regulation of mitophagy and apoptosis.
  48. Baitouweng decoction regulates ferroptosis-mediated mitophagy and apoptosis through the SLC7A11/GPX4/FTH1 pathway in ulcerative colitis.
  49. Nicotinamide phosphoribosyltransferase activates the mitochondrial unfolded protein response to promote pulmonary arterial endothelial cell proliferation.
  50. Turning Off the Powerhouse: Mitochondria-Targeted DPPZ-Ru(II)/Ir(III)/Re(I) Complexes Trigger Dual Mitophagy and Apoptosis To Halt Triple-Negative Breast Cancer.
  51. PGAM1-dependent VDAC1 oligomerization disrupts mitochondrial quality control to drive doxorubicin cardiotoxicity via the cGAS-STING-ferroptosis axis.
  52. MiR-499-5P/PACS2/TRPV1 Axis Maintains Mitochondrial Homeostasis and Left Ventricular Function after Extreme Cold Stress.
  53. Role of LONP1 in human diseases: molecular mechanisms and therapeutic potential.
  54. Curcumin-loaded silk fibroin scaffold promotes cartilage regeneration by inhibiting angiogenesis via Drp1/ROS-mediated mitochondrial regulation.
  55. Cis or trans: a puzzle of Parkin activation mechanism.
  56. [The mechanism of the effect of GalNAc-T4 on the mitochondrial autophagy of the injury of H9c2 cardiomyocytes induced by hypoxia/reoxygenation under high glucose environment via extracellular signal regulated kinase 1/2 signaling pathway].
  57. Recovery from apoptosis in photoreceptor cells: A role for mitophagy.
  58. Melittin alleviates osteoarthritis via mitophagy mediated by the AMPK/PINK1/Parkin Axis.
  59. MIRO1-mediated mitochondrial fusion is required for stomatal immunity in Arabidopsis.
  60. CLIPPER Regulates LPIN1-Mediated Mitochondrial Biogenesis and Heart Regeneration.
  61. Exosomal miR-21 mitigates pulmonary hypertension-induced right-heart remodeling by preserves mitochondrial homeostasis.
  62. LONP-1 deficiency causes dysregulated protein synthesis within mitochondria that is restored by mitoribosomal mutations.
  63. TRIM28 aggravates myocardial infarction-induced cardiomyocyte apoptosis through regulating the stability of ATF5 via ubiquitination and SUMOylation.
  64. Effect of Tofogliflozin on Skeletal Muscle Mitochondrial Function in Male Diabetic Mice With Muscle Atrophy.
  65. Biomimetic carboxymethyl β-glucan-ZIF-8 nanocarrier enhances structural stability, gastrointestinal release, and antioxidant efficacy of urolithin A via dectin-1-engaged mitophagy.
  66. NRAS and SREBF1 identified as mitophagy-associated risk genes for rheumatoid arthritis through interpretable machine learning and experimental validation studies.
  67. Kaempferol alleviates T-cell immunosenescence and inflammaging in aged mice via the SIRT3-LKB1-AMPK-mitophagy pathway.
  1. Naunyn Schmiedebergs Arch Pharmacol. 2026 Feb 05.
    Leonurine alleviates DSS-induced colitis in mice by activating the PINK1/Parkin-mediated mitophagy pathway: an integrated network pharmacology and experimental validation study.
    Tingting Cao, Juan Zhang, Wei Song, Guozhong Ji, Honggang Wang.
      Ulcerative colitis (UC) is a chronic inflammatory disease with an unclear pathogenesis. This study aimed to investigate the therapeutic mechanism of leonurine in UC. Using network pharmacology and bioinformatics analysis, we identified the PINK1/Parkin-mediated mitophagy pathway as a key target. Validation in a DSS-induced colitis mice model showed that leonurine significantly alleviated colonic injury, reduced inflammatory cytokines, and restored intestinal barrier function. Mechanistically, leonurine upregulated the expression of mitophagy-related proteins (PINK1, Parkin, LC3II) and improved mitochondrial morphology. In conclusion, leonurine ameliorates UC by activating the PINK1/Parkin-mediated mitophagy pathway, providing a scientific basis for its development as a potential therapeutic agent.
    Keywords:  Leonurine; Mitophagy; PINK1/Parkin pathway; Ulcerative colitis
    DOI:  https://doi.org/10.1007/s00210-026-05058-6
  2. Ren Fail. 2026 Dec;48(1): 2620218
    Targeting mitochondrial quality control in diabetic kidney disease: emerging therapeutic opportunities.
    Jiajun Luo, Fuer Lu, Magdalena Cuciureanu, XiaoHu Xu, Hui Dong, Minmin Gong.
      Diabetic kidney disease (DKD) is one of the most common microvascular complications among individuals with diabetes and has become a leading cause of end-stage renal disease (ESRD). The mechanisms underlying DKD are complex, and effective therapeutic strategies remain limited. Mitochondrial dysfunction occurs earlier than proteinuria and renal morphological changes, and is considered a key event in the progression of DKD. Mitochondrial dysfunction in diabetic kidneys involves several processes, including excessive production of mitochondrial reactive oxygen species, reduced mitochondrial biogenesis, impaired mitophagy, and disturbances in mitochondrial dynamics. Recently, mitochondria-targeted drugs, including antioxidants, CD38 inhibitors, glucose-linked transport 2 sodium inhibitor (SGLT2i), and compounds derived from traditional Chinese medicine, have shown positive effects in animal experiments or clinical trials. This review aims to highlight the role of mitochondrial quality control and dysfunction in DKD, the specific mitochondrial regulators of different renal cell types, as well as the therapeutic potential of some emerging drugs and the limitations of existing preclinical evidence, thereby identifying promising therapeutic targets and strategies for the disease.
    Keywords:  Diabetic kidney disease; mitochondrial dysfunction; mitochondrial quality control; oxidative stress
    DOI:  https://doi.org/10.1080/0886022X.2026.2620218
  3. Phytomedicine. 2026 Jan 20. pii: S0944-7113(26)00100-5. [Epub ahead of print]153 157860
    Anti-tumor effects of Guggulsterone in osteosarcoma: Role of SIRT3-mediated PINK1-Parkin mitophagy activation.
    Lingyuan Zeng, Shuwei Li, Kaidong Wu, Xiaoyu Bai, Long Zhang.
      Osteosarcoma (OS) is an aggressive primary bone malignancy characterized by limited therapeutic options and poor prognosis in advanced stages. Guggulsterone (GS), a naturally occurring plant-derived sterol, has recently been reported to suppress OS progression by inhibiting glycolysis via the MAPK signaling pathway. Although these findings underscore the therapeutic potential of GS in OS, the contribution of mitochondrial quality control to its antitumor activity remains unclear. Here, we report that GS disrupts mitochondrial integrity, elevates oxidative stress, and drives enhanced mitophagy in OS cells. RNA sequencing combined with functional assays revealed significant enrichment of mitophagy-related pathways, while rescue experiments confirmed that blocking mitophagy or SIRT3 activity markedly alleviated GS-induced mitochondrial damage, apoptosis, and growth inhibition. Mechanistically, GS activated the SIRT3-dependent PINK1/Parkin axis in a time-dependent manner, providing compelling evidence for its involvement in mitophagy regulation. Importantly, GS markedly inhibited OS tumor growth in vivo without causing detectable systemic toxicity. Collectively, our findings identify a mechanism distinct from the previously reported glycolysis/MAPK pathway, thereby broadening the mechanistic understanding of GS and underscoring its potential as a mitochondria-targeted therapeutic strategy for OS.
    Keywords:  Guggulsterone; Mitophagy; Osteosarcoma; PINK1-Parkin; SIRT3
    DOI:  https://doi.org/10.1016/j.phymed.2026.157860
  4. Mitochondrion. 2026 Feb 04. pii: S1567-7249(26)00010-3. [Epub ahead of print]88 102120
    Mitochondrial iron overload is associated with lysosomal dysfunction-mediated mitophagy impairment in the heart of Friedreich's ataxia.
    Eunbin Jee, Maisha Medha, Hwayoung Baek, Jonghan Kim, Yuho Kim.
      Friedreich's ataxia (FRDA) is a rare disease caused by deficiency of frataxin, a mitochondrial protein essential for iron-sulfur cluster assembly and iron homeostasis. In addition to neurological symptoms, cardiac dysfunction is common and represents a major cause of premature death in FRDA. Although iron overload has been suggested as a major player for FRDA-related cardiomyopathy, its underlying mechanisms remain unclear. Using heart-specific frataxin deficient mice, we observed that FRDA-related cardiac hypertrophy is accompanied by mitochondrial iron overload. Transmission electron microscopy (TEM) revealed iron aggregates within cardiac mitochondria, whose ultrastructure was severely altered. Along with the iron deposits and structural abnormalities, mitochondrial respiration was markedly impaired in FRDA hearts, despite the absence of increased oxidative stress. Notably, although dysfunctional mitochondria accumulate in parallel with enhanced mitochondrial biogenesis, the clearance of damaged or dysfunctional mitochondria (i.e., mitophagy) is disrupted, as evidenced by excessive accumulation of p62 and Parkin proteins. The lysosomal system, which plays a central role for mitochondrial turnover, appears to be dysregulated via the mTOR-TFEB axis. Hyperactivation mTOR inhibits lysosomal biogenesis and function, although lysosomal content remains unchanged. Collectively, our study provides mechanistic insight into the role of mitochondrial iron aggregates in the pathogenesis of FRDA-related cardiomyopathy and suggests a potential contribution of lysosomal dysfunction to impaired mitochondrial quality control in the context of cardiac frataxin deficiency.
    Keywords:  Cardiomyopathy; Frataxin; Iron overload; Lysosome; Mitophagy
    DOI:  https://doi.org/10.1016/j.mito.2026.102120
  5. Biol Res. 2026 Feb 05.
    UBA5 deficiency disrupts mitochondrial autophagy via the PINK1-parkin pathway and impairs myoblast proliferation.
    Haoran Shi, YaFei Cai, Yang Liu.
      
    Keywords:  Mitochondrial homeostasis; Proliferation; UBA5; UFMylation
    DOI:  https://doi.org/10.1186/s40659-026-00676-z
  6. Purinergic Signal. 2026 Feb 05. 22(1): 18
    A2AR antagonist IDPU facilitates the restoration of mitochondrial dynamics in 6-OHDA-induced primary mid-brain neuronal cells, via regulating p38MAPK/Parkin/DJ-1/DRP1 axis.
    Vaishali Walecha, Jyoti Mishra, Tuithung Sophronea, Namrata Kumari, Pratibha Mehta Luthra.
      Parkinson's disease (PD) is marked by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Adenosine receptors (A2ARs) modulate the striatopallidal non-dopaminergic pathway to alleviate PD symptoms. In the present study, the neuroprotective mechanism of the selective A2AR antagonist exhibiting a non-purine scaffold, IDPU (Ki = 0.0038 nM), was explored using the primary mid-brain neuronal (PMDN) cells isolated from P0/P1 rat pups that differentiated to form dopaminergic neurons, as validated using tyrosine hydroxylase. PMDN cells, when treated with IDPU (0-10 μM) alone, showed insignificant toxicity. However, they exhibited < 60% cell viability when treated with 6-OHDA (150 μM) after 24h. Cell viability improved to > 80%, and dopamine levels were restored in 6-OHDA- (150 μM) induced PMDN cells when 3h post-treated with IDPU (0.7 μM, 1 μM), including the depletion in ROS generation and [Ca2+]i levels observed after 24h. IDPU treatment further impacts the mitochondrial control by attenuating both mitochondrial SOD production and its membrane potential loss in PD-like conditions. To investigate the mechanism of A2AR intervention on governing the mitochondrial-associated signalling cascades, the proteins were isolated from 6-OHDA (150 μM) induced PMDN cells 3h post-treated with IDPU (0.7 μM, 1 μM) and ZM241385 (1 μM) for western blot analysis. Our results exhibited that the phosphorylation of both DRP1 (Ser616) (78 kDa) and p38MAPK (Tyr182) (41 kDa) proteins was enhanced when exposed to 6-OHDA; however, the protein levels reduced post-treatment with both A2AR antagonists. In contrast, 6-OHDA toxicity alleviated the levels of both Parkin (58 kDa) and DJ-1(23 kDa), while exposure to A2AR antagonists (IDPU and ZM241385) improved their protein levels. This suggests the possible involvement of A2AR blockade in regulating mitochondrial dynamics, thus promoting survival. These findings present the first evidence that IDPU demonstrates neuroprotection in PDlike conditions via the p38MAPK/DRP1/Parkin signalling, offering a potential therapeutic mechanism for targeting mitochondrial dynamics through A2AR antagonism.
    Keywords:  6-OHDA; A2AR antagonist IDPU; Mitochondrial dysfunction; Mitophagy and mitochondrial fission; Primary mid-brain neuronal cells
    DOI:  https://doi.org/10.1007/s11302-025-10124-4
  7. Inflammation. 2026 Feb 05.
    Enhancing Mitophagy with PEP-1-CAT Attenuates Vascular Inflammation and Atherogenesis in Mice.
    Shuang Wei, Lei Zhang, Xuan-Ren Wang, Fei Zheng, Yu-Wen Yan, Lu Wang, Jian-Ye Yang, Jian Fu, Zhi-Jian Wang.
      The gradual decline of endothelial function and the intensification of inflammatory responses form the basis for the occurrence and development of age-related diseases such as atherosclerosis (AS). Mitochondrial dysfunction-manifested by excessive reactive oxygen species (ROS) production, reduced mitochondrial membrane potential, and impaired mitophagic flux-and sterile inflammation are hallmarks of aged vasculature. We investigated whether bolstering mitochondrial quality control via the novel cell-penetrating antioxidant PEP-1-Catalase (CAT) could mitigate these key features of vascular aging. To model age-associated vascular pathology, ApoE⁻/⁻ mice were fed a high-fat diet (HFD) and treated with PEP-1-CAT. Endothelial cell function, plaque burden, and inflammation were analyzed. In vitro, human endothelial cells (HUVECs) were subjected to inflammatory stress and treated with PEP-1-CAT, with or without modulators of mitophagy. We assessed mitochondrial ROS, membrane potential, NOD-like receptor protein 3 (NLRP3) inflammasome activation, and the PINK1-Parkin pathway. PEP-1-CAT treatment significantly ameliorated atherogenesis and improved features of plaque stability in mice. It suppressed vascular oxidative stress, restored mitochondrial membrane potential, enhanced mitophagic flux, and inhibited NLRP3-driven inflammation. In endothelial cells, PEP-1-CAT attenuated mitochondrial oxidative stress and dysfunction. Crucially, it activated the PINK1-Parkin pathway to promote mitophagy, which was essential for its anti-inflammatory effects, as mitophagy inhibition abrogated the suppression of the NLRP3 inflammasome. Our findings demonstrate that targeting mitochondrial health with PEP-1-CAT alleviates hallmarks of atherosclerotic vascular pathology, including endothelial dysfunction and inflammation, by enhancing mitophagy. This strategy of restoring mitochondrial quality control presents a promising therapeutic approach to delay atherosclerotic vascular pathology.
    Keywords:  Atherosclerosis; Mitochondrial damage; Mitophagy; NF-κB; NLRP3 inflammasome; PEP-1-CAT
    DOI:  https://doi.org/10.1007/s10753-026-02463-0
  8. Neurotherapeutics. 2026 Feb 05. pii: S1878-7479(26)00016-4. [Epub ahead of print] e00846
    Parkin protects against traumatic brain injury through regulating mitochondrial quality control.
    Xiuquan Wu, Weihao Lv, Hongqing Chen, Yihao Fu, Xiaowei Fei, Yanan Dou, Peng Luo, Yang Yu, Zhanfeng Niu, Yu Huan, Jialiang Wei, Jimeng Zhang, Chenchen Ji, Sanzhong Li, Yuefei Zhou, Yunchao Yuan, Wangshu Chao, Yaowen Luo, Changcai Xie, Yujie Qiang, Hao Chang, Dakuan Gao, Xia Li.
      Traumatic brain injury (TBI) is a critical neurological condition, with neuronal damage being its fundamental pathological basis. However, molecular targets for the prevention and treatment of neuronal injury remain to be further explored. Parkin is an important molecule closely associated with neurodegenerative diseases, yet relatively few studies have investigated its relationship with TBI. In this study, we first established and validated both the controlled cortical impact (CCI) and traumatic neuronal injury (TNI) models. Using these models, we revealed that TBI led to the upregulation of Parkin expression, with a peak occurring 24 h post-injury. Furthermore, at the in vitro level, lentivirus-mediated modulation of Parkin expression revealed that Parkin overexpression alleviated TNI-induced neurotoxicity, apoptosis, oxidative stress, and mitochondrial dysfunction, whereas Parkin knockdown exacerbated neuronal damage. At the mechanistic level, the study demonstrated that Parkin promoted mitochondrial biogenesis and fission while inhibiting mitochondrial fusion and attenuated the impairment of mitophagy after TBI. In other words, Parkin exerts a neuroprotective role through regulating mitochondrial quality control. We further employed adeno-associated viruses and Parkin knockout mice to modulate Parkin expression in vivo. The results showed that Parkin attenuated CCI-induced brain damage, edema, and behavioral deficits, whereas Parkin knockout exacerbated brain injury and functional impairments. Finally, we designed and synthesized a recombinant Parkin protein and preliminarily validated its protective effects at the cellular level. In summary, this study provides new insights for the therapeutic targets against TBI.
