bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2025–04–13
73 papers selected by
Gavin McStay, Liverpool John Moores University
  1. Exploring mitochondrial dynamics and localization under cellular stress: A comprehensive insight.
  2. Heat shock protein 60 manipulates Foot-and-Mouth disease virus replication by regulating mitophagy.
  3. DRP1, fission and apoptosis.
  4. Mitochondrial dynamics at the intersection of macrophage polarization and metabolism.
  5. Early Life Stress Induces Brain Mitochondrial Dynamics Changes and Sex-Specific Adverse Effects in Adulthood.
  6. Galectin-8 drives ERK-dependent mitochondrial fragmentation, perinuclear relocation and mitophagy, with metabolic adaptations for cell proliferation.
  7. Harmine derivative H-2-168 induces the death of Echinococcus granulosus by regulating mitochondrial fusion and fission.
  8. The Structure of the Drp1 Lattice on Membrane.
  9. Targeted activation on Bnip3 enhances mitophagy to prevent the progression of osteoarthritis.
  10. The effective-compound compatibility of JHF inhibits fibroblast activation in pulmonary fibrosis by enhancing PINK1/PARK2-mediated mitophagy.
  11. Exercise enhances cardiomyocyte mitochondrial homeostasis to alleviate left ventricular dysfunction in pressure overload induced remodelling.
  12. TCE-mediated neuroprotection against rotenone-induced dopaminergic neuronal death in PD mice: insights into the Nrf-2/PINK1/Parkin-mitophagy pathway.
  13. Xanthohumol Regulates Mitophagy in Osteosarcoma Cells via AMPK-ULK1-FUNDC1 Signaling Pathway.
  14. Unraveling cell death mechanisms in traumatic brain injury: dynamic roles of ferroptosis and necroptosis.
  15. [Research progress on the relationship between mitochondrial dynamics imbalance and novel coronavirus infection-related acute respiratory distress syndrome].
  16. A novel dual CCK/ GLP-1 receptor agonist ameliorates cognitive impairment in 5 × FAD mice by modulating mitophagy via the PINK1/Parkin pathway.
  17. Mitophagy in perioperative neurocognitive disorder: mechanisms and therapeutic strategies.
  18. Mitochondrial fusion reduces T cell susceptibility to HIV infection through citrate modulation.
  19. Hijacking the powerhouse: Mitochondrial transfer and mitophagy as emerging mechanisms of immune evasion.
  20. USP7 promotes PINK1/Parkin-dependent mitophagy to ameliorate cerebral ischemia-reperfusion injury by deubiquitinating and stabilizing SIRT1.
  21. Mapping the evolution of mitochondrial dynamics research: A bibliometric analysis of global trends and collaborations.
  22. The role and therapeutic potential of mitophagy in major depressive disorder.
  23. ARMC1 partitions between distinct complexes and assembles MIRO with MTFR to control mitochondrial distribution.
  24. Rab GTPases as "eat me" signals for selective autophagy.
  25. Curcumin alleviates atrazine-induced nephrotoxicity by enhancing mitophagy through PINK1/Parkin signaling pathway in mice.
  26. UBC9 ameliorates diabetic cardiomyopathy by modulating cardiomyocyte mitophagy through NEDD4/RUNX2/PSEN2 axis.
  27. Activation of FANCC attenuates mitochondrial ROS-driven necroptosis by targeting TBK1-dependent mitophagy in astrocytes after spinal cord injury.
  28. The Role of Autophagy in Excitotoxicity, Synaptic Mitochondrial Stress and Neurodegeneration.
  29. CaMK2A/CREB pathway activation is associated with enhanced mitophagy and neuronal apoptosis in diabetic retinopathy.
  30. Apigenin-Mediated ESCRT-III Activation and Mitophagy Alleviate LPS-Induced Necroptosis in Renal Cells.
  31. Human neural stem cell-derived exosomes activate PINK1/Parkin pathway to protect against oxidative stress-induced neuronal injury in ischemic stroke.
  32. Dipeptidyl Peptidase 3 Induces Myocardial Ischemia-Reperfusion Injury by Mediating Mitophagy and the Intrinsic Apoptotic Pathway.
  33. Novel in vivo models of autosomal optic atrophy reveal conserved pathological changes in neuronal mitochondrial structure and function.
  34. Miro1- a key player in β-cell function and mitochondrial dynamics under diabetes mellitus.
  35. Metabolite tunes MDV pathway to maintain mitochondrial fitness.
  36. Urolithin A enhances diabetic wound healing: Insights from parkin-mediated mitophagy in endothelial progenitor cells.
  37. Tetrahydrobenzimidazole TMQ0153 targets OPA1 and restores drug sensitivity in AML via ROS-induced mitochondrial metabolic reprogramming.
  38. Autophagy: a double-edged sword in ischemia-reperfusion injury.
  39. Smaller-Sized Silica Nanoparticles Exacerbated Cardiomyocyte Pyroptosis by Impairing Mitophagy to Activate mtDNA-cGAS-STING Signaling.
  40. Correction: AOH1996 targets mitochondrial dynamics and metabolism in leukemic stem cells via mitochondrial PCNA inhibition.
  41. Mitochondrial calcium uniporter regulates human fibroblast-like synoviocytes invasion via altering mitochondrial dynamics and dictates rheumatoid arthritis pathogenesis.
  42. Mdivi-1 Attenuates Sepsis-Associated Acute Lung Injury by Inhibiting M1 Alveolar Macrophage Polarization and Pyroptosis.
  43. Neopterin extends C. elegans lifespan in an ATFS-1-dependent manner.
  44. BNIP3-mediated mitophagy in macrophages regulates obesity-induced adipose tissue metaflammation.
  45. VPS35-Retromer: Multifunctional Roles in Various Biological Processes - A Focus on Neurodegenerative Diseases and Cancer.
  46. In situ cryo-ET visualization of mitochondrial depolarization and mitophagic engulfment.
  47. Exosomal 4EBP1 promotes head and neck cancer progression via regulating mitochondrial fission.
  48. Atrazine Exposure Induces TDP-43 Protein Translocation: A Potential Mechanism for Prefrontal Cortical Neurodegeneration Induced by Environmental Pollutants.
  49. Aconiti Lateralis Radix Praeparata ameliorates heart failure via PI3K/AKT/Bnip3 pathway.
  50. Identifying sex-based disparities in porcine mitochondrial function.
  51. [Retracted] Grooved hydroxyapatite scaffold modulates mitochondria homeostasis and thus promotes osteogenesis in bone mesenchymal stromal cells.
  52. Luteolin attenuates LPS-induced damage in IPEC-J2 cells by enhancing mitophagy via AMPK signaling pathway activation.
  53. Deubiquitination of DNM1L by USP3 triggers the development and metastasis of gallbladder carcinoma.
  54. Sanshen San Formula Hinders Cognitive Function and Pathology in Alzheimer's Disease Through Potentiating the Function of Synapse.
  55. Browning of inguinal white adipose tissue by the novel lignan (-)-secoisolariciresinol 4-O-methyl ether attenuates diet-induced obesity through mitochondrial and Peroxisomal activation.
