bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2025–05–18
sixty papers selected by
Gavin McStay, Liverpool John Moores University
  1. Snapshots of mitochondrial fission imaged by cryo-scanning transmission electron tomography.
  2. PINK1 deficiency alleviates bleomycin-induced pulmonary fibrosis in mice.
  3. The mitophagy receptors BNIP3 and NIX mediate tight attachment and expansion of the isolation membrane to mitochondria.
  4. Mitochondrial quality control and transfer communication in neurological disorders and neuroinflammation.
  5. TBK1 alleviates triptolide-induced nephrotoxic injury by up-regulating mitophagy in HK2 cells.
  6. Inactivation of SIAH-1 E3 ligase attenuates Aβ toxicity by suppressing ubiquitin-dependent DVE-1 degradation in C. elegans models of Alzheimer's disease.
  7. [Mechanism of BNIP3-mediated mitophagy in m.3635G>A related Leber hereditary optic neuropathy].
  8. Verbenalin protects against coronavirus pneumonia by promoting host immune homeostasis: Evidences for its mechanism of action.
  9. Overcoming drug resistance by harnessing mitochondrial divisome for treating cholangiocarcinoma.
  10. Death-Associated Protein 3 Triggers Intrinsic Apoptosis via Miro1 Upon Inducing Intracellular Calcium Changes.
  11. Daidzein Attenuates Cadmium-Induced Neurotoxicity via Inhibiting Apoptosis and Mitophagy in the Cerebral Cortex of Sprague-Dawley Rats.
  12. NLRP3 inflammasome inhibits mitophagy during the progression of temporal lobe epilepsy.
  13. Mitochondrial Genome-Encoded lncND5 Regulates Mitophagy in Hypoxic Pulmonary Artery Smooth Muscle Cell.
  14. Hyperglycemia-induced α-Klotho downregulation impairs mitophagy and promotes placental dysfunction in T2DM pregnancies.
  15. c-FLIP Protects Cardiac Microcirculation in Sepsis-Induced Myocardial Dysfunction Via FUNDC1-Mediated Regulation of Mitochondrial Autophagy.
  16. MTFR2-Mediated Fission Drives Fatty Acid and Mitochondrial Co-Transfer from Hepatic Stellate Cells to Tumor Cells Fueling Oncogenesis.
  17. Detection of mitophagy in live cells with indole derived near-infrared fluorogenic probes.
  18. Mitochondrial Dysfunction in Genetic and Non-Genetic Parkinson's Disease.
  19. OPA1 Enhances Microglial Amyloid-β Clearance and Alleviates Cognitive Impairments in an Alzheimer's Disease Model.
  20. NRF1 coordinates mitochondrial adaptations to dampen intracellular ROS and inflammatory responses during ischemia reperfusion.
  21. Optimally Aligned Nerve Scaffolds with Sustained Astaxanthin Release Improve the Inflammatory Microenvironment through Mitophagy Activation.
  22. The regulatory mechanisms of mitophagy and oxidative stress in androgenetic alopecia.
  23. Lipopolysaccharide-induced DNA damage response activates DNA-PKcs to drive actin cytoskeleton disruption and cardiac microvascular dysfunction in endotoxemia.
  24. Irisin attenuates cardiac injury and improves prognosis in rats with hemorrhagic shock by maintaining mitochondrial homeostasis via the AMPK/Drp1 pathway.
  25. Endothelial major vault protein alleviates vascular remodeling via promoting Parkin-mediated mitophagy.
  26. Tollip deficiency enhances mitophagy and reduces STING activation in influenza A virus-infected mice.
  27. Targeting mitochondria in bone and cartilage diseases: A narrative review.
  28. The active metabolite of Epimedii Folium promotes hippocampal neurogenesis in APP/PS1 mice by alleviating mitochondrial dysfunction.
  29. A data-driven model for mitochondrial inner membrane remodeling as a driving force of organelle shaping.
  30. PTPN22 as a therapeutic target in intervertebral disc degeneration: Modulating mitophagy and pyroptosis through the PI3K/AKT/mTOR axis.
  31. Therapeutic Effect of V8 Affecting Mitophagy and Endoplasmic Reticulum Stress in Acute Myeloid Leukemia Mediated by ROS and CHOP Signaling.
  32. PINK1 activation by MTK458 ameliorates neurological impairments and pyroptosis after intracerebral hemorrhage in mice.
  33. BdUth1 Mediates Mitophagy by Recruiting BdAtg8 to Govern the Pathogenicity of Botryosphaeria dothidea.
  34. CREG1 alleviates bone loss in osteoporosis by enhancing the osteogenic differentiation of BMSCs through mitophagy.
  35. [Verification of resveratrol ameliorating vascular endothelial damage in sepsis-associated encephalopathy through HIF-1α pathway based on network pharmacology and experiment].
  36. Mesenchymal stem cell-mediated mitochondrial transfer regulates the fate of B lymphocytes.
  37. A Nanosystem Alleviates Severe Acute Pancreatitis via Reactive Oxygen Species Scavenging and Enhancing Mitochondrial Autophagy.
  38. Mitochondrial unfolded protein response (UPRmt) as novel therapeutic targets for neurological disorders.
  39. Reprogramming of Hypoxia-Induced Metabolic Disorder in Mouse Kidneys by Mesenchymal Stem Cells Through Improving Mitochondrial Dynamics and Function.
  40. Corrigendum to "Urolithin A inhibits breast cancer progression via activating TFEB-mediated mitophagy in tumor macrophages" [J. Adv. Res. 69 (2025) 125-138].
  41. Molecular machineries shaping the mitochondrial inner membrane.
  42. Iron Metabolism and Muscle Aging: Where Ferritinophagy Meets Mitochondrial Quality Control.
  43. Quality control of un-imported mitochondrial proteins at a glance.
  44. Mitochondrial calcium overload contributes to mechanical allodynia in neuropathic pain via inducing mitochondrial dynamic imbalance.
  45. Creatine Ameliorates the Adverse Effects of High-Fat Diet on Hepatic Lipid Metabolism via Activating Mfn2-Mediated Mitochondrial Fusion in Juvenile Grass Carp.
  46. High-dose vitamin C promotes mitochondrial biogenesis in HCT116 colorectal cancer cells by regulating the AMPK/PGC-1α signaling pathway.
  47. DUT (p.Y116C)-Mutation-Induced Thrombocytopenia in Rabbits.
  48. [Regulatory effect of electroacupuncture at "Neiguan" (PC6) on mitochondrial autophagy during the ischemia and reperfusion phases in rats with myocardial ischemia-reperfusion injury].
  49. Disruption of the caspase-1/IL-1β axis alleviates myocardial Ischemia/Reperfusion injury via improvement of mitochondrial homeostasis and reduction of Pyroptosis.
  50. Isolation and Characterization of Earthworm Peptides with Neuroprotective Effects in Parkinson's Disease Models.
  51. METTL14-mediated lncRNA NEAT1 promotes asthma progression by regulating the miR-302a-3p/March5 axis.
  52. An Iron Balance Dual-Drive Strategy (IBDS) Promotes Bone Regeneration in Smokers by Regulating Mitochondrial Iron Homeostasis.
  53. Therapeutic Effects of Hemerocallis citrina Baroni Extract on Animal Models of Neurodegenerative Diseases Through Serotonin and HLH-30/TFEB-Dependent Mechanisms.
  54. Estrogen-related receptors regulate innate and adaptive muscle mitochondrial energetics through cooperative and distinct actions.
  55. Aquaporin 9: Exacerbation of Vulnerable Carotid Plaque Formation.
  56. [Effect of total secondary ginsenosides on apoptosis and energy metabolism of H9c2 cells under hypoxia based on mitochondrial biogenesis].
  57. Discovery of Golgi Membrane-associated Degradation Pathway, GOMED: A Focus on 15 Years of Ultrastructural Analyses.
  58. Vital Role of PINK1/Parkin-Mediated Mitophagy of Pulmonary Epithelial Cells in Severe Pneumonia Induced by IAV and Secondary Staphylococcus aureus Infection.
  59. Sequentially assembled co-delivery nanoplatform of SIRT1 protein and SOX9-expressing plasmid for multipronged therapy of intervertebral disc degeneration.
  60. Gut microbiota regulation by Lactiplantibacillus plantarum SG5 enhances mitochondrial function in Parkinson's disease mice via the GLP-1/PGC-1α pathway.
  1. J Cell Sci. 2025 May 01. pii: jcs263639. [Epub ahead of print]138(9):
    Snapshots of mitochondrial fission imaged by cryo-scanning transmission electron tomography.
    Peter Kirchweger, Sharon Grayer Wolf, Neta Varsano, Tali Dadosh, Guenter P Resch, Michael Elbaum.
      Mitochondria undergo constant remodeling via fission, fusion, extension and degradation. Fission, in particular, depends on the accumulation of mitochondrial fission factor (MFF) and subsequent recruitment of the dynamin-related protein DRP1 (also known as DNM1L). We used cryo-scanning transmission electron tomography (cryo-STET) to investigate mitochondrial morphologies in MFF mutant (MFF-/-) mouse embryonic fibroblast (MEF) cells in ATP-depleting conditions that normally induce fission. The capability of cryo-STET to image through the cytoplasmic volume to a depth of 1 µm facilitated visualization of intact mitochondria and their surroundings. We imaged changes in mitochondrial morphology and cristae structure, as well as contacts with the endoplasmic reticulum (ER), degradative organelles and the cytoskeleton at stalled fission sites. We found disruption of the outer mitochondrial membrane at contact sites with the ER and degradative organelles at sites of mitophagy. We identified fission sites where the inner mitochondrial membrane is already separated while the outer membrane is still continuous. Although MFF is a general fission factor, these observations demonstrate that mitochondrial fission can proceed to the final stage in its absence. The use of cryo-STET allays concerns about the loss of structures due to sample thinning required for tomography using cryo-transmission electron microscopy.
    Keywords:  Cryo-ET; Cryo-FM; Cryo-STET; Mitochondrial dynamics; Mitochondrial fission; Mitochondrial fission factor
    DOI:  https://doi.org/10.1242/jcs.263639
  2. Cell Signal. 2025 May 13. pii: S0898-6568(25)00283-9. [Epub ahead of print] 111868
    PINK1 deficiency alleviates bleomycin-induced pulmonary fibrosis in mice.
    Yu-Qing Gu, Jing Wu, Tong Wang, Yi-Fan Yu, Jia Han, Ya-Ling Chen, Xiao-Long Hu, Ming Wu, Hu Hu, Wei-Ping Zhang, Yun-Bi Lu, Bo Jiang.
      Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disorder marked by deteriorating dyspnea and declining pulmonary function. Despite its rising prevalence and incidence, therapeutic options remain limited. PTEN-induced kinase 1 (PINK1), known for its role in PINK1/Parkin-dependent mitophagy, contributes to the pathogenesis of various lung diseases. In this study, we elucidate a previously unrecognized mechanism of PINK1, beyond its canonical mitophagy function, during pulmonary fibrosis. We established a bleomycin (BLM)-induced pulmonary fibrosis model in Pink1 knockout (Pink1-/-) mice and treated BEAS-2B cells with transforming growth factor-beta 1 (TGF-β1) to simulate the microenvironment of pulmonary fibrosis. A significant elevation in PINK1 expression was observed in vivo and in vitro systems. While PINK1/Parkin-dependent mitophagy was activated, mitophagy mediated by BCL2-interacting protein 3 (BNIP3) and FUN14 domain-containing 1 (FUNDC1) was suppressed. Further experiments in carbonyl cyanide m-chlorophenyl hydrazone (CCCP)-treated PINK1 knockout (KO) HEK293 cells and YFP-Parkin-expressing HeLa cells demonstrated that PINK1 deficiency enhanced BNIP3- and FUNDC1-mediated mitophagy, whereas PINK1 overexpression inhibited it. Moreover, dual BNIP3/FUNDC1 knockdown significantly reversed the anti-apoptotic effect of PINK1 KO. We conclude that PINK1 deficiency promotes the clearance of damaged mitochondria via BNIP3/FUNDC1 upregulation, preserving mitochondrial homeostasis, mitigating alveolar epithelial injury, and attenuating fibrosis. Thus, PINK1 may inhibit BNIP3- and FUNDC1-mediated mitophagy besides driving PINK1-dependent mitophagy during pulmonary fibrosis.
    Keywords:  Apoptosis; Lung epithelial cell; Mitophagy; PINK1; Pulmonary fibrosis
    DOI:  https://doi.org/10.1016/j.cellsig.2025.111868
  3. J Cell Biol. 2025 Jul 07. pii: e202408166. [Epub ahead of print]224(7):
    The mitophagy receptors BNIP3 and NIX mediate tight attachment and expansion of the isolation membrane to mitochondria.
    Shun-Ichi Yamashita, Ritsuko Arai, Hiroshi Hada, Benjamin Scott Padman, Michael Lazarou, David C Chan, Tomotake Kanki, Satoshi Waguri.
      BNIP3 and NIX are the main receptors for mitophagy, but their mechanisms of action remain elusive. Here, we used correlative light EM (CLEM) and electron tomography to reveal the tight attachment of isolation membranes (IMs) to mitochondrial protrusions, often connected with ER via thin tubular and/or linear structures. In BNIP3/NIX-double knockout (DKO) HeLa cells, the ULK1 complex and nascent IM formed on mitochondria, but the IM did not expand. Artificial tethering of LC3B to mitochondria induced mitophagy that was equally efficient in DKO cells and WT cells. BNIP3 and NIX accumulated at the segregated mitochondrial protrusions via binding with LC3 through their LIR motifs but did not require dimer formation. Finally, the average distance between the IM and the mitochondrial surface in receptor-mediated mitophagy was significantly smaller than that in ubiquitin-mediated mitophagy. Collectively, these results indicate that BNIP3 and NIX are required for the tight attachment and expansion of the IM along the mitochondrial surface during mitophagy.
    DOI:  https://doi.org/10.1083/jcb.202408166
  4. Front Immunol. 2025 ;16 1542369
    Mitochondrial quality control and transfer communication in neurological disorders and neuroinflammation.
    Yinrui Ma, Rui Song, Chenyang Duan.
      Mitochondria, as the primary energy factories of cells, play a pivotal role in maintaining nervous system function and regulating inflammatory responses. The balance of mitochondrial quality control is critical for neuronal health, and disruptions in this balance are often implicated in the pathogenesis of various neurological disorders. Mitochondrial dysfunction not only exacerbates energy deficits but also triggers neuroinflammation through the release of damage-associated molecular patterns (DAMPs), such as mitochondrial DNA (mtDNA) and reactive oxygen species (ROS). This review examines the mechanisms and recent advancements in mitochondrial quality control in neurological diseases, focusing on processes such as mitochondrial fusion and fission, mitophagy, biogenesis, and protein expression regulation. It further explores the role of mitochondrial dysfunction and subsequent inflammatory cascades in conditions such as ischemic and hemorrhagic stroke, neurodegenerative diseases and brain tumors. Additionally, emerging research highlights the significance of mitochondrial transfer mechanisms, particularly intercellular transfer between neurons and glial cells, as a potential strategy for mitigating inflammation and promoting cellular repair. This review provides insights into the molecular underpinnings of neuroinflammatory pathologies while underscoring the translational potential of targeting mitochondrial quality control for therapeutic development.
    Keywords:  mitochondrial; mitochondrial quality control; mitochondrial transfer; neuroinflammation; neurological disorders
    DOI:  https://doi.org/10.3389/fimmu.2025.1542369
  5. Biol Chem. 2025 May 07.
    TBK1 alleviates triptolide-induced nephrotoxic injury by up-regulating mitophagy in HK2 cells.
    Xinxin Lu, Qionghui Huang, Zhaohui He, Huanjie Zhou, Zhenwei Chen, Youjian Zhou, Tiecheng Yang, Lang-Jing Zhu.