    Keywords:  Mitochondrial quality control; Mitophagy; Neuron; Parkin; Traumatic brain injury
    DOI:  https://doi.org/10.1016/j.neurot.2026.e00846
  9. Adv Sci (Weinh). 2026 Feb 06. e20051
    Xanthatin Targets CISD1 to Drive Ferroptosis and Mitophagy as a Dual Anticancer Strategy in Triple-Negative Breast Cancer.
    Qinwen Liu, Haojie Chen, Xiang Li, Jingxin Liu, Yiwen Li, Zhenyi Shi, Shenshen Guo, Qingfeng Du, Aiping Lu, Daogang Guan.
      Triple-negative breast cancer (TNBC) is an aggressive subtype with poor prognosis. Here, we identify xanthatin, a sesquiterpene lactone from Xanthium species, as a potent inhibitor of TNBC cell growth with minimal toxicity to normal cells. Transcriptomic analyses revealed that xanthatin activates ferroptosis, evidenced by elevated ROS, lipid peroxidation, and Fe2 + accumulation, together with GSH depletion and downregulation of SLC7A11 and GPX4. Target identification by drug affinity responsive target stability and mass spectrometry uncovered CDGSH iron sulfur domain 1 (CISD1) as the direct binding partner of xanthatin. Cellular thermal shift assay, surface plasmon resonance, and dynamics simulations consistently demonstrated that tryptophan-75 is the critical residue mediating this interaction. Functionally, xanthatin promotes CISD1 ubiquitination and proteasomal degradation, thereby disrupting mitochondrial iron homeostasis and inducing ferroptosis. CISD1 destabilization further impaired mitochondrial integrity and activated PINK1/Parkin-dependent mitophagy, establishing a dual ferroptosis-mitophagy mechanism. Importantly, genetic knockdown of CISD1 markedly attenuated the anticancer activity of xanthatin, confirming its essential role. In an orthotopic TNBC mouse model, xanthatin significantly suppressed tumor growth without causing systemic toxicity. Collectively, our findings provide the first demonstration that xanthatin directly targets CISD1 at the Trp-75 site to trigger ferroptosis and mitophagy, highlighting its promise as a therapeutic candidate for TNBC.
    Keywords:  CISD1; Xanthatin; ferroptosis; mitochondrial autophagy; triple‐negative breast cancer
    DOI:  https://doi.org/10.1002/advs.202520051
  10. Curr Opin Neurol. 2026 Jan 30.
    Peripheral alterations of mitochondrial function and mitophagy in Alzheimer's disease: from fundamental research to clinical perspectives.
    Fanny Eysert, Gaëlle Deportes, Elodie Delaquaize, Mounia Chami.
       PURPOSE OF REVIEW: Alzheimer's disease (AD) is commonly defined by its hallmark brain pathologies, yet mounting evidence shows that metabolic impairment particularly linked to mitochondrial dysfunction, is a central and systemic feature of the disease. This review highlights consistent abnormalities in mitochondrial function, and turnover (mitophagy) across multiple AD-derived peripheral cells, including skin fibroblasts, lymphocytes, platelets, and peripheral blood mononuclear cells. We also report on potential peripheral AD biomarkers linked to mitochondria dysfunction in AD.
    RECENT FINDINGS: Mitochondrial abnormalities in peripheral cells from individuals with AD robustly correlate with disease development. These mitochondrial dysfunctions mostly include reduced respiratory chain activity, increased accumulation of reactive oxygen species (ROS), altered mitochondrial membrane potential, and consequently decreased ATP production. Studies have also identified a complex pattern of mitochondrial hyperactivity and hypoactivity in peripheral cells of AD patients that appears to depend on the stage of AD and whether the disease is sporadic or familial. Furthermore, multiple steps of the mitophagy pathway are disrupted in peripheral cells as AD progresses. Finally, biochemical and proteomic analyses of peripheral fluids further support the loss of mitochondrial homeostasis in AD patients.
    SUMMARY: Collectively, the reviewed findings support mitochondrial homeostasis disruption as a core pathophysiological component of AD and a promising target for biomarker development and therapeutic intervention.
    Keywords:  Alzheimer's disease; biomarkers; mitochondria; mitophagy; peripheral cells and fluids
    DOI:  https://doi.org/10.1097/WCO.0000000000001457
  11. iScience. 2026 Feb 20. 29(2): 114639
    Thrombospondin 1 aggravates cardiac remodeling in heart failure with preserved ejection fraction by inhibiting mitophagy.
    Xingpeng Bu, Shuo Sha, Zhenzhen Zhang, Sicheng Bian, Shuhui Feng, Chunxia Li, Lei Wang, Huanzhen Chen.
      Heart failure with preserved ejection fraction (HFpEF) accounts for over half of all heart failure cases, but its underlying mechanisms remain unclear. Mitochondrial dysfunction and defective mitophagy are increasingly recognized as central features of HFpEF. Thrombospondin 1 (Thbs1), a matricellular protein involved in cardiovascular remodeling, has not been explored in this context. Here, we show that Thbs1 expression is elevated in HFpEF myocardium and that Thbs1 aggravates cardiac dysfunction by inhibiting mitophagy. In a "two-hit" HFpEF mouse model induced by high-fat diet and L-NAME, AAV9-mediated Thbs1 knockdown improved diastolic function, reduced fibrosis and inflammation, and mitigated PI3K/Akt/mTOR pathway activation revealed by transcriptomic and proteomic profiling. Mechanistically, Thbs1 silencing restored autophagic flux, enhanced mitochondrial clearance, and preserved mitochondrial homeostasis in cardiomyocytes. These findings identify Thbs1 as a key suppressor of mitophagy in HFpEF and a potential therapeutic target for this prevalent condition.
    Keywords:  Cell biology; Model organism; Omics
    DOI:  https://doi.org/10.1016/j.isci.2026.114639
  12. Cell Death Discov. 2026 Feb 05.
    Mitophagy in pancreatic cancer: mechanistic insights and implications for novel therapeutic strategies.
    Zhefang Wang, Zicheng Lyu, Raphael Palmen, Qi Bao, Felix Popp, Qiongzhu Dong, Christiane J Bruns, Yue Zhao.
      Pancreatic ductal adenocarcinoma (PDAC) presents significant treatment challenges, primarily due to its propensity for developing resistance to therapeutic interventions. While the underlying mechanisms remain elusive, they are closely associated with mitochondrial adaptation in response to treatment. Mitophagy, a selective subtype of autophagy that eliminates damaged or surplus mitochondria, is crucial for tumorigenesis, progression, and treatment resistance in cancers. This review discusses the intricate regulatory pathways of mitophagy in PDAC, focusing on the PINK1/Parkin pathway and receptor-mediated pathways. Furthermore, it explores the therapeutic potential of targeting mitophagy to increase the effectiveness of existing treatments and improve patient survival. Current evidence indicates that combining mitophagy inhibition with conventional chemotherapy yields promising yet inconsistent results, which may be attributed to the context-dependent functions of mitophagy and a lack of specific inhibitors. This review highlights the therapeutic potential of targeting mitophagy in PDAC and underscores the necessity for biomarker-driven patient stratification and the development of pathway-specific modulators in future clinical efforts.
    DOI:  https://doi.org/10.1038/s41420-026-02948-9
  13. Arch Pharm Res. 2026 Feb 02.
    PF protects retinal pigment epithelial cells from oxidative injury by enhancing mitophagy through a CUL3-dependent AMPK/ULK1 pathway.
    Xi Chen, Wei Shi, Yujie Zhu, Kai Li, Ying Xia, Hao Wu, Tianming Hu, Chengyao Qin, Wei Wei.
      Mitophagy dysfunction is a critical contributor to retinal pigment epithelial (RPE) cell damage during the progression of retinal degenerative diseases, including age-related macular degeneration (AMD). In this study, we investigated the effects of paeoniflorin (PF) on mitophagy in RPE cells, with a particular focus on the CUL3/LKB1/AMPK/ULK1 signaling pathway. ARPE-19 cells were treated with different concentrations of PF to evaluate cytotoxicity, and its protective effects were further examined in H₂O₂-induced oxidative stress models in vitro and in sodium iodate (NaIO₃)-induced RPE injury models in vivo. Protein levels of CUL3, apoptosis-related factors, mitophagy markers, and components of the LKB1/AMPK/ULK1 pathway were assessed by western blotting, and mitophagy was visualized using MitoTracker labeling. Cycloheximide (CHX) and coimmunoprecipitation (Co-IP) assays were performed to analyze the interaction between CUL3 and LKB1. PF treatment enhanced mitophagy in H₂O₂-stimulated ARPE-19 cells, whereas Parkin knockdown markedly attenuated this effect. In oxidatively damaged cells, PF promoted AMPK and ULK1 phosphorylation, increased mitophagy-associated protein expression, and alleviated mitochondrial dysfunction; these protective effects were abolished by pharmacological inhibition of AMPK or ULK1. In addition, CUL3 overexpression significantly attenuated PF-induced mitophagy activation and reduced PF-associated phosphorylation of LKB1, AMPK, and ULK1. Mechanistically, PF downregulated CUL3 expression, while CUL3 promoted the ubiquitination and degradation of LKB1. Silencing CUL3 induced mitophagy in H₂O₂-treated cells, whereas concurrent knockdown of CUL3 and LKB1 abolished this effect. In vivo, PF mitigated RPE cell loss, enhanced mitophagy, and activated the CUL3/LKB1/AMPK/ULK1 signaling pathway in the retinal tissues of NaIO₃-induced mice. Collectively, these findings indicate that PF protects against RPE injury in an NaIO₃-induced AMD-like model by downregulating CUL3 expression and activating LKB1/AMPK/ULK1-mediated mitophagy.
    Keywords:  ARPE-19 cells; Age-related macular degeneration (AMD); CUL3; LKB1/AMPK/ULK1; Paeoniflorin (PF); Retinal pigment epithelial (RPE)
    DOI:  https://doi.org/10.1007/s12272-026-01597-x
  14. Cell Biol Toxicol. 2026 Feb 05.
    HUWE1 regulates mitophagy to protect dopaminergic neurons from 6-OHDA- and MPP⁺-induced neurotoxicity.
    Chanhaeng Lee, Dong Yeol Kim, Sang-Min Kim, Inn-Oc Han.
      Parkinson's disease (PD) is characterized by dopaminergic neuronal loss, often associated with mitochondrial dysfunction and impaired mitophagy. Here, we investigated the role of HUWE1, an E3 ubiquitin ligase, in regulating mitophagy and neuronal survival in a cellular PD model. HUWE1 promoted mitophagy, whereas its depletion sensitized SH-SY5Y cells to 6-hydroxydopamine (6-OHDA)- and 1-methyl-4-phenylpyridinium (MPP⁺)-induced cytotoxicity and mitochondrial dysfunction. Notably, both toxins downregulated HUWE1, suggesting that loss of HUWE1 contributes to dopaminergic vulnerability. Conversely, HUWE1 overexpression preserved mitochondrial integrity and enhanced mitophagy under neurotoxic stress. Importantly, BL-918, a ULK1 activator that promotes AMBRA1 recruitment, facilitated HUWE1-mediated mitophagy in SH-SY5Y cells. BL-918 treatment significantly attenuated 6-OHDA- and MPP⁺-induced neurotoxicity and protected mitochondrial function via HUWE1 activation. Collectively, these findings identify HUWE1 as a key mechanistic regulator of mitophagy linked to dopaminergic neuronal vulnerability, and provide a conceptual framework for future investigations examining its role in PD-relevant model systems.
    Keywords:  Dopaminergic neurons; HUWE1; Mitophagy; Parkinson’s disease; SH-SY5Y cells
    DOI:  https://doi.org/10.1007/s10565-026-10146-7
  15. J Mol Neurosci. 2026 Feb 05. 76(1): 26
    Mitophagy Inhibition Suppresses Seizures in Status Epilepticus Mice by Decreasing Hippocampal NLRC4 Expression.
    Zhi-Cheng Dong, Min Liu, Jin-Yi Zhou, Li-Qun Geng, Mei Li, Xu-Qin Chen.
      
    Keywords:  Hippocampus; Mitophagy; NLRC4 inflammasome; Status epilepticus; Temporal lobe epilepsy
    DOI:  https://doi.org/10.1007/s12031-025-02471-z
  16. Mol Neurobiol. 2026 Feb 07. 63(1): 426
    Mesenchymal Stem Cell-derived Exosomes Alleviate Oxidative Stress and Brain Injuries Through Promoting OPA1 Mediated Mitochondrial Fusion After Intracerebral Hemorrhage.
    Yanni Xu, Yong Du, Qing Hu, Ping Wang, Yaning Cai, Gaoyang Zhou, Haixiao Liu, Wei Guo.
      Oxidative stress (OS) is a hallmark of secondary brain damage after intracerebral hemorrhage (ICH), contributing to the progression of neurological damage and poor clinical outcomes. While mesenchymal stem cell-derived exosomes (MSC-Exo) demonstrate antioxidative potential, the specific mechanisms underlying their protective effects, particularly concerning mitochondrial dynamics, remain unclear. This study identifies OPA1-mediated mitochondrial fusion as a novel mechanism through which MSC-Exo alleviates oxidative stress and brain injury after ICH. In vivo fluorescence imaging and immunofluorescence assay revealed that intravenously injected MSC-Exo could be effectively internalized by neuronal cells in ICH mice. MRI assay indicated that although MSC-Exo had little effect on the volume of hematoma, it significantly relieved brain edema and improved the neurological outcomes. MSC-Exo effectively reduced oxidative stress and neuronal apoptosis in the peri-hematoma tissues. Notably, both in vivo and in vitro studies showed that MSC-Exo significantly alleviated mitochondrial morphological damage following ICH. MSC-Exo substantially reversed the downregulation of OPA1 after ICH but showed no significant impact on other proteins associated with mitochondrial dynamics. Neuron-specific knockout of OPA1 (Opa1cko) aggravated the impairment of mitochondrial morphology, the accumulation of superoxide production, and the deficits of mitochondrial respiratory capacities following ICH. Moreover, MSC-Exo failed to restore mitochondrial morphology and functionality, alleviate oxidative stress-induced damage, enhance neuronal viability, and facilitate functional recovery subsequent to ICH in Opa1cko mice models.
    Keywords:  Exosome; Intracerebral hemorrhage; Mesenchymal stem cells; Mitochondrial fusion; OPA1; Oxidative stress
    DOI:  https://doi.org/10.1007/s12035-026-05703-4
  17. Sports Med Health Sci. 2026 Jan;8(1): 23-33
    Leveraging mitochondrial stress to improve healthy aging.
    Abril Gorgori-Gonzalez, Silvana Soto-Rodriguez, Eva Tamayo-Torres, Esther Garcia-Dominguez, Vicente Sebastia, Juan Gambini, Gloria Olaso-Gonzalez, Maria Carmen Gomez-Cabrera.
      Aging is characterized by a progressive decline in physiological function, driven by intrinsic mechanisms (primary aging) and modifiable factors (secondary aging), ultimately leading to multimorbidity, disability, and mortality. Mitochondrial dysfunction, a major hallmark of aging, plays a central role in the loss of muscle mass and strength observed in frailty and sarcopenia. With age, mitochondrial quality control processes, including biogenesis, mitophagy, and dynamics, become dysregulated, impairing energy metabolism and muscle homeostasis. Mitochondrial dysfunction correlates with clinical biomarkers of sarcopenia and frailty, such as the decrease in walking speed and muscle strength, making it a therapeutic target for mitohormesis-based strategies aimed at preserving functional capacity. Mitohormetic agents induce reversible mitochondrial stress, triggering adaptive responses that enhance function. Among these interventions, physical exercise, particularly endurance and resistance training (RT), has been reported to be among the most effective, as it may modulate mitochondrial biogenesis, dynamics, and mitophagy through increases in proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and mitochondrial transcription factor A (TFAM) expression, mitochondrial deoxyribonucleic acid (mtDNA) copy number, and mitochondrial content. Chronic RT can also elevate fusion and fission markers, potentially as a compensatory mechanism to mitigate mitochondrial damage. Apart from exercise, mitohormetic compounds such as harmol and piceid are emerging as promising supplements in the aging field. By modulating mitochondrial bioenergetics and dynamics, they may complement lifestyle-based interventions to improve mitochondrial fitness and extend health span.
