bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2026–03–15
75 papers selected by
Gavin McStay, Liverpool John Moores University
  1. Correction: Targeting mitochondria to protect the heart: a matter of balance?
  2. Impaired mitophagy contributes to osteogenesis and mineralization disorders in fibrous dysplasia.
  3. Mitochondrial quality control modulating chondrocyte behavior and fate in knee osteoarthritis: mechanistic insights and therapeutic prospects.
  4. FUNDC1-dependent mitophagy determines axon regeneration capacity.
  5. Targeting NME3 to Restore Mitochondrial Fission-Fusion Balance Defines a Novel Disease-Modifying Strategy for Parkinson's Disease.
  6. Ginsenoside Rb2 Attenuates Microvascular Endothelial Stress Injury by Mediating Mitochondrial Pathway Pyroptosis via the DNA-PKcs-SIRT5 Axis.
  7. SARM1 Regulates BNIP3-Mediated Mitochondrial Quality Control in Diabetic Hearts.
  8. Effects of tDCS on Cognitive Function in MCAO/R Rats by Regulating Mitochondrial Autophagy Mediated by the PINK1/Parkin Signaling Pathway.
  9. Non-thermal plasma enhances boar sperm quality via FOXO3-PINK1/Parkin-mediated mitophagy.
  10. Mitochondrial Dynamics in Diabetic Kidney Disease: Underlying Mechanisms and Novel Therapeutics.
  11. [Salidroside suppresses ferroptosis in HT22 cells following oxygen-glucose deprivation/reoxygenation through regulation of non-ubiquitinated FUNDC1-dependent mitophagy pathway].
  12. DRP1/DMNL-1-mediated mitochondrial fission augments Rickettsia parkeri replication in macrophages.
  13. Asperuloside Protects Against Age-Related Muscle Dysfunction by Enhancing FOXO3-Mediated Mitophagy.
  14. Scutellarein Attenuates Intervertebral Disc Degeneration by Promoting PINK1/Parkin-Mediated Mitophagy to Alleviate Inflammation, Ferroptosis, and Mitochondrial Dysfunction in Nucleus Pulposus Cells.
  15. Mitochondrial quality in aging and neurodegeneration: The emerging role of mitochondria-derived vesicles.
  16. Modulation of mitochondrial quality by exercise mimetics: A potential strategy for the prevention and treatment of Alzheimer's disease.
  17. Asperosaponin VI delays the progression of facet joint osteoarthritis by promoting mitophagy, inhibiting the cGAS/STING pathway, and attenuating chondrocyte pyroptosis.
  18. Kenny is the adaptor protein for ubiquitin-dependent mitophagy in Drosophila melanogaster.
  19. Near infrared enhanced palladium loaded siraitia grosvenorii carbon dots amplify mitophagy for acute lung injury immunotherapy.
  20. AMBRA1 activation alleviates zearalenone-induced swine testicular cell ferroptosis by facilitating mitophagy.
  21. Thermally denatured dermal matrix enhances diabetic wound vascularization by reactivating mitophagy.
  22. Ajugol ameliorates mitochondrial dysfunction and cognitive decline in Alzheimer's Disease via BNIP3-dependent mitophagy.
  23. QingShen granules activates mitophagy to suppress renal tubular epithelial-mesenchymal transition via the miR-23b-5p/Nrf2/PINK1 axis.
  24. PARKIN overexpression confers cardioprotection via suppressing the mtDNA-cGAS-STING axis in myocardial ischemia/reperfusion injury.
  25. Pogostone Suppresses Microglial NLRP3 Inflammasome Activation-Promoted Remyelination Through RXRγ Regulation of Mitophagy.
  26. Cerebral Ischemia-Reperfusion Injury: Unraveling the Mitophagy-Oxidative Stress Axis for Neuroprotective Strategies.
  27. Melitidin alleviates escitalopram-induced sub-chronic cardiotoxicity via regulating mitochondrial fission-fusion machinery and redox signaling: A biochemical, echocardiographic, and histological study.
  28. Fasting Enhances Cardiomyocyte Hypoxia Tolerance by Regulating Ca2+ Transport at Mitochondria-Endoplasmic Reticulum Contact Sites.
  29. The interplay between mitophagy and ferroptosis in Alzheimer's disease: Mechanisms and therapeutic implications.
  30. USP1 promotes hepatocellular carcinoma progression by modulating mitophagy via stabilizing MCM3 to regulate the Keap1-Nrf2 axis.
  31. The H2S donor sulforaphane inhibits NLRP3 inflammasome activation by inducing mitochondrial autophagy and mitigating CBS-H2S axis damage in in-vitro and in-vivo models of Parkinson's disease.
  32. Targeting mitochondrial quality control in osteoarthritis with GrpE-like 1-loaded synovial mesenchymal stromal/stem cell small extracellular vesicles.
  33. Ceritinib Induces Mitochondrial Fragmentation in Thyroid Cancer Cells by Targeting Drp-1.
  34. TG2 (transglutaminase 2) promotes PINK1/Parkin-dependent mitophagy in pulmonary hypertension by regulating the TRPC6.
  35. ANGPTL2 inhibits macrophage pyroptosis and alleviates rheumatoid arthritis progression by regulating mitophagy via IGFBP5.
  36. The Mitochondrial Enigma: Deciphering Mechanisms and Identifying Drug Targets in Polyploid Giant Cancer Cells.
  37. Mechanistic Study of the Pink1/Parkin Signaling Pathway in Mitochondrial Dysfunction and Podocyte Injury.
  38. TANK-binding kinase 1 protects against MASH progression via mitochondrial quality control.
  39. Quercetin prevents age-related hearing loss in C57BL/6J mice by activating mitophagy and inhibiting the NLRP3 inflammasome.
  40. Mitochondrial fusion orchestrated by hepatitis E virus couples pro-viral autophagy and innate immune evasion for efficient replication.
  41. PINK1/Parkin-mediated mitophagy is involved in calcium-sensing receptor-induced cardiac damage and apoptosis in spontaneously hypertensive rats.
  42. Corrigendum to "High glucose-induced mitochondrial fission drives pancreatic cancer progression through the H3K18la/TTK/BUB1B signal pathway" [Cellular Signalling 135 (2025) 112027].
  43. [Exploration in molecular mechanism of icariin for ameliorating postmenopausal osteoporosis based on estrogen receptor α-mediated regulation of mitophagy in osteoblasts].
  44. Nuclear factor erythroid 2-related factor 2 induction abrogates mitochondrial stress through parkin regulation.
  45. A coenzyme-based "interface-welding" hydrogel coating for titanium implants promotes diabetic osseointegration by regulating mitochondrial dynamics.
  46. Pathogenic roles of the IMNEPD-associated PTRH2 mutants in aggravating mitochondrial dynamics and its rescue.
  47. Curcumin augments mitophagy via Nrf2-PINK1-mediated, Parkin-dependent ubiquitination to suppress ferroptosis in post-cardiac arrest brain injury.
  48. Integrated multi-omics analysis identifies and validates endoplasmic reticulum stress and mitophagy-related biomarkers in MASLD.
  49. Inonotus obliquus (Ach. ex Pers.) Pilát aqueous extract alleviates acute cold exposure/rewarming-induced myocardial injury by regulating mitochondrial dynamics via liver kinase B1/adenosine monophosphate-activated protein kinase/peroxisome proliferator-activated receptor gamma coactivator-1 alpha signaling pathway activation.
  50. ALKBH3 m1A Demethylase Deficiency Reduces Alzheimer's Amyloid-β Pathology.
  51. Mitochondrial-targeted therapy for osteoarthritis: Challenges and opportunities from basic research to clinical translation.
  52. Mitochondria transplantation reduces intraocular pressure by improving mitochondrial function and remodeling trabecular meshwork.
  53. Gentiopicroside activates PINK1-dependent mitophagy to inhibit ferroptosis and promote flap survival.
  54. A novel zebrafish model unveils folate deficiency disrupts embryonic development via p53-driven cell cycle arrest.
  55. Atmospherically relevant PM2.5 promotes age-related muscle atrophy in an age-dependent manner.
  56. T-2 toxin induces ER stress-dependent liver injury via mitophagy-mediated ER-phagy suppression: Berbamine blocks SNARE complex for hepatoprotection.
  57. Targeting a novel tamoxifen-using pathway to preserve ovarian reserve in rats with experimental chemotherapy-induced ovarian failure.
  58. Dusp15 modulates mtHsp70 Thr116 phosphorylation state to preserve mito-UPR and attenuate cardiac dysfunction in diabetic cardiomyopathy.
  59. Pharmacological potential of Chinese botanical drugs in managing chronic kidney disease by targeting mitochondrial quality control.
  60. Integrating machine learning of bulk and single cell RNA data to characterize immune mechanism of m6A related mitophagy genes in malignant gastric cancer.
  61. Corrigendum to "Stachydrine mitigates high glucose-induced apoptosis in human lens epithelial cells by activating mitophagy" [Exp. Eye Res. 260 (2025) 110568].
  62. Targeting Autophagy for Otoprotection: Translating Basic Mechanisms into Clinical Strategies.
  63. Topical NAMPT activation restores mitophagic flux to rescue diabetic keratopathy via the NAD⁺/PINK1 pathway.
  64. Circ-0030167/IGF2BP1 Induces Mitophagy-Mediated Ferroptosis via HMOX1 mRNA Stabilization in Pancreatic Cancer.
  65. CRISPR-Cas-based activation of PPARGC1A boosts endogenous mitochondria and enhances cardiac function after myocardial infarction.
  66. Identification of mitochondrial dynamics-related biomarkers in psoriasis using bioinformatics and Mendelian randomization.
  67. ATG9B Regulates Mitochondrial Integrity and Apoptotic Tumor Cell Death.
  68. Mechanisms and therapeutic potential of mitochondrial-targeted therapies in bone repair.
  69. Smarca4 maintains mitochondrial homeostasis and energy metabolism during cardiac development.
  70. NCOA2 promotes the return of hematopoietic stem cells to quiescence after irradiation stress by regulating FOXO3a-dependent mitophagy.
  71. SELENOF Mitigates Bovine Mastitis by Preserving Mitochondrial Homeostasis and Suppressing NLRP3-Mediated Pyroptosis.
  72. Mitochondrial Quantity-Quality Imbalance in Cellular Senescence: Practical Readouts and Minimal Assay Bundles.
  73. Rejuvenation of THY1+ nucleus pulposus-derived stem cells promotes intervertebral disc regeneration through FGF10-FGFR1-CREB pathway and mitochondrial fission.
  74. Autophagy in ocular diseases: from mechanisms to therapeutic potential.
  75. Targeting PGAM5-driven mitochondrial integrated stress response slows ALS progression across subtypes.
  1. Clin Sci (Lond). 2026 Apr 15. 140(4): 491
    Correction: Targeting mitochondria to protect the heart: a matter of balance?
    Fouad A Zouein, George W Booz.
      
    Keywords:  cardiac myocyte; ischemia-reperfusion injury; mitochondrial dynamics; mitochondrial fission; mitochondrial fusion; myocardial infarction
    DOI:  https://doi.org/10.1042/CS20258287_COR
  2. Autophagy. 2026 Mar 09.
    Impaired mitophagy contributes to osteogenesis and mineralization disorders in fibrous dysplasia.
    Ziji Ling, Lingran Hu, Shenghao Jin, Feng Ling, Chengyu Jin, Xiaodie Yuan, Xingyu Chen, Hanyu Xie, Hongbing Jiang, Yu Fu.
      Fibrous dysplasia (FD) is a bone mesenchymal stromal cells (BMSCs)-derived disorder caused by GNAS gene mutation, characterized by excessive fibrous tissue proliferation in bone and the formation of immature trabecular bone. Although impaired osteogenesis of BMSCs is central to FD pathogenesis, the underlying mechanism remains largely elusive. Here we demonstrate that hyperactivation of the cAMP-PRKA/PKA signaling axis disrupts mitochondrial homeostasis through impaired mitophagy, ultimately leading to diminished amorphous calcium phosphate (ACP) secretion and consequent mineralization failure in FD. Mechanistically, in FD BMSCs, PRKA activation inhibits DNM1L/DRP1 recruitment to mitochondria through phosphorylation at S637, thereby suppressing mitochondrial fission. Consequently, excessive mitochondrial fusion leads to an elevated mitochondrial membrane potential, impaired mitophagy, and diminished ACP release. Collectively, our findings reveal a novel signaling nexus linking cAMP-PRKA signaling, mitochondrial dynamics, and biomineralization processes in FD pathogenesis, providing critical insights into the molecular basis of this disorder.
    Keywords:  Amorphous calcium phosphate; biomineralization; cAMP-PRKA pathway; fibrous dysplasia; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2026.2643409
  3. Front Immunol. 2026 ;17 1671502
    Mitochondrial quality control modulating chondrocyte behavior and fate in knee osteoarthritis: mechanistic insights and therapeutic prospects.
    Yi Li, Wen Zhong, Lan Li, Fengyuan Zhang, Xin Duan, Haibo Si.
      Osteoarthritis (OA) is a highly prevalent and debilitating joint disorder that imposes a heavy burden on global public health due to its high incidence, prevalence, and disability rate, as well as the associated substantial healthcare costs. Early intervention is critical for OA management, yet current therapeutic options are limited by suboptimal efficacy, along with concerns regarding prosthetic lifespan and function in surgical treatment. While the complete etiology of OA remains elusive, cartilage degeneration is widely recognized as a core pathological feature of OA. A major barrier to optimizing OA therapeutic strategies is the lack of comprehensive insights into the underlying molecular mechanisms governing disease progression. Chondrocyte behavior and fate determination are pivotal to the onset and progression of OA: OA chondrocytes exhibit an imbalanced synthetic/catabolic profile, cluster formation, and autophagy dysregulation, accompanied by phenotypic alterations including hypertrophy and senescence. Additionally, multiple forms of chondrocyte death (apoptosis, chondroptosis, necrosis, necroptosis, autophagic cell death, pyroptosis, and ferroptosis) are implicated in driving OA development. Mitochondrial quality control (MQC), a cellular process encompassing redox homeostasis, mitophagy, mitochondrial dynamics (fusion and fission), and mitochondrial biogenesis, is essential for maintaining mitochondrial function and cellular homeostasis. Accumulating evidence indicates that MQC is closely involved in regulating chondrocyte behavior and fate in OA, and impaired MQC function may compromise chondrocyte viability and function, thereby promoting cartilage degeneration. Elucidating the MQC-mediated pathological mechanisms underlying abnormal chondrocyte behavior and fate in OA is expected to identify novel therapeutic targets for early-stage OA, thus providing new avenues for the development of more effective preventive and therapeutic strategies for this disorder.
    Keywords:  cartilage; cell behavior; cell fate; chondrocytes; mitochondrial quality control; osteoarthritis
    DOI:  https://doi.org/10.3389/fimmu.2026.1671502
  4. Autophagy. 2026 Mar 08. 1-17
    FUNDC1-dependent mitophagy determines axon regeneration capacity.
    Wenlei Li, Yujiao Liu, Ruixuan Liu, Yuyuan Fan, Jinming Liu, Yingjie Guo, Zeping Hu, Lei Liu, Quan Chen, Bing Zhou.
      Neuronal axon regeneration is a complex and coordinated reorganization process that requires the involvement of mitochondria. Here, we demonstrated that FUNDC1 (FUN14 domain containing 1)-mediated mitophagy played a crucial role in determining the intrinsic capacity for axonal regrowth and peripheral nerve recovery. We found that acute nerve injury resulted in the accumulation of impaired mitochondria at the axonal injury site, accompanied by an increase in the expression of the mitophagy receptor FUNDC1. Strikingly, overexpression of FUNDC1 enhanced axonal regeneration both in vitro and in vivo, likely by maintaining a healthy mitochondrial population through mitophagy. Similarly, treatment with urolithin A (UA), a natural mitophagy inducer, promoted axon regrowth after injury. Conversely, fundc1 deletion impaired regeneration, an effect reversed by reintroducing wild type (WT) FUNDC1 in neurons but not an MAP1LC3B/LC3 (microtubule associated protein 1 light chain 3 beta)-interacting region (LIR) mutant. Metabolic profiling further demonstrated that FUNDC1-mediated mitophagy drives dorsal root ganglion (DRG) neurons regeneration through enhanced carnosine biosynthesis. Mechanistically, sciatic nerve injury (SNI) in Fundc1 transgenic (TG) mice upregulated NRF1 (nuclear respiratory factor 1) and PPARGC1A/PGC-1α (PPARG coactivator 1 alpha), which stimulated mitochondrial biogenesis and activated Carns1 (carnosine synthase 1) transcription. This increased carnosine biosynthesis, aiding peripheral nerve recovery through its antioxidant effects. Our findings highlighted FUNDC1-mediated mitophagy as a key mechanism in nerve regeneration, linking mitochondrial quality control, metabolic adaptation, and nerve regeneration.Abbreviations: Δψm: mitochondrial membrane potential; DIV: days in vitro; DRG: dorsal root ganglion; KO: knockout; LIR: LC3-interacting region; P60: postnatal day 60; PNS: peripheral nervous system; PSI: post sciatic nerve injury; ROS: reactive oxygen species; SD: standard deviation; SNI: sciatic nerve injury; TEM: transmission electron microscopy; TG: transgenic; TMRE: tetramethylrhodamine ethylester; UA: urolithin A; WT: wild type.
    Keywords:  Axon regeneration; FUNDC1; NRF1; carnosine; mitochondrial quality; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2026.2629721
  5. CNS Neurosci Ther. 2026 Mar;32(3): e70822
    Targeting NME3 to Restore Mitochondrial Fission-Fusion Balance Defines a Novel Disease-Modifying Strategy for Parkinson's Disease.
    Chen Qiao, Xiang-Qi Hu, Shen-Han Xu, Meng-Fan Yao, Jun-Peng Liu, Lei Cao.
       AIMS: Parkinson's disease (PD) lacks effective disease-modifying therapies, despite mitochondrial dysfunction being a key pathogenic factor. This study aimed to identify novel regulators of mitochondrial dynamics and explore their therapeutic relevance.
    METHODS: Transcriptomic analysis was conducted on the substantia nigra (SN) of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice. SN-specific lentiviral knockdown or overexpression of nucleoside diphosphate kinase 3 (NME3) was performed in mice. Motor behavior, dopaminergic neuron survival, mitochondrial ultrastructure, and reactive oxygen species (ROS) levels were assessed. Mitochondrial fission was pharmacologically inhibited using the Drp1 inhibitor Mdivi-1.
    RESULTS: RNA sequencing revealed a marked reduction of Nme3 in the SN of MPTP-treated mice. Nme3 knockdown in healthy mice induced PD-like motor deficits and dopaminergic neurodegeneration, mimicking the MPTP model. Mechanistically, NME3 deficiency disrupted mitochondrial fission-fusion balance, causing abnormal mitochondrial morphology, excessive ROS production, and neuronal injury. Mdivi-1 treatment significantly alleviated mitochondrial dysfunction and neurotoxicity. Conversely, SN-specific Nme3 overexpression in MPTP-treated mice improved motor performance and preserved dopaminergic neurons by suppressing pathological mitochondrial fission.
    CONCLUSION: NME3 is a previously unrecognized regulator of mitochondrial dynamics and a critical contributor to PD pathogenesis. Restoring mitochondrial fission-fusion balance through genetic or pharmacological approaches provides neuroprotection, highlighting NME3 as a promising target for disease-modifying PD therapies.
    Keywords:  NME3; Parkinson's disease; disease‐modifying intervention; mitochondrial dynamics; neuroprotection
    DOI:  https://doi.org/10.1002/cns.70822
  6. Phytother Res. 2026 Mar 12.
    Ginsenoside Rb2 Attenuates Microvascular Endothelial Stress Injury by Mediating Mitochondrial Pathway Pyroptosis via the DNA-PKcs-SIRT5 Axis.