      Tripterygium wilfordii has been used for a long time to treat autoimmune diseases. Its toxic side effects limit its clinical application. Mitophagy plays a protective role in various diseases. TANK-binding kinase 1 (TBK1) is a mitophagy-promoting molecule. This study aimed to investigate whether TBK1 could alleviate triptolide (TP)-induced nephrotoxicity by regulating mitophagy. To establish TP-induced nephrotoxic injury in animal model, 16 Sprague-Dawley rats were administered with TP by gavage, then renal tissues were collected for hematoxylin and eosin (HE) staining, western blotting and immunofluorescence analysis. To investigate whether up-regulation of TBK1 could alleviate TP-induced nephrotoxic injury and the specific mechanism, HK-2 cells were cultured in vitro, transfected with TBK1-overexpression recombinant lentivirus, then treated with TP. Western blotting, immunofluorescence, flow cytometry, multifunctional microplate detector were used to detect the relevant molecules. Here we found that TP caused kidney function damage, declined mitophagy levels, decreased the expression of TBK1 and mitophagy-related proteins in rats. TP stimulation decreased cell viability, mitochondrial membrane potential, mitophagy-protein, the formation of mito-autophagosomes and mito-autophagolysosomes in HK-2 cells. Upregulating TBK1 could reverse these damages. In summary, TP-induced cell injury had decreased mitophagy levels. Up-regulating TBK1 could increase mitophagy and further alleviate TP-induced cell injury.
    Keywords:  TBK1; mitophagy; nephrotoxicity; triptolide
    DOI:  https://doi.org/10.1515/hsz-2024-0141
  6. J Biol Chem. 2025 May 09. pii: S0021-9258(25)02076-9. [Epub ahead of print] 110226
    Inactivation of SIAH-1 E3 ligase attenuates Aβ toxicity by suppressing ubiquitin-dependent DVE-1 degradation in C. elegans models of Alzheimer's disease.
    Lihua Sun, Jiahui Liu, Menghan Lu, Yingying Zhou, Shuqi Guo, Zhipeng Qin, Zekun Wang, Xiaojuan Sun.
      The mitochondrial unfolded protein response (UPRmt), an evolutionarily conserved proteostasis pathway, plays a critical role in the pathogenesis of Alzheimer's disease (AD), characterized by amyloid-β peptide (Aβ) aggregation. Although the transcription factor DVE-1 regulates UPRmt activation in C. elegans and has been implicated in Aβ pathology, its regulatory mechanisms under AD-like conditions remain unclear. Here, using the classical C. elegans muscle-specific AD model (CL2006 strain), we observed UPRmt induction in young adults despite paradoxical depletion of DVE-1 protein concurrent with elevated dve-1 transcript levels. Through integrated genetic and biochemical analyses, we identified SIAH-1, a conserved E3 ubiquitin ligase that partners with the E2 enzyme UBC-25 to interact with DVE-1 and mediate its K48-linked polyubiquitination, as targeting DVE-1 for proteasomal degradation. Disruption of SIAH-1 E3 ubiquitin ligase function or overexpression of DVE-1 significantly reduced Aβ toxicity in both the muscle-expressed Aβ (CL2006) and neuronal Aβ models (gnaIs2). These interventions concurrently suppressed Aβ aggregation in the heat shock-inducible Aβ aggregation model (xchIs15). Mechanistically, this protective effect was associated with restored mitochondrial homeostasis, as evidenced by MitoTracker Red staining and TOMM-20::mCherry fluorescence imaging in muscle-expressed Aβ animals. These assays demonstrated that Aβ accumulation compromises mitochondrial integrity, a phenotype markedly rescued in siah-1 deletion mutants and DVE-1-overexpressing strains. Collectively, these findings establish the SIAH-1/DVE-1 axis as a conserved proteostasis regulator and highlight ubiquitin-dependent mitochondrial quality control as a potential therapeutic target for AD and related proteopathies.
    Keywords:  Aβ toxicity; C. elegans; DVE-1; E3 ubiquitin ligase SIAH-1; UPR(mt); proteasomal degradation
    DOI:  https://doi.org/10.1016/j.jbc.2025.110226
  7. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2025 Feb 10. 42(2): 198-205
    [Mechanism of BNIP3-mediated mitophagy in m.3635G>A related Leber hereditary optic neuropathy].
    Zhen Liu, Wei Guan, Juanjuan Zhang, Minxin Guan.
       OBJECTIVE: To explore the mechanism of BNIP3-mediated mitophagy in m.3635G>A related Leber's hereditary optic neuropathy (LHON).
    METHODS: A trans-mitochondrial cybrid cell line derived from a Chinese LHON patient carrying the m.3635G>A, diagnosed at the Eye Hospital of Wenzhou Medical University in September 2013, was selected as the study subject. A trans-mitochondrial cybrid cell line from a healthy control with an identical mitochondrial background was included as a control. Immunofluorescence, real-time quantitative PCR (RT-qPCR), and Western blotting were employed to assess the expression of autophagy-related proteins, aiming to explore the role of BNIP3-mediated mitophagy in m.3635G>A related LHON. This study was approved by the Medical Ethics Committee of the Eye Hospital of Wenzhou Medical University (Ethics No. 2023-J-096).
    RESULTS: Compared with the control group, the protein expression levels of autophagy-related markers LC3 (LC3-II/LC3-I) and LAMP1 were significantly reduced in the variant group (P < 0.05). Additionally, the protein levels of macroautophagy-related proteins ATG12, ATG7, and ATG5 were also significantly decreased (P < 0.05). Compared with the control cells, the mRNA and protein expression levels of mitophagy-associated protein BNIP3 were significantly reduced in the cells of the variant group (P < 0.05). Compared with the control group, both mRNA and protein expression levels of the mitophagy-related protein BNIP3 were significantly reduced in the variant group (P < 0.05).
    CONCLUSION: The m.3635G>A inhibits BNIP3-mediated mitophagy, thereby contributing to the pathogenesis of LHON.
    DOI:  https://doi.org/10.3760/cma.j.cn511374-20221101-00574
  8. Phytomedicine. 2025 Apr 30. pii: S0944-7113(25)00458-1. [Epub ahead of print]143 156820
    Verbenalin protects against coronavirus pneumonia by promoting host immune homeostasis: Evidences for its mechanism of action.
    Qiyue Sun, Ronghua Zhao, Shuran Li, Weiqin Zhou, Jingsheng Zhang, Bo Pang, Shilan Ding, Lei Bao, Zihan Geng, Rui Xie, Dan Xie, Xiaolan Cui, Shanshan Guo, Jing Sun.
       BACKGROUND: Coronavirus has caused high-mortality viral pneumonia worldwide. The pathogenesis is characterized by hyperinflammatory reactions resulting from immune homeostasis dysregulation. Verbenalin, an iridoid glucoside derived from Verbena officinalis L., is widely used in Traditional Chinese Medicine (TCM) clinical practice for its antioxidant, anti-inflammatory and antiviral properties.
    PURPOSE: This study aimed to investigate the pharmacological effects and underlying mechanisms of verbenalin on coronavirus pneumonia both in vivo and in vitro.
    METHODS: A coronavirus pneumonia mouse model and macrophage injury models, including mouse alveolar macrophage cell line (MH-S) cells and primary macrophages, were established to initially confirm the antiviral effects of verbenalin. Time-resolved proteomic were then employed to uncover proteomic changes and identify potential therapeutic targets for coronavirus treatment. Subsequently, flow cytometry and Western blot were employed to investigate verbenalin's effects on NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome pathway. Additionally, the targeting regulation of phosphatase and tensin homolog-induced putative kinase 1 (PINK1) / E3 ubiquitin ligase Parkin (Parkin) pathway by verbenalin was validated through molecular docking, surface plasmon resonance (SPR), immunofluorescent staining, RNA interference (RNAi), and mitophagy inhibition both in vivo and in vitro.
    RESULTS: Verbenalin reduced cell injury and inflammation in Human coronavirus 229E (HCoV-229E)-infected macrophages and improved lung inflammation in mice. Proteomics analysis highlighted the roles of nucleotide-binding oligomerization domain (NOD)-like receptor signaling and mitophagy pathways in coronavirus pneumonia. Verbenalin bound strongly to PINK1 and Parkin proteins, increased mitochondrial membrane potential (MMP), decreased mitochondrial reactive oxygen species (mtROS) levels, reduced the opening of mitochondrial permeability transition pore (MPTP), maintained mitochondrial mass, promoted mitophagy flux, upregulated the expression of PINK1, Parkin, and microtubule-associated protein 1A/1B-light chain 3BII (LC3BII). Additionally, verbenalin inhibited the activation of the NLRP3 inflammasome and downregulated the expression of Interleukin-1 beta (IL-1β), cysteine aspartate-specific protease 1 (caspase-1), and gasdermin D (GSDMD) both in vivo and in vitro. Furthermore, treatment with a mitophagy inhibitor and RNAi attenuated the inhibitory effects of verbenalin on NLRP3 activation, confirming the involvement of the PINK1/Parkin/NLRP3 pathway in verbenalin's protective effects.
    CONCLUSION: Verbenalin enhances PINK1/Parkin-mediated mitophagy to suppress NLRP3 activation, thereby promoting immune homeostasis and mitigating HCoV-229E-induced inflammation.
    Keywords:  Coronavirus pneumonia; Immune homeostasis; NLRP3 signaling pathways; PINK1/Parkin; Verbenalin
    DOI:  https://doi.org/10.1016/j.phymed.2025.156820
  9. J Hepatol. 2025 May 09. pii: S0168-8278(25)02197-X. [Epub ahead of print]
    Overcoming drug resistance by harnessing mitochondrial divisome for treating cholangiocarcinoma.
    Mengwei Niu, Wen-Xing Ding.
      
    Keywords:  Autophagy; DRP1; ER-Phagy; INF2; Mitophagy
    DOI:  https://doi.org/10.1016/j.jhep.2025.04.038
  10. MedComm (2020). 2025 May;6(5): e70214
    Death-Associated Protein 3 Triggers Intrinsic Apoptosis via Miro1 Upon Inducing Intracellular Calcium Changes.
    Dongxue Hu, Qiaoyun Yang, Hongxu Xian, Minghao Wang, Hong Zheng, Karthik Babu Mallilankaraman, Victor C Yu, Yih-Cherng Liou.
      Mitochondrial homeostasis is essential for cell survival and function, necessitating quality control mechanisms to ensure a healthy mitochondrial network. Death-associated protein 3 (DAP3) serves as a subunit of the mitochondrial ribosome, playing a pivotal role in the translation of mitochondrial-encoded proteins. Apart from its involvement in protein synthesis, DAP3 has been implicated in the process of cell death and mitochondrial dynamics. In this study, we demonstrate that DAP3 mediates cell death via intrinsic apoptosis by triggering excessive mitochondrial fragmentation, loss of mitochondrial membrane potential (ΔΨm), ATP decline, and oxidative stress. Notably, DAP3 induces mitochondrial fragmentation through the Mitochondrial Rho GTPase 1 (Miro1), independently of the canonical fusion/fission machinery. Mechanistically, DAP3 promotes mitochondrial calcium accumulation through the MCU complex, leading to decreased cytosolic Ca2+ levels. This reduction in cytosolic Ca2+ is sensed by Miro1, which subsequently drives mitochondrial fragmentation. Depletion of Miro1 or MCU alleviates mitochondrial fragmentation, oxidative stress, and cell death. Collectively, our findings reveal a novel function of the mitoribosomal protein DAP3 in regulating calcium signalling and maintaining mitochondrial homeostasis.
    Keywords:  calcium; cell death; death‐associated protein 3; mitochondrial dynamics; reactive oxygen species
    DOI:  https://doi.org/10.1002/mco2.70214
  11. J Biochem Mol Toxicol. 2025 May;39(5): e70299
    Daidzein Attenuates Cadmium-Induced Neurotoxicity via Inhibiting Apoptosis and Mitophagy in the Cerebral Cortex of Sprague-Dawley Rats.
    Shuangquan Wen, Yu Zhao, Liang Wang, Yan Yuan.
      Cadmium (Cd), a prevalent environmental pollutant, is of significant concern owing to its neurotoxicity; thus, the identification of effective interventions for nerve injury caused by Cd is crucial. Mitochondrial signaling pathway-mediated apoptosis and PTEN-induced putative kinase protein 1 (PINK1)/E3 ubiquitin ligase (Parkin)-mediated mitophagy are the primary mechanisms responsible for the neurotoxic effects of Cd. Daidzein (Dz), a naturally occurring isoflavone found in leguminous plants, exhibits a wide range of pharmacological effects in the brain. To investigate the short-term protective effects of Dz against Cd-induced neurotoxicity in the rat cerebral cortex, 24 male Sprague-Dawley rats were treated with Dz (100 mg/kg) and/or CdCl2 (2 mg/kg) for 12 days. Histological changes in the cerebral cortex were assessed by Nissl staining. Apoptosis- and mitophagy-related indices were detected using TUNEL staining, western blotting, and immunofluorescence assays. The administration of Dz attenuated Cd-induced nerve injury. Additionally, Dz reduced cell apoptosis by 66%, and the expression of apoptosis-related proteins Bax/Bcl-2 ratio by 27%, cleaved caspase-9 by 42%, and cleaved caspase-3 by 42%. Dz also decreased the expression of the mitophagy-related proteins LC3 by 35%, PINK1 by 37%, and Parkin by 29%, and increased that of COX IV by 36%. Furthermore, Dz abolished the Cd-induced colocalization of PINK1 and Parkin in the cerebral cortex of rats. In summary, our results indicate that Dz exerts neuroprotective effects in the cerebral cortex of rats by inhibiting mitochondrial signaling pathway-mediated apoptosis and PINK1/Parkin-mediated mitophagy. Therefore, Dz is a promising novel neuroprotective agent. However, some challenges remain, such as efficacy, bioavailability, and potential side effects. Further studies are needed to assess its potential as a therapeutic agent for Cd-induced neurotoxicity in humans.
    Keywords:  apoptosis; cadmium neurotoxicity; cerebral cortex; daidzein; isoflavone; mitophagy
    DOI:  https://doi.org/10.1002/jbt.70299
  12. Sci Rep. 2025 May 10. 15(1): 16341
    NLRP3 inflammasome inhibits mitophagy during the progression of temporal lobe epilepsy.
    Mengqian Wu, Cong Yu, Fuli Wen, Yunfei Li, Xu Zhang, Yinzhou Wang, Xiaoqian Chen, Xingyong Chen.
      Epilepsy is a neurological disorder involving mitochondrial dysfunction and neuroinflammation. This study examines the relationship between NLRP3 inflammasome activation and mitophagy in the temporal lobe epilepsy, which has not been reported before. A pilocarpine-induced epileptic rat model was used to assess seizure activity and neuronal loss. Pyroptosis markers (NLRP3, cleaved Gasdermin D, IL-1β/IL-18), and autophagy/mitophagy activity (LC3B-II/I, BNIP3, TOMM20/LC3B colocalization) were analyzed via immunofluorescence, Western blot, and transmission electron microscopy. NLRP3 inhibitors and anti-IL-1β antibodies were administered to evaluate therapeutic effects. Epileptic rats exhibited progressive neuronal loss and seizure aggravation, correlating with NLRP3 inflammasome activation and pyroptosis. While general autophagy was upregulated, mitophagy was selectively impaired in the hippocampus. NLRP3 activation promoted IL-1β release, which suppressed mitophagy via PPTC7 upregulation. NLRP3 activation inhibitor (MCC950) and anti-IL-1β treatment restored mitophagy and reduced seizures. NLRP3 inflammasome-driven pyroptosis exacerbates epilepsy by impairing mitophagy activity via IL-1β/PPTC7. Targeted NLRP3 inhibition mitigates this cascade, offering a promising strategy for refractory epilepsy.
    Keywords:  Autophagy; Mitophagy; NLRP3 inflammasome; Pyroptosis; Temporal lobe epilepsy
    DOI:  https://doi.org/10.1038/s41598-025-01087-y
  13. FASEB J. 2025 May 31. 39(10): e70618
    Mitochondrial Genome-Encoded lncND5 Regulates Mitophagy in Hypoxic Pulmonary Artery Smooth Muscle Cell.
    June Bai, Siyu He, Xiaoying Wang, Lixin Zhang, Cui Ma, Danni Gao, Hao Yuan, Jian Mei, Xiaoyu Guan, Hang Yu, Kuiyu Wan, Daling Zhu.
