bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2026–04–19
seventy papers selected by
Gavin McStay, Liverpool John Moores University
  1. A ULK1-MTFR1L feedback loop links mitochondrial fission, mitophagy and apoptosis.
  2. Molecular mechanisms of PINK1/Parkin-mediated mitochondrial quality control.
  3. BNIP3/BNIP3L-Dependent Mitophagy Protects Against Hippocampal Neuronal Damage and Apoptosis in a Model of Vascular Dementia.
  4. Schisandrol B protects against lithocholic acid-induced cholestatic liver injury in mice through mitochondrial biogenesis.
  5. Extracellular vesicle delivery of Myricetin suppresses ovarian cancer through mitochondrial dynamics by downregulating the ECM1/NF-κB/TGFβ signaling pathway.
  6. OGT Ameliorates Diabetes-Associated Cognitive Decline via Modulation of DRP1 Function and Mitochondrial Homeostasis.
  7. PINK1-Parkin-Mediated mitophagy alleviates hepatocyte injury induced by α-amanitin.
  8. Kaempferol inhibited pyroptosis in preeclampsia by modulating the NLRP3 inflammasome through the STAT3-associated mitophagy pathway.
  9. Roles of mitophagy and immune infiltration in Parkinson's disease: new perspectives from bioinformatics analysis and A53T transgenic mice.
  10. PINK1-PARKIN-Dependent Mitophagy Links Diphenyltin Exposure to Steroidogenic Collapse in Rat Leydig Cells During puberty.
  11. Impaired mitochondrial stress signaling mediates bone loss in male mice in the absence of BNIP3.
  12. Mitochondrial Fission and Fusion Disorders and Autophagy Abnormalities in Parkinson's Disease.
  13. Adenine Nucleotide Translocase: From Nucleotide Carrier to a Modulator of Mitochondrial Bioenergetics, Quality Control, and Cellular Communication.
  14. Steroids and flavonoids in TRQ ameliorates chronic obstructive pulmonary disease involving Pink1/Parkin-mediated mitophagy.
  15. PINK1‑mediated mitophagy enhances breast cancer proliferation through metabolic reprogramming.
  16. Allyl-substituted ALT001 promotes alternative mitophagy and improves therapeutic outcomes in Alzheimer's disease models.
  17. Fumarate inhibits the formation of neutrophil extracellular traps (NETs) in a Nrf2-controlled and Annexin-A1-dependent manner associated with mitochondrial fusion.
  18. The role of exercise-mediated mitochondrial quality control remodeling in aging.
  19. FTMT-mediated suppression of mitophagy links iron accumulation to osteoporosis.
  20. Senkyunolide I attenuates radiation-induced cognitive dysfunction by restoring PINK1-Parkin-mediated mitophagy and redox homeostasis.
  21. Mitochondrial homeostasis: the central hub governing the progression of atherosclerosis.
  22. Hdac11 promotes idiopathic pulmonary fibrosis through macrophage M2-type polarization and myofibroblast accumulation by inhibiting Parkin-dependent mitophagy.
  23. Protective role of sodium propionate against glycerol or fractionated doses of gamma rays-induced acute kidney injury via ATF5-induced mitophagy in rats.
  24. The mitochondrial fission-mitophagy axis drives neuronal S-phase arrest and hippocampal damage in co-exposure to polystyrene nanoplastics and lead.
  25. From collapse to comeback: Luteolin rejuvenates nucleus pulposus progenitor cells via SIRT1/ATF5-UPRmt to reverse intervertebral disc degeneration cascade.
  26. Mitophagy protects renal tubular epithelial cells from intermittent hypoxia-induced injury via the HIF-1α/BNIP3 pathway.
  27. Advances in understanding mitophagy's role in lung injury.
  28. Integrative multi‑omics and experimental validation reveal that Duhuo Jisheng Decoction alleviates IVDD by inhibiting MAPK signaling‑mediated inflammation, apoptosis, and mitochondrial dysfunction.
  29. GFRAL is required to mediate changes in systemic metabolism in response to mitochondrial stress in brown adipose tissue.
  30. Saikosaponin D Alleviates Liver Ischemia-Reperfusion Injury by Inhibiting Mitophagy-Associated Ferroptosis via the STAT3/PINK1 Pathway.
  31. Mitophagy promotes lung repair and regeneration by restoring epithelial metabolic fitness.
  32. The PPTC7/BNIP3/NIX axis induces cGAS/STING-mediated senescence and augments CAR-T efficacy by repressing tumor-intrinsic mitophagy.
  33. Gene expression profile, and role of baicalein in the inhibition of thyroid cancer.
  34. Beyond energy production: targeting mitochondrial biogenesis in aging and cancer with phytochemical intervention.
  35. Polyphyllin VI induces Forkhead box O3 nuclear liquid-liquid phase separation to promote mitophagy in breast cancer.
  36. The role and mechanism of UPRmt in adipocytes.
  37. The mitochondrial signature of sperm motility loss: a study of mitophagy and apoptosis in asthenozoospermia.
  38. L-BMAA induces neurotoxicity through AMPK/Akt-TSC1/2-mTOR-mediated mitophagy dysregulation and apoptosis.
  39. Agrimol B inhibits pancreatic ductal adenocarcinoma by induction of lethal mitophagy through decreasing mitochondrial transcription termination factor 3.
  40. Irisin as a Regulator of Brain Energy Homeostasis: Implications for Age-Related Neurodegenerative Diseases.
  41. Mitochondrial redox homeostasis links organellar stress surveillance to germline and somatic integrity in Caenorhabditis elegans.
  42. An Integrative Analysis of the Role of Mitophagy in Comorbid Myocardial Infarction and Type 2 Diabetes Mellitus.
  43. Tucatinib alleviates postmenopausal osteoporosis by suppressing osteoclast differentiation via regulating the DRP1/NFATc1/CTSK signaling pathway.
  44. Ziziphora clinopodioides Flavonoids improve ischemic stroke by targeting FUNDC1-mediated mitophagy to reduce ferroptosis.
  45. Beyond the neuron: Exosomes as intercellular modulators of mitochondrial networks in the pathogenesis and treatment of Alzheimer's disease.
  46. Schisandrin B confers multi-organ protection via regulation of mitochondrial homeostasis: mechanistic integration, organ-specific differences, and translational challenges-a review.
  47. Resveratrol Attenuates Liver Inflammation in Non-Alcoholic Fatty Liver Disease by Activating PINK1-Mediated Mitophagy.
  48. Engineering Tfh-Specific Nanoadjuvant to Counteract Bile Acid-Induced Mitophagy and Vaccine Hyporesponsivenes.
  49. Corylin inhibits liver cancer cell growth through the endogenous apoptosis and mitophagy.
  50. CuO-NPs Suppress Esophageal Squamous Cell Carcinoma by Altering Oxidant-Dependent Energy Metabolism, Leading to Mitophagy.
  51. A 3-N nose-to-brain urolithin a nanomotor targeting microglial mitophagy in neuroinflammation.
  52. Ghrelin Receptor Deletion or Pharmacological Inhibition Improves Muscle Function in Aging Male Mice.
  53. SIRT1 plays a critical role in maintaining the viability of Yak Sertoli cells by regulating mitochondrial biogenesis via activating the PGC-1α-NRF-1-TFAM pathway.
  54. Shenqi Oral Liquid regulates reactive oxygen species production by modulating autophagy, thereby regulating mitochondrial dynamics in cardiomyocytes and alleviating chronic heart failure in mice via adenosine 5'-monophosphate-activated protein kinase/mechanistic target of rapamycin axis.
  55. Editorial: Mitochondrial dynamics and endothelial dysfunction: implications for metabolic disorders.
  56. Hexavalent chromium induces death of porcine spermatogonial stem cells via promoting mitophagy and ferroptosis.
  57. The role of mitochondrial dysfunction, oxidative stress, and gender in cardiac fibrosis and vascular remodeling in an induced aged rat model with possible mitigation by eugenol nano-emulsion.
  58. GPR176 represses mitophagy to promote the progression of osteosarcoma by facilitating mTORC1 activity via PI3K-AKT pathway.
  59. Mitochondrial Fission Regulator 1-Like Protein Protects the Heart from Ischemia/Reperfusion Injury via Dual Mitochondrial Mechanisms.
  60. Mitophagy activation for jawbone radiation injury therapy via angiogenesis/osteogenesis-active nanozymes.
  61. Graded activation of the CLEAR network through mTORC1 suppression on cargo-harboring lysosomes.
  62. Metabolic Control of Immunity and Inflammation: Mitochondrial Dynamics, Pharmacological Targets, and Therapeutic Opportunities.
  63. Pestiviruses utilize pyrimidine metabolism to regulate mitophagy for viral replication.
  64. Brusatol derivative ameliorates rheumatoid arthritis and atherosclerosis with associated suppression of mitochondrial fission.
  65. SIRT3-mediated mitochondrial fatty acid oxidation protects against hepatic lipid deposition in fatty liver hemorrhagic syndrome.
  66. Lipid metabolism and autophagy maintain cellular homeostasis under chloroplast dysfunction in Chlamydomonas reinhardtii.
  67. Macrophage membrane-biomimetic cinnamaldehyde nanomedicine ameliorates inflammatory bowel disease by suppressing macrophage M1 polarization.
  68. Roles of mitochondria in oocyte fertility decline in the interspecific hybrids between Argopecten irradians irradians and A. purpuratus.
  69. Rhesus macaques with an OPA1 mutation demonstrate features of autosomal dominant optic atrophy.
  70. Inhibition of NCOA4-mediated ferritinophagy improves cardiac remodeling in diabetic cardiomyopathy via MITOL/parkin signaling.
  1. J Cell Sci. 2026 Apr 13. pii: jcs.264577. [Epub ahead of print]
    A ULK1-MTFR1L feedback loop links mitochondrial fission, mitophagy and apoptosis.
    Riccardo Babic, Leon Lucya, Christoph Reiter, Franziska Kriegenburg, Ramón Castellanos-Martínez, David M Hollenstein, Florian Becker, Carola Hunte, Claudine Kraft.
      Mitophagy, the selective degradation of damaged mitochondria, preserves mitochondrial quality, yet how mitochondrial fission is coordinated with autophagy initiation remains unclear. Here we identify the mitochondrial outer membrane protein MTFR1L as a key component of mitophagy initiation hubs after using a synthetic FKBP-FRB system to tether ULK1 kinase to mitochondria independently of damage. We find that MTFR1L is enriched at ULK1 foci together with additional fission factors and constitutive mitochondrial targeting of MTFR1L shifts mitochondrial morphology towards fragmentation. MTFR1L depletion decreases respiratory capacity, elevates apoptosis, and impairs mitophagy flux. Upon mitophagy induction, MTFR1L is phosphorylated in a ULK1 kinase-dependent manner, and reciprocally modulates ULK1 activity, establishing a feedback loop. Moreover, MTFR1L is required for proper ATG13 stability. These findings position MTFR1L as a critical link between mitochondrial fission and the autophagy machinery, coordinating mitophagy initiation and cell survival.
    Keywords:  ATG13; Autophagy; MTFR1L; Mitophagy; ULK1
    DOI:  https://doi.org/10.1242/jcs.264577
  2. Trends Biochem Sci. 2026 Apr 16. pii: S0968-0004(26)00061-7. [Epub ahead of print]
    Molecular mechanisms of PINK1/Parkin-mediated mitochondrial quality control.
    Andrew N Bayne, Jean-François Trempe.
      PINK1/Parkin-mediated mitophagy and other related mitochondrial quality control pathways are critical to maintaining cellular homeostasis and neuronal health, and indeed, mutations in PINK1 and PRKN that disrupt this pathway cause early-onset Parkinson's disease. While PINK1-dependent Parkin recruitment to damaged mitochondria has been established for over a decade, recent structural and biochemical advances have illuminated the mechanisms governing their allosteric activation and integration into broader cellular signaling networks. This review synthesizes these insights, focusing on the molecular determinants of PINK1/Parkin activation and the regulatory crosstalk that integrates mitophagy with other cellular stress responses. These mechanistic advances position the PINK1/Parkin pathway as a promising, tractable therapeutic target for Parkinson's disease and related pathologies.
    Keywords:  PINK1; Parkin; Parkinson’s disease; mitochondrial quality control (MQC); mitophagy; stress response; therapeutic development
    DOI:  https://doi.org/10.1016/j.tibs.2026.02.014
  3. Cells. 2026 Mar 25. pii: 585. [Epub ahead of print]15(7):
    BNIP3/BNIP3L-Dependent Mitophagy Protects Against Hippocampal Neuronal Damage and Apoptosis in a Model of Vascular Dementia.
    Yujiao Wang, Daojun Xie, Shijia Ma, Yuhe Wang, Chengcheng Zhang, Zhuyue Chen.
      Mitophagy serves as an essential quality control mechanism that maintains mitochondrial homeostasis through selective autophagic clearance of damaged organelles. Vascular dementia (VD) has been increasingly associated with mitophagy dysregulation in recent studies. However, the precise molecular mechanisms underlying mitophagy's involvement in VD pathogenesis remain poorly characterized. To elucidate the role of mitophagy in VD, we systematically examined the expression of key mitophagy pathways in hippocampal neurons of bilateral common carotid artery occlusion (BCCAO) rats and in oxygen-glucose deprivation (OGD)-treated HT22 cells. Intriguingly, under autophagy-deficient conditions, both BNIP3 and BNIP3L were markedly downregulated, whereas FUNDC1 expression increased; PINK1/Parkin levels remained unaltered. To further dissect the functional contributions of BNIP3 and BNIP3L, we administered the mitochondrial fission inhibitor Mdivi-1 to BCCAO model rats. Histopathological analysis revealed pronounced neuronal damage and apoptosis in the hippocampal region, which was further exacerbated upon Mdivi-1 treatment. In vitro, BNIP3 silencing significantly compromised cell viability, elevated reactive oxygen species (ROS) accumulation, disrupted mitochondrial membrane potential (ΔΨm), suppressed mitophagy, and increased apoptotic rates. Conversely, BNIP3 overexpression reversed these detrimental effects. Notably, treatment with the autophagy inhibitor 3-methyladenine (3-MA) diminished LC3B-Tomm20 colocalization and intensified apoptosis, reinforcing the critical role of BNIP3-mediated mitophagy in neuronal survival. Similarly, BNIP3L overexpression enhanced cell viability, attenuated ROS production, restored ΔΨm, and mitigated apoptosis, while 3-MA treatment again impaired mitophagic flux and worsened cell death. Collectively, these findings underscore the critical and distinct roles of BNIP3 and BNIP3L in maintaining mitochondrial homeostasis and neuronal survival under ischemic conditions.
    Keywords:  BNIP3; BNIP3L; ROS; apoptosis; mitophagy; vascular dementia
    DOI:  https://doi.org/10.3390/cells15070585
  4. Chin Med. 2026 Apr 14. pii: 116. [Epub ahead of print]21(1):
    Schisandrol B protects against lithocholic acid-induced cholestatic liver injury in mice through mitochondrial biogenesis.
    Xiao Yang, Hangfei Liang, Xuan Li, Jianing Tian, Shicheng Fan, Min Huang, Jianbo Wan, Zhong Zuo, Haibiao Guo, Huichang Bi.
       BACKGROUND: Mitochondrial biogenesis plays a vital role in various types of hepatocyte injury. Schisandrol B (SolB), a bioactive lignan isolated from Schisandra sphenanthera, exerts a significant hepatoprotective effect against lithocholic acid (LCA)-induced cholestatic liver injury. Whether mitochondrial biogenesis is involved in the anti-cholestasis effect of SolB remains unknown.
    METHODS: A mouse model of cholestatic liver injury was induced by intraperitoneal injection of LCA. SolB was administered orally twice a day. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total bile acids (TBA) and total bilirubin (TBILI), as well as hepatic superoxide dismutase (SOD) activity were measured. Liver pathology was evaluated by toxylin and eosin (H&E) staining. Mitochondrial morphology was examined using electron microscopy. Furthermore, the expression of mitochondrial biogenesis-related genes or proteins was analyzed by RT-qPCR or Western blot.
    RESULTS: We confirmed that SolB pretreatment (200 mg/kg/d) alleviated LCA-induced liver injury as evidenced by histological and biochemical analyses. SolB alleviated LCA-induced mitochondrial dysfunction in mice, as evidenced by increased mitochondrial DNA (mtDNA) content, superoxide dismutase (SOD) levels, and peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α) and mitochondrially encoded cytochrome c oxidase subunit 1 (MTCO1) expression, together with decreased fibroblast growth factor 21 (Fgf21) and growth differentiation factor 15 (Gdf15) gene levels. Transmission electron microscope analysis showed that LCA elicited small, fragmented mitochondria, which were not reversed after SolB pretreatment. However, western blot analysis showed that the expression of mitochondrial dynamics-related proteins, such as dynamin-related protein1 (DRP1), optic atrophy 1 (OPA1), mitofusin 1 (MFN1), and MFN2, was significantly decreased after LCA treatment. Pretreatment with SolB could significantly upregulate DRP1, mitochondrial fission factor (MFF), and fission1 (FIS1) which are crucial to regulate mitochondrial fission. It is worth noting that the protective effect of SolB against LCA-induced liver injury was independent of parkin RBR E3 ubiquitin-protein ligase (PARKIN)-mediated mitophagy as evidenced by decreased PARKIN and microtubule-associated protein light chain 3 (LC3)-II.
    CONCLUSION: In summary, this study demonstrated that SolB improved mitochondrial function but had no effect on LCA-induced mitochondrial fragmentation, which provides new insights into better understanding hepatoprotective mechanism of SolB against cholestatic liver injury.
    Keywords:  Cholestatic liver injury; Mitochondrial biogenesis; Mitochondrial dynamics; Schisandrol B
    DOI:  https://doi.org/10.1186/s13020-026-01342-y
  5. Sci Rep. 2026 Apr 16.
    Extracellular vesicle delivery of Myricetin suppresses ovarian cancer through mitochondrial dynamics by downregulating the ECM1/NF-κB/TGFβ signaling pathway.
    Kaumudi Pande, Sridevi Annapurna Singh, Anbarasu Kannan.
      
    Keywords:  CHO cell-derived extracellular vesicles; Mitochondrial fission; Mitochondrial fusion; Myricetin; Ovarian cancer
    DOI:  https://doi.org/10.1038/s41598-026-46901-3
  6. Diabetes Obes Metab. 2026 Apr 14.
    OGT Ameliorates Diabetes-Associated Cognitive Decline via Modulation of DRP1 Function and Mitochondrial Homeostasis.
    Ting Li, Xiaoqing Deng, Yahui Miao, Man Zhang, Xinxin Huangfu, Shi Wu, Bei Sun, Liming Chen.
       BACKGROUND: Diabetes-associated cognitive decline (DACD) is gradually gaining attention as a major complication of diabetes. However, to date, the specific molecular mechanisms underlying DACD have not been thoroughly characterized.
    METHODS: Db/db and streptozotocin (STZ) treated high-fat diet (HFD)-induced mice were established. Different behavioural assessments were performed, followed by evaluation of mitochondrial homeostasis, including mitochondrial morphology and function. Mitochondrial dynamics proteins, synaptic-related proteins and O-GlcNAc cycling enzymes were examined. Thereafter, OGT-interacting proteins were identified using co-immunoprecipitation mass spectrometry. Additionally, mouse hippocampal neuronal cells were treated with OGT siRNA and subsequent changes were measured. Mice were stereotaxically injected with adeno-associated viruses to overexpress OGT specifically in the hippocampus, and relevant in vivo experiments were performed. Finally, mice received semaglutide for 16 weeks and subsequent changes were assessed.