    Keywords:  Frailty; Mitochondrial dysfunction; Mitohormesis; Muscle homeostasis; Phytochemicals; Resistance training
    DOI:  https://doi.org/10.1016/j.smhs.2025.10.003
  18. Eur J Pharmacol. 2026 Jan 28. pii: S0014-2999(26)00091-9. [Epub ahead of print]1016 178609
    Proton pump inhibitors accelerate vascular calcification via COX-2-mediated mitophagy inhibition in chronic kidney disease.
    Zhuo-Chao Xiong, Xiong-Zhi Li, Si You, Ze-Gui Huang, Yu-Biao Wu, Zhao-Yu Liu, Shao-Ling Zhang, Bing Yang, Jing-Feng Wang, Jing-Wei Gao, Pin-Ming Liu.
      Prolonged use of proton pump inhibitors (PPIs) is associated with increased cardiovascular risks, including vascular calcification (VC). Patients with chronic kidney disease (CKD) are particularly vulnerable to the adverse vascular effects of PPIs. However, the underlying mechanism remains poorly understood. Clinical data from CKD patients treated with PPIs showed a higher incidence of elevated coronary artery calcium scores (adjusted odds ratio = 5.365, 95 % CI: 2.539-11.338, P < 0.001), indicating a link between PPI use and accelerated vascular damage. In CKD rats, omeprazole treatment dose-dependently induced aortic calcification, accompanied by a phenotypic switch of vascular smooth muscle cells (VSMCs) from a contractile to an osteoblastic state. This pathological process was associated with mitochondrial dysfunction and inhibited PINK1/Parkin-mediated mitophagy, as evidenced by reduced TOMM20, LC3B-II, PINK1, and Parkin protein levels, impaired mitochondrial-lysosomal colocalization (MitoTracker Green/LysoTracker Red staining), and swollen mitochondria with fewer mitophagosomes (transmission electron microscopy). Enhancement of mitophagy by rapamycin effectively mitigated omeprazole-induced VC. RNA sequencing identified cyclooxygenase-2 (COX-2) as a key mediator, with omeprazole significantly upregulating its expression. Silencing COX-2 reversed omeprazole-induced mitophagy inhibition and VSMC calcification. Esomeprazole and lansoprazole recapitulated these pro-calcific effects, indicating a class effect. Collectively, PPIs promote VC in CKD by upregulating COX-2, which directly inhibits PINK1/Parkin-related mitophagy. This study provides a novel COX-2-mitophagy axis in PPI-accelerated vascular injury, highlighting a potential therapeutic target for high-risk patients.
    Keywords:  Chronic kidney disease; Mitophagy; Omeprazole; Proton pump inhibitors; Vascular calcification; Vascular smooth muscle cells
    DOI:  https://doi.org/10.1016/j.ejphar.2026.178609
  19. Eur J Pharm Sci. 2026 Feb 02. pii: S0928-0987(26)00031-X. [Epub ahead of print] 107457
    ROS-responsive diselenide exosomes restores mitophagy to resolve sterile inflammation in liver IRI.
    Tao Zhou, Zhiwei Jiang, Qingluan Hu, Siqi Qiu, Junda Gao, Jianjun Zhang, Feng Xue, Lin Lu, Ling Chang.
      Liver ischemia-reperfusion injury (IRI) drives graft dysfunction and postsurgical morbidity. We show that hepatocellular MST1 is markedly upregulated in IRI and exacerbates damage by blocking PINK1-dependent mitophagy. Defective mitochondrial clearance causes mtDNA leakage, which activates macrophage cGAS-STING signaling and fuels inflammatory injury. Curcumin inhibits this MST1-PINK1 axis, restoring mitophagy and limiting mtDNA release. To translate these insights, we engineered Curcumin@EV@Se-stem-cell-derived extracellular vesicles surface-modified with diselenide-PEG for ROS-responsive, "stealth" delivery. In oxygen-glucose deprivation/reoxygenation models, Curcumin@EV@Se improved hepatocyte viability, preserved mitochondrial potential, reduced ROS and inflammatory cytokines, and promoted reparative/angiogenic programs. In a murine hepatic IRI model, systemic Curcumin@EV@Se decreased necrosis and TUNEL positivity and improved serum transaminases and histology, indicating enhanced liver function and regeneration. These data identify MST1-mediated mitophagy blockade with secondary cGAS-STING activation as a central pathogenic axis in IRI and present Curcumin@EV@Se as a mechanism-guided therapy that restores mitochondrial quality control and dampens innate immune activation, with translational promise for liver transplantation and acute hepatic injury.
    Keywords:  curcumin; stem cells; vesicle
    DOI:  https://doi.org/10.1016/j.ejps.2026.107457
  20. Eur J Med Res. 2026 Jan 31.
    HIF-1α/BNIP3-mediated mitophagy mitigates cerebral ischemia/reperfusion injury in rats by suppressing NLRP3 inflammasome activation.
    Qifan Huo, Yuming Zhang, Jing Zhao, Ning Bai, Jun Wang.
       BACKGROUND: The hypoxia-inducible factor-1α (HIF-1α)/Bcl-2/adenovirus E1B 19-kDa interacting protein (BNIP3) pathway, a key regulator of mitophagy, has demonstrated protective effects in renal and cardiac ischemia/reperfusion (I/R) injury. However, its specific role and mechanism in cerebral I/R injury (CIRI) are not fully understood.
    METHODS: An oxygen-glucose deprivation/reoxygenation (OGD/R) model in SH-SY5Y neuroblastoma cells and a transient middle cerebral artery occlusion (MCAO) model in rats were established to simulate CIRI. HIF-1α overexpression plasmids was then introduced into the two models. Mitophagic activity was assessed through immunoblotting of BNIP3, microtubule-associated protein 1 light chain 3B (LC3B), and p62 protein, quantification of LC3B-mitochondria colocalization, and transmission electron microscopic analysis of mitochondrial ultrastructure and autophagosomes. NOD-, LRR-, and pyrin domain-containing 3 (NLRP3) inflammasome activation was evaluated by measuring levels of NLRP3, cleaved caspase-1, interleukin (IL)-1β, and IL-18. The cell-type specificity of the HIF-1α/BNIP3/mitophagy pathway was evaluated by comparative analysis in SH-SY5Y neuronal cells and BV-2 microglia. Mechanistic dependency was tested NLRP3 agonist nigericin using the autophagy inhibitor 3-methyladenine (3-MA) and the specific NLRP3 inflammasome agonist nigericin in rescue experiments. In addition, cerebral infarction and neurological deficits were assessed in rats.
    RESULTS: HIF-1α transcriptionally upregulated BNIP3 in SH-SY5Y cells. HIF-1α overexpression increased BNIP3 and LC3B II levels, reduced p62 level, increased autophagosome accumulation, and enhanced mitophagy in SH-SY5Y cells. This enhanced mitophagy suppressed OGD/R-induced apoptosis and NLRP3 inflammasome activation, while these effects were abolished by 3-MA or nigericin. Comparative analysis revealed the HIF-1α/BNIP3/mitophagy pathway to be a predominant and potent mechanism in SH-SY5Y cells, rather than BV-2 microglia. In addition, HIF-1α overexpression enhanced mitophagy and attenuated NLRP3 inflammasome activation in brain tissues, thereby alleviating cerebral infarction and neurological deficits in MCAO rats.
    CONCLUSIONS: Activation of the HIF-1α/BNIP3 pathway drives protective mitophagy to suppress the NLRP3 inflammasome in neuronal cells, thereby conferring neuroprotection against CIRI. This study provides mechanistic insights into the protective role of HIF-1α/BNIP3-mediated mitophagy against CIRI, highlighting its potential as a therapeutic target for ischemic injury.
    Keywords:  BNIP3; Cerebral I/R injury; HIF-1α; Mitophagy; NLRP3 inflammasome
    DOI:  https://doi.org/10.1186/s40001-026-03954-4
  21. Free Radic Biol Med. 2026 Jan 31. pii: S0891-5849(26)00060-2. [Epub ahead of print]246 668-681
    Crocin alleviates doxorubicin-mediated cardiotoxicity by activating PINK1-dependent cardiomyocyte mitophagy.
    Xin Su, Teng Fan, Zeyu Liu, Yuanyuan Huang, Jun Kan, Chuwen Liang, Yuwen Chen, Zhangqi Cao, Shuangli Zhu, Sijia Li, Kai Fu, Can Pan, Fang Wang, Bei Zhang, Liwu Fu.
       INTRODUCTION: Doxorubicin (DOX) is a widely used chemotherapeutic agent, but its clinical application is limited by dose-dependent cardiotoxicity. Currently, there are no effective strategies to prevent or reverse DOX-mediated myocardial injury, highlighting the urgent need for novel therapeutic approaches.
    OBJECTIVES: In this study, the cardioprotective effects of crocin, a natural compound derived from Crocus sativus, were investigated in the context of DOX-mediated cardiotoxicity.
    METHODS: Cardiac function, mitochondrial morphology, ROS production, and ATP content were evaluated in both in vitro and in vivo models of DOX-mediated cardiotoxicity. RNA sequencing was performed to identify key regulatory pathways affected by crocin. Mitophagy-related mechanisms were investigated through molecular and cellular assays, including immunofluorescence and Western blot analysis of PTEN-induced kinase 1 (PINK1)-associated signaling. PINK1 knockdown and mitophagy inhibition were performed to assess the impact on the cardioprotective effects of crocin.
    RESULTS: Crocin treatment preserved cardiac function and mitigated DOX-mediated myocardial injury in both in vitro and in vivo models, as evidenced by restored left ventricular ejection fraction, reduced mitochondrial ROS accumulation, restoration of ATP production, and improved mitochondrial morphology. Transcriptomic analysis revealed that crocin upregulated PINK1 expression, a key initiator of mitophagy. Functional assays further confirmed that crocin restored mitophagy activity suppressed by DOX exposure. The cardioprotective effects of crocin were abolished upon PINK1 knockdown or mitophagy inhibitor, highlighting the essential role of PINK1-dependent mitophagy in mediating crocin's effects.
    CONCLUSIONS: Crocin protects against doxorubicin-induced cardiotoxicity by activating PINK1-mediated mitophagy and maintaining mitochondrial homeostasis. These findings highlight crocin as a potential therapeutic agent for mitigating DOX-mediated cardiotoxicity.
    Keywords:  Cardiotoxicity; Crocin; Doxorubicin; Mitophagy; PTEN-induced kinase 1
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.01.040
  22. J Physiol. 2026 Feb 03.
    Role of Septin7 in mitochondrial dynamics and oxidative metabolism in C2C12 skeletal muscle cells.
    Andrea Telek, Ivett Gabriella Szabó, Anikó Keller-Pintér, Mónika Gönczi, Eliza Guti, László Szabó, Brigitta Tillmann, Zoltán Márton Kohler, László Juhász, Péter Bai, Szilárd Póliska, Zsuzsanna Gaál, László Csernoch, János Fodor.
      Mitochondria are dynamic organelles that undergo fusion and fission. Key proteins are needed to create mitochondrial networks, as well as facilitate biogenesis, fragmentation or movement within the cell. Septins are considered as the fourth component of the cytoskeleton, providing attachment sites for proteins. Besides that, they have important roles in different cellular processes, including mitochondrial fission and fusion (remodelling). Septins form oligomeric complexes comprising various septin subgroups, which can create higher-order structures. Septin7 is the sole member of its subgroup. We aimed to examine how mitochondrial dynamics and oxidative phosphorylation (OXPHOS) are affected in Septin7 downregulated C2C12 (S7-KD) myoblasts and terminally differentiated myotubes compared to scrambled short hairpin RNA-transfected control cells. We detected altered expression of genes related to mitochondrial biogenesis (PGC1α), dynamics (DRP1, OPA1 and MFN2) and autophagy (PINK1 and BNIP3); furthermore, a significant decrease in differentiation-dependent mRNA expression of OXPHOS markers (ATP synthase, COX1 and SDH). Septin7 downregulation also affected the expression of post-translational modifications of MFN2 and DRP1. Functional measurements of OXPHOS revealed decreased O2 consumption (flux) and higher O2 concentration in Septin7 KD cultures following selective inhibition of electron transport complexes. We observed significant alterations in basal respiration and OXPHOS pathways in Septin7 KD cultures. Our results suggest that Septin7, as a cytoskeletal protein, could be a significant regulator of mitochondrial dynamics and oxidative metabolism. Therefore, these molecules, as mitochondrial dynamics modulators, can serve as potential therapeutic targets in diseases related to changes in mitochondrial function. KEY POINTS: Knockdown of Septin7 results in altered gene and protein expression of markers controlling mitochondrial dynamics. Diminished level of Septin7 causes decreased gene expression of members of oxidative phosphorylation. Knockdown of Septin7 has an impact on microRNAs involved in the regulation of mitochondrial markers. Septin7 has an impact on mitochondrial respiration.
    Keywords:  electron transport; mitochondria; remodelling; septin; skeletal muscle
    DOI:  https://doi.org/10.1113/JP288715
  23. Curr Biol. 2026 Feb 03. pii: S0960-9822(26)00006-0. [Epub ahead of print]
    The mitochondrial intermembrane space nuclease Nuc1 (endonuclease G) prevents mitophagy-mediated mtDNA escape in yeast.
    Ryan R Cupo, Eunice Domínguez-Martín, Richard Youle.
      Mitochondria contain a genome (mtDNA) encoding a handful of proteins essential for cellular respiration. mtDNA can leak into the cytosol and drive fitness defects. The first genes associated with mtDNA escape were discovered in yeast and aptly named "yeast mitochondrial escape" (YME) genes. We identify the mechanism by which an intermembrane space nuclease, endonuclease G (human ENDOG; yeast Nuc1), prevents mtDNA escape to the cytosol in yeast. Nuc1 nuclease activity and mitochondrial localization are essential for preventing mtDNA escape and suggest a direct role of Nuc1 in degrading mtDNA bound for escape. We find that blocking autophagy via atg1 and atg8 mutants prevents mtDNA escape in the absence of Nuc1. We further demonstrate that blocking mitophagy via atg11 and atg32 mutants prevents mtDNA escape, whereas inducing mitophagy increases mtDNA escape in the absence of Nuc1. Finally, we demonstrate that Nuc1 degrades mtDNA bound for escape via the vacuole, as an atg15 mutant that prevents disassembly of autophagic bodies in the vacuole also prevents mtDNA escape. Overall, our results implicate vacuolar entry of mitochondria during mitophagy as an important mtDNA escape pathway in yeast, which is normally mitigated via the degradation of mtDNA by Nuc1.
    Keywords:  Atg1; Atg32; Drp1; NUMT; STING; autophagy; fission; lysosome; nucleoid; vacuole
    DOI:  https://doi.org/10.1016/j.cub.2026.01.006
  24. Phytother Res. 2026 Feb 01.
    Citronellal Alleviates Myocardial Senescence by Enhancing Mitochondrial Autophagy via AMPKα-PINK1/Parkin Pathway.
    Yi-Wen Qian, Yao Lu, Miao-Miao Chang, Qian-Qian Niu, Jia-Xin Fan, Shi-Ying Xing, Peng Li, Ling Liu.
      Cardiomyocyte senescence contributes to the progression of multiple cardiac diseases, with oxidative stress identified as a central pathophysiological mechanism. Previous animal experiments demonstrated that citronellal (CT), administered at 200 mg/kg in rats, exerted significant cardioprotective effects. However, the molecular mechanisms underlying these effects remain unclear. This study aimed to investigate the role of CT in mitigating myocardial senescence and to elucidate its mechanistic pathways. Doxorubicin-induced myocardial senescence mouse models and H9C2 cardiomyocyte senescence models were established. SA-β-gal staining, Western blotting, immunofluorescence, and immunohistochemistry were employed to evaluate senescence and oxidative stress markers. Network pharmacology analysis and molecular docking were conducted to predict CT targets. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to identify potential mechanisms of action. CT treatment significantly reduced myocardial oxidative stress levels, ameliorated senescent phenotypes in both in vivo and in vitro models, and enhanced mitophagy by activating the AMPKα-mediated PINK1/Parkin pathway. Bioinformatics analyses further supported the involvement of oxidative stress resistance and mitophagy regulation as central mechanisms underlying CT's cardioprotective effects. Citronellal effectively alleviates cardiomyocyte senescence by reducing oxidative stress and promoting mitophagy through activation of the AMPKα-PINK1/Parkin signaling pathway. These findings provide experimental evidence supporting CT as a promising cardioprotective agent and highlight a novel mechanism of action that may inform future therapeutic strategies for cardiac aging and related diseases.
    Keywords:  AMPKα; cardiomyocyte senescence; citronellal; mitophagy; oxidative stress
    DOI:  https://doi.org/10.1002/ptr.70241
  25. Curr Res Toxicol. 2026 ;10 100281
    Scoparone induces mitophagy and apoptosis via ROS accumulation in pancreatic cancer cells.