      Long noncoding RNAs (lncRNAs) are implicated in pulmonary hypertension (PH) progression. However, the underlying mechanisms remain largely unknown. Although mitophagy plays a crucial role in hypoxia-induced PH pathogenesis, the role of lncRNAs in mitophagy remains unclear. Especially, the mechanism of lncRNA encoded by the mitochondrial genome in regulating mitophagy needs to be elucidated. We explored the role of lncND5 in human pulmonary artery smooth muscle cells (PASMCs) and Sugen5416 plus hypoxia (SuHx)-induced PH mouse model in vitro and in vivo. LncND5 expression and localization were detected using real-time quantitative polymerase chain reaction (RT-qPCR) and fluorescence in situ hybridization (FISH). We investigated the molecular mechanism of lncND5 using western blotting, flow cytometry, RNA immunoprecipitation, RNA pulldown, transmission electron microscopy (TEM), immunofluorescence (IF), and echocardiography. Mitochondrial lncND5 expression was decreased under hypoxia in human PASMCs. Mechanistically, in the mitochondria, lncND5 maintains complex I activity by binding with mitochondrial ADH-ubiquinone oxidoreductase chain 5 (MT-ND5) at nucleotides 1086-1159 bp, thereby regulating mitochondrial reactive oxygen species (mROS) release and alleviating mitophagy. Additionally, lncND5 regulates mitophagy via cardiolipin (CL), which regulates complex I activity, inhibiting ROS release then relieving mitophagy. In the cytoplasm, lncND5 inhibits mitophagy by directly interacting with hydroxymethylglutaryl-CoA synthase 1 (HMGCS1). Notably, lncND5 is transported from the mitochondria to the cytoplasm and is mediated by TAR DNA-binding protein 43 (TDP-43). Our findings, for the first time, reveal that lncND5 may be a potential therapeutic approach for PH.
    Keywords:  CL; HMGCS1; LncND5; MT‐ND5; Mitophagy; Pulmonary hypertension; ROS
    DOI:  https://doi.org/10.1096/fj.202500389R
  14. Placenta. 2025 Apr 27. pii: S0143-4004(25)00135-3. [Epub ahead of print]167 95-103
    Hyperglycemia-induced α-Klotho downregulation impairs mitophagy and promotes placental dysfunction in T2DM pregnancies.
    Jianhua Niu, Bing Han, Shuxian Wang, Yumei Wei, Zhe Liu, Huixia Yang.
       INTRODUCTION: Placental dysfunction in pregnancies complicated by type 2 diabetes mellitus (T2DM) is associated with adverse maternal and fetal outcomes. α-Klotho, a multifunctional anti-aging protein, plays a critical role in maintaining cellular homeostasis, but its role in T2DM-induced placental dysfunction remains poorly understood.
    METHODS: Placental tissues from T2DM pregnancies and normoglycemic controls were analyzed for α-Klotho expression using qRT-PCR, Western blot, and immunohistochemistry. BeWo trophoblast cells were cultured under normoglycemic and hyperglycemic conditions, with α-Klotho knockdown and overexpression to explore its regulatory effects. Transcriptomic analysis was conducted to identify affected pathways, and markers of mitophagy and reactive oxygen species (ROS) were analyzed.
    RESULTS: α-Klotho expression was significantly reduced in the placentas of T2DM pregnancies and in trophoblast cells under hyperglycemic conditions. Transcriptomic analysis identified pathways related to mitochondrial dysfunction and impaired mitophagy as key processes regulated by α-Klotho. Hyperglycemia and α-Klotho knockdown suppressed mitophagy, while ROS production was increased, further exacerbating oxidative stress. Overexpression of α-Klotho restored mitophagy and mitigated ROS activation.
    DISCUSSION: This study reveals that α-Klotho downregulation contributes to T2DM-induced placental dysfunction by impairing mitophagy and increasing oxidative stress. These findings provide new insights into the molecular mechanisms underlying placental abnormalities in diabetic pregnancies and highlight α-Klotho as a potential therapeutic target.
    Keywords:  Mitophagy; Oxidative stress; Placental dysfunction; Type 2 diabetes mellitus; α-Klotho
    DOI:  https://doi.org/10.1016/j.placenta.2025.04.024
  15. JACC Basic Transl Sci. 2025 Mar 31. pii: S2452-302X(25)00074-9. [Epub ahead of print]
    c-FLIP Protects Cardiac Microcirculation in Sepsis-Induced Myocardial Dysfunction Via FUNDC1-Mediated Regulation of Mitochondrial Autophagy.
    Lan Gao, Qindong Shi, Bin Sun, Xiaoyu Zhang, Peiying Zheng, Linjing Zhou, Gang Tian, Hao Li.
      This study investigates the role of c-FLIP in sepsis-induced myocardial dysfunction (SIMD), focusing on cardiac microcirculation and mitochondrial autophagy. Using SIMD rat and LPS-induced cardiac microvascular endothelial cell injury models, we found that c-FLIP deficiency disrupts mitochondrial homeostasis, exacerbating microcirculatory damage. c-FLIP differentially regulates mitochondrial autophagy via FUNDC1. Overexpression of c-FLIP balances autophagy, protects mitochondria, reduces inflammation, and ameliorates SIMD, highlighting its potential as a therapeutic target.
    Keywords:  FUNDC1; JNK pathway; c-FLIP; cardiac microcirculation; mitochondrial autophagy; sepsis-induced myocardial dysfunction (SIMD)
    DOI:  https://doi.org/10.1016/j.jacbts.2025.02.016
  16. Adv Sci (Weinh). 2025 May 14. e2416419
    MTFR2-Mediated Fission Drives Fatty Acid and Mitochondrial Co-Transfer from Hepatic Stellate Cells to Tumor Cells Fueling Oncogenesis.
    La Zhang, Baoyong Zhou, Jun Yang, Cong Ren, Jing Luo, Zhenghang Li, Qiang Liu, Zuotian Huang, Zhongjun Wu, Ning Jiang.
      The tumor margin of hepatocellular carcinoma (HCC) is a critical zone where cancer cells invade the surrounding stroma, exhibiting unique and more invasive metabolic and migratory features compared to the tumor center, driving tumor expansion beyond the primary lesion. Studies have shown that at this critical interface, HCC cells primarily rely on fatty acid oxidation to meet their energy demands, although the underlying mechanisms remain unclear. This study demonstrates that activated hepatic stellate cells (HSCs) at the tumor margin play a pivotal role in sustaining the metabolic needs of HCC cells. Specifically, it is discovered that mitochondrial fission regulator 2 (MTFR2) in HSCs interacts with dynamin-related protein 1 (DRP1, a known mitochondrial fission machinery), preventing its lysosomal degradation, which in turn promotes mitochondrial fission. This MTFR2-driven mitochondrial fission enhances the transfer of both fatty acids and mitochondria to HCC cells, supplying essential metabolic substrates and reinforcing the mitochondrial machinery critical for tumor growth. The findings suggest that targeting MTFR2-driven mitochondrial fission may offer a novel therapeutic avenue for interfering with the metabolic crosstalk between tumor cells and the stromal niche.
    Keywords:  fatty acid transfer; hepatic stellate cell; hepatocellular carcinoma; mitochondrial dynamics; mitochondrial transfer
    DOI:  https://doi.org/10.1002/advs.202416419
  17. Spectrochim Acta A Mol Biomol Spectrosc. 2025 May 10. pii: S1386-1425(25)00674-2. [Epub ahead of print]340 126368
    Detection of mitophagy in live cells with indole derived near-infrared fluorogenic probes.
    Xuanyuan Wang, Wen Chen, Shuangling Liu, Yihong Xu, Zhimei Xiong, Yingzi Li, Leyuan Huang, Lu Jiang, Jingting Zhang, Leying Sun, Yuan Zhang, Mengqin Liu.
      Mitophagy is an indispensable cellular process that plays a crucial role in regulating mitochondrial quality control and cellular metabolism. Therefore, monitoring the changes in the mitochondrial and lysosomal microenvironment during the mitophagy process is extremely important. However, existing mitophagy probes only target changes in a single indicator (viscosity, pH value, or polarity) within the microenvironment, which may reduce the selectivity and accuracy of assessing mitophagy in complex biological settings. To address this, we have developed a dual-channel detection near-infrared (NIR) fluorescent probe (ADMI). In vitro analysis experiments have shown that ADMI not only responds to pH and activates the NIR fluorescence channel but also that the green fluorescence channel exhibits high sensitivity to changes in polarity. This dual-response mechanism probe enables dual fluorescent detection of pH and polarity, providing a highly promising tool for monitoring the microenvironment of mitophagy in living cells. Ultimately, we applied ADMI to real-time monitoring of mitophagy induced by starvation or rapamycin, during which the decrease in pH and polarity resulted in a red shift in wavelength and increased fluorescence. Additionally, ADMI was able to observe changes in mitochondria during ferroptosis. This probe may serve as a useful tool for imaging mitophagy in living cells.
    Keywords:  Dual-targeting; Fluorescence imaging; Mitophagy; Two-channel
    DOI:  https://doi.org/10.1016/j.saa.2025.126368
  18. Int J Mol Sci. 2025 May 07. pii: 4451. [Epub ahead of print]26(9):
    Mitochondrial Dysfunction in Genetic and Non-Genetic Parkinson's Disease.
    Martina Lucchesi, Letizia Biso, Marco Bonaso, Biancamaria Longoni, Bianca Buchignani, Roberta Battini, Filippo Maria Santorelli, Stefano Doccini, Marco Scarselli.
      Mitochondrial dysfunction is a hallmark of Parkinson's disease (PD) pathogenesis, contributing to increased oxidative stress and impaired endo-lysosomal-proteasome system efficiency underlying neuronal injury. Genetic studies have identified 19 monogenic mutations-accounting for ~10% of PD cases-that affect mitochondrial function and are associated with early- or late-onset PD. Early-onset forms typically involve genes encoding proteins essential for mitochondrial quality control, including mitophagy and structural maintenance, while late-onset mutations impair mitochondrial dynamics, bioenergetics, and trafficking. Atypical juvenile genetic syndromes also exhibit mitochondrial abnormalities. In idiopathic PD, environmental neurotoxins such as pesticides and MPTP act as mitochondrial inhibitors, disrupting complex I activity and increasing reactive oxygen species. These converging pathways underscore mitochondria as a central node in PD pathology. This review explores the overlapping and distinct mitochondrial mechanisms in genetic and non-genetic PD, emphasizing their role in neuronal vulnerability. Targeting mitochondrial dysfunction finally offers a promising therapeutic avenue to slow or modify disease progression by intervening at a key point of neurodegenerative convergence.
    Keywords:  Parkinson’s disease; genetic PD; mitochondrial dysfunction; neurotoxins; oxidative stress
    DOI:  https://doi.org/10.3390/ijms26094451
  19. Aging Dis. 2025 Apr 20.
    OPA1 Enhances Microglial Amyloid-β Clearance and Alleviates Cognitive Impairments in an Alzheimer's Disease Model.
    Qing Wang, Mengqi Dong, Xue Xia, Xinyu Bao, Mengsha Hu, Lei Ye, Yun Xu.
      Amyloid deposition is thought to be a pathologic hallmark of Alzheimer disease (AD), which is associated with cognitive decline. Microglia play a crucial role in the pathology of AD, especially in the clearance of Aβ. Optic atrophy 1 (OPA1) is a GTPase primarily on the inner mitochondrial membrane, related to mitochondrial dynamics and cellular energy metabolism. Here, we found that decreased OPA1 expression and defective mitochondrial morphology in microglia during AD. Next, we utilized an OPA1 activator BGP-15, an OPA1 inhibitor myls22 and an OPA1 overexpression virus to investigate the role of OPA1 in AD. Our findings demonstrate that OPA1 promotes ATP production and Aβ clearance by microglia, leading to improved cognitive function. This may relate to down-regulation of hexokinase-2 (HK2) expression. These results suggest a critical role for OPA1 in Aβ clearance by microglia and a promising new direction for therapeutic approaches in AD.
    DOI:  https://doi.org/10.14336/AD.2025.0082
  20. Cell Death Discov. 2025 May 15. 11(1): 236
    NRF1 coordinates mitochondrial adaptations to dampen intracellular ROS and inflammatory responses during ischemia reperfusion.
    Jiakun Li, Jiawei Yan, Guowei Tu, Wenjiao Jiang, Yue Qiu, Ying Su, Changhong Miao, Zhe Luo, Tiffany Horng.
      Ischemia reperfusion injury (IRI) is commonly seen in surgical procedures involving cardiopulmonary bypass and post-shock reperfusion. Sudden restoration of blood flow after a period of ischemia triggers a rapid accumulation of reactive oxygen species (ROS) and oxidative stress that promote pathological injury. Macrophage-derived inflammatory responses are also thought to contribute to such injury, but how ROS influences tissue macrophages and their elaboration of inflammatory cytokines in IRI remains poorly understood. In this study, we showed that macrophages mobilize mitochondrial adaptations during reoxygenation, including mitochondrial fission and ubiquitin proteasome system (UPS) flux. Furthermore, the transcription factor Nuclear Factor Erythroid 2 Like 1 (NRF1) is rapidly induced during reoxygenation in response to rising levels of ROS. Induction of NRF1 upregulates ubiquitin proteasome system (UPS) and mitophagy pathways to mediate mitochondrial fusion/fission dynamics and dampen ROS production, allowing for alleviation of oxidative stress and the inflammatory response. Conversely, the absence of myeloid NRF1 leads to increased ROS, driving enhanced inflammation and kidney injury in a mouse model of IRI. We thus identify macrophage NRF1 as a master regulator of mitochondrial homeostasis, antioxidant defense, and inflammatory responses in IRI.
    DOI:  https://doi.org/10.1038/s41420-025-02461-5
  21. Small. 2025 May 15. e2502939
    Optimally Aligned Nerve Scaffolds with Sustained Astaxanthin Release Improve the Inflammatory Microenvironment through Mitophagy Activation.
    Xuehan Jin, Shengfu Liu, Jiaqi Fang, Feng Chen, Bo Xu, Liping Nan, Shihong Zhao, Zhong Wu, Zhiyuan Guan, Kun Tao, Junjian Liu.
      Effective repair of peripheral nerve injury (PNI) depends on the scaffold orientation and immunomodulatory capabilities of functionalized scaffolds, both of which substantially influence nerve regeneration. In this study, composite nerve scaffolds incorporating astaxanthin (AXT) and polycaprolactone (PCL) are developed to investigate the influence of scaffold orientation and blend concentration on cellular behavior, including adhesion, migration, and proliferation. In vitro analysis identifies 0.2% AXT/PCL fabricated at a rotational speed of 400 rpm as the optimal configuration for facilitating directed cell growth and guiding nerve repair. Moreover, the controlled release of AXT improves the microenvironment by preserving mitochondrial homeostasis, promoting mitophagy, and reducing oxidative stress and inflammation. In vivo assessments reveal that the AXT/PCL group (0.2% AXT/PCL-400) achieves better morphological, histological, electrophysiological, and functional recovery than the PCL, AXT/PCL+M0, and AXT/PCL+M4 groups, approaching the outcomes observed in the autograft (Auto) group. Moreover, the AXT/PCL+M4 group demonstrates better regenerative outcomes than the PCL and AXT/PCL+M0 groups, underscoring the critical role of mitophagy in regulating the regenerative microenvironment.
    Keywords:  aligned nerve scaffold; astaxanthin; mitophagy; oxidative stress and inflammation; peripheral nerve regeneration
    DOI:  https://doi.org/10.1002/smll.202502939
  22. Cell Signal. 2025 May 13. pii: S0898-6568(25)00277-3. [Epub ahead of print]132 111862
    The regulatory mechanisms of mitophagy and oxidative stress in androgenetic alopecia.
    Dezhao Bi, Yunyao Hu, Songmao Hua, Jia Liu, Shun Guo.
      Androgenetic alopecia (AGA), the most common type of non-scarring hair loss in dermatology, result from a multifaceted interplay of genetic susceptibility, abnormal androgen metabolism, and dysregulation within the follicular microenvironment. Recent studies have highlighted the crucial roles of mitophagy and oxidative stress in the pathogenesis and progression of AGA. Mitophagy, a selective process by which damaged mitochondria are eliminated, is essential for maintaining cellular energy metabolism homeostasis and redox balance. In contrast, oxidative stress results from excessive accumulation of reactive oxygen species (ROS), which induces cellular damage and accelerates disease progression. The disruption of the dynamic balance between mitophagy and oxidative stress is increasingly recognized as a key factor in the development and exacerbation of AGA. Despite initial studies elucidating the interaction between these two processes, the precise molecular mechanisms and regulatory networks governing AGA remain insufficiently understood. This review aims to systematically synthesize the latest findings concerning the interplay between mitophagy and oxidative stress in AGA. By examining their roles in the disease's onset and progression, we identify potential therapeutic targets for intervention. Additionally, we discuss relevant signaling pathways and cellular mechanisms, evaluating the therapeutic potential of targeting mitophagy and oxidative stress for the treatment of AGA.