    Xiangyi Pu, Zhaoqi Yan, Jinfeng Liu, Yanli Wang, Xuanke Guan, Qiaomi Wu, Qin Zhang, Ruxiu Liu, Xing Chang.
      The core pathogenic mechanism of coronary microvascular injury is endothelial damage following ischemic injury, subsequently triggering inflammatory responses and oxidative stress damage. This study investigated the interaction mechanism between SIRT5 and DNA-PKcs in regulating coronary microvascular endothelial injury and further validated the therapeutic potential in mitochondrial homeostasis dysregulation. We used single-cell sequencing analysis to identify dysregulation of mitochondrial homeostasis as a key regulatory phenotype in endothelial injury. The synergistic regulation of Ginsenoside Rb2 (GS-Rb2) on mitochondrial function in endothelial cells was confirmed by Western blot, RT-PCR, and other techniques. The interaction mechanism between SIRT5 and DNA-PKcs was finally identified in vitro and in vivo. By promoting the overexpression of SIRT5 and the downregulation of DNA-PKcs, GS-Rb2 intervention was able to restore heart function and reverse coronary microvascular damage during ischemia-reperfusion. Elevated DNA-PKcs expression can exacerbate microvascular endothelium inflammatory injury and disrupt endothelial cell mitochondrial homeostasis and redox balance stability. Endothelium pyroptosis was activated by SIRT5 loss, which led to a marked reduction in mitophagy and mitochondrial biogenesis. The aforesaid alterations were restored by transgenic therapy of SIRT5 and DNA-PKcs deletion, which also raised mitophagy levels, prevented excessive endothelial pyroptosis activation, and preserved microvascular cell homeostasis. At the cellular level, GS-Rb2 can boost autophagy, prevent the excessive release of DNA-PKcs in the nucleus, and improve endothelial cell activity following injury. Through SIRT5, GS-Rb2 can control DNA-PKc activity and restore mitochondrial homeostasis in the endothelium following hypoxic stress. A viable therapy approach for coronary microvascular damage was proposed.
    Keywords:  DNA‐PKcs; SIRT5; coronary microvascular endothelial injury; mitochondrial homeostasis; pyroptosis
    DOI:  https://doi.org/10.1002/ptr.70201
  7. Circ Res. 2026 Mar 13.
    SARM1 Regulates BNIP3-Mediated Mitochondrial Quality Control in Diabetic Hearts.
    Hina Lateef Nizami, Keaton E Minor, Patrycja E Szybowska, Ignacy Gorecki, Lindsay Best, Christine M Light, Pratyaksh Singhal, Xiaolu A Cambronne, Ying Ann Chiao, Chi Fung Lee.
      
    Keywords:  cardiovascular diseases; heart diseases; hyperglycemia; mitophagy; transcription factors
    DOI:  https://doi.org/10.1161/CIRCRESAHA.125.328001
  8. Neurochem Res. 2026 Mar 13. pii: 107. [Epub ahead of print]51(2):
    Effects of tDCS on Cognitive Function in MCAO/R Rats by Regulating Mitochondrial Autophagy Mediated by the PINK1/Parkin Signaling Pathway.
    Mengzhen Shang, Yan Yu, Tianshan Wen, Biaoping Xu, Gaofeng Rao, Chen Xie, Xinling Wei, Lifeng Tang, Youliang Wen.
      
    Keywords:  Cognitive dysfunction; MCAO/R; Mitophagy; PINK1/Parkin; tDCS
    DOI:  https://doi.org/10.1007/s11064-026-04699-6
  9. Theriogenology. 2026 Mar 04. pii: S0093-691X(26)00080-4. [Epub ahead of print]258 117890
    Non-thermal plasma enhances boar sperm quality via FOXO3-PINK1/Parkin-mediated mitophagy.
    Yao Tang, Yunping Tang, Qian Wang, Jiangwei Liu, Yin Li, Lijuan Wang, Yi Wang, Xianzhong Wang, Jiaojiao Zhang.
      Boar sperm quality is a key intrinsic factor of reproductive success, and its optimization is crucial for improving pig production efficiency. Here, this study investigated the effect of non-thermal dielectric barrier discharge (DBD) plasma on boar sperm quality and the underlying regulatory mechanism. Results showed that optimized DBD plasma improved boar sperm viability and motility, adenosine triphosphate level, mitochondrial membrane potential, and mitochondrial respiratory chain enzyme activity, while reducing the opening degree of mitochondrial permeability transition pore. Transcriptome sequencing revealed significant changes in sperm mitophagy-related genes after DBD plasma treatment. Correspondingly, mitophagy-related proteins including Forkhead box O3 (FOXO3), PTEN induced kinase 1 (PINK1), Parkin, BCL2 interacting protein 3 (BNIP3), and LC3 II/LC3 I ratio exhibits increased at protein levels, while the protein levels of P62 and TOM20 were decreased in DBD plasma-treated spermatozoa. Mitophagy inhibitor Mdivi-1 decreased sperm mitophagy level, mitochondrial function and sperm quality, but these effects were rescued by DBD plasma. Moreover, DBD plasma increased the binding interaction of FOXO3-PINK1 and PINK1-Parkin. Silencing FOXO3, PINK1, and Parkin by using siRNAs inhibited mitophagy level, mitochondrial function, and sperm quality, but these effects were alleviated by DBD plasma. These findings illustrated appropriate DBD plasma enhanced mitochondrial function by activating FOXO3-PINK1/Parkin-mediated mitophagy, leading to improved boar sperm quality without disrupting sperm DNA integrity and acrosome integrity. Therefore, non-thermal plasma technology provides a novel strategy to enhance sperm quality through the regulation of targeted mitophagy, offering promising potential for its application in livestock reproduction.
    Keywords:  FOXO3; Mitochondrial function; Mitophagy; Non-thermal plasma; Sperm quality
    DOI:  https://doi.org/10.1016/j.theriogenology.2026.117890
  10. Int J Mol Sci. 2026 Mar 06. pii: 2429. [Epub ahead of print]27(5):
    Mitochondrial Dynamics in Diabetic Kidney Disease: Underlying Mechanisms and Novel Therapeutics.
    Nan Shao, Jinghan Wang, Jiaoying Liu, Junhua Zhang, Bin Zhang, Xiaobo Sun, Xiaoqiu Liu.
      Diabetic kidney disease (DKD) is a prevalent and serious complication of diabetes and a leading cause of end-stage renal disease (ESRD). As the central organelles for cellular energy metabolism, mitochondria play a pivotal role in the pathogenesis of DKD. Structural and functional impairments of mitochondria trigger multiple renal pathological processes, such as oxidative stress, apoptosis, chronic inflammation, and fibrosis. Mitochondrial dynamics are crucial for maintaining mitochondrial integrity, and their involvement in the progression of DKD is increasingly recognized. Nevertheless, comprehensive reviews addressing the relationship between mitochondrial dynamic homeostasis and DKD are still lacking. This review systematically summarizes the pivotal role of imbalanced mitochondrial dynamics in the pathogenesis and progression of DKD. It details the underlying regulatory mechanisms and stage-specific pathological contributions across different renal cell types, discusses potential diagnostic and therapeutic applications, and evaluates the prospects of natural products that target mitochondrial dynamics in DKD. By integrating current evidence, this work aims to provide a theoretical foundation and strategic guidance for innovative drug development and precision medicine in DKD.
    Keywords:  diabetic kidney disease; mitochondrial dynamics; mitophagy
    DOI:  https://doi.org/10.3390/ijms27052429
  11. Zhongguo Zhong Yao Za Zhi. 2026 Jan;51(1): 191-201
    [Salidroside suppresses ferroptosis in HT22 cells following oxygen-glucose deprivation/reoxygenation through regulation of non-ubiquitinated FUNDC1-dependent mitophagy pathway].
    Qiu-Si DU, Jun Liao.
      This study aims to investigate whether the mitophagy receptor FUN14 domain-containing 1(FUNDC1) serves as a molecular link between mitophagy and neuronal ferroptosis, and to determine whether salidroside(Sal) can inhibit neuronal ferroptosis after oxygen-glucose deprivation/reoxygenation(OGD/R) by inducing FUNDC1 expression and regulating mitophagy, thereby exerting neuroprotective effects. An in vitro model of neuronal ischemia-reperfusion injury was established with HT22 cells subjected to OGD/R. The experiment consisted of three parts:(1) control, OGD/R, ferrostatin-1(Fer-1), FUNDC1 overexpression(OV-FUNDC1), and OV-FUNDC1+Fer-1 groups;(2) control, OGD/R, 3-methyladenine(3MA, an autophagy inhibitor), Sal, and Sal+3MA groups;(3) control, OGD/R, Sal, FUNDC1 silencing(Si-FUNDC1), and Sal+Si-FUNDC1 groups. In the first part of the experiment, the survival rate of cells in each group was detected by the CCK-8 assay, and the protein levels of p62, microtubule-associated protein light chain 3(LC3), acyl-CoA synthetase long-chain family 4(ACSL4), and glutathione peroxidase 4(GPX4) were measured by Western blot. The results showed that compared with the control group, the OGD/R group had down-regulated protein levels of p62 and GPX4(P<0.05, P<0.01) and up-regulated protein level of ACSL4(P<0.01); compared with the OGD/R group, the OV-FUNDC1 group showed increased protein levels of LC3 and GPX4(P<0.05, P<0.01) and decreased protein levels of p62 and ACSL4(P<0.05, P<0.01). In the second part of the experiment, after Sal intervention, the protein levels of FUNDC1, p62, LC3, ACSL4, and GPX4 were determined by Western blot, and changes in mitochondrial membrane potential were measured via JC-1. The results showed that compared with the OGD/R group, the Sal group had up-regulated protein levels of FUNDC1, LC3, and GPX4(P<0.01), down-regulated protein levels of p62 and ACSL4(P<0.01), and increased mitochondrial membrane potential(P<0.01); the 3MA group showed decreased mitochondrial membrane potential(P<0.01). In the third part of the experiment, after silencing of FUNDC1, the intracellular Fe~(2+) content was measured via a ferrous ion assay kit; reactive oxygen species(ROS) levels were measured by flow cytometry; the mitochondrial function was assessed via MitoTracker Red; adenosine triphosphate(ATP) and glutathione(GSH) levels were detected using assay kits; the expression of ACSL4 and GPX4 was detected by immunofluorescence; the protein levels of p62, LC3, ACSL4, and GPX4 were measured by Western blot. The results showed that compared with the Si-FUNDC1 group, the Sal group had decreased Fe~(2+) concentration(P<0.01), reduced ROS level(P<0.01), increased MitoTracker Red fluorescence intensity(P<0.01) and GSH content(P<0.01), weakened ACSL4 fluorescence intensity(P<0.01), enhanced GPX4 fluorescence intensity(P<0.01), up-regulated protein levels of LC3 and GPX4(P<0.01), and down-regulated protein levels of p62 and ACSL4(P<0.01). This study reveals that FUNDC1 may be a key protein linking mitochondrial autophagy and ferroptosis in neurons after ischemia-reperfusion injury, and Sal intervention can inhibit neuronal ferroptosis after ischemia-reperfusion by promoting the non-ubiquitinated FUNDC1-dependent mitophagy pathway.
    Keywords:  cerebral ischemia-reperfusion injury; ferroptosis; mitophagy; salidroside
    DOI:  https://doi.org/10.19540/j.cnki.cjcmm.20250902.401
  12. Infect Immun. 2026 Mar 09. e0008626
    DRP1/DMNL-1-mediated mitochondrial fission augments Rickettsia parkeri replication in macrophages.
    Elliott Collins, Natasha Kelly, Heather Green, William Beavers, Basel Abuaita, Juan J Martinez.
      Pathogenic Spotted Fever Group (SFG) Rickettsia species, including Rickettsia parkeri, replicate in endothelial cells and macrophages in vitro and during infections in murine models of disease. We demonstrated that infection of human macrophage-like cells with a related SFG Rickettsia, R. conorii, resulted in a significant increase in mitochondria-associated proteins. However, the role of mitochondrial functions in Rickettsia pathogenesis is unknown. Here, we found that R. parkeri exploits mitochondrial dynamics to promote intracellular replication in mouse and human macrophages by activating the mitochondrial fission regulator, the dynamin-related protein 1 (DRP1). R. parkeri proliferated in macrophages, which coincided with a significant increase in mitochondria fission, mitochondria content, and host cell ATP production, primarily due to mitochondrial respiration compared to uninfected cells. In addition, R. parkeri infection also led to a temporal increase in DRP1 serine phosphorylation that was dependent on rickettsial de novo protein synthesis. Importantly, R. parkeri growth was significantly impacted in DRP1-deficient macrophages. These results suggest that the modulation of mitochondrial fission, content, and function is important for replication and survival of pathogenic SFG Rickettsia species in macrophages. Our data highlight that hijacking mitochondrial dynamics and function is essential for intracellular replication of Rickettsia species and may be a shared mechanism utilized by related obligate intracellular pathogens for growth.
    Keywords:  DRP1; Rickettsia; mitochondria
    DOI:  https://doi.org/10.1128/iai.00086-26
  13. Phytother Res. 2026 Mar 10.
    Asperuloside Protects Against Age-Related Muscle Dysfunction by Enhancing FOXO3-Mediated Mitophagy.
    Qi Chen, Qinjun Zhang, Jing Wang, Amel Thanina Amrouche, Kejie Peng, Weisu Huang, Jian Mu, Baiyi Lu.
      Mitophagy enhancers show great potential as therapeutic agents for preventing age-related muscle disorders. Asperuloside (ASP), a naturally occurring iridoid, has been shown to activate mitophagy and maintain mitochondrial homeostasis. However, the exact mechanisms underlying its action and its overall efficacy in relation to muscle aging have yet to be fully elucidated. In senescent myoblasts, techniques such as cell staining, western blotting, fluorescence imaging, and Seahorse analysis were employed to study the effects of ASP on senescence phenotypes, mitochondrial health, mitophagy, and related upstream regulators. Using small interfering RNA, the study explored whether mitophagy and its regulators mediated the effects of ASP. The efficacy of ASP on muscular health was characterized in 17-18-month-old high-fat diet-induced aging mice. Our study demonstrated that 2.5 μM ASP significantly alleviated senescence-associated phenotypes and enhanced mitochondrial health in senescent C2C12 myoblasts. Mechanistic investigations revealed that ASP induced BNIP3-dependent mitophagy by modulating the FOXO3 transcription factor, thus contributing to the maintenance of mitochondrial homeostasis. Moreover, the ASP intervention at a dose of 50 mg/kg BW/day reduced fat accumulation and other pathological changes in the gastrocnemius muscle of aging mice. Similarly, ASP supplementation also improved mouse muscle function and the morphology of muscular mitochondria. This study further identified ASP as a potential natural active component for the prevention of muscle aging. It emphasized the importance of mitochondrial homeostasis and the activation of appropriate mitophagy pathways in maintaining muscle health during the aging process.
    Keywords:  FOXO3; asperuloside; iridoid; mitochondria; muscle aging; phytochemicals
    DOI:  https://doi.org/10.1002/ptr.70297
  14. Phytother Res. 2026 Mar 12.
    Scutellarein Attenuates Intervertebral Disc Degeneration by Promoting PINK1/Parkin-Mediated Mitophagy to Alleviate Inflammation, Ferroptosis, and Mitochondrial Dysfunction in Nucleus Pulposus Cells.
    Shuanggong Liu, Jie Zhao, Shuhang Dong, Yang Zhang, Yachao Zhao, Ning Ran, Guowei Yang, Changliang Peng, Xu Yang, Guangxu Song, Yingze Zhang, Dongjin Wu.
      Intervertebral disc degeneration (IVDD) is a major cause of chronic low back pain and is driven by oxidative stress, inflammation, and ferroptosis. While mitophagy regulates ferroptosis in other diseases, its role in IVDD remains unclear. The potential of scutellarein, a flavonoid with antioxidant properties, to treat IVDD has not yet been explored. Primary human nucleus pulposus (HNP) cells were treated with tert-butyl hydroperoxide (TBHP) to establish an in vitro IVDD model. Mitophagy was inhibited by cyclosporin A (CsA) treatment. Radiographic and histopathological analyses were performed in a rodent IVDD model. Key markers (IL-1β, ACSL4, GPX4, PINK1, LC3, and PI3K/mTOR) were assessed. Scutellarein preserved the NPC phenotype, reduced inflammation, and suppressed ferroptosis by activating PINK1/Parkin-mediated mitophagy. It restored mitochondrial function and inhibited the PI3K/AKT/mTOR pathway. In vivo, scutellarein attenuated IVDD progression; downregulated the expression of IL-1β and ACSL4; and upregulated the expression of collagen II, GPX4, PINK1, and LC3. Scutellarein mitigates IVDD by inducing mitophagy to inhibit ferroptosis and restore mitochondrial function, highlighting its therapeutic potential.
    Keywords:  IVDD; PI3K/AKT/mTOR signaling pathway; ferroptosis; inflammation; mitophagy; scutellarein
    DOI:  https://doi.org/10.1002/ptr.70291
  15. Mech Ageing Dev. 2026 Mar 05. pii: S0047-6374(26)00019-9. [Epub ahead of print]231 112167
    Mitochondrial quality in aging and neurodegeneration: The emerging role of mitochondria-derived vesicles.
    Emanuele Marzetti, Rosa Di Lorenzo, Riccardo Calvani, Hélio José Coelho-Júnior, Ettore D'Argento, Vito Pesce, Francesco Landi, Cecilia Bucci, Flora Guerra, Anna Picca.
      Mitochondria are central to cellular energy metabolism, redox balance, and signaling, and their integrity is maintained by a multilayered mitochondrial quality control (MQC) system. This system includes proteostasis, dynamics, biogenesis, and mitophagy, which together repair or remove damaged organelles. Mitochondria-derived vesicles (MDVs) have emerged as an additional MQC component. MDVs are small vesicles that bud from mitochondria and selectively transport damaged mitochondrial proteins, lipids, and nucleic acids to endolysosomal compartments or other intracellular destinations, enabling rapid and localized responses to mitochondrial stress. Acting upstream of or in parallel with mitophagy, MDVs can avoid or delay irreversible mitochondrial damage and help preserve cellular homeostasis. Aging and age-associated disorders are characterized by progressive mitochondrial dysfunction and chronic inflammation. Age-related changes in intracellular trafficking, lysosomal function, and vesicle dynamics may impair MDV formation, cargo selection, and targeting. Under conditions of defective degradation, mitochondrial components may also appear in extracellular vesicles, potentially contributing to altered intercellular signaling and inflammation. In the nervous system, where energetic demands are high and mitochondrial turnover requires tight regulation, such alterations may be especially harmful. This review summarizes MQC mechanisms in neurons, with a focus on MDVs, their dysregulation during aging and neurodegeneration, and implications for biomarkers and therapeutic strategies.
    Keywords:  Alzheimer’s disease; Huntington’s disease; Parkinson’s disease; Tau protein, α-synuclein
    DOI:  https://doi.org/10.1016/j.mad.2026.112167
  16. J Alzheimers Dis. 2026 Mar 10. 13872877261424276
    Modulation of mitochondrial quality by exercise mimetics: A potential strategy for the prevention and treatment of Alzheimer's disease.
    Zhiwei Ke, Bo Wang, Rongxiang Liang.
      Decline in mitochondrial quality is a prominent pathological feature of Alzheimer's disease (AD), manifested by impaired energy metabolism, disrupted mitochondrial biogenesis, abnormal mitochondrial dynamics, and defective mitophagy. Increasing evidence indicates that mitochondrial dysfunction contributes to the exacerbation of amyloid-β (Aβ) deposition and tau protein hyperphosphorylation, thereby accelerating AD pathogenesis. Of particular interest, physical exercise has been shown to effectively enhance mitochondrial quality and help prevent or slow the progression of AD, largely through the activation of key signaling pathways such as adenosine monophosphate-activated protein kinase (AMPK) and sirtuin 1 (SIRT1). However, regular physical activity may not be feasible for individuals in the prodromal or clinical stages of AD. In this context, exercise mimetics-compounds that pharmacologically simulate the molecular effects of exercise-have emerged as a promising alternative intervention. This review analyzes the mechanistic roles of exercise mimetics in improving mitochondrial quality under AD conditions, with a focus on their regulation of mitochondrial homeostasis via key signaling pathways. It further aims to provide theoretical insight for the development of mitochondria-targeted exercise mimetics and offer a potential strategy for addressing the growing global burden of AD.