  56. The Regulation of ZAR1 on Apoptosis and Mitophagy in Ovarian Granular Cells and Primary Ovarian Insufficiency (POI) Mice.
  57. Curcumin targets YAP1 to enhance mitochondrial function and autophagy, protecting against UVB-induced photodamage.
  58. A collaborative immunohistochemical study of Drp1 and cortactin in the epithelial dysplasia and oral squamous cell carcinoma.
  59. NHR-85 modulates mitochondrial and lipid homeostasis to protect against α-synuclein aggregation in C. elegans.
  60. HRI protein kinase in cytoplasmic heme sensing and mitochondrial stress response: relevance to hematological and mitochondrial diseases.
  61. Rab GTPases are evolutionarily conserved signals mediating selective autophagy.
  62. Excessive dietary fat and fructose enhance hepatic lipogenesis and impair mitochondrial dynamics to cause MASLD in C57BL/6 mice.
  63. The mitochondrial unfolded protein response inhibits pluripotency acquisition and mesenchymal-to-epithelial transition in somatic cell reprogramming.
  64. Repurposing chlorpromazine for the treatment of triple-negative breast cancer growth and metastasis based on modulation of mitochondria-mediated apoptosis and autophagy/mitophagy.
  65. Myeloma mesenchymal stem cells' bioenergetics afford a novel selective therapeutic target.
  66. Scutellarein ameliorates pulmonary arterial hypertension via sirtuin 1 mediated deacetylation of nicotinamide nucleotide transhydrogenase.
  67. Bazibushen attenuates fibroblast senescence in silica-induced pulmonary fibrosis via FOXO1/PINK1/Parkin Axis.
  68. Cisplatin-induced Disruption of Mitochondrial Divisome Leads to Enhanced Cisplatin Resistance in Cholangiocarcinoma.
  69. Aminolevulinate/iron exposure elicited Nrf-2-mediated cytoprotection in DARS2 deficient fibroblasts with impaired energy and antioxidant metabolisms.
  70. Genipin attenuates oxidative damage in periodontal tissues by alleviating mitochondrial dysfunction and abnormal glucose uptake through inhibition of UCP2.
  71. Regulating Sirtuin 3-mediated mitochondrial dynamics through vanillic acid improves muscle atrophy in cancer-induced cachexia.
  72. Correction: Small molecule induces mitochondrial fusion for neuroprotection via targeting CK2 without affecting its conventional kinase activity.
  73. Epigenetics and Mitochondrial Biogenesis: The Role of Sirtuins in HIV Neuropathogenesis.
  1. J Biosci. 2025 ;pii: 23. [Epub ahead of print]50
    Exploring mitochondrial dynamics and localization under cellular stress: A comprehensive insight.
    Saloni Agarwal, Kavikumar Angamuthu Karuppusamy, Abhishek K Gupta.
      Within a cell, the mitochondrion serves various functions, including ATP synthesis, generation of reactive oxygen species, maintenance of iron and calcium ion homeostasis, and apoptosis, all of which are essential for the cell's function. Recent studies have highlighted the significance of mitochondrial dynamics and spatial distribution in ensuring proper mitochondrial function and cell survival, particularly under various cellular stress conditions. Mitochondrial dynamics include various processes such as mitochondrial fission and fusion, mitophagy, mitochondrial biogenesis, and mitochondrial transport. This review article explores the impact of cellular stressors on mitochondrial dynamics and distribution. It also sheds light on the critical role of stress-induced alterations in mitochondrial dynamics and distribution from the perspective of cell survival.
  2. Cell Mol Life Sci. 2025 Apr 07. 82(1): 141
    Heat shock protein 60 manipulates Foot-and-Mouth disease virus replication by regulating mitophagy.
    Jianli Tang, Sahibzada Waheed Abdullah, Shiqi Sun, Huichen Guo.
      Mitochondria serve as the hubs of cellular signaling, energetics, and redox balance under physiological conditions. Mitochondria play an essential role in defending against pathogenic infections upon virus invasion. As a critical intracellular physiological process, mitophagy is crucial for maintaining mitochondrial homeostasis. Accumulating evidence suggests that mitophagy contributes to modulating viral infection. In our previous study, we reported that heat shock protein 60 (HSP60) is involved in orchestrating autophagy; however, the underlying mechanisms remain elusive. Here, we examined the role of HSP60 in priming mitophagy to regulate foot-and-mouth disease virus (FMDV) replication. We first reported that mitophagy was elicited post-FMDV infection and further restricted FMDV replication. Regarding HSP60, our results showed that HSP60 depletion triggered Parkin-dependent mitophagy via activating dynamin-related protein 1 (Drp1) phosphorylation at Ser616 and promoting Drp1 translocation to mitochondria. Furthermore, calmodulin-dependent protein kinase II (CaMKII) was essential for phosphorylating Drp1 at Ser616 in HSP60-depleted cells. Taken together, HSP60 manipulates FMDV replication by governing mitophagy. Importantly, HSP60 could be a promising antiviral target for controlling FMDV infection.
    Keywords:  Dynamin-related protein 1; Foot-and-Mouth disease virus; Heat shock protein 60; Mitophagy; Parkin
    DOI:  https://doi.org/10.1007/s00018-025-05623-x
  3. Cell Death Discov. 2025 Apr 07. 11(1): 150
    DRP1, fission and apoptosis.
    Nan Wang, Xinwai Wang, Beiwu Lan, Yufei Gao, Yuanyuan Cai.
      Mitochondrial fission is a critical physiological process in eukaryotic cells, participating in various vital activities such as mitosis, mitochondria quality control, and mitophagy. Recent studies have revealed a tight connection between mitochondrial fission and the mitochondrial metabolism, as well as apoptosis, which involves multiple cellular events and interactions between organelles. As a pivotal molecule in the process of mitochondrial fission, the function of DRP1 is regulated at multiple levels, including transcription, post-translational modifications. This review follows the guidelines for Human Gene Nomenclature and will focus on DRP1, discussing its activity regulation, its role in mitochondrial fission, and the relationship between mitochondrial fission and apoptosis.
    DOI:  https://doi.org/10.1038/s41420-025-02458-0
  4. Front Immunol. 2025 ;16 1520814
    Mitochondrial dynamics at the intersection of macrophage polarization and metabolism.
    Pan Li, Zhengbo Fan, Yanlan Huang, Liang Luo, Xiaoyan Wu.
      Macrophages are vital sentinels in innate immunity, and their functions cannot be performed without internal metabolic reprogramming. Mitochondrial dynamics, especially mitochondrial fusion and fission, contributes to the maintenance of mitochondrial homeostasis. The link between mitochondrial dynamics and macrophages in the past has focused on the immune function of macrophages. We innovatively summarize and propose a link between mitochondrial dynamics and macrophage metabolism. Among them, fusion-related FAM73b, MTCH2, SLP-2 (Stomatin-like protein 2), and mtSIRT, and fission-related Fis1 and MTP18 may be the link between mitochondrial dynamics and macrophage metabolism association. Furthermore, post-translational modifications (PTMs) of mtSIRT play prominent roles in mitochondrial dynamics-macrophage metabolism connection, such as deacetylates and hypersuccinylation. MicroRNAs such as miR-150, miR-15b, and miR-125b are also possible entry points. The metabolic reprogramming of macrophages through the regulation of mitochondrial dynamics helps improve their adaptability and resistance to adverse environments and provides therapeutic possibilities for various diseases.