    Keywords:  Androgenetic alopecia; Mitophagy; Oxidative stress; Reactive oxygen species (ROS)
    DOI:  https://doi.org/10.1016/j.cellsig.2025.111862
  23. Theranostics. 2025 ;15(12): 5969-5997
    Lipopolysaccharide-induced DNA damage response activates DNA-PKcs to drive actin cytoskeleton disruption and cardiac microvascular dysfunction in endotoxemia.
    Ying Tan, Yue Ouyang, Lushan Xiao, Jianming Huang, Fuye Li, Zisheng Ma, Chuhong Tan, Weibin Feng, Erica Davis, Yaoping Tang, Xing Chang, Haixia Li.
      Rationale: Sepsis-induced cardiomyopathy is characterized by microvascular injury, which is linked to lipopolysaccharide (LPS)-induced DNA damage response (DDR). This study investigates the role of DNA-PKcs, a key enzyme in the DDR pathway, in driving actin disruption and microvascular dysfunction following LPS exposure. Methods: We analyzed diverse transcriptomic datasets from septic human and murine models using bioinformatics tools to assess DDR pathway activation, correlations, and prognosis. In vivo, LPS-challenged mice were treated with inhibitors of DNA-PKcs or mitochondrial fission, and we evaluated cardiac function, microvascular integrity, mitochondrial status, and actin polymerization. Results: Bioinformatic analyses consistently revealed significant activation of the DDR pathway and upregulation of key genes across diverse septic models. Notably, elevated DDR pathway activity was significantly correlated with poor 28-day survival in human sepsis patients. Single-cell analysis localized this DDR gene upregulation predominantly to cardiac endothelial cells (ECs), fibroblasts, and macrophages during sepsis. Within septic capillary ECs, DDR pathway activity scores strongly correlated spatially and functionally with heightened mitochondrial fission and cytoskeletal remodeling pathway activities. In vivo experiments confirmed that LPS induced severe systolic and diastolic dysfunction, microvascular damage, and mitochondrial fragmentation, as well as significant actin depolymerization. Inhibition of DNA-PKcs with NU7441 markedly attenuated all these LPS-induced pathologies, improving cardiac function, preserving microvascular structure, preventing mitochondrial fragmentation, and normalizing related gene expression and actin cytoskeleton stability. Additionally, inhibiting mitochondrial fission with Mdivi-1 significantly ameliorated LPS-induced cardiac dysfunction and microvascular injury. Conclusions: Our findings suggest that LPS triggers a DNA-PKcs-dependent DDR that promotes mitochondrial fragmentation and actin disruption, particularly in cardiac ECs, contributing to sepsis-induced cardiomyopathy. Targeting DNA-PKcs or mitochondrial fission may hold therapeutic potential for the treatment of sepsis-induced cardiomyopathy.
    Keywords:  DNA damage response; DNA-PKcs; actin; cytoskeleton; mitochondria
    DOI:  https://doi.org/10.7150/thno.111266
  24. Front Pharmacol. 2025 ;16 1560608
    Irisin attenuates cardiac injury and improves prognosis in rats with hemorrhagic shock by maintaining mitochondrial homeostasis via the AMPK/Drp1 pathway.
    Zheng Zhang, Yufang Zhang, Xiaofang Zou, Jiake Li, Yunfei Chi, Hailiang Bai, Bin Wei, Huiting Yun, Quanxi Zhang, Weihua Cao, Haiyan Liu, Hongjie Duan.
       Objective: Hemorrhagic shock (HS) is a critical clinical condition in which cardiac dysfunction and failure are leading causes of mortality. Mitochondrial dysfunction is central to the pathogenesis of cardiac dysfunction in HS. Irisin has been shown to improve mitochondrial function and protect against ischemia-reperfusion injury (IRI), but its specific effects on myocardial injury in HS are unknown. This study investigates irisin's therapeutic potential in a rat model of HS.
    Methods: For in vivo studies, a rat HS model was established via controlled blood withdrawal and Animals were allocated to four groups: Sham, HS, HS + Vehicle (HS + Veh), and HS + Irisin. Physiological responses were evaluated through temporal sampling at 1, 3, and 6 h post-HS. For in vitro studies, H9c2 cardiomyocytes were exposed to oxygen-glucose deprivation to establish a hypoxic model. Cells were categorized into six groups: normoxia (N), normoxia + AMPK inhibitor compound C (N + Cc), hypoxia (H), hypoxia + Cc (H + Cc), hypoxia + irisin (H + Irisin), and hypoxia + Cc + irisin (H + Cc + Irisin). Cellular functional outcomes were analyzed following 3-h hypoxia exposure.
    Results: HS significantly reduced serum irisin levels. Exogenous irisin administration enhanced survival rates, stabilized mean arterial pressure (MAP), lowered lactate (LAC) levels, improved cardiac structure and function, and reduced myocardial injury biomarkers in HS rats. Mechanistically, irisin activated AMP-activated protein kinase (AMPK) and Sirtuin 1(SIRT1), to suppress the expression of dynamin-related protein 1 (Drp1) and fission protein 1 (Fis1), while upregulating mitofusin 1 (Mfn1). This modulation of mitochondrial dynamics preserved cardiomyocyte mitochondrial membrane potential (MMP), ATP production, and structural integrity. Hypoxic H9c2 cardiomyocytes exhibited consistent results. To confirm AMPK/Drp1-dependent mechanisms, Cc was administered to inhibit irisin-induced AMPK activation. Cc abolished irisin's suppression of Drp1/Fis1 and its Mfn1 upregulation. Furthermore, Cc eliminated irisin-mediated protection in both H9c2 cardiomyocytes and mitochondria.
    Conclusion: Our study demonstrates that irisin ameliorates cardiac function and enhances early prognosis in HS. These cardioprotective effects are achieved through attenuation of myocardial damage and SIRT1/AMPK/Drp1 pathway-dependent restoration of mitochondrial homeostasis.
    Keywords:  AMPK/Drp1 pathway; cardiac injury; hemorrhagic shock; irisin; mitochondrial homeostasis
    DOI:  https://doi.org/10.3389/fphar.2025.1560608
  25. Nat Commun. 2025 May 10. 16(1): 4365
    Endothelial major vault protein alleviates vascular remodeling via promoting Parkin-mediated mitophagy.
    Bin Jiang, Fan Bai, Yunfu Hu, Yu Ren, Yuan Su, Wanxuan Song, Kunxin Xie, Dongdong Wang, Junlu Pan, Yuying Liu, Yuxin Feng, Xiaoyu Li, Hanwen Zhang, Xudong Zhu, Hui Bai, Qing Yang, Jingjing Ben, Qi Chen.
      Many important vascular diseases including neointimal hyperplasia and atherosclerosis are characterized by the endothelial cell (EC) injury-initiated pathological vascular remodeling. However, the endogenous regulatory mechanisms underlying it are not fully understood. The present study investigates regulatory role of major vault protein (MVP) in the pathogenesis of vascular remodeling via controlling EC injury. By generating male murine vascular disease models, we find that ablation of endothelial MVP increases neointima formation and promotes atherosclerosis. Mechanistically, MVP directly binds with Parkin and inhibits the ubiquitination and proteasomal degradation of Parkin by dissociating the E3 ligase NEDD4L from Parkin, leading to activation of Parkin-mediated mitophagy pathway in the EC. Genetic modulation of endothelial MVP and Parkin influences the mitophagy, apoptosis, and neointima formation. These results demonstrate that MVP acts as an intracellular regulator promoting Parkin-mediated mitophagy. Our findings suggest that MVP/NEDD4L/Parkin axis may serve as the therapeutic target for treating intimal hyperplasia and atherosclerosis.
    DOI:  https://doi.org/10.1038/s41467-025-59644-y
  26. J Immunol. 2025 May 16. pii: vkaf058. [Epub ahead of print]
    Tollip deficiency enhances mitophagy and reduces STING activation in influenza A virus-infected mice.
    Hamid Reza Nouri, Niccolette Schaunaman, Monica Kraft, Mari Numata, Donata Vercelli, Hong Wei Chu.
      Toll-interacting protein (Tollip) is an intracellular adaptor protein with diverse functions including regulation of autophagy of mitochondria-mitophagy. Tollip deficiency promotes viral infection, but whether mitophagy is involved remains unclear. We sought to determine if mitophagy and associated signaling such as mitochondrial DNA (mtDNA) release and activation of stimulator of interferon genes (STING) contribute to worsened viral infection due to Tollip deficiency. Wild-type and Tollip knockout (KO) C57/BL6 mice were intranasally infected with influenza A virus (IAV), and then treated with or without a STING agonist 2'3'cGAMP for 4 d. PINK1 (an initiator of mitophagy) KO mouse tracheal epithelial cells (mTECs) or PINK1 KO mice were infected with IAV to reveal the role of mitophagy in viral infection. In IAV-infected mice, Tollip deficiency enhanced lung mitophagy (more PINK1 and BNIP3L, but less p62), and decreased release of mtDNA. Furthermore, Tollip deficiency suppressed STING activation and the antiviral response (eg IFN-β and MX1), and increased viral load. In IAV-infected Tollip KO mice, 2'3'cGAMP activated STING and increased antiviral response coupled with less virus. PINK1-deficient mice increased lung release of mtDNA and augmented STING activation and antiviral responses. PINK1 deficiency in mTECs increased STING activation and significantly decreased the viral load. Our findings suggest that enhanced mitophagy due to Tollip deficiency reduces mtDNA release and STING activation during viral infection, resulting in decreased antiviral responses. Reduction of mitophagy and/or STING activation may open novel avenues for therapeutic intervention in human subjects with Tollip deficiency and viral infection.
    Keywords:  PINK1; STING; influenza A virus; mitophagy
    DOI:  https://doi.org/10.1093/jimmun/vkaf058
  27. Redox Biol. 2025 May 07. pii: S2213-2317(25)00180-6. [Epub ahead of print]83 103667
    Targeting mitochondria in bone and cartilage diseases: A narrative review.
    Daniel H Mendelsohn, Nike Walter, Wing-Hoi Cheung, Ronald Man Yeung Wong, Rebecca Schönmehl, Lina Winter, Thaqif El Khassawna, Christian Heiss, Christoph Brochhausen, Markus Rupp.
      Mitochondria are essential regulators of bone health, controlling cell differentiation, cellular energy production, immune function, osteogenesis, and osteoclast activity. Their dysfunction is linked to orthopedic disorders such as osteoporosis, osteoarthritis, and osteomyelitis, contributing to impaired bone homeostasis and increased fracture risk. While mitochondrial research has been more advanced in fields such as cardiology and neurology, emerging therapeutic strategies from these areas are beginning to show potential for translation into orthopedics. These include mitochondrial biogenesis stimulation, mitochondrial fission inhibition, antioxidant therapies, mitochondrial transplantation, and photobiomodulation, which have demonstrated success in enhancing tissue repair, reducing oxidative stress, and improving overall cellular function in non-orthopedic applications. The novel inhibitor of mitochondrial fission and accumulation of reactive oxygen species Mdivi-1 offers potential to improve clinical outcomes of bone diseases by alleviating cellular dysfunction and preventing bone loss. While these treatments are still in the developmental phase, they present innovative approaches to address mitochondrial dysfunction in orthopedic conditions, potentially transforming bone disease management and enhancing patient outcomes. This report explores research regarding the involvement of mitochondrial health in bone and joint function and discusses possible future treatment strategies targeting mitochondria in orthopedic conditions.
    Keywords:  Bone; Cartilage; Mitochondria; Mitochondrial dynamics; Osteoarthritis; Osteomyelitis; Osteoporosis
    DOI:  https://doi.org/10.1016/j.redox.2025.103667
  28. Front Pharmacol. 2025 ;16 1546256
    The active metabolite of Epimedii Folium promotes hippocampal neurogenesis in APP/PS1 mice by alleviating mitochondrial dysfunction.
    Jia-Ming Bai, Tong Li, Xue Di, Jing-Xian Yang, Zhao-Qi Cui, Dong-Yu Min, Yu-Feng Shen, Si-Yu Shan, Ye-Xin Zhang, Yi-Jun Shi, Zhi-Li Xu, De-Qiang Dou, Hong-He Xiao.
       Introduction: Alzheimer's disease (AD), the most common form of dementia, currently has no effective cure. Epimedii Folium (EF), a traditional Chinese medicine known as Yin-yang-huo, has demonstrated significant neuroprotective properties.
    Methods: In this study, neural stem cells overexpressing the APPswe gene (APP-NSCs) were used as an in vitro AD model. The CCK-8, LDH, neurosphere formation, and BrdU incorporation assays were employed to identify the most effective bioactive metabolite of EF in promoting NSC proliferation. Subsequently, JC-1 staining, ATP quantification, and ROS assays were conducted to evaluate the protective effects of Icariside II (ICS II)-identified as the most effective metabolite-on mitochondrial function. APP/PS1 transgenic mice received an oral administration of 10 mg/kg ICS II for 7 weeks. Cognitive function was assessed using the Morris water maze and nest-building tests, while H&E and Nissl staining were used to evaluate brain tissue pathology. Transmission electron microscopy (TEM) examined the ultrastructural integrity of hippocampal neurons, immunofluorescence assessed hippocampal neurogenesis, and Western blotting quantified proteins involved in mitochondrial dynamics. Additionally, Rotenone (Rot), a mitochondrial respiratory chain inhibitor, was applied to disrupt mitochondrial function, allowing an evaluation of whether the neurogenesis-promoting effect of ICS II depends on maintaining mitochondrial structure and function.
    Results and discussion: The results demonstrated that ICS II exhibited the strongest capacity to promote APP-NSC proliferation (P < 0.01, η2 = 0.845), followed by Icariin and Icaritin. ICS II treatment significantly ameliorated cognitive deficits (P < 0.01, η2 = 0.883), neuronal damage, and impairments in neurogenesis in adult APP/PS1 mice. Moreover, ICS II rescued mitochondrial damage by upregulating fusion proteins (Mfn1 and Mfn2) and downregulating fission proteins (p-Drp1/Drp1 and Mff); however, these protective effects were negated by Rot administration. In conclusion, this study identifies ICS II as one of the most effective metabolites of EF, promoting hippocampal neurogenesis and alleviating mitochondrial dysfunction in APP/PS1 mice, thereby offering promising therapeutic potential for AD.
    Keywords:  Alzheimer’s disease; Epimedii folium; hippocampal neurogenesis; mitochondria; neural stem cell
    DOI:  https://doi.org/10.3389/fphar.2025.1546256
  29. J Cell Sci. 2025 May 15. pii: jcs.263850. [Epub ahead of print]
    A data-driven model for mitochondrial inner membrane remodeling as a driving force of organelle shaping.
    Noga Preminger, Ben Zucker, Sarah Hassdenteufel, Till Stephan, Stefan Jakobs, Michael M Kozlov, Maya Schuldiner.
      Mitochondria are dynamic organelles exhibiting diverse shapes. While the variation of shapes, ranging from spheres to elongated tubules, and the transition between them, are clearly seen in many cell types, the molecular mechanisms governing this morphological variability remain poorly understood. Here, we propose a biophysical model for the shape transition between spheres and tubules based on the interplay between the inner and outer mitochondrial membranes. Our model suggests that the difference in surface area, arising from the folding of the inner membrane into cristae, correlates with mitochondrial elongation. Analysis of live cell super-resolution microscopy data supports this correlation, linking elongated shapes to the extent of cristae in the inner membrane. Knocking down cristae shaping proteins further confirms the impact on mitochondrial shape, demonstrating that defects in cristae formation correlate with mitochondrial sphericity. Our results suggest that the dynamics of the inner mitochondrial membrane are important not only for simply creating surface area required for respiratory capacity, but go beyond that to affect the whole organelle morphology. This work explores the biophysical foundations of individual mitochondrial shape, suggesting potential links between mitochondrial structure and function. This should be of profound significance, particularly in the context of disrupted cristae shaping proteins and their implications in mitochondrial diseases.
    Keywords:  Biophysical model; Cristae; Membrane remodeling; Mitochondrial membranes; Mitochondrial shape; Organelle shape
    DOI:  https://doi.org/10.1242/jcs.263850
  30. J Adv Res. 2025 May 09. pii: S2090-1232(25)00311-X. [Epub ahead of print]
    PTPN22 as a therapeutic target in intervertebral disc degeneration: Modulating mitophagy and pyroptosis through the PI3K/AKT/mTOR axis.