    Ningna Weng, Luping Lin, Tong Lin, Jinlu Liu, Kai Zhu, Sha Huang.
      Pancreatic cancer (PC) is one of the deadliest malignancies worldwide. In the present study, we demonstrated that a traditional Chinese medicine extract monomer, scoparone (Scop), significantly inhibited the growth of PC cells both in vitro and in vivo. Further studies revealed that Scop could induce PINK1/Parkin-mediated mitophagy and apoptosis in PC cells; thus, inhibition of mitophagy could alleviate the anti-PC effect and apoptosis of Scop. Mechanistically, Scop exerts its anti-PC effects via the Akt/mTOR pathway. In addition, Scop increases the level of cellular reactive oxygen species (ROS) in PC cells, which may be a key factor, as the ROS inhibitor N-acetylcysteine significantly reversed the effects of mitophagy and apoptosis in PC cells. Our findings highlight Scop shows potential as a therapeutic lead candidate, offering novel insights into the antitumor potential of traditional Chinese medicine. This study elucidates the critical role of Scop in regulating mitophagy and apoptosis in PC cells, providing a foundation for future therapeutic development.
    Keywords:  Apoptosis; Mitophagy; Pancreatic cancer; ROS; Scoparone
    DOI:  https://doi.org/10.1016/j.crtox.2026.100281
  26. Neurobiol Aging. 2026 Jan 27. pii: S0197-4580(26)00012-6. [Epub ahead of print]161 47-63
    Human in vitro and rodent in vivo models highlight progressive mitochondrial dysfunction as a starting point of cerebral amyloidosis.
    Zahra Motamed, Gisela Novack, Daniel Heutschi, Carine Gaiser, Corina Garcia, Sonia Do Carmo, A Claudio Cuello, Laura Morelli, Laura Suter-Dick.
      Mitochondrial dysfunction is a well-established hallmark of Alzheimer's disease (AD), particularly in the context of amyloid-beta (Aβ) accumulation. Here, we explored the progression of mitochondrial impairment associated with cerebral amyloidosis in human and rodent systems expressing AD-relevant APP mutations. We investigated mitochondrial function, dynamics, and degradation in human neural progenitor cells differentiated for two and six weeks, carrying the APP (Swedish/London) mutations. These analyses were complemented by studies in 3- and 9-month-old McGill-R-Thy1-APP transgenic (Tg) rats expressing the APP (Swedish/Indiana) mutations. We observed a consistent accumulation of pathogenic Aβ species associated with mitochondrial damage. In vitro, early indicators of oxidative stress and initial alterations in mitochondrial network dynamics were evident, including increased mitochondrial reactive oxygen species and elevated total DRP1 levels. Later, after 6 weeks of differentiation, significant mitochondrial dysfunction emerged, including reduced membrane potential, increased mitochondrial network fragmentation, and decreased GSH/GSSG ratio. Mitophagy was also disrupted, as evidenced by reduced localization of TOMM20 to the lysosomes, suggesting impaired mitochondrial clearance. Similarly, hippocampal mitochondria fraction of 9-month-old Tg rats showed elevated fission markers, nitrosative stress, and mitochondrial p62 accumulation, which were absent in 3-month-old Tg animals. Hence, we identified both early and late molecular alterations in mitochondrial homeostasis revealing accumulation of mitochondrial stress, altered dynamics, and mitophagy failure in response to sustained Aβ release. Our results underscore mitochondrial vulnerability during early amyloidosis, identifying it as a potential therapeutic target at initial disease stages. It also reinforces the utility of in vitro models for studying cerebral amyloid pathologies.
    Keywords:  APP mutations; Alzheimer´s disease; Amyloid beta; Amyloidosis; Mitochondrial impairment; Mitophagy
    DOI:  https://doi.org/10.1016/j.neurobiolaging.2026.01.006
  27. JBMR Plus. 2026 Mar;10(3): ziag004
    USP34 attenuates cartilage degradation in temporomandibular joint osteoarthritis by ANT1-mediated mitophagy.
    Shuang Jiang, Danling Chen, Rui Sheng, Quan Yuan, Jian Pan, Yuchen Guo.
      The pain and dysfunction caused by temporomandibular joint osteoarthritis (TMJ OA) can be debilitating. However, effective disease-modifying medicine for TMJ OA remains an unfulfilled need. While progressive cartilage degradation represents the hallmark of TMJ OA, the underlying molecular mechanisms remain incompletely understood. Here, we identify ubiquitin-specific protease 34 (USP34) as a key regulator of mitochondrial quality control in TMJ chondrocytes through its stabilization of adenine nucleotide translocase 1 (ANT1). Using chondrocyte-specific Usp34 KO (Usp34icKO ) mice, we first demonstrated age-dependent TMJ OA development characterized by cartilage destruction. Subsequent unilateral bite-raising experiments revealed that USP34 deficiency exacerbated mechanical stress-induced TMJ degeneration. Our results disclosed the dual protective role of USP34 against both age-related and mechanical stress-related TMJ degeneration. Mechanistically, we define the USP34-ANT1 axis as a component upstream of the PINK1-Parkin pathway. USP34 deubiquitinates and stabilizes ANT1, thereby promoting the initiation of Parkin-dependent mitophagy. Additionally, USP34 overexpression confers protection to chondrocytes against cellular injury. These findings establish USP34 as a critical node linking ubiquitin signaling to mitochondrial homeostasis in TMJ chondrocytes and propose targeting USP34 or ANT1 as a potential disease-modifying strategy.
    Keywords:  cell signaling; chondrocytes; deubiquitinating enzymes; osteoarthritis; temporomandibular joint disorders
    DOI:  https://doi.org/10.1093/jbmrpl/ziag004
  28. Ageing Res Rev. 2026 Feb 03. pii: S1568-1637(26)00043-7. [Epub ahead of print] 103051
    Mitochondrial transfer: A novel mechanism and promising therapeutic strategy in ageing kidney.
    Jingge Xu, Xingyi Li, Zhiyu Zhang, Jiahui Wu, Haiyang Yu, Yuzheng Wu, Dan Wang, Ruixia Bao, Tao Wang, Yi Zhang, Qian Chen.
      As a metabolically active organ, kidney has to challenge progressive functional decline with ageing. Meantime, in the pathogenesis of kidney diseases, renal dysfunction also accelerates an individual's ageing trajectory, leading to premature senescence and a disconnect between biological age and chronological age. Mitochondrial dysfunction is a well-recognized characteristic of kidney ageing, whereas preserving mitochondrial homeostasis can effectively delay the ageing process. This review summarizes classical alterations in mitochondrial function across renal health and disease, including impaired biogenesis with peroxisome proliferator's-activated receptor γ coactivator α (PGC-1α) suppression, fission-fusion imbalance with overactivation of dynamin-related protein 1 (DRP1), mitophagy defects linked to abnormalities in the PTEN-induced putative kinase 1 (PINK1)/Parkin pathway, oxidative stress cascades featuring mitochondrial reactive oxygen species (mtROS)-mediated damage, and dysregulation of mitochondrial protein quality control. Moreover, we critically evaluate mitochondrial transfer as novel, non-canonical pathways beyond classical bioenergetics, generally through tunneling nanotubes (TNTs)/ extracellular vesicle-containing mitochondria (EVMs)/ free mitochondrial, and inter-organelle communication. We also discuss alternative mitochondria-targeted therapeutics and dissect their clinical translation hurdles. Appropriate interventions on mitochondrial transfer represents a promising strategy for preventing kidney ageing to maintain long-term renal health and extend lifespan. However, the majority of the studies we reviewed are based on animal and cellular models of other diseases, the relationship between renal ageing and mitochondrial transfer has not been adequately explored in clinical trials, and there is still a long way to go.
    Keywords:  Ageing kidney; Mitochondrial donor cells; Mitochondrial homeostasis; Mitochondrial transfer; Pharmacological therapeutics
    DOI:  https://doi.org/10.1016/j.arr.2026.103051
  29. Neural Regen Res. 2026 Jan 27.
    Far-infrared irradiation restores mitochondrial dynamics to ameliorate ischemic stroke.
    Wanyu Wu, Yuping Wang, Bo Qin, Xiongfei Xu, Yuanqing Qu, Nick Wang, Wuyan Zheng, Xiaoyun Yun, Betty Yuen-Kwan Law, Jianfeng Sun, Wei Zhang, Chang Chen, Vincent Kam-Wai Wong.
       ABSTRACT: Far-infrared irradiation exhibits promise in chronic diseases, and its role in ischemic stroke specifically in modulating mitochondrial dynamics remains unknown. This study explored the neuroprotective effects of far-infrared irradiation using a rat middle cerebral artery occlusion model and oxygen-glucose deprivation-injured neuronal cells. In middle cerebral artery occlusion rats, daily 30-minute far-infrared irradiation treatment reduced infarct volume, alleviated cerebral edema, and improved neurological function. Proteomic analysis identified far-infrared irradiation-mediated upregulation of eight proteins, including the mitochondrial fusion regulator optic atrophy 1. In oxygen-glucose deprivation-exposed cells, far-infrared irradiation restored mitochondrial membrane potential, and enhanced fusion via optic atrophy 1 induction. Mechanistically, far-infrared irradiation stabilized mitochondrial dynamics by boosting optic atrophy 1 expression, thereby reducing oxidative stress and maintaining energy production. Optic atrophy 1 knockdown partly abolished the protective effects of far-infrared irradiation therapy. These results establish far-infrared irradiation as a non-pharmacological intervention targeting mitochondrial redox homeostasis in ischemic stroke, offering a novel therapeutic avenue for cerebrovascular disorders.
    Keywords:  energy metabolism; far-infrared irradiation; ischemic stroke; middle cerebral artery occlusion (MCAO); mitochondrial dynamics; mitochondrial fusion; neuroprotection; optic atrophy 1 (Opa1); oxidative stress
    DOI:  https://doi.org/10.4103/NRR.NRR-D-25-00399
  30. Ecotoxicol Environ Saf. 2026 Feb 02. pii: S0147-6513(26)00145-4. [Epub ahead of print]310 119816
    Melatonin protects against fluoride-induced developmental neurotoxicity by alleviating abnormal mitophagy and apoptosis via the PINK1/Parkin pathway.
    Chun Wang, Runjiang Ma, Wenqi Qin, Chulin Yan, Meng Zhang, Yajie Li, Yongkang Liang, Huayong Wu, Jingjing Zhang, Qiang Niu.
      Fluoride induces developmental neurotoxicity, although the underlying mechanisms remain unclear. This study aimed to elucidate the roles of mitophagy and apoptosis mediated by the PTEN-induced kinase 1 (PINK1)/E3 ubiquitin-protein ligase Parkin (Parkin) pathway in fluoride-induced developmental neurotoxicity, as well as the protective effects of melatonin. A sodium fluoride (NaF) exposure model with melatonin intervention was established in F₁-generation Sprague-Dawley (SD) rats. Exposure to NaF impaired spatial learning and memory performance in offspring rats, promoted mitophagy initiation, but disrupted autophagic flux, resulting in accumulation of autophagosomes and subsequent neuronal apoptosis-evidenced by elevated levels of PINK1, Parkin, translocase of outer mitochondrial membrane 20 (TOMM20), Voltage-dependent anion channel (VDAC1), OMA1 zinc metallopeptidase (OMA1), microtubule-associated protein 1 light chain 3-II (LC3-II), sequestosome 1 (SQSTM1/p62), cleaved poly (ADP-ribose) polymerase (cleaved PARP), and BCL-2 Associated X protein (BAX), reduced levels of B-cell lymphoma 2 (Bcl-2) in brain tissues. Notably, melatonin treatment attenuated NaF-induced neurotoxicity by enhancing mitophagic clearance via activation of the PINK1/Parkin pathway, thereby restoring autophagic flux and suppressing apoptotic cell death. Collectively, our findings demonstrate that NaF activates the PINK1/Parkin-mediated mitophagy pathway; however, incomplete autophagic degradation leads to mitochondrial dysfunction and neuronal apoptosis, contributing to developmental neurotoxicity. Importantly, melatonin mitigates these adverse effects, suggesting its potential as a therapeutic agent for preventing fluoride-induced neurodevelopmental impairment through modulation of the PINK1/Parkin signaling axis.
    Keywords:  Fluoride; Melatonin; Mitophagy; Neurotoxicity; PINK1/Parkin
    DOI:  https://doi.org/10.1016/j.ecoenv.2026.119816
  31. ACS Sens. 2026 Feb 03. XXX
    Visualizing PINK1 Activity Dynamics in Single Cells with a Phase Separation-Based Kinase Activity Reporter.
    Katie G Vineall, Alexia Andrikopoulos, Michael J Sun, Anna Yan, Ethan R Hartanto, Danielle L Schmitt.
      Phosphatase and tensin homologue-induced kinase 1 (PINK1) is a serine/threonine kinase that plays roles in mitophagy, cell death, and regulation of cellular bioenergetics. Current approaches for studying PINK1 function depend on bulk techniques that can only provide snapshots of activity and could miss the dynamics and cell-to-cell heterogeneity of PINK1 activity. Therefore, we sought to develop a novel PINK1 kinase activity reporter to characterize PINK1 activity. Taking advantage of the separation of phase-based activity reporter of kinase (SPARK) design, we developed a phase separation-based PINK1 biosensor (PINK1-SPARK). With PINK1-SPARK, we observe real-time PINK1 activity in single cells treated with mitochondria-depolarizing agents or pharmacological activators. We then developed a HaloTag-based PINK1-SPARK for multiplexed imaging of PINK1 activity with live-cell markers of mitochondrial damage. Thus, PINK1-SPARK is a new tool that enables temporal measurement of PINK1 activity in single live cells, allowing for further elucidation of the role of PINK1 in mitophagy and cell function.
    Keywords:  PINK1; biosensor; fluorescence; kinase activity reporter; mitophagy
    DOI:  https://doi.org/10.1021/acssensors.5c03859
  32. Inflammation. 2026 Jan 30.
    Inhibition of TRPV4 Regulates Mitophagy Through the Sirt1/FoxO1 Signaling Pathway To Alleviate Acute Lung Injury.
    Xiuyun Wu, Shasha Liu, Qin Zhao, Mu Xu, Changxin Jia, Jia Shi, Jianbo Yu, Shu'an Dong.
      The transient receptor potential vanilloid 4 (TRPV4) channel has emerged as a key mediator of calcium dysregulation in acute lung injury (ALI), but its role in mitophagy-the selective autophagic clearance of dysfunctional mitochondria-and crosstalk with the Sirtuin 1(Sirt1)signaling axis remain unclear. Lipopolysaccharide (LPS) induced the upregulation of TRPV4, oxidative stress (ROS), and apoptosis in both in vivo and in vitro models. TRPV4 activation (GSK1016790A) exacerbated ALI by impairing mitophagy, as evidenced by reduced LC3/Translocase of the outer mitochondrial membrane 20 (TOMM20) co-localization and decreased PTEN induced kinase 1(PINK1)/PARK2 expression. Conversely, TRPV4 inhibition (GSK2193874) or knockout attenuated lung injury, enhanced mitophagic flux, and reduced mitochondrial damage. Mechanistically, TRPV4 inhibition upregulated Sirt1/Forkhead box O1(FoxO1) signaling, driving PINK1/PARK2-dependent mitophagy. Sirt1 inhibition abrogated these protective effects, confirming its critical role in the TRPV4-mitophagy axis. TRPV4 knockout༈Trpv4⁻/⁻༉mice exhibited reduced pulmonary inflammation, apoptosis, and improved mitochondrial ultrastructure compared to wild-type controls.TRPV4 exacerbated LPS-induced ALI by suppressing Sirt1/FoxO1-mediated mitophagy. Genetic or pharmacological inhibition of TRPV4 restored mitophagic clearance of dysfunctional mitochondria, offering a promising therapeutic strategy for septic ALI. These findings highlighted the TRPV4-Sirt1/FoxO1 axis as a novel target for improving outcomes in critical care settings.
    Keywords:  Acute lung injury; Ca2+ ; Mitophagy; Sirtuin 1; Transient receptor potential vanilloid 4
    DOI:  https://doi.org/10.1007/s10753-025-02433-y
  33. Free Radic Biol Med. 2026 Jan 29. pii: S0891-5849(26)00054-7. [Epub ahead of print]246 442-455
    (Pro)renin receptor (PRR) exacerbates diabetic cardiomyopathy by suppressing LRRK2-Mediated mitophagy and promoting senescence.
    Lihui Deng, Boyang Wang, Haipeng Jie, Meitong Liu, Luyao Yu, Shuzhen Wu, Lanlan Wang, Shengnan Li, Xiaohui Hu, Yalin Yu, Guohua Song, Bo Dong.