    Keywords:  fission; fusion; macrophage; metabolism; mitochondrial dynamics
    DOI:  https://doi.org/10.3389/fimmu.2025.1520814
  5. J Neurosci Res. 2025 Apr;103(4): e70023
    Early Life Stress Induces Brain Mitochondrial Dynamics Changes and Sex-Specific Adverse Effects in Adulthood.
    Angeliki-Maria Vlaikou, Markus Nussbaumer, Aikaterini Iliou, Maria P Papageorgiou, Chrysoula Komini, Daniela Theodoridou, Dimitra Benaki, Emmanuel Mikros, Evangelos Gikas, Maria Syrrou, Michaela D Filiou.
      Early life stress exposure exerts detrimental effects in adulthood and is a risk factor for psychiatric disorders. Studies addressing the molecular mechanisms of early life stress have primarily focused on hormones and stress circuits. However, little is known on how mitochondria and mitochondrial dynamics (i.e., the orchestration of mitochondrial fission, fusion, mitophagy, and biogenesis) modulate early life stress responses. Here, we used a maternal separation with early weaning (MSEW) paradigm to investigate the behavioral and molecular early life stress-elicited effects in male and female C57BL/6 mice in adulthood. We first applied a behavioral test battery to assess MSEW-driven, anxiety-related and stress-coping alterations. We then looked for MSEW-induced, mitochondria-centered changes in cingulate cortex, hippocampus and cerebellum, as well as in plasma by combining protein, mRNA, mitochondrial DNA copy number (mtDNAcn) and metabolomics analyses. We found that MSEW mice are more anxious, show decreased antioxidant capacity in the cingulate cortex and have higher mRNA levels of the fission regulator Fis1 and the mitophagy activator Pink1 in the hippocampus, indicating a shift towards mitochondrial degradation. Hippocampal mRNA level alterations of apoptotic markers further suggest an MSEW-driven activation of apoptosis accompanied by a dysregulation of purine catabolism in the cerebellum in MSEW mice. Sex-specific analysis revealed distinct MSEW-induced changes in male and female mice at the molecular level. Our work reveals a previously unexplored role of mitochondrial dynamics in regulating early life stress effects and highlights a mitochondria-centered dysregulation as a persistent outcome of early life stress in adulthood.
    Keywords:  anxiety; fission; maternal separation; mice; mitochondria; mitophagy
    DOI:  https://doi.org/10.1002/jnr.70023
  6. Eur J Cell Biol. 2025 Apr 04. pii: S0171-9335(25)00013-5. [Epub ahead of print]104(2): 151488
    Galectin-8 drives ERK-dependent mitochondrial fragmentation, perinuclear relocation and mitophagy, with metabolic adaptations for cell proliferation.
    Adely de la Peña, Claudio Retamal, Francisca Pérez-Molina, Nicole Díaz-Valdivia, Francisco Veloso-Bahamondes, Diego Tapia, Jorge Cancino, Felix Randow, Alfonso González, Claudia Oyanadel, Andrea Soza.
      Mitochondria adapt to the cell proliferative demands induced by growth factors through dynamic changes in morphology, distribution, and metabolic activity. Galectin-8 (Gal-8), a carbohydrate-binding protein that promotes cell proliferation by transactivating the EGFR-ERK signaling pathway, is overexpressed in several cancers. However, its impact on mitochondrial dynamics during cell proliferation remains unknown. Using MDCK and RPTEC kidney epithelial cells, we demonstrate that Gal-8 induces mitochondrial fragmentation and perinuclear redistribution. Additionally, mitochondria adopt donut-shaped morphologies, and live-cell imaging with two Keima-based reporters demonstrates Gal-8-induced mitophagy. ERK signaling inhibition abrogates all these Gal-8-induced mitochondrial changes and cell proliferation. Studies with established mutant versions of Gal-8 and CHO cells reveal that mitochondrial changes and proliferative response require interactions between the N-terminal carbohydrate recognition domain of Gal-8 and α-2,3-sialylated N-glycans at the cell surface. DRP1, a key regulator of mitochondrial fission, becomes phosphorylated in MDCK cells or overexpressed in RPTEC cells in an ERK-dependent manner, mediating mitochondrial fragmentation and perinuclear redistribution. Bafilomycin A abrogates Gal-8-induced cell proliferation, suggesting that mitophagy serves as an adaptation to cell proliferation demands. Functional analysis under Gal-8 stimulation shows that mitochondria maintain an active electron transport chain, partially uncoupled from ATP synthesis, and an increased membrane potential, indicative of healthy mitochondria. Meanwhile, the cells exhibit increased extracellular acidification rate and lactate production via aerobic glycolysis, a hallmark of an active proliferative state. Our findings integrate mitochondrial dynamics with metabolic adaptations during Gal-8-induced cell proliferation, with potential implications for physiology, disease, and therapeutic strategies.
    Keywords:  Galectin-8; Glycosylation; Mitochondrial dynamics; Mitophagy; Proliferation
    DOI:  https://doi.org/10.1016/j.ejcb.2025.151488
  7. Pharm Biol. 2025 Dec;63(1): 188-200
    Harmine derivative H-2-168 induces the death of Echinococcus granulosus by regulating mitochondrial fusion and fission.
    Yuehong Gong, Meiling Zhao, Meichi Pan, Yicong Zhao, Junpeng Liu, Hao Wen, Jianhua Wang.
       CONTEXT: H-2-168 has pharmacological effects similar to those of harmine, with less toxicity. The health of cells and organisms depends on a delicate balance between mitochondrial fusion and fission.
    OBJECTIVE: This study investigated the roles of H-2-168 and mitochondrial fusion and fission in Echinococcus granulosus.
    MATERIALS AND METHODS: Notably, E. granulosus were isolated from fresh sheep livers, and then treated with H-2-168 (25 μg/mL), mitochondrial division inhibitor 1 (Mdivi-1, 25 μg/mL) or the combination of H-2-168:Mdivi-1 (25 μg/mL:12.5 μg/mL). After 24 h of culture, the indices related to E. granulosus were measured. Additionally, Drp1 was knocked down to explore its effects on E. granulosus growth.
    RESULTS: The EC50 values of H-2-168, Mdivi-1 and H-2-168:Mdivi-1 against E. granulosus were 44.171, 117.882 and 32.924 μg/mL, respectively. Compared with H-2-168 or Mdivi-1, the combination of H-2-168 and Mdivi-1 showed better inhibitory effects on E. granulosus viability, as well as increased levels of ROS and LDH, decreased ATP levels, inhibited mitochondrial activity and reduced mitochondrial membrane potential (p < 0.05), with the upregulation of Caspase-3, Cyt-c, Drp1, Fis1 and downregulation of Bcl-2, Mfn2 and OPA1. Additionally, Drp1 knockdown was successfully performed in E. granulosus, which significantly inhibited E. granulosus viability (p < 0.05) and further downregulated Mfn2 expression induced by H-2-168.