    RESULTS: Decreased OGT expression disrupted mitochondrial homeostasis and led to neuronal injury and cognitive impairment in diabetic mice. In addition, hippocampus-specific OGT overexpression improved DACD. Mechanistically, OGT deficiency resulted in a reduced mitochondrial membrane potential, promoting mitochondrial fission and impairing mitochondrial function by modulating DRP1 function. Furthermore, our results showed that semaglutide alleviated DACD through the OGT/DRP1 pathway.
    CONCLUSIONS: OGT deficiency-mediated mitochondrial homeostasis imbalance contributes to the occurrence of DACD, and semaglutide with an OGT protective effect may be a potential therapeutic approach for DACD.
    Keywords:  O‐GlcNAc transferase; O‐GlcNAcylation; diabetes‐associated cognitive decline; dynamin‐related protein 1; mitochondrial homeostasis
    DOI:  https://doi.org/10.1111/dom.70758
  7. Ecotoxicol Environ Saf. 2026 Apr 11. pii: S0147-6513(26)00446-X. [Epub ahead of print]316 120117
    PINK1-Parkin-Mediated mitophagy alleviates hepatocyte injury induced by α-amanitin.
    Yang Zhao, Ziheng Zou, Peng Wu, Zehui Li, Zhijie Liu, Zhengwang Yi, Juyu Wang, Yi Wu, Weijie Qu, Bundit Tengjaroensakul, Jian Sun, Xiaolong Gu.
      The death cap mushroom (Amanita phalloides) is one of the most toxic fungi worldwide, with α-amanitin (α-AMA) identified as its primary lethal toxin. Mitophagy selectively eliminates damaged mitochondria via the autophagy pathway and plays a critical role in maintaining mitochondrial quality and cellular homeostasis. However, its function in α-AMA-induced liver injury remains unclear. To elucidate the role and underlying mechanism of mitophagy in α-AMA hepatotoxicity, this study investigated its effects on α-AMA-exposed hepatocytes using both in vitro and in vivo models. The results showed that α-AMA treatment significantly reduced hepatocyte viability and increased reactive oxygen species (ROS) levels, confirming its hepatotoxic effects. Subsequently, mitophagy was activated to assess its functional role. Activation of mitophagy markedly alleviated α-AMA-induced hepatocyte damage. Further mechanistic analysis revealed that mitophagy activation also significantly attenuated oxidative stress and apoptosis-two key pathological processes associated with mitochondrial dysfunction under α-AMA toxicity. In summary, this study provides new evidence that enhancing mitophagy protects hepatocytes against α-AMA-induced injury. These findings highlight mitophagy as a promising therapeutic target for developing treatment strategies against life-threatening α-AMA poisoning.
    Keywords:  Apoptosis; Mitophagy; Reactive oxygen species (ROS); α-amanitin
    DOI:  https://doi.org/10.1016/j.ecoenv.2026.120117
  8. Naunyn Schmiedebergs Arch Pharmacol. 2026 Apr 11.
    Kaempferol inhibited pyroptosis in preeclampsia by modulating the NLRP3 inflammasome through the STAT3-associated mitophagy pathway.
    Haiyan Yang, Chunfang Li.
      Preeclampsia (PE) is driven by placental dysfunction, where oxidative stress triggers mitochondrial damage. Damaged mitochondria, in turn, activate the NLRP3 inflammasome, leading to cell pyroptosis and exacerbating placental injury. Kaempferol (KAE), a natural flavonol with antioxidant properties, whether it acts by enhancing mitochondrial clearance to interrupt this damaging cycle, remains unknown. We employed an L-NAME-induced PE rat model and a cellular hypoxia/reoxygenation model using HTR-8/SVneo trophoblasts. KAE's effects were evaluated by monitoring clinical symptoms, placental histology, oxidative stress (DHE staining, MitoSOX), and key protein expression (Western blot, ELISA). The involvement of mitophagy was assessed through detection of PINK1 and Parkin. STAT3 subcellular localization was examined by fractionation, and its functional role was validated using STAT3 siRNA knockdown. Pyroptosis was evaluated by GSDMD-N cleavage, LDH release assay, and propidium iodide (PI) uptake. The specific roles of STAT3 signaling and mitophagy in the therapeutic effects of KAE were investigated using Stattic (STAT3 inhibitor) and Mdivi-1 (mitophagy inhibitor). KAE treatment dose dependently alleviated maternal hypertension, proteinuria, and fetal growth restriction in PE rats. Mechanistically, KAE reduced oxidative stress, restored autophagy flux (increased LC3-Ⅱ/LC3-Ⅰ; decreased p62), upregulated mitophagy-specific markers PINK1 and Parkin, promoted STAT3 phosphorylation and its mitochondrial translocation, and suppressed NLRP3 inflammasome activation and pyroptosis. KAE promoted STAT3 phosphorylation. In vitro, the protective effects of KAE on cell function were reversed by Stattic and Mdivi-1. Stattic blocked KAE's action on STAT3, mitophagy, and pyroptosis, while Mdivi-1 only reversed its effects on mitophagy and downstream pyroptosis without affecting STAT3 activation. STAT3 knockdown confirmed its essential role in KAE-induced mitophagy enhancement and pyroptosis suppression. KAE ameliorates PE through a STAT3-associated mechanism involving enhanced mitophagy, thereby inhibiting NLRP3-driven pyroptosis and improving trophoblast function. This study identifies a STAT3-associated mitophagy pathway as a potential therapeutic target in PE.
    Keywords:  Cell pyroptosis; Kaempferol; Mitochondrial autophagy; NLRP3 inflammasome; Preeclampsia; STAT3 signaling pathway
    DOI:  https://doi.org/10.1007/s00210-026-05217-9
  9. Inflamm Res. 2026 Apr 17. pii: 95. [Epub ahead of print]75(1):
    Roles of mitophagy and immune infiltration in Parkinson's disease: new perspectives from bioinformatics analysis and A53T transgenic mice.
    Xuesong Li, Yujia Zhang, Qianwen Yang, Junwei Gong, Ningning Zhang, Yifan Huang, Tao Chen, Di Zhou, Zhao Zou, Zongduo Guo.
       BACKGROUND: Mitophagy plays a critical role in the pathology of Parkinson's disease (PD) via mitochondrial quality control, making it a promising therapeutic target. However, the precise mechanistic role of mitophagy in PD pathogenesis and progression remains unclear.
    METHODS: We conducted a bioinformatic analysis to identify hub mitophagy-related differentially expressed genes (hub-MPDEGs). The mRNA expression levels of these identified genes were validated using two single-cell RNA sequencing datasets (GSE178265 and PRJNA1145007) and further confirmed in an α-synuclein A53T transgenic mouse model.
    RESULTS: Five hub-MPDEGs were identified: CANX, GABARAPL1, HSPD1, PPARGC1A, and TOMM20. Transcriptomic analysis revealed elevated abundance of these genes in α-synuclein A53T mice compared to controls. Single-cell resolution analysis demonstrated significant differential expression of these genes in astrocytes, dopamine neurons, glutamatergic neurons, endothelial cells, and oligodendrocyte precursor cells within the substantia nigra of PD samples compared to controls. Furthermore, significant differences in mRNA levels were observed in peripheral immune cells, specifically CD4+ T cells, CD8+ T cells, monocytes, and NK cells, between control and PD samples.
    CONCLUSIONS: This study identifies and validates five key mitophagy-related genes that are differentially regulated in the central nervous system and peripheral immune cells in the context of Parkinson's disease. These findings highlight the systemic nature of mitophagy dysregulation in PD.
    Keywords:  Bioinformatics; CANX; GABARAPL1; HSPD1; Immune infiltration; Inflammation; Mitochondrion; Mitophagy; Neuron; PPARGC1A; Parkinson’s disease; TOMM20
    DOI:  https://doi.org/10.1007/s00011-026-02243-4
  10. Chem Biol Interact. 2026 Apr 12. pii: S0009-2797(26)00189-4. [Epub ahead of print] 112081
    PINK1-PARKIN-Dependent Mitophagy Links Diphenyltin Exposure to Steroidogenic Collapse in Rat Leydig Cells During puberty.
    Qiqi Zhu, Jianqin Yu, Nianci Chen, Lili Tian, Chunnan Hu, Quanxu Chen, Yang Zhu, Ren-Shan Ge, Yi Liu, Xingwang Li.
      Diphenyltin (DPT) is an organotin and an endocrine disruptor, impairing the male reproductive system. However, the effect of DPT on Leydig cell function during puberty remains unknown. DPT exhibits selective testicular toxicity without altering gross reproductive organ weights. In rats administered 2.5-10 mg/kg DPT from postnatal day 35 to 57, serum testosterone levels were significantly reduced at 5 and 10 mg/kg, while luteinizing hormone and follicle-stimulating hormone levels remained unchanged. Histological and immunohistochemical analyses revealed decreased Leydig cell numbers and reduced expression of steroidogenic markers (STAR, LHCGR, SCARB1, CYP11A1, and INSL3). Testicular oxidative stress was evident, with downregulated SOD1, SOD2, and CAT and elevated malondialdehyde. Autophagy markers (LC3B, Beclin1) were upregulated alongside decreased phosphorylated mTOR, as well as increased 4-hydroxynonenal, 8-hydroxy-2'-deoxyguanosine, and LC3B staining in Leydig cells, suggesting oxidative stress-induced autophagy. In vitro, adult Leydig cells displayed ROS accumulation, mitochondrial membrane potential loss, and autophagosome formation. In adult Leydig cells, DPT enhanced mitochondrial fission by upregulating DRP1 and FIS1, downregulating MFN1, and activating PINK1-PARKIN-mediated mitophagy. The fission inhibitor mdivi-1 mitigated mitochondrial fragmentation, decreased mitophagy, and partially restored steroidogenesis. These findings indicate that DPT disrupts Leydig cell function through oxidative stress, mitochondrial fission, and mitophagy, ultimately leading to testosterone suppression and compromised sperm production. Therapeutic targeting of mitochondrial dynamics may protect steroidogenic cells from toxin-induced damage.
    Keywords:  Diphenyltin; Mitophagy; PARKIN; PINK1; Steroidogenic impairment
    DOI:  https://doi.org/10.1016/j.cbi.2026.112081
  11. bioRxiv. 2026 Apr 08. pii: 2026.04.06.710936. [Epub ahead of print]
    Impaired mitochondrial stress signaling mediates bone loss in male mice in the absence of BNIP3.
    Li Tian, Victoria Van Berlo, Vivin Karthik, Joshua P Passarelli, Victoria E DeMambro, Patience Mudjgiwa, Calvin Vary, Anyonya R Guntur.
      Osteoblasts generate bone by secreting collagen and mineralizing it in response to various signaling cues. We have previously shown that the majority of ATP generated by differentiated osteoblasts in response to glucose is through glycolysis in contrast to undifferentiated cells that are more dependent on oxidative phosphorylation. To confirm our previous findings, metabolomics was performed for unlabeled polar metabolites, revealing elevated glycolytic metabolites at the later stages of differentiation. Krebs cycle (TCA cycle) metabolites were also changed confirming metabolic rerouting with differentiation. We hypothesized that an increase in mitophagy shifts ATP generation towards glycolysis resulting in the observed bioenergetic and metabolic changes. Utilizing calvarial osteoblasts isolated from a mitophagy reporter mouse model (MitoQC), an increase in mitophagy and the mitophagy receptor, Bnip3, was observed with osteoblast differentiation. KD of Bnip3 in osteoblasts inhibited differentiation and mineralization arising from impaired mitochondrial function. In vivo, male Bnip3 null mice exhibited a significant decrease in osteoblast numbers resulting in lower bone mass. Mechanistically we identified decreased fusion and increased fission factors, impaired stress signaling and increased proapoptotic factors in the absence of Bnip3 . These data demonstrate for the first time that BNIP3 expression and mitophagy during osteoblast differentiation are necessary for relieving mitochondrial stress to maintain optimal bone mass.
    DOI:  https://doi.org/10.64898/2026.04.06.710936
  12. Neurochem Res. 2026 Apr 11. pii: 136. [Epub ahead of print]51(2):
    Mitochondrial Fission and Fusion Disorders and Autophagy Abnormalities in Parkinson's Disease.
    Yufei Liu, Haoran Li, Jie Bai.
      
    Keywords:  Mitochondria; Mitochondrial autophagy; Mitochondrial fission and fusion; Parkinson’s disease
    DOI:  https://doi.org/10.1007/s11064-026-04752-4
  13. Cells. 2026 Apr 02. pii: 646. [Epub ahead of print]15(7):
    Adenine Nucleotide Translocase: From Nucleotide Carrier to a Modulator of Mitochondrial Bioenergetics, Quality Control, and Cellular Communication.
    Ursula Rauch-Kroehnert, Jacqueline Heger, Ulf Landmesser, Andrea Dörner.
      Adenine nucleotide translocase (ANT) has traditionally been defined as the ADP/ATP exchanger of the inner mitochondrial membrane. However, accumulating mechanistic evidence reveals a substantially broader functional spectrum that extends beyond nucleotide transport. In this review, we integrate these advances into a unified conceptual framework that positions ANT isoforms as modulators of mitochondrial bioenergetics, quality control, and cellular communication. Beyond its canonical exchange activity, ANT influences permeability transition thresholds and membrane potential stability, participates in regulated uncoupling and redox control, and contributes to inner membrane organization and cristae integrity. ANT further modulates TIMM23-dependent protein import and PINK1-Parkin-mediated mitophagy, thereby shaping mitochondrial quality control decisions. In addition, ANT regulates mitochondrial nucleic acid release and inflammasome activation, linking bioenergetic imbalance to innate immune signaling. Emerging evidence for alternative subcellular localizations suggests that ANT-dependent signaling extends mitochondrial state information to extracellular and intercellular contexts. Collectively, these findings support an expanded view of ANT as a multifunctional modulator linking mitochondrial energetic state to stress adaptation, inflammatory signaling, and tissue-level communication.
    Keywords:  adenine nucleotide translocase; dsRNA transport; extracellular vesicles; immunometabolism; mitochondrial dynamics; mitochondrial permeability transition pore; mitochondrial signaling; mitochondrial uncoupling; mitophagy; mtDNA stability
    DOI:  https://doi.org/10.3390/cells15070646
  14. Sci Rep. 2026 Apr 17.
    Steroids and flavonoids in TRQ ameliorates chronic obstructive pulmonary disease involving Pink1/Parkin-mediated mitophagy.
    Hao Wang, Ziying Xu, Hongzhi Du, Jianchao Liu, Tianyi Zhang, Xiaolu Wei, Yan Liu, Tengfei Chen, Yunhang Gao, Ling Song, Shan Wang, Zuguang Ye, Guangping Zhang, Hongping Hou, Lihua Liu.
      Chronic obstructive pulmonary disease (COPD) is a progressive lung disorder linked to oxidative stress, mitochondrial damage, and impaired mitophagy. Tanreqing (TRQ) inhalation solution is widely used for respiratory diseases but its mechanism against COPD remains poorly defined. Here we investigated the protective effects of TRQ and its underlying pathway in a COPD rat model and cigarette smoke extract (CSE)-stimulated A549 cells. Our results showed that TRQ treatment alleviated body weight loss, lung pathological injury, alveolar destruction, and airway remodeling in rats. TRQ reduced ROS and MDA levels, restored SOD activity, and improved mitochondrial function including ATP production, mitochondrial membrane potential, and mitochondrial permeability transition pore homeostasis. Moreover, TRQ enhanced autophagy and mitophagy by upregulating Bnip3, Nix, Pink1, and Parkin expression. In vitro, knockdown of Pink1 abolished TRQ-mediated mitophagy activation, confirming that the Pink1/Parkin pathway was essential for TRQ action. In conclusion, TRQ inhalation solution ameliorates COPD by suppressing oxidative stress and restoring mitochondrial homeostasis via activating Pink1/Parkin-mediated mitophagy. This study identifies TRQ as a promising candidate for COPD treatment.
    Keywords:  Active components; Chronic obstructive pulmonary disease; Mitophagy; Pink1/Parkin; Traditional Chinese Medicine
    DOI:  https://doi.org/10.1038/s41598-026-47064-x
  15. Oncol Rep. 2026 Jun;pii: 112. [Epub ahead of print]55(6):
    PINK1‑mediated mitophagy enhances breast cancer proliferation through metabolic reprogramming.
    Zong Jin Guo, Qian Yu, Rui Sha, Wei Li, Hui Juan Dai.
      Breast cancer is a predominant cause of cancer‑related mortality among women, particularly aggressive subtypes such as triple‑negative breast cancer (TNBC), which currently lack effective targeted therapies. While PTEN‑induced kinase 1 (PINK1) is known for its role in maintaining mitochondrial homeostasis via mitophagy, its specific contributions to breast cancer progression and metabolic regulation remain poorly defined. The present study aimed to investigate the oncogenic potential of PINK1 and its influence on metabolic reprogramming. To achieve this, the PINK1 expression levels in breast cancer tissues and cell lines were assessed. Gain‑ and loss‑of‑function methodologies were employed in luminal (MCF‑7) and TNBC (MDA‑MB‑231) cells. Then, mitophagy was evaluated by measuring LC3‑II levels, Parkin expression and utilizing transmission electron microscopy. Glucose uptake assays and metabolite quantification (including pyruvate and acetyl‑CoA) were conducted. Reverse transcription‑quantitative polymerase chain reaction identified phosphoglycerate kinase 2 (PGK2) as a downstream target of PINK1. Functional assays were then performed to examine the proliferation, migration and invasion of cells with PINK1 overexpression. The results demonstrated that PINK1 overexpression increased mitophagy and induced a glycolytic phenotype, characterized by enhanced glucose uptake and elevated PGK2 levels. Elevated concentrations of pyruvate and acetyl‑CoA indicated increased metabolic flux. Functionally, PINK1 promoted proliferation, migration and invasion in both cell types. Knockdown of PGK2 reversed these effects, underscoring its critical role in PINK1‑mediated metabolic reprogramming. Transcriptomic data obtained from online databases revealed a correlation between high PINK1 expression and immunosuppressive tumor microenvironments, as well as poor prognosis. The PINK1‑PGK2 axis constitutes a critical mechanism linking mitophagy to glycolytic reprogramming in breast cancer, representing a novel therapeutic target, particularly for TNBC. Targeting this axis may yield new strategies for addressing treatment‑resistant, metabolically adaptive breast cancer.
    Keywords:  PTEN‑induced kinase 1‑phosphoglycerate kinase 2 axis; breast cancer; glycolysis; mitophagy; therapeutic target
    DOI:  https://doi.org/10.3892/or.2026.9117
  16. Sci Rep. 2026 Apr 17.
    Allyl-substituted ALT001 promotes alternative mitophagy and improves therapeutic outcomes in Alzheimer's disease models.
    Jee-Hyun Um, Se Myeong Choi, Young Yeon Kim, Dong Jin Shin, Eunhee Yoo, Han-Joo Maeng, Alen Benhur Pravin Nathan, Jihoon Jo, Jong Hyun Cho, Jeanho Yun.
      The impairment of mitophagy plays a key role in the pathology of Alzheimer's disease (AD). We previously demonstrated that ALT001 induces mitophagy via the alternative mitophagy pathway and ameliorates mitochondrial dysfunction and cognitive deficits in AD models. In this study, we synthesized a novel derivative, namely, ALT001-4a, by introducing an allyl group at the C13 position of ALT001. Compared with ALT001, ALT001-4a exhibited an approximately fivefold lower EC50 for inducing mitophagy, while maintaining low cytotoxicity, and it exerted this effect via the alternative mitophagy pathway. Similarly, ALT001-4a induced mitophagy in the hippocampus of mice at a fourfold lower dose than ALT001. Importantly, ALT001-4a successfully restored mitochondrial and cognitive function in both a cellular AD model and a 5xFAD AD model. These findings suggest that the structural modification of ALT001 can generate derivatives with superior potency and potential for treating Alzheimer's disease and that further optimization could enable the development of ALT001-4a as a viable therapeutic agent for AD.