       BACKGROUND: Diabetic cardiomyopathy (DCM) is a major complication of diabetes mellitus, leading to significant mortality. The (Pro)renin Receptor (PRR) is implicated in cardiovascular pathology, but its specific role in regulating mitochondrial quality control and cellular senescence in the context of DCM remains poorly understood. This study aimed to elucidate the mechanism by which PRR contributes to myocardial injury in DCM.
    METHODS: DCM was induced in mice using a high-fat diet combined with streptozotocin injection. The function of PRR was investigated in vivo and in high-glucose (HG)-stimulated neonatal rat cardiomyocytes (NRCMs) in vitro using adenoviral vectors for overexpression and knockdown. Cardiac function, myocardial remodeling (fibrosis, hypertrophy), mitophagy, and senescence were assessed using echocardiography, histological and immunofluorescence staining, Western blot, and RT-qPCR. RNA-sequencing was employed to identify downstream targets of PRR, and the protein-protein interaction was validated by co-immunoprecipitation and pull-down assays.
    RESULTS: PRR expression was significantly upregulated in the myocardium of DCM mice and in HG-treated NRCMs. Overexpression of PRR exacerbated cardiac dysfunction, myocardial fibrosis, and hypertrophy, which was associated with impaired mitophagy and increased cellular senescence. Conversely, genetic knockdown of PRR ameliorated these pathological changes. Mechanistically, PRR was found to physically interact with and suppress kinase activity of Leucine-rich repeat kinase 2 (LRRK2). Silencing LRRK2 abolished the protective effects of PRR knockdown, confirming that LRRK2 is a critical downstream mediator of PRR's detrimental effects.
    CONCLUSIONS: PRR exacerbates diabetic cardiomyopathy by suppressing LRRK2, leading to impaired mitophagy and accelerated cellular senescence. The PRR/LRRK2 axis may be a potentially promising and novel therapeutic paradigm for treating DCM, and targeting PRR may represent a possibly promising therapeutic strategy.
    Keywords:  Diabetic cardiomyopathy; LRRK2; Mitophagy; PRR; Senescence
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.01.036
  34. Biochem Biophys Res Commun. 2026 Jan 26. pii: S0006-291X(26)00118-X. [Epub ahead of print]804 153354
    Mitochondrial changes in clear cell renal cell carcinoma: mechanisms and potential targets.
    Jiayi Yang, Xiaoyan Pan, Xiaoyan Luo, Xueting Zheng, Jiali Wang.
      Renal cell carcinoma (RCC), the most common type of urogenital cancer, accounts for about 80 % of malignant renal tumors. Clear cell renal cell carcinoma (ccRCC), composed of cells filled with lipid droplets in cytoplasm, is the most common subtype of RCC. Mechanisms underlying ccRCC progression and metastasis are complicated and remain far from being clarified. Mitochondria, which serve as cellular energy supplier and central signal hubs, are involved in various physiological and pathological processes. Mounting evidence has revealed that mitochondrial changes, such as mutations, abnormal mitophagy and metabolisms and excessive reactive oxide species (ROS) are closely related with the progression, prognosis, metastasis and drug resistance of RCC and ccRCC. In this review, we'll provide an overview on mitochondrial changes in RCC, especially in ccRCC, and discuss their possible roles in the tumorigenesis and prognosis as well as their potential in serving as biomarkers and therapeutic targets.
    Keywords:  Clear cell renal cell carcinoma; Metabolic reprogramming; Mitochondrial dynamics; Mitophagy; mtDNA
    DOI:  https://doi.org/10.1016/j.bbrc.2026.153354
  35. Autophagy. 2026 Feb 04. 1-19
    PRKN activation for mitophagy requires an NME3-regulated phosphatidic acid signal that separates mitochondria from endoplasmic reticulum tethering.
    Chih-Wei Chen, Ying-Jung Chen, Xiaojing Cuili, Yi-Han Chen, Zee-Fen Chang.
      PINK1-dependent activation of PRKN/parkin on depolarized mitochondria causes mitophagy. The deficiency of NME3, a nucleoside diphosphate kinase/NDPK on the outer mitochondria membrane (OMM), is associated with a fatal neurodegenerative disorder. Here, we report that NME3 deficiency impairs p-S65-ubiquitin (Ub)-dependent PRKN binding on depolarized mitochondria without involving the loss of Ub phosphorylation by PINK1. Our mechanistic investigation revealed that NME3 interacts with PLD6/MitoPLD to generate phosphatidic acid (PA) from cardiolipin on the OMM of damaged mitochondria after depolarization. This lipid signal is essential for positioning MFN2 nearby PINK1 for phosphorylation of Ub conjugates on MFN2, thus enabling the subsequent amplification of PRKN binding to mitochondria. We provide further evidence that mitochondria-endoplasmic reticulum (Mito-ER) tethering prohibits the proximity of MFN2 with PINK1 and PRKN amplification on mitochondria. Importantly, the loss of NME3-regulated PA signal causes Mito-ER tethering. Overall, our findings suggest that NME3 cooperates with PLD6 to generate PA as a critical step in Mito-ER untethering, allowing MFN2 access to PINK1 for p-S65-poly-Ub-dependent feedforward activation of PRKN.Abbreviation ACTB: actin beta; BDNF brain derived neurotrophic factor; CL: cardiolipin; CRISPR: clustered regularly interspaced short palindromic repeats; DAG: diacylglycerol; ER: endoplasmic reticulum; FCCP: carbonyl cyanide p-(trifluoromethoxy) phenylhydrazone; FRET: Förster resonance energy transfer; IF: immunofluorescence; KO: knockout; KD: knockdown; LPIN1: lipin 1; MERCS: mitochondria-endoplasmic reticulum contact sites; MFN2: mitofusin 2; Mito: mitochondria; OMM: outer mitochondrial membrane; p-Ub: phosphorylated ubiquitin; PA: phosphatidic acid; PD: Parkinson disease; PINK1: PTEN induced kinase 1; PLA: proximity ligation assay; PLD6/MitoPLD: phospholipase D family member 6; PRKN: parkin RBR E3 ubiquitin protein ligase; RA: retinoic acid; RT-qPCR: reverse transcription-quantitative polymerase chain reaction; TEM: transmission electron microscopy; TN-NME3: TOMM20-NΔ-NME3; TOMM20: translocase of outer mitochondrial membrane 20; TUBB: tubulin beta class I; Ub: ubiquitin; VDAC: voltage dependent anion channel; WB: western blot.
    Keywords:  MFN2; NME3; PINK1; PRKN; mitophagy; phosphatidic acid
    DOI:  https://doi.org/10.1080/15548627.2026.2623981
  36. Environ Int. 2026 Jan 24. pii: S0160-4120(26)00060-7. [Epub ahead of print]208 110102
    Co-exposure to PFOA, PFBA and nanoplastics synergistically exacerbates neurotoxicity by impairing PINK1/Parkin-mediated mitophagy.
    Helei Cai, Shihao Luo, Zhengrong Zhou, Feixia Chen, Jiawei Ying, Qiufang Wu, Yize Wu, Shihua Chen, Xinxin Yao, Feiqin Xie, Wenhui Xu, Ke Xu, Renyi Peng.
      Perfluorooctanoic acid (PFOA) and perfluorobutyric acid (PFBA), as representative long-chain and short-chain per- and polyfluoroalkyl substances (PFAS), are widely distributed in the environment. These compounds can interact with nanoplastics (NPs) to form complex mixed pollutants, posing potential threats to aquatic organisms and human health. The nervous system, characterized by high sensitivity and energy dependence, is particularly vulnerable to such pollutants. However, the mechanisms underlying neurological toxicity induced by co-exposure to PFOA, PFBA, and NPs remain largely unclear. In this study, zebrafish larvae and human neuroblastoma SH-SY5Y cells were employed as model systems to systematically evaluate the effects of PFOA and PFBA, alone or in combination with NPs, on neural development, behavior, cell viability, mitochondrial function, and autophagy. The results demonstrated that NPs exhibited a significantly higher adsorption capacity for PFOA than for PFBA, and that co-exposure exacerbated neurodevelopmental impairments, behavioral abnormalities, and reductions in cell viability. At the molecular level, co-exposure markedly inhibited the PINK1/Parkin-mediated mitophagy pathway, resulting in mitochondrial damage accumulation, disruption of energy metabolism, and blockade of autophagic flux. Through PINK1 overexpression and pharmacological activation experiments, the pivotal role of the PINK1/Parkin-mediated mitophagy pathway in mitigating neurotoxicity was functionally validated. Collectively, this study elucidates the molecular mechanism by which co-exposure to PFOA, PFBA, and NPs induces neurotoxicity via suppression of mitophagy. These findings identify a potential molecular target for the prevention and treatment of PFAS- and NPs-induced neurological injury and provide valuable theoretical and experimental evidence for evaluating the neurotoxic risks of mixed environmental pollutants.
    Keywords:  Mitophagy; NPs; Neurotoxicity; PFBA; PFOA; Zebrafish larvae
    DOI:  https://doi.org/10.1016/j.envint.2026.110102
  37. Front Pharmacol. 2025 ;16 1713681
    Bushen Huoxue decoction alleviates bisphenol a-induced infertility through the PMK-1 mitogen-activated protein kinases signaling pathway and downstream mitochondrial unfolded protein response in Caenorhabditis elegans.
    Linlin Chen, Kanglu Wu, Chenyi Shou, Lijun Zhang, Mengya Tu, Borui Wang, Yun Cai, Zihui Zheng, Jia Sun, Qinli Ruan, Jun Guo.
       Introduction: Bushen Huoxue (BSHX) decoction is a traditional Chinese medicine formula that has been utilized clinically to treat Diminished Ovarian Reserve. However, the underlying mechanisms by which BSHX decoction increases fertility from the perspective of systemic stress protective responses remain poorly understood. This study aims to investigate how BSHX decoction improves female fertility by improving systemic stress resistance in a fertility-defective Caenorhabditis elegans model.
    Methods: Bisphenol A (BPA) was utilized to create a fertility-defective C. elegans model. Brood size was used to evaluate fertility. Survival under heat stress was used to evaluate stress resistance. Loss-of-function mutants and fluorescent protein transgenic strains were used to evaluate gene function. Polymerase chain reaction and RNA interference were used to detect gene expression levels or protein function.
    Results and Discussion: BSHX decoction significantly increased the fertility of BPA-exposed nematodes by inhibiting the accumulation of RHO-1 proteins in proximal oocytes. BSHX enhanced the heat stress resistance of germ cells, which is mediated by the PMK-1 and JNK mitogen-activated protein kinases (MAPK) pathways in germ cells. BSHX upregulated the transcriptional level and fluorescent protein level of the innate peptide T24B8.5 via the PMK-1 MAPK pathway. PMK-1 MAPK, induced by BSHX, further activated the mitochondrial unfolded protein response (UPRmt) in the gonad and intestine. The UPRmt -regulated gene hsp-6 was required to maintain mitochondrial function by reducing mitochondrial ROS levels and elevating the mitochondrial membrane potential, ultimately increasing the female fertility. In addition, a combination of metabolites (salvianolic acid B, quercetin, and asperosaponin VI), derived from the BSHX decoction, significantly enhanced the fertility of BPA-exposed nematodes through a mechanism highly similar to that of the BSHX decoction. Therefore, BSHX decoction increases fertility through the PMK-1 MAPK pathway and hsp-6-mediated UPRmt in BPA-exposed C. elegans.
    Keywords:  Bushen Huoxue decoction; fertility; metabolites combination; mitochondrial unfolded protein response; proteostasis; systemic stress resistance
    DOI:  https://doi.org/10.3389/fphar.2025.1713681
  38. Reproduction. 2026 Feb 02. pii: xaag016. [Epub ahead of print]
    MRPL13 Deficiency Triggers Trophoblast Mitochondrial Unfolded Protein Response in Early-Onset Preeclampsia.
    Xiaoxu Chen, Qinying Zhu, Wang Liying, Chen Ziyi, Zhao Qingyang, Shi Xiaohua, Hu Huiying, Tang Pingping, Zhong Yifeng, Liu Juntao, Gao Jinsong.
      This study investigated the critical role of mitochondrial dysfunction in early-onset preeclampsia (EOPE), a major contributor to perinatal morbidity and mortality. We enrolled 12 patients diagnosed with EOPE and 8 healthy control women. Placental trophoblasts from these participants underwent comprehensive proteomic sequencing to identify differentially expressed proteins between the two groups. Key findings from proteomics were rigorously cross-verified using western blotting and immunofluorescence techniques. To further elucidate the functional consequences, we utilized the human placental trophoblast cell line HTR8/SVneo and BeWo, employing siRNA to reduce the expression of a target protein gene, subsequently observing its effects on mitochondrial function and overall trophoblast cell behavior. Our results revealed 280 differentially expressed proteins, with a notable downregulation of mitochondrial ribosomal proteins. Specifically, the expression of mitochondrial ribosomal proteins L13 (MRPL13) and MRPL9 was significantly decreased in the EOPE group, alongside a significant reduction in the mitochondrial unfolded protein response (UPRmt) related protein caseinolytic protease P (CLPP). In vivo experiments, we found that the UPRmt became more severe in HTR8/SVneo and BeWo with reducing MRPL13, leading to a significant inhibition of cell migration and an enhancement of autophagy. Specifically, under the tunicamycin (TM)-induced endoplasmic reticulum (ER) stress, MRPL13-knockdown also depleted HSP60 and CLPP, aggravated UPRmt and promoted mitochondrial dysfunction. In conclusion, our findings suggest that downregulation of MRPL13 may induce mitochondrial dysfunction via participating in the UPRmt, thereby negatively impacting the migration, proliferation, and invasion of trophoblast cells, and contributing to the pathogenesis of EOPE.
    Keywords:  early-onset preeclampsia; mitochondrial dysfunction; mitochondrial ribosomes; placental trophoblast; unfolded protein response
    DOI:  https://doi.org/10.1093/reprod/xaag016
  39. ACS Chem Neurosci. 2026 Feb 05.
    CHCHD2, Rather than FBXO7, Plays an Essential Role in Modulating the MPP+-Induced mtUPR.
    Dongni Wen, Yunjing Li, Lina Chen, Haoling Xu, Yingqing Wang, Yanhong Weng, Jing Zhang, Xiaochun Chen, En Huang, Yuqi Zeng, Qinyong Ye.
      Parkinson's disease (PD) is characterized by mitochondrial dysfunction and impaired protein homeostasis, with the mitochondrial unfolded protein response (mtUPR) emerging as a key regulatory pathway in mitigating mitochondrial stress. This study aimed to explore the impact of shRNAs targeting CHCHD2 or FBXO7 on the mitochondrial unfolded protein response (mtUPR) in a Parkinson's disease (PD) cell model, clarify the mitochondrial-nuclear signaling pathways involving CHCHD2 and FBXO7, elucidate the mechanisms underlying mitochondrial dysfunction induced by these genes, and identify new therapeutic targets for early stage PD. An in vitro PD model was established by treating SH-SY5Y cells with MPP+; mitochondrial morphology was evaluated using transmission electron microscopy, and qRT-PCR and Western blot were employed to determine the expression levels of mRNAs and proteins associated with mtUPR, autophagy, CHCHD2, and FBXO7 under oxidative stress. In the MPP+-induced PD cell model, we knocked down CHCHD2 and FBXO7 via shRNA and treated the cells with JNK and AKT agonists to observe their effects on mtUPR protein expression. The results showed that mtUPR was activated in MPP+-exposed SH-SY5Y cells, and the expression of CHCHD2 and FBXO7 genes was significantly upregulated after MPP+ intervention; knockdown of CHCHD2 via shRNA resulted in a marked decrease in the expression of mtUPR-related proteins such as HSPA9, HSPD1, YME1L1, and CLPP, while shRNA targeting FBXO7 exerted only a minimal effect on these mtUPR proteins. Furthermore, the administration of JNK or AKT agonists significantly enhanced the expression of MPP+-induced mtUPR proteins, including HSPA9, HSPD1, YME1L1, and CLPP. Collectively, these findings indicate that CHCHD2, rather than FBXO7, plays an essential role in modulating the MPP+-induced mtUPR and suggest that CHCHD2 may regulate mitochondrial protein homeostasis by activating the mtUPR through the JNK/c-Jun and AKT/ERα pathways.
    Keywords:  CHCHD2; FBXO7; Parkinson’s disease; mtUPR
    DOI:  https://doi.org/10.1021/acschemneuro.5c00792
  40. Free Radic Biol Med. 2026 Jan 29. pii: S0891-5849(26)00072-9. [Epub ahead of print]
    SLC7A11-FUNDC1 Axis Drives Cr(VI)-Induced Renal Injury through Mitophagy-Ferroptosis Crosstalk.
    Changxi Qi, Huiling Xu, Muzi Li, Guodong Cheng, Jiayi Li, Yue Yu, Zhiyuan Lu, Xiaozhou Wang, Jianzhu Liu, Xiaona Zhao.