    Haibo Liang, Shu Yang, Yeheng Huang, Yuxuan Zhu, Qihang Wu, Zhouwei Wu, Sunlong Li, Yifeng Shi, Zhenya Chen, Haiming Jin, Xiangyang Wang.
       INTRODUCTION: Intervertebral disc degeneration (IDD) is a predominant risk factor for low back pain (LBP). However, the mechanisms underlying IDD progression remain unclear.
    OBJECTIVES: The protein tyrosine phosphatase non-receptor type 22 (PTPN22) is associated with various chronic inflammatory and autoimmune conditions. However, its role in the progression of IDD remains obscure. This investigation delves into the function of PTPN22 within IDD and examines its molecular mechanisms.
    METHODS: The expression levels of PTPN22 in human and rat degenerative nucleus pulposus (NP) cells were analyzed using Western blot and immunohistochemistry. Following PTPN22 knockdown via lentiviral transfection, pyroptosis, extracellular matrix (ECM) degradation, mitophagy, and mitochondrial function were assessed using Western blot, immunofluorescence, Calcein-AM/PI staining, qPCR, Seahorse, JC-1, and MitoSOX assays. The roles of autophagy and the PI3K/AKT/mTOR pathway were further investigated using the autophagy inhibitor 3-MA, Baf-A1, and the PI3K agonist 740Y-P. A puncture-induced rat model was established, and the effects of LV-shPTPN22 on IDD were evaluated through imaging and histological analyses.
    RESULTS: We noted an upregulation of PTPN22 in degenerative NP cells. A deficiency in PTPN22 was found to enhance mitophagy, thereby alleviating hydrogen peroxide (H2O2)-induced mitochondrial dysfunction and consequently mitigating NP cell pyroptosis and ECM degradation. Inhibition of the PI3K/AKT/mTOR pathway appears to play a pivotal role in the protective effects of PTPN22 deficiency against IDD. Experiments conducted in vivo revealed that PTPN22 knockdown significantly curtails the progression of IDD.
    CONCLUSION: In summary, PTPN22 knockdown alleviates IDD progression by reducing pyroptosis and ECM degradation through enhanced mitophagy. This highlights PTPN22 as a critical contributor to IDD and a promising therapeutic target.
    Keywords:  IDD; Mitophagy; PI3K/AKT/mTOR; PTPN22; Pyroptosis
    DOI:  https://doi.org/10.1016/j.jare.2025.05.017
  31. FASEB J. 2025 May 15. 39(9): e70622
    Therapeutic Effect of V8 Affecting Mitophagy and Endoplasmic Reticulum Stress in Acute Myeloid Leukemia Mediated by ROS and CHOP Signaling.
    Yong-Jian Guo, Meng-Yuan Zhu, Zhan-Yu Wang, Hong-Yu Chen, Ying-Jie Qing, Hong-Zheng Wang, Jing-Yan Xu, Hui Hui, Hui Li.
      Acute myeloid leukemia (AML) is characterized by the malignant proliferation of abnormally or poorly differentiated myeloid cells in the hematopoietic system. However, there is a lack of effective drugs for treating non-M3 AML. V8, a newly synthesized derivative of the natural flavonoid wogonin, which is a potential anticancer drug, has demonstrated significant antitumor activity both in vitro and in vivo. Here, we investigated the effects of V8 on AML cell lines and primary AML cells as well as its underlying mechanisms. Our results showed that V8 exerted significant concentration-dependent growth inhibition and apoptosis induction in AML cells, accompanied by characteristic pathological features including lysosomal functions suppression, mitochondrial dysfunction, and endoplasmic reticulum stress (ERS) activation. Mechanistic investigations revealed that V8 induced mitochondrial membrane potential collapse through elevation of intracellular reactive oxygen species (ROS) levels, while concurrently blocking mitophagy via lysosomal functional inhibition. Furthermore, V8 selectively activated the PERK/p-eIF2α/ATF4 and IRE1α/XBP1 signaling axes of ERS, ultimately triggering CHOP-mediated apoptosis through the ERS-specific pathway. In vivo studies confirmed that V8 treatment significantly prolonged survival duration in NOD/SCID mice bearing primary AML xenografts and suppressed tumor progression in BALB/c nude mice with U937 cell xenografts, with antitumor efficacy closely associated with CHOP-dependent ERS pathway modulation. These findings not only elucidate the multi-targeted mechanism of V8 against AML through coordinated regulation of the ROS-mitochondria-lysosome-ERS signaling network, but also provide critical theoretical foundations for developing natural product-based therapeutics for AML. The multi-pathway synergistic characteristics exhibited by V8 underscore its considerable potential as a clinically translatable candidate drug.
    Keywords:  AML; CHOP; ERS; V8; apoptosis; mitochondrial injury; mitophagy
    DOI:  https://doi.org/10.1096/fj.202500599R
  32. Brain Res. 2025 May 12. pii: S0006-8993(25)00259-8. [Epub ahead of print] 149700
    PINK1 activation by MTK458 ameliorates neurological impairments and pyroptosis after intracerebral hemorrhage in mice.
    Jianliang Li, Yincheng Li, Zhe Chen, Liang Yang, Lin Zhao, Jingchen Li.
      Intracerebral hemorrhage (ICH) is often linked to severe neurological impairments, including cognitive deficits and anxiety-like behaviors. This study aimed to evaluate the therapeutic potential of PTEN-induced kinase 1 (PINK1), which is activated during ICH, as a target for mitigating these effects. C57/BL6 wild-type mice underwent ICH induction through an intrastriatal injection of autologous blood. The PINK1 activator, MTK458, was administered daily doses of 10-50 mg/kg starting one week before ICH induction and continuing for three days post-surgery. The modified neurological severity score (mNSS) was used to assess neurological deficits, while brain edema was measured through brain water content. The open field test and Y-maze test were used to evaluate anxiety-like behavior, and cognitive function respectively. The effects of ICH on cortical cell pyroptosis, Parkin/PINK1-mediated mitophagy, and the activation of the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome were analyzed via Western blotting, ELISA, and qRT-PCR. MTK458 effectively reduced brain water content in the basal ganglia, ipsilateral cortex, and cerebellum, with improvements in mNSS extending to 14 days post-injury. Additionally, MTK458 alleviated both neurological deficits and anxiety-like behavior in ICH mouse models. It also reversed ICH-induced cortical cell pyroptosis by promoting Parkin/PINK1-mediated mitophagy and inhibiting NLRP3 inflammasome activation, as well as the expression of IL-1β and IL-18. These results suggest that MTK458 effectively reduces neurological impairments, brain edema, and anxiety-related behaviors in mice following ICH, highlighting PINK1 activation as a promising therapeutic strategy for ICH-induced neurological deficits.
    Keywords:  Intracerebral hemorrhage; MTK458; Mitophagy; Neurological impairments; PINK1; Pyroptosis
    DOI:  https://doi.org/10.1016/j.brainres.2025.149700
  33. Plant Cell Environ. 2025 May 11.
    BdUth1 Mediates Mitophagy by Recruiting BdAtg8 to Govern the Pathogenicity of Botryosphaeria dothidea.
    Shuai Meng, Meng Xiong, Yu Sun, Xiong Xiong, Longjun Cheng, Chaoxi Luo, Li Wang, Shufen Chao.
      
    Keywords:  Atg8; Botryosphaeria dothidea; Uth1; canker; mitophagy
    DOI:  https://doi.org/10.1111/pce.15615
  34. Int Immunopharmacol. 2025 May 15. pii: S1567-5769(25)00857-4. [Epub ahead of print]158 114867
    CREG1 alleviates bone loss in osteoporosis by enhancing the osteogenic differentiation of BMSCs through mitophagy.
    Shiyu Sha, Yi Liu, Weiping Xie, Haoling Li, Zhaocheng Jing, Qingfeng Yin, Shenghou Liu, Heng Zhao, Wenguang Liu.
      The pathological process of osteoporosis involves accelerated bone resorption and a decline in bone formation, among which the disruption of the balance between adipogenic and osteogenic differentiation in bone marrow mesenchymal stem cells (BMSCs) is a crucial part. Cellular repressor of E1A-stimulated genes 1 (CREG1), a small glycoprotein, is mainly localized to the endosomal-lysosomal compartment and is associated with the regulation of mitophagy and cell differentiation. However, its roles in BMSCs osteogenic differentiation and skeletal degenerative disorders, including osteoporosis, are poorly understood. We previously identified CREG1 as being highly expressed in the bone marrow through database analysis and found that its expression increased in the process of BMSCs osteogenic differentiation. In the present study, we demonstrated that the expression of CREG1 was reduced in osteoporosis patients and animal models, and the overexpression of CREG1 contributed to higher bone mass compared with ovariectomy (OVX)-induced bone loss models. Further research revealed that the knockdown of CREG1 inhibited the osteogenic differentiation of BMSCs, while CREG1 overexpression promoted this process. Additionally, we found that CREG1 overexpression was accompanied by an increase in mitophagy levels, and the osteogenic differentiation induced by this overexpression was blocked when mitophagy was inhibited, indicating that CREG1 promoted osteogenic differentiation through inducing mitophagy. Therefore, our findings demonstrated that CREG1 is involved in regulating the osteogenic differentiation of BMSCs, thereby providing new therapeutic targets and pathways for the treatment of osteoporosis.
    Keywords:  BMSCs; CREG1; Mitophagy; Osteogenic differentiation; Osteoporosis
    DOI:  https://doi.org/10.1016/j.intimp.2025.114867
  35. Zhongguo Zhong Yao Za Zhi. 2025 Feb;50(4): 1087-1097
    [Verification of resveratrol ameliorating vascular endothelial damage in sepsis-associated encephalopathy through HIF-1α pathway based on network pharmacology and experiment].
    Rong Li, Yue Wu, Wen-Xuan Zhu, Meng Qin, Si-Yu Sun, Li-Ya Wang, Mei-Hui Tian, Ying Yu.
      This study aims to investigate the mechanism by which resveratrol(RES) alleviates cerebral vascular endothelial damage in sepsis-associated encephalopathy(SAE) through network pharmacology and animal experiments. By using network pharmacology, the study identified common targets and genes associated with RES and SAE and constructed a protein-protein interaction( PPI) network. Gene Ontology(GO) analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analysis were performed to pinpoint key signaling pathways, followed by molecular docking validation. In the animal experiments, a cecum ligation and puncture(CLP) method was employed to induce SAE in mice. The mice were randomly assigned to the sham group, CLP group, and medium-dose and high-dose groups of RES. The sham group underwent open surgery without CLP, and the CLP group received an intraperitoneal injection of 0. 9% sodium chloride solution after surgery. The medium-dose and high-dose groups of RES were injected intraperitoneally with 40 mg·kg-1 and 60 mg·kg~(-1) of RES after modeling, respectively, and samples were collected 12 hours later. Neurological function scores were assessed, and the wet-dry weight ratio of brain tissue was detected. Serum superoxide dismutase(SOD), catalase( CAT) activity, and malondialdehyde( MDA) content were measured by oxidative stress kit. Histopathological changes in brain tissue were examined using hematoxylin-eosin(HE) staining. Transmission electron microscopy was employed to evaluate tight cell junctions and mitochondrial ultrastructure changes in cerebral vascular endothelium. Western blot analysis was performed to detect the expression of zonula occludens1( ZO-1), occludin, claudins-5, optic atrophy 1( OPA1), mitofusin 2(Mfn2), dynamin-related protein 1(Drp1), fission 1(Fis1), and hypoxia-inducible factor-1α(HIF-1α). Network pharmacology identified 76 intersecting targets for RES and SAE, with the top five core targets being EGFR, PTGS2, ESR1, HIF-1α, and APP. GO enrichment analysis showed that RES participated in the SAE mechanism through oxidative stress reaction. KEGG enrichment analysis indicated that RES participated in SAE therapy through HIF-1α, Rap1, and other signaling pathways. Molecular docking results showed favorable docking activity between RES and key targets such as HIF-1α. Animal experiment results demonstrated that compared to the sham group, the CLP group exhibited reduced nervous reflexes, decreased water content in brain tissue, as well as serum SOD and CAT activity, and increased MDA content. In addition, the CLP group exhibited disrupted tight junctions in cerebral vascular endothelium and abnormal mitochondrial morphology. The protein expression levels of Drp1, Fis1, and HIF-1α in brain tissue were increased, while those of ZO-1, occludin, claudin-5, Mfn2, and OPA1 were decreased. In contrast, the medium-dose and high-dose groups of RES showed improved neurological function, increased water content in brain tissue and SOD and CAT activity, and decreased MDA content. Cell morphology in brain tissue, tight junctions between endothelial cells, and mitochondrial structure were improved. The protein expressions of Drp1, Fis1, and HIF-1α were decreased, while those of ZO-1, occludin, claudin-5, Mfn2, and OPA1 were increased. This study suggested that RES could ameliorate cerebrovascular endothelial barrier function and maintain mitochondrial homeostasis by inhibiting oxidative stress after SAE damage, potentially through modulation of the HIF-1α signaling pathway.
    Keywords:  HIF-1α; mitochondrial dynamics; resveratrol; sepsis-associated encephalopathy; vascular endothelial damage
    DOI:  https://doi.org/10.19540/j.cnki.cjcmm.20241012.301
  36. Eur J Clin Invest. 2025 May 15. e70073
    Mesenchymal stem cell-mediated mitochondrial transfer regulates the fate of B lymphocytes.
    Veronika Somova, Natalie Jaborova, Bianka Porubska, Daniel Vasek, Natalie Fikarova, Martin Prevorovsky, Zuzana Nahacka, Jiri Neuzil, Magdalena Krulova.
       BACKGROUND: Mitochondrial transfer is becoming recognized as an important immunomodulatory mechanism used by mesenchymal stem cells (MSCs) to influence immune cells. While effects on T cells and macrophages have been documented, the influence on B cells remains unexplored. This study investigates the modulation of B lymphocyte fate by MSC-mediated mitochondrial transfer.
    METHODS: MSCs labelled with MitoTracker dyes or derived from mito::mKate2 transgenic mice were co-cultured with splenocytes. Flow cytometry assessed mitochondrial transfer, reactive oxygen species (ROS) levels, apoptosis and mitophagy. Glucose uptake was measured using the 2-NBDG assay. RNA sequencing analysed gene expression changes in CD19+ mitochondria recipients and nonrecipients. Pathway analysis identified affected processes. In an LPS-induced inflammation model, mito::mKate2 MSCs were administered, and B cells from different organs were analysed for mitochondrial uptake and phenotypic changes. MSC-derived mitochondria were also isolated to confirm uptake by FACS-sorted CD19+ cells.
    RESULTS: MSCs transferred mitochondria to CD19+ cells, though less than to other immune cells. Transfer correlated with ROS levels and mitophagy induction. Mitochondria were preferentially acquired by activated B cells, as indicated by increased CD69 expression and glycolytic activity. Bidirectional transfer occurred, with immune cells exchanging dysfunctional mitochondria for functional ones. CD19+ recipients exhibited increased viability, proliferation and altered gene expression, with upregulated cell division genes and downregulated antigen presentation genes. In vivo, mitochondrial acquisition reduced B cell activation and inflammatory cytokine production. Pre-sorted B cells also acquired isolated mitochondria, exhibiting a similar anti-inflammatory phenotype.
    CONCLUSIONS: These findings highlight mitochondrial trafficking as a key MSC-immune cell interaction mechanism with immunomodulatory therapeutic potential.
    Keywords:  B cell; immunoregulation; mesenchymal stem cell; metabolism; mitochondria
    DOI:  https://doi.org/10.1111/eci.70073
  37. Nano Lett. 2025 May 14.
    A Nanosystem Alleviates Severe Acute Pancreatitis via Reactive Oxygen Species Scavenging and Enhancing Mitochondrial Autophagy.
    Liying Wang, Zerui Gao, Mengxiang Tian, Li Liu, Jinyan Xie, Muxiong Chen, Zihao Huang, Bingzhi Dong, Weiqi Li, Liang Shi, Yifan Tong, Hongxia Xu, Bo Shen, Dong Cen, Hong Yu, Xin Yu.