    DISCUSSION AND CONCLUSION: Drp1 is closely associated with mitochondrial fusion and fission, and H-2-168 may promote E. granulosus death through disrupting the balance between mitochondrial fusion and fission.
    Keywords:  Cystic echinococcosis; Drp1; E. granulosus; mitochondria; viability
    DOI:  https://doi.org/10.1080/13880209.2025.2485898
  8. J Mol Biol. 2025 Apr 02. pii: S0022-2836(25)00191-3. [Epub ahead of print] 169125
    The Structure of the Drp1 Lattice on Membrane.
    Ruizhi Peng, Kristy Rochon, Anelise N Hutson, Scott M Stagg, Jason A Mears.
      Mitochondrial health relies on the membrane fission mediated by dynamin-related protein 1 (Drp1). Previous structural studies of Drp1 on remodeled membranes were hampered by heterogeneity, leaving a critical gap in the understanding of the mitochondrial fission mechanisms. Here we present a cryo-electron microscopy structure of full-length human Drp1 decorated on membrane tubules. Using the reconstruction of average subtracted tubular regions (RASTR) technique, we report that Drp1 forms a locally ordered lattice along the tubule without global helical symmetry. The filaments in the lattice are similar to dynamin rungs with conserved stalk interactions. Adjacent filaments are connected by GTPase domain interactions in a novel stacked conformation. We identified two states of the Drp1 lattice among the heterogenous dataset representing conformational changes around hinge 1. Additionally, we observed contact between Drp1 and membrane that can be assigned to the variable domain sequence. Together these structures revealed a putative mechanism by which Drp1 constricts mitochondria membranes in a stepwise, "ratchet" manner.
    Keywords:  Drp1; cryo-EM; membrane remodeling; mitochondria
    DOI:  https://doi.org/10.1016/j.jmb.2025.169125
  9. J Orthop Translat. 2025 Mar;51 242-255
    Targeted activation on Bnip3 enhances mitophagy to prevent the progression of osteoarthritis.
    Yong Gou, Chenggui Wang, Kejian Fu, Shenkai Su, Hangjin Zhou, Chunkai Bao, Hui Nan, Xiang Zhang, Yiyuan Xu, Qi Chen, Xinchen Gu, Baiting Chen, Lin Zheng, Chenglong Xie, Man Zhang, Enxing Xue, Jiawei Li.
       Background: The production of reactive oxygen species (ROS) and mitochondrial dysfunction in chondrocytes are closely related to cartilage degeneration in the procedure of osteoarthritis (OA). Mitophagy is responsible for the scavenging of ROS and dysfunctional mitochondria and is considered a key therapeutic target for the treatment of OA. Tiopronin, a classic thiol antioxidant, has been widely studied for the treatment of various oxidative stress-related diseases.
    Methods: The expression of mitophagy (PINK1, PARKIN, and TOMM20) in intact and damaged cartilage of OA patients was analyzed by Western blot and histological analysis. RNA sequencing (RNA-seq) analysis was performed to explore the molecular mechanism of tiopronin in regulating mitophagy in chondrocytes, and then to find the specific target of tiopronin. The therapeutic effects of tiopronin were evaluated in the OA model induced by destabilisation of the medial meniscus (DMM), chondrocytes degenerative model with the primary chondrocytes from mouse and human cartilage explants experiment. The downstream molecular mechanisms of tiopronin were further investigated by si-RNA knockdown of mitophagy-related proteins.
    Results: The level of mitophagy in cartilage was negatively correlated with the severity of OA. We revealed that tiopronin promoted the anabolism of the extracellular matrix (ECM) of hyaline chondrocytes and alleviates ROS in vitro and in vivo by strengthening mitophagy. Moreover, tiopronin strongly activated the expression of Bnip3, a protein anchored in the mitochondrial membrane, and subsequently enhanced the Pink1/Parkin signaling pathway.
    Conclusion: These findings indicate that the Bnip3-Pink1-Parkin signaling pathway, targeted and activated by tiopronin, plays a key role in inhibiting the progression of OA.
    The translational potential of this article: As a classical drug in clinic, tiopronin was developed a new therapeutic approach in the treatment in OA via this study. Based the significant and efficient effect of tiopronin in inhibiting the cartilage degermation and delay the progression of OA, it was believed that tiopronin may become an effective therapeutic candidate for OA treatment in clinical settings.
    Keywords:  BNIP3; Cartilage degeneration; Mitophagy; Osteoarthritis; Tiopronin
    DOI:  https://doi.org/10.1016/j.jot.2025.01.012
  10. Sci Rep. 2025 Apr 08. 15(1): 11935
    The effective-compound compatibility of JHF inhibits fibroblast activation in pulmonary fibrosis by enhancing PINK1/PARK2-mediated mitophagy.
    Yunping Bai, Xiaohong Yin, Qin Zhang, Xingjie Sang, Wenjing Wu, Dong Shao, Peng Zhao, Jiansheng Li.
      This work aimed to elucidate the anti-PF mechanism of ECC-JHF.The effects of ECC-JHF on lung fibrosis and fibroblast activation were investigated by establishing a BLM-induced PF rat model and a transforming growth factor-beta (TGF-β)-induced fibroblast activation model. Furthermore, the effects of ECC-JHF on Nrf2 signaling and mitophagy were explored both in vivo and in vitro. In the PF model rats, ECC-JHF mitigated pathological damage, reduced collagen deposition, decreased levels of malondialdehyde (MDA) and P62, and increased levels of total superoxide dismutase (T-SOD) as well as the expression of Nrf2, HO-1, PINK1, PARK2, and LC3B in lung tissues. These results suggest that the anti-PF mechanism of ECC-JHF may be associated with the inhibition of oxidative stress and the enhancement of mitophagy. The medium dose of ECC-JHF and pirfenidone were similar in improving pulmonary fibrosis in rats. In the TGF-β-induced lung fibroblast activation, ECC-JHF inhibited fibroblast activation by downregulating the levels of fibronectin, alpha-smooth muscle actin (α-SMA), and collagen I. Additionally, ECC-JHF upregulated the level of Nrf2 and its target proteins, including HO-1 and NQO1, as well as mitophagy-related proteins PINK1, PARK2, and LC3B. This led to an increase in the co-localization of TOM20 and LC3, thereby enhancing mitochondrial autophagy. The application of Nrf2 siRNA and Nrf2 inhibitors significantly diminished the effects of ECC-JHF on Nrf2 signaling, PINK1/PARK2-mediated mitophagy, and fibroblast activation. ECC-JHF exerts a protective effect against PF by suppressing fibroblast activation through the upregulation of Nrf2 and PINK1/PARK2-mediated mitophagy, it provides a new target and strategy for the treatment of pulmonary fibrosis.
    Keywords:  Effective-compound combination; Fibroblasts activation; Mitophagy; Nrf2; Pulmonary fibrosis
    DOI:  https://doi.org/10.1038/s41598-025-95175-8
  11. Sci Rep. 2025 Apr 05. 15(1): 11698
    Exercise enhances cardiomyocyte mitochondrial homeostasis to alleviate left ventricular dysfunction in pressure overload induced remodelling.
    Zhichao Ma, Yanling Cen, Weiwei Xun, Caiying Mou, Junwen Yu, Yarui Hu, Chen Liu, Jun Sun, Rui Bi, Yanli Qiu, Mingchao Ding, Li Jin.