      Hexavalent chromium [Cr(VI)] is a widespread environmental contaminant known to cause severe organ damage, with acute exposure leading to significant nephrotoxicity. To elucidate the underlying mechanisms, this study investigated the role of the mitophagy-ferroptosis axis in Cr(VI)-induced renal injury using mouse models and renal tubular epithelial cells (mRTECs). We found that Cr(VI) exposure disrupted mitochondrial iron homeostasis in mRTECs, leading to Mito-Fe2+ accumulation and mitochondrial damage. Consequently, this triggered an overproduction of mitochondrial and total reactive oxygen species (Mito-ROS/total ROS) and initiated lipid peroxidation. Furthermore, our mechanistic studies revealed that Cr(VI) induced FUNDC1-dependent mitophagy, which specifically targeted the degradation of SLC7A11. This event downregulated GPX4 and impaired the glutathione antioxidant system, thereby exacerbating lipid peroxidation and ultimately driving ferroptosis. In vivo studies corroborated these findings, demonstrating evident renal injury in Cr(VI)-exposed mouse. Collectively, Our data reveal a novel mechanism whereby FUNDC1-mediated mitophagy participates in hexavalent Cr(VI)-induced renal ferroptosis through degradation of SLC7A11. These results not only clarify a key pathological pathway but also highlight the therapeutic potential of targeting the SLC7A11-FUNDC1 axis to mitigate Cr(VI) nephrotoxicity.
    Keywords:  Cr(VI); FUNDC1; Ferroptosis; Mitophagy; SLC7A11
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.01.052
  41. Chem Biol Drug Des. 2026 Feb;107(2): e70260
    Identification of Mitophagy-Related Genes With Diagnostic Value in Atherosclerosis Using Bioinformatics Analysis and Experiment Validation.
    Zhe Chen, Zhongying Chen, Yuhao Wang, Jianzhi Shao, Qizeng Wang.
      Atherosclerosis (AS) is a chronic inflammatory condition with complex molecular underpinnings, where mitophagy-selective mitochondrial autophagy-plays a critical yet poorly defined role. By integrating bulk and single-cell RNA sequencing data from human atherosclerotic plaques, we analyzed 20 mitophagy-related genes and identified 15 that were dysregulated in AS. Machine learning approaches (Random Forest and SVM-RFE) pinpointed four hub genes-PINK1, TOMM40, TOMM7, and VDAC1-which formed the basis of a diagnostic model with solid predictive performance. Single-cell analysis of over 106,000 cells revealed endothelial cells as mitophagy-active and dominant in AS lesions. Trajectory analysis distinguished disease-associated endothelial subtypes, while CellChat uncovered intensified MIF signaling via CD74-CD44 and CD74-CXCR4 axes in mitophagy-high endothelial cells. SCENIC analysis further identified CEBPD, FOS, and JUN family transcription factors as key regulators. Experimental validation using ox-LDL-treated RAW264.7 macrophages confirmed differential expression of all four hub genes. Collectively, our findings highlight endothelial mitophagy dysregulation and immune crosstalk as central to AS pathogenesis and offer promising diagnostic markers and therapeutic targets.
    Keywords:  MIF signaling; atherosclerosis; diagnostic model; endothelial cells; machine learning; mitophagy; single‐cell RNA sequencing
    DOI:  https://doi.org/10.1111/cbdd.70260
  42. Free Radic Biol Med. 2026 Jan 30. pii: S0891-5849(26)00061-4. [Epub ahead of print]246 580-597
    Acetate ameliorates glucolipid metabolic dysregulation and neuroinflammation in diabetic cognitive impairment via enhanced mitophagy.
    Jie Zheng, Yu An, Xin Zhang, Zhaoming Cao, Guangyi Xu, Jing Li, Jingya Wang, Li Chen, Yanhui Lu.
       BACKGROUND: Diabetic cognitive impairment (DCI) is an increasingly recognized complication of type 2 diabetes mellitus (T2DM) with limited effective therapies. Short-chain fatty acids (SCFAs) have been implicated in metabolic regulation and neuronal health, yet comparisons of acetate, propionate, butyrate, and their mixture are limited, and the mechanisms underlying neuroprotection in DCI remain insufficiently clarified.
    METHODS: Ninety participants (healthy controls, T2DM, and DCI groups) were assessed for serum SCFA levels and cognitive performance using the Montreal Cognitive Assessment (MoCA). In parallel, a DCI mouse model established by a 24-week high-fat diet received 8-week supplementation with acetate, propionate, butyrate, or a mixture of the three. Glucolipid metabolism, spatial learning and memory, hippocampal neuronal damage, neuroinflammation, and mitophagy were evaluated. Based on consistency across the clinical and animal datasets, acetate was selected for mitophagy-focused mechanistic experiments, and pathway dependence was examined by co-administration of the autophagy inhibitor 3-methyladenine (3-MA).
    RESULTS: Clinically, serum acetate, propionate, and butyrate were lower in T2DM and DCI than in healthy controls; only acetate showed a further significant reduction in DCI compared with T2DM. All three SCFAs were positively associated with MoCA score and inversely associated with fasting blood glucose, whereas acetate additionally showed inverse associations with lipid parameters. In mice, SCFA supplementation alleviated metabolic dysfunction, spatial learning and memory, neuronal loss, and neuroinflammation, with acetate generally producing more consistent and numerically greater improvements across these endpoints. Mechanistically, acetate enhanced hippocampal mitophagy by restoring LC3-TOMM20 colocalization and activating the PINK1/Parkin pathway. Importantly, 3-MA partially attenuated these benefits, indicating a mitophagy-dependent mechanism.
    CONCLUSIONS: These integrated clinical and experimental data support a "SCFAs-mitophagy-neuroinflammation" axis linking systemic metabolism to neuronal vulnerability in DCI, and identify acetate as a promising SCFA that may enhance neuronal resilience through mitophagy activation.
    Keywords:  Acetate; Diabetic cognitive impairment; Mitophagy; Neuroinflammation; PINK1/Parkin pathway; Short-chain fatty acids
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.01.041
  43. Adv Sci (Weinh). 2026 Jan 30. e16488
    Targeting the GPX4-FUNDC1 Interaction with Magnesium Lithospermate B Attenuates Sepsis-Associated Lung Injury.
    Zhixi Li, Chang Liu, Zhaoxue Ma, Dongyou Zheng, Renkai Wang, Yongjing Yu, Guangmin Chen, Chenglong Li, Yue Bu, Hang Cao, Bing Zhang.
      Sepsis-associated lung injury (SALI) remains a critical clinical challenge, partly driven by ferroptosis-induced endothelial dysfunction. The pathological interaction between FUN14 domain-containing protein 1 (FUNDC1) and glutathione peroxidase 4 (GPX4) promotes ferroptosis and disrupts mitophagic flux. Magnesium lithospermate B (MLB), an active compound derived from Salvia miltiorrhiza, possesses anti-inflammatory and antioxidant properties and exhibits potential for vascular protection. Here, it is demonstrated that MLB mitigates sepsis-associated pulmonary vascular injury by suppressing ferroptosis and restoring mitochondrial homeostasis. Mechanistically, MLB directly binds GPX4 at Gly79, thereby disrupting the GPX4-FUNDC1 interaction, stabilizing GPX4 enzymatic activity, and preventing its FUNDC1-mediated mitophagic degradation. To enhance pulmonary targeting, P-selectin-binding peptide-engineered adipose-derived stem cell extracellular vesicles were constructed to deliver MLB, substantially improving its therapeutic efficacy in SALI. Furthermore, a silver-citrate nanostructure-based surface-enhanced Raman spectroscopy platform was developed, enabling precise identification of MLB's Raman fingerprint spectrum with nanogram-level sensitivity and time-resolved in vivo biodistribution profiling. Collectively, these findings reveal a novel therapeutic mechanism and efficacy of MLB in SALI, highlighting a promising translational strategy that integrates targeted drug delivery with molecular detection for potential clinical applications.
    Keywords:  endothelial cells; ferroptosis; lung injury; mitophagy; sepsis
    DOI:  https://doi.org/10.1002/advs.202516488
  44. bioRxiv. 2026 Jan 17. pii: 2026.01.16.699897. [Epub ahead of print]
    A Recombinant Antibody Against Human DRP1 Serine 616 Phosphorylation Enables Detection of BRAF V600E -Associated Mitochondrial Division in Cancer.
    Shanon T Nizard, Yiyang Chen, Madhavika N Serasinghe, Ruben Fernandez-Rodriguez, Kamrin D Shultz, Jesminara Khatun, Anthony Mendoza, Juan F Henao-Martinez, Jesse D Gelles, Stella G Bayiokos, J Andrew Duty, Shane Meehan, Mihaela Skobe, Jerry Edward Chipuk.
      Mitochondria are dynamic organelles that continuously undergo balanced cycles of fusion and division to meet cellular demands. Mitochondrial division is mediated by Dynamin-Related Protein 1 (DRP1), a cytosolic large GTPase whose phosphorylation at serine 616 (DRP1-S616Ⓟ) promotes its translocation to the outer mitochondrial membrane and organelle division. Dysregulated, mitochondrial division disrupts cellular homeostasis and contributes to disease pathogenesis, including cancer. Our prior work demonstrated that the oncogene-induced mitogen-activated protein kinase (MAPK) pathway constitutively phosphorylates DRP1 at serine 616 (DRP1-S616Ⓟ), which is essential to cellular transformation and correlates with oncogene status in patient tissues. Similarly, DRP1-S616Ⓟ is subject to pharmacologic control by targeted therapies against oncogenic MAPK signaling. Building upon this foundation, we developed a human recombinant monoclonal antibody with high specificity for DRP1-S616Ⓟ, referred to as 3G11. Using diverse biochemical platforms, we demonstrate the robust utility of 3G11 to detect DRP1-S616Ⓟ in melanoma cell extracts and isolated organelles. Immunofluorescence revealed that pharmacologic inhibition of oncogenic MAPK signaling reduces DRP1-S616Ⓟ levels which correlates with mitochondrial hyperfusion; while immunohistochemistry showed that elevated DRP1-S616Ⓟ expression in human tissues correlates with BRAF V600E disease. Together, these findings establish 3G11 as a specific, versatile, renewable, and cost-effective tool for studying mitochondrial division, with strong potential for clinical applications.
    DOI:  https://doi.org/10.64898/2026.01.16.699897
  45. Adv Sci (Weinh). 2026 Feb 04. e17108
    Targeted Extracellular Vesicles Deliver Asiaticoside to Inhibit AURKB/DRP1-Mediated Mitochondrial Fission and Attenuate Hypertrophic Scar Formation.
    Luyu Li, Chenli Si, Xue Wang, Xiaojin Wu, Ying Shang, Shengfang Ge, Yong Wang, Yong Zuo, Zhen Zhang.
      Hypertrophic scars (HS) are fibroproliferative lesions arising from aberrant wound healing, their high incidence is countered by a lack of effective interventions owing to an incomplete understanding of pathogenesis. Here, we identify dysregulated mitochondrial dynamics as a key driver of HS and develop a new targeted therapy. Specifically, excessive mitochondrial fission was observed in macrophages derived from both human and murine HS tissues. In vitro and in vivo experiments revealed that this imbalance is governed by AURKB-mediated phosphorylation of DRP1 at Ser616 site. Through machine-learning coupled with biological validation, we identified the natural small-molecule Asiaticoside (AS) as a potent AURKB inhibitor. However, AS has limited targeting accuracy and poor bioavailability. To overcome these challenges, we developed cRGD-decorated extracellular vesicles (EVs) loaded with AS (AS@cRGD-EVs), enabling targeted delivery of AS to macrophages within wound tissue. In vitro and in vivo studies showed that AS@cRGD-EVs effectively restrained macrophage mitochondrial fission, rebalanced the inflammatory milieu, and conferred significant anti-scarring efficacy in murine HS models. This work establishes mitochondrial dynamics as a therapeutic axis for HS and delivers a targeted nanotherapeutic ready for translational evaluation.
    Keywords:  engineered EVs; hypertrophic scars; machine‐learning; mitochondrial fission; target delivery
    DOI:  https://doi.org/10.1002/advs.202517108
  46. Pharmacol Res. 2026 Jan 31. pii: S1043-6618(26)00038-1. [Epub ahead of print]225 108123
    Endothelial versus global METRNL reveals importance of endothelial METRNL against atherosclerosis via mitochondrial homeostasis.
    Dao-Xin Wang, Pin Wang, Zhu-Wei Miao, Shu-Na Wang, Si-Li Zheng, Xue-Lian Wang, Jia-Xin Li, Zhi-Yong Li, Yu Chen, Tian-Guang Zhang, Chao-Yu Miao.
      We recently showed that METRNL (Meteorin-like) protects against atherosclerosis. However, the mechanism for METRNL in atherosclerosis is largely unclear. This study aimed to demonstrate the relative importance of endothelial METRNL in atherosclerosis by comparing the effects of whole-body METRNL deficiency to endothelial-specific deficiency, and to show the subcellular distribution of endothelial METRNL and its role in mitochondrial homeostasis against atherosclerosis. Our study demonstrated that a deficiency in either endothelial or global METRNL exacerbated atherosclerosis to a similar degree in both spontaneous (age-related) and high fat diet-induced atherosclerosis, suggesting that endothelial METRNL is pivotal in the progression of atherosclerosis due to METRNL deficiency. Endothelial METRNL was diffusely distributed in the cytoplasm with subcellular localization to mitochondria, nucleus, endoplasmic reticulum, and Golgi apparatus (especially enriched in mitochondria and nucleus). In both an in vivo apolipoprotein E-deficient (ApoE-/-) mouse model and an in vitro oxidized low density lipoprotein (ox-LDL)-treated endothelial cell model, METRNL inhibited ox-LDL- or high fat diet-induced atherosclerosis by alleviating endothelial mitochondrial dysfunction and apoptosis which was achieved through a balance between PPARγ co-activator-1α (PGC-1α)-mediated mitochondrial biogenesis and PTEN induced putative kinase protein 1 (PINK1)-Parkin-mediated mitophagy. These findings highlight the pivotal importance of endothelial METRNL against atherosclerosis by comparison with whole-body METRNL. This is the first demonstration of METRNL localization to mitochondria in endothelial cells and its role in maintaining endothelial mitochondrial stability against atherosclerosis. Furthermore, targeting METRNL to stabilize endothelial mitochondrial function represents a novel and promising therapeutic strategy for atherosclerotic cardiovascular diseases.
    Keywords:  Atherosclerosis; Endothelial cells; METRNL; Mitochondrial homeostasis
    DOI:  https://doi.org/10.1016/j.phrs.2026.108123
  47. Mol Biol Rep. 2026 Feb 02. 53(1): 345
    Dapagliflozin attenuates hypothyroidism induced liver and lung dysfunction via regulation of mitophagy and apoptosis.
    Marwa Abdeltawab Mohammed, Esraa Mohamed Ali, Manar Fouad Ahmed, Sarah A Eweda, Maha Tarek Mohammed, Dina Sayed Abdelrahim.
       BACKGROUND: Thyroid hormones are mainly concerning with regulation of organs metabolism. Hypothyroidism is a pathological condition characterized by decrease of T3 and T4 level that negatively impact various organs especially liver and lung. Dapagliflozin (DAPA) is an anti diabetic drug posses antioxidant and anti apoptotic properties AIM OF THE STUDY: The aim of this work is to identify the effect of DAPA on disturbance of liver and lung functions result from hypothyroidism MATERIALS AND METHODS: Twenty four rats (6 rats/group) were divided into four groups: control group, DAPA group that received DAPA (1 mg/kg/day for five weeks), PTU group that received propylthiouracil (15 mg/kg/day for five weeks), PTU+ DAPA group that received PTU and DAPA as described in the other groups RESULTS: Hypothyroidism induced oxidative stress associated mitophagy disturbance in both lung and liver with development of apoptosis in liver. DAPA avoided this effect CONCLUSION: DAPA protects against liver and lung injury result from hypothyroidism.
    Keywords:  Apoptosis; Dapagliflozin; Hypothyroidism; Mitophagy; Oxidative stress
    DOI:  https://doi.org/10.1007/s11033-026-11503-9
  48. Phytomedicine. 2026 Jan 29. pii: S0944-7113(26)00137-6. [Epub ahead of print]153 157898
    Baitouweng decoction regulates ferroptosis-mediated mitophagy and apoptosis through the SLC7A11/GPX4/FTH1 pathway in ulcerative colitis.
    Liuliang Zhang, Xiaolan Zhu, Xiaochao Hu, Hui Feng, Guoqing Wang, Ying Zhang, Xuan Wang, Jiayu Su, Tongtong Liu, Xingyue Du, Huimin Zhu, Limei Gu, E-Hu Liu, Shijia Liu.