      Severe acute pancreatitis (SAP) is a life-threatening condition characterized by excessive reactive oxygen species (ROS) production and impaired mitochondrial function, resulting from disrupted autophagic flux. Current clinical treatment for SAP fails to address the condition comprehensively, with the treatment targeting only a single pathogenesis. Herein, we report an innovative acid-responsive biomimetic nanozyme. This system features a hollow Prussian blue (PB) core, serving as an ROS scavenger encapsulated within a porous ZIF-8 shell, enabling the efficient delivery of celastrol that activates autophagic flux. Encased in a macrophage membrane, this system selectively targets inflamed pancreatic tissues and is readily internalized by pancreatic acinar cells. This dual-scavenging mechanism effectively attenuates inflammatory cytokine levels and restores mitochondrial homeostasis in three distinct SAP mouse models. Overall, this study presents a promising synergistic strategy for the dual scavenging of damaged mitochondria and ROS, offering a novel therapeutic approach to the treatment of SAP.
    Keywords:  biomimetic nanoparticle; celastrol; combination therapy; mitophagy; severe acute pancreatitis
    DOI:  https://doi.org/10.1021/acs.nanolett.5c01495
  38. J Cereb Blood Flow Metab. 2025 May 15. 271678X251341293
    Mitochondrial unfolded protein response (UPRmt) as novel therapeutic targets for neurological disorders.
    Xi Chen, Hong An, Jiachen He, Jiaqi Guo, Shuaili Xu, Chuanjie Wu, Di Wu, Xunming Ji.
      Neurological disorders, including brain cancer, neurodegenerative diseases and ischemic/reperfusion injury, pose a significant threat to global human health. Due to the high metabolic demands of nerve cells, mitochondrial dysfunction is a critical feature of these disorders. The mitochondrial unfolded protein response (UPRmt) is an evolutionarily conserved mitochondrial response, which is critical for maintaining mitochondrial and energetic homeostasis under stress. Previous studies have found that UPRmt participates in diverse physiological processes especially metabolism and immunity. Currently, increasing evidence suggest that targeted regulation of UPRmt can also effectively delay the progression of neurological diseases and improve patients' prognosis. This review provides a comprehensive overview of UPRmt in the context of neurological diseases, with a particular emphasis on its regulatory functions. Additionally, we summarize the mechanistic insights into UPRmt in neurological disorders as investigated in preclinical studies, as well as its potential as a therapeutic target in the clinical management of neurological tumors. By highlighting the importance of UPRmt in the complex processes underlying neurological disorders, this review aims to bridge current knowledge gaps and inspire novel therapeutic strategies for these conditions.
    Keywords:  Mitochondria; aging; neurological disorders; therapy; unfolded protein response
    DOI:  https://doi.org/10.1177/0271678X251341293
  39. J Biochem Mol Toxicol. 2025 May;39(5): e70291
    Reprogramming of Hypoxia-Induced Metabolic Disorder in Mouse Kidneys by Mesenchymal Stem Cells Through Improving Mitochondrial Dynamics and Function.
    Yanjun Wang, Yanling Ding, Tana Wuren, Pengli Luo.
       OBJECTIVE: To assess the effects of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) on mitochondrial damage and metabolic disorders induced by acute and chronic hypoxia in mouse kidneys.
    METHOD: Comprehensive analyses were conducted, including histopathology, mitochondrial morphology analysis, biochemical assessments, transcriptomics and metabolomics.
    RESULTS: The results revealed that hUC-MSCs significantly improved renal mitochondrial integrity and maintained mitochondrial dynamic balance under both acute and chronic hypoxia. This improvement was achieved by upregulating the expression of peroxisome proliferator-activated receptor gamma coactivator-1 alpha, which ultimately enhanced mitochondrial function. Furthermore, hUC-MSCs reprogrammed renal metabolic disorders, particularly improvements in urea and purine metabolic dysfunction, increased fatty acid oxidation and amelioration of lipid metabolic disorders.
    CONCLUSION: These findings suggest that hUC-MSCs could be part of a promising strategy for enhancing renal health and metabolic stability in individuals exposed to high altitudes or other hypoxic environments, highlighting their potential therapeutic value in addressing hypoxia-induced mitochondrial damage and renal metabolic disorders.
    Keywords:  human umbilical cord‐derived mesenchymal stem cells; hypobaric hypoxia, kidney injury; mitochondrial dynamics, metabolic reprogramming
    DOI:  https://doi.org/10.1002/jbt.70291
  40. J Adv Res. 2025 May 10. pii: S2090-1232(25)00305-4. [Epub ahead of print]
    Corrigendum to "Urolithin A inhibits breast cancer progression via activating TFEB-mediated mitophagy in tumor macrophages" [J. Adv. Res. 69 (2025) 125-138].
    Bowen Zheng, Yuying Wang, Baian Zhou, Fengyuan Qian, Diya Liu, Danrong Ye, Xiqian Zhou, Lin Fang.
      
    DOI:  https://doi.org/10.1016/j.jare.2025.05.012
  41. Nat Rev Mol Cell Biol. 2025 May 14.
    Molecular machineries shaping the mitochondrial inner membrane.
    Oliver Daumke, Martin van der Laan.
      Mitochondria display intricately shaped deep invaginations of the mitochondrial inner membrane (MIM) termed cristae. This peculiar membrane architecture is essential for diverse mitochondrial functions, such as oxidative phosphorylation or the biosynthesis of cellular building blocks. Conserved protein nano-machineries such as F1Fo-ATP synthase oligomers and the mitochondrial contact site and cristae organizing system (MICOS) act as adaptable protein-lipid scaffolds controlling MIM biogenesis and its dynamic remodelling. Signal-dependent rearrangements of cristae architecture and MIM fusion events are governed by the dynamin-like GTPase optic atrophy 1 (OPA1). Recent groundbreaking structural insights into these nano-machineries have considerably advanced our understanding of the functional architecture of mitochondria. In this Review, we discuss how the MIM-shaping machineries cooperate to control cristae and crista junction dynamics, including MIM fusion, in response to cellular signalling pathways. We also explore how mutations affecting MIM-shaping machineries compromise mitochondrial functions.
    DOI:  https://doi.org/10.1038/s41580-025-00854-z
  42. Cells. 2025 May 03. pii: 672. [Epub ahead of print]14(9):
    Iron Metabolism and Muscle Aging: Where Ferritinophagy Meets Mitochondrial Quality Control.
    Rosa Di Lorenzo, Emanuele Marzetti, Helio José Coelho-Junior, Riccardo Calvani, Vito Pesce, Francesco Landi, Christiaan Leeuwenburgh, Anna Picca.
      In older adults with reduced physical performance, an increase in the labile iron pool within skeletal muscle is observed. This accumulation is associated with an altered expression of mitochondrial quality control (MQC) markers and increased mitochondrial DNA damage, supporting the hypothesis that impaired MQC contributes to muscle dysfunction during aging. The autophagy-lysosome system plays a critical role in MQC by tagging and engulfing proteins and organelles for degradation in lysosomes. The endolysosomal system is also instrumental in transferrin recycling, which, in turn, regulates cellular iron uptake. In the neuromuscular system, the autophagy-lysosome system supports the structural integrity of neuromuscular junctions, and its dysfunction contributes to muscle atrophy. While MQC was thought to protect against iron-induced cell death, the discovery of ferroptosis, a form of iron-dependent cell death, has highlighted a complex interplay between MQC and iron-inflicted damage. Ferritinophagy, the autophagic degradation of ferritin, if overactivated, can induce ferroptosis. Alternatively, aging may impair ferritinophagy, leading to ferritin accumulation and the release of toxic labile iron under stress, exacerbating oxidative damage and cellular senescence. Physical activity supports muscle health also by preserving mitochondrial quantity and quality and enhancing bioenergetics. However, therapeutic strategies for preventing or reversing physical function decline in aging are still lacking due to the insufficient understanding of the underlying mechanisms. Unveiling how disruptions in iron homeostasis impact muscle quality in older adults may allow for the development of therapeutic strategies targeting iron handling to alleviate age-associated muscle decline.
    Keywords:  autophagy; cytokine; endolysosomal system; hepcidin; inflammation; labile iron; mitophagy; physical performance; sarcopenia; transferrin
    DOI:  https://doi.org/10.3390/cells14090672
  43. J Cell Sci. 2025 May 01. pii: jcs263757. [Epub ahead of print]138(9):
    Quality control of un-imported mitochondrial proteins at a glance.
    Megan Balzarini, John Kim, Hilla Weidberg.
      Mitochondria are metabolic hubs that are essential for cellular homeostasis. Most mitochondrial proteins are translated in the cytosol and imported into the organelle. However, import machineries can become overwhelmed or disrupted by physiological demands, mitochondrial damage or diseases, such as metabolic and neurodegenerative disorders. Impaired import affects mitochondrial function and causes un-imported pre-proteins to accumulate not only in the cytosol but also in other compartments, including the endoplasmic reticulum and nucleus. Quality control pathways have evolved to mitigate the accumulation of these mistargeted proteins and prevent proteotoxicity. In this Cell Science at a Glance article and the accompanying poster, we summarize the fate of un-imported mitochondrial proteins and the compartment-specific quality control pathways that regulate them.
    Keywords:  Mitochondrial protein import; Mitochondrial stress; Protein quality control
    DOI:  https://doi.org/10.1242/jcs.263757
  44. Int Immunopharmacol. 2025 May 12. pii: S1567-5769(25)00853-7. [Epub ahead of print]158 114863
    Mitochondrial calcium overload contributes to mechanical allodynia in neuropathic pain via inducing mitochondrial dynamic imbalance.
    Dan-Yang Li, Lin Liu, Dai-Qiang Liu, Long-Qing Zhang, Ya-Qun Zhou, Wei Mei.
      Neuropathic pain is a chronic and devastating clinical problem with few effective treatments. Mitochondrial dysfunction plays a critical role in the pathological process of neuropathic pain. Recently, mitochondrial calcium overload has been identified as the initial part of mitochondrial dysfunction, such as dynamic imbalance and excessive superoxide. Mitochondrial Ca2+ uniporter (MCU) serves as the primary channel for mitochondrial Ca2+ uptake, and Na+/Ca2+ exchanger (NCLX) is the dominant mechanism for mitochondrial calcium ion excretion. Herein, we investigated the role of mitochondrial calcium overload and its regulated channels in a rat model of neuropathic pain. Our results showed significant mitochondrial calcium overload in the spinal dorsal horn of SNI rats, accompanied by the upregulation of MCU and downregulation of NCLX. MCU inhibition or NCLX overexpression remarkably relieved mechanical allodynia and mitochondrial high calcium levels in SNI rats. Conversely, upregulation of MCU or downregulation of NCLX induced mitochondrial calcium overload and mechanical allodynia in naïve rats. We also observed excessive mitochondrial fission and reduced fusion in the spinal cord of SNI rats, which could be mitigated by MCU inhibition and NCLX overexpression, respectively. Notably, mitochondrial fission inhibitor or mitochondrial fusion promoter effectively reversed the MCU overexpression or NCLX knockdown-induced mechanical allodynia. Collectively, our data indicate that the MCU/NCLX-mediated mitochondrial calcium overload drives excessive mitochondrial fission, which promotes the progression of SNI.
    Keywords:  Mitochondrial calcium overload; Mitochondrial dynamic; Neuropathic pain
    DOI:  https://doi.org/10.1016/j.intimp.2025.114863
  45. Aquac Nutr. 2025 ;2025 1151656
    Creatine Ameliorates the Adverse Effects of High-Fat Diet on Hepatic Lipid Metabolism via Activating Mfn2-Mediated Mitochondrial Fusion in Juvenile Grass Carp.
    Nan-Jun Hu, Guang-Li Feng, Xiao-Hong Lai, Mo Peng, Yu-Feng Song.
      With the increasing prevalence of high-fat diets (HFD) in aquaculture practices, the detrimental effects of HFD on farmed fish have garnered significant attention. Creatine has emerged as a promising green feed additive for aquaculture species; however, its potential role in mitigating the negative impacts of HFD remains poorly understood. To address this knowledge gap, the present study was designed to investigate the protective effects of dietary creatine supplementation on HFD-induced hepatic lipid metabolism disorders and muscle quality deterioration in juvenile grass carp (Ctenopharyngodon idella). Three experimental diets were formulated: a control diet (5.20% lipid, control), a HFD (8.11% lipid, HFD), and a HFD supplemented with 2% creatine (HFD + creatine). Juvenile grass carp (initial weight: 4.12 ± 0.02 g) were randomly allocated into nine 300-L indoor tanks and fed the experimental diets for 8 weeks. The key findings of this study revealed that (1) Dietary creatine supplementation significantly ameliorated the adverse effects of HFD on growth performance and feed utilization efficiency in juvenile grass carp. (2) Creatine supplementation improved muscle quality parameters in juvenile grass carp. (3) Dietary creatine attenuated HFD-induced hepatic lipid accumulation through enhanced fatty acid β-oxidation, which was mediated by mfn2-dependent mitochondrial fusion. Notably, this study elucidates a novel molecular mechanism whereby creatine activates mitochondrial fusion through the binding of pparα transcription factor to specific sites on the mitofusin 2 (Mfn2) gene promoter. To our knowledge, this is the first comprehensive investigation from a multi-organ/tissue perspective combined with mitochondrial dynamics analysis, providing valuable insights for developing effective nutritional strategies to counteract HFD-induced adverse effects in farmed fish through creatine supplementation.
    Keywords:  creatine; grass carp; hepatic lipid metabolism; high-fat diet; mitochondrial fusion
    DOI:  https://doi.org/10.1155/anu/1151656
  46. J Cancer Res Clin Oncol. 2025 May 15. 151(5): 167
    High-dose vitamin C promotes mitochondrial biogenesis in HCT116 colorectal cancer cells by regulating the AMPK/PGC-1α signaling pathway.
    RuiYang Hong, Su Min, Jia Huang, Mou Zou, DongYu Zhou, Yun Liang.
       BACKGROUND: Mitochondrial dysfunction is closely associated with cancer development. Colorectal cancer (CRC) cells often exhibit altered energy metabolism, characterized by increased glycolysis and reduced oxidative phosphorylation. Enhancing mitochondrial biogenesis and function may represent a promising therapeutic approach. High-dose vitamin C has demonstrated anti-tumor properties and the ability to reverse the Warburg effect, but its role in regulating mitochondrial biogenesis and function remains unclear.
    METHODS: We evaluated the altered mitochondrial functional status of HCT116 colorectal cancer cells compared to FHC colorectal epithelial cells, assessed the effects of high-dose vitamin C on mitochondrial biogenesis and function in HCT116 cells, and explored the underlying regulatory mechanisms.
    RESULTS: HCT116 cells exhibited mitochondrial dysfunction compared to FHC cells, including decreased expression of electron transport chain complexes III and IV, reduced TFAM levels, and lower mtDNA content. Vitamin C treatment significantly enhanced mitochondrial biogenesis and function, as reflected by increased AMPK phosphorylation, upregulation of PGC-1α, SOD2, NRF2, TFAM, MT-CYB, and MTCO1, elevated mtDNA content, restored membrane potential, enhanced oxidative phosphorylation, and reduced glycolytic activity. Furthermore, vitamin C markedly suppressed HCT116 cell viability and clonogenic capacity, while these effects were substantially diminished by cotreatment with Compound C.
    CONCLUSION: This study demonstrates that high-dose vitamin C ameliorates mitochondrial dysfunction and promotes mitochondrial biogenesis and function in colorectal cancer cells through activation of the AMPK-PGC-1α signaling pathway, thereby suppressing tumor cell proliferation. These findings suggest that vitamin C may serve as a promising therapeutic agent for targeting mitochondrial metabolism in colorectal cancer.
    Keywords:  AMPK; Colorectal cancer; Mitochondrial biogenesis; PGC-1α; Vitamin C
    DOI:  https://doi.org/10.1007/s00432-025-06211-z
  47. Int J Mol Sci. 2025 Apr 28. pii: 4169. [Epub ahead of print]26(9):
    DUT (p.Y116C)-Mutation-Induced Thrombocytopenia in Rabbits.
    Mengmeng Fang, Shujun Yang, Ruonan Liu, Xinyu Wu, Liqiang Jiang, Jie Yang, Xin Liu, Gerong Wang, Chao Mu, Xiuwen Wang, Yuning Song.