      This study aims to explore how exercise enhances mitochondrial regulation and mitigates pathological cardiac hypertrophy. Rat groups were assigned as the control group (CN, n = 8), sham group (sham, n = 8), model group (SC, n = 16) and exercise group (SE, n = 20). A bioinformatics analysis was conducted to uncover the underlying mechanisms.H9C2 cells were divided into: the Ang II 0 h group (CON), Ang II 48 h group (Ang II), Ang II 48 h + sh-control group (sh-GFP + Ang II), Ang II 48 h + sh-ndufb10 group (sh-ndufb10 + Ang II), Ang II 48 h + overexpressedndufb10 control group (Ad-GFP + Ang II) and Ang II 48 h + over-expressedndufb10group (Ad-ndufb10 + Ang II). Mitochondrial function was measured. mRNA and protein expression were assessed by qPCR or western blot analysis respectively. In the SC group, a significant increase was observed in cardiomyocyte diameter, cardiac function, autophagy, and apoptosis. After 8 weeks of swimming exercise, there was a substantial reduction in cardiomyocyte diameter, an improvement in cardiac function, a mitigation of mitochondrial fission and autophagy. Ndufb10 was markedly enriched in oxidative phosphorylation and downregulated in the SC group, while it was upregulated in the SE group. In the sh-ndufb10 group, mitochondrial fusion was suppressed; fission and autophagy were further facilitated; mitochondrial membrane potential, mPTP, and ROS levels increased; and TUNEL positive nuclei and apoptosis-related proteins showed significant upregulation. Overexpression of ndufb10 reversed pathological hypertrophy, mitochondrial autophagy, mitochondrial dysfunction, and cardiomyocyte apoptosis in vitro. Swimming exercise improves mitochondrial abnormalities and reduces cardiomyocyte hypertrophy through regulation of the ndufb10 in left ventricular hypertrophy.
    Keywords:  Cardiomyocyte; Exercise; Mitochondrial dynamics; Ndufb10; Pathological cardiac hypertrophy
    DOI:  https://doi.org/10.1038/s41598-025-95637-z
  12. Metab Brain Dis. 2025 Apr 07. 40(4): 172
    TCE-mediated neuroprotection against rotenone-induced dopaminergic neuronal death in PD mice: insights into the Nrf-2/PINK1/Parkin-mitophagy pathway.
    Hagera Dilnashin, Shekhar Singh, Poonam Rawat, Aaina Singh Rathore, Richa Singh, Priyanka Kumari Keshri, Nitesh Kumar Gupta, Singh Ankit Satyaprakash, Surya Pratap Singh.
      Oxidative stress-induced mitochondrial dysfunction is implicated in the pathogenesis of Parkinson's disease (PD). In a previous study, we reported that an extract of T. cordifolia (TCE) possessed antioxidant and anti-apoptotic properties that improved mitochondrial function against rotenone-induced neurotoxicity. However, the underlying molecular mechanism remains unclear. In this study, we found that rotenone (ROT)-induced PD mice exhibited mitochondrial abnormalities, including defective mitophagy, mitochondrial reactive oxygen species (ROS) overexpression, and mitochondrial fragmentation, accompanied by reduced expression of Pink1 and Parkin and increased apoptosis. These changes were partially reversed following oral administration of TCE. Moreover, TCE restored the activity and translocation of NF-E2-related factor 2 (Nrf2) and upregulated the expression of antioxidant enzymes (SOD1, SOD2, GSH, and GSSH). Interestingly, ROT also activates mitophagy. Our results suggest that ROT toxicity can cause neuronal cell death through mitophagy-mediated signaling in PD mice. However, TCE reversed this activity by inhibiting autophagic protein (LC3B-II/LC3B-I) activation and increasing specific mitochondrial proteins (TOM20, Pink1, and Parkin). Our findings indicated that TCE provides neuroprotection against rotenone-induced toxicity in PD mice by stimulating endogenous antioxidant enzymes and inhibiting ROT-induced oxidative stress by potentiating the Nrf-2/Pink1/Parkin-mediated survival mechanism.
    Keywords:   T. cordifolia ; Mitochondrial dysfunction.; Mitophagy; Nrf-2; Oxidative stress; PINK1/Parkin
    DOI:  https://doi.org/10.1007/s11011-025-01595-w
  13. Phytother Res. 2025 Apr 07.
    Xanthohumol Regulates Mitophagy in Osteosarcoma Cells via AMPK-ULK1-FUNDC1 Signaling Pathway.
    Qiaofeng Ge, Zhiliang Yan, Qian Tian, Jiyan Zhang, Jia Li, Fang Cai, Long Zhang, Yonggang Zhu.
      Osteosarcoma (OS) is the most common primary bone malignancy. The therapeutic efficacy for OS patients has remained stagnant in recent decades. Xanthohumol (XN), a flavonoid naturally found in hops, has demonstrated significant anticancer properties in lung and breast cancer. However, its effect on OS and the underlying molecular mechanisms remains uncertain. Therefore, the purpose of this study is to explore the relationship between XN and OS. Firstly, we assessed the impact of XN on OS cell proliferation and migration using CCK-8, wound-healing, transwell, and clonogenicity assays. Subsequently, we examined the effect of XN on mitophagy in OS cells through flow cytometry, immunofluorescence, transmission electron microscopy, and western blot analysis. Finally, we constructed siRNA targeting AMPK to validate the pathway. In vitro, we demonstrated that XN inhibited the proliferation and migration of OS cells in a concentration- and time-dependent manner. Furthermore, XN induced mitochondrial damage in OS cells and increased reactive oxygen species (ROS) levels. RNA-seq analysis suggested a potential mitophagy pathway, which we confirmed experimentally by showing that XN reduced ATP levels, altered mitochondrial membrane potential, and increased the expression of Atg5, Beclin-1, and LC3 proteins. Interestingly, the mitophagy inhibitor Mdivi-1 reversed the damage caused by XN to OS cells. Furthermore, we found that XN induced mitophagy and exerted anti-OS effects through the activation of the AMPK-ULK1-FUNDC1 signaling pathway, which was effectively reversed after AMPK knockdown. In vivo, we demonstrated the therapeutic potential of XN using a subcutaneous OS nude mouse model without any organ toxicity. XN emerges as a promising pharmaceutical agent for targeting OS.
    Keywords:  AMPK‐ULK1‐FUNDC1; cell death; mitophagy; osteosarcoma; xanthohumol
    DOI:  https://doi.org/10.1002/ptr.8468
  14. Mol Biol Rep. 2025 Apr 10. 52(1): 381
    Unraveling cell death mechanisms in traumatic brain injury: dynamic roles of ferroptosis and necroptosis.
    Mohd Anash, Kousik Maparu, Shamsher Singh.