    Keywords:  Alternative mitophagy; Alzheimer’s disease; Mitophagy inducer; Structural optimization
    DOI:  https://doi.org/10.1038/s41598-026-48974-6
  17. Front Immunol. 2026 ;17 1770063
    Fumarate inhibits the formation of neutrophil extracellular traps (NETs) in a Nrf2-controlled and Annexin-A1-dependent manner associated with mitochondrial fusion.
    Gabriela Burczyk, Elzbieta Kolaczkowska.
      Neutrophil extracellular traps (NETs) constitute a critical antimicrobial mechanism, yet excessive or dysregulated NET release contributes to endothelial injury and tissue damage. Therefore, identifying physiological and pharmacological regulators of NET formation remains an important goal. Although the role of mitochondrial dynamics in NETs remains incompletely elucidated, accumulating evidence suggests that mitochondria may be underexplored regulators with therapeutic potential. In fact, in certain NET forms, their DNA is of mitochondrial origin. Here, we investigated how exogenous dimethyl fumarate (DMF), an ester of the tricarboxylic acid cycle (TCA) metabolite fumarate, modulates NET formation. Foremost, we observed that DMF markedly suppresses PAD4-dependent NET release by LPS-stimulated neutrophils of wild-type and PAD4-deficient mice. Mechanistic analyses demonstrated that DMF activates the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway and increases the secretion of anti-inflammatory Annexin A1 (ANXA1). Functionally, inhibition of either Nrf2 or the ANXA1 receptor Fpr2 restores NET formation. To integrate these observations with mitochondrial function, we examined markers of mitochondrial dynamics. We found that DMF decreases phosphorylation of dynamin-related protein 1 (DRP1) at Serine 616, a modification typically associated with reduced mitochondrial fission. Consistently, pharmacological inhibition of DRP1 (Mdivi-1) also diminishes NET formation, whereas induction of mitochondrial fragmentation (CCCP) triggers PANoptotic neutrophil death and extracellular DNA release, both of which were prevented by DMF. Collectively, these data identify DMF as a mitochondria-linked immunometabolic regulator that suppresses NET formation through coordinated engagement of Nrf2 and ANXA1 signaling and modulation of mitochondrial dynamics. These findings highlight mitochondrial remodeling as a promising avenue for future exploration and position DMF as a potential pharmacological tool for controlling excessive neutrophil activation.
    Keywords:  ANXA1; Annexin A1; Nrf2; PANoptosis; fumarate; mitochondria fission; mitochondria fusion; neutrophils
    DOI:  https://doi.org/10.3389/fimmu.2026.1770063
  18. Front Cell Dev Biol. 2026 ;14 1792645
    The role of exercise-mediated mitochondrial quality control remodeling in aging.
    Tao Cai, Yating Li, Yunsong Zhang, Chunyan Li, Shanhui Li, Qi Zhang.
      Aging is intimately associated with multisystem functional decline and an increased risk of chronic diseases. A pivotal cytological basis underlying this process is the progressive dysregulation of the mitochondrial quality control (MQC) network. Emerging evidence suggests that MQC is not a singular process but rather a multitiered synergistic system encompassing mitochondrial biogenesis, dynamic remodeling, selective autophagy (mitophagy), proteostasis maintenance, and coordinated mitochondrial-organelle communication. This integrated network is critical for preserving cellular energy homeostasis, redox balance, and stress tolerance. During aging, impairments in mitochondrial genomic coordination, network topology, autophagic flux, and protein import and folding collectively contribute to bioenergetic decline, chronic low-grade inflammation, and metabolic imbalance. As a safe and sustainable nonpharmacological intervention, regular exercise systematically remodels MQC structure and function by integrating signaling axes such as AMPK, SIRT1, and p38 MAPK, thereby promoting coordinated mitochondrial renewal and partially reversing aging-associated mitochondrial dysfunction. On the basis of a systematic elucidation of the core mechanisms of MQC and its dysregulation during aging, this review highlights the differential regulatory effects of distinct exercise modalities-specifically endurance training, high-intensity interval training (HIIT), and resistance training-on mitochondrial dynamics, autophagic flux, proteostasis, and mitochondrial turnover. Furthermore, the intrinsic associations among exercise-MQC coupling, inflammatory responses, metabolic imbalances, and emerging peripheral biomarkers are explored. Finally, current research limitations and challenges in clinical translation are analyzed, and future research directions regarding dose-response relationships, multimodal exercise prescriptions, personalized strategies, and systemic integrated regulation are proposed. This review aims to provide a refined theoretical basis for optimizing exercise-based anti-aging interventions.
    Keywords:  age; aging; exercise; mitochondrial quality control; physical training
    DOI:  https://doi.org/10.3389/fcell.2026.1792645
  19. Redox Biol. 2026 Apr 06. pii: S2213-2317(26)00155-2. [Epub ahead of print]93 104157
    FTMT-mediated suppression of mitophagy links iron accumulation to osteoporosis.
    Ruizhi Zhang, Yike Wang, Lei Li, Junjie Li, Guangchen Feng, Yutong Hu, Gongwen Liu, Xiongyi Wang, Jiajun Zhang, Peng Wei, Houfu Lai, Keyu Zhu, Xiao Wang, Xueqin Gao, Wen Wei, Yixuan Fang, Jianrong Wang, Na Yuan, Youjia Xu.
      Primary osteoporosis is a major age-related disease with a significant global health burden. While iron accumulation is a known risk factor, the mechanisms linking it to bone loss remain unclear. Here, we report that impaired mitophagy in bone marrow mesenchymal stem cells (BMSCs) is a hallmark of osteoporosis and is critically exacerbated by iron accumulation. We found that iron accumulation in BMSCs inhibits mitophagy, leading to mitochondrial dysfunction, increased oxidative stress, and cellular senescence, ultimately impairing osteogenic differentiation. Importantly, targeted activation of mitophagy, either pharmacologically or genetically, restored mitochondrial health, reduced senescence, and rescued bone formation. Conversely, Pink1 deficiency in BMSCs was sufficient to induce osteoporosis. Mechanistically, we identified that the mitochondrial ferritin FTMT is upregulated under iron-loading conditions and binds to PINK1, suppressing its phosphorylation and thereby preventing mitophagy initiation. This pathway is clinically relevant, as BMSCs from osteoporotic patients with high ferritin levels showed elevated FTMT and reduced PINK1 phosphorylation. Therefore, we identify a novel pathway in which FTMT-mediated disruption of mitophagy drives iron-induced osteoporosis. Our findings highlight mitophagy activation as a therapeutic strategy to prevent and treat bone loss under iron accumulation.
    Keywords:  Bone marrow mesenchymal stem cells; Iron accumulation; Mitochondrial ferritin; Mitophagy; Osteoporosis
    DOI:  https://doi.org/10.1016/j.redox.2026.104157
  20. Phytomedicine. 2026 Mar 31. pii: S0944-7113(26)00370-3. [Epub ahead of print]155 158136
    Senkyunolide I attenuates radiation-induced cognitive dysfunction by restoring PINK1-Parkin-mediated mitophagy and redox homeostasis.
    Tao Yan, Shun Guo, Song Zhang, Qinhui Wang, Zhimin Zhang, Weihe Zhao, Xi Li, Nannan Lai, Wei Jiang, Yuan Xu, Le Yang.
       BACKGROUND: Radiation-induced cognitive dysfunction (RICD) is a prevalent and long-term complication of cranial radiotherapy, characterized by hippocampal-dependent learning and memory impairment that severely compromises quality of life in cancer survivors. Accumulating evidence implicates sustained mitochondrial damage and oxidative stress as central drivers of RICD pathogenesis; however, clinically effective disease-modifying interventions remain lacking.
    PURPOSE: This study investigated the neuroprotective efficacy and molecular mechanisms of Senkyunolide I (SI), a bioactive phthalide derived from Ligusticum chuanxiong, in experimental models of RICD, with particular emphasis on mitochondrial quality control and antioxidant signaling.
    METHODS: RICD was modeled using fractionated head-neck irradiation (7 × 3 Gy) in mice and X-ray-irradiated PC12 cells. Behavioral and cognitive performance was assessed using open field, novel object recognition, Y-maze, and Morris water maze paradigms. Longitudinal monitoring of body weight and intake behavior was conducted to characterize irradiation-associated physiological alterations. The systemic pharmacokinetic profile and hippocampal distribution of SI following oral administration were quantified by LC-MS/MS. Mechanistic analyses included biochemical assays of oxidative and inflammatory markers, immunofluorescence evaluation of glial activation, assessment of mitochondrial membrane potential and mitochondrial ROS, ultrastructural examination by transmission electron microscopy, and Western blot analysis of proteins involved in mitophagy, antioxidant defense, and apoptosis.
    RESULTS: Oral SI administration markedly improved radiation-induced cognitive and behavioral impairments and exhibited rapid systemic absorption with enhanced hippocampal accumulation following irradiation. SI significantly attenuated oxidative stress and neuroinflammatory responses in hippocampal tissue, accompanied by preservation of mitochondrial structure and function. Mechanistically, SI restored PINK1-Parkin-mediated mitophagic flux and activated the KEAP1-Nrf2 antioxidant pathway. Pharmacological inhibition of autophagy and genetic silencing of PINK1 abolished SI-induced mitochondrial protection and antioxidant activation, confirming mitophagy as an essential upstream mechanism underlying SI-mediated neuroprotection.
    CONCLUSION: Senkyunolide I effectively mitigates radiation-induced cognitive dysfunction by coordinating mitochondrial quality control and endogenous antioxidant defenses. These findings highlight the therapeutic potential of orally administered SI and support targeting mitochondrial homeostasis as a viable strategy for the treatment of RICD.
    Keywords:  Cognitive dysfunction; Ionizing radiation; Mitophagy; Redox homeostasis; Senkyunolide I
    DOI:  https://doi.org/10.1016/j.phymed.2026.158136
  21. Precis Clin Med. 2026 Jun;9(2): pbag010
    Mitochondrial homeostasis: the central hub governing the progression of atherosclerosis.
    Hao Liu, Shuaiyong Zhao, Huiqin Gao, Yue Wang, Junyan Gao, Ping Guo, Yiting Yang, Wenrui Cui, Shuanglin Zhang, Yaping Shi, Guanxing Xie, Yutong Han, Junya Zhou, Qingqi Zhang, Yunzeng Zou.
      Atherosclerosis is a disease centered on chronic inflammation, in which mitochondrial damage plays a key role in its initiation and progression. Traditionally, atherosclerosis is thought to be triggered by cholesterol accumulation, but recent studies have revealed that mitochondrial dysfunction has emerged as an important driving factor by inducing innate immune imbalance. In atherosclerosis, mitochondria undergo changes in membrane permeability, metabolic disorders, and dynamic imbalance due to oxidative stress and other factors, releasing mitochondrial damage-associated molecular patterns (mt-DAMPs). These mt-DAMPs activate innate immune pathways, promote the production of type I interferons and the release of pro-inflammatory factors such as interleukin 1β, and accelerate plaque progression. Mitophagy exerts a protective effect by eliminating damaged mitochondria. Specifically, the PINK1-Parkin pathway labels damaged mitochondria through ubiquitination; mitophagy receptors (such as NIX, FUNDC1, and BNIP3) directly bind to LC3 to initiate ubiquitination-independent mitophagy; and mitochondrial-derived vesicles selectively encapsulate damaged components and target them to lysosomes for degradation. All these processes can reduce mt-DAMP-induced damage and inhibit excessive immune activation. In this review, we summarize that innate immune imbalance caused by mitochondrial damage is a key mechanism for atherosclerosis progression. Mitochondrial quality control clears damaged mitochondria through multiple pathways, alleviates inflammatory responses and plaque burden, and provides potential targets for atherosclerosis treatment. Its precise regulatory mechanisms and drug development are future research directions.
    Keywords:  atherosclerosis; immunometabolism; mitochondrial DNA (mtDNA); mitochondrial homeostasis; mitochondrial quality control; mt-DAMPs
    DOI:  https://doi.org/10.1093/pcmedi/pbag010
  22. Nat Commun. 2026 Apr 17.
    Hdac11 promotes idiopathic pulmonary fibrosis through macrophage M2-type polarization and myofibroblast accumulation by inhibiting Parkin-dependent mitophagy.
    Yunjuan Nie, Li Xu, Yanyan Liu, Jiao Li, Zhixu Wang, Xiaorun Zhai, Xiaoru Sun, Chunxiao Hu, Bo Xu, Yaxian Wu, Haitao Yu, Manjula Karpurapu, Huaqi Guo, Gaoshang Chai.
      Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease where macrophages drive fibrogenesis, yet Hdac11's role is unclear. We first identify pronounced Hdac11 upregulation in IPF lungs, which is associated with an enrichment in alveolar macrophages (AMs). Genetic ablation of Hdac11 or adoptive transfer of Hdac11-deficient macrophages markedly attenuates fibrosis. Specifically, Hdac11 deficiency significantly reduces M2 macrophage polarization in vivo and vitro and is associated with reduced macrophage-myofibroblast transition (MMT) like phenotypic reprogramming, thereby decreasing myofibroblast accumulation and profibrotic gene expression. Mechanistically, impaired mitophagy mediates Hdac11-mediated M2 macrophage polarization and is associated with MMT-like changes. Hdac11 regulates mitochondrial quality control by deacetylating Parkin at lysine 76, promoting its ubiquitination and degradation, which impairs mitophagy and drives profibrotic macrophage activation. Pharmacological Hdac11 inhibition effectively reverses bleomycin-induced fibrosis. Taken together, our work identifies Hdac11 as a target of Parkin-mediated mitophagy in macrophages, establishing Hdac11-Parkin axis disruption as an important mechanism in IPF and highlighting Hdac11 inhibition as a potential therapeutic strategy.
    DOI:  https://doi.org/10.1038/s41467-026-71639-x
  23. Sci Rep. 2026 Apr 12. pii: 12073. [Epub ahead of print]16(1):
    Protective role of sodium propionate against glycerol or fractionated doses of gamma rays-induced acute kidney injury via ATF5-induced mitophagy in rats.
    Mahmoud E Habieb, Maha M Ali, Amira Abd-ElRaouf, Fatma Y Abdou.
      Acute kidney injury (AKI), whether induced by nephrotoxins like glycerol or by gamma radiation, is characterized by severe oxidative stress and subsequent mitochondrial dysfunction. We investigated the protective mechanism of sodium propionate (SP) against AKI in a rat model. Six experimental groups were established: (I) control rats were given saline; (II) rats were administered SP (37.5 mg/kg, p.o.) for two weeks; (III) rats were given an intramuscular injection of glycerol 10 mL/kg body weight; (IV) rats were given glycerol followed by SP treatment for two weeks; (V) rats were exposed to fractionated gamma-radiation (8 Gy; delivered as 2 Gy x 4 times); and (VI) γ-irradiated rats were treated with SP for two weeks. In comparison to AKI rats, SP treatment significantly preserved renal function, reduced serum urea and creatinine, and improved histopathological features. Biochemically, SP reduced lipid peroxidation and protein oxidation (malondialdehyde MDA, protein carbonyl PC, and lipofuscin) while restoring antioxidant defenses as reduced glutathione (GSH) and methionine sulfoxide reductase A (MSRA). SP restored mitophagy flux by increasing microtubule-associated protein light chain 3 (LC3II/LC3I) ratio and PTEN-induced putative kinase 1 (PINK-1) levels, promoting p62 clearance, and downregulating the mitochondrial stress marker, activating transcription factor 5 (ATF5), relative to the untreated AKI groups. These findings demonstrate that SP confers protection against AKI by attenuating oxidative stress and re-establishing mitochondrial quality control through re-establishment of autophagic flux. Hence, SP represents a promising candidate for therapeutic intervention in nephrotoxin- and γ-radiation-induced renal injury.
    Keywords:  Acute kidney injury; Gamma radiation; Glycerol; Mitophagy; Rats; Sodium propionate
    DOI:  https://doi.org/10.1038/s41598-026-46553-3
  24. Toxicol Lett. 2026 Apr 14. pii: S0378-4274(26)00079-2. [Epub ahead of print] 111896
    The mitochondrial fission-mitophagy axis drives neuronal S-phase arrest and hippocampal damage in co-exposure to polystyrene nanoplastics and lead.
    Qian Li, Yingwei Zhang, Yanjing Hu, Ziheng Liu, Shize Cui, Dongqiong Wei, Lu Yue, Qian Du, Tao Liu, Dejun Huang, Yongmei Qi.
      Smaller polystyrene nanoplastics (PS-NPs) can act as vectors for co-existing environmental heavy metals like lead (Pb). The complex neurological health risks posed by these co-exposures are concerning, but their combined neurotoxicity mechanism remains unclear. This study investigated the individual and combined toxic impacts of PS-NPs (5mg/kg in mice, 50μg/mL in HT22 cells) and Pb (100mg/L in mice, 10μg/mL in HT22 cells) on hippocampal neurons, and explored the underlying mechanisms. The results show that PS-NPs facilitate Pb accumulation in the mouse hippocampus and HT22 cells via clathrin-mediated endocytosis. Co-exposure to Pb and PS-NPs, but not either alone, synergistically induced hippocampal neuronal damage, manifesting as synaptic loss and memory deficits in mice, and triggered S-phase cell cycle arrest alongside oxidative stress in HT22 cells. Mechanistically, Pb+PS-NPs caused mitochondrial dysfunction and shifted mitochondrial dynamics towards excessive fission, evidenced by upregulated DRP1/p-DRP1ser⁶¹⁶ and downregulated MFN1/2, and activated PINK1/Parkin-mediated mitophagy. Crucially, inhibition of this mitochondrial fission-mitophagy axis by Mitochondrial Division Inhibitor 1 or cyclosporin A attenuated mitochondrial damage, rescued S-phase arrest, and alleviated hippocampal neuronal injury. Our findings unveil a novel pathway wherein the mitochondrial fission-mitophagy axis drives neuronal cell cycle arrest and cognitive impairment, providing new insights into the risks of combined pollutant exposure.
    Keywords:  Combined exposure; Lead neurotoxicity; Mitochondrial fission-mitophagy axis; Polystyrene nanoplastics; S-phase arrest
    DOI:  https://doi.org/10.1016/j.toxlet.2026.111896
  25. Stem Cell Res Ther. 2026 Apr 16.
    From collapse to comeback: Luteolin rejuvenates nucleus pulposus progenitor cells via SIRT1/ATF5-UPRmt to reverse intervertebral disc degeneration cascade.
    Huofeng Wu, Shuangjia Zai, Xuan You, Chen Liu, Zhaoyu Li, Zhengguang Li, Yuhui Mei, Benkui Hua, Yuping Tao, Yiming Wu, Liang Zhang.
       BACKGROUND: Intervertebral disc degeneration (IVDD) is a major contributor to low back pain (LBP) and one of the foremost causes of disability worldwide. Oxidative stress-induced senescence of nucleus pulposus progenitor cells (NPPC) and mitochondrial dysfunction are key drivers of IVDD. The mitochondrial unfolded protein response (UPRmt), orchestrated by the Silent Information Regulator 1 (SIRT1)-Activating Transcription Factor 5 (ATF5) axis, plays a pivotal role in maintaining mitochondrial proteostasis. However, its involvement in IVDD remains insufficiently characterized. Luteolin (Lut), a naturally occurring flavonoid with well-documented antioxidant and anti-senescence properties, has emerged as a promising disease-modifying candidate.