    Keywords:  Alzheimer's disease; brain-derived neurotrophic factor; exercise mimetics; irisin; metformin; mitochondrion; resveratrol
    DOI:  https://doi.org/10.1177/13872877261424276
  17. Phytomedicine. 2026 Mar 05. pii: S0944-7113(26)00274-6. [Epub ahead of print]154 158038
    Asperosaponin VI delays the progression of facet joint osteoarthritis by promoting mitophagy, inhibiting the cGAS/STING pathway, and attenuating chondrocyte pyroptosis.
    Shuang Chen, Fei Hu, Nan Wang, Huanxi Wu, Chenyu Wang, Lin Xie, Xiaojuan Cao, Zhipeng Xi.
       BACKGROUND: Facet joint osteoarthritis (FJOA) is increasingly recognized as a key pathological contributor to low back pain, but effective treatment strategies remain elusive. Asperosaponin VI (ASA VI) exhibits significant anti-inflammatory effects and promotes mitophagy. However, the mechanism of ASA VI's action in FJOA remains unclear.
    OBJECTIVE: This study explores ASA VI's impact on mitophagy and cellular pyroptosis in FJOA chondrocytes and elucidates the underlying mechanisms.
    METHODS: The therapeutic mechanism of ASA VI in FJOA was initially investigated through network pharmacology analysis. A rat model of FJOA and an IL-1β-induced chondrocyte model to assess the protective effects of ASA VI on lumbar facet joint (LFJ) cartilage. Additionally, untargeted metabolomics and cellular transcriptomics analyses were performed to assess the roles of ASA VI in FJOA.
    RESULTS: Network pharmacology identified a strong link between ASA VI's effects and mitophagy. In vivo and in vitro tests confirmed ASA VI's biocompatibility, facilitated subchondral bone and cartilage extracellular matrix (ECM) remodeling, and delayed FJOA progression. Untargeted metabolomics indicated that ASA VI modulated the metabolic environment in FJOA by reducing excess metabolites, enhancing tricarboxylic acid (TCA) cycle activity, and promoting mitophagy. Mechanistically, ASA VI activated the PINK1/Parkin pathway, restoring mitochondrial function and autophagy in chondrocytes. Further experiments confirmed that ASA VI induces mitophagy via the PINK1/Parkin pathway, inhibits the cGAS/STING pathway, and reduces chondrocyte pyroptosis.
    CONCLUSIONS: ASA VI induces mitophagy in chondrocytes via the PINK1/Parkin pathway, suppresses the cGAS/STING signaling pathway, and reduces chondrocyte pyroptosis, thereby slowing FJOA progression. ASA VI consequently represents a promising treatment option for FJOA.
    Keywords:  Asperosaponin VI; Facet joint osteoarthritis; Mitophagy; Pyroptosis; cGAS–STING pathway
    DOI:  https://doi.org/10.1016/j.phymed.2026.158038
  18. Autophagy Rep. 2026 ;5(1): 2638025
    Kenny is the adaptor protein for ubiquitin-dependent mitophagy in Drosophila melanogaster.
    Hubert Osei Acheampong, Ryan Insolera.
      Mitophagy is the selective degradation program for damaged and unnecessary mitochondria to maintain cellular mitostasis and survival. Specific mutations in the mediators for the canonical ubiquitin (ub)-dependent mitophagy pathway have been identified with unique neurological diseases like Parkinson disease and ALS (amyotrophic lateral sclerosis), metabolic diseases, and cancer. Mammalian OPTN (optineurin) has been shown as a SAR (selective autophagy receptor) for ub-dependent mitophagy in vitro with direct connections of its mutations with glaucoma and ALS. Despite the in vitro demonstration of OPTN's role in mitophagy, the in vivo physiological characterization of OPTN's mitophagy function is largely unexplored. In our recent study, we provide in vivo evidence that the Drosophila melanogaster (Dm) protein, Kenny, directly mediates the sequestration of target mitochondria for the progression and completion of ub-dependent mitophagy. This result establishes Kenny as the Dm homolog of OPTN. Previously, Kenny had only been characterized for its role in innate immune activation and modulation. The conclusion from this study provides avenues for further understanding the in vivo signaling regulating Kenny's role in mitophagy and investigating homologous disease-relevant mutations of OPTN in Dm.
    Keywords:  ALS; Kenny; VPS13D; autophagosome; autophagy; mitochondria; mitophagy adaptor; optineurin; phagophore; ubiquitin
    DOI:  https://doi.org/10.1080/27694127.2026.2638025
  19. Bioact Mater. 2026 Aug;62 1-16
    Near infrared enhanced palladium loaded siraitia grosvenorii carbon dots amplify mitophagy for acute lung injury immunotherapy.
    Jing Zhang, Kunpeng Duan, Qianyue Liu, Shurong Chen, Hongshuai Zheng, Yan Liu, Jing Qian, Mingjing Yin, Jing Liu, Jiaxiao Li, Zhijian Li, Min Chen, Ximei Huang, Faquan Lin, Ming Gao, Lin Liao.
      Mitophagy is a self-protection mechanism for cells to eliminate dysfunctional mitochondria, and maintain mitochondrial homeostasis. Thus, precisely inducing mitophagy represents a promising strategy for acute lung injury (ALI) immunotherapy. Here, the mitochondrial targeted palladium loaded siraitia grosvenorii derived carbon dots (CPs@SS31) were engineered designed to integrate PTT, mitophagy induction, and immunoregulation for synergistic enhanced ALI therapy. CPs@SS31 combining with near infrared (NIR) irradiation not only directly scavenged reactive oxygen species to achieve antioxidant and anti-inflammation, but also amplified mitophagy via activating PINK1/Parkin pathway. Furthermore, it specifically targeted mitochondria to increase ATP production and mitochondrial membrane potential, thereby repairing the mitochondrial function of lipopolysaccharide induced cells. Meanwhile, it also demonstrated that CPs@SS31+NIR efficiently induced macrophage M2 polarization, and upregulated CD4+ T cells number and CD4+/CD8+ ratio, thereby activating immunoregulation, and achieving ALI repair therapy. In vitro and in vivo studies both demonstrated the robust alleviated lung inflammation, and accelerated lung tissue repair in ALI rats models. This work proposed an innovative "mitophagy induction-immunoregulation" paradigm, offering a promising strategy for ALI therapy, and being extended to the treatment of other inflammation related diseases.
    Keywords:  Acute lung injury immunotherapy; Mitochondrial targeting; Mitophagy induction; Pd loaded carbon dots; ROS scavenging
    DOI:  https://doi.org/10.1016/j.bioactmat.2026.02.040
  20. J Anim Sci Biotechnol. 2026 Mar 14. pii: 49. [Epub ahead of print]17(1):
    AMBRA1 activation alleviates zearalenone-induced swine testicular cell ferroptosis by facilitating mitophagy.
    Ziyan Hu, Shangjia Yang, Xiaoyi Zhang, Ming Lou, Qi Yu, Yue Cheng, Yuanhuang Chang, Fuwei Jiang, Mingshan Chen, Jiaxin Wang, Yijia Song, Jing Zheng, Xinyue Mao, Yibo Wang, Jinlong Li, Yi Zhao.
       BACKGROUND: Mycotoxin contamination poses a major challenge to public health and has garnered increasing attention across the world in recent decades. Zearalenone (ZEA), as one of the most prevalent contaminants, induces reproductive toxicity and then poses potential threats to animal health. Autophagy/beclin-1 regulator 1 (AMBRA1) is a protein critical for autophagy induction, and can enhance mitophagy by co-localizing with LC3. However, the potential health risk caused by ZEA in male germ cells of animals is unclear. This study aimed to investigate the underlying mechanisms of ZEA-induced swine testicular (ST) cell injury and to clarify the role of AMBRA1 in this process.
    METHODS: We established ST cell models to explore the effects of AMBRA1 on ferroptosis induced by ZEA. Multiple experimental approaches were applied to assess cell viability, mitochondrial dysfunction, oxidative stress, iron accumulation, and mitophagy. Mechanistic insights were further validated using AMBRA1 overexpression, RNA-seq, molecular docking, western blotting, immunofluorescence, and qRT-PCR analyses.
    RESULTS: In this study, ZEA induced mitochondrial structural damage and impaired mitochondrial function, leading to excessive ROS generation and loss of mitochondrial membrane potential. We also found that ZEA disrupted the iron homeostasis and thus led to the accumulation of ferrous iron, which further induce ferroptosis. In addition, ZEA reduced autophagy activity and autophagic flux, ultimately suppressing mitophagy. Of note, AMBRA1 overexpression effectively relieved ZEA-induced ferroptosis through restoration of mitophagy in ST cells.
    CONCLUSIONS: In conclusion, our study demonstrated that ZEA targeted the AMBRA1, leading to down-regulation of AMBRA1 expression, which in turn inhibited mitophagy and thus resulted in ferroptosis in ST cells. Given the potential role of AMBRA1 in ST cells, our results uncover a previously unrecognized mechanism in which AMBRA1-mediated mitophagy functions as a crucial defense target against ferroptosis in testicular cells. Importantly, our results propose a unique insight which AMBRA1 as a promising therapeutic target for counteracting mycotoxin-induced testicular injury in animals.
    Keywords:  AMBRA1; Ferroptosis; Mitophagy; Swine testicular cells; Zearalenone
    DOI:  https://doi.org/10.1186/s40104-026-01359-1
  21. Free Radic Biol Med. 2026 Mar 07. pii: S0891-5849(26)00212-1. [Epub ahead of print]249 117-137
    Thermally denatured dermal matrix enhances diabetic wound vascularization by reactivating mitophagy.
    Xiaoyang Wang, Meiqi Lu, Yujie Hu, Xiao Wang, Yongjun Qi, Shanshan Jia, Jingjuan Zhang, Xiaochuan Wang, Ya Jiao, Chao Wang, Jie Zhao, Jixun Zhang, Duyin Jiang.
       BACKGROUND: Delayed wound healing in diabetes mellitus (DM) is closely associated with endothelial mitochondrial dysfunction and impaired mitophagy. We therefore developed a liquid dermal matrix (LDM) and investigated its therapeutic efficacy and underlying mechanisms in diabetic wound repair.
    METHODS: The release behavior and biocompatibility of LDM were characterized. Its therapeutic effects were evaluated in a streptozotocin (STZ)-induced diabetic mouse full-thickness wound model, and mechanistic studies were conducted in high glucose (HG)-treated human umbilical vein endothelial cells (HUVECs).
    RESULTS: LDM exhibited sustained protein release over 96 h. In STZ-diabetic mice, topical application of Gel + LDM markedly accelerated wound closure; the wound closure rate at day 12 increased from 68.87 ± 3.98% in the Gel group to 94.80 ± 1.35% in the Gel + LDM group (P < 0.001). Laser speckle imaging confirmed enhanced wound perfusion at day 12, with perfusion units increasing from 489.96 ± 33.74 (Gel) to 707.21 ± 24.21 (Gel + LDM) (P < 0.001). Histological analyses revealed improved re-epithelialization and collagen remodeling, alongside increased angiogenesis as indicated by elevated CD31 and VEGFA staining. Mechanistically, in HG-treated HUVECs, LDM restored autophagic flux, evidenced by increased LC3-II and reduced P62 accumulation, and promoted PINK1/Parkin-dependent mitophagy. This was accompanied by attenuated mitochondrial fragmentation, reduced mtROS, and improved mitochondrial membrane potential (ΔΨm). Functionally, LDM improved endothelial proliferation, migration, and tube formation, while these protective effects were largely attenuated by 3-MA, MG-149, or PINK1 knockdown, supporting a mitophagy-dependent mechanism.
    CONCLUSIONS: LDM accelerates diabetic wound healing and improves wound perfusion by restoring mitophagy and mitochondrial homeostasis in endothelial cells, highlighting LDM as a promising therapeutic strategy for DM-associated chronic wounds.
    Keywords:  Diabetic wounds; Endothelial cells; Liquid Dermal Matrix (LDM); Mitophagy; Temperature-responsive
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.03.021
  22. Neuropharmacology. 2026 Mar 10. pii: S0028-3908(26)00096-1. [Epub ahead of print]291 110923
    Ajugol ameliorates mitochondrial dysfunction and cognitive decline in Alzheimer's Disease via BNIP3-dependent mitophagy.
    Yuan Qiao, Mengmeng Huang, Cuiting Sun, Xiaochen Du, Yuye Wang, Yuchen Liu, Linwei Zhang, Yingjie Guo, Liang Peng, Dantao Peng.
      Defective mitophagy plays key roles in mitochondrial dysfunction, inflammation, and energy deprivation, and this defect can lead to synaptic loss and cognitive decline in Alzheimer's disease (AD). Although pharmacological enhancement of mitophagy has been found to ameliorate cognitive impairment in AD models, therapeutic strategies directly targeting this pathway remain limited. Ajugol, a bioactive iridoid glycoside isolated from Rehmannia glutinosa, has recently been identified as a potential metabolic regulator. In this study, we demonstrated that ajugol markedly alleviates mitochondrial damage and mitophagy impairment in 5 × FAD mice and HT22 cells. Mechanistically, ajugol upregulates BCL2-interacting protein 3 (BNIP3), which recruits LC3 to damaged mitochondria, thereby promoting mitophagosome formation and ultimately contributing to improved cognitive function. Notably, Bnip3 knockdown in hippocampal neurons abolished the beneficial effects of ajugol in 5 × FAD mice, exacerbating mitophagy defects and mitochondrial dysfunction, ultimately impairing cognitive performance. These findings highlight a previously unrecognized mechanism by which ajugol mitigates amyloid pathology, synaptic dysfunction, and cognitive decline in 5 × FAD mice and HT22 cells by enhancing BNIP3-mediated mitophagy, providing a potential therapeutic strategy for AD intervention.
    Keywords:  Ajugol; Alzheimer's disease; BNIP3; Cognitive decline; Mitophagy
    DOI:  https://doi.org/10.1016/j.neuropharm.2026.110923
  23. J Ethnopharmacol. 2026 Mar 05. pii: S0378-8741(26)00336-3. [Epub ahead of print]364 121485
    QingShen granules activates mitophagy to suppress renal tubular epithelial-mesenchymal transition via the miR-23b-5p/Nrf2/PINK1 axis.
    Xu Li, Lan Hu, Qin Hu, Hua Jin.
       ETHNOPHARMACOLOGICAL RELEVANCE: Renal fibrosis (RF) is a pivotal pathological process in chronic kidney disease (CKD), driven by tubular epithelial-mesenchymal transition (EMT). Although Qingshen Granules (QSG) demonstrate clinical efficacy against CKD, their anti-fibrotic mechanisms, particularly concerning mitophagy regulation, remains poorly defined.
    AIM OF THE STUDY: This study sought to determine if QSG alleviates renal fibrosis by modulating the miR-23b-5p/Nrf2/PINK1 axis, thereby activating mitophagy, and consequently suppressing renal tubular EMT.
    MATERIALS AND METHODS: An adenine-induced rat renal fibrosis model and a TGF-β1-induced EMT model in NRK-52E cells were established and treated with QSG or QSG-containing serum, respectively. In vivo, adeno-associated virus was administered via tail vein injection to overexpress miR-23b-5p. Gain- and loss-of-function experiments were conducted in cells using miR-23b-5p mimic/inhibitor, Nrf2 overexpression plasmid, and siRNA. The evaluated parameters included renal function, renal histopathology, ultrastructure, mitochondrial membrane potential, oxidative stress levels, and the expression of relevant proteins and genes.
    RESULTS: QSG significantly improved renal function in the adenine-induced model rats, alleviated renal tubular injury and collagen deposition, and reversed the aberrant expression of EMT markers. Furthermore, QSG upregulated miR-23b-5p, inhibited Keap1, facilitated Nrf2 nuclear translocation, and thereby activated PINK1/Parkin-mediated mitophagy both in vivo and in vitro. Overexpression of miR-23b-5p mimicked the protective effects of QSG, whereas inhibition of miR-23b-5p or knockdown of Nrf2 significantly attenuated QSG's beneficial effects on mitophagy and EMT.
    CONCLUSION: QSG activates mitophagy via the miR-23b-5p/Nrf2/PINK1 axis, thereby inhibiting renal tubular EMT and fibrosis progression.
    Keywords:  Epithelial-mesenchymal transition; Mitophagy; QingShen granules; Renal fibrosis
    DOI:  https://doi.org/10.1016/j.jep.2026.121485
  24. Basic Res Cardiol. 2026 Mar 13.
    PARKIN overexpression confers cardioprotection via suppressing the mtDNA-cGAS-STING axis in myocardial ischemia/reperfusion injury.
    Yujing Li, Yuhan Wang, Hao Zhang, Pengfei Xu, Xiaosu Yuan, Hailong Yuan, Chaofan Yang, Yanan Zhou, Jianghua Shen, Heng Du, Zeyu Gao, Jingyi Zang, Siwen Liang, Jing Qu, Moshi Song.
      Myocardial ischemia/reperfusion (I/R) injury is exacerbated by inflammation, yet the upstream triggers of this cascade and their amenability to therapeutic intervention remain unclear. The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is a driver of sterile inflammation in I/R injury, but whether its activation can be suppressed via enhanced mitochondrial quality control has not been explored. We hypothesized that augmenting PARKIN-mediated mitophagy would limit cGAS-STING activation and attenuate I/R injury by clearing damaged mitochondria and preventing the release of its agonist, mitochondrial DNA (mtDNA). Cardiomyocyte-specific PARKIN overexpression in mice was well tolerated at baseline and conferred cardioprotection following I/R injury, attenuating adverse remodeling and preserving cardiac function. Mechanistically, PARKIN overexpression enhanced mitophagy, which limited cytosolic mtDNA accumulation, thereby inhibiting cGAS-STING activation and its downstream inflammatory response. The therapeutic potential of this pathway was further supported by lentiviral PARKIN delivery in wild-type mouse hearts, which also improved cardiac outcomes following I/R injury. Taken together, our findings delineate a PARKIN-mtDNA-cGAS-STING axis as a regulatory mechanism of I/R injury and support PARKIN augmentation as a potential therapeutic strategy.
    Keywords:  Inflammation; Mitophagy; Myocardial ischemia/reperfusion injury; PARKIN; cGAS–STING activation; mtDNA
    DOI:  https://doi.org/10.1007/s00395-026-01169-6
  25. Phytother Res. 2026 Mar 09.
    Pogostone Suppresses Microglial NLRP3 Inflammasome Activation-Promoted Remyelination Through RXRγ Regulation of Mitophagy.
    Menghan Qian, Xingzong Sun, Yue Jia, Yunjie Zhao, Lin Li, Faling Shao, Hongliang Li, Lili Dai, Hongkun Bao.