      Traumatic brain injury (TBI) remains a major cause of mortality and long-term disability worldwide, with ferroptosis and necroptosis emerging as key drivers of secondary neuronal damage. Ferroptosis, characterized by iron-dependent lipid peroxidation and mitochondrial dysfunction, exacerbates oxidative stress and neuronal cell death. In parallel, necroptosis, mediated by receptor-interacting protein kinases (RIPK1 and RIPK3), amplifies inflammation through membrane rupture and the release of cellular components. Mitochondrial dynamics, involving fission and fusion processes, play a dual role in regulating these pathways. While mitochondrial fusion preserves cellular integrity and reduces oxidative stress, excessive mitochondrial fission driven by dynamin-related protein 1 (DRP1) accelerates necroptotic signaling and neuronal injury. This intricate interplay between ferroptosis, necroptosis, and mitochondrial dynamics highlights potential therapeutic targets. Modulating these pathways through tailored interventions could reduce neuronal damage, mitigate neuroinflammation, and improve functional outcomes in TBI patients. Advancing our understanding of these mechanisms is essential for developing precision therapies that address the complex pathology of traumatic brain injury.
    Keywords:  Dynamin-related protein 1(DRP1); Ferroptosis; Labile iron pools (LIP); Necroptosis; Reactive oxygen species (ROS); Traumatic brain injury (TBI)
    DOI:  https://doi.org/10.1007/s11033-025-10489-0
  15. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2025 Mar;37(3): 300-304
    [Research progress on the relationship between mitochondrial dynamics imbalance and novel coronavirus infection-related acute respiratory distress syndrome].
    Zijia Zhang, Bin Du, Xunyao Wu, Xiaoyun Hu, Shitong Diao, Run Dong.
      Patients with severe pneumonia caused by novel coronavirus infection are often complicated with acute respiratory distress syndrome (ARDS), which has a high mortality. ARDS is characterized by diffuse alveolar damage, pulmonary edema, and hypoxemia. Mitochondria are prone to morphological and functional abnormalities under hypoxia and viral infection, which can lead to cell apoptosis and damage, severely impacting the disease progression. Mitochondria maintain homeostasis through fission and fusion. In ARDS, hypoxia leads to the phosphorylation of dynamin-related protein 1 (Drp1), triggering excessive mitochondrial fission and damaging the alveolar epithelial barrier. Animal experiments have shown that inhibiting this process can alleviate lung injury, providing a potential direction for treatment. The pathology of novel coronavirus infection-related ARDS is similar to that of typical ARDS but more severe. Viral infection and hypoxia disrupt the mitochondrial balance, causing fission and autophagy abnormalities, promoting oxidative stress and mitochondrial DNA (mtDNA) release, activating inflammasomes, inducing the expression of hypoxia-inducible factor-1α (HIF-1α), exacerbating viral infection, inflammation, and coagulation reactions, and resulting in multiple organ damage. Mechanical ventilation and glucocorticoids are commonly used in the treatment of novel coronavirus infection-related ARDS. Mechanical ventilation is likely to cause lung and diaphragm injuries and changes in mitochondrial dynamics, while the lung protective ventilation strategy can reduce the adverse effects. Glucocorticoids can regulate mitochondrial function and immune response and improve the patient's condition through multiple pathways. The mitochondrial dynamics imbalance in novel coronavirus infection-related ARDS is caused by hypoxia and viral proteins, leading to lung and multiple organ injuries. To clarify the pathophysiological mechanism of mitochondrial dynamics imbalance in novel coronavirus infection-related ARDS and explore effective strategies for regulating mitochondrial dynamics balance to treat this disease, so as to provide new treatment targets and methods for patients with novel coronavirus infection-related ARDS. The existing treatments have limitations. Future research needs to deeply study the mechanism of mitochondrial dysfunction, develop new therapies and regulatory strategies, and improve the treatment effect.
    DOI:  https://doi.org/10.3760/cma.j.cn121430-20241126-00957
  16. Int Immunopharmacol. 2025 Apr 03. pii: S1567-5769(25)00602-2. [Epub ahead of print]154 114612
    A novel dual CCK/ GLP-1 receptor agonist ameliorates cognitive impairment in 5 × FAD mice by modulating mitophagy via the PINK1/Parkin pathway.
    Rihong Luo, Yuhan Kang, He Ma, Zhenqiang Zhang, Christian Hölscher, Li Hao, Zijuan Zhang.
      To date, no therapeutic drugs available on the market can effectively reverse the progression of Alzheimer's disease (AD). Although Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) and Cholecystokinin (CCK) RAs have shown some promise in AD research, little is known about the neuroprotective effects of a novel dual CCK/GLP-1 RA in AD. This study sought to examine the effects of the novel dual CCK/GLP-1 RA on cognitive performance in an AD mouse model and to explore the associated mechanisms. Our findings indicate that dual CCK/GLP-1 RA improved cognitive deficits, reduced amyloid-beta (Aβ) accumulation, and alleviated mitochondrial damage in 5 × FAD mice by inducing mitophagy. In an in vitro model of AD cells induced by Aβ, CCK/GLP-1 RA could exert neuroprotective effects by regulating PINK1/Parkin-mediated mitophagy. These data reveal for the first time that the new CCK/GLP-1 RA modulates mitophagy via PINK1/Parkin pathway and enhances cognitive function in the 5 × FAD animal model. Moreover, the performance of the CCK/GLP-1 RA in certain indicators was superior to that of GLP-1 analogue liraglutide, suggesting that it may represent a more promising therapeutic option for AD.
    Keywords:  Alzheimer's disease; Cognitive deficits; Dual CCK/GLP-1 RA; Mitophagy; PINK1/Parkin
    DOI:  https://doi.org/10.1016/j.intimp.2025.114612
  17. Eur J Med Res. 2025 Apr 11. 30(1): 270
    Mitophagy in perioperative neurocognitive disorder: mechanisms and therapeutic strategies.
    Zhen Feng, Yan Hou, Chang Yu, Ting Li, Haoyang Fu, Feng Lv, Ping Li.
      Perioperative neurocognitive disorder (PND) is a common neurological complication after surgery/anesthesia in elderly patients that affect postoperative outcome and long-term quality of life, which increases the cost of family and social resources. The pathological mechanism of PND is complex and not fully understood, and the methods of prevention and treatment of PND are very limited, so it is particularly important to analyze the mechanism of PND. Research indicates that mitochondrial dysfunction is pivotal in the initiation and progression of PND, although the precise mechanisms remain elusive and could involve disrupted mitophagy. We reviewed recent studies on the link between mitophagy and PND, highlighting the role of key proteins in abnormal mitophagy and discussing therapeutic strategies aimed at mitophagy regulation. This provides insights into the mechanisms underlying PND and potential therapeutic targets.
    Keywords:  Mitophagy; NLRP3 inflammasome; Perioperative neurocognitive disorder; Pyroptosis
    DOI:  https://doi.org/10.1186/s40001-025-02400-1
  18. J Leukoc Biol. 2025 Apr 11. pii: qiaf042. [Epub ahead of print]
    Mitochondrial fusion reduces T cell susceptibility to HIV infection through citrate modulation.
    Zichen Song, Jiangrong Wang, Zhihang Zheng, Zhixiang He, Jingna Xun, Ling Gu, Yinzhong Shen, Jun Chen.