    METHODS: We employed an integrated approach combining network pharmacology, molecular docking, and Mendelian randomization to identify and validate SIRT1 as a central target of Lut in IVDD. Human nucleus pulposus (NP) tissues spanning Pfirrmann grades II-V were analyzed to assess the expression of SIRT1 and UPRmt-related proteins. Functional assays in TBHP-induced NPPC senescence models were conducted to evaluate the effects of Lut on proliferation, senescence, mitochondrial function, and UPRmt activation, with or without SIRT1 knockdown. Finally, a puncture-induced rat IVDD model was employed to assess the therapeutic efficacy of Lut with imaging, histological, and behavioral analyses.
    RESULTS: Human NP specimens exhibited a progressive decline in SIRT1, ATF5, and UPRmt effectors (HSP60, LONP1, CLPP) with advancing degeneration grades. Lut was found to directly bind SIRT1, thereby stabilizing mitochondrial function and alleviating NPPC senescence through activation of the SIRT1-ATF5-UPRmt pathway. Genetic silencing of SIRT1 abolished the protective effects of Lut on cellular senescence, UPRmt activation, and bioenergetics. In vivo, Lut administration attenuated disc height loss, preserved extracellular matrix integrity and partially alleviated pain-like behaviors in rats with IVDD.
    CONCLUSION: This study establishes SIRT1 as a central therapeutic target of Lut and underscores the SIRT1-ATF5-UPRmt axis as a critical mechanism mediating its protective effects. By restoring mitochondrial proteostasis and delaying NPPC senescence, Lut emerges as a promising disease-modifying strategy for IVDD management.
    Keywords:  Intervertebral disc degeneration; Mendelian randomization; Mitochondrial unfolded protein response; Molecular dynamics; Network pharmacology
    DOI:  https://doi.org/10.1186/s13287-026-05003-7
  26. Sleep Biol Rhythms. 2026 Apr;24(2): 259-266
    Mitophagy protects renal tubular epithelial cells from intermittent hypoxia-induced injury via the HIF-1α/BNIP3 pathway.
    Xiao-Bin Zhang, Qi-Feng Gan, Yu-Xin Guo, Li-Da Chen, Li-Qin Zhang, Ling Cai, Ya-Ting Yuan, Jing-Huang Cai, Xiang-Xin Chen.
      This study aimed to investigate the role of mitophagy mediated by the hypoxia-inducible factor-1α (HIF-1α)/Bcl-2/adenovirus E1B 19-kDa interacting protein (BNIP3) pathway in mitigating renal injury induced by intermittent hypoxia (IH), a hallmark of obstructive sleep apnea (OSA). Human renal tubular epithelial cells (RTECs) were exposed to IH conditions using a hypoxia-reoxygenation chamber for 24 h. Cells were divided into five groups: normoxia, IH, IH with HIF-1α siRNA (IH + si-HIF-1α), IH with BNIP3 siRNA (IH + siBNIP3), and IH with HIF-1α siRNA plus BNIP3 overexpression (IH + si-HIF-1α + BNIP3). Cell viability, apoptosis, mitochondrial morphology, and mitophagy levels were assessed using flow cytometry, western blotting, transmission electron microscopy, and immunofluorescence. Under IH conditions, inhibition of HIF-1α or BNIP3 significantly reduced cell viability, increased apoptosis, disrupted mitochondrial structure, and decreased mitophagy levels in RTECs. Overexpression of BNIP3 in the presence of HIF-1α inhibition restored mitophagy levels, attenuated cellular damage and apoptosis, and improved mitochondrial morphology. These findings demonstrate that mitophagy mediated by the HIF-1α/BNIP3 signaling pathway plays a protective role in IH-induced renal injury, suggesting that targeted enhancement of mitophagy may provide a potential therapeutic strategy for OSA-related kidney dysfunction.
    Supplementary Information: The online version contains supplementary material available at 10.1007/s41105-025-00625-5.
    Keywords:  BNIP3; HIF-1α; Intermittent hypoxia; Mitophagy; Renal tubular epithelial cells
    DOI:  https://doi.org/10.1007/s41105-025-00625-5
  27. Chin J Traumatol. 2026 Apr 03. pii: S1008-1275(26)00070-2. [Epub ahead of print]
    Advances in understanding mitophagy's role in lung injury.
    Wenyu Du, Youjing Yang, Tao Zhang, Junyu Jiang, Dingyuan Du, Guangbin Huang, Shasha Tao.
      Mitophagy has emerged as a key regulator in lung injury, presenting new avenues for therapeutic intervention. Lung injury, often caused by infections, trauma, or inhalation of toxic gases, disrupts lung tissue integrity and function, frequently leading to pulmonary fibrosis. Mitophagy serves a dual purpose: it removes damaged mitochondria, reducing oxidative stress and preventing cell death, thereby offering protection in acute lung injury. However, excessive mitophagy can deplete mitochondria, impair energy metabolism, and aggravate tissue damage. Throughout the progression of lung injury, mitophagy finely tunes inflammation, immune responses, and cell survival, helping to modulate cytokine storms and delay fibrosis. Additionally, it influences metabolic reprogramming and intercellular communication, affecting critical cell types such as alveolar epithelial cells, macrophages, and fibroblasts, which are essential for tissue repair and regeneration. Although the precise molecular mechanisms remain under investigation, mitophagy is increasingly recognized as a promising therapeutic target for lung injury and fibrosis. The future challenge lies in achieving a precise balance in the regulation of mitophagy to maximize its protective effects while minimizing potential harm, thereby opening new pathways for innovative therapeutic strategies.
    Keywords:  Acute lung injury; Intercellular communication; Mitophagy; Pulmonary fibrosis
    DOI:  https://doi.org/10.1016/j.cjtee.2025.06.004
  28. Tissue Cell. 2026 Apr 15. pii: S0040-8166(26)00228-4. [Epub ahead of print]102 103535
    Integrative multi‑omics and experimental validation reveal that Duhuo Jisheng Decoction alleviates IVDD by inhibiting MAPK signaling‑mediated inflammation, apoptosis, and mitochondrial dysfunction.
    Fei Liu, Chao Song, Yinjing Luo, Xiaoqiang Wang, Zhangchao Wei, Qian Yan, Zhijiang Fu, Zongchao Liu, Feng Chen.
       BACKGROUND: Intervertebral disc degeneration (IVDD) is a chronic and progressive condition with limited therapeutic options. Duhuo Jisheng Decoction (DHJSD), a traditional Chinese medicine formula, is clinically used to alleviate IVDD, but its underlying mechanisms remain unclear.
    PURPOSE: This study aims to investigate the active components and molecular mechanisms of DHJSD in treating IVDD, with a focus on the p38MAPK signaling pathway and mitochondrial homeostasis.
    METHODS: Bioinformatic analyses, including transcriptomic profiling, single-cell RNA sequencing, and network pharmacology, were performed to identify active components and potential targets. The findings were validated using in vitro (LPS-induced degenerated nucleus pulposus cells) and in vivo (rat tail puncture-induced IVDD model) experiments.
    RESULTS: Transcriptomic analysis revealed 2202 differentially expressed genes, and 10 hub genes (e.g., TP53, AKT1, TNF) were identified. Single-cell analysis identified 12 cell types in degenerated NP tissues, with immune cells enriched in early degeneration and fibrotic NP cells in advanced stages. Network pharmacology screened 28 hub targets, with 11 core targets (e.g., IL-1β, TNF, CASP3) enriched in MAPK and inflammation-related pathways. In vivo, DHJSD treatment significantly improved disc height (DR imaging) and water content (MRI), restored histological structure (HE and Safranin-O staining), and reduced serum TNF-α and IL-1β levels (*p < 0.05). In vitro, DHJSD-containing serum (medium dose, 48 h) significantly reversed LPS-induced decreases in cell proliferation (CCK-8), upregulated Col II and Agg expression, and downregulated TNF-α, IL-1β, MMP-2, CASP3, and p38MAPK/JNK phosphorylation (*p < 0.05). DHJSD also partially restored mitochondrial membrane potential, indicating improved mitophagy.
    CONCLUSION: DHJSD alleviates IVDD by suppressing inflammation, ECM degradation, and NP cell apoptosis, likely via regulating mitophagy through the p38MAPK signaling pathway. Collectively, this work not only establishes DHJSD as a modulator of the p38MAPK-mitophagy axis but also offers a mechanistic paradigm that shifts the understanding of TCM-based IVDD therapy from broad efficacy to pathway-specific intervention.
    Keywords:  Apoptosis; Duhuo Jisheng Decoction; Intervertebral degenerative disc; MAPK pathway; Mitophagy
    DOI:  https://doi.org/10.1016/j.tice.2026.103535
  29. J Mol Med (Berl). 2026 Apr 14. pii: 64. [Epub ahead of print]104(1):
    GFRAL is required to mediate changes in systemic metabolism in response to mitochondrial stress in brown adipose tissue.
    Ayushi Sood, Joshua Peterson, Jayashree Jena, Vamsi Challa, Caden Washburn, Randy J Seeley, Renata O Pereira.
      Growth differentiation factor 15 (GDF15) is a cytokine induced in several tissues in response to stress. GDF15 suppresses food intake and increases energy expenditure via its actions on the glial-derived neurotrophic factor receptor α family-like specific receptor (GFRAL), located in the hindbrain. We recently showed that selective deletion of the mitochondrial fusion protein optic atrophy 1 (OPA1) in brown adipocytes (OPA1 BKO) leads to GDF15 secretion, partially mediating resistance to diet-induced obesity (DIO), and improving thermoregulation. To investigate whether GDF15 signaling through GFRAL is necessary to mediate these metabolic effects, we crossed OPA1 BKO mice with GFRAL global knockout mice (DKO). Under isocaloric conditions, DKO mice had similar body weight as control and OPA1 BKO mice. Upon high-fat diet feeding, DKO mice were partially resistant to DIO, but lacked the improvement in glucose homeostasis and insulin sensitivity observed in OPA1 BKO mice. Finally, DKO mice were susceptible to cold-induced hypothermia, suggesting a role for GFRAL in core body temperature regulation in the OPA1 BKO mice. Our data reveals a novel BAT-GDF15-GFRAL axis that modulates resistance to DIO and improves thermoregulation in mice in the context of mitochondrial stress. KEY MESSAGES: OPA1 deletion induces a BAT-GDF15-GFRAL axis to regulate systemic metabolic homeostasis. GDF15-signaling through GFRAL partially mediates resistance to DIO in mice lacking OPA1 in BAT. GFRAL mediates GDF15's effects on energy homeostasis in DIO OPA1 BKO mice. GDF15-GFRAL signaling is required to maintain core body temperature in cold-exposed OPA1 BKO mice.
    Keywords:  Brown adipose tissue; GDF15; GFRAL; OPA1; Obesity; Thermoregulation
    DOI:  https://doi.org/10.1007/s00109-026-02671-z
  30. Phytother Res. 2026 Apr 12.
    Saikosaponin D Alleviates Liver Ischemia-Reperfusion Injury by Inhibiting Mitophagy-Associated Ferroptosis via the STAT3/PINK1 Pathway.
    Xingyun Liu, Yaru Xu, Xiaolan Yu, Xiao Feng, Youwen Han, Haijian Cai, Jian Du, Lijian Chen.
      Liver ischemia-reperfusion injury (LIRI) may cause severe complications in liver surgery, primarily involving damage to hepatocytes and endothelial cells, as well as an inflammatory response from immune cells. Saikosaponin D, a plant widely used in traditional Chinese medicine for treating inflammation, fever, and liver diseases. This research was intended to elucidate the function and mechanism of Saikosaponin D (SSD) in ameliorating liver ischemia-reperfusion injury. The effect of SSD on liver ischaemia-reperfusion injury was studied in mice following oral gavage administration. Liver injury was assessed using haematoxylin and eosin (H&E) staining and serum biochemical analysis. To evaluate ferroptosis levels, various methods were used, including reactive oxygen species (ROS), lipid peroxidation, glutathione (GSH) and oxidized glutathione (GSSG) levels, Malondialdehyde (MDA), Fe2+ indicator FerroOrange, Western blotting and transmission electron microscopy (TEM). The effect of Saikosaponin D in combination with signal transducer and activator of transcription 3 (STAT3) overexpression or PTEN-induced putative kinase 1 (PINK1) knockdown on ferroptosis in a hypoxia-reoxygenation model was studied in vitro. SSD alleviated liver ischemia-reperfusion injury by activating mitophagy and inhibiting ferroptosis. The mitochondrial autophagy inhibitor Mdivi-1 reversed the pharmacodynamic effects of SSD. Importantly, in hypoxia-reoxygenation of AML12 cells, STAT3 overexpression inhibited PINK1-associated mitophagy, aggravated Fe2+ accumulation, lipid peroxidation and malondialdehyde levels, accelerated GSH depletion, aggravated the downregulation of Glutathione Peroxidase 4 (GPX4) and Solute carrier family 7 membrane 11 (SLC7A11) and upregulation of Transferrin receptor (TFR), while PINK1 silencing produced similar results. The inhibitory effect of SSD on ferroptosis in a hypoxia-reoxygenation model was counteracted by STAT3 overexpression and PINK1 silencing. SSD protects the liver against ischemia-reperfusion injury by inhibiting ferroptosis through STAT3/PINK1/PARKIN-mediated mitophagy, highlighting its potential as a therapeutic agent in liver ischemia-reperfusion injury treatment.
    Keywords:  STAT3/PINK1; Saikosaponin D; ferroptosis; liver ischemia–reperfusion injury; mitophagy
    DOI:  https://doi.org/10.1002/ptr.70333
  31. Nat Commun. 2026 Apr 14.
    Mitophagy promotes lung repair and regeneration by restoring epithelial metabolic fitness.
    Pei Wu, Jiawei Chen, Li Liu, Ping Wang, Tiantian Lu, Shengxi Shen, Yiyuan Cao, Yuandong Sui, Run Liu, Xiajuan Huan, Ning Ding, Ying Xi.
      Alveolar Type II cells (AT2s) are the stem cells responsible for both lung homeostasis and regeneration. Mitochondrial dysfunction in AT2 cells has been implicated in both chronic and acute injury-induced alveolar diseases, including idiopathic pulmonary fibrosis (IPF) and viral pneumonia. However, the role of mitochondrial homeostasis in post-injury lung repair and regeneration remains elusive. Here we demonstrate that genetic depletion of Ubiquitin Specific Peptidase 30 (USP30), a negative regulator of mitophagy, boosts mitophagy and restores mitochondrial function in AT2 cells, leading to protection from injury-induced apoptosis and enhanced stem cell activity. Both global and AT2-specific Usp30 knockout (KO) promote alveolar regeneration, protecting the mice from bleomycin-induced lung fibrosis and influenza pneumonia. Moreover, pharmacological inhibition of USP30 effectively alleviates these conditions. Together, our findings reveal a previously underappreciated role for mitophagy in lung injury and repair and highlight USP30 inhibition as a promising therapeutic strategy for treating alveolar diseases.
    DOI:  https://doi.org/10.1038/s41467-026-71728-x
  32. J Exp Clin Cancer Res. 2026 Apr 18.
    The PPTC7/BNIP3/NIX axis induces cGAS/STING-mediated senescence and augments CAR-T efficacy by repressing tumor-intrinsic mitophagy.
    Kuai Yu, Xinxin Xiong, Bo Lu, Yaqun Wang, Tiantian Sun, Mei Xie, Xiaojun Xu, Yuanbin Song, Wei Xiao.
      
    Keywords:  BNIP3/NIX; CGAS/STING Pathway; Chimeric Antigen Receptor T Cell; Mitophagy; Multiple Myeloma; Protein Phosphatase Targeting Cofactor 7
    DOI:  https://doi.org/10.1186/s13046-026-03713-7
  33. Transl Cancer Res. 2026 Mar 31. 15(3): 163
    Gene expression profile, and role of baicalein in the inhibition of thyroid cancer.
    Nan Wu, Qian Zhang, Muhammad Naeem, Ren Jing, Yuanbin Luo, Yang Wu, Shijian Yi.
       Background: Anaplastic thyroid cancer (ATC) is the highly undifferentiated form of thyroid cancer, and its incidence is still high all around the globe. The current treatment for ATC includes surgery, chemotherapy, and radioactive iodine therapy. These treatment options are not reliable due to high cost, drug resistance, and toxicity issues. Baicalein (BA) is a natural flavonoid isolated from Scutellaria baicalensis that exhibits several pharmacological activities, including anticancer, anti-inflammatory, antioxidant, and antitumor. The role of BA in elucidating the mechanism of ATC, emphasizing the CLU-mediated mitophagy, remains unclear. This study was designed to investigate the impact of BA on gene expression and cellular pathways in CAL62 ATC cells by CLU-mediated mitophagy.
    Methods: Differential gene expression and pathway enrichment were assessed using RNA sequencing and gene set enrichment analysis (GSEA). Mitochondrial fluorescence and mitophagy markers (PINK1, PRKN, ATG5, MFN1) were evaluated by quantitative polymerase chain reaction (qPCR) and fluorescence microscopy. CLU expression and its correlation with cancer progression were analyzed using The Cancer Genome Atlas (TCGA) data.
    Results: BA treatment altered gene expression and pathway activity, impacting processes including cell proliferation, mitophagy, and epithelial-mesenchymal transition. It reduced the mitochondrial fluorescence intensity and mitophagy marker levels, consistent with an inhibition of mitophagy. BA also modulated thyroid cancer markers, indicating the induced dedifferentiation. TCGA analysis confirmed the CLU upregulation in thyroid cancer, linking it to disease progression and survival. BA inhibits ATC cell growth, an effect associated with the alteration of CLU-linked mitophagy and key signaling pathways.
    Conclusions: These findings highlight that CLU as a potential therapeutic target and suggested BA as a promising strategy for thyroid cancer intervention.
    Keywords:  Anaplastic thyroid cancer (ATC); baicalein (BA); clusterin (CLU); dedifferentiation; mitophagy
    DOI:  https://doi.org/10.21037/tcr-2025-aw-2437
  34. Naunyn Schmiedebergs Arch Pharmacol. 2026 Apr 17.
    Beyond energy production: targeting mitochondrial biogenesis in aging and cancer with phytochemical intervention.
    Adelene Gan-Yin-Xuen, Soni Thakur, Mohd Adnan, Sreenivasan Sasidharan.
      Mitochondrial biogenesis, the process by which cells generate new mitochondria, is crucial for maintaining cellular homeostasis, energy production, and overall health. Mitochondrial dysfunction is a key factor in both aging and cancer, where it contributes to the decline in cellular function and facilitates the progression of disease. In aging, mitochondrial alterations lead to impaired metabolic function, increased oxidative stress, and cellular senescence. Similarly, cancer cells often exhibit altered mitochondrial dynamics, which support rapid proliferation and resistance to apoptosis. Despite their differences, aging and cancer share common molecular mechanisms, particularly in mitochondrial dysregulation, that offer insights into potential therapeutic strategies. Recent research has highlighted the potential of medicinal plants and their bioactive compounds in modulating mitochondrial biogenesis and mitigating dysfunction. Phytochemicals have shown promise in enhancing mitochondrial function, promoting healthy aging, and inhibiting cancer progression. This review explores the molecular mechanisms underlying mitochondrial biogenesis, its dysregulation in aging and cancer, and the therapeutic potential of plant-based compounds in targeting mitochondrial dysfunction. By understanding the intricate relationship between mitochondria, aging, and cancer, novel therapeutic strategies can be developed to improve cellular health and combat age-related diseases and cancer.
    Keywords:  Aging; Cancer; Mitochondrial biogenesis; Mitochondrial dysfunction; Phytochemicals
    DOI:  https://doi.org/10.1007/s00210-026-05299-5
  35. Phytomedicine. 2026 Apr 06. pii: S0944-7113(26)00400-9. [Epub ahead of print]155 158166
    Polyphyllin VI induces Forkhead box O3 nuclear liquid-liquid phase separation to promote mitophagy in breast cancer.