      Multiple sclerosis (MS) is a chronic autoimmune disease involving central nervous system nerve demyelination accompanied by intense neuroinflammation. Pogostone (PO), a major component of Pogostemon cablin, has anti-inflammatory, immunosuppressive, and antioxidant properties. In this study, we characterized the therapeutic potential of PO in remyelination and elucidated the underlying mechanisms. In cuprizon (CPZ)-induced demyelinating mice, rotarod test, RNA sequence, molecular docking, immunofluorescence, and western blotting were used to analyze the targets and signaling pathways involved in PO treatment. Meanwhile, the changes of mitophagy and NLRP3 inflammasome were detected after further treatment with RXRγ antagonist UVI3003. In lipopolysaccharide (LPS)-induced BV2 microglia, after interference with RXRγ or blockade of mitophagy by 3-methyladenine (3-MA), the effects of PO on mtROS, mitochondrial membrane potential (MMP), NLRP3 inflammasome and mitophagy were measured by flow cytometry, immunofluorescence and western blotting. PO treatment effectively promoted remyelination in the CPZ model, and this effect was achieved by activating RXRγ. Meanwhile, PO suppressed microglial NLRP3 inflammasome activation through enhancement of PINK1/Parkin-mediated mitophagy, but this change was reversed by the RXRγ antagonist UVI3003. In LPS-induced BV2 microglia, interference with RXRγ reversed the inhibitory effect of PO on mtROS production, MMP decline, and NLRP3 activation. In addition, blockade of mitophagy by 3-MA reversed the inhibitory effects of PO on mtROS production and NLRP3 inflammasome activity. The present study demonstrated that PO suppresses microglial NLRP3 inflammasome activation-promoted remyelination via RXRγ regulation of mitophagy, which suggests PO as a promising drug candidate for the treatment of MS.
    Keywords:  NLRP3 inflammasome; Pogostone; RXRγ; mitophagy; multiple sclerosis
    DOI:  https://doi.org/10.1002/ptr.70277
  26. Int J Mol Sci. 2026 Mar 06. pii: 2448. [Epub ahead of print]27(5):
    Cerebral Ischemia-Reperfusion Injury: Unraveling the Mitophagy-Oxidative Stress Axis for Neuroprotective Strategies.
    Yanling Zhou, Baochun Luo, Tong Shang, Zengrong Wei, Wei Zou.
      Cerebral ischemia-reperfusion (I/R) injury is a major pathological contributor to neurological deterioration following ischemic stroke (IS) and remains a critical barrier to effective neuroprotection. Accumulating evidence indicates that cerebral I/R injury is driven not by isolated stress responses but by coordinated and dynamic interactions among multiple cellular pathways. Among these, the bidirectional crosstalk between mitophagy and oxidative stress has emerged as a central regulatory axis. Moderate oxidative stress can function as an adaptive signal, activating protective mitophagy through key pathways such as AMPK/ULK1 signaling and cardiolipin externalization, thereby facilitating mitochondrial quality control and maintaining cellular homeostasis. Conversely, appropriately regulated mitophagy limits excessive reactive oxygen species (ROS) production by removing dysfunctional mitochondria, forming a negative feedback mechanism. However, dysregulation or excessive activation of either process disrupts this balance, leading to a self-amplifying cycle of mitochondrial dysfunction and oxidative damage that exacerbates neuronal injury. This review systematically summarizes the molecular mechanisms governing the oxidative stress-mitophagy crosstalk in cerebral I/R injury, highlighting key signaling nodes and regulatory pathways that determine protective versus detrimental outcomes. Furthermore, we discuss emerging therapeutic strategies aimed at precisely modulating this axis in a spatiotemporal- and intensity-dependent manner. By integrating mechanistic insights with translational perspectives, this review provides a conceptual framework for developing targeted neuroprotective interventions based on coordinated regulation of mitochondrial quality control and redox homeostasis.
    Keywords:  cerebral ischemia–reperfusion injury; ischemic stroke; mitophagy; oxidative stress; signaling pathway
    DOI:  https://doi.org/10.3390/ijms27052448
  27. Tissue Cell. 2026 Mar 06. pii: S0040-8166(26)00128-X. [Epub ahead of print]101 103435
    Melitidin alleviates escitalopram-induced sub-chronic cardiotoxicity via regulating mitochondrial fission-fusion machinery and redox signaling: A biochemical, echocardiographic, and histological study.
    Yuting Wang, Hafsa Ashfaq, Mansour Abdulaziz Alsaleem, Mohammed Alissa, Abdullah Alghamdi, Alaa S Alhegaili, Ahmed Al-Emam, Hesham M Hassan.
      Escitalopram (ETP) is a selective serotonin reuptake inhibitor anti-depressant drug that is reported to cause cardiac impairments. Melitidin (MLD) is a natural flavanone that exhibits marked biological and pharmacological properties. This study was commenced to explore the cardioprotective efficacy of MDL against ETP-induced cardiotoxicity. Thirty-two Sprague Dawley rats categorized into control, ETP (10 mg/kg), ETP (10 mg/kg) + MLD (23 mg/kg), and MLD (23 mg/kg) treated group. ETP exposure significantly (p < 0.05) upregulating the mRNA expressions of Mitochondrial fission 1 protein (FIS1), Mitochondrial fission factor (MFF), and dynamin-related protein 1 (Drp1) while inhibiting the expressions of Mitofusin-1 (MFN1), Mitofusin-2 (MFN2), and Optic atrophy 1 (OPA1). The catalytic activity of hemeoxygnase-1 (HO-1, -83%), glutathione peroxidase (GPx, -80%), superoxide dismutase (SOD, -79%), glutathione reductase (GSR, -85%), glutathione S-transferase (GST, -70%), and catalase (CAT, -65%) were substantially (p < 0.05) inhibited while the levels of reactive oxygen species (ROS, -1031%) and malondialdehyde (MDA, -1027%) were promoted remarkably (p < 0.05) following the administration of ETP. Besides, ETP intoxication reduced heart (-13%) coupled with thickness of posterior ((+ 38%) and septal wall (+ 29%) and enlargement of ventricular dimensions (+ 23%). A sharp escalation was observed in the levels of B-type natriuretic peptide (BNP, +238%), cyclooxygenase-2 (COX-2), lactate dehydrogenase (LDH, +509%), interleukin-1 beta (IL-1β), troponin-T, troponin I (+301%), interleukin-6 (IL-6), Pro-B-type natriuretic peptide (proBNP), Creatine phosphokinase (CPK), tumor necrosis factor- alpha (TNF-α, +845%), C-reactive protein, Creatine kinase-MB (CK-MB, +123%), and nuclear factor-kappa B (NF-κB, +642%) after ETP administration. Moreover, ETP exposure exerted adverse impacts on cardiac histology. Importantly, con-current administration of MLD alleviated cardiac toxicity via regulated mitochondrial dynamics, redox profile, echocardiographic alterations, cardiac injury markers, and histopathological impairments. Furthermore, in-silico analysis showed strong association of MLD with key regulatory mitochondrial dynamic genes. Our biochemical, radiological, histological, and in-silico findings showed that MLD confers cardio-protection against ETP-induced cardiotoxicity.
    Keywords:  Apoptosis; Cardiotoxicity; Escitalopram; Inflammation; Melitidin; Oxidative stress
    DOI:  https://doi.org/10.1016/j.tice.2026.103435
  28. Int J Mol Sci. 2026 Feb 24. pii: 2117. [Epub ahead of print]27(5):
    Fasting Enhances Cardiomyocyte Hypoxia Tolerance by Regulating Ca2+ Transport at Mitochondria-Endoplasmic Reticulum Contact Sites.
    Xiangning Chen, Bo Jiao, Tong Xue, Manjiang Xie, Zhibin Yu.
      Mitochondria-endoplasmic reticulum contacts (MERCs) are physical structures formed between mitochondria and the endoplasmic reticulum (ER) through various tethering proteins, playing crucial roles in multiple physiological processes, including Ca2+ and lipid exchange between the ER and mitochondria, regulation of mitochondrial morphology and dynamics (fusion and fission), as well as the induction of autophagy and apoptosis. Mitofusin 2 (MFN2), a key mitochondrial fusion protein, has been identified as an essential structural component of MERCs. Our research demonstrates that 16:8 circadian intermittent fasting (CIF) leads to enhanced mitochondrial fusion. The upregulation of MFN2 reinforces MERC stability, thereby facilitating efficient Ca2+ transfer between the ER and mitochondria. This process sustains the activity of mitochondrial oxidative phosphorylation (OXPHOS) enzymes, elevates mitochondrial oxygen utilization efficiency, and ultimately augments ATP production. Consequently, these adaptations enhance cardiomyocyte tolerance to hypoxic conditions. This study elucidates a novel mechanism by which MERCs regulate cellular hypoxia resistance and proposes a potential therapeutic strategy for improving acute hypoxia tolerance through the modulation of Ca2+ transport at MERCs.
    Keywords:  MERC; calcium transport; cardiomyocyte; circadian intermittent fasting; hypoxia; mitofusin 2
    DOI:  https://doi.org/10.3390/ijms27052117
  29. J Alzheimers Dis. 2026 Mar 13. 13872877261420211
    The interplay between mitophagy and ferroptosis in Alzheimer's disease: Mechanisms and therapeutic implications.
    Annan Liu, Liping Xing, Jianhui Li, Mingyuan Yao, Jing Song, Wang Guo, Peihan Duan, Honglin Li.
      Alzheimer's disease (AD) is pathologically characterized by the accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles composed of hyperphosphorylated tau protein. In recent years, two cellular processes have emerged as pivotal drivers of neurodegeneration in AD: mitophagy, the selective autophagic clearance of damaged mitochondria, and ferroptosis, an iron-dependent form of regulated cell death. This review outlines the molecular mechanisms of mitophagy and ferroptosis, with a focus on their interplay in AD. We propose that impaired mitophagy disrupts intracellular redox and iron homeostasis, thereby increasing neuronal susceptibility to ferroptosis. Conversely, ferroptosis-executing events, such as lethal lipid peroxidation, can further exacerbate mitochondrial dysfunction. This establishes a self-amplifying vicious cycle that accelerates disease progression. Furthermore, we summarize potential therapeutic strategies targeting this interactive network (e.g., Urolithin A, ferroptosis inhibitors) and highlight promising directions for future research. In contrast to previous reviews that have focused on each process in isolation, this work synthesizes evidence for a self-amplifying feedback loop between impaired mitophagy and exacerbated ferroptosis in AD. We posit that targeting this self-amplifying loop between mitophagy and ferroptosis may offer a novel and effective therapeutic paradigm for halting Alzheimer's disease progression.
    Keywords:  Alzheimer’s disease; ferroptosis; mechanism; mitochondria; mitophagy; therapeutic targets
    DOI:  https://doi.org/10.1177/13872877261420211
  30. iScience. 2026 Mar 20. 29(3): 114927
    USP1 promotes hepatocellular carcinoma progression by modulating mitophagy via stabilizing MCM3 to regulate the Keap1-Nrf2 axis.
    Zhonge Chen, Chengqin Sun, Ye Wang, Xiaojuan Duan, Huaxing Ma, Xiaoqian Zhou, Shaojie Chen, Pailan Peng.
      Hepatocellular carcinoma (HCC) is a common malignant tumor with a high mortality rate. High mitophagy levels can promote hepatic tumor progression; therefore, inhibiting mitophagy may be a promising therapeutic strategy. This study shows that minichromosome maintenance protein 3 (MCM3) was upregulated in HCC. Knocking down MCM3 suppressed the biological behaviors of tumor cells, promoted tumor cell apoptosis, and inhibited mitophagy. We found that USP1 binds to MCM3 and stabilizes it via deubiquitination of K48-linked ubiquitin chains. Excessive MCM3 proteins bind to Keap1, disrupting the Keap1-Nrf2 interaction and activating the Nrf2 signaling pathway to modulate mitophagy, promoting HCC progression. In addition, our in vivo experiments showed that MCM3 knockdown significantly suppressed xenograft tumor growth. In summary, MCM3 functions as a key oncoprotein. USP1-mediated deubiquitination of MCM3 influences the Keap1-Nrf2 axis, regulates mitophagy, and facilitates HCC progression. MCM3 may be a potential therapeutic target for liver cancer.
    Keywords:  Cancer; Molecular interaction; Molecular mechanism of gene regulation
    DOI:  https://doi.org/10.1016/j.isci.2026.114927
  31. Bioorg Chem. 2026 Mar 02. pii: S0045-2068(26)00244-0. [Epub ahead of print]174 109708
    The H2S donor sulforaphane inhibits NLRP3 inflammasome activation by inducing mitochondrial autophagy and mitigating CBS-H2S axis damage in in-vitro and in-vivo models of Parkinson's disease.
    Wenyu Xie, Ke Wu, Lin Zhang, Xiyu Feng, Shangshen Yang, Siyu Jia, Yutong Li, Xiaoming Wang.
      Hydrogen sulfide (H₂S) plays a crucial neuroprotective role in Parkinson's disease (PD). Cystathionine-β-synthase (CBS), a key enzyme involved in H₂S biosynthesis, exhibits expression deficiencies that are closely linked to PD progression. This suggests that enhancing the CBS-H₂S signaling axis to restore H₂S homeostasis may be a critical approach for preventing and treating PD. In the present study, the H₂S donor sulforaphane (SFN) was investigated to elucidate its neuroprotective mechanisms through activation of the CBS-H₂S axis. siRNA-mediated silencing of Nrf2 and CBS was employed to clarify the role of each in SFN's effects. Our findings demonstrate that SFN promotes CBS expression and H₂S synthesis, activates mitophagy to clear damaged mitochondria, reduces mitochondrial-derived reactive oxygen species (mtROS) levels, and inhibits the activation of NLRP3 inflammasomes and caspase-1. In the MPTP-induced PD mouse model, SFN improved motor performance, increased the survival rate of tyrosine hydroxylase (TH)-positive dopaminergic neurons in the substantia nigra, and restored dopamine metabolism in the striatum, normalizing the DOPAC/DA and 5-HIAA/5-HT ratios. Electron microscopy revealed that SFN facilitated the clearance of damaged mitochondria through autophagosomes and blocked mtROS-mediated NLRP3 inflammasome activation. In the MPP+-induced BV-2 microglial cell model, SFN upregulated CBS expression, enhanced H₂S synthesis, increased the LC3-II/I ratio, and inhibited p62 degradation, thereby promoting the recovery of mitochondrial membrane potential and reducing ROS release. These effects were still observed under Nrf2 silencing conditions, indicating that SFN's neuroprotective effects are mediated through the CBS-H₂S axis independently of Nrf2 signaling. Collectively, these findings indicate that SFN reshapes the CBS-H₂S signaling axis, activates mitochondrial autophagy, and suppresses inflammation, offering novel insights into multi-target therapeutic approaches for PD and underscoring the essential role of H₂S in neuroprotection.
    Keywords:  CBS–H₂S axis; Mitophagy; NLRP3 inflammasome; Parkinson's disease; Sulforaphane
    DOI:  https://doi.org/10.1016/j.bioorg.2026.109708
  32. World J Stem Cells. 2026 Feb 26. 18(2): 114303
    Targeting mitochondrial quality control in osteoarthritis with GrpE-like 1-loaded synovial mesenchymal stromal/stem cell small extracellular vesicles.
    Zhuo-Jin Shi, Xiao-Mei Ying, Wei Liu.
      Recent studies have demonstrated that synovial mesenchymal stem cell-derived small extracellular vesicles (EVs) engineered to deliver GrpE-like 1 activated PTEN-induced kinase 1-dependent mitophagy and restored chondrocyte homeostasis. This study revealed that interleukin-1β-challenged chondrocytes exhibited efficient cargo transfer, increased mitophagy signaling with reduced p62 levels, lower oxidative stress, and a shift toward matrix preservation, characterized by higher collagen II and aggrecan levels, and lower matrix metallopeptidase 13 and ADAM metallopeptidase with thrombospondin type 1 motif 5 levels. In a rat knee osteoarthritis model, intra-articular dosing preserved cartilage architecture and improved histological scores. Collectively, these findings suggest that EV-based delivery of mitochondrial regulators is a plausible disease-modifying strategy, rather than purely symptomatic care. Building on this evidence, this editorial distills key advances and outlines near-term research and translational priorities, including standardized EV characterization, pharmacokinetics, dosing, safety, and manufacturability. The suitability of GrpE-like 1-loaded small EVs for early-stage osteoarthritis was also evaluated.
    Keywords:  Extracellular vesicles; GrpE-like 1; Osteoarthritis; PTEN-induced kinase 1/Parkin-mediated mitophagy; Synovial mesenchymal stem cells
    DOI:  https://doi.org/10.4252/wjsc.v18.i2.114303
  33. Drug Dev Res. 2026 Apr;87(2): e70258
    Ceritinib Induces Mitochondrial Fragmentation in Thyroid Cancer Cells by Targeting Drp-1.
    Dongguang Qin, Wei Ding, Xuesong Wu, Chen Peng, Yunfeng Bo, Dapeng Wang, Yanchao Qin.
      Mitochondrial dynamics play a crucial role in thyroid cancer progression by regulating apoptosis, metabolism, and oxidative stress. Ceritinib, a tyrosine kinase inhibitor, shows potential anticancer effects; however, its impact on mitochondrial function in thyroid cancer remains obscure. Herein, we aim to investigate the impact of ceritinib on the mitochondrial functionality in TPC-1 thyroid carcinoma cells and the underlying mechanism. Cell viability was assessed with the CCK-8 assay, and the cytotoxicity was determined by evaluation of the lactate dehydrogenase (LDH) release assay. Mitochondrial reactive oxygen species (ROS) were detected by MitoSOX Green staining. Enzyme-linked immunosorbent assay (ELISA) was applied for 8-hydroxydeoxyguanosine (8-OHdG) determination. Real-time PCR was employed for mRNA levels assessment, and western blotting was applied for protein levels. The morphology of mitochondria was evaluated by means of Mitotracker Red CMXRos staining. Ceritinib triggered mitochondrial oxidative stress, evidenced by elevated ROS and 8-OHdG levels, while suppressing manganese superoxide dismutase (Mn-SOD) activity. It also impaired mitochondrial respiration, ATP production, and Complex III activity, leading to dysfunction. Notably, ceritinib promoted mitochondrial fragmentation by enhancing dynamin-related protein 1 (Drp1) translocation to mitochondria, reducing l-OPA1 and increasing S-OPA1 levels, without altering mitofusins 1 and 2 (Mfn-1 and -2) expression. Mechanistically, ceritinib activated the Mitochondrial Calcium Uniporter (MCU)/calpain pathway, increasing MCU, calpain1/2, and calpain activity. Inhibition of MCU by RU360 reversed ceritinib-induced Drp1 mitochondrial translocation, fragmentation, and ATP depletion. Our findings reveal that ceritinib disrupts mitochondrial dynamics via the MCU/calpain/Drp1 axis. This study identifies a previously unreported mechanism for ceritinib in thyroid carcinoma, suggesting a novel therapeutic strategy.
    Keywords:  Drp‐1; ceritinib; mitochondrial function; thyroid carcinoma cell
    DOI:  https://doi.org/10.1002/ddr.70258
  34. Free Radic Biol Med. 2026 Mar 09. pii: S0891-5849(26)00180-2. [Epub ahead of print]
    TG2 (transglutaminase 2) promotes PINK1/Parkin-dependent mitophagy in pulmonary hypertension by regulating the TRPC6.
    Linqing Li, Bo Liu, Minhao Zhang, Dong Wang, Yuhan Qin, Mingkang Li, Gaoliang Yan, Jiantong Hou, Yong Qiao, Yuyu Yao, Guoqiu Wu, Chengchun Tang.
      Hypoxia pulmonary hypertension (HPH) is a fatal progressive lung vasculopathy for which no efficacious interventions are currently available. This study investigated the potential mechanisms of TG2, a multifunctional enzyme, in HPH progression. The expression of TG2 was significantly upregulated in patients with pulmonary hypertension, HPH mice, and hypoxia-induced human pulmonary smooth muscle cells. Vascular smooth muscle-specific TG2 knockout (TG2VSMCKO) mice significantly ameliorated hypoxia+SU5416 and HPH. TG2 knockdown in human pulmonary smooth muscle cells remarkably decreased transient receptor potential canonical 6 (TRPC6) protein levels and calcium activity. Thus, we hypothesized that TRPC6 may serve as a novel target for TG2 regulation. TG2 deficiency decreased the mitophagy proteins PINK1 and Parkin and autophagy marker LC3 expression, whereas it increased autophagy receptor protein p62/SQSTM expression and inhibited mitophagy flux in human pulmonary smooth muscle cells exposed to hypoxia. Further investigations on mitochondrial function demonstrated that knockdown of TG2 significantly increased reactive oxygen species levels in the mitochondria and impeded depolarization of the mitochondrial membrane. Under conditions of mitochondrial dysfunction, the activation of TG2 engendered hyper-proliferation and an anti-apoptotic phenotype in human pulmonary smooth muscle cells through the process of mitophagy. Furthermore, we confirmed that TG2 regulates TRPC6 expression through serotonylation. Our findings provide a strong molecular explanation for the association between TG2, mitochondrial function, and HPH. This study identified a novel target for the treatment of HPH.