      Inhibiting the metabolic activity of CD4+ T cells can effectively reduce HIV infection. Mitochondria, as critical organelles in eukaryotic metabolism, play a significant role in the progression of many diseases. The change of mitochondrial dynamics is an important process of mitochondrial regulation of cell metabolic activity. However, it remains uncertain whether regulating mitochondrial dynamics is a viable approach to reducing HIV infection. In this study, we demonstrated that promoting mitochondrial fusion in Jurkat cells through treatment with the mitochondrial fusion promoter M1 and the dynamin-related protein 1 (Drp1) inhibitor Mdivi1 conferred resistance to single-round VSVG-HIVNL4-3-GFP viral infection. Targeted metabolomics analysis revealed and subsequently confirmed the potential involvement of citrate in reducing HIV infection, which has been subsequently verified. And we found that plasma citrate level was negatively associated with HIV disease progression. Multi-omics results showed that citric acid leads to a decrease in the level of nucleotide metabolism in Jurkat cells. In conclusion, increased citrate levels resulting from mitochondrial fusion significantly impair the ability of HIV to infect cells, which may due to regulate nucleotide metabolism.
    Keywords:  HIV; citrate; mitochondrial dynamic; nucleotide metabolism
    DOI:  https://doi.org/10.1093/jleuko/qiaf042
  19. Mol Cell. 2025 Apr 03. pii: S1097-2765(25)00188-1. [Epub ahead of print]85(7): 1258-1259
    Hijacking the powerhouse: Mitochondrial transfer and mitophagy as emerging mechanisms of immune evasion.
    Maria T Diaz-Meco, Juan F Linares, Jorge Moscat.
      Cancer cells subvert the immune system by reprogramming their metabolism. In a recent study in Nature, Ikeda et al.1 show how cancer cells can directly transfer mitophagy-resistant mitochondria to tumor-infiltrating lymphocytes, promoting their homoplasmic replacement and undermining cancer immunity.
    DOI:  https://doi.org/10.1016/j.molcel.2025.02.026
  20. Brain Res. 2025 Apr 09. pii: S0006-8993(25)00197-0. [Epub ahead of print] 149638
    USP7 promotes PINK1/Parkin-dependent mitophagy to ameliorate cerebral ischemia-reperfusion injury by deubiquitinating and stabilizing SIRT1.
    Dan Hou, Yujie Hu, Tian Yun, Dan Yu, Guoshuai Yang.
       BACKGROUND: Cerebral ischemia-reperfusion (CI/R) injury, a major complication of ischemic stroke, is characterized by mitochondrial dysfunction and neuronal apoptosis, and understanding its underlying molecular mechanisms is essential for the development of effective therapeutic strategies. This study aimed to investigate the role of ubiquitin-specific protease 7 (USP7) in CI/R injury and elucidate its regulatory mechanisms.
    METHODS: A rat model of middle cerebral artery occlusion/reperfusion (MCAO/R) and an in vitro neuronal model subjected to oxygen-glucose deprivation/reperfusion (OGD/R) was used to mimic CI/R injury. USP7 was overexpressed or knocked down, with or without co-treatment, using the autophagy inhibitor 3-methyladenine (3-MA). Neurological function was evaluated using standardized scoring systems, and cerebral infarct volume was quantified by TTC staining. Histopathological alterations in the cortex and hippocampus were assessed using hematoxylin-eosin (HE) and Nissl staining. Neuronal viability and apoptosis were measured by CCK-8 assay, TUNEL staining, and flow cytometry. To assess cellular metabolism and oxidative stress, ATP and LDH levels, along with antioxidant markers including SOD, GSH, and GSH-Px, were analyzed using commercial biochemical kits. Mitochondrial morphology and autophagosome formation were visualized using transmission electron microscopy. Gene and protein expression levels were quantified by qRT-PCR and Western blotting, respectively. Immunofluorescence microscopy was performed to evaluate subcellular localization of target proteins and co-localization with mitochondrial membrane markers. Lastly, protein-protein interactions and ubiquitination modification were analyzed by co-immunoprecipitation assays.
    RESULTS: USP7 overexpression significantly alleviated neurological deficits, reduced infarct volume, attenuated histological damage, and decreased neuronal apoptosis in the MCAO/R model. In parallel, in the OGD/R model, USP7 overexpression markedly enhanced neuronal viability, suppressed apoptosis, restored ATP production, improved antioxidant capacity (as indicated by increased levels of SOD, GSH, and GSH-Px), and reduced LDH release. Mechanistically, USP7 stabilized SIRT1 protein expression through deubiquitination, which in turn activated the PINK1/Parkin pathway and enhanced mitophagy. This activation was demonstrated by an increased LC3II/LC3I ratio, elevated ATG5 expression, enhanced co-localization of Tomm20 and Parkin, and increased autophagosome formation. Moreover, these protective effects could be abolished when either 3-MA treatment was applied or SIRT1/PINK1 expression was knocked down.
    CONCLUSION: USP7 mitigates CI/R injury by promoting PINK1/Parkin-dependent mitophagy through SIRT1 deubiquitination and stabilization, supporting USP7 as a potential therapeutic target for ischemic stroke.
    Keywords:  CI/R injury; Mitophagy; PINK1/Parkin axis; SIRT1; USP7
    DOI:  https://doi.org/10.1016/j.brainres.2025.149638
  21. Adv Clin Exp Med. 2025 Apr 11.
    Mapping the evolution of mitochondrial dynamics research: A bibliometric analysis of global trends and collaborations.
    Fugang Huang, Ke Sun, Zexuan Wu, Guanqun Xie, Jie Bao, Yongsheng Fan.
       BACKGROUND: Mitochondrial dynamics is an important field in cell biology, encompassing mitochondrial fission and fusion. The balance between fission and fusion is responsible for the stability of the mitochondrial network and can be a regulator of mitochondrial function. Recent studies have emphasized that an imbalance in mitochondrial dynamics is the root cause of dysfunction and is involved in various stages, such as oxidative stress, inflammation and apoptosis. Reversing this imbalance can effectively alleviate disease conditions. Although the importance of mitochondrial dynamics has been widely recognized, there is still a lack of literature on the qualitative and quantitative description and analysis of advances in this field.
    OBJECTIVES: This study is a bibliometric analysis of research trends, collaboration networks and thematic evolution in mitochondrial dynamics from 2000 to 2023.
    MATERIAL AND METHODS: Using the Web of Science Core Collection (WoSCC) database, we performed a bibliometric review, applying VOSviewer and CiteSpace to visualize and analyze publications, citations, collaborations, and key word trends.
    RESULTS: We analyzed 332 publications, identifying China and the USA as leaders in research output and international collaborations. Significant contributions were made by institutions like Chiang Mai University and the California Institute of Technology (Caltech), with major research shifts from basic mitochondrial functions to roles in diseases like Alzheimer's and cardiovascular disease.
    CONCLUSION: Mitochondrial dynamics research has expanded, with increasing attention to its role in disease mechanisms. Future research should further explore these connections, potentially leading to innovative treatments.
    Keywords:  CiteSpace; Science Citation Index; VOSviewer; bibliometrics; mitochondrial dynamics
    DOI:  https://doi.org/10.17219/acem/196720
  22. Front Pharmacol. 2025 ;16 1564276
    The role and therapeutic potential of mitophagy in major depressive disorder.
    Xin-Nuan Shi, Chen-Yue Liu, Lin Li, Ming-Li Yao, Zhen Zhong, You-Ming Jiang.