      Thrombocytopenia is a hematologic disorder characterized by an abnormally low platelet count in peripheral blood. Recent studies have identified mutations in DUT as the primary cause of bone marrow failure and diabetes mellitus syndrome (BMFDMS), a condition commonly associated with thrombocytopenia. In this study, a novel rabbit model of thrombocytopenia carrying the DUT c.3020A>G (p.Y116C) mutation was established using SpRY-ABEmax-mediated base editing. This model accurately recapitulates the clinical manifestations of human thrombocytopenia. Phenotypic analysis has revealed that mutant rabbits exhibited significant reductions in megakaryocyte numbers, platelet counts, and survival rates when compared to wild-type controls. Mechanistic investigations showed that the DUT mutation leads to mitochondrial structural abnormalities and functional impairments. Notably, platelets from DUT (p.Y116C)-mutant rabbits exhibited markedly reduced DUT protein expression and enhanced mitophagy, potentially mediated through the Park2 pathway. This study presents the first genetic model of thrombocytopenia that closely mimics the human DUT (p.Y116C) mutation, offering new insights into the relationship between DUT mutations and platelet function, and highlighting potential therapeutic targets for human thrombocytopenia.
    Keywords:  DUT; mitochondria; mitophagy; rabbit model; thrombocytopenia
    DOI:  https://doi.org/10.3390/ijms26094169
  48. Zhongguo Zhen Jiu. 2025 May 12. 45(5): 646-656
    [Regulatory effect of electroacupuncture at "Neiguan" (PC6) on mitochondrial autophagy during the ischemia and reperfusion phases in rats with myocardial ischemia-reperfusion injury].
    Qirui Yang, Xinghua Qiu, Xingye Dai, Daonan Liu, Baichuan Zhao, Wenyi Jiang, Yanhua Song, Tong Pu, Kai Cheng.
       Objective: To investigate the regulatory effect of electroacupuncture (EA) at "Neiguan" (PC6) on mitochondrial autophagy in rats with myocardial ischemia-reperfusion injury (MIRI) at different phases (ischemia and reperfusion phases), and to explore the bidirectional regulatory effects of EA at "Neiguan" (PC6) and its potential mechanism.
    Methods: Forty-five male SD rats were randomly divided into 6 groups according to the random number table method, namely, sham-operation group (n=9), model-A group (n=6), model-B group (n=9), EA-A1 group (n=6), EA-B1 group (n=6), and EA-B2 group (n=9). Except the rats in the sham-operation group, the MIRI model was established in the other groups with the physical ligation and tube pushing method. In the model-A group, the samples were collected directly after ligation, and in the model-B group, the samples were collected after ligation and reperfusion. In the EA-A1 group, EA was delivered while the ligation was performed, and afterwards, the samples were collected. In the EA-B1 group, while the ligation was performed, EA was operated at the same time, and after reperfusion, the samples were collected. In the EA-B2 group, during ligation and the opening of the left anterior descending branch of the coronary artery, EA was delivered, and after reperfusion, the samples were collected. EA was performed at bilateral "Neiguan" (PC6), with a disperse-dense wave, a frequency of 2 Hz/100 Hz, a current of 1 mA, and a duration of 30 min. HE staining was employed to observe the morphology of cardiomyocytes, TUNEL was adopted to detect the apoptosis of cardiomyocytes, transcriptome sequencing was to detect the differentially expressed genes in the left ventricle, JC-1 flow cytometry was to detect the mitochondrial membrane potential (MMP) of cardiomyocytes, Western blot was to detect the protein expression of phosphatase and tensin homolog-induced kinase 1 (Pink1), Parkin and p62 in the left ventricle of rats, and ELISA was to detect the levels of serum creatine kinase isoenzyme (CK-MB) and cardiac troponin I (cTn-I) in the rats.
    Results: Compared with the sham-operation group, the cardiomyocytes of rats in the model-B group were severely damaged, with disordered arrangement, unclear boundaries, broken muscle fibers, edema and loose distribution; and the cardiomyocytes in the EA-B2 group were slightly damaged, the cell structure was partially unclear, the cells were arranged more regularly, and the intact cardiomyocytes were visible. Compared with the sham-operation group, the apoptosis of cardiomyocytes increased in the model-B group (P<0.001); and when compared with the model-B group, the apoptosis alleviated in the EA-B2 group (P<0.001). The differentially expressed genes among the EA-B2 group, the sham-operation group and the model-B group were closely related to cell autophagy and mitochondrial autophagy. Compared with the sham-operation group, MMP of cardiomyocytes was reduced (P<0.001), the protein expression of Pink1, Parkin, and p62 of the left ventricle and the levels of serum CK-MB and cTn-I were elevated in the model B group (P<0.001). In comparison with model-A group, the MMP of cardiomyocytes and the levels of serum CK-MB and cTn-I were reduced (P<0.001, P<0.05), and the protein expression of Pink1 in the left ventricle rose in the EA-A1 group (P<0.01). Compared with the model-B group, MMP of cardiomyocytes increased (P<0.001), the protein expression of Pink1, Parkin, and p62 of the left ventricle, and the levels of serum CK-MB and cTn-I decreased (P<0.001) in the EA-B1 group and the EA-B2 group. When compared with the EA-A1 group, MMP of cardiomyocytes increased (P<0.001), and the protein expression of Pink1, Parkin, and p62 of the left ventricle, and the levels of serum CK-MB and cTn-I decreased in the EA-B1 group (P<0.01).
    Conclusion: EA at "Neiguan" (PC6) can ameliorate MIRI in rats, which may be achieved through the Pink1/Parkin-mediated mitochondrial autophagy pathway. EA can alleviate myocardial injury by enhancing mitochondrial autophagy at the ischemia phase, and it can reduce reperfusion injury by weakening mitochondrial autophagy at the reperfusion phase.
    Keywords:  Point PC6 (Neiguan); bidirectional regulation; electroacupuncture; mitochondrial autophagy; myocardial ischemia-reperfusion injury
    DOI:  https://doi.org/10.13703/j.0255-2930.20241031-k0001
  49. Clin Exp Hypertens. 2025 Dec;47(1): 2506619
    Disruption of the caspase-1/IL-1β axis alleviates myocardial Ischemia/Reperfusion injury via improvement of mitochondrial homeostasis and reduction of Pyroptosis.
    ChenKai Hu, FengXia Yuan, YingXing Wu, Shan Xiao, Yuan Xu, Xiang Peng, Lei He.
       BACKGROUND: Pyroptosis is a novel kind of programmed cell death and Caspase-1 plays key roles in driving pyroptosis. The current study aims to elucidate the molecular mechanism affecting cardiomyocyte pyroptosis in myocardial ischemia/reperfusion (I/R) injury, both in vivo and in vitro.
    METHODS: A murine model of myocardial I/R injury was established and then treated with lentivirus-mediated shRNA targeting Caspase-1 to evaluate the effect of Caspase-1 on myocardial I/R injury. Further, Caspase-1 was silenced in the cardiomyocytes following hypoxia-reoxygenation (H/R) to detect the function of Caspase-1 in mitochondrial homeostasis and cardiomyocyte pyroptosis.
    RESULTS: Knockdown of Caspase-1 inhibited the secretion of interleukin-1 beta (IL-1β), improved cardiac dysfunction and decreased pyroptosis in vivo. The cardio-protective effect was verified in the H/R-induced cardiomyocyte model. Recombinant IL-1β protein reversed the inhibitory effect of Caspase-1 knockdown on pyroptosis.
    CONCLUSION: Overall, activating the Caspase-1/IL-1β axis by myocardial I/R injury causes mitochondrial homeostasis imbalance, pyroptosis, and the consequent cardiomyocyte injury.
    Keywords:  IL-1β; Myocardial ischemia/reperfusion injury; cardiomyocyte injury; caspase-1; mitochondrial homeostasis; pyroptosis
    DOI:  https://doi.org/10.1080/10641963.2025.2506619
  50. Molecules. 2025 Apr 28. pii: 1952. [Epub ahead of print]30(9):
    Isolation and Characterization of Earthworm Peptides with Neuroprotective Effects in Parkinson's Disease Models.
    Guangyu Shi, Yikao Hu, Xiaolin Bai, Xun Liao.
      The aim of this study was to identify peptides from Lumbricus terrestris with neuroprotective effects. Two peptides (GYSFTTTAER and AVFPSIVGR) isolated from earthworms improved cell viability of the SH-SY5Y human neuroblastoma cell line treated with 1-methyl-4-phenyl-1,2,3-tetrahydropyridinehydrochloride (MPP+), a commonly used model of Parkinson's disease (PD). Both peptides increased the mitochondrial membrane potential and upregulated the mRNAs of mitophagy regulators PINK1 and Parkin in the MPP+-damaged cells. The in vitro assay and molecular docking indicated that both peptides exhibited moderate PINK1 agonistic activity. Furthermore, GYSFTTTAER and AVFPSIVGR extended the lifespan, improved locomotor behavior, and raised the ATP and dopamine levels at all ages in PINK1B9 mutant flies, a PD model characterized by loss-of-function of PINK1. These findings suggest that earthworm-derived peptides possess anti-neurodegenerative properties and hold potential for the development of health products and therapeutic agents for PD.
    Keywords:  PINK1 agonistic activity; PINK1B9 flies; anti-Parkinson’s disease; earthworm; neuroprotection
    DOI:  https://doi.org/10.3390/molecules30091952
  51. Int Immunopharmacol. 2025 May 12. pii: S1567-5769(25)00840-9. [Epub ahead of print]158 114850
    METTL14-mediated lncRNA NEAT1 promotes asthma progression by regulating the miR-302a-3p/March5 axis.
    Yawei Wu, Qiuyun Ye, Dandan Chen, Linhui Huang, Rubing Mo, Xingjun Cai.
      Asthma is a chronic inflammatory airway disease with airway remodeling as its main pathological basis. LncRNA NEAT1 has been reported to be up-regulated in asthma, but its upstream and downstream regulatory mechanisms are unclear. This study explored the role and functional mechanism of lncRNA NEAT1 in asthma. Airway smooth muscle cells (ASMCs) isolated from the bronchial tissues of asthmatic patients and healthy volunteers were employed and transfected with an overexpression lentivirus and short hairpin lentivirus. Real-time quantitative PCR (qRT-PCR) and western blotting were used to determine the expression levels of genes. The proliferation and migration of ASMCs were evaluated, and the levels of pro-inflammatory cytokines, inflammasomes, and ROS were determined. Mitophagy was observed by transmission electron microscopy (TEM). An asthma model was established to further confirm the effects of lncRNA NEAT1 on asthma. Our results showed that lncRNA NEAT1 was highly expressed in asthma patient-derived ASMCs. LncRNA NEAT1 enhanced ASMC proliferation and migration, promoted inflammation, and inhibited mitophagy. Treatment with a mitophagy inducer reversed the effects of lncRNA NEAT1. The regulatory axis of lncRNA NEAT1/miR-302a-3p/March5 was confirmed, and lncRNA NEAT1 was found to influence ASMC function via the miR-302a-3p/March5 axis. Moreover, METTL14 was found to enhance lncRNA NEAT1 m6A modification and promote its expression, and thereby participate in the functional regulation of ASMCs. The role of lncRNA NEAT1 was also confirmed in an asthma mouse model, where it alleviated asthma pathology in lncRNA NEAT1 knockdown mice. Collectively, our present study confirmed that METTL14 mediated m6A modification of lncRNA NEAT1 and improved lncRNA NEAT1 expression, which further inhibited mitophagy and promoted asthma progression by regulating the miR-302a-3p/March5 axis. Our study elucidated the mechanism by which lncRNA NEAT1 affects airway remodeling. It also provides valuable insights into the pathogenesis of asthma, and suggests lncRNA NEAT1 as a possible biomarker for asthma.
    Keywords:  Airway remodeling; Asthma; Inflammation; LncRNA NEAT1; Mitophagy
    DOI:  https://doi.org/10.1016/j.intimp.2025.114850
  52. Adv Mater. 2025 May 16. e2501933
    An Iron Balance Dual-Drive Strategy (IBDS) Promotes Bone Regeneration in Smokers by Regulating Mitochondrial Iron Homeostasis.
    Kai Xiang, Zhiying Xiao, Zheng Jing, Yuzhou Li, Meng Li, Zhikang Su, Ziyu Huang, Tianli Wu, Ping He, Yining Zhang, Fengyi Liu, Mingxing Ren, Sheng Yang.
      Cigarette smoke (CS) disrupts mitochondrial iron homeostasis, causing excess free iron to generate reactive oxygen species, leading to oxidative stress and impairing tissue repair. For smokers undergoing bone defect repair, achieving precise control over the balance between mitochondrial free iron and stored iron, while simultaneously enhancing endogenous iron homeostasis, poses a considerable challenge. This study introduces the iron balance dual-drive strategy (IBDS), which efficiently chelates mitochondrial free iron and promotes ferritin synthesis to create a FerritinBank for iron deposition, thus optimizing endogenous iron homeostasis. IBDS is delivered through an injectable, biodegradable iron-capturing hydrogel (SilMA/gelMA/DPT). The released DPT selectively targets and chelates free iron within mitochondria, modulating mitochondrial dynamics to restore their function. This action is complemented by the promotion of ferritin synthesis, which serves to bolster endogenous iron homeostasis and suppress ferroptosis. Transcriptomic sequencing and experimental data suggest that DPT corrects energy metabolism abnormalities and promotes mitochondrial macromolecule synthesis. In vivo studies confirm that the iron-capturing hydrogel significantly improves the healing of smoking-induced calvarial bone defects. This is the first report of nanoparticles promoting ferritin synthesis to build an endogenous iron reservoir, highlighting the potential of the IBDS strategy for bone regeneration in smokers and other iron-overload-related conditions.
    Keywords:  bone regeneration; hydrogel; iron metabolism; mitochondria; smoker
    DOI:  https://doi.org/10.1002/adma.202501933
  53. Int J Mol Sci. 2025 Apr 27. pii: 4145. [Epub ahead of print]26(9):
    Therapeutic Effects of Hemerocallis citrina Baroni Extract on Animal Models of Neurodegenerative Diseases Through Serotonin and HLH-30/TFEB-Dependent Mechanisms.
    Jorge H Fernandes, Marta Daniela Costa, Daniela Vilasboas-Campos, Bruna Ferreira-Lomba, Joana Pereira-Sousa, Qiong Wang, Andreia Teixeira-Castro, Xinmin Liu, Fengzhong Wang, Alberto C P Dias, Patrícia Maciel.
      Hemerocallis citrina is an herbaceous perennial plant used in Asian cuisine and Traditional Chinese Medicine. Here, we tested the therapeutic potential of extracts (HCE30%, HCE50%, and HCN) in vivo, using models of two human genetic neurodegenerative diseases-Machado-Joseph Disease/Spinocerebellar Ataxia type 3 (MJD/SCA3) and Frontotemporal Dementia with Parkinsonism associated to chromosome 17 (FTDP-17). Chronic treatment with HCE30% extract ameliorated the motor deficits typically observed in these models. Interestingly, we found that the effect on the motor phenotype of the MJD/SCA3 model was dependent on serotonergic signaling and on the action of the HLH-30/TFEB transcription factor, known to regulate the cellular response to amino acid starvation, the autophagy and mitophagy pathways, lysosome localization and biogenesis, exocytosis, and mitochondrial biogenesis. Altogether, our findings reinforce the idea that phytochemicals act through the modulation of serotonergic neurotransmission and introduce a novel layer to the HLH-30/TFEB regulatory network. Thus, it also strengthens the use of these pathways as therapeutic targets for protein-related neurodegenerative disorders and confirms the utility of medicinal plants as a source of innovation in the quest for new therapeutic agents.
    Keywords:  Frontotemporal Dementia with Parkinsonism associated to chromosome 17; Machado–Joseph disease/spinocerebellar ataxia type 3; medicinal plants; neurodegenerative diseases
    DOI:  https://doi.org/10.3390/ijms26094145
  54. Proc Natl Acad Sci U S A. 2025 May 20. 122(20): e2426179122
    Estrogen-related receptors regulate innate and adaptive muscle mitochondrial energetics through cooperative and distinct actions.
    Weiwei Fan, Tae Gyu Oh, Hui J Wang, Lillian Crossley, Mingxiao He, Hunter Robbins, Chandra Koopari, Yang Dai, Morgan L Truitt, Christopher Liddle, Ruth T Yu, Annette R Atkins, Michael Downes, Ronald M Evans.