       BACKGROUND: The prevalence of ulcerative colitis (UC) has increased recently, with severe cases potentially progressing to colon cancer. The classic herbal formula Baitouweng Decoction (BTW) has a centuries-long clinical application in UC treatment, but its underlying mechanism remains unclear.
    PURPOSE: This study aimed to investigate BTW's efficacy against Dextran Sodium Sulfate (DSS)-induced UC and clarify its mechanisms.
    RESULTS: Proteomic analysis identified ferroptosis as a key pathogenic mechanism in UC. In vitro and in vivo experiments showed that BTW reduced UC-associated inflammatory symptoms, normalized the levels of inflammatory factors, and maintained intestinal barrier integrity. Notably, BTW inhibited ferroptosis and restored the antioxidant capacity of the SCL7A11/GSH/GPX4 system, thereby suppressing UC inflammation. Transcriptomic analysis revealed apoptosis and ferroptosis as core pathways for BTW's intervention in UC, with mitophagy serving as a pivotal hub connecting these processes. BTW regulated the PINK1/PARKIN-mediated mitophagy pathway and apoptosis, and this regulation was closely linked to ferroptosis.
    CONCLUSION: BTW alleviates UC-related inflammation and intestinal barrier damage by modulating apoptosis, mitophagy, and ferroptosis, while mitigating oxidative stress.
    Keywords:  Apoptosis; Baitouweng decoction; Ferroptosis; Mitophagy; Oxidative stress; Ulcerative colitis
    DOI:  https://doi.org/10.1016/j.phymed.2026.157898
  49. bioRxiv. 2026 Jan 16. pii: 2026.01.15.699710. [Epub ahead of print]
    Nicotinamide phosphoribosyltransferase activates the mitochondrial unfolded protein response to promote pulmonary arterial endothelial cell proliferation.
    Angelia D Lockett, Pontian Adogamhe, Aaron Snow, Marta T Gomes, Roberto F Machado.
      Vascular remodeling leading to occlusion of the pulmonary artery and increased pulmonary vascular resistance is the central feature of Pulmonary Arterial Hypertension (PAH) which leads to death due to right heart failure. The expression of Nicotinamide phosphoribosyltransferase (Nampt) is increased in the lungs and isolated PAECs of PAH patients. Inhibition of NAMPT is protective in preclinical models of pulmonary hypertension. NAMPT regulates multiple mitochondrial processes that control cell proliferation and survival. Using rodent models of PH, we demonstrated that the mitochondrial unfolded protein response (UPR mt ) promotes vascular remodeling. Hence we, hypothesized that NAMPT activates the UPR mt to promote abnormal pulmonary arterial endothelial cell proliferation. Analysis of PAECs isolated from PAH patients show increased expression of the UPR mt pathway mediators, ATF-5, mtHSP70 and ClpP. Human PAEC cell lines were exposed to recombinant Nampt or transduced with lentiviral-Nampt. We observed increased phosphorylation and activation of eIF2α which permits preferential translation of the ATF-5 transcription factor. ATF-5 expression and nuclear localization was increased. Further, we observed increased expression of ATF-5 target genes, mtHSP70, HSP60, ClpP and LonP1 as well as increased PAEC proliferation. Blocking mtHSP70 function reversed the Nampt induced increase in proliferation. Neither UPR mt activation nor proliferation was increased in the presence of enzymatically inactive-Nampt. Our observations demonstrate that Nampt can promote PAEC proliferation by activating the UPR mt and uncovers novel potential targets to address vascular remodeling in PAH.
    DOI:  https://doi.org/10.64898/2026.01.15.699710
  50. J Med Chem. 2026 Feb 02.
    Turning Off the Powerhouse: Mitochondria-Targeted DPPZ-Ru(II)/Ir(III)/Re(I) Complexes Trigger Dual Mitophagy and Apoptosis To Halt Triple-Negative Breast Cancer.
    Utpal Das, Shanooja Shanavas, Shubhangi More, Rishav Das, Pavan Gutti, Meena Jayaprakash, Annamalai Senthil Kumar, Sourav Ghosh, Debasish Mondal, Prasanta Ghosh, Debasish Mishra, Sudheer Shenoy P, Bipasha Bose, Rinku Chakrabarty, Priyankar Paira.
      A systematic evaluation of dppz-based Ru(II), Ir(III), and Re(I) complexes has identified [UDRu] as a potent therapeutic candidate against triple-negative breast cancer stem cells (TNBCSCs). [UDRu] exhibits optimal hydrophilic-lipophilic balance, enabling effective solubility, cellular uptake, and mitochondrial targeting. It induces oxidative stress by depleting GSH and NAD(P)H, promotes ROS generation, disrupts mitochondrial membrane potential, causes DNA damage, and arrests the cell cycle at G2/M. Furthermore, [UDRu] inhibits 3D mammosphere formation and triggers apoptosis through BAX/Bcl-2 regulation and caspase-9 activation. Notably, it also triggers mitophagy through PINK1/Parkin upregulation, offering dual mitochondrial-targeted cytotoxicity. These findings position [UDRu] as a next-generation Ru(II) complex with multitargeted action, holding significant promise for overcoming resistance in TNBC therapy.
    DOI:  https://doi.org/10.1021/acs.jmedchem.5c02210
  51. Free Radic Biol Med. 2026 Feb 04. pii: S0891-5849(26)00085-7. [Epub ahead of print]
    PGAM1-dependent VDAC1 oligomerization disrupts mitochondrial quality control to drive doxorubicin cardiotoxicity via the cGAS-STING-ferroptosis axis.
    Yukun Li, Sicheng Zheng, Haowen Zhuang, Ji Wu, Junyan Wang, Xing Chang.
       OBJECTIVES: Doxorubicin (Dox) is a potent chemotherapeutic agent whose clinical use is limited by severe cardiotoxicity. The underlying molecular mechanisms remain incompletely understood. This study aimed to investigate the role of the phosphoglycerate mutase 1 (PGAM1)/voltage-dependent anion channel 1 (VDAC1) axis in early-stage Dox-induced cardiotoxicity, focusing on its impact on mitochondrial quality control (MQC), endoplasmic reticulum (ER) stress, and the subsequent activation of innate immune signaling.
    METHODS: We established a short-term cumulative Dox-induced cardiomyopathy model using wild-type and cardiomyocyte-specific PGAM1 knockout (PGAM1-CKO) mice. Cardiac function was assessed by echocardiography. In vitro experiments were performed on neonatal mouse cardiomyocytes (NMCMs) and HL-1 cells. Molecular techniques including Western blotting, immunofluorescence, co-immunoprecipitation, and quantitative PCR were used to dissect the signaling pathway. Key pathway components were validated using specific pharmacological inhibitors and activators.
    RESULTS: Dox treatment significantly upregulated PGAM1 expression in cardiomyocytes. PGAM1-CKO mice were protected from Dox-induced cardiac dysfunction, fibrosis, and inflammation. Mechanistically, Dox-induced PGAM1 promoted the pathological oligomerization of VDAC1. This PGAM1-VDAC1 interaction triggered the collapse of MQC and induced ER stress, leading to the leakage of mitochondrial DNA (mtDNA) into the cytosol. The released cytosolic mtDNA subsequently activated the cGAS-STING innate immune pathway, which we identified as a critical upstream driver of cardiomyocyte ferroptosis. Pharmacological induction of VDAC1 oligomerization or STING activation abolished the cardioprotective effects observed in PGAM1-CKO mice.
    CONCLUSION: Our findings reveal a novel PGAM1/VDAC1 signaling axis that triggers early Dox-induced cardiotoxicity. This axis disrupts mitochondrial homeostasis, leading to mtDNA release, which activates the cGAS-STING pathway and ultimately culminates in cardiomyocyte ferroptosis. Targeting the PGAM1/VDAC1 interaction presents a promising therapeutic strategy to mitigate Dox-induced cardiac injury.
    Keywords:  Doxorubicin cardiotoxicity; Ferroptosis; Mitochondria quality surveillance; PGAM1/VDAC1 axis; cGAS-STING pathway
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.01.065
  52. J Cardiovasc Transl Res. 2026 Feb 05. 19(1): 18
    MiR-499-5P/PACS2/TRPV1 Axis Maintains Mitochondrial Homeostasis and Left Ventricular Function after Extreme Cold Stress.
    Renzheng Chen, Yan Ma, Sijia Chen, Cheng Qin, Hui Li, Naiyuan Sun, Feng Cao.
      Exposure to cold environments is physiologically challenging, with extreme cold stress (ECS) impairing the function of the left ventricle (LV) of the heart. We aimed to determine the role and mechanism of action of the miR-499-5p/phosphofurin acidic cluster sorting protein 2 (PACS2)/transient receptor potential cation channel subfamily V member 1 (TRPV1) axis in ECS-induced cardiomyocyte injury and LV dysfunction. Mice were placed in a -20 °C chamber to simulate an extremely cold environment. MiR-499-5p overexpression in the mice decreased PACS2 levels, and mitochondrial function was inhibited in vivo following ECS. Inhibiting miR-499-5p enhanced PACS2 expression, thereby reversing the structural and functional LV deficits caused by ECS. Cardiac-specific Pacs2 knock-in restored the decreases in mitophagy and mitochondrial energy metabolism caused by ECS via enhancing endoplasmic reticulum-mitochondrial calcium flux through TRPV1, a nonselective calcium channel. The findings indicate targets for preventing cardiac disease during exposure to extremely cold environments.
    Keywords:  Cardioprotective; Endoplasmic reticulum–mitochondrial calcium flux; Left ventricle deficits; Left ventricle structure; Mitochondrial energy metabolism; Mouse model
    DOI:  https://doi.org/10.1007/s12265-025-10742-8
  53. Cell Mol Biol Lett. 2026 Jan 31.
    Role of LONP1 in human diseases: molecular mechanisms and therapeutic potential.
    Mingkang Li, Anguo Wang, Chengchun Tang, Yong Qiao, Wenkang Zhang, Yamei Wu.
      
    Keywords:  Cell death and proliferation; Human diseases; Lon protease 1; Mitochondrial homeostasis; Therapeutic targets
    DOI:  https://doi.org/10.1186/s11658-026-00858-3
  54. J Biol Eng. 2026 Feb 02.
    Curcumin-loaded silk fibroin scaffold promotes cartilage regeneration by inhibiting angiogenesis via Drp1/ROS-mediated mitochondrial regulation.
    Zitong Zhao, Jingyue Fu, Jun Han, Yalan Pan, Baojun Xue, Xiaoxian Sun, Yong Ma, Bin Li, Kan Chen, Zining Li, Zhongqing Liang, Xin Zhou, Yang Guo, Pengcheng Tu.
      Articular cartilage injury often leads to vascular endothelial cell (VEC) infiltration, disrupting the microenvironment between cartilage and subchondral bone, thereby compromising cartilage repair quality. Curcumin (Cur) is a natural polyphenol with anti-inflammatory and anti-angiogenic properties that holds promise for therapeutic applications. However, its clinical utility is limited due to poor solubility and instability. To address these challenges, we developed a curcumin-loaded silk fibroin nanoparticle (Cur-SN) delivery system to inhibit VEC infiltration and promote cartilage regeneration. Cur-SNs were prepared and characterised to evaluate their physicochemical properties. The effects of Cur-SN on VEC apoptosis and senescence were assessed, and the underlying mechanism by which Cur-SN regulates mitochondrial homeostasis via the Drp1/ROS pathway was investigated. Additionally, a rat knee cartilage defect model was established, in which Cur-SN combined with a BMSC-loaded hydrogel was implanted. Cartilage differentiation and VEC infiltration levels in newly formed tissues were subsequently analysed. In vitro experiments demonstrated that Cur-SN upregulated Drp1 and ROS levels, leading to mitochondrial homeostasis disruption. This, in turn, induced VEC apoptosis and senescence while significantly inhibited VEC infiltration. Furthermore, Cur-SN effectively counteracted the inhibitory effects of VEC activation on BMSC chondrogenic differentiation. In vivo experiments revealed that Cur-SN reduced VEC infiltration and angiogenesis in newly formed tissues, thereby promoting hyaline cartilage regeneration at the defect site. Cur-SN enhances cartilage repair by upregulating Drp1 expression and ROS levels, thereby disrupting mitochondrial homeostasis, inducing VEC apoptosis and senescence, and inhibiting VEC infiltration.
    Keywords:  Cartilage regeneration; Curcumin; Mitochondrial homeostasis; Tissue engineering; Vascular endothelial cells
    DOI:  https://doi.org/10.1186/s13036-026-00624-1
  55. Essays Biochem. 2026 Feb 02. pii: EBC20253048. [Epub ahead of print]69(5):
    Cis or trans: a puzzle of Parkin activation mechanism.
    Mohini Sherawat, Ankit Kumar, Dipti Ranjan Lenka, Atul Kumar.
      The PARK2 gene, which encodes the E3 ubiquitin ligase Parkin, and the PARK6 gene, encoding phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1), are frequently mutated in patients with Parkinson's disease (PD). Parkin is normally maintained in an autoinhibited conformation, and its activation is triggered by PINK1-mediated phosphorylation of both ubiquitin or NEDD8 and Parkin's ubiquitin-like (Ubl) domain. This review provides a comprehensive overview of the models proposed over the past decade to explain Parkin's autoinhibition and activation. We summarize key structural and biophysical studies that have progressively uncovered the molecular basis of Parkin activation, tracing the evolution of these insights. This review concludes by discussing the intriguing and still unresolved question of whether Parkin activation occurs through a cis or trans mechanism and outlines future directions for research aimed at understanding these pathways.
    Keywords:  PINK1; Parkin; Parkinson’s; mitophagy; ubiquitin
    DOI:  https://doi.org/10.1042/EBC20253048
  56. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2026 Feb;42(2): 129-139
    [The mechanism of the effect of GalNAc-T4 on the mitochondrial autophagy of the injury of H9c2 cardiomyocytes induced by hypoxia/reoxygenation under high glucose environment via extracellular signal regulated kinase 1/2 signaling pathway].
    Dayou Ding, Guangrong Zhao.
      Objective To investigate the effect of N-acetylglucosamine transferase 4 (GalNAc-T4) on the mitochondrial autophagy in H9c2 cell injury model induced by hypoxia/reoxygenation (H/R) in high glucose (HG) environment, and its regulatory mechanism on extracellular signal regulated kinase 1/2 (ERK1/2) signaling pathway. Methods The cell experiments were divided into five groups. Control group (Control): Cells were transfected with pc-NC cells. HG group: 50 mmol/L glucose was added to the culture medium, and cells were transfected with pc-NC. HG+H/R group: In addition to the HG treatment, cells were subjected to a low oxygen environment for 6 hours, followed by transfection with the pc-NC vector. Overexpression group (pc): Cells were transfected with the pc while undergoing HG+H/R treatment. ERK1/2 agonist epidermal growth factor (EGF) group: Cells were treated with HG+H/R and transfected with the pc, supplemented with 20 ng/mL EGF in the culture medium. The proliferation activity, apoptosis rate, mitochondrial membrane potential, the levels of reactive oxygen species (ROS), iron ions, and mitochondrial autophagy in each group of cells were detected. The expressions of GalNAc-T4, ERK1/2, phosphorylated ERK1/2 (p-ERK1/2), translocase of outer mitochondrial membrane 20 (TOM20), translocase of inner mitochondrial membrane 23 (TIM23), B cell lymphoma 2 (Bcl2), and Bcl2 associated X protein (BAX) were detected in cells. Results Overexpression of GalNAc-T4 significantly increased the proliferation activity, the mitochondrial membrane potential, and the expression of TOM20, TIM23, and Bcl2 in H9c2 cells in HG+H/R group, and decreased the cell apoptosis rate, the levels of ROS and iron ion. Meanwhile, it inhibited the mitochondrial autophagy and downregulated the expression of p-ERK1/2/ERK1/2 and BAX in cells. EGF partially reversed the protective effect of the overexpression of GalNAc-T4 on cardiomyocytes, and the differences were statistically significant. Conclusion Overexpression of GalNAc-T4 could significantly improve the mitochondrial dysfunction in H9c2 cells undergoing hypoxia/reoxygenation under high glucose conditions, inhibit oxidative stress and excessive mitochondrial autophagy, and reduce the apoptosis rate of cardiomyocytes. This may be related to its ability to block the activation of ERK1/2 signaling pathway.
  57. Cell Death Dis. 2026 Jan 30. 17(1): 167
    Recovery from apoptosis in photoreceptor cells: A role for mitophagy.
    Bhavneet Kaur, Bruna Miglioranza Scavuzzi, Jingyu Yao, Mengling Yang, Lin Jia, Stephen I Lentz, Jaya Sadda, Andrew J Kocab, Sumathi Shanmugam, David N Zacks.