    Xiangrong Zhan, Yifan Zhong, Xuewen Liu, Wenkang Peng, Xu Zhang, Ke Xiang, Qingqing Yu, Yanting Chai, Yingli Chen, Ying Liu, Yuan Si.
       BACKGROUND: Mitochondrial dysfunction and defective mitophagy are closely associated with cancer progression. Forkhead box O3 (FOXO3), a key transcription factor, promotes autophagy by activating autophagy-related genes. Polyphyllin VI (PPVI), a Paris polyphylla-derived steroidal saponin, displays potent antitumor activity.
    PURPOSE: To investigate the antitumor effect of PPVI in breast cancer (BC) and elucidate its underlying mechanism.
    METHODS: Differential gene expression and pathway enrichment were analyzed using RNA sequencing. Mitochondrial autophagic flux was assessed using the mKeima-Red-Mito-7 plasmid. Expression of mitophagy-related markers was evaluated by qPCR and Western blot. FOXO3 was identified as a direct PPVI-binding protein using a biotin-labeled PPVI and mass spectrometry. Their interaction was validated by Microscale thermophoresis. The role of FOXO3 in PPVI-induced mitophagy was studied using gene knockout, gene/protein expression analysis, and functional assays. FOXO3-driven liquid-liquid phase separation (LLPS) and PPVI's regulatory role were analyzed by live-cell imaging, fluorescence recovery after photobleaching, truncation mutants, and molecular dynamics simulations. The in vivo anticancer activity of PPVI was evaluated using zebrafish and xenograft mouse models. Drug toxicity was assessed in zebrafish, while pharmacokinetics and tissue distribution were evaluated in rats.
    RESULTS: PPVI induced BNIP3/NIX-mediated mitophagy and mitochondrial dysfunction. It directly bound FOXO3, promoting nuclear translocation and transcriptional activation. FOXO3 underwent LLPS, mainly driven by its C2 region (151-673 aa), and PPVI enhanced the nuclear LLPS of FOXO3. PPVI suppressed tumor growth in vivo but exhibited cardiotoxicity in zebrafish. It primarily accumulated in the liver, had a short half-life, and showed extremely low oral bioavailability.
    CONCLUSION: PPVI exerts its anti-BC activity by directly binding FOXO3, inducing its nuclear condensation with LLPS-like properties, and thereby predominantly engages BNIP3/NIX-mediated mitophagy. These findings reveal that the antitumor effects of PPVI rely on an unrecognized critical role of FOXO3 phase behavior, establishing PPVI as a unique pharmacological probe and lead compound that functions through direct modulation of FOXO3, offering a new direction for therapeutic development.
    Keywords:  BNIP3/NIX; Breast cancer; FOXO3; Liquid-liquid phase separation; Mitophagy; Polyphyllin VI
    DOI:  https://doi.org/10.1016/j.phymed.2026.158166
  36. Adipocyte. 2026 Dec;15(1): 2651605
    The role and mechanism of UPRmt in adipocytes.
    Hao Liu, Jie Chen, Dan-Qi Qiu, Miao-Wei Jiang, Hao-Qi Chen, Li Li, Shu-Qin Chen.
      Obesity is one of the most significant health challenges today, with its prevalence increasing rapidly worldwide. The associated inflammatory state is a major risk factor for developing type 2 diabetes, cardiovascular diseases, and sleep apnoea, putting immense pressure on global healthcare systems. Abnormal accumulation or dysfunction of adipose tissue can lead to obesity, which is a major risk factor for metabolic and cardiovascular diseases. The mitochondrial unfolded protein response (UPRmt) serves as a critical adaptive mechanism that safeguards cellular homoeostasis during mitochondrial proteostatic stress by orchestrating the expression of chaperones, proteases, and metabolic regulators to restore protein folding capacity and mitigate organelle dysfunction. This review discusses the role of UPRmt in adipocytes, a key player in maintaining metabolic homoeostasis and thermogenesis. Understanding UPRmt's mechanisms could offer novel therapeutic strategies to combat obesity and its complications.
    Keywords:  Mitochondrial unfolded protein response; UPRmt; adipocyte; metabolism
    DOI:  https://doi.org/10.1080/21623945.2026.2651605
  37. J Assist Reprod Genet. 2026 Apr 11.
    The mitochondrial signature of sperm motility loss: a study of mitophagy and apoptosis in asthenozoospermia.
    Kübra Nur Uzun, Adile Merve Baki, Ayşe Altun Akpınar, İlknur Keskin, Şule Ayla.
       PURPOSE: To investigate whether mitophagy contributes to the pathophysiology of asthenozoospermia through its association with apoptosis and oxidative stress, and to elucidate potential mechanisms underlying impaired sperm motility.
    METHODS: This controlled study included a total of 60 semen samples collected from male patients between 2023 and 2024. Participants were categorized into asthenozoospermic (A, n = 30) and normozoospermic (N, n = 30) groups based on sperm motility, according to WHO criteria. The expression of ATG5 and cyt-c was examined using immunofluorescence and western blotting. Mitochondrial membrane potential (MMP) was measured with JC-1 dye, and oxidative stress markers (MDA and AOPP) were quantified in seminal plasma. Transmission electron microscopy was performed to evaluate mitochondrial ultrastructure.
    RESULTS: Sperm with preserved MMP were significantly reduced in the asthenozoospermic group (p < 0.0001, d = 2.12). Elevated MDA (p < 0.0001, d = 2.58) and AOPP (p < 0.0001, r = 0.71) levels seen in asthenozoospermic group are indicative of increased oxidative stress. ATG5 and cyt-c expression levels were significantly higher in astehenozoospermic sperm (p = 0.003, d = 1.38; p = 0.0003, r = 0.51, respectively), and a strong correlation was found between these two markers in both groups (N, p < 0.0001; A, p = 0.0002). However, no significant correlation was found between mitophagy/apoptosis markers and oxidative stress levels. Ultrastructural examination revealed mitochondrial damage and autophagosome-like structures in asthenozoospermic samples.
    CONCLUSIONS: Asthenozoospermia is characterized by increased mitophagy and apoptosis independent of MDA and AOPP, suggesting impaired mitochondrial quality control as a potential mechanism for reduced sperm motility. These findings provide insights into the molecular basis of sperm dysfunction and support further research into mitochondrial-targeted strategies for managing asthenozoospermia.
    Keywords:  ATG5; Apoptosis; Asthenozoospermia; Mitophagy; Oxidative stress
    DOI:  https://doi.org/10.1007/s10815-026-03867-5
  38. J Hazard Mater. 2026 Apr 13. pii: S0304-3894(26)01052-6. [Epub ahead of print]509 142074
    L-BMAA induces neurotoxicity through AMPK/Akt-TSC1/2-mTOR-mediated mitophagy dysregulation and apoptosis.
    Tingting Yan, Xinyi Zheng, Guangyin Jia, Zhencheng Liang, Liujun Guo, Feng Ding, Zhongyuan Fang, Yinan Li, Yan Zhao.
      Under the context of global climate change, the growing frequency of cyanobacterial blooms has heightened scientific focus on the neurotoxicity of β-N-methylamino-L-alanine (L-BMAA)-an environmental neurotoxin linked to neurodegeneration disorders. However, the precise cellular mechanisms underlying its neurotoxicity remain unclear. In this study, we aimed to elucidate these mechanisms using both in vitro (human SH-SY5Y neuroblastoma cells) and in vivo (zebrafish) models, and utilized transcriptomics, biochemical assays, and behavioral analyses. In vitro studies revealed that L-BMAA enhances oxidative stress, disrupts mitochondrial function, and triggers destructive mitophagy and apoptosis. Transcriptomic (RNA-seq) and proteomic (mass spectrometry) analyses identified apoptosis- and mitochondrial function-related pathways as central targets. Mechanistically, Western blots demonstrated that L-BMAA promotes mitophagy in SH-SY5Y cells by enhancing AMPK-TSC1/2-mTOR signaling while concurrently weakening the Akt-TSC1/2-mTOR axis, a pathway shift validated by specific inhibitor experiments. Consistent with these cellular mechanisms, in vivo results demonstrate that L-BMAA exposure impairs zebrafish learning, spatial memory, and induces anxiety-like behaviors. These behavioral deficits are linked to brain mitochondrial dysfunction and oxidative stress. Furthermore, transcriptomic analysis of zebrafish brain tissue confirmed significant dysregulation of genes involved in mitochondrial function. Overall, our study establishes that mitochondrial dysfunction and exaggerated mitophagy contribute to L-BMAA-induced injury in both zebrafish brains and SH-SY5Y cells, offering a potential therapeutic target for treating therapy-refractory neurodegenerative diseases caused by environmental factors.
    Keywords:  L-BMAA; Mitochondrial dysfunction; Mitophagy; Neurodegenerative diseases; Oxidative stress
    DOI:  https://doi.org/10.1016/j.jhazmat.2026.142074
  39. Precis Clin Med. 2026 Jun;9(2): pbag009
    Agrimol B inhibits pancreatic ductal adenocarcinoma by induction of lethal mitophagy through decreasing mitochondrial transcription termination factor 3.
    Yifei Ma, Ying Zheng, Ying Zhou, Yang Yang, Jinlu Liu, Ningna Weng, Junhong Han, Qing Zhu.
       Objective: To investigate the inhibitory effect of the natural polyphenol Agrimol B on pancreatic ductal adenocarcinoma (PDAC) and its underlying molecular mechanisms.
    Methods: The effects of Agrimol B on PDAC cell proliferation and apoptosis were assessed using Cell Counting Kit-8, colony formation, and flow cytometry assays. An in vivo PDAC xenograft mouse model was established for evaluation. Label-free quantitative proteomics, western blotting, immunofluorescence, and transmission electron microscopy were employed to analyze mitochondrial function, autophagy, and related signaling pathways. A patient-derived organoid model was used to evaluate the synergistic effects of Agrimol B with first-line chemotherapy drugs.
    Results: Agrimol B significantly inhibited PDAC growth and induced apoptosis both in vitro and in vivo. Mechanistically, Agrimol B downregulated the expression of mitochondrial transcription termination factor 3, and promoted the accumulation of PTEN induced kinase 1 (PINK1) in mitochondria and Parkin translocation, thereby excessively activating PINK1/Parkin-dependent mitophagy. Concurrently, Agrimol B blocked lysosome biogenesis, leading to autophagosome accumulation and impaired autophagic flux. This dysfunctional autophagy ultimately mediated the anti-PDAC effect of Agrimol B. Furthermore, in PDAC patient-derived organoids, Agrimol B exhibited synergistic effects with first-line chemotherapy drugs such as gemcitabine and nab-paclitaxel.
    Conclusion: Agrimol B exerts its anti-PDAC effects by downregulating mitochondrial transcription termination factor 3, hyperactivating PINK1/Parkin-mediated mitophagy, and obstructing autophagic flux. Its synergistic effect with chemotherapy drugs provides experimental evidence supporting its potential clinical translation.
    Keywords:  Agrimol B; MTERF3; PINK1/Parkin; mitophagy; pancreatic ductal adenocarcinoma
    DOI:  https://doi.org/10.1093/pcmedi/pbag009
  40. Cells. 2026 Mar 28. pii: 603. [Epub ahead of print]15(7):
    Irisin as a Regulator of Brain Energy Homeostasis: Implications for Age-Related Neurodegenerative Diseases.
    Bartosz Osuch, Patrycja Młotkowska, Elżbieta Marciniak, Tomasz Misztal.
      Aging is associated with disturbances in brain energy metabolism, mitochondrial dysfunction, and increased oxidative stress, all of which increase neuronal vulnerability and contribute to the development of neurodegenerative disorders. Growing evidence indicates that physical exercise exerts neuroprotective effects through the release of exerkines-exercise-induced signaling molecules that mediate communication between peripheral tissues and the brain. Among them, irisin, a proteolytic cleavage product of the membrane protein FNDC5, has emerged as an important mediator of the muscle-brain axis. This review summarizes current knowledge on the molecular mechanisms underlying irisin activity in the central nervous system, with particular emphasis on the AMPK-PGC-1α-FNDC5/BDNF signaling axis, rapid receptor-mediated pathways involving the cAMP/PKA/CREB and ERK/CREB cascades, and the regulation of mitochondrial homeostasis, including biogenesis, dynamics, autophagy, and mitophagy. Experimental studies suggest that irisin may improve neuroplasticity, neuronal survival, mitochondrial function, and reduce oxidative stress, thereby alleviating cognitive deficits in models of aging and neurodegeneration. Although the precise receptor mechanisms and intracellular signaling events remain incompletely understood, accumulating evidence identifies irisin as a promising therapeutic target linking metabolic adaptation with neuroprotection. Further investigation of irisin-dependent pathways may facilitate the development of novel strategies aimed at preserving brain function and delaying the progression of age-related neurodegenerative diseases.
    Keywords:  AMPK–PGC-1α; BDNF; FNDC5; irisin; mitochondrial homeostasis; mitophagy; neurodegenerative diseases
    DOI:  https://doi.org/10.3390/cells15070603
  41. Redox Biol. 2026 Mar 09. pii: S2213-2317(26)00113-8. [Epub ahead of print]93 104115
    Mitochondrial redox homeostasis links organellar stress surveillance to germline and somatic integrity in Caenorhabditis elegans.
    Marina Valenzuela-Villatoro, Patricia de la Cruz-Ruiz, David Guerrero-Gómez, Eva Gómez-Orte, Alfonso Schiavi, Silvia Maglioni, Mayte Montero, Rosalba I Fonteriz, José Carlos Casas-Martínez, Nicole E Briand, Jingxiu Xu, María Jesús Rodriguez-Palero, Marta Artal-Sanz, Katarzyna Olek, Justyna Polaczyk, Michal Turek, Wojciech Pokrzywa, Suhong Xu, Javier E Irazoqui, Brian McDonagh, Javier Álvarez, María Olmedo, Natascia Ventura, Juan Cabello, Antonio Miranda-Vizuete.
      Mitochondrial redox homeostasis is essential for cellular metabolism and organismal development. To investigate the consequences of disrupting redox homeostasis in this organelle in a metazoan organism, we generated a double mutant lacking mitochondrial glutathione reductase (gsr-1a) and thioredoxin reductase (trxr-2) genes in Caenorhabditis elegans. While gsr-1a or trxr-2 single mutants are phenotypically normal, double gsr-1a trxr-2 mutants displayed small body size, gonadal migration defects, reduced brood size, and prolonged egg-laying period, without developmental delay or lethality. Transcriptomic analysis revealed strong induction of ATFS-1-dependent stress and detoxification genes. Consistent with this, gsr-1a trxr-2 worms exhibited constitutive ATFS-1 nuclear localization and robust Phsp-6::gfp expression. Triple gsr-1a trxr-2; atfs-1 mutants were nonviable, demonstrating that unfolded protein response (UPRmt) activation is essential under mitochondrial redox stress. Despite the induction of a stress response at the transcriptional level, gsr-1a trxr-2 double mutants were not more resistant to oxidative or pathogen stressors. Moreover, these mutants maintained normal respiration, ATP and ROS production while displaying altered mitochondrial morphology in a tissue-specific manner, independent of mitophagy genes but dependent on mitochondrial fission or fusion machinery. Functionally, gsr-1a trxr-2 mutants showed impaired motility, reduced calcium uptake upon carbachol stimulation, enhanced hypodermal wound repair, and decreased fertilization efficiency associated with lower muscle exopher production. Overall, our data show that simultaneous loss of mitochondrial GSR-1a and TRXR-2 compromises growth, fertility and muscle performance and triggers a constitutive ATFS-1-dependent UPRmt that sustains viability revealing mitochondrial redox control as a core determinant of organismal proteostasis.
    Keywords:  ATFS-1; Elegans; Glutathione reductase; Mitochondria; Thioredoxin reductase; Unfolded protein response
    DOI:  https://doi.org/10.1016/j.redox.2026.104115
  42. Endocr Metab Immune Disord Drug Targets. 2026 Apr 08.
    An Integrative Analysis of the Role of Mitophagy in Comorbid Myocardial Infarction and Type 2 Diabetes Mellitus.
    Ying Yang, Feiyan Wan, Xuelian Xu, Wei Xu, Lingli Jiang, Pei Pan.
       INTRODUCTION: Coexisting myocardial infarction (MI) and type 2 diabetes mellitus (T2DM) is a common condition. We aimed to investigate the association between MI and type 2 diabetes (T2D) with mitophagy-related differentially expressed genes (MRDEGs) and the impact thereof on disease progression.
    METHODS: R package was used for data retrieval and normalization of the MI (GSE48060 and GSE29532) and T2D (GSE76894 and GSE25724) datasets. Gene set enrichment analysis indicated significant associations between biological functions and pathways. Protein-protein interaction networks constructed using STRING and GeneMANIA revealed interconnected MRDEGs.
    RESULTS: Principal component and differential gene expression analyses identified 45 MRDEGs. Through key gene screening, least absolute shrinkage, and selection operator (LASSO) risk model construction, nine MRDEGs were identified: ATG14, BIRC2, CSK, FBXO7, HNRNPH1, HNRNPL, SNX6, TFEB, and YES1. A diagnostic nomogram model exhibited high reliability and validity when utilizing these genes. Using LASSO regression analysis, the risk score formula demonstrated diagnostic accuracy for MI and T2D.
    DISCUSSION: This study highlights the significance of immune cell infiltration in the context of MI and T2D. This analysis is primarily based on publicly available datasets, and future research will incorporate independent patient cohorts to assess the role of mitochondrial autophagy in these diseases.
    CONCLUSION: The screened genes may be therapeutic targets to prevent progression and improve clinical outcomes in patients with MI and T2D. This study provides an integrative view of mitochondrial metabolism and immune infiltration in MI and T2D, offering a novel direction to further elucidate the pathogenesis and medical interventions for these diseases.
    Keywords:  Myocardial infarction; immune infiltration.; mitophagy; molecular mechanism; type 2 diabetes mellitus
    DOI:  https://doi.org/10.2174/0118715303431252260315125017
  43. Biochem Pharmacol. 2026 Apr 11. pii: S0006-2952(26)00295-9. [Epub ahead of print] 117962
    Tucatinib alleviates postmenopausal osteoporosis by suppressing osteoclast differentiation via regulating the DRP1/NFATc1/CTSK signaling pathway.
    Xin Liu, Shuang Liu, Guoqiang Xu, Wendi Chen, Yuxuan Shi, Guolong Wang, Yongzhi Cao, Gang Lu, Yunna Ning, Yueran Zhao.
      Postmenopausal osteoporosis (PMOP) represents the most prevalent metabolic bone disease among postmenopausal women worldwide. Cathepsin K (CTSK), a key mediator of osteoclastic bone resorption, serves as a critical therapeutic target for PMOP. Through structure-based virtual screening coupled with functional validation, we identified Tucatinib as a potent CTSK inhibitor. Microscale thermophoresis (MST), molecular docking, and CTSK activity assays confirmed that Tucatinib directly binds to and inhibits CTSK, effectively suppressing osteoclast-mediated bone resorption. Notably, Tucatinib attenuated NFATc1-driven osteoclast differentiation in bone marrow-derived monocytes/macrophages (BMMs). In ovariectomized mouse models, Tucatinib significantly prevented estrogen deficiency-induced bone loss. Mechanistic investigations revealed that Tucatinib maintains mitochondrial homeostasis by inhibiting dynamin-related protein 1 (DRP1) phosphorylation at Ser616 during early-stage osteoclast differentiation and reducing mitochondrial reactive oxygen species (mtROS) production, thereby stabilizing mitochondrial fission/fusion dynamics and suppressing NFATc1 activation. By simultaneously modulating of the DRP1/NFATc1 axis and CTSK enzymatic activity, offering a promising dual-action therapeutic strategy for PMOP. Our findings demonstrate that Tucatinib alleviates osteoporotic bone loss by simultaneously modulating the DRP1/NFATc1 axis and CTSK enzymatic activity, offering a promising dual-action therapeutic strategy for PMOP.