      Mitochondrial energy metabolism is vital for muscle function and is tightly controlled at the transcriptional level, both in the basal state and during adaptive muscle remodeling. The importance of the transcription factors estrogen-related receptors (ERRs) in controlling innate mitochondrial energetics has been recently demonstrated. However, whether different ERR isoforms display distinct functions in glycolytic versus oxidative myofibers is largely unknown. Moreover, their roles in regulating exercise-induced adaptive mitochondrial biogenesis remain unclear. Using muscle-specific single and combinatorial knockout mouse models, we have identified both cooperative and distinct roles of the ERR isoforms ERRα and ERRγ in regulating mitochondrial energy metabolism in different muscles. We demonstrate the essential roles of both these ERRs in mediating adaptive mitochondrial biogenesis in response to exercise training. We further show that PGC1α-induced mitochondrial biogenesis is completely abolished in primary myotubes with ERRα deletion but not ERRγ, highlighting distinct roles of these two isoforms in adaptive mitochondrial remodeling. Mechanistically, we find that both ERRs directly bind to the majority of mitochondrial energetic genes and control their expression, largely through collaborative binding to the same genomic loci. Collectively, our findings reveal critical and direct regulatory roles of ERRα and ERRγ in governing both innate and adaptive mitochondrial energetics in skeletal muscle.
    Keywords:  PGC1; energy metabolism; estrogen-related receptor; mitochondria; muscle
    DOI:  https://doi.org/10.1073/pnas.2426179122
  55. Biotechnol Appl Biochem. 2025 May 13.
    Aquaporin 9: Exacerbation of Vulnerable Carotid Plaque Formation.
    Bin Xu, Yifei Zheng, Yi Wang, Jie Sun, Dehai Lang, Qiyang Xu.
      Aquaporin 9 (AQP9) expression is significantly elevated in vulnerable carotid plaque (VCP). Hence, we probed the mechanism of AQP9 in VCP formation. The VCP model was established in ApoE-/- C57BL/6 mice. Dataset GSE163154 was analyzed by R software. Human aortic endothelial cells (HAECs) were incubated with 50 µg/mL oxidized low-density lipoprotein (ox-LDL) and 20 mM l-(+)-lactic acid for 24 h. Mice (AQP9 overexpression plasmid) and HAECs (AQP9 overexpression/dynamin-related protein 1 [DRP1] silencing plasmids) were infected by lentivirus. Mouse plasma lipid level was estimated. The histopathological condition of model mice was observed by oil red lipid staining, hematoxylin-eosin (H&E) staining, and Masson staining. Levels of AQP9 and DRP1 in model mice and HAECs were quantified by quantitative real-time polymerase chain reaction (qRT-PCR). Levels of AQP9, DRP1, and mitochondrial fission-/endothelium-mesenchymal transition (EndMT)-related factors in model mice and HAECs were assayed by western blot. Lactate level in model mice was detected. Promoter histone lactylation level of DRP1 was measured by chromatin immunoprecipitation (ChIP). Behaviors of HAECs were tested by cell counting kit-8 (CCK-8), colony formation test, and scratch test. AQP9 was highly expressed in intraplaque hemorrhage patients. AQP9 overexpression promoted levels of DRP1, lactate, histone lactylation, mitochondrial fission factor, vimentin, and N-cadherin, while inhibiting vascular endothelial (VE)-cadherin level and plaque stability in model mice and facilitating viability, proliferation, and migration of HAECs. DRP1 silencing reversed the impacts of AQP9 overexpression on cell viability, proliferation, migration, and levels of mitochondrial fission-/EndMT-related factors in HAECs. AQP9 enhances DRP1-mediated mitochondrial fission by lactate and thus promotes EndMT to exacerbate the VCP formation.
    Keywords:  Aquaporin 9; dynamin‐related protein 1; endothelium–mesenchymal transition; lactate; mitochondrial fission; vulnerable carotid plaque
    DOI:  https://doi.org/10.1002/bab.2776
  56. Zhongguo Zhong Yao Za Zhi. 2025 Mar;50(5): 1255-1266
    [Effect of total secondary ginsenosides on apoptosis and energy metabolism of H9c2 cells under hypoxia based on mitochondrial biogenesis].
    Zhong-Jie Yuan, Yue Xiao, Zhen Liu, Ai-Qun Zhang, Bin Li, Shang-Xian Gao.
      This study explores the effect of total secondary ginsenosides(TSG) on apoptosis and energy metabolism in H9c2 cells under hypoxia and its potential mechanisms. H9c2 cell viability was observed and the apoptosis rate was calculated to determine suitable intervention concentrations of TSG, antimycin A complex(AMA), and coenzyme Q10(CoQ10), along with the duration of hypoxia. H9c2 cells at the logarithmic phase were divided into a normal group, a model group, a TSG group, an AMA group, a TSG+AMA group, and a CoQ10 group. All groups, except the normal group, were treated with their respective intervention drugs and cultured under hypoxic conditions. Adenosine triphosphate(ATP) content and creatine kinase(CK) activity were measured using an ATP chemiluminescence assay kit and a CK colorimetric assay kit. Flow cytometry was used to assess apoptosis rates, and Western blot evaluated the expression levels of apoptosis-related proteins, including B-cell lymphoma 2(Bcl-2), Bcl-2-associated X protein(Bax), cysteinyl aspartate-specific protease(caspase)-3, caspase-8, and caspase-9, as well as mitochondrial biogenesis-related proteins peroxisome proliferator-activated receptor-γ coactivator 1α(PGC-1α), estrogen-related receptor-α(ERRα), nuclear respiratory factor(NRF)-1, NRF-2, peroxisome proliferator activated receptor-α(PPARα), and Na~+-K~+-ATPase. RT-PCR was employed to analyze the mRNA expression of mitochondrial biogenesis factors, including PGC-1α, ERRα, NRF-1, NRF-2, PPARα, mitochondrial transcription factor A(TFAM), mitochondrial cytochrome C oxidase 1(COX1), and mitochondrial NADH dehydrogenase subunit 1(ND1), ND2. The selected intervention concentrations were 7.5 μg·mL~(-1) for TSG, 10 μmol·L~(-1) for AMA, and 1×10~(-4) mol·L~(-1) for CoQ10, with a hypoxia duration of 6 h. Compared with the normal group, the model group showed decreased ATP content and CK activity, increased apoptosis rates, decreased Bcl-2 expression, and increased Bax, caspase-3, caspase-8, and caspase-9 expression in H9c2 cells. Additionally, the protein and mRNA expression levels of mitochondrial biogenesis-related factors(PGC-1α, ERRα, NRF-1, NRF-2, PPARα), mRNA expression of TFAM, COX1, and ND1, ND2, and protein expression of Na~+-K~+-ATPase in mitochondrial DNA, were also reduced. In the TSG and CoQ10 groups, ATP content and CK activity increased, and apoptosis rates decreased compared with those in the model group. The TSG group showed decreased protein expression of apoptosis-related proteins Bax, caspase-3, caspase-8, and caspase-9, increased protein and mRNA expression of mitochondrial biogenesis factors PGC-1α, ERRα, NRF-1, and PPARα, and increased NRF-2 protein expression and TFAM mRNA expression in mitochondrial DNA. Conversely, in the AMA group, ATP content and CK activity decreased, the apoptosis rate increased, Bcl-2 expression decreased, and Bax, caspase-3, caspase-8, and caspase-9 expression increased, alongside reductions in PGC-1α, ERRα, NRF-1, NRF-2, PPARα protein and mRNA expression, as well as TFAM, COX1, ND1, ND2 mRNA expression and Na~+-K~+-ATPase protein expression. Compared with the TSG group, the TSG+AMA group exhibited decreased ATP content and CK activity, increased apoptosis rates, decreased Bcl-2 expression, and increased Bax, caspase-3, caspase-8, and caspase-9 expression, along with decreased PGC-1α, ERRα, NRF-1, NRF-2, and PPARα protein and mRNA expression and TFAM, COX1, and ND1, ND2 mRNA expression. Compared with the AMA group, the TSG+AMA group showed increased CK activity, decreased apoptosis rate, increased Bcl-2 expression, and decreased Bax, caspase-8, and caspase-9 expression. Additionally, the protein and mRNA expression of PGC-1α, ERRα, NRF-1, PPARα, mRNA expression of TFAM, COX1, ND1, ND2, and Na~+-K~+-ATPase protein expression increased. In conclusion, TSG enhance ATP content and CK activity and inhibit apoptosis in H9c2 cells under hypoxia, and the mechanisms may be related to the regulation of PGC-1α, ERRα, NRF-1, NRF-2, PPARα, and TFAM expression, thus promoting mitochondrial biogenesis.
    Keywords:  Panax ginseng; cell apoptosis; energy metabolism; heart failure; hypoxia; total secondary ginsenosides
    DOI:  https://doi.org/10.19540/j.cnki.cjcmm.20240919.405
  57. Microscopy (Oxf). 2025 May 13. pii: dfaf023. [Epub ahead of print]
    Discovery of Golgi Membrane-associated Degradation Pathway, GOMED: A Focus on 15 Years of Ultrastructural Analyses.
    Satoko Arakawa, Hirofumi Yamaguchi, Shigeomi Shimizu.
      In this review, we focus on the ultrastructural characteristics of the Golgi membrane-associated degradation (GOMED) pathway, which have been clarified by electron microscopy and highlight recent advances in the elucidation of its molecular mechanism and physiological roles. The discovery of GOMED, an Atg5/Atg7-independent degradation pathway that differs from canonical autophagy in membrane origin, stimuli, and substrate specificity, has substantially expanded our understanding of intracellular degradation systems. In 2009, we identified GOMED as a novel, evolutionarily conserved autophagic pathway and demonstrated its role in intracellular degradation across eukaryotes, from yeast to mammals. We identified the conserved protein Hsv2/Wipi3 as an essential GOMED protein, which translocates to the trans-Golgi upon induction and remodels Golgi membranes into cup-shaped structures that engulf cytoplasmic components for lysosomal degradation. These processes contribute to organelle and secretory granule turnover, as well as mitochondrial clearance during erythroid differentiation. Moreover, neuronal-specific ablation of Wipi3 in mice causes severe cerebellar degeneration, implicating GOMED in tissue development and homeostasis. As these mechanisms are associated with diseases, such as neurodegenerative disorders and cancer, GOMED mechanisms should also be considered when establishing therapeutic strategies for these diseases.
    Keywords:  Autophagy; GOMED; Golgi; Mitophagy; Neurodegeneration; Wipi3
    DOI:  https://doi.org/10.1093/jmicro/dfaf023
  58. Int J Mol Sci. 2025 Apr 27. pii: 4162. [Epub ahead of print]26(9):
    Vital Role of PINK1/Parkin-Mediated Mitophagy of Pulmonary Epithelial Cells in Severe Pneumonia Induced by IAV and Secondary Staphylococcus aureus Infection.
    Caiyun Huo, Yuli Li, Yuling Tang, Ruijing Su, Jiawei Xu, Hong Dong, Yanxin Hu, Hanchun Yang.
      Influenza A virus (IAV) infection causes considerable morbidity and mortality worldwide, and the secondary bacterial infection further exacerbates the severity and fatality of the initial viral infection. Mitophagy plays an important role in host resistance to pathogen infection and immune response, while its role on pulmonary epithelial cells with viral and bacterial co-infection remains unclear. The present study reveals that the secondary Staphylococcus aureus infection significantly increased the viral and bacterial loads in human lung epithelial cells (A549) during the initial H1N1 infection. Meanwhile, the secondary S. aureus infection triggered more intense mitophagy in A549 cells by activating the PINK1/Parkin signaling pathway. Notably, mitophagy could contribute to the proliferation of pathogens in A549 cells via the inhibition of cell apoptosis. Furthermore, based on an influenza A viral and secondary bacterial infected mouse model, we showed that activation of mitophagy was conducive to the proliferation of virus and bacteria in the lungs, aggravated the inflammatory damage and severe pneumonia at the same time, and eventually decreased the survival rate. The results elucidated the effect and the related molecular mechanism of mitophagy in pulmonary epithelial cells following IAV and secondary S. aureus infection for the first time, which will provide valuable information for the pathogenesis of virus/bacteria interaction and new ideas for the treatment of severe pneumonia.
    Keywords:  Staphylococcus aureus; influenza A virus; mitophagy; pulmonary epithelial cells; secondary infection
    DOI:  https://doi.org/10.3390/ijms26094162
  59. J Nanobiotechnology. 2025 May 10. 23(1): 340
    Sequentially assembled co-delivery nanoplatform of SIRT1 protein and SOX9-expressing plasmid for multipronged therapy of intervertebral disc degeneration.
    Xiaoyu Zhang, Qianping Guo, Jiawei Fang, Qi Cheng, Zhuang Zhu, Qifan Yu, Huan Wang, Youzhi Hong, Chengyuan Liu, Huilin Yang, Caihong Zhu, Bin Li, Li Ni.
      Nucleus pulposus cells (NPCs) undergo metabolic disorders and matrix pathological remodeling under the influence of various adverse factors during intervertebral disc degeneration (IVDD), whereas post-translational modifications (PTMs) can confer cells with the capacity to respond quickly and adapt to complex environmental changes. Here, SIRT1 protein, a key regulator within PTMs framework, was applied against the hostile degenerative microenvironment. Then, it was sequentially assembled with SOX9-expressing plasmid, an essential transcription factor to promote extracellular matrix (ECM) biosynthesis, onto a phenylboronic acid-functionalized G5-dendrimer to construct a multifunctional nanoplatform for IVDD therapy. In vitro, the nanoplatforms showed antioxidant capacity, and the ability to restore mitochondrial homeostasis and normal ECM metabolism, as well as to maintain cellular phenotypes. RNA sequencing suggested that inhibition of the Nod-like receptor signaling might be the mechanism behind their therapeutic effects. The nanoplatforms were then wrapped in a designed dynamic hydrogel, not only prolonging the retention time of the loaded cargoes, but also well maintaining the disc structure, height, and water content in vivo. Overall, this study presents a convenient assembled strategy to inhibit the multiple adverse factors, and hold promise for the IVDD treatment.
    Keywords:  Co-delivery; Intervertebral disc degeneration; Mitochondrial homeostasis; Post-translational modifications; Sequentially assembled nanoplatform
    DOI:  https://doi.org/10.1186/s12951-025-03401-2
  60. J Nutr Biochem. 2025 May 12. pii: S0955-2863(25)00117-2. [Epub ahead of print] 109954
    Gut microbiota regulation by Lactiplantibacillus plantarum SG5 enhances mitochondrial function in Parkinson's disease mice via the GLP-1/PGC-1α pathway.
    Yueyan Qi, Siyou Xie, Jinhu Chen, Cancan Zhang, Xin Ma, Yang Yu, Xueping Yu, Yanqin Wang.
      Motor dysfunction constitutes a prominent characteristic of Parkinson's disease (PD), a neurodegenerative disorder associated with compromised mitochondrial activity, perturbed gut microbial composition, and neuronal loss. In this study, we examined the regulatory mechanisms of Lactiplantibacillus plantarum SG5 (SG5) on mitochondrial function in PD mouse models, with a particular emphasis on its interaction with the GLP-1/PGC-1α pathway. Findings revealed that MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, MPTP) induced (male 6-8 weeks C57BL/6 mice) motor impairments and damage to dopaminergic (DA) neurons in PD mice, resulting in mitochondrial dysfunction, decreased mitochondrial biogenesis, disrupted dynamics, and autophagy, while promoting fission and apoptosis. Additionally, MPTP modified gut microbial diversity and community structure. Nevertheless, supplementation with SG5 alleviated motor deficits and DA neurons damage in PD mice, enhancing mitochondrial quality by elevating PGC-1α expression and restoring biogenesis, dynamics, and autophagy levels. Mechanistic investigations demonstrated that SG5 increased colonic GLP-1 expression, suggesting that GLP-1 might regulate mitochondrial function via the GLP-1R-mediated PGC-1α. Furthermore, SG5 counteracted MPTP-induced gut dysbiosis. Notably, both GLP-1R antagonists and PGC-1α inhibitors attenuated the protective effects of SG5 in PD mice. In conclusion, L. plantarum SG5 may enhance mitochondrial function in the substantia nigra (SN) of PD mice through the GLP-1/PGC-1α pathway, potentially delaying neurodegeneration. Its mechanism is closely related to the regulation of the gut microenvironment and GLP-1 levels, presenting novel microbiota-based therapeutic targets for PD.
    Keywords:  GLP-1; L. plantarum SG5; PGC-1α; Parkinson disease; mitochondria quality control; oxidative stress
    DOI:  https://doi.org/10.1016/j.jnutbio.2025.109954
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