    Keywords:  Hypoxia; Mitophagy; Pulmonary artery smooth muscle cells; Pulmonary vascular remodeling; Serotonylation; Transglutaminase 2; Transient receptor potential cation channel 6
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.03.002
  35. Cell Death Dis. 2026 Mar 12.
    ANGPTL2 inhibits macrophage pyroptosis and alleviates rheumatoid arthritis progression by regulating mitophagy via IGFBP5.
    Yuqi Liu, Qiudong Yang, Zhendong Huang, Jiahui Sun, Junhong Xiao, Zhengkun Yang, Xin Huang, Li Ma, Xiaoxuan Wang, Chuan Wang, Zhengguo Cao.
      Dysregulated macrophage pyroptosis and impaired mitophagy have emerged as critical drivers of rheumatoid arthritis (RA) progression, yet their upstream regulatory mechanisms remain unclear. Previous studies have demonstrated that ANGPTL2 deficiency aggravates alveolar bone loss in periodontitis, a condition that shares mechanistic similarities with RA in terms of bone destruction. Given the established link between periodontitis and RA, these findings suggest that ANGPTL2 may also play a protective role in RA-related joint pathology. In this study, we demonstrate that ANGPTL2 deficiency worsens joint inflammation, bone erosion, and macrophage pyroptosis in mice with collagen-induced arthritis (CIA). Mechanistically, ANGPTL2 loss impairs mitophagy and promotes mitochondrial dysfunction by inhibiting IGFBP5, leading to sustained NLRP3 inflammasome activation. Intra-articular administration of AAV-Angptl2 restores mitophagy, suppresses pyroptosis, and alleviates RA pathology. These findings identify ANGPTL2 as a key regulator of macrophage mitophagy and suggest its therapeutic potential in RA.Schematic diagram of the mechanism of ANGPTL2 in the treatment of rheumatoid arthritis.
    DOI:  https://doi.org/10.1038/s41419-026-08537-z
  36. Cancer Lett. 2026 Mar 11. pii: S0304-3835(26)00191-6. [Epub ahead of print] 218428
    The Mitochondrial Enigma: Deciphering Mechanisms and Identifying Drug Targets in Polyploid Giant Cancer Cells.
    Srimanta Patra, Prakash Priyadarshi Praharaj, Mrutyunjay Jena, Antonio Zorzano.
      Polyploid giant cancer cells (PGCCs) are a major driver of tumor recurrence, drug resistance, and stemness, and are a significant obstacle in cancer therapy. These highly unstable cells form via mitotic slippage, failed cytokinesis, or cell fusion, and are implicated in chemotherapy-induced senescence. The survival and proliferation of PGCCs are critically dependent on altered mitochondrial dynamics and physiology, which includes a shift towards hyperfusion and asymmetric fission. PGCCs possess a higher mitochondrial content, indicating increased biogenesis to support their high metabolic demand, which is often met through glycolysis. After chemotherapy, these cells can bypass senescence to produce aggressive, proliferative progeny with enhanced stemness. This review documents the profound link between mitochondrial dynamics and the formation of PGCCs, their acquired drug resistance, and their ability to drive tumor relapse. We propose that targeting mitochondrial dynamics and physiology offers a promising therapeutic strategy to combat PGCCs, providing a novel approach for next-generation personalized and precision cancer care.
    Keywords:  Cancer; Mitochondrial Dynamics; Mitosis; Polyploid Giant Cancer Cells (PGCCs); Stemness
    DOI:  https://doi.org/10.1016/j.canlet.2026.218428
  37. Crit Rev Eukaryot Gene Expr. 2026 ;36(1): 37-50
    Mechanistic Study of the Pink1/Parkin Signaling Pathway in Mitochondrial Dysfunction and Podocyte Injury.
    Shengyou Yu, Qingke Xie, Li Yu.
      PTEN-Induced Putative Kinase 1 (Pink1) is a key regulatory protein in mitochondrial autophagy: upon mitochondrial damage, Pink1 selectively binds to the mitochondrial outer membrane, thereby recruiting and phosphorylating Parkin. However, the mechanism by which the Pink1/Parkin signaling pathway functions in podocytes remains unclear, and this study aimed to investigate the role of this pathway in mitochondrial dysfunction associated with glomerular podocyte injury. For this purpose, flow cytometry was used to detect podocyte apoptosis rate; transmission electron microscopy was employed to observe the quantity and morphological changes of podocyte mitochondrial autophagosomes; and reverse transcription-polymerase chain reaction (RT-PCR) and western blot were performed to quantify the mRNA and protein expression levels of Pink1, Parkin, and LC3-II, respectively. The results showed that compared with the Control and Pink1 groups, the PAN group exhibited a significantly increased podocyte apoptosis rate; in the Pink1 group, mitochondria gradually became swollen and rounded, with disordered arrangement. These findings confirmed that PAN can induce podocyte injury and that this process is associated with the Pink1/Parkin pathway. In conclusion, the Pink1/Parkin signaling pathway plays a crucial role in mitochondrial dysfunction during glomerular podocyte injury, and these results provide a new perspective for the potential clinical application of the Pink1/Parkin signaling pathway in podocyte injury and future related research.
    DOI:  https://doi.org/10.1615/CritRevEukaryotGeneExpr.2026061692
  38. Exp Mol Med. 2026 Mar 13.
    TANK-binding kinase 1 protects against MASH progression via mitochondrial quality control.
    Sung-Min An, Jun Hee Jang, Jin Hyun Sung, Ji Won Myung, Yong Geun Jeon, Won Taek Lee, Jin Won Jeon, Kyung Min Yim, Jae-Ho Lee, Bichen Zhang, Jong Bae Seo, Seung Soon Im, Jae Bum Kim, Alan R Saltiel, Jin Young Huh.
      Mitochondrial dysfunction is a critical driver of metabolic dysfunction-associated steatotic liver disease progression to steatohepatitis (MASH), yet the mechanisms governing mitochondrial quality control in hepatocytes remain poorly defined. Here we identify TANK-binding kinase 1 (TBK1) as an essential regulator of hepatic mitophagy and lysosomal activity. Using TBK1-deficient hepatocytes and liver-specific TBK1-knockout mice, we show that TBK1 loss leads to the accumulation of depolarized, reactive oxygen species-producing mitochondria due to impaired mitophagy flux, including defective lysosomal degradation. Mechanistically, TBK1 is required for p62 phosphorylation at Ser403 and partially modulates mTOR signaling to preserve lysosomal activity. Notably, both human samples and murine steatohepatitis models exhibited a substantial decline in TBK1 kinase activity. Therapeutic restoration of TBK1 expression via AAV8 delivery in MASH mouse model enhanced mitophagy, reduced mitochondrial burden and ameliorated liver fibrosis. Collectively, these findings establish TBK1 as a critical guardian of mitochondrial and lysosomal homeostasis in MASH.
    DOI:  https://doi.org/10.1038/s12276-026-01672-9
  39. PLoS One. 2026 ;21(3): e0342423
    Quercetin prevents age-related hearing loss in C57BL/6J mice by activating mitophagy and inhibiting the NLRP3 inflammasome.
    Menglong Feng, Xiaoqing Zhou, Ting Yang, Zhiji Chen, Guijun Yang, Xu Jiang, Wei Yuan.
       OBJECTIVE: Age-related hearing loss (ARHL), the most prevalent sensory impairment in older adults, is closely associated with NOD-like receptor thermal protein domain-containing protein 3 (NLRP3) inflammasome activation and mitochondrial dysfunction. Quercetin, a natural flavonoid, shows anti-inflammatory and antioxidant properties, but its role in ARHL remains unclear. In this study, we investigated the protective effects and underlying mechanisms of quercetin on ARHL in a mouse model, focusing on both NLRP3 inflammasome and mitophagy.
    MATERIALS AND METHODS: Quercetin was administered intragastrically to C57BL/6J mice from the age of 6 months to 12 months. The function of the hearing system was evaluated by auditory brainstem response (ABR) and hematoxylin and eosin (HE) staining of the cochlea. The levels of oxidative stress markers were detected using specific kits. Gene expression was detected by quantitative reverse transcripation polymerase chain reaction (qRT-PCR) and Western blot.
    RESULTS: The results showed that quercetin effectively reduced the ABR threshold shift at 8, 16, and 32 kHz frequencies and improved cochlear tissue morphology. It also reduced oxidative stress and inflammatory factors such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-18 (IL-18), and interleukin-1β (IL-1β), in the cochlea and auditory cortex of C57BL/6J mice. Notably, the activation of the NLRP3 inflammasome was attenuated in the quercetin-treated group, as evidenced by decreased expression of NLRP3, apoptosis-associated speck-like protein (ASC), IL-1β, IL-18, caspase-1 and cleaved caspase-1. Additionally, quercetin treatment promoted the expression of autophagy-related genes in the cochlea and auditory cortex, such as PTEN induced putative kinase 1 (PINK1), Parkinson disease-related protein 2 (PARKIN), BCL2 interacting protein 3 (BNIP3) and microtubule-associated protein 1 light chain 3B (LC3B), and increased the LC3B-II/LC3B-I ratio.
    CONCLUSION: These findings indicated that quercetin exerted a protective effect against ARHL by suppressing NLRP3 inflammasome activation and modulating mitophagy, providing a theoretical basis for applying quercetin to treat ARHL.
    DOI:  https://doi.org/10.1371/journal.pone.0342423
  40. Free Radic Biol Med. 2026 Mar 10. pii: S0891-5849(26)00216-9. [Epub ahead of print]249 260-272
    Mitochondrial fusion orchestrated by hepatitis E virus couples pro-viral autophagy and innate immune evasion for efficient replication.
    Xiaoman Liu, Yiyun Jiang, Chen Wang, Jialei Li, Yizhou Zhang, Chunling Wang, Yining Liang, Hongyang Liu, Jing Yuan, Yijin Wang.
      Hepatitis E virus (HEV) is a major cause of acute hepatitis globally, yet the mechanisms underlying its replication and pathogenesis remain poorly understood. While mitochondrial dynamics are increasingly recognized as central to antiviral responses, their role in HEV infection has not been defined. Here, we demonstrate that HEV induces profound mitochondrial structural remodeling-characterized by elongated morphology in patient liver biopsies and active mitochondrial fusion in cell culture models, a process essential for viral replication. Mechanistically, this remodeling is driven by a biphasic regulatory program: acute infection preferentially upregulates inner membrane fusion protein OPA1, whereas chronic infection shifts dependence to outer membrane mediator MFN1. Genetic ablation of OPA1 or MFN1 not only reversed mitochondrial elongation but also significantly suppressed HEV replication. Integrated transcriptomic and functional analyses revealed that this virus-induced fusion licenses a pro-viral autophagic response while concurrently dampening interferon-stimulated gene expression. Furthermore, we identified that HEV orchestrates a G0/G1 cell cycle arrest to actively enforce and maintain this pro-fusion mitochondrial state. Clinically, the presence of elongated mitochondrial profiles in patient livers correlated with disease severity, and HEV ORF2 protein levels positively correlated with OPA1/MFN1 expression. Our study establishes mitochondrial fusion as a critical host pathway co-opted by HEV, revealing a previously unrecognized viral strategy that integrates organelle dynamics, autophagy, cell cycle control, and immune evasion to promote replication. These findings position mitochondrial fusion machinery as a promising target for therapeutic intervention against hepatitis E.
    Keywords:  Anti-virus; HEV; Mitochondrial dynamics
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.03.025
  41. J Hypertens. 2026 Feb 20.
    PINK1/Parkin-mediated mitophagy is involved in calcium-sensing receptor-induced cardiac damage and apoptosis in spontaneously hypertensive rats.
    Siting Hong, Yuanyuan Jin, Yang Li, Dongxue Liu, Haoruo Zhang, Haoran Tong, Yu Fu, Xiaohui Zhang, Wenjia Chen, Wenxiu Liu, Jingzhi Wang, Rui Xu, Jiaxin Xue, Xinhua Yin, Yue Liu, Xin Zhang.
       INTRODUCTION: Hypertension poses a significant threat to human health through its induction of cardiac damage. The calcium-sensing receptor (CaSR) has been implicated in cardiovascular diseases; however, its specific role in cardiomyocyte injury in spontaneously hypertensive rats (SHRs) remains unclear. This study therefore investigated the effects of Calhex231, a CaSR antagonist, on cardiac damage in SHRs.
    METHODS: Cardiac function and structure were evaluated by echocardiography, histological staining and transmission electron microscopy. To explore the underlying mechanisms, CaSR expression along with markers of mitophagy, autophagy and apoptosis were assessed in rat hearts tissues via Western blotting. Furthermore, mitochondrial membrane potential and intracellular calcium levels were measured in angiotensin II (Ang II)-treated cardiomyocytes at the cellular level.
    RESULTS: Relative to WKY rats, SHRs showed elevated blood pressure, cardiac injury (hypertrophy, fibrosis, apoptosis), and upregulated CaSR, mitophagy and autophagy. Calhex231 reversed these in-vivo pathologies and, in vitro, protected cardiomyocytes against Ang II-induced apoptosis. This protection was achieved by inhibiting mitophagy/autophagy, lowering [Ca2+]i, and preserving mitochondrial membrane potential. The pivotal role of CaSR was underscored by the fact that its knockdown reproduced the protective effects against Ang II.
    CONCLUSION: These findings suggests that Calhex231 protects against cardiomyocyte apoptosis by inhibiting both the PINK1/Parkin-mediated mitophagy pathway and general autophagy. Therefore, targeting the CaSR represents a promising therapeutic strategy to prevent cardiac damage induced by hypertension.
    Keywords:  Ang II; Angiotensin II; CaSR; Calcium-sensing receptor; Calhex231; EDV; ESV; G protein-coupled receptor; GPCR; IP3; LV Mass; LVEF; LVFS; LVIDd; LVIDs; PINK1; PLC; PTEN-induced putative kinase 1; PW; RT-PCR; SHR; Septum; WKY; Wistar-Kyoto rats; apoptosis; calcium-sensing receptor; cardiac damage; diastolic left ventricular internal dimension; end diastolic volume; end systolic volume; hypertension; inositol 1*4*5-trisphophate; left ventricular ejection fraction; left ventricular fractional shortening; left ventricular muscle mass; mitophagy; phospholipase C; real-time PCR; spontaneously hypertensive rats; systolic left ventricular internal dimension; thickness of posterior wall at end-systole; thickness of septum at end-systole
    DOI:  https://doi.org/10.1097/HJH.0000000000004273
  42. Cell Signal. 2026 Mar 09. pii: S0898-6568(26)00117-8. [Epub ahead of print] 112467
    Corrigendum to "High glucose-induced mitochondrial fission drives pancreatic cancer progression through the H3K18la/TTK/BUB1B signal pathway" [Cellular Signalling 135 (2025) 112027].
    Fadian Ding, Yikun Guo, Han Zhang, Yun Zhong, Denghan Zhang, Qiang Huang, Zhou Zheng, Guozhong Liu, Xiang Zhang, Shangeng Weng.
      
    DOI:  https://doi.org/10.1016/j.cellsig.2026.112467
  43. Zhongguo Zhong Yao Za Zhi. 2026 Feb;51(4): 1016-1030
    [Exploration in molecular mechanism of icariin for ameliorating postmenopausal osteoporosis based on estrogen receptor α-mediated regulation of mitophagy in osteoblasts].
    Ning Wang, Nan Cong, Xuan Liu, Si Chen, Jiao-Jiao Yang, Nian Liu, Yu-Xi Dong, Pi-Wen Zhao.
      This study investigated the molecular mechanism by which icariin regulates mitophagy via the estrogen receptor α(ERα)-mediated silencing of the regulatory protein 1(SIRT1)/forkhead box protein O3a(FOXO3a) pathway and its downstream PTEN-induced kinase 1(PINK1)/Parkin signaling axis, thereby influencing bone metabolism and osteoblast differentiation to ameliorate postmenopausal osteoporosis(PMOP). Network pharmacology and molecular docking were initially employed to identify key targets of icariin and potential signaling pathways related to PMOP, followed by validation of icariin's binding affinity to these targets. For in vivo experiments, 36 female C57BL/6J mice were randomly divided into six groups: sham-operation, model, estradiol(E_2)-treated, and low-, medium-and high-dose icariin-treated groups, respectively. In the sham operation group, some fat pads around the ovaries were removed from the mice, while the PMOP models were established through castration surgery in other groups. The drug administration groups were respectively given estradiol or icariin for continuous intervention for 8 weeks. Estrus cycle changes were monitored, while serum hormone and bone metabolism levels were measured by ELISA. Meanwhile, the femoral microstructure was evaluated using Micro-CT and HE staining, and bone anabolism was assessed by Western blot, Masson staining, and Goldner staining, respectively. In addition, mitophagy and expression of related proteins were examined by Western blot and transmission electron microscopy, while SIRT1/FOXO3a pathway proteins were analyzed by Western blot. For in vitro experiments, MC3T3-E1 cells were divided into control(osteogenic induction) and icariin-treated groups(low, medium, and high doses), with additional ERα antagonist and SIRT1 inhibitor interventions. Osteogenic differentiation and extracellular matrix mineralization were evaluated using ALP staining, alizarin red staining, and Western blot. Mitophagy and expression of related proteins were examined by Western blot and immunofluorescence detection, while the expression of proteins related to SIRT1/FOXO3a pathway was detected by Western blot. The results of network pharmacology analysis showed that SIRT1/FOXO3a was identified as a critical pathway to regulate PMOP, with icariin exhibiting high binding affinity to ERα. The results of in vivo experiments showed that compared to the sham operation group, the model group exhibited disrupted estrous cycles along with significantly decreased serum E_2 and procollagen type Ⅰ N-terminal propeptide(P1NP) levels, while follicle-stimulating hormone(FSH), luteinizing hormone(LH), and C-terminal telopeptide of type Ⅰ collagen(CTX-1) levels were markedly elevated, indicating successful establishment of the PMOP model. Following icariin intervention, the treatment group showed significantly increased serum P1NP levels and decreased CTX-1 levels compared to the model group. Meanwhile, icariin improved femoral microstructure, increased the areas of collagen deposition and mineralized bone matrix, and upregulated osteogenic-specific proteins, such as osteopontin(OPN) and osteoprotegerin(OPG). Icariin promoted the formation of autophagolysosome-like structures in osteoblasts. It inhibited the expression of autophagy-related protein P62 while upregulating mitophagy-related proteins PINK1, Parkin, microtubule-associated protein 1A/1B light chain 3A(LC3Ⅱ/LC3Ⅰ) and Beclin1, as well as the key pathway proteins SIRT1 and FOXO3a. The results of in vitro experiments demonstrated that icariin upregulated the expression of OPN and OPG, while promoting osteogenic differentiation and extracellular matrix mineralization. It downregulated P62 protein expression while enhancing the expression of PINK1, Parkin, LC3Ⅱ/LC3Ⅰ and Beclin1. Additionally, icariin increased the co-localization fluorescence intensity of LC3 with MitoTracker. Upon the addition of the ERα antagonist, the expression levels of SIRT1, FOXO3a, PINK1, and Parkin were significantly reduced, accompanied by weakened co-localization fluorescence intensity. When the SIRT1 inhibitor was introduced, the expression of acetylated FOXO3a increased, while the expression of PINK1, Parkin, and FOXO3a markedly decreased, along with diminished co-localization fluorescence intensity. In summary, icariin ameliorates PMOP by enhancing PINK1/Parkin-dependent mitophagy via the ERα-SIRT1/FOXO3a pathway, thereby regulating bone metabolism and promoting bone remodeling.