    Keywords:  CTSK; DRP1; Mitochondrial homeostasis; Osteoclast; Tucatinib
    DOI:  https://doi.org/10.1016/j.bcp.2026.117962
  44. Phytomedicine. 2026 Apr 05. pii: S0944-7113(26)00386-7. [Epub ahead of print]155 158152
    Ziziphora clinopodioides Flavonoids improve ischemic stroke by targeting FUNDC1-mediated mitophagy to reduce ferroptosis.
    Xingjie Zhuo, Shuxian Ding, Jinhua Li, Mingcong Deng, Xinyue Zhang, Weijun Yang, Lili Gu, Qin Li.
       BACKGROUND: Ischemic stroke (IS) is a major global cause of disability and death, with its complex pathophysiology posing a significant challenge for effective therapy. Although flavonoids from Ziziphora clinopodioides Flavonoids (ZCF) have demonstrated neuroprotective potential, their comprehensive mechanisms of action remain incompletely understood.
    OBJECTIVE: The purpose of this study is to systematically elucidate the improvement effect of ZCF on ischemic stroke and its potential mechanism by integrating multi-omics analysis and in vitro and in vivo experimental verification.
    METHODS: In this study, the neuroprotective mechanism of ZCF on MCAO/R-treated SD rats and OGD/R-treated PC12 cells was studied by combining transcriptomics, non-targeted metabolomics, and molecular biology verification (Western blot, q-PCR, immunofluorescence, etc.). The key role of FUNDC1 in this pathway was verified by siRNA knockdown.
    RESULTS: ZCF administration significantly improved neurological function, reduced cerebral infarction volume, and reduced neuronal apoptosis. Integrated transcriptomics and metabolomics analysis found that ZCF reversed disease-related changes, and its core effects were the mitophagy and ferroptosis pathways. Mechanistically, ZCF alleviates pathological TDP-43 aggregation, activates FUNDC1-mediated mitophagy, and inhibits ferroptosis. Crucially, siRNA knockdown of FUNDC1 eliminated these protective effects.
    CONCLUSION: ZCF improves ischemic stroke by enhancing FUNDC1-dependent mitophagy to remove pathological TDP-43, thereby inhibiting the mechanism of ferroptosis.
    Keywords:  FUNDC1; Ferroptosis; Ischemic stroke; Mitophagy; TDP-43; Ziziphora clinopodioides Flavonoids
    DOI:  https://doi.org/10.1016/j.phymed.2026.158152
  45. Alzheimers Dement. 2026 Apr;22(4): e71330
    Beyond the neuron: Exosomes as intercellular modulators of mitochondrial networks in the pathogenesis and treatment of Alzheimer's disease.
    Liping Xing, Annan Liu, Wei Gao, Jianhui Li, Mingyuan Yao, Jing Song, Peihan Duan, Honglin Li.
      Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by β-amyloid deposition, hyperphosphorylated tau protein, and progressive neuronal loss. Mitochondria form a dynamic interconnected network within the central nervous system, and their dysfunction plays a central role in AD, involving oxidative stress, kinetic dysregulation, and impaired mitochondrial autophagy. As key mediators of intercellular communication, exosomes carry bioactive components that regulate mitochondrial function in recipient cells. This review summarizes advances in research on exosomes as coordinators of the mitochondrial network in the central nervous system, regulating mitochondrial quality control across different neuronal cell types. It systematically outlines the molecular mechanisms by which exosomes modulate mitochondrial function in AD through regulating mitochondrial biogenesis, fusion-fission dynamics, mitochondrial autophagy, and related signaling pathways. Furthermore, it explores the potential of engineered exosome-based targeted therapies for AD intervention, aiming to provide a theoretical foundation and research direction for developing novel therapeutic strategies targeting mitochondrial dysfunction.
    Keywords:  Alzheimer's disease; exosomes; mitochondria; neuroprotection; targeted therapy
    DOI:  https://doi.org/10.1002/alz.71330
  46. Front Pharmacol. 2026 ;17 1781376
    Schisandrin B confers multi-organ protection via regulation of mitochondrial homeostasis: mechanistic integration, organ-specific differences, and translational challenges-a review.
    Siyi Guo, Fei Yu, Chao Wang, Wenbing Zhao, Xuan Li, Jiayi Liu, Zhida Lyu.
      Schisandrin B (Sch B) is a dibenzocyclooctadiene lignan derived from plants of the Schisandra genus. Owing to its pronounced lipophilicity, Sch B may readily cross biological membranes and is increasingly discussed in association with the regulation of mitochondrial homeostasis. Mitochondrial dysfunction underlies key pathological processes involved in multi-organ injury and a broad range of chronic diseases, manifested as redox imbalance, reduced mitochondrial membrane potential (ΔΨm), impaired ATP production, mitochondrial DNA (mtDNA) damage, disrupted mitochondrial dynamics, failure of mitochondrial quality control, and amplified inflammation, thereby promoting cell death and tissue remodeling. Accumulating evidence in recent years suggests that Sch B exerts biological effects associated with improved mitochondrial function in multiple models involving the liver, kidney, heart, brain, lung, and tumors. However, previous reviews have primarily focused on overall pharmacological activities or individual diseases, and a cross-organ integrative framework with "mitochondria" as the central axis remains limited. Based on current evidence, the mitochondria-related actions of Sch B can be summarized at several complementary levels: maintaining redox balance; stabilizing ΔΨm and potentially modulating the threshold of the mitochondrial permeability transition pore (mPTP); improving calcium homeostasis and bioenergetic output; reshaping the balance between fusion and fission; context-dependently regulating autophagy/mitophagy and autophagic flux; and bidirectionally influencing mitochondria-mediated apoptotic pathways in distinct cellular settings. At the organ level, the effects of Sch B exhibit a "pathology-driven matching" pattern: in acute stresses such as ischemia-reperfusion, Sch B tends to enhance mitochondrial stress tolerance and promote energy recovery; in toxin/drug-induced injury, it more prominently delays membrane structural disruption and oxidative damage; whereas in metabolic chronic diseases, its actions are associated with metabolic flexibility and the continuity of quality control processes. Despite the cross-organ consistency of Sch B in mitochondrial regulation, its translation remains constrained by factors including in vivo exposure, effective intramitochondrial concentration, delivery and targeting strategies, safety boundaries, and interindividual variability. Therefore, this review proposes a multi-organ mechanistic model centered on "mitochondrial homeostasis regulation," providing a theoretical basis for understanding the cross-system effects of Sch B and for future drug development and optimization.
    Keywords:  mechanism; mitochondrial homeostasis; multi-organ protection; schisandrin B; translational challenges
    DOI:  https://doi.org/10.3389/fphar.2026.1781376
  47. Animals (Basel). 2026 Mar 27. pii: 1022. [Epub ahead of print]16(7):
    Resveratrol Attenuates Liver Inflammation in Non-Alcoholic Fatty Liver Disease by Activating PINK1-Mediated Mitophagy.
    Shujing Tan, Ran Yu, Longwei Sun, Manman Shen, Juan Framirez Pedroso, Osmani Chacón Chacón, Chengmin Li, Weiguo Zhao.
      Resveratrol (RES) has been shown to exhibit therapeutic efficacy against fatty liver disease. Yet, the molecular mechanisms by which RES ameliorates liver injury remain unclear. The aim of this study was to investigate the therapeutic effect and mechanism of resveratrol in fatty liver disease. It was found that dairy cows with fatty liver exhibit characteristic hepatic pathologies, including ballooning degeneration, lipid accumulation and elevated serum AST and ALT levels. Parallel to these changes, we observed significant upregulation of the NLRP3 inflammasome alongside suppression of mitophagy in the liver. Additionally, it was demonstrated in vitro that resveratrol pretreatment effectively alleviated PA-triggered NLRP3 inflammasome activation and mitochondrial dysfunction. Furthermore, RES's mitigating effects against NLRP3 inflammation and mitochondrial injury were reversed by suppressing PINK1-medicated mitophagy. In vivo experiments further demonstrated that resveratrol administration attenuated HFD-induced liver injury and lipid accumulation in a mouse model, concurrent with suppressed NLRP3 activation and an increase in mitophagy, further confirming the mechanism identified in vitro. Our findings reveal that RES ameliorates fatty liver injury primarily by inhibiting the NLRP3 inflammasome through PINK1-mediated mitophagy, which provides a potential novel therapeutic strategy for mitigating fatty liver disease.
    Keywords:  NLRP3 inflammasome; PINK1; fatty liver disease; mitophagy; resveratrol; transition dairy cows
    DOI:  https://doi.org/10.3390/ani16071022
  48. Theranostics. 2026 ;16(10): 5741-5758
    Engineering Tfh-Specific Nanoadjuvant to Counteract Bile Acid-Induced Mitophagy and Vaccine Hyporesponsivenes.
    Huimin Wu, Zhigang Zheng, Haifeng Chen, Jinchuan Liu, Xiandong Zeng, Xiaochun Huang, Xu Fang, Junlin Zhu, Yuanjia Tang, Jun Deng, Qiang Xia, Feng Xue.
      Bile acids were involved in vaccine response and modulating immune cells. Follicular helper T (Tfh) cells serve a critical immunoregulatory function in vaccine response. However, the precise role of bile acids in modulating Tfh cells and the underlying mechanisms remain unclear. Nano-adjuvant targeting and modulating Tfh cells may offer a promising strategy to improve vaccine response. In this study, we first discovered that 3-oxo-lithocholic acid (3-oxoLCA) impaired the differentiation and function of cultured Tfh vacells both in human and mice in vitro. In vivo, 3-oxoLCA gavage significantly reduced the proportion of Tfh cells in spleen and antibody responses in WT mice under NP-OVA immunization. Mechanistically, 3-oxoLCA promoted intracellular mitophagy of Tfh cells by RNA sequencing analysis and rescue experiment. Leveraging these insights, we engineered a mitophagy-inhibiting, Tfh cells-targeted nano-adjuvant (M-1@NP) decorated with anti-CXCR5 and anti-ICOS antibodies to precisely increased Tfh cells generation and function. This nanoplatform not only boosted cultured Tfh cells generation in vitro but also amplified germinal center (GC) responses and specific antibody production in immunized mice, with high targeting specificity and biocompatibility. In conclusion, 3-oxoLCA inhibited the differentiation and function of mouse and human Tfh cells by promoting intracellular mitophagy. Tfh cells-targeted nano-adjuvant effectively enhanced the ratio and functions of Tfh cells. M-1@NP represents a potentially valuable option for promoting vaccine response in clinical applications.
    Keywords:  3-oxoLCA; bile acids; follicular helper T cell; mitophagy; nanoparticles
    DOI:  https://doi.org/10.7150/thno.125668
  49. Transl Cancer Res. 2026 Mar 31. 15(3): 190
    Corylin inhibits liver cancer cell growth through the endogenous apoptosis and mitophagy.
    Renshuang Zhao, Xin Wang, Mingming Cao, Yaru Li, Shanzhi Li, Zhiru Xiu, Yilong Zhu, Yiquan Li.
       Background: Corylin is a bioactive extract of Psoralea corylifolia L. with reported antioxidant, anti-tumor, and anti-inflammatory effects. Its anti-tumor effects have been investigated, but mechanistic explanations are lacking. This study mainly focuses on the role and mechanism of Corylin in inducing liver cancer cell death.
    Methods: The effects of Corylin on liver cancer cell proliferation were analyzed using crystal violet staining and cell counting kit-8 (CCK-8) assays. Nuclear changes were detected via Hoechst staining, while apoptosis levels were assessed using Annexin V- fluorescein isothiocyanate (FITC)/propidium iodide (PI) staining. Changes in mitochondrial membrane potential and reactive oxygen species (ROS) levels were analyzed using JC-1 and tetramethylrhodamine methyl ester (TMRM) staining combined with flow cytometry. Immunofluorescence staining and Western blot (WB) experiments assessed alterations in apoptosis- and autophagy-related proteins. Finally, the effects of Corylin on liver cancer cells in vivo were validated by establishing a subcutaneous tumor model.
    Results: In this study, we found that Corylin had a significant anti-liver cancer effect and significantly increased the apoptosis level of liver cancer cells. Additionally, Corylin was found to significantly reduce mitochondrial membrane potential and significantly increase ROS release. It was also observed that Corylin significantly influenced autophagy levels in liver cancer cells. Further analysis revealed that Corylin induced mitophagy, with the increase in autophagy levels being directly proportional to the rise in apoptosis levels. Finally, the establishment of a subcutaneous tumor-bearing model showed that Corylin also had a significant anti-liver cancer effect in vivo.
    Conclusions: The above results demonstrated that Corylin mainly caused the death of liver cancer cells through the endogenous apoptosis and mitophagy pathway and had great potential as an anti-liver cancer drug.
    Keywords:  Psoralea corylifolia; apoptosis; autophagy; liver cancer; mitochondria
    DOI:  https://doi.org/10.21037/tcr-2025-aw-2517
  50. Free Radic Biol Med. 2026 Apr 09. pii: S0891-5849(26)00300-X. [Epub ahead of print]
    CuO-NPs Suppress Esophageal Squamous Cell Carcinoma by Altering Oxidant-Dependent Energy Metabolism, Leading to Mitophagy.
    Yue Liu, Xiying Yu, Xiaowu Zhang, Kai Zhang, Mengfan Li, Siyuan Jia, Yan Fu, Yuan Guo, Xiao Li, Wei Jiang.
      Nanoparticles coupled with metals hold great promise for biomedical applications. While previous studies have shown the cytotoxic effects of copper oxide nanoparticles (CuO-NPs) on esophageal squamous cell carcinoma (ESCC), the underlying mechanisms are unclear. Here, we demonstrate that CuO-NPs accumulate around mitochondria in esophageal cells, substantially inducing reactive oxygen species (ROS), which activates NRF2 in ESCC cells compared to normal esophageal keratinocytes. Transcriptomic analysis reveals that NRF2-downstream genes play crucial roles in both antioxidant activity and energy metabolism, which activate the protein kinase AMPK and inhibit AMPK downstream target mTORC1, ultimately leading to mitochondrial dysfunction and cell death in ESCC cells. We show that the critical mitophagy regulators, PINK1 and Parkin, are significantly upregulated in CuO-NP-treated ESCC cells. Since the transcription factor TFEB is a mTORC1 downstream target that has been shown to directly control PINK1/Parkin expression, we find that the mTORC1-TFEB-PINK1-Parkin (mTTPP) axis is involved in CuO-NP-induced cytotoxicity in ESCC cells. CuO-NPs inhibit mTORC1-mediated TFEB phosphorylation, thereby inducing TFEB nuclear translocation that increases PINK1/Parkin expression and activates the PINK1/Parkin-mediated mitophagy pathway. Ablation of the mTTPP axis by RNA interference attenuates the cytotoxicity induced by CuO-NPs in ESCC cells. The tumor-killing effects of CuO-NPs observed in vitro are also evident in the subcutaneous ESCC xenograft model in vivo. Taken together, our results suggest that CuO-NPs have potential for ESCC treatment and warrant further preclinical study.
    Keywords:  CuO-NPs; ESCC; ROS-NRF2; mTTPP axis; mitophagy
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.04.016
  51. Biomaterials. 2026 Apr 03. pii: S0142-9612(26)00186-9. [Epub ahead of print]333 124162
    A 3-N nose-to-brain urolithin a nanomotor targeting microglial mitophagy in neuroinflammation.
    Yifei Fu, Gang Zhao, Hongyun Zou, Kaiqi Zhu, Yushan Zhou, Li Yang, Yinfei Zhao, Jiaqi Yang, Bing Niu, Zhiheng Liu, Xuesheng Liu, Han Lu.
      Cognitive impairment is the primary manifestation of neuroinflammation-related central nervous system diseases. Intranasal administration is an effective method, bypassing the blood-brain barrier and delivering drugs to the brain. Herein, we designed a biomimetic self-propelled nanomotor with an inflammation-targeting capacity. This nanomotor comprised a hollow mesoporous manganese dioxide (HMnO2) core and a polydopamine (PDA) shell. HMnO2 effectively catalyzed the conversion of endogenous H2O2 into H2O and O2, enabling the movement of the nanomotor into a wider area to reduce neuroinflammation. The nanomotor was loaded with the natural compound urolithin A (UA), which significantly improved the bioavailability of the compound and enhanced mitophagy. Furthermore, PDA modification imparted the nanomotor with strong adhesive properties, enabling them to anchor effectively to the olfactory nerve and enhancing delivery to the brain. In vitro, PDA@HMnO2@UA alleviated mitochondrial dysfunction, oxidative stress, and inflammation levels by enhancing mitophagy in lipopolysaccharide (LPS)-induced BV2 cells. Following intranasal administration, PDA@HMnO2@UA exerted neuroprotective effects by alleviating microglial activation, neuroinflammation, and neuronal loss, ultimately rescuing the neurocognitive function in the LPS-induced neuroinflammation model. In summary, this study presents an ideal nanomotor platform based on the 3-N strategy, which means "Nanomotor loaded with a Natural product to traverse a Natural anatomical pathway," that can alleviate cognitive impairments caused by neuroinflammation, offering a promising delivery approach for treating neuroinflammatory diseases.
    Keywords:  Cognitive impairments; Mitophagy; Nose-brain pathway; Urolithin A; nanomotors
    DOI:  https://doi.org/10.1016/j.biomaterials.2026.124162
  52. Aging Cell. 2026 Apr;25(4): e70472
    Ghrelin Receptor Deletion or Pharmacological Inhibition Improves Muscle Function in Aging Male Mice.
    Haiming L Kerr, Kora Krumm, Nornubari Myree, Artur Rybachok, Elizabeth Dacek, Brynn Irwin, Siyi Jiang, Lucas Caeiro, Barbara Anderson, Theresa Li, Amanda Chen, Ross Burnside, Jessica Li, Morgan Sydor, David J Marcinek, Gennifer E Merrihew, James W MacDonald, Theo K Bammler, Michael J MacCoss, Jose M Garcia.
      Sarcopenia is characterized by age-related declines in muscle strength and mass, along with impaired physical function. It remains an unmet medical need, and there are no pharmacological interventions approved for this indication. The activation of growth hormone secretagogue receptor (GHSR)-1a, also known as ghrelin receptor, stimulates food intake and has acute anabolic effects. However, its impact on aging muscles remains uncertain. We examined the effects of GHSR-1a deletion on sarcopenia measurements (muscle mass, strength, and endurance) by comparing young and aged male GHSR-1a knockout (KO) and wildtype (WT) mice (6-, 24-, and 28-month-old). Deletion of GHSR-1a improved muscle fatigue resistance, endurance, and muscle strength during aging without affecting muscle mass or longevity. Since muscle endurance is closely related to mitochondrial function, we examined mitochondrial biogenesis marker PGC-1α and mitophagy signaling via PINK1/p62 and found them improved in old mice with GHSR deletion. Proteomics analysis also revealed that mitochondrial components remain central for maintaining muscle mass and function. We further investigated the effects of pharmacological inhibition of GHSR-1a by its inverse agonist, PF-5190457, in male WT mice. PF-5190457 mimicked the effects of GHSR-1a deletion, including improved endurance and increased markers of mitochondrial biogenesis (PGC-1α) and different mitophagy markers (LC3II and Bnip3). PF-5190457 also reduced body weight and adiposity, which were not observed with GHSR-1a deletion. Overall, these findings suggest that GHSR-1a is a promising therapeutic target for age-related sarcopenia.