      Photoreceptors (PRs) are specialized light-sensitive cells responsible for vision, and their death is the primary cause of retinal degeneration and vision loss. Recent studies using cells such as HeLa and PC12 have demonstrated cellular recovery even from late stages of apoptosis. Here, we demonstrate for the first time that PR cells can recover from features of apoptosis following exposure to apoptotic stressors. Upon apoptotic stimuli (staurosporine or hypoxia), 661 W cells, a murine cone PR cell line, exhibited morphological and functional features of apoptosis, such as rounding and blebbing, caspase-3 activation, PARP cleavage, and phosphatidylserine externalization. These processes were reversed upon the alleviation of stress. We also observed that mitochondrial function is central to apoptotic recovery of photoreceptor cells, as evidenced by the restoration of intracellular ATP levels and reduction in mitochondrial reactive oxygen species (mROS). Mitophagy was demonstrated to play a crucial role in cell survival, with increased protein and mRNA expression of mitophagy markers during recovery from apoptosis. Furthermore, the modulation of mitophagy confirmed its protective role in the recovery phase, as its induction with MF-094 reduced apoptosis while its inhibition with Mdivi-1 exacerbated cell death. In vivo, we demonstrate the recovery of PRs from apoptosis using an experimental model of transient retinal detachment. Altogether, the findings of this study indicate that PR cells can recover from entry into the apoptotic cascade, and that mitophagy is essential for apoptotic recovery in these cells.
    DOI:  https://doi.org/10.1038/s41419-026-08436-3
  58. Int Immunopharmacol. 2026 Feb 04. pii: S1567-5769(26)00152-9. [Epub ahead of print]173 116309
    Melittin alleviates osteoarthritis via mitophagy mediated by the AMPK/PINK1/Parkin Axis.
    Congcong Wu, JianYuan Gao, Chunhui Chen, Zhiguang Zhang.
      Osteoarthritis (OA) is a common degenerative joint disease, mainly characterized by cartilage extracellular matrix (ECM) degradation, inflammatory response and chondrocyte apoptosis, with mitochondrial dysfunction as its key pathogenic factor. Melittin (Mel), the main active component of bee venom, has been confirmed to possess anti-inflammatory, antioxidant and anti-apoptotic effects, but its therapeutic effect and specific mechanism on OA have not been fully elucidated. This study explored the therapeutic effect and mechanism of Mel on OA through in vitro and in vivo experiments. In vitro experiments showed that Mel could dose-dependently reverse IL-1β-induced OA-like changes in rat chondrocytes: it not only upregulated ECM anabolic markers such as type II collagen (COL2) and aggrecan (ACAN), downregulated ECM catabolic markers such as matrix metalloproteinase-13 (MMP-13) and a disintegrin and metalloproteinase with thrombospondin motifs-5 (ADAMTS5), but also inhibited inflammatory markers such as IL-1β, IL-18, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), while restoring PINK1/Parkin-mediated mitophagy. Mechanistically, Mel exerted a protective effect against the pathological progression of OA induced by destabilization of the medial meniscus (DMM). In conclusion, Mel is expected to be a potential candidate for OA treatment.
    Keywords:  AMPK phosphorylation; Chondrocyte apoptosis; Extracellular matrix; Melittin; Mitochondrial autophagy; Osteoarthritis
    DOI:  https://doi.org/10.1016/j.intimp.2026.116309
  59. Nat Plants. 2026 Feb 05.
    MIRO1-mediated mitochondrial fusion is required for stomatal immunity in Arabidopsis.
    Pengfei Lu, Jintong Liu, Haijia Yu, Jiejie Li.
      Stomatal immunity is a critical first barrier in plant defence, yet the organelle-level mechanisms underpinning this process remain poorly understood. Here we show that the outer mitochondrial membrane protein MIRO1 is essential for flg22-triggered stomatal closure in Arabidopsis. Upon immune activation, MIRO1 promotes mitochondrial fusion in guard cells. This mitochondrial remodelling is necessary to maintain mitochondrial function, including membrane potential, ATP synthesis, mitochondrial reactive oxygen species production and the activation of organic acid metabolism. In miro1 mutants, these mitochondrial functions are compromised, which is associated with defective stomatal closure and increased bacterial entry. We further show that flg22 triggers MPK3/6-dependent phosphorylation of MIRO1 at Ser14. Phosphorylated MIRO1 displays enhanced oligomerization at mitochondrial contact sites to facilitate fusion. Mutations disrupting MIRO1 phosphorylation or oligomerization abolish its immune function. Collectively, our findings establish MIRO1 as a key molecular link between immune signalling and mitochondrial dynamics during stomatal defence regulation.
    DOI:  https://doi.org/10.1038/s41477-026-02224-9
  60. Circ Res. 2026 Feb 05.
    CLIPPER Regulates LPIN1-Mediated Mitochondrial Biogenesis and Heart Regeneration.
    Francesco Ruberto, Daniel Maric, Tatjana Kleele, Mohamed Nemir, Isabelle Plaisance, Luca Braga, Hashim Ali, Chang Jie Mick Lee, Thong Beng Lu, Alexandre Sarre, Parisa Aghagolzadeh, Roger S-Y Foo, Suliana Manley, Mauro Giacca, Thierry Pedrazzini.
       BACKGROUND: The adult mammalian heart lacks the significant regenerative potential needed to cope with the massive loss of cardiomyocytes following myocardial infarction. Ultimately, irreversible cardiac damage leads to heart failure, which is associated with a poor prognosis. Given this, reactivating dormant regenerative processes in the injured heart represents an attractive therapeutic approach. When regeneration does occur, newly formed cardiomyocytes are derived from preexisting ones.
    METHODS: We aimed to identify novel regulators of cardiomyocyte proliferation. In this context, the genome is transcribed for a large part into RNAs with little or no protein-coding potential. Among noncoding RNAs, long noncoding RNAs represent the most diverse class of molecules and are implicated in numerous epigenetic mechanisms, making them ideal targets for controlling cell identity and behavior. In this project, we developed a high-throughput screening assay to identify long noncoding RNAs that promote cardiomyocyte proliferation upon knockdown. Using a stringent selection pipeline, we identified Clipper, an enhancer-associated long noncoding RNA regulating the expression of its cognate protein-coding gene Lpin1 in cis.
    RESULTS: Clipper was found to control mitochondrial biogenesis via LPIN1. Specifically, productive mitochondrial division, characterized by fission site positioning at the midzone of the mitochondrion, was stimulated by Clipper or Lpin1 silencing. The process was associated with a change in mitochondrial bioenergetics, particularly decreased oxidative metabolism, reduced production of reactive oxygen species, and dampened DNA damage, creating favorable conditions for cardiomyocyte proliferation. Importantly, Clipper knockdown in vivo following myocardial infarction stimulated cardiac regeneration in the damaged myocardium, leading to the restoration of heart function. Importantly, CLIPPER is positionally and functionally conserved in humans.
    CONCLUSIONS: Our data identify CLIPPER as a promising therapeutic target for heart regeneration, acting through control of LPIN1-dependent mitochondrial biogenesis and cardiomyocyte proliferation.
    Keywords:  cardiovascular diseases; heart; myocardial infarction; organelle biogenesis; regeneration
    DOI:  https://doi.org/10.1161/CIRCRESAHA.125.326739
  61. J Transl Med. 2026 Feb 06.
    Exosomal miR-21 mitigates pulmonary hypertension-induced right-heart remodeling by preserves mitochondrial homeostasis.
    Wei-Ting Chang, Jhih-Yuan Shih, Chia-Hung Lin, Chih-Hsin Hsu, Yu-Wen Lin, Zhih-Cherng Chen.
      
    Keywords:  Exosomal miR-21; Mitochondrial; PAH; Parabiosis; RV adaptation
    DOI:  https://doi.org/10.1186/s12967-026-07795-x
  62. bioRxiv. 2026 Jan 15. pii: 2026.01.14.699555. [Epub ahead of print]
    LONP-1 deficiency causes dysregulated protein synthesis within mitochondria that is restored by mitoribosomal mutations.
    Levi Ali, Avijit Mallick, Yunguang Du, Rui Li, Lihua Julie Zhu, Kuang Shen, Cole M Haynes.
      Mitochondrial homeostasis is maintained by multiple molecular chaperones and proteases located within the organelle. The mitochondrial matrix-localized protease LONP-1 degrades oxidatively damaged or misfolded proteins. Importantly, LONP-1 also regulates mitochondrial DNA replication. Here, we show that mutations in C. elegans that impair LONP-1 function cause dysregulation of mitochondrial DNA replication, mitochondrial RNA transcription and protein synthesis within the mitochondrial matrix. LONP-1 deficient worms had reduced levels of oxidative phosphorylation proteins despite increased mtDNA-encoded protein synthesis. Via a forward genetic screen, we identified three mutations that restored mitochondrial function and the rate of development in lonp-1 mutants to levels comparable to those in wildtype worms. Interestingly, all three suppressor mutations were found in genes encoding mitochondrial ribosome proteins. A point mutation in the mitochondrial ribosome protein MRPS-38 restored oxidative phosphorylation in lonp-1 mutant worms. Combined, our results suggest that LONP-1 regulates mitochondrial protein synthesis and that the suppressor mutations within MRPS-38 or MRPS-15 enhance oxidative phosphorylation complex assembly by slowing translation.
    DOI:  https://doi.org/10.64898/2026.01.14.699555
  63. Free Radic Biol Med. 2026 Jan 29. pii: S0891-5849(26)00075-4. [Epub ahead of print]246 598-613
    TRIM28 aggravates myocardial infarction-induced cardiomyocyte apoptosis through regulating the stability of ATF5 via ubiquitination and SUMOylation.
    Yanying Wang, Mingyu Yang, Junting Ren, Wei Liu, Han Sun, Guangze Wang, Siyu Wang, Ying Zhang, Haodong Li, Dongping Liu, Mengmeng Li, Yanwei Zhang, Hao Wang, Xuewen Yang, Xiyang Zhang, Yuhan Liu, Lei Jiao, Lihua Sun, Lina Xuan, Xuelian Li, Shasha Fan, Manyu Gong, Ying Zhang.
      Myocardial infarction (MI) stands as a leading contributor to global cardiovascular morbidity and mortality, defined by ischemic myocardial cell death and subsequent impairment of cardiac function. The tripartite motif (TRIM) protein family has been shown to regulate myocardial ischemia-reperfusion injury. As a key member of the TRIM protein family, tripartite motif-containing protein 28 (TRIM28) exhibits dysregulated expression in the heart during MI yet its pathophysiological role remains to be fully elucidated. This study aimed to investigate the functional roles and underlying mechanisms of TRIM28 in MI. We observed a significant upregulation of TRIM28 in ischemic myocardium and hypoxic cardiomyocytes. Genetic knockout of TRIM28 ameliorated cardiac function and attenuated apoptosis in MI mice, whereas its overexpression exacerbated contractile dysfunction, and promoted cardiomyocyte apoptosis and mitochondrial injury. Mechanistically, TRIM28 directly interacts with activating transcription factor 5 (ATF5) and suppresses its SUMOylation, thereby enhancing the ubiquitin-mediated degradation of ATF5, inhibiting the mitochondrial unfolded protein response (UPRmt), and ultimately culminating in increased apoptosis. Via molecular docking, we identified a TRIM28-targeting compound, Oolonghomobisflavan B (OFB), which attenuated post-MI apoptosis and facilitated cardiac function recovery. Collectively, these findings demonstrate that TRIM28 acts as a critical regulator of MI progression, and OFB holds therapeutic potential as a candidate drug.
    Keywords:  ATF5; Apoptosis; Mitochondrial unfolded protein response; Myocardial infarction; TRIM28
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.01.055
  64. J Endocr Soc. 2026 Feb;10(2): bvaf171
    Effect of Tofogliflozin on Skeletal Muscle Mitochondrial Function in Male Diabetic Mice With Muscle Atrophy.
    Chiaki Kishida, Maki Murakoshi, Hiroko Sakuma, Terumi Shibata, Yusuke Suzuki, Tomohito Gohda.
      Sodium-glucose cotransporter-2 (SGLT2) inhibitors are effective medications for type 2 diabetes (T2D), chronic kidney disease, and chronic heart failure regardless of diabetic status. However, concerns remain about their potential to reduce skeletal muscle mass. This study clearly demonstrates that tofogliflozin (Tofo), an SGLT2 inhibitor, improves skeletal muscle mitochondrial function, morphology, and performance in a mouse model of T2D with dexamethasone (Dex)-induced muscle atrophy. Obese diabetic KK-Ay mice and nondiabetic KK mice were used. Muscle atrophy was induced in the KK-Ay mice by intraperitoneal Dex injections for 2 weeks, followed by Tofo administration (0.015%) in the diet for 2 weeks. Tofo treatment enhanced exercise endurance, restored mitochondrial morphology, increased succinate dehydrogenase activity, and elevated protein expression of optic atrophy 1 and dynamin-related protein 1. These changes were associated with AMPK (adenosine monophosphate-activated protein kinase) activation and reduced expression of the mitokine growth differentiation factor-15. Although Tofo increased muscle cross-sectional area, it did not significantly affect overall body or muscle mass, nor grip strength, suggesting a preferential effect on slow-twitch oxidative fibers. Importantly, these benefits occurred without weight loss, likely due to maintained or increased food intake. These findings suggest that Tofo specifically ameliorates mitochondrial dysfunction and improves muscle quality and endurance in diabetic sarcopenia, especially under preserved nutritional conditions. Because Tofo is a highly selective SGLT2 inhibitor with distinct pharmacokinetic properties, these results are specific to Tofo and should not be generalized to all SGLT2 inhibitors. Further studies are warranted to determine whether similar effects are observed with other agents in this class.
    Keywords:  AMP-activated protein kinase; exercise endurance; mitochondrial dynamics; sarcopenia; sodium-glucose cotransporter-2 inhibitor
    DOI:  https://doi.org/10.1210/jendso/bvaf171
  65. Food Res Int. 2026 Mar 01. pii: S0963-9969(25)02654-7. [Epub ahead of print]227 118314
    Biomimetic carboxymethyl β-glucan-ZIF-8 nanocarrier enhances structural stability, gastrointestinal release, and antioxidant efficacy of urolithin A via dectin-1-engaged mitophagy.
    Fangcheng Hu, Xingyuan Liu, Chunping Chen, Yushan Liu, Xiaotong Xu, Lin Han, Caian He, Min Wang.
      The clinical translation of urolithin A (UA), an ellagitannin-derived metabolite with antioxidant and mitophagy-inducing properties, is hampered by its poor solubility, limited stability, and low oral bioavailability. To address these limitations, we developed a core-shell nanoplatform (UA@ZIF-8@CMG) comprising a ZIF-8 core for efficient encapsulation and a carboxymethyl β-glucan (CMG) shell for enhanced stability and potential targeting. The optimized formulation exhibited a high drug-loading capacity (12.65 %), markedly improved UA stability, and demonstrated pH-responsive release, with minimal leakage (22 %) under simulated gastric conditions followed by sustained release in the intestinal environment. In vitro studies revealed reduced cytotoxicity and a dual cellular uptake mechanism, involving putative Dectin-1-mediated endocytosis in macrophages and nonspecific uptake in intestinal cells. This uptake profile resulted in superior preservation of mitochondrial membrane potential and more effective ROS scavenging compared with free UA. The key innovation of this system lies in the synergistic ZIF-8@CMG architecture, which integrates robust protection, controlled release, and cell-type-specific uptake, thereby distinguishing it from previously reported delivery platforms. Collectively, this work presents a translatable strategy to enhance UA bioavailability and therapeutic performance, underscoring its promise for both nutraceutical and pharmaceutical applications.
    Keywords:  Antioxidant; Carboxymethyl β-glucan; Nanoscale delivery system; Urolithin A; ZIF-8
    DOI:  https://doi.org/10.1016/j.foodres.2025.118314
  66. BMC Rheumatol. 2026 Feb 07.
    NRAS and SREBF1 identified as mitophagy-associated risk genes for rheumatoid arthritis through interpretable machine learning and experimental validation studies.
    Hongman Li, Peng Liu, Xiao Han, Shengyong Si, ZhiJing Li, Chun Zhao, Xue Zhao, Xue Zhou, Mengdie Liu.
      
    Keywords:  Biomarkers; Diagnostic model; Machine learning; Mitophagy; Molecular docking; RA
    DOI:  https://doi.org/10.1186/s41927-026-00620-4
  67. Immun Ageing. 2026 Feb 02.
    Kaempferol alleviates T-cell immunosenescence and inflammaging in aged mice via the SIRT3-LKB1-AMPK-mitophagy pathway.
    Wendi Chen, Shuang Liu, Guoqiang Xu, Xin Liu, Yuxuan Shi, Guolong Wang, Yunna Ning, Chenfeng Yuan, Zhiming Lu, Yongzhi Cao, Yueran Zhao.
      
    Keywords:  Immunosenescence; Inflammaging; Mitophagy; SIRT3; Senescent T cells
    DOI:  https://doi.org/10.1186/s12979-026-00560-0
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