    Keywords:  SIRT1/FOXO3a pathway; estrogen receptor; icariin; mitophagy; osteoblast differentiation; postmenopausal osteoporosis
    DOI:  https://doi.org/10.19540/j.cnki.cjcmm.20251113.707
  44. Free Radic Biol Med. 2026 Mar 11. pii: S0891-5849(26)00225-X. [Epub ahead of print]
    Nuclear factor erythroid 2-related factor 2 induction abrogates mitochondrial stress through parkin regulation.
    Narukkottil Safreena, Jimna Mohamed Ameer, Indu C Nair, Sibi P Ittiyavirah, Jason Cannon, Goutam Chandra.
      Mitochondrial stress (MS) is a hallmark of a number of aging-associated neurodegenerative diseases, including Parkinson's disease (PD). Chronic MS in PD disrupts neuronal proteostasis, causing dopaminergic neurodegeneration through inactivation of an E3 ubiquitin ligase, parkin, although the mechanism of its inactivation is not understood. Here, we elucidate a mechanistic framework linking progressive changes in mitochondrial mass with MS-induced alterations in parkin activity. We showed that acute and chronic MS differentially modulate parkin activity and regulate mitochondrial biogenesis by transcriptional control of peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α), through parkin substrate PARIS (parkin-interacting substrate). Acute exposure to the PD neurotoxin, 1-methyl-4-phenylpyridinium (MPP+), activates the parkin-PARIS-PGC1α pathway, transiently facilitating mitochondrial biogenesis. However, sustained and repetitive MS leads to parkin mis localization, inactivation, and aggregation, resulting in PARIS accumulation, repression of PGC1α activity, and loss of mitochondrial mass. Nuclear Factor Erythroid 2-related Factor 2 (NFE2L2 or NRF2) activation by methylene blue (MB) transcriptionally upregulates parkin expression by enhancing its binding to NRF2/ antioxidant responsive element (ARE) within the PARK2 promoter. MB treatment in cells exposed to chronic MPP+ reduces PARIS levels, restores PGC1α activity, and rejuvenates mitochondria. These findings underscore the impact of chronic mitochondrial damage on parkin dysfunction in PD and suggest a promising role for MB in protecting against mitochondrial and proteostatic failure in PD by targeting the NRF2-parkin axis.
    Keywords:  E3 ubiquitin ligase; dopaminergic neurodegeneration; mitochondria; parkin; proteostasis
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.03.034
  45. Biomaterials. 2026 Mar 05. pii: S0142-9612(26)00139-0. [Epub ahead of print]331 124115
    A coenzyme-based "interface-welding" hydrogel coating for titanium implants promotes diabetic osseointegration by regulating mitochondrial dynamics.
    Qiaojian Duan, Wenbo Geng, Tingting He, Junli Yang, Kai Li, Feiya Yang, Zhanglei Fu, Xuemei Liao, Han Luo, Peng Zhao, Kaiyong Cai.
      The impaired bone healing and osseointegration in diabetes are largely driven by hyperglycemia-induced mitochondrial dysfunction in bone marrow mesenchymal stem cells (BMSCs). To rescue this cellular deficit and enhance bone repair, this study aimed to develop an adhesive, self-healing, mitochondrial coenzyme-based hydrogel coating for titanium (T) implants. We synthesized p(LA-AcAln) hydrogel through the copolymerization of α-lipoic acid (LA) and acrylated alendronate sodium (AcAln). This coating achieved robust "interface-welding" adhesion by forming a stable covalent "surface-S-S-gel" interface through dynamic thiol-disulfide exchange between the disulfide bonds (-S-S-) in p(LA) and the thiolated titanium surface. In vitro experiments demonstrated that the released LA monomers from the coating activate the Keap1/Nrf2 signaling pathway, suppress oxidative stress, restore the mitochondrial membrane potential of BMSCs, and significantly inhibit cell apoptosis in a hyperglycemic environment. Moreover, Ti/p(LA-AcAln) regulated mitochondrial dynamics by promoting fusion and inhibiting fission, thereby restoring ATP production and compensating for the energy deficit in bone formation. In vivo evaluations using a diabetic rat femoral defect model revealed that this coating can significantly improve bone osseointegration. This study not only developed a promising surface modification strategy for orthopedic implants but also provided a viable approach for the treatment of diabetic bone defects and mitochondrial-related orthopedic diseases.
    Keywords:  Diabetic osseointegration; Hydrogel coating; Mitochondrial dynamics; Titanium implants; ɑ-lipoic acid
    DOI:  https://doi.org/10.1016/j.biomaterials.2026.124115
  46. Mol Med. 2026 Mar 10.
    Pathogenic roles of the IMNEPD-associated PTRH2 mutants in aggravating mitochondrial dynamics and its rescue.
    DoHyeong Na, Seungmin Yoo, Muhah Jeong, Nahyun Lee, Youngwon Kim, Youbin Kim, Dong-Hyung Cho, Yong-Keun Jung.
      
    Keywords:  FKBP8; IMNEPD; Mitochondrial dynamics; Mitofusins; PTRH2
    DOI:  https://doi.org/10.1186/s10020-026-01452-1
  47. Phytomedicine. 2026 Mar 03. pii: S0944-7113(26)00271-0. [Epub ahead of print]154 158035
    Curcumin augments mitophagy via Nrf2-PINK1-mediated, Parkin-dependent ubiquitination to suppress ferroptosis in post-cardiac arrest brain injury.
    Zheng Li, Wanling Xu, Shurui Ren, Qiang Zheng, Jihong Xing.
       BACKGROUND: Cardiac arrest (CA) remains a major public health challenge with high incidence and mortality. Post-cardiac arrest brain injury (PCABI) is the primary determinant of poor neurological outcomes and survival. Although curcumin (Cur) exhibits neuroprotective effects in multiple cerebral injury models, its precise pharmacological mechanisms in PCABI remain incompletely understood.
    PURPOSE: This study aimed to systematically evaluate the therapeutic efficacy of Cur on PCABI and to elucidate its molecular mechanisms, focusing on mitophagy and ferroptosis regulation.
    METHODS: Neuroprotective effects of Cur were investigated using in vitro oxygen-glucose deprivation/reperfusion and in vivo CA/cardiopulmonary resuscitation (CA/CPR) models. Neurological function was assessed using the Neurological Deficit Score, and neuronal damage was evaluated by Nissl and hematoxylin-eosin staining. Ferroptosis markers (Fe²⁺ levels, glutathione, 4-hydroxynonenal, malondialdehyde, and lipid peroxidation) were measured. Mitophagy flux was assessed by fluorescence-based co-localization with mitophagy or lysosomal markers. Expression of ferroptosis- and mitophagy-related proteins was assessed by immunoblotting and immunofluorescence. Proteomics-based bioinformatics, molecular docking, and molecular dynamics simulations were used to validate molecular targets.
    RESULTS: Cur significantly improved neurological outcomes and reduced histopathological brain damage in CA/CPR rats. Mechanistically, Cur reduced iron overload, disrupted amino acid metabolism, and excessive lipid peroxidation, while enhancing mitophagy via upregulation of Nrf2 and modulation of PINK1-Parkin pathway protein ubiquitination. Cur was predicted to bind to Keap1, promoting dissociation of the Keap1-Nrf2 complex, Nrf2 nuclear translocation, and downstream gene expression activation.
    CONCLUSION: Cur protects against PCABI by activating the Nrf2-PINK1 axis, enhancing mitophagy and suppressing ferroptosis, highlighting its therapeutic potential after CA.
    Keywords:  Curcumin; Nuclear factor erythroid factor 2; PTEN-induced putative kinase 1; Post-cardiac arrest brain injury; ferroptosis; mitophagy
    DOI:  https://doi.org/10.1016/j.phymed.2026.158035
  48. Sci Rep. 2026 Mar 08.
    Integrated multi-omics analysis identifies and validates endoplasmic reticulum stress and mitophagy-related biomarkers in MASLD.
    Quanrun Chen, Limin Liu, Jinqiu Feng, Chong Zhang, Zongming Zhang.
      Metabolic dysfunction-associated steatotic liver disease (MASLD) is one of the most prevalent chronic liver diseases worldwide. Growing evidence indicates that endoplasmic reticulum stress (ERS) and mitophagy play critical roles in MASLD progression. However, the specific mechanism by which ERS and mitophagy participate in MASLD is not clear, and there is still a lack of treatment strategies for these pathways. Therefore, this study aims to integrate GEO data mining, machine learning, and scRNA-seq analysis to elucidate potential mechanisms by which ERS and mitophagy mediate MASLD progression, and to identify candidate therapeutic agents targeting these pathways through high-throughput virtual screening. Nuclear receptor subfamily 4 group A member 1 (NR4A1) was identified as a key target involved in the progression of MASLD mediated by ERS and mitophagy. Functional enrichment and immune infiltration analyses suggested that NR4A1 participates in immunoregulatory and adaptive responses under metabolic stress. scRNA-seq analysis confirmed that the expression of NR4A1 decreases gradually during the progression of MASLD, particularly throughout macrophage activation and differentiation. Experimental validation further demonstrated that NR4A1 was downregulated in FFA-treated hepatocytes, MASLD mice, and human liver tissues. A ceRNA network centered on NR4A1 was constructed, and potential therapeutic compounds were identified via molecular docking. Taken together, this study highlights NR4A1 as a key target in ERS- and mitophagy-mediated MASLD progression and provides novel insights into therapeutic strategies for alleviating MASLD by targeting ERS and mitophagy pathways.
    Keywords:  Biomarker; Endoplasmic reticulum stress; MASLD; Machine learning; Mitophagy; NR4A1
    DOI:  https://doi.org/10.1038/s41598-026-43311-3
  49. J Ethnopharmacol. 2026 Mar 06. pii: S0378-8741(26)00319-3. [Epub ahead of print]364 121468
    Inonotus obliquus (Ach. ex Pers.) Pilát aqueous extract alleviates acute cold exposure/rewarming-induced myocardial injury by regulating mitochondrial dynamics via liver kinase B1/adenosine monophosphate-activated protein kinase/peroxisome proliferator-activated receptor gamma coactivator-1 alpha signaling pathway activation.
    Miao Yu, Wenwen Fu, Shuting Feng, Wenli Ma, Shunfang Zuo, Zihao Zhang, Han Sun, Yue Chen, Yi Wu, Yan Xue.
       ETHNOPHARMACOLOGICAL RELEVANCE: Acute cold exposure affects the cardiovascular system substantially. Inonotus obliquus (Ach. ex Pers.) Pilát (IO), commonly referred to as "Chaga" in Russian traditional medicine, is a fungus that primarily parasitizes birch trees in cold climate regions. IO is extensively employed in Russian folk medicine for the treatment of cardiovascular diseases, including hypertension, hyperlipidemia, atherosclerosis, and symptoms of coronary heart disease. It is purported to holistically modulate cardiovascular function. However, despite the widespread use of I. obliquus aqueous extract (IOE), its cardioprotective effects against acute cold exposure/rewarming (ACE/R)-induced myocardial injury are yet to be elucidated.
    AIM OF THE STUDY: To assess the cardioprotective efficacy of IOE against ACE/R-induced myocardial injury in rats and to elucidate its underlying mechanism of action.
    MATERIALS AND METHODS: An ACE/R injury model was established by exposing rats to a temperature of -15 °C for 6 h, and then rewarming them to a temperature of 24 °C for 12 h. The rats were administered IOE (300 and 600 mg/kg) or 0.5% CMC-Na (vehicle control) via the intragastric route for 7 consecutive days prior to acute cold exposure. The ACE/R model was established 1 h after the final administration. Cardiac function, hemorheological parameters, myocardial histopathology, and serum levels of myocardial injury markers were assessed to evaluate the cardioprotective efficacy of IOE against ACE/R. Subsequently, in vivo transcriptomic analyses were performed to elucidate the underlying mechanism of IOE. To assess the expression levels of proteins and genes related to mitochondrial dynamics, mitochondrial function, energy metabolism, and the LKB1/AMPK/PGC-1α signaling pathway, western blotting and qRT-PCR were performed.
    RESULTS: IOE significantly attenuated ACE/R-induced hemorheological abnormalities, cardiac dysfunction, and myocardial injury. Transcriptomic sequencing analyses revealed the cardioprotective effects of IOE to be potentially mediated via regulation of mitochondrial dynamics and function. Western blotting and qRT-PCR analyses further confirmed that IOE significantly upregulated the expression of proteins and genes associated with cellular energy metabolism, mitochondrial dynamics, and the LKB1/AMPK/PGC-1α signaling pathway in myocardial tissues.
    CONCLUSION: These findings demonstrate that IOE alleviates ACE/R-induced myocardial injury in rats by activating the LKB1/AMPK/PGC-1α signaling pathway, thereby modulating mitochondrial dynamics in cardiomyocytes. However, the present study exclusively assessed the prophylactic effects of IOE via pretreatment prior to ACE/R exposure, while the therapeutic potential of post-injury IOE administration remains to be determined. Furthermore, given the inherent variability of the constituents of natural products, further studies need to be carried out using multiple batches of extracts to validate these findings.
    Keywords:  Acute cold exposure/rewarming; Inonotus obliquus (Ach. ex Pers.) Pilát; LKB1/AMPK/PGC-1α pathway; Mitochondrial dynamics; Myocardial injury
    DOI:  https://doi.org/10.1016/j.jep.2026.121468
  50. Adv Sci (Weinh). 2026 Mar 12. e22572
    ALKBH3 m1A Demethylase Deficiency Reduces Alzheimer's Amyloid-β Pathology.
    Yueyang Li, Sifei Yu, Kaidong Lu, Yujie Zhang, Mingjie Dong, Yan Peng, Liang Xue, Waleed Alam, Yuxuan Shui, Yi Zhou, Wuyunhan Ma, Meng Bao, Peiming Li, Peiyi Luo, Tiezhan Lu, Jiajia Li, Kang Zhang, Yuying Wang, Shuchen Yang, Nuoya Yin, Francesco Faiola, Zilong Gao, Jingfeng Zhou, Fei Zhao, Yali He, Magdalena J Koziol.
      Amyloid-beta (Aβ) aggregation, mitochondrial dysfunction, and cognitive decline are hallmarks of Alzheimer's disease (AD), but its initiating molecular events remain unknown. Given that RNA modifications regulate neurodevelopment and neurodegeneration, we explore their functional role in 5xFAD mice, an Aβ AD model. We discover that N1-methyladenosine (m1A) is the most altered RNA modification, and that its regulator demethylase, ALKBH3 is upregulated. Strikingly, Alkbh3 reduction decreases Aβ plaques and restores cognition. Conversely, elevated ALKBH3 levels, observed in AD patients, compromise neuronal morphology and mitochondrial function by impairing mitophagy (degradation of dysfunctional mitochondria), a known driver of neuronal dysfunction. Mechanistically, we reveal that ALKBH3 removes m1A from PINK1 mRNA, the mitophagy master regulator. Given that ALKBH3 is elevated in human AD, causally linked to mitophagy impairment, and confers neuroprotection when depleted, we present ALKBH3 as a mechanistically validated therapeutic target in AD.
    Keywords:  ALKBH3; Alzheimer's disease (AD); Amyloid‐β, m1A; mitochondrial; mitophagy
    DOI:  https://doi.org/10.1002/advs.202522572
  51. Front Immunol. 2026 ;17 1696120
    Mitochondrial-targeted therapy for osteoarthritis: Challenges and opportunities from basic research to clinical translation.
    Song-Ou Zhang, Zhi-Qian Gu, Jian Ruan, Jian Zhang, Hong Chen.
      Osteoarthritis is a high-burden degenerative joint disease. Existing therapies only alleviate symptoms but fail to halt disease progression. Studies have identified mitochondrial dysfunction as a core driver of cartilage degeneration in OA. Key mechanisms include mitochondrial reactive oxygen species bursts that activate inflammatory and cell death pathways; imbalances in mitochondrial dynamics leading to fragmentation; autophagy defects causing damage accumulation; and reduced biogenesis coupled with hyperglycolysis, which exacerbates the energy crisis. Collectively, these processes accelerate cartilage destruction. This review focuses on mitochondrial-targeted therapeutic strategies, including antioxidants, dynamics regulators to restore fission-fusion balance, autophagy activators to clear damaged mitochondria, biogenesis enhancers to improve metabolism, and the emerging approach of mitochondrial transplantation to directly replenish functional units. While preclinical studies have demonstrated that these strategies can significantly slow cartilage degeneration, their clinical translation data in OA remain limited. Substantial, translational efforts face three major challenges: drug delivery barriers, disease heterogeneity, and limitations of animal models. Future work will require the development of intelligent delivery systems, patient stratification, and humanized models to promote clinical translation.
    Keywords:  clinical translation; drug delivery; mitochondrial dysfunction; mitophagy; osteoarthritis; oxidative stress; targeted therapy
    DOI:  https://doi.org/10.3389/fimmu.2026.1696120
  52. J Transl Med. 2026 Mar 07. pii: 331. [Epub ahead of print]24(1):
    Mitochondria transplantation reduces intraocular pressure by improving mitochondrial function and remodeling trabecular meshwork.
    Xiaoling Wang, Beibei Lin, Xuegu Xu, Zhishu Bao, Ruiyi Ren, Peizhen Lin, Guangying Luo, Yongzhen Yu, Yuanbo Liang.
      
    Keywords:  Glaucoma; Mitochondria transplantation; Mitophagy; OHT; POAG; Trabecular meshwork
    DOI:  https://doi.org/10.1186/s12967-026-07964-y
  53. J Ethnopharmacol. 2026 Mar 10. pii: S0378-8741(26)00355-7. [Epub ahead of print]364 121504
    Gentiopicroside activates PINK1-dependent mitophagy to inhibit ferroptosis and promote flap survival.
    Hebin Pan, Kaitao Wang, An Wang, Jiapeng Deng, Jialong Yang, Pan Tan, Weilong Song, Panshen Xu, Guodong Chen, Zhigang Bian, Kai Chen, Sihan Chen, Dingsheng Lin.
       ETHNOPHARMACOLOGICAL RELEVANCE: Distal necrosis remains a major challenge in reconstructive flap surgery due to ischemia-reperfusion injury. Gentiana manshurica Kitagawa (Longdan), traditionally used to clear heat and dampness, relieve swelling and pain, and treat ischemic-inflammatory disorders, has a long history in Chinese medicine. Gentiopicroside, its bioactive component, exhibits anti-inflammatory and antioxidant activities, yet its effect on flap survival has not been fully elucidated.
    AIM OF THE STUDY: This work explored whether gentiopicroside improves flap viability and elucidated the biological processes underlying its action.
    MATERIALS AND METHODS: A rat McFarlane flap model was used to evaluate flap survival, microcirculatory perfusion, histology, and protein expression. In vitro, HUVECs subjected to oxygen-glucose deprivation/reoxygenation were treated with gentiopicroside, with or without PINK1 silencing. Cellular proliferation and migration, mitochondrial integrity, oxidative stress, and key pathways related to mitophagy, ferroptosis, apoptosis, and inflammation were systematically evaluated. Bioinformatics and molecular docking analyses were performed to identify potential GPS-PINK1 interaction.
    RESULTS: Gentiopicroside significantly enhanced flap survival, perfusion, angiogenesis, and endothelial cell proliferation and migration. Molecular docking confirmed strong GPS-PINK1 binding and bioinformatics linked GPS to autophagy and inflammation pathways via 28 targets. It activated PINK1-dependent mitophagy both in vivo and in vitro, alleviated oxidative stress, and suppressed ferroptosis, apoptosis, and inflammation. These protective effects were markedly attenuated by PINK1 silencing.
    CONCLUSION: Gentiopicroside enhances flap survival by activating PINK1-mediated mitophagy, thereby alleviating ischemic and inflammatory tissue injury and reducing distal flap necrosis.