    Keywords:  GHSR‐1a; aging; mice; mitochondria; mitophagy; sarcopenia
    DOI:  https://doi.org/10.1111/acel.70472
  53. Anim Biosci. 2026 Apr 16.
    SIRT1 plays a critical role in maintaining the viability of Yak Sertoli cells by regulating mitochondrial biogenesis via activating the PGC-1α-NRF-1-TFAM pathway.
    Dongju Liu, Xiaodong Dong, Huai Zhang, Wending Zhou, Gan Yang, Xianrong Xiong, Yan Xiong, Jian Li, Daoliang Lan, Shi Yin.
       Objective: Sertoli cells are somatic cells located within the seminiferous tubules that play a critical role in spermatogenesis through various mechanisms, such as paracrine signaling and the formation of the blood-testis barrier. Sirtuin 1 (SIRT1), a member of the evolutionarily conserved sirtuin family, is an NAD⁺-dependent class III histone deacetylase. SIRT1 involvement has been documented in multiple key biological processes; however, its role in Sertoli cells remains unknown.
    Methods: In this study, yak Sertoli cells were isolated, and the impact of SIRT1 on cell viability and its related regulatory mechanisms was investigated using RNA interference (RNAi).
    Results: The findings revealed that after SIRT1 knockdown, the viability and function of yak Sertoli cells were significantly impaired. Transcriptome sequencing revealed a significant impact on mitochondrial structure following SIRT1 knockdown. Further studies demonstrated that knockdown of SIRT1 in yak Sertoli cells led to significant downregulation of genes related to mitochondrial morphology, reduced membrane potential, decreased mitochondrial gene expression, and diminished ATP synthesis capacity. The PGC-1α-NRF-1-TFAM pathway, a key signaling cascade in mitochondrial biogenesis, was inhibited after SIRT1 knockdown. Overexpression of PGC-1α in SIRT1-knockdown yak Sertoli cells rescued the decline in cell viability and impaired mitochondrial biogenesis to some extent. These findings indicate that SIRT1 regulates mitochondrial biogenesis in yak Sertoli cells by activating the PGC-1α-NRF-1-TFAM signaling pathway, thereby maintaining cellular viability.
    Conclusion: The present study preliminarily elucidates the regulatory role and mechanism of SIRT1 in yak Sertoli cells, providing fundamental data and new insights for further research on the function of SIRT1 in reproductive regulation in yaks.
    Keywords:  Mitochondria; PGC-1α-NRF-1-TFAM pathway; SIRT1; Sertoli cells; Yak
    DOI:  https://doi.org/10.5713/ab.251005
  54. J Ethnopharmacol. 2026 Apr 15. pii: S0378-8741(26)00511-8. [Epub ahead of print] 121660
    Shenqi Oral Liquid regulates reactive oxygen species production by modulating autophagy, thereby regulating mitochondrial dynamics in cardiomyocytes and alleviating chronic heart failure in mice via adenosine 5'-monophosphate-activated protein kinase/mechanistic target of rapamycin axis.
    Xueqing Xie, Hongyao Ge, Xianrun Hu, Xuan Gao, Yingying Song, Longfei Xie, Hui Wu, Fei Huang, Changhong Wang, Hailian Shi, Xiaojun Wu.
       ETHNOPHARMACOLOGICAL RELEVANCE: Shenqi Oral Liquid (SOL) originated from the"Discerning Internal and External Injuries" is a Chinese formula composed of two herbs: Codonopsis pilosula (Franch.) Nannf. (Dang-shen) and Astragalus membranaceus (Fisch.) Bunge. (Huang-qi). This formula has been used clinically for many years to treat chronic heart failure (CHF). However, the specific mechanism of SOL in treating CHF is still unclear.
    AIM OF THE STUDY: The aim of this study was to evaluate the protective effect of SOL on the decline in cardiac function in doxorubicin (DOX)-induced CHF mice and to explore the potential molecular mechanisms.
    MATERIALS AND METHODS: A CHF mouse model was established by administering 5 mg/kg/w DOX via intraperitoneal injection for 6 consecutive weeks. Then, CHF model mice were treated with low-dose (0.6 g/kg) and high-dose (1.2 g/kg) SOL via oral gavage for 4 consecutive weeks. Therapeutic effects of SOL on heart failure were evaluated using cardiac ultrasound, electrocardiography, biochemical index, and histological staining. Network pharmacology and transcriptomics were employed to identify potential molecular mechanisms. Autophagy and mitochondrial dynamics were assessed using transmission electron microscope (TEM), dihydroethidium (DHE) staining, quantitative polymerase chain reaction (qPCR), western blotting (WB), and other methods. SOL-medicated serum and Rapamycin (Rapm) were applied to H9c2 cells to assess adenosine triphosphate (ATP) levels, autophagy occurrence, autophagy proteins, intracellular reactive oxygen species (ROS) levels, mitochondrial ROS levels, and mitochondrial membrane potential.
    RESULTS: SOL significantly alleviated the decline of cardiac function in CHF mice, with the high-dose group showing the most pronounced effect. Network pharmacology and transcriptomics analysis indicated that SOL relieved CHF via modulation of autophagy, mitochondrial function, redox processes and apoptosis in cardiomyocytes. Further validation experiments indicated that SOL inhibited excessive autophagy by restraining the phosphoinositide 3-kinase (PI3K) / protein kinase B (AKT)/ mechanistic target of rapamycin (mTOR) and adenosine 5'-monophosphate-activated protein kinase (AMPK) pathways in cardiomyocytes. Additional in vitro and in vivo experiments demonstrated that SOL rescued mitochondrial dysfunction and apoptosis in cardiomyocytes through inhibiting excessive autophagy.
    CONCLUSIONS: SOL modulates myocardial mitochondrial dynamics by regulating ROS production through autophagy via the AMPK/mTOR axis, mitigating DOX-induced injury and alleviating CHF in mice.
    Keywords:  Apoptosis; Autophagy; Chronic heart failure; Mitochondrial dynamics; Shenqi Oral Liquid
    DOI:  https://doi.org/10.1016/j.jep.2026.121660
  55. Front Physiol. 2026 ;17 1829446
    Editorial: Mitochondrial dynamics and endothelial dysfunction: implications for metabolic disorders.
    Dorota Dymkowska, Aneta Balcerczyk.
      
    Keywords:  endothelial dysfunction; endothelial mitochondria; energy metabolism in endothelium; functioning of mitochondria in metabolic disorders; metabolic disorders; reactive oxygen species
    DOI:  https://doi.org/10.3389/fphys.2026.1829446
  56. Environ Toxicol Pharmacol. 2026 Apr 11. pii: S1382-6689(26)00098-0. [Epub ahead of print]124 105020
    Hexavalent chromium induces death of porcine spermatogonial stem cells via promoting mitophagy and ferroptosis.
    Tianjiao Li, Rongnan Li, Zhucheng Wang, Ming Guo, Meimei Wang, Xin Li, Chang Liu, Wenxian Zeng, Tao Li.
      Pigs are the world's primary domesticated species for meat production and play a vital role in the development of the livestock industry. The reproductive health of boars not only affects their own breeding performance but also directly impacts the reproductive efficiency of the entire herd. Hexavalent chromium (Cr (VI)), a naturally occurring heavy metal pollutant, exhibited reproductive toxicity. This study aims to investigate the damage mechanism of Cr (VI) on porcine spermatogonial stem cells (SSCs) and the protective effect of melatonin. Here, we found that Cr (VI) induced mitophagy, ferroptosis, and apoptosis in porcine SSCs in a dose-dependent manner. Furthermore, Cr (VI) respectively activated mitophagy and ferroptosis pathways, synergistically promoting cell apoptosis. Melatonin, as a potent endogenous free radical scavenger, effectively mitigated Cr (VI) -induced damage in porcine SSCs. This study provides a reference for livestock health breeding and prevention under environmental pollution conditions, and promotes livestock breeding work.
    Keywords:  Apoptosis; Chromium (VI); Ferroptosis; Melatonin; Mitophagy
    DOI:  https://doi.org/10.1016/j.etap.2026.105020
  57. Naunyn Schmiedebergs Arch Pharmacol. 2026 Apr 13.
    The role of mitochondrial dysfunction, oxidative stress, and gender in cardiac fibrosis and vascular remodeling in an induced aged rat model with possible mitigation by eugenol nano-emulsion.
    Rawan H Hanafi, Marwa S Khattab, Sara M Baraka, Saber Ibrahim, Samar H Elsharkawy, Reda M S Korany.
      Cardiac diseases are strongly associated with aging and pose a major threat to survival. This study evaluated the cardioprotective effects of oral eugenol and its nano-emulsion (20 mg/kg) in a D-galactose-induced aging model (300 mg/kg, i.p.) in male and female rats over 12 weeks. Particle size and zeta potential analyses confirmed the successful development of a stable, well-dispersed nano-emulsion system. At the end of treatment, echocardiography, biochemical assays, histopathology, and immunohistochemistry were performed. Cardiac dysfunction and dilatation were more pronounced in males than females following D-galactose administration, as evidenced by left ventricular internal diameter in diastole (LVIDd) and left ventricular internal diameter in systole (LVIDs), and reduced ejection fraction (EF) and fractional shortening (FS). Both eugenol and its nano-emulsion preserved cardiac architecture and mitigated histopathological alterations, including myofibrillar distortion, necrosis, vascular remodeling, and fibrosis. Treatment significantly reduced oxidative stress and mitochondrial dysfunction by restoring GSH, lowering MDA, and modulating the PINK1/Mfn2 pathway. Furthermore, eugenol and its nano-emulsion attenuated cardiac inflammation, apoptosis, and fibrosis through downregulation of TGF-β1, MMP-9, TNF-α, and caspase-3 expression. In conclusion, eugenol nano-emulsion demonstrates promising anti-aging potential against cardiac complications by regulating mitochondrial dynamics, mitophagy, oxidative stress, inflammatory and apoptotic responses, and the SIRT1/TGF-β/MMP9 signaling pathway.
    Keywords:  Aging; Eugenol; Histopathology; Mitophagy; Nanoemulsion
    DOI:  https://doi.org/10.1007/s00210-026-05262-4
  58. Transl Cancer Res. 2026 Mar 31. 15(3): 193
    GPR176 represses mitophagy to promote the progression of osteosarcoma by facilitating mTORC1 activity via PI3K-AKT pathway.
    Jiyong Jiang, Bowen Zheng, Jing Wang, Yi Fang, Lianbo Yang, Jinghang Lv, Haidong Liang.
       Background: Osteosarcoma (OS) is a common primary malignant tumor of the bone. It is reported that abnormal GPR176 expression contributes to the occurrence and subsequent progression of tumors. However, the role of GPR176 in OS has not been elucidated. Thus, the aim of this study was to evaluate the role of GPR176 in the progression of OS.
    Methods: The expression level and prognosis of GPR176 were explored based on Gene Expression Omnibus (GEO), TARGET and Genotype-Tissue Expression (GTEx) databases, as well as the involved pathways. Effects of GPR176 on the proliferation, migration, invasion, and apoptosis of U2OS cells, as well as in a mouse tumor xenograft model. Multiple parameters were employed to explore the role of GPR176 in mitophagy, including mitochondrial membrane potential (MMP), reactive oxygen species (ROS), and mitophagy-related proteins. The protein levels of downstream substrates of mTORC1 were analyzed by Western blot.
    Results: The expression level of GPR176 was obviously elevated in OS, and increased GPR176 expression associated with poor prognosis in patients with OS. Gene Set Enrichment Analysis (GSEA) showed that GPR176 is mainly involved in the oxidative phosphorylation, retinol metabolism, and ErbB signaling pathways. GPR176 knockdown suppressed the proliferation, migration, and invasion of U2OS cells and enhanced their apoptosis. GPR176 downregulation also induced mitophagy in U2OS cells, as evidenced by an increase in ROS levels; a decrease in MMP, adenosine triphosphate (ATP), and mitochondrial DNA (mtDNA); and concomitant changes in mitophagy-related proteins. GPR176 knockdown suppresses mTORC1 activity in U2OS cells. Moreover, GPR176 knockdown represses the growth of tumor xenografts in vivo while promoting mitophagy. The levels of phosphorylated-mechanistic target of rapamycin complex 1 (p-mTORC1)/mTORC1, p-v-akt murine thymoma viral oncogene homolog 1 (AKT)/AKT, and p-phosphatidylinositol-3 kinase (PI3K)/PI3K were significantly downregulated following GPR176 knockdown.
    Conclusions: GPR176 is upregulated in OS and is associated with a poor prognosis. GPR176 suppresses mitophagy to promote OS progression by facilitating mTORC1 activity via the PI3K-AKT pathway.
    Keywords:  GPR176; Osteosarcoma (OS); PI3K-AKT pathway; mTORC1; mitophagy
    DOI:  https://doi.org/10.21037/tcr-2025-2146
  59. Research (Wash D C). 2026 ;9 1241
    Mitochondrial Fission Regulator 1-Like Protein Protects the Heart from Ischemia/Reperfusion Injury via Dual Mitochondrial Mechanisms.
    Mingyu Wei, Yuanxiu Song, Min Zhu, Xianjing Hu, Shuhong Ma, Shuai Zhang, Pengxin Xie, Rui Guo, Zhen Ma, Xiaojie Hou, Siyao Zhang, Jiaqi Fan, Xian Yang, Amina Saleem, Feng Lan, Xujie Liu, Ming Cui.
      Mitochondrial dysfunction is pivotal in the pathogenesis of cardiac ischemia/reperfusion (I/R) injury. Restoring mitochondrial function represents a promising strategy for mitigating I/R-induced cardiac injury. Mitochondrial fission regulator 1-like protein (MTFR1L), a recently identified mitochondrial dynamics protein, is abundantly expressed in the cardiac tissues. However, its functional role in I/R injury remains undefined. Here, Mtfr1l-knockout mice and human embryonic-stem-cell-derived cardiomyocytes are utilized to investigate the role of MTFR1L in myocardial I/R injury and elucidate its contribution to mitochondrial integrity and function. MTFR1L deficiency markedly worsened I/R-induced cardiac injury and mitochondrial dysfunction. These phenotypes were partially reversed by mitochondria-anchored apoptosis-inducing factor (AIF) overexpression. Mechanistically, MTFR1L protects the heart via 2 interconnected pathways. First, MTFR1L sustains AIF dimerization and stabilizes the AIF-CHCHD4 (coiled-coil-helix-coiled-coil-helix domain containing 4) complex, thereby preserving mitochondrial contact site and cristae organizing system integrity and cristae architecture to facilitate electron transport chain supercomplex assembly, sustain mitochondrial respiration, and limit reactive oxygen species production. Second, by physically interacting with AIF, MTFR1L prevents its mitochondrial release and nuclear translocation, thereby suppressing intrinsic apoptosis. Overall, these findings identify MTFR1L as a cardioprotective protein against myocardial I/R injury through a dual mechanism, providing new insights into the functional repertoire of MTFR1L beyond its previously recognized role in mitochondrial dynamics. Targeting MTFR1L or its interactors may offer novel therapeutic strategies for alleviating mitochondrial dysfunction and myocardial injury.
    DOI:  https://doi.org/10.34133/research.1241
  60. Sci China Life Sci. 2026 Apr 09.
    Mitophagy activation for jawbone radiation injury therapy via angiogenesis/osteogenesis-active nanozymes.
    Tianxiao Wang, Weihua Shao, Ting Zhou, Yuchao Li, Ran Qin, Ziyu Chen, Jikang Cao, Xinyu Hu, Jingxuan Cang, Chang Sun, Yuli Wang, Huijun Jiang, Feng Han, Yongchu Pan, Hua Yuan, Jiandong Jiang, Fan Wu.
      Radiotherapy-induced osteoradionecrosis of the jaw (ORNJ) affects quality of life by causing severe pain, persistent infections, and stomatognathic dysfunction. Current ORNJ treatments are limited by several factors, including surgical trauma and notable individual differences. Oxidative stress, which is a critical driver of radiation-induced injury, promotes inflammation and disrupts the balance between bone formation and resorption. Here, we developed ceria-doped silicate nanozymes (CeSNs) to eliminate reactive oxygen species (ROS) by inducing a superoxide dismutase-like (SOD-like) and catalase-like (CAT-like) cascade. ROS-eliminating mitophagy contributed to the restoration of jawbone radiation injury. Dl-3-n-butylphthalide (NBP) encapsulated in CeSNs (NBP@CeSNs) demonstrated improved pH-responsive release for enhanced angiogenesis, while the silicon ions of silicate enhanced jawbone osteogenesis, thus providing the nanozymes with angiogenesis and osteogenesis capabilities. Our NBP@CeSNs nanozymes provided a promising pathway for ORNJ treatment.
    Keywords:  Dl-3-n-butylphthalide; angiogenesis/osteogenesis activities; jawbone radiation injury; mitophagy; nanozymes
    DOI:  https://doi.org/10.1007/s11427-025-3104-4
  61. Cell Rep. 2026 Apr 09. pii: S2211-1247(26)00306-2. [Epub ahead of print]45(4): 117228
    Graded activation of the CLEAR network through mTORC1 suppression on cargo-harboring lysosomes.
    Cheng-Wei Hsieh, Guang-Chao Chen, Wei Yuan Yang.
      Cellular lysosomal capacity is tightly controlled to match catabolic demands and sustain lysosomal signaling pathways. Here, we report that cells can adjust their lysosomal capacity in response to varying autophagy loads. Manipulating the number of mitochondria targeted for mitophagy leads to a proportional upregulation of transcription factor EB (TFEB)-mediated lysosome adaptation programs. This quantitative control is exerted through Rag GTPase-driven mTORC1 suppression. GATOR1 is selectively recruited to lysosomes containing autophagic cargo, initiating local Rag GTPase-dependent suppression of mTORC1 activities. This mitophagy-induced mTORC1 suppression leads to TFEB activation and dephosphorylation of TOS-motif-containing substrates (S6K and 4EBP) under nutrient-rich conditions. This phenomenon similarly occurs during aggrephagy. These findings suggest that autophagic cargo-harboring lysosomes exhibit consistently low mTORC1 activity. Lysosomes can, therefore, sense the magnitude of autophagy loads and quantitatively translate this signal into TFEB activation to support self-regulated homeostasis.
    Keywords:  CP: molecular biology; GATOR1; TFEB; aggregate autophagy; folliculin; lysosome; mTORC1; mitophagy
    DOI:  https://doi.org/10.1016/j.celrep.2026.117228
  62. Pharmacol Res. 2026 Apr 15. pii: S1043-6618(26)00109-X. [Epub ahead of print] 108194
    Metabolic Control of Immunity and Inflammation: Mitochondrial Dynamics, Pharmacological Targets, and Therapeutic Opportunities.
    Chunling Wang, Wangzheqi Zhang, Yue Shu, Lizhou Song, Yiwen Wan, Haoling Zhang, Lulong Bo, Yadong Guo.
      Immune responses and inflammation are not stand-alone processes linearly regulated by the canonical signaling pathways but complex systems biology events, which are deeply rooted in the metabolic state of cells and dynamically modulated. However, immunometabolic studies have identified that programmed alterations of metabolic circuits also occur during activation of immune cells, effector function maintenance and the induction of tolerance. Mitochondria represent a unique point of convergence between energetics, inflammation and immunity, particularly as they are key orchestrators of immune responses. In addition to their classical roles in oxidative phosphorylation (OXPHOS) and metabolic intermediate synthesis, mitochondria are involved in innate immune perception of inflammatory signals and the amplification of these responses by generating reactive oxygen species (ROS), bioenergetic signaling intermediates, and mitochondrial DNA. Crucially, mitochondria are not stable entities but are tightly regulated by dynamic events such as fusion, fission, trafficking and selective degradation. These structural alterations dynamically influence the metabolic commitment, inflammatory response potency and fate choices of immune cells. Mitochondrial dynamics should not be regarded as a mere auxiliary regulatory layer of immunometabolism; instead, they represent the central organizing principles between metabolic states, inflammatory cues, and immune cell fate determination, thereby defining a new hierarchical organization of immune and inflammatory regulation.