    Keywords:  Ferroptosis; Flap; Gentiopicroside; Mitophagy; PINK1
    DOI:  https://doi.org/10.1016/j.jep.2026.121504
  54. J Adv Res. 2026 Mar 05. pii: S2090-1232(26)00188-8. [Epub ahead of print]
    A novel zebrafish model unveils folate deficiency disrupts embryonic development via p53-driven cell cycle arrest.
    Kai Zhu, Hongyan Liu, Kun Zhou, Tao Cheng, Liyuan Mo, Peng-Fei Xu, Yan Li.
       INTRODUCTION: Folate (vitamin B9) is a fundamental cofactor in one-carbon metabolism, essential for embryonic development. While maternal folate deficiency is a well-established risk factor for neural tube and congenital heart defects, its specific impact on early embryogenesis, particularly during early post-blastula stages, and the underlying molecular mechanisms remain insufficiently characterized.
    OBJECTIVES: This study aimed to establish a vertebrate model to facilitate real-time visualization and mechanistic dissection of how folate deficiency drives diverse developmental defects.
    METHODS AND RESULTS: We used CRISPR/Cas9 to generate a folrΔ1 zebrafish line harboring a one-nucleotide deletion in the folate receptor gene (folr), resulting in maternal folate deficiency. Embryos derived from folrΔ1 homozygote females exhibited embryonic lethality and defective dorsoventral patterning. Untargeted metabolomics analysis revealed that folate deficiency disrupts nucleotide biosynthesis and mitochondrial homeostasis. Specifically, maternal folate deficiency impaired embryonic DNA synthesis, exacerbated DNA damage, and induced G1/S phase cell cycle arrest. It also compromised mitochondrial integrity, triggering compensatory mitophagy. Notably, suppression of p53 activation in folr mutants improved dorsoventral patterning and alleviated cell cycle arrest. However, it did not mitigate the extent of DNA damage or mitophagy, suggesting p53 acts downstream of these metabolic stresses.
    CONCLUSION: We have established a robust zebrafish model of maternal folate deficiency that recapitulates key metabolic and developmental features of the human condition. Our findings demonstrated that folate deficiency disrupts metabolism, leading to DNA damage and mitochondrial dysfunction. Crucially, this pathology activates p53, which drives G1/S cell cycle arrest and severe embryonic defects, including impaired body axis formation. This model provides a powerful platform for further delineating the precise roles of folate in vertebrate development and in the pathogenesis of congenital anomalies.
    Keywords:  Cell cycle arrest; Dorsoventral patterning; Folate; Mitophagy; P53
    DOI:  https://doi.org/10.1016/j.jare.2026.02.054
  55. Exp Gerontol. 2026 Mar 10. pii: S0531-5565(26)00069-0. [Epub ahead of print]217 113091
    Atmospherically relevant PM2.5 promotes age-related muscle atrophy in an age-dependent manner.
    Zilin Wang, Wenduo Liu, Sang Hyun Kim.
       BACKGROUND: Maintaining the quality and function of skeletal muscle in the older adult has become a key topic in successful aging. However, the impact of environmental factors on skeletal muscle aging is often overlooked.
    METHODS: This study used male mice aged 1, 6, and 15 months, which were each exposed to PM2.5 (50 μg/m3, 2 h/day) for 5 days, and the skeletal muscles of each age group were analyzed one month after the end of the treatment to verify the age-specific effects of PM2.5 on the skeletal muscle system.
    RESULTS: Total body weight and lean body weight were significantly affected by age and PM2.5 exposure. However, fat levels were not affected by PM2.5 exposure. PM2.5 exposure promoted the development of age-related muscle atrophy by inducing oxidative stress and increased expression of Myostatin in skeletal muscle of older adults. On the other hand, the damaging effect of PM2.5 exposure on skeletal muscle mitochondria was age-related. Young and older adult mice showed extensive mitochondrial damage after PM2.5 exposure. In particular, older adults showed a marked increase in mitochondrial fission and mitophagy after PM2.5 exposure.
    CONCLUSIONS: The effects of PM2.5 exposure on the skeletal muscle system are age-specific, with distinct damaging effects during growth and aging, whereas skeletal muscles in middle-aged mice are resistant to PM2.5-induced damage.
    Keywords:  Age groups; Air pollution; Atrophy; Mitochondrial damage; Mitophagy
    DOI:  https://doi.org/10.1016/j.exger.2026.113091
  56. J Hazard Mater. 2026 Mar 06. pii: S0304-3894(26)00671-0. [Epub ahead of print]507 141693
    T-2 toxin induces ER stress-dependent liver injury via mitophagy-mediated ER-phagy suppression: Berbamine blocks SNARE complex for hepatoprotection.
    Qiang Xu, Luyu Deng, Jintao Xu, Zhikai Wu, Ruqin Lin, Yiqun Deng, Jikai Wen.
      T-2 toxin is a persistent, bioaccumulative environmental contaminant that poses major health threats to humans and animals. Endoplasmic reticulum (ER) stress and autophagy are two interconnected stress responses critical for maintaining cellular homeostasis. Berbamine (BBM) is an important member of bis-benzy lisoquinoline alkaloid with diverse biological activities. This study aimed to identify the molecular target of BBM against T-2 toxin-induced hepatotoxicity, focusing on autophagy-ER stress crosstalk. We systematically evaluated autophagy and ER stress in human HepaRG cells using immunoblotting, transmission electron microscopy and an autophagy reporter assay. T-2 toxin was found to concurrently activate PINK1/Parkin-mediated mitophagy and suppress Keap1-mediated FAM134B ubiquitination-dependent ER-phagy, thereby triggering ER stress. Integrated evidence from molecular dynamics and western blot demonstrated that BBM upregulated and stabilized BNIP3, blocking the VAMP8-SNAP29 interaction to inhibit T-2 toxin-induced autophagy and subsequent ER stress. Moreover, in vivo mouse experiments demonstrated that 30 mg/kg BBM significantly alleviated T-2 toxin-induced liver injury by suppressing both autophagic flux and ER stress; BBM significantly reduced serum levels of liver enzymes, ALT, and AST. Collectively, our findings elucidate a novel mechanism wherein T-2 toxin-induced mitophagy inhibits ER-phagy to drive ER stress-mediated liver injury and highlight the therapeutic potential of BBM in alleviating T-2 toxin-induced liver injury.
    Keywords:  BNIP3; Berbamine; ER stress; ER-phagy; T-2 toxin, Mitophagy
    DOI:  https://doi.org/10.1016/j.jhazmat.2026.141693
  57. BMC Pharmacol Toxicol. 2026 Mar 11.
    Targeting a novel tamoxifen-using pathway to preserve ovarian reserve in rats with experimental chemotherapy-induced ovarian failure.
    Amira S Ahmed, Mahmoud S Sabra, Asmaa Youssef A Abbas, Asmaa A Kamal, Zainab S Abdelqader.
      
    Keywords:  Anti-inflammatory cytokines; Cyclophosphamide; Mitochondrial fission; Oxidative stress; Premature ovarian insufficiency
    DOI:  https://doi.org/10.1186/s40360-026-01103-5
  58. Cardiovasc Diabetol. 2026 Mar 07.
    Dusp15 modulates mtHsp70 Thr116 phosphorylation state to preserve mito-UPR and attenuate cardiac dysfunction in diabetic cardiomyopathy.
    Yan Liu, Hongshuo Shi, Chun Li, Haowen Zhuang, Yinglong Li, Xiuling He, Ying Jiang, Zhiyu Jin, Zhijiang Guo, Sangbing Ong, Yuanyuan Wang, Xing Chang, Guipeng An, Junyan Wang.
       BACKGROUND: Diabetic cardiomyopathy (DCM) involves cardiac dysfunction/remodeling with mitochondrial stress and impaired mitochondrial proteostasis. The role of dual-specificity phosphatases (DUSPs) in these processes remains unclear. We examined whether Dusp15 modulates diabetic cardiac injury and whether mtHsp70/mito-UPR-linked proteostasis is involved.
    METHODS: DCM was induced in mice by high-fat diet (HFD) combined with low-dose streptozotocin (STZ). We studied cardiomyocyte-specific Dusp15 knockout (Dusp15Cko) mice, a Dusp15 gain-of-function line, and high-glucose-treated HL-1 cardiomyocytes. Cardiac function/remodeling were assessed by echocardiography and molecular/histological analyses. Dusp15-mtHsp70 signaling was interrogated by protein interaction assays and mtHsp70 Thr116 genetic models.
    RESULTS: Dusp15 was reduced in diabetic hearts and associated with impaired contractility. Dusp15 gain-of-function improved cardiac function and reduced remodeling/inflammation, whereas Dusp15Cko worsened diabetic injury, indicating a cardiomyocyte-necessary role for Dusp15. Dusp15 associated with mtHsp70 and supported mtHsp70-linked mitochondrial proteostasis/mito-UPR in cardiomyocytes. Genetically, mtHsp70T116A knock-in mice were substantially protected from diabetic cardiac dysfunction/remodeling. Finally, dapagliflozin (DAPA) improved diabetic cardiac outcomes, and its benefit was reduced in Dusp15Cko mice, suggesting Dusp15 as an important mediator.
    CONCLUSION: Dusp15 is a stress-responsive regulator that protects against diabetic cardiac dysfunction and remodeling through mtHsp70-associated mito-UPR signaling. Targeting the Dusp15-mtHsp70 axis may represent a therapeutic strategy for diabetic cardiomyopathy.
    Keywords:  Diabetic cardiomyopathy; Dusp15; Mitochondrial unfolded protein response; mtHsp70
    DOI:  https://doi.org/10.1186/s12933-026-03125-z
  59. Front Pharmacol. 2025 ;16 1725842
    Pharmacological potential of Chinese botanical drugs in managing chronic kidney disease by targeting mitochondrial quality control.
    Hongyu Liu, Shumin Huang, Shichun Chen, Shuzhen Liang, Minying Huang, Shiyu Li, Yongxiang Xu, Baocheng Xie.
      Chronic kidney disease (CKD) is a multifactorial health issue characterized by structural and functional impairments of the kidneys, with significant incidence and mortality rates in global populations. Mitochondrial quality control (MQC) comprises cellular mechanisms that maintain mitochondrial health, and imbalances in the MQC system, including abnormalities in mitochondrial oxidative stress, dynamics, biogenesis, autophagy, and apoptosis, have been implicated in the onset and progression of CKD. In addition, the interplay between gut microbiota, microbial metabolites, and mitochondrial integrity has gained increasing attention in CKD research. Consequently, therapeutic strategies targeting MQC have attracted considerable research interest. Chinese botanical drugs (CBD), known for their multi-component, multi-target profiles and favorable safety, demonstrate considerable potential in slowing CKD progression by modulating MQC. This review systematically summarizes current evidence on CBD metabolites and formulations that ameliorate CKD through MQC regulation. Firstly, we outline the mechanisms of action of MQC system, with a focus on its role in CKD. We then discussed the pivotal role of the gut microbiota-microbial metabolites-mitochondria axis in the progression of CKD. Finally, we provide a summary of CBD metabolites and formulations that target the MQC system for CKD treatment to date, and explore their specific therapeutic mechanisms. Despite promising preclinical findings, we also critically assess limitations within the available literature, such as methodological variability and a lack of clinical validation. By integrating current knowledge and identifying key research gaps, this review aims to inform future studies and advance the development of CBD-based therapies for CKD.
    Keywords:  Chinese botanical drugs; chronic kidney disease; gut-kidney axis; mitochondrial dysfunction; mitochondrial quality control
    DOI:  https://doi.org/10.3389/fphar.2025.1725842
  60. Comput Methods Programs Biomed. 2026 Mar 03. pii: S0169-2607(26)00075-1. [Epub ahead of print]279 109307
    Integrating machine learning of bulk and single cell RNA data to characterize immune mechanism of m6A related mitophagy genes in malignant gastric cancer.
    Liting Yan, Jingying Sun, Yangmeng Feng, Xiaoli Yang, Cuixiang Xu, Jianhua Wang.
       BACKGROUND AND OBJECTIVE: Gastric cancer is a heterogeneous and complicated epithelial cancers. Chronic H. pylori and EBV infection, as well as intestinal microbiota exposure make gastric cancer encountered a complex tumor immune microenvironment. Mitophagy and m6A are deeply involved in immune microenvironment in the development of tumors.
    METHODS: We used integrating machine learning of bulk and single cell RNA sequencing to explore the immune mechanisms of m6A related mitophagy genes (MRMGs) in gastric cancer. RT-qPCR and immunochemistry were used to verify gene expression.
    RESULTS: Prognostic model that involves a total of 20 DE-MRMGs exhibited a performance property in prognosis, immunotherapy prediction and tumor mutation burden in patients with gastric cancer. And significant difference between high-risk group and low-risk group focus on T cells which clarified in both bulk RNA and single cell RNA data. In terms of mechanism, vimentin may participates in T cell differentiation of malignant gastric cancer. Meanwhile, vimentin expression in patients display a significant increasing in low differentiated gastric cancer than high differentiated gastric cancer.
    CONCLUSIONS: Vimentin may be a diagnostic marker to draw the distinction between low and high differentiated gastric cancer in the mechanism of probably affecting T cell differentiation.
    Keywords:  DE-MRMGs; Gastric cancer; Integrating machine learning; Single cell RNA sequencing; Vimentin
    DOI:  https://doi.org/10.1016/j.cmpb.2026.109307
  61. Exp Eye Res. 2026 Mar 06. pii: S0014-4835(26)00097-7. [Epub ahead of print] 110941
    Corrigendum to "Stachydrine mitigates high glucose-induced apoptosis in human lens epithelial cells by activating mitophagy" [Exp. Eye Res. 260 (2025) 110568].
    Guijia Wu, Xiteng Chen, Wei Wang, Zhenyu Kou, Han Mao, Yijing Wang, Lijie Dong, Tingting Lin, Fang Tian.
      
    DOI:  https://doi.org/10.1016/j.exer.2026.110941
  62. Int J Mol Sci. 2026 Feb 27. pii: 2229. [Epub ahead of print]27(5):
    Targeting Autophagy for Otoprotection: Translating Basic Mechanisms into Clinical Strategies.
    Fei Wang, Tiantian Zhang, Bin Bai, Lian Hui, Yan Wang, Jian Zang.
      Sensorineural hearing loss (SNHL), the predominant form of global hearing impairment, stems from the irreversible loss of inner ear sensory cells and neurons. Since mammalian cochlea lacks regenerative capacity, cell death represents a final common pathway for diverse insults. Current therapies are merely compensatory, underscoring an urgent need for mechanistic, targeted interventions. Autophagy, a critical homeostatic process, plays complex and dynamic roles in the cochleae. This review synthesizes current evidence on its regulation, highlighting its stage-specific and dual roles in SNHL. We emphasize mitophagy and its context-dependent effects on cell survival. Critically, we discuss an emerging therapeutic paradigm: a dual-phase autophagy modulation strategy. This approach proposes enhancing cytoprotective autophagy in early stages to maintain homeostasis, while inhibiting excessive autophagic flux later to prevent catastrophic cell death. This precision-targeting framework holds significant promise for guiding novel drug development and future clinical translation, moving beyond symptomatic management towards transformative treatment.
    Keywords:  autophagy; mTOR signaling; mitophagy; pexophagy; sensorineural hearing loss; therapeutic targets
    DOI:  https://doi.org/10.3390/ijms27052229
  63. Cell Commun Signal. 2026 Mar 09.
    Topical NAMPT activation restores mitophagic flux to rescue diabetic keratopathy via the NAD⁺/PINK1 pathway.
    Qian Guo, Guannan Huang, Wanting Li, Yunjing Ma, Haini Liu, Zihao Liu, Limin Zhu, Lechong Ma, Qingjun Zhou, Shaozhen Zhao.
      
    Keywords:  Apoptosis; Diabetic keratopathy; Mitophagy; NAD; NAMPT; Neuroprotection; P7C3; ROS
    DOI:  https://doi.org/10.1186/s12964-026-02784-5
  64. Cancer Sci. 2026 Mar 07.
    Circ-0030167/IGF2BP1 Induces Mitophagy-Mediated Ferroptosis via HMOX1 mRNA Stabilization in Pancreatic Cancer.
    Qun Zhao, Xihao Yao, Jingjing Lu, Qiyang Chen, Zhiwei Wang, Xiaohong Li, Yuhua Lu.
      Pancreatic cancer (PC) represents a highly aggressive malignancy characterized by a 5 year survival rate of less than 12%. Recent investigations suggest that mitophagy may constitute a potential therapeutic target for PC. This study aims to elucidate the molecular mechanisms underlying circ-0030167's regulation of PC, extending our prior investigations. mRNA sequencing analysis demonstrated significant enrichment of mitophagy-related signaling pathways in PC cells overexpressing circ-0030167. Integrated analysis utilizing RNA-binding protein (RBP) databases identified IGF2BP1 as a binding partner, a finding corroborated by RNA pull-down assays, RNA immunoprecipitation (RIP) experiments, and fluorescence in situ hybridization (FISH) validation. Cell-derived xenograft (CDX) assays confirmed that circ-0030167 enhances IGF2BP1 protein stability. Subsequent bioinformatic analysis combined with mRNA-seq data revealed HMOX1 as a downstream target gene within the circ-0030167/IGF2BP1-mediated mitophagy pathway. Functional assays measuring ferroptosis-related parameters-cell viability, reactive oxygen species (ROS) levels, malondialdehyde (MDA) content, and Fe2+ concentration-established that the circ-0030167/IGF2BP1 axis modulates mitophagy-mediated ferroptosis through HMOX1. Furthermore, in vivo animal studies demonstrated that circ-0030167 overexpression markedly suppresses PC tumor growth. In conclusion, our findings identify the circ-0030167/IGF2BP1/HMOX1 axis as a critical regulatory factor targeting mitochondria-mediated ferroptosis, thereby presenting a novel therapeutic target for PC combination therapies.
    Keywords:  Circ‐0030167; HMOX1; IGF2BP1; ferroptosis; mitophagy
    DOI:  https://doi.org/10.1111/cas.70356
  65. Mol Ther. 2026 Mar 09. pii: S1525-0016(26)00113-9. [Epub ahead of print]
    CRISPR-Cas-based activation of PPARGC1A boosts endogenous mitochondria and enhances cardiac function after myocardial infarction.
    Mario Escobar, Saad A Malik, Mira A Srinivasa, Miguel A Mendez-Sosa, Jessica M Miller, Samantha L Lydon, Sandy N Luong, Pretty R Mathew, Riham R E Abouleisa, Suridh Chakravarty, Saliha Pathan, Tamer M A Mohamed, Ravi K Ghanta, Isaac B Hilton.
      Insufficient energy supply due to impaired mitochondria has emerged as a key pathological factor in the development of heart failure (HF) after myocardial infarction (MI). Unfortunately, no current therapeutic strategies directly augment myocardial energy production. While mitochondrial biogenesis is orchestrated by the activity of multiple genes, activation of PPARGC1A, a key regulator, can increase cellular mitochondria; however, supraphysiological levels of PPARGC1A result in adverse tissue remodeling and heart dysfunction. CRISPR activation (CRISPRa) technologies present a unique opportunity to address these shortcomings, as they enable tunable control over endogenous target gene expression. Here, we demonstrate that transcriptional activation of PPARGC1A using CRISPRa increases cellular mitochondria in human cell types. This effect is mediated through the activation of transcriptional programs driving mitochondrial biogenesis, mitochondrial function, and cellular bioenergetics. These activated transcriptional programs synergize to increase ATP production and reserve capacity in human cardiomyocytes. CRISPRa targeting of PPARGC1A in vivo increases cardiac mitochondria to recover heart ejection fraction in an acute MI model. Furthermore, CRISPRa acts on the adult human heart to increase PPARGC1A protein and cellular mitochondria, elevating mitochondrial function in both normal and HF-diagnosed hearts. These results provide the first proof of concept that endogenous gene activation via CRISPRa can improve heart function after MI.