    Keywords:  Immunometabolism; immune cell fate; inflammatory responses; mitochondrial dynamics; pharmacological targets; therapeutic opportunities
    DOI:  https://doi.org/10.1016/j.phrs.2026.108194
  63. Autophagy. 2026 Apr 12.
    Pestiviruses utilize pyrimidine metabolism to regulate mitophagy for viral replication.
    Bingqian Zhao, Jing Chen, Yan Cheng, Yuhang Li, Linhan Zhong, Jinxia Chen, Xiaoqing Bi, Jishan Bai, Qi Dai, Yinbo Ye, Linke Zou, Li Wang, Bin Zhou.
      DHODH (dihydroorotate dehydrogenase (quinone)) has been demonstrated as a critical regulator of programmed cell death, yet its role in macroautophagy/autophagy remains poorly defined. Flaviviridae pose a significant threat to global public health, and their replication is closely associated with autophagy. Building upon our previous findings that DHODH is a broad-spectrum target for Flaviviridae and a key regulator of Pestiviruses replication, this study employed RNA-seq screening coupled with functional validation to demonstrate that DHODH affects Pestiviruses replication by regulating mitophagy. Notably, we observed remarkable virus genus specificity in this regulatory mechanism. For autophagy-dependent Pestiviruses, DHODH deficiency impaired autophagosome-lysosome fusion, thereby suppressing viral replication. Conversely, in autophagy-inhibiting Flaviviruses, the blockade of autophagy flux facilitated viral replication. These observations underscore the specificity of DHODH-mediated viral replication regulation. Additionally, compound supplementation assays indicated that DHODH regulated autophagy via pyrimidine nucleotide metabolism, as exogenous pyrimidine precursors restored autophagosome-lysosome fusion. Furthermore, our research uncovered a novel mechanism whereby classical swine fever virus (CSFV) non-structural protein 4A (NS4A) recruited DHODH to mitochondria, facilitating its interaction with MAP1LC3/LC3 (microtubule associated protein 1 light chain 3) through the LC3-interacting region (LIR) domain to activate mitophagy. Collectively, our findings highlight DHODH as a promising antiviral target within the metabolism-autophagy axis, providing novel insights for antiviral drug development.
    Keywords:  Autolysosome formation; CSFV; DHODH; LIR; mitophagy; viral non-structural proteins
    DOI:  https://doi.org/10.1080/15548627.2026.2659305
  64. Phytomedicine. 2026 Apr 10. pii: S0944-7113(26)00405-8. [Epub ahead of print]155 158171
    Brusatol derivative ameliorates rheumatoid arthritis and atherosclerosis with associated suppression of mitochondrial fission.
    Ruicong Ma, Jiaqing Liu, Siwen Yang, Guanghong Chen, Jinyi Ren, Cheng Zhang, Xianmei Chen, Ying Zhao, Junsheng Zhang, Chunlai Yin, Xia Li.
       BACKGROUND: Brusatol (BRU), a major bioactive quassinoid isolated from Brucea javanica, has shown potential in the treatment of inflammatory diseases. As mitochondrial dysfunction has been implicated in chronic inflammatory disorders, modulation of mitochondrial homeostasis may offer a potential approach for the treatment of rheumatoid arthritis (RA) and atherosclerosis (AS).
    PURPOSE: To develop a novel BRU derivative through rational modification at the C11‑hydroxyl group and to compare the therapeutic effects of BRU and its derivative BRUD in experimental models of RA and AS, with particular focus on mitochondrial regulation and Drp1-associated signaling.
    STUDY DESIGN: This study combined in vivo and in vitro experiments to evaluate the pharmacological effects of BRU and BRUD and investigate the underlying mechanisms.
    METHODS: The chemical constituents of BRU and BRUD were confirmed by HPLC and NMR spectroscopy (1H and 13C). Their effects were evaluated in vivo using collagen-induced arthritis (CIA) rats and apolipoprotein E-deficient (ApoE-/-) mice, and in vitro using RA fibroblast-like synoviocytes (RA-FLS), as well as IL-8-stimulated normal endothelial cells (ECs) and smooth muscle cells (SMCs). Cell viability, apoptosis, migration, invasion, adhesion, and tube formation assays were performed to assess cellular responses. Histological, biochemical, flow cytometric, confocal imaging, Western blot, molecular docking/molecular dynamics, surface plasmon resonance (SPR), and Drp1 overexpression rescue assays were performed to assess disease phenotypes, mitochondrial alterations, and Drp1-associated signaling.
    RESULTS: In vivo studies demonstrated that both compounds ameliorated joint damage in CIA rats and reduced atherosclerotic lesion burden in ApoE-/- mice. In vitro, BRUD more effectively inhibited pathogenic FLS activation than BRU, and restored normal EC and SMC function. Mechanistically, the stronger activity of BRUD was associated with attenuation of Drp1-related mitochondrial fission, accompanied by reduced mtROS levels and restoration of ΔΨm.
    CONCLUSIONS: These findings suggest that BRUD exhibits improved activity compared with BRU in RA and AS models, with protective effects associated with modulation of mitochondrial dysfunction, supporting its further evaluation as a lead compound.
    Keywords:  Atherosclerosis; Brusatol derivative; Drp1; Inflammation; Mitochondrial fission; Rheumatoid arthritis
    DOI:  https://doi.org/10.1016/j.phymed.2026.158171
  65. Poult Sci. 2026 Apr 07. pii: S0032-5791(26)00529-8. [Epub ahead of print]105(7): 106901
    SIRT3-mediated mitochondrial fatty acid oxidation protects against hepatic lipid deposition in fatty liver hemorrhagic syndrome.
    Panpan Cao, Jinyan Chen, Chun Zeng, Yang Hu, Jianyun Yuan, Xiaoquan Guo, Huabin Cao, Caiying Zhang, Yu Zhuang, Guoliang Hu.
      Fatty liver hemorrhagic syndrome (FLHS) is a nutrition-related metabolic disorder in laying hens characterized by excessive hepatic lipid accumulation and hemorrhagic lesions, leading to reduced productivity and increased mortality. However, the regulatory mechanisms linking mitochondrial dysfunction to hepatic lipid metabolism remain unclear. This study investigated the role of SIRT3 in modulating mitochondrial fatty acid oxidation during FLHS progression. An in vivo FLHS model was established by feeding laying hens with a high-energy, low-protein (HELP) diet, and an in vitro hepatic steatosis model was induced by free fatty acid (FFA) treatment in primary hepatocytes. Both models exhibited pronounced lipid accumulation in hepatic cells and altered hepatocellular injury-related parameters, which were associated with mitochondrial dysfunction and impaired fatty acid oxidation. Mechanistically, hepatic tissues and hepatocytes showed suppression of the SIRT3-AMPKα-PGC-1α signaling cascade, accompanied by reduced expression of mitochondrial biogenesis markers (NRF1, TFAM), impaired respiratory chain components (NDUFA9, SDHA, UQCRC1, COX4I1, ATP5B), and decreased transcription of fatty acid oxidation-related genes (PPARα, ACOX1, CPT1A, CPT2, ACADL, ACADM). Pharmacological activation of SIRT3 with AR-C17 restored AMPKα-PGC-1α signaling, enhanced mitochondrial biogenesis and respiratory function, and promoted fatty acid oxidation, thereby alleviating lipid accumulation in hepatocytes in both models. Collectively, these results demonstrate that SIRT3 is a key metabolic regulator maintaining mitochondrial oxidative function and lipid homeostasis in laying hens. Targeted activation of SIRT3 may provide a novel nutritional strategy for preventing or ameliorating FLHS and related metabolic disturbances in poultry production.
    Keywords:  Fatty acid oxidation; Fatty liver hemorrhagic syndrome; Mitochondrial biogenesis; SIRT3
    DOI:  https://doi.org/10.1016/j.psj.2026.106901
  66. New Phytol. 2026 Apr 18.
    Lipid metabolism and autophagy maintain cellular homeostasis under chloroplast dysfunction in Chlamydomonas reinhardtii.
    Huanling Yang, Chunyang Zhang, Junting Pan, Jiale Xing, Song Bin, Fei Han, Meimei Wang, Guanghou Shui, Wenqiang Yang.
      Lipid rearrangement is a fundamental adaptive response to cellular stress. This study elucidates the global lipid metabolic adjustments in response to chloroplast dysfunction following the depletion of Orf2971, a plastid-encoded protein essential for protein import in Chlamydomonas reinhardtii. We utilized an integrated approach, combining lipidomics, fluorescence/electron microscopy, flow cytometry, and biochemical assays to comprehensively profile lipid dynamics, organelle ultrastructure, and gene and protein expression after Orf2971 depletion in Chlamydomonas reinhardtii. Orf2971 depletion triggered biphasic triacylglycerol (TAG) dynamics: initial accumulation via de novo synthesis followed by autophagic degradation (lipophagy). Concurrently, elevated cardiolipin drove mitochondrial remodeling with associated morphological changes, enhanced respiratory capacity, and upregulated cardiolipin-translocating genes, indicating the potential induction of mitophagy. Our study reveals a coordinated inter-organellar adaptation to chloroplast stress, where rapid TAG turnover via lipophagy and cardiolipin-mediated mitochondrial enhancement collectively compensate for compromised chloroplast function to maintain cellular homeostasis.
    Keywords:  Chlamydomonas reinhardtii; Orf2971 depletion; autophagy; chloroplast dysfunction; lipid metabolism; mitochondrial remodeling
    DOI:  https://doi.org/10.1111/nph.71139
  67. Theranostics. 2026 ;16(10): 5589-5608
    Macrophage membrane-biomimetic cinnamaldehyde nanomedicine ameliorates inflammatory bowel disease by suppressing macrophage M1 polarization.
    Zebin Huang, Lingna Xie, Qi Shu, Yongyu Xu, Xiao-Chun Guo, Shimin Wang, Shuyi Li, Yaoxun Zeng, Xiu-Cai Chen, Mingtao Huang, Fujun Jin, Yu-Jing Lu.
       Rationale: Inflammatory bowel disease (IBD), known for its complexity and frequent relapses, urgently demands novel therapeutics due to the limited efficacy of current treatments. Cinnamaldehyde (CMA), a bioactive compound derived from Cinnamomum cassia Presl, has exhibited therapeutic potential for IBD. However, the therapeutic mechanism of CMA remains incompletely elucidated, and clinical translation is hampered by its poor oral pharmacokinetics.
    Methods: Using RAW 264.7 cells stimulated with either LPS or IL-4, we evaluated the effects of CMA on macrophage polarization. Subsequently, the impact of CMA on glucose metabolism in M1 macrophages was analyzed. RNA sequencing identified the signaling pathways through which CMA inhibits M1 macrophage polarization, and this was further validated through genetic or pharmacological blockade. To overcome the pharmacokinetic challenges of CMA, macrophage membrane-biomimetic CMA-loaded nanoparticles (MM@CMANP) were designed, and their pharmacokinetics and targeting to intestinal inflammation sites were evaluated. Finally, the efficacy of MM@CMANP was assessed in DSS-induced IBD mice.
    Results: CMA suppresses M1 macrophage polarization in vitro. Notably, CMA disrupted M1 macrophage glucose metabolic reprogramming, characterized by glycolysis suppression and enhanced oxidative phosphorylation. RNA sequencing demonstrated a clear association with mitophagy pathway following CMA treatment, and mechanistic studies verified that CMA promotes BCL2/adenovirus E1B 19 kDa-interacting protein 3 (BNIP3)-mediated mitophagy activation. Crucially, CMA-induced inhibition of M1 macrophages was mitigated by BNIP3 knockdown or autophagy inhibitors. MM@CMANP enhanced CMA accumulation in inflamed colonic tissues. In IBD mice, MM@CMANP significantly alleviated epithelial barrier disruption and mucosal inflammation. Consistent with in vitro findings, CMA modulated macrophage polarization and autophagy in vivo.
    Conclusions: These results establish mitophagy as a central mechanism underlying anti-IBD effects of CMA and position MM@CMANP as a clinically translatable nanotherapeutic platform for IBD.
    Keywords:  IBD; cinnamaldehyde; macrophage membrane-biomimetic nanoplatform; macrophage polarization; mitophagy
    DOI:  https://doi.org/10.7150/thno.124748
  68. Comp Biochem Physiol B Biochem Mol Biol. 2026 Apr 11. pii: S1096-4959(26)00034-5. [Epub ahead of print] 111226
    Roles of mitochondria in oocyte fertility decline in the interspecific hybrids between Argopecten irradians irradians and A. purpuratus.
    Jinjing Wang, Min Shen, Jiawei Fan, Jingyong Wang, Jianbai Zhang, Guilong Liu, Yinchu Wang, Shaoxuan Wu, Tieying Yu, Xin Xu, Junhao Ning, Chunde Wang.
      Fertility decline is common in interspecific hybrids, as observed in the F1 hybrids between the bay scallop (Argopecten irradians irradians) and Peruvian scallop (A. purpuratus). While it is known that mitochondria may regulate fertility, their role in hybrid fertility decline remains unclear. This study investigated mitochondrial ultrastructure, regulatory gene expression, and function in relation to fertility decline in F1 hybrids. Fertility assessment revealed significant differences in fertilization rates at 30 min after fertilization between the low fertility group (Group L), the high fertility group (Group H), and the control group (self-crosses of Ai, Group N). Group L exhibited significant mitochondrial abnormalities, such as swelling, matrix vacuolization, compared to Group H and Group N. Gene expression analysis revealed significant alteration in mitochondrial regulation in hybrids, particularly the down-regulation of MFN2 (mitofusin 2) and NRF1 (nuclear respiratory factor 1) and up-regulation of DRP1 (dynamin-related protein 1), especially in Group L. Additionally, the expression of the autophagy gene ATG5 (autophagy-related gene 5) was up-regulated in Group H and down-regulated in Group L. ATP6 (ATP synthase gene) and other electron transport chain genes were significantly down-regulated in Group L. The antioxidant defense gene SOD2 (superoxide dismutase 2) expression increased in Group H but significantly decreased in Group L. Functionally, hybrids showed reduced mitochondrial membrane potential, disrupted calcium ion homeostasis, increased membrane permeability, and decreased ATP production, with the most severe impairments in Group L. These findings emphasize the possible key role of mitochondrial in the hybrid infertility of marine bivalves.
    Keywords:  Argopecten scallop; Hybrid fertility; Mitochondrial dynamics; Mitochondrial dysfunction
    DOI:  https://doi.org/10.1016/j.cbpb.2026.111226
  69. Proc Natl Acad Sci U S A. 2026 Apr 21. 123(16): e2509165123
    Rhesus macaques with an OPA1 mutation demonstrate features of autosomal dominant optic atrophy.
    Tracy N Jaggers, Ana Ripolles-Garcia, Ala Moshiri, Brett D Story, Jun Wang, Rui Chen, Lucy G Moore, Leandro B C Teixeira, Jaeho Shim, Ana C Raposo, Maria Isabel Casanova, Sophie M Le, Sangwan Park, Laura J Young, Soohyun Kim, Karolina P Roszak, Vanessa Ureno, Paige M Karpinen, Nayeli Echeverria, Monica Ardon, Brian C Leonard, Marguerite Knipe, Eliza Bliss-Moreau, Brad Fortune, J Timothy Stout, Jeffrey Rogers, Nicholas Marsh-Armstrong, Sara M Thomasy.
      Autosomal dominant optic atrophy (ADOA) is an inherited optic neuropathy primarily caused by mutations in OPA1. We identified and defined a spontaneous nonhuman primate (NHP) model of ADOA using rhesus macaques heterozygous for a missense mutation (OPA1A8S). With ocular examinations, ophthalmic imaging, electroretinography, histopathology, immunohistochemistry, and transmission electron microscopy (TEM), we documented retinal nerve fiber layer (RNFL) thinning, retinal ganglion cell (RGC) loss and dysfunction, OPA1 mislocalization, and reduced axonal mitochondrial density in affected macaques. Our investigation revealed substantial phenotypic variability among affected macaques, shedding light on the pathogenesis of ADOA. The retinas were evaluated using techniques such as spectral-domain optical coherence tomography and fundus photography facilitating observation of structural changes in the retina and optic nerve. Thinning of the RNFL and optic nerve head degeneration, hallmark features of ADOA, were observed in affected macaques. Decreased RGC function in the OPA1 heterozygotes was demonstrated with pattern electroretinography. Histopathological analysis and immunohistochemical staining of postmortem retinal tissue suggested RGC loss in the papillomacular bundle, with reduced OPA1 and mitochondria in the RGC axons, indicating dysfunctional mitochondrial dynamics and reduced function consistent with ADOA. Ultrastructural changes were evident with TEM including dysmorphic mitochondria, axonal loss, myelin disruption, and hypertrophic astrocytic processes. The observed similar pattern of RGC loss and dysfunction coupled with phenotypic heterogeneity in our NHP model reflects the clinical variability observed in human ADOA patients indicating that therapeutic interventions in this foveate model will likely translate to the human condition.
    Keywords:  OPA1; autosomal dominant optic atrophy; nonhuman primate; optic neuropathy; retinal ganglion cell
    DOI:  https://doi.org/10.1073/pnas.2509165123
  70. Mol Cell Biochem. 2026 Apr 11.
    Inhibition of NCOA4-mediated ferritinophagy improves cardiac remodeling in diabetic cardiomyopathy via MITOL/parkin signaling.
    Linhe Lu, Yang Liu, Yalan Shao, Xiang Xiong, Mengen Zhai, Jian Yang, Lifang Yang.
      Diabetic cardiomyopathy (DCM) is a diabetes mellitus-induced pathophysiological condition caused by unfavorable myocardial sequelae, with more severe cardiac dysfunction observed in patients with diabetes than in those without diabetes. Recently, ferroptosis has been implicated in DCM; however, its role in DCM remains incompletely elucidated. This study was conducted to examine the impact of mitochondrial ubiquitin ligase (MITOL/March5) and the mitophagy receptor Parkin on DCM-induced cardiac dysfunction, as well as the effect of ferritinophagy. Wild-type and db/db mice were fed normal chow or a high-fat diet and subjected to streptozotocin treatment. Cardiac geometry and function, as well as ferroptosis-related biomarkers, were assessed upon completion of experiments. Our findings revealed that DCM induced notable alterations in cardiac geometry by increasing myocardial fibrosis and ferroptosis, involving increased reactive oxygen species production and lipid accumulation. Nuclear receptor coactivator 4 (NCOA4)-related ferroptosis was significantly activated, whereas Parkin-dependent mitophagy was dramatically inhibited. However, adeno-associated virus (AAV)-MITOL treatment markedly attenuated cardiac dysfunction and ferroptosis with those in the DCM group. Furthermore, Ad Parkin alleviated NCOA4-mediated ferroptosis and suppressed myocardial apoptosis compared with those in the high-glucose/high-fat group. Our in vitro analysis demonstrated that MITOL inhibition compromised cardiomyocyte function and elicited mitochondrial injury and lipid peroxidation, the effects of which were negated by Parkin activation. This study underscores the pivotal protective role of the MITOL/Parkin signaling pathway against DCM-induced cardiac dysfunction in NCOA4-mediated ferritinophagy.
    Keywords:  Diabetic cardiomyopathy; Ferroptosis; Fibrosis; Mitochondrial ubiquitin ligase; Nuclear receptor coactivator 4; Parkin
    DOI:  https://doi.org/10.1007/s11010-026-05513-1
This page is being maintained by Thomas Krichel. It was last updated on 2026‒05‒17 at 8:03.