    Keywords:  CRISPRa; MI; PGC-1α; bioenergetics; cardiomyopathies; gene therapies; mitochondrial biogenesis; myocardial infarction
    DOI:  https://doi.org/10.1016/j.ymthe.2026.02.027
  66. Medicine (Baltimore). 2026 Mar 13. 105(11): e47937
    Identification of mitochondrial dynamics-related biomarkers in psoriasis using bioinformatics and Mendelian randomization.
    Baolan Zhang, Jing Shi, Jianhang Jiang, Litao Zhang.
      Mitochondrial dynamics (MD) are crucial in various inflammatory disorders, yet the specific mechanisms involved in psoriasis remain inadequately understood. Thus, this study aims to discover potential biomarkers and explore the mechanisms related to MD in psoriasis by employing bioinformatics methods in conjunction with the Mendelian randomization (MR) approach. In this investigation, datasets associated with psoriasis, specifically (GSE14905, GSE13355, and ukb-a-100), alongside genes pertinent to MD (MDRGs), were employed. The initial step involved the identification of significant module genes associated with MD through weighted gene co-expression network analysis. Subsequently, the identified module genes were cross-referenced with differentially expressed genes discerned between psoriasis and control groups to extract differentially expressed MDRGs. Additionally, MR analysis was conducted to identify potential candidate genes. The definitive potential biomarkers were determined through protein-protein interaction (PPI) networks, machine learning methodologies, receiver operating characteristic analysis, and expression profiling. Finally, gene set enrichment analysis, alongside immune infiltration and immune response assessments, was executed to elucidate the underlying mechanisms by which the potential biomarkers function in the context of psoriasis. There were 3136 key module genes through weighted gene co-expression network analysis and 643 differentially expressed MDRGs by crossing key module genes and 4310 differentially expressed genes. Afterward, 56 candidate genes with causal relationship to psoriasis were selected by MR analysis. Then 19 hub genes from PPI network were used to further screen 6 feature genes by machine learning, and they had a better ability to distinguish psoriasis (area under the curve > 0.7). C1orf43, SNF8, STOML2, and MRPS16 were identified as potential biomarkers in psoriasis, and were co-enriched in pyrimidine metabolism, DNA_replication, and proteasome. Eventually, there were 11 differential immune cells (memory B cells, activated dendritic cells, etc) and 13 differential immune responses (antigen processing and presentation, antimicrobials, etc) between psoriasis and control samples in psoriasis (P < .05). C1orf43, SNF8, STOML2, and MRPS16 were identified as potential biomarkers linked to MD in psoriasis, which provide promising leads for further investigation. These biomarkers require experimental validation to confirm their role in the pathogenesis of psoriasis and their potential as therapeutic targets.
    Keywords:  Mendelian randomization; bioinformatics; mitochondrial dynamics; psoriasis
    DOI:  https://doi.org/10.1097/MD.0000000000047937
  67. Mol Biol Cell. 2026 Mar 11. mbcE25070334
    ATG9B Regulates Mitochondrial Integrity and Apoptotic Tumor Cell Death.
    Hong Cao, Lixia Guo, Jing Chen, Eugene Krueger, Gina Razidlo, Mark A McNiven.
      It is well established that many tumor types possess defective autophagic pathways. Several studies have reported that the transmembrane, autophagic lipid scramblase ATG9B is altered in multiple cancers, suggesting that this dysregulation could contribute to oncogenesis. Therefore, the goal of this study was to define the cellular distribution of ATG9B in two different tumor cell types and to provide insights into its cellular function. Surprisingly, we found that ATG9B shows a modest association with autophagic structures and exhibits a unique and prominent localization to mitochondria, in contrast to its related form ATG9A. Upon expression of tagged ATG9B forms, this mitochondrial distribution was accompanied by aberrant changes in mitochondrial morphology as well as a reduction in the mitochondrial membrane potential and the release of mtDNA. Few indicators for ATG9B-dependent mitophagy were noted. Instead, ATG9B overexpression led to pronounced apoptotic cell death as assessed by a variety of indicators. Further, we find that the N-terminal sequence of ATG9B acts as a mitochondrial targeting domain and that expression of this peptide alone can induce apoptotic cell death. These findings provide new insights into a putative cellular localization and function for ATG9B. [Media: see text] [Media: see text] [Media: see text].
    DOI:  https://doi.org/10.1091/mbc.E25-07-0334
  68. Ann Med. 2026 Dec;58(1): 2641277
    Mechanisms and therapeutic potential of mitochondrial-targeted therapies in bone repair.
    Nanjian Xu, Weihu Ma, Guanyi Liu, Fang Yang.
      Bone defect repair remains a significant challenge in orthopedics, particularly for critical-sized bone defects, which often result in nonunion. Traditional treatments have numerous limitations. Recent studies have highlighted the pivotal role of mitochondria as cellular energy and metabolic hubs influencing the function of osteoblasts, osteoclasts, and chondrocytes. Mitochondria regulate energy metabolism, ROS signaling, mitochondrial dynamics, and apoptosis, all of which are essential for maintaining proper bone function. Mitochondrial dysfunction has been identified as a key intrinsic factor contributing to the failure of bone repair. Thus, targeting mitochondria has emerged as a promising therapeutic strategy. This article systematically reviewed the various functional roles of mitochondria in bone repair and evaluated the current progress of mitochondrial-targeted therapeutic strategies. We focused on the mechanisms of action and preclinical advancements related to small molecule compounds, functionalized biomaterials, and advanced cell therapies, offering a theoretical foundation for their potential clinical application. Mitochondrial-targeted therapies show significant promise for enhancing bone repair by improving cellular energy metabolism, restoring redox homeostasis, optimizing mitochondrial quality control, and promoting cell survival. However, this field faces several challenges, including improving targeted delivery efficiency, ensuring long-term safety, and translating these strategies into clinical practice. Future research should prioritize the development of more precise delivery technologies, exploration of multi-target synergistic approaches, and rigorous clinical trials to support the practical application of mitochondrial-targeted therapies for clinical bone regeneration.
    Keywords:  Mitochondria; bone repair; energy metabolism; mitochondrial dynamics; reactive oxygen species; targeted therapy
    DOI:  https://doi.org/10.1080/07853890.2026.2641277
  69. Cell Mol Life Sci. 2026 Mar 07.
    Smarca4 maintains mitochondrial homeostasis and energy metabolism during cardiac development.
    Deung-Dae Park, Sujin Kim, Alena Boos, Yannik Andrasch, Leonie Krieg, Wolfgang Rottbauer, Steffen Just.
      Mitochondrial metabolism is fundamental to cardiac and skeletal muscle function due to the high adenosine triphosphate (ATP) demand required for sustained contractility. Although mitochondrial dysfunction is central to metabolic myopathies, the epigenetic mechanisms regulating mitochondrial structure and function remain poorly defined. Here, we identify the SWI/SNF chromatin remodeling ATPase subunit Smarca4 as a critical regulator of mitochondrial homeostasis and cellular energy metabolism. Using a smarca4a-deficient zebrafish model (smarca4aa8-/-), we show that Smarca4 loss causes ventricular hypoplasia, pericardial edema, and disorganized skeletal muscle, leading to pronounced impairment of cardiac and muscular function. Heart-specific RNA-seq, ATAC-seq, and single-cell RNA-seq analyses revealed that Smarca4 deficiency reduces chromatin accessibility and suppresses the transcription of genes controlling mitochondrial biogenesis and oxidative phosphorylation. Consistently, high-resolution confocal imaging and Seahorse-based metabolic profiling demonstrated marked reductions in mitochondrial content, respiratory capacity, and ATP generation. AAV-mediated SMARCA4 knockdown in human cardiomyocytes and murine myotubes reproduced these mitochondrial defects. Collectively, these findings establish Smarca4 as a conserved chromatin remodeling factor linking nuclear regulation to mitochondrial energy homeostasis during vertebrate muscle development.
    Keywords:  ATP; Heart; Mitochondrial respiration; SMARCA4; SWI/SNF complex; Skeletal muscle
    DOI:  https://doi.org/10.1007/s00018-026-06168-3
  70. Hemasphere. 2026 Mar;10(3): e70334
    NCOA2 promotes the return of hematopoietic stem cells to quiescence after irradiation stress by regulating FOXO3a-dependent mitophagy.
    Fang Chen, Naicheng Chen, Linjie Wang, Hao Zeng, Yukai Lu, Yanying Liu, Jing Chen, Yang Xu, Mo Chen, Song Wang, Mingqiang Shen, Junping Wang, Mengjia Hu.
      Hematopoietic stem cells (HSCs) are responsible for replenishing blood cells under stress conditions through increasing proliferation and differentiation. After the hematopoietic function has reconstructed, HSCs must re-enter a quiescent state to avoid their depletion, whereas the underlying mechanisms remain to be elucidated. Here, we show that the translocation of nuclear receptor coactivator 2 (NCOA2) into the nucleus is gradually increased in HSCs during the hematopoietic recovery phase after sub-lethal dose irradiation (IR). Although deletion of NCOA2 only slightly affects the steady state hematopoiesis, its deficiency leads to HSC pool exhaustion and delayed hematopoietic recovery after exposure to IR. Further investigations reveal that loss of NCOA2 decreases the quiescence, survival, and long-term reconstituting ability of HSCs following IR due to increased mitochondria-derived oxidative stress. Mechanistically, NCOA2 promotes the clearance of activated or damaged mitochondria by coactivating FOXO3a-dependent transcription of PINK1, which drives HSCs to return to quiescence after being activated by IR stress. Collectively, our findings demonstrate a critical role of NCOA2 in facilitating the restoration of HSC homeostasis after IR via the FOXO3a-PINK1-mediated mitophagy axis and thus provide an additional strategy to prevent hematopoietic failure induced by IR.
    DOI:  https://doi.org/10.1002/hem3.70334
  71. Animals (Basel). 2026 Mar 04. pii: 793. [Epub ahead of print]16(5):
    SELENOF Mitigates Bovine Mastitis by Preserving Mitochondrial Homeostasis and Suppressing NLRP3-Mediated Pyroptosis.
    Xue Qi, Ling Shi, Xinhuai Shi, Changmin Hu.
      Bovine mastitis threatens the dairy industry with limited effective therapies. The selenoprotein family offers potential anti-inflammatory interventions, yet the role of Selenoprotein F (SELENOF) remains unclear. This study investigated SELENOF in mitochondrial damage and pyroptosis using clinical mammary biopsies and a Staphylococcus aureus-induced Mammary alveolar cell-type T (MAC-T) cell model. Histology, TEM, immunofluorescence, Western blot, qPCR, RNA-seq, and mitochondrial staining (MitoTracker Red and JC-1) were employed. Mastitic mammary tissue exhibited severe architectural disruption, including focal necrosis with coalescing vacuoles of variable size, extensive epithelial denudation, and interstitial thickening with dense inflammatory infiltrates. At the ultrastructural level, mitochondrial swelling, cristae loss, and plasma membrane rupture were evident. Additionally, these tissue specimens exhibited marked upregulation of inflammatory mediator transcripts, notably IL-1β, IL-6, and TNF-α, alongside heightened abundance of pyroptosis-associated proteins including NOD-like receptor family pyrin domain containing 3 (NLRP3), cleaved caspase-1, and GSDMD-N (Gasdermin D N-terminal domain). RNA-seq identified SELENOF as significantly downregulated. The MAC-T model recapitulated the mitochondrial dysfunction, inflammatory response, and pyroptosis observed in mastitic tissue. SELENOF overexpression restored mitochondrial membrane potential, dampened the output of inflammatory signaling molecules, and suppressed NLRP3-mediated pyroptosis via attenuation of caspase-1/GSDMD-N pathway activation. These findings establish SELENOF as a novel target that mitigates bovine mastitis by preserving mitochondrial homeostasis and suppressing NLRP3-mediated pyroptosis.
    Keywords:  NLRP3 inflammasome; SELENOF; bovine mastitis; mitochondrial dysfunction; pyroptosis
    DOI:  https://doi.org/10.3390/ani16050793
  72. BMB Rep. 2026 Mar 09. pii: 6743. [Epub ahead of print]
    Mitochondrial Quantity-Quality Imbalance in Cellular Senescence: Practical Readouts and Minimal Assay Bundles.
    Myeongwoo Jung, Seongho Cha, Eun Kyung Lee.
      Cellular senescence is an irreversible program of cell-cycle arrest that accumulates with age, contributing to chronic inflammation and various age-related diseases. A key feature of senescence paradigms is mitochondrial dysfunction, which involves not just a single defect but a series of coordinated changes in bioenergetics, redox homeostasis, mitochondrial quality control, and organelle interaction. Senescent cells often display a "quantity-quality imbalance" in their mitochondria: while the mitochondrial mass may increase, their efficiency in oxidative phosphorylation decreases, leading to a destabilized membrane potential (ΔΨm) and elevated levels of mitochondrial reactive oxygen species (mtROS). These interrelated changes can exacerbate senescence through persistent stress signaling, impaired turnover of damaged mitochondrial components, and alterations in organelle contacts, such as those between endoplasmic reticulum (ER) and mitochondria, and between mitochondria and lysosomes. Given that these phenotypes differ depending on cell type, triggering factors, and timing, no single assay can adequately define senescence-associated mitochondrial dysfunction. In this review, we present practical, complementary strategies that include extracellular flux-based respiration profiling, ATP output measurement, ΔΨm and ROS assessments, flux-based mitophagy reporters, quantitative network imaging, and contact-site assays. We propose minimal assay bundles that allow for a thorough multidimensional analysis. By establishing standardized, orthogonal measures of mitochondrial quantity and quality, we aim to enhance mechanistic understanding and facilitate the rational evaluation of mitochondria-targeted senolytic and senomorphic therapies.
  73. J Adv Res. 2026 Mar 09. pii: S2090-1232(26)00227-4. [Epub ahead of print]
    Rejuvenation of THY1+ nucleus pulposus-derived stem cells promotes intervertebral disc regeneration through FGF10-FGFR1-CREB pathway and mitochondrial fission.
    Haoxin Zhai, Zexin Wang, Shaoyi Wang, Zhicheng Liu, Dawang Zhao, Yiming Zhang, Kaiwen Liu, Xiangzhen Kong, Qunbo Meng, Hanwen Gu, Lin Chen, Yuanqiang Zhang, Lei Cheng.
       INTRODUCTION: Intervertebral disc degeneration (IVDD), a major cause of low back pain, is primarily characterized by compromised regeneration ability of nucleus pulposus-derived stem cells (NPSCs) owing to their senescence. The role of NPSCs as major regenerative cells in IVDD is garnering attention. However, the drivers and mechanisms of NPSCs reactivation and regeneration are poorly understood, limiting the development of targeted therapies. The fibroblast growth factor (FGF) family has shown increasing promise in tissue regeneration; however, the key factors involved in IVDD remain unclear.
    OBJECTIVES: To elucidate the regenerative driver of NPSCs and the underlying anti-senescence mechanism to provide a potential therapeutic strategy.
    METHODS: Single cell RNA sequencing (scRNA-seq) and bulk RNA sequencing were performed to identify the key NPSCs clusters and regenerative drivers in IVDD. Clinical IVDD samples were collected to determine the alterations in the NPSCs subset proportion and the expression of regeneration factors. Further, NPSCs senescence and in vivo models were used to investigate the specific mechanisms and therapeutic effects.
    RESULTS: Thy-1 membrane glycoprotein (THY1)+ NPSCs, which are depleted in IVDD, were the key cells involved in intervertebral disc degeneration based on scRNA-seq. THY1+ NPSCs exhibited stemness and regeneration potential. The RNA-seq analysis of senescent THY1+ NPSCs indicated fibroblast growth factor 10 (FGF10) as a pivotal rejuvenation factor. Multiplex fluorescence staining demonstrated diminished FGF10 expression in IVDD. FGF10 mitigated THY1+ NPSCs senescence by interacting with fibroblast growth factor receptor 1 (FGFR1). The FGF10-FGFR1 axis inhibited CREB phosphorylation and further alleviated ARG2-DRP1-related mitochondrial fission, reversing THY1+ NPSC senescence. Inhibition of CREB and downregulation of ARG2 regulate cellular senescence via modulation of mitochondrial fission. The transplantation of FGF10-overexpression NPSCs prominently alleviated nucleus pulposus degeneration and demonstrated regeneration potential in vivo.
    CONCLUSION: Our findings elucidate the pivotal roles of THY1+ NPSCs and FGF10 in intervertebral disc regeneration and NPSCs activation, respectively, contributing to the development of regenerative therapeutic strategies for IVDD.
    Keywords:  Cellular senescence; FGF10; Intervertebral disc degeneration; Regeneration; THY1(+) nucleus pulposus-derived stem cells
    DOI:  https://doi.org/10.1016/j.jare.2026.03.008
  74. Front Cell Dev Biol. 2026 ;14 1727005
    Autophagy in ocular diseases: from mechanisms to therapeutic potential.
    Qi Zhao, Yumeng Lin, Zhongyu Han, Yiwei Tian, Yaqi Yang, Qiaoyin Gou, Yuan Ju, Duoduo Xu, Lijuan Wei.
      Autophagy represents a fundamental and evolutionarily preserved mechanism of degradation and metabolism in eukaryotic cells. This process is triggered by a variety of stressors, including nutrient deprivation, energy deficits, protein misfolding, low oxygen levels, and pathogen infections by pathogens. Autophagy plays a vital role in maintaining cellular equilibrium. The process of vision is notably complex, making the eye one of the most metabolically active tissues in the human body. The proper function of the eye relies on the preservation of metabolic homeostasis and the structural integrity of organelles within various types of cells, including those found in the cornea, lens, retina, and optic nerve. As a result, any disruption in autophagy is closely linked to numerous ocular conditions. This review meticulously examines and elucidates the role of autophagy in ophthalmic diseases and explores its involvement in disease progression and treatment strategies, with the aim of presenting potential therapeutic approaches and a foundational framework for future research into the management of ophthalmic disorders.
    Keywords:  autophagy; corneal disease; glaucoma; mitophagy; retina
    DOI:  https://doi.org/10.3389/fcell.2026.1727005
  75. Neuron. 2026 Mar 11. pii: S0896-6273(26)00086-3. [Epub ahead of print]
    Targeting PGAM5-driven mitochondrial integrated stress response slows ALS progression across subtypes.
    Zhilong Zheng, Wangju Yang, Zhen Chen, Panpan Chen, Mengdan Tao, Shengda Wang, Bowei Cui, Zeyue Yang, Yanqing Yan, Xiao Han, Yongjie Zhang, Zijian Ren, Xiaoxin Yan, Yueqing Jiang, Jing Wang, Tingyou Li, Yan Liu, Xing Guo.
      Amyotrophic lateral sclerosis (ALS) is genetically and clinically heterogeneous, yet convergent pathogenic mechanisms remain poorly defined. A CRISPR-Cas9 screen identified phosphoglycerate mutase-5 (PGAM5) as a common mediator of ALS pathogenesis. PGAM5 activates the mitochondrial integrated stress response (mtISR) via dephosphorylation of metallopeptidase OMA1 at Ser223 and Ser237, thereby driving neuromuscular junction disruption and motor deficits. We show that PGAM5 is a substrate of valosin-containing protein (VCP) and is consistently elevated in spinal cords from sporadic ALS patients, in human spinal cord organoids derived from sporadic or familial ALS, and in ALS mouse models. The disruption of PGAM5-OMA1 interaction by a selective inhibitor (TAT-PO1) or pharmacological inhibition of PGAM5 with telmisartan suppresses mtISR activation and ameliorates ALS-related phenotypes by reshaping mtISR outputs in a manner distinct from those elicited by activation of translation initiation factor 2B (eIF2B). These findings establish PGAM5 as a convergent and actionable therapeutic target across ALS subtypes.
    Keywords:  ALS; NMJ; PGAM5; VCP; amyotrophic lateral sclerosis; mitochondrial integrated stress response; mitochondrial phosphatase phosphoglycerate mutase 5; mtISR; neuromuscular junction; valosin-containing protein
    DOI:  https://doi.org/10.1016/j.neuron.2026.02.003
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