      Major depressive disorder, also known as MDD, affects more than 264 million people globally, making it a prevalent and critical health challenge. Traditional treatments show limited efficacy in many patients. Therefore, exploring new treatment methods is particularly crucial. Mitophagy, as a regulatory process, can help understand and treat MDD. This paper focuses on the molecular mechanisms of mitophagy, starting from proteins and related pathways, and its role in MDD. The study also explores the associations between mitophagy and neuroinflammation, oxidative stress, neurotransmitter synthesis, and neuroplasticity in MDD and discusses the progress of clinical research on the role of mitophagy in MDD. In addition, the article describes the current pharmaceutical and non-pharmaceutical interventions that can regulate mitophagy in MDD and unravels the potential and challenges of these therapeutic strategies in clinical settings. This article offers a deeper insight into the pathogenesis of MDD and offers a scientific basis for the development of new treatment strategies.
    Keywords:  major depressive disorder; mitophagy; mitophagy-related pathways; mitophagy-related proteins; therapeutic potential
    DOI:  https://doi.org/10.3389/fphar.2025.1564276
  23. Sci Adv. 2025 Apr 11. 11(15): eadu5091
    ARMC1 partitions between distinct complexes and assembles MIRO with MTFR to control mitochondrial distribution.
    Michael J McKenna, Felix Kraus, João P L Coelho, Muskaan Vasandani, Jiuchun Zhang, Benjamin M Adams, Joao A Paulo, J Wade Harper, Sichen Shao.
      Maintaining an optimal mitochondrial distribution is critical to ensure an adequate supply of energy and metabolites to support important cellular functions. How cells balance dynamic mitochondrial processes to achieve homeostasis is incompletely understood. Here, we show that ARMC1 partitioning between distinct mitochondrial protein complexes is a key determinant of mitochondrial distribution. In one complex, the mitochondrial trafficking adaptor MIRO recruits ARMC1, which mediates the assembly of a mitochondrial fission regulator (MTFR). MTFR stability depends on ARMC1, and MIRO-MTFR complexes specifically antagonize retrograde mitochondrial movement. In another complex, DNAJC11 facilitates ARMC1 release from mitochondria. Disrupting MIRO-MTFR assembly fails to rescue aberrant mitochondrial distributions clustered in the perinuclear area observed with ARMC1 deletion, while disrupting ARMC1 interaction with DNAJC11 leads to excessive mitochondrially localized ARMC1 and distinct mitochondrial defects. Thus, the abundance and trafficking impact of MIRO-MTFR complexes require ARMC1, whose mito-cytoplasmic shuttling balanced by DNAJC11 tunes steady-state mitochondrial distributions.
    DOI:  https://doi.org/10.1126/sciadv.adu5091
  24. J Cell Biol. 2025 May 05. pii: e202502030. [Epub ahead of print]224(5):
    Rab GTPases as "eat me" signals for selective autophagy.
    Yan G Zhao.
      Selective autophagy targets specific cellular cargo for degradation. In this issue, Zhao et al. (https://doi.org/10.1083/jcb.202410150) uncovered that Rab GTPases serve as pivotal "autophagy cues" for recruitment of cargo receptors to facilitate mitophagy, lipophagy, and xenophagy, contributing to the precise spatiotemporal regulation of selective autophagy.
    DOI:  https://doi.org/10.1083/jcb.202502030
  25. Ecotoxicol Environ Saf. 2025 Apr 09. pii: S0147-6513(25)00454-3. [Epub ahead of print]295 118118
    Curcumin alleviates atrazine-induced nephrotoxicity by enhancing mitophagy through PINK1/Parkin signaling pathway in mice.
    Zhenyu Zou, Xinyi Cheng, Jinyan Chen, Chenghong Xing, Caiying Zhang, Xiaoquan Guo, Huabing Cao, Guoliang Hu, Yu Zhuang.
      Atrazine (ATR), a widely used herbicide, poses significant environmental and health risks due to its high solubility and adsorption in soil. ATR exposure can lead to nephrotoxicity in humans and animals. Curcumin (Cur), an active compound in Curcuma species, is renowned for its antioxidant and anti-inflammatory properties, with potential to mitigate chronic disease risks. We hypothesized that the addition of Cur could alleviate renal impairment associated with ATR exposure and carried out experiments using mice as subjects. This study investigates whether Cur can attenuate ATR-induced nephrotoxicity in mice by modulating mitophagy and apoptotic pathways. Our findings illustrate that consumption with Cur attenuates nephrotoxicity induced by ATR, as evidenced by lowered serum concentrations of uric acid (UA), blood urea nitrogen (BUN), and creatinine (CRE), established biomarkers of renal injury. Moreover, Curcumin enhances renal antioxidant defense mechanisms in ATR-exposed mice, as indicated by elevated levels of total antioxidant capacity (T-AOC), catalase (CAT), and glutathione peroxidase (GSH-Px), alongside reduced levels of malondialdehyde (MDA). Histopathological and electron microscopy analyses further corroborate these findings, showing reduced organelle damage, particularly mitochondrial ridge breakage and vacuolization, and increased autophagic lysosomes. Cur further enhances PINK1/Parkin-mediated autophagy, as evidenced by elevated levels of PINK1, Parkin, LC3BII, and P62 compared to ATR-treated mice. Moreover, Cur mitigates the mitochondrial apoptotic pathway, indicated by the down-regulation of apoptosis-related genes (Cytochrome C (Cyto-C), Caspase3, Caspase9) and the pro-apoptotic marker (Bax), along with the up-regulation of the anti-apoptotic marker (Bcl-2) at both transcriptional and translational levels compared to ATR-treated mice. In summary, Cur demonstrates nephroprotective properties against ATR-induced injury through the enhancement of mitochondrial autophagy and display of anti-apoptotic actions, underscoring its curative potency as a treatment for nephrotoxicity caused by ATR.
    Keywords:  Apoptosis; Autophagy; Herbal extracts; Kidney injury; Oxidative stress; Pesticide residues
    DOI:  https://doi.org/10.1016/j.ecoenv.2025.118118
  26. Metabolism. 2025 Apr 08. pii: S0026-0495(25)00133-7. [Epub ahead of print] 156264
    UBC9 ameliorates diabetic cardiomyopathy by modulating cardiomyocyte mitophagy through NEDD4/RUNX2/PSEN2 axis.
    Hanlin Wu, Zheming Yang, Ting Zhou, Jing Wang, Yuxin Bu, Haixu Song, Chenghui Yan, Dan Liu, Yaling Han.
       AIM: Diabetic cardiomyopathy (DCM) is one of the most significant cardiovascular complications in patients with diabetes. Ubiquitin conjugating enzyme 9 (UBC9) is the only SUMO-E2 enzyme that plays a key role in cardiomyocytes homeostasis. This study aimed to elucidate the roles and mechanisms of UBC9 in DCM development.
    METHODS: We established cardiomyocyte-specific UBC9 knockout mice and UBC9-overexpressing mice in vivo. A DCM model was established by feeding a high-fat diet and administering a low-dose streptozotocin injection. Proteomics, H&E staining, Sirius Red staining, WGA staining, real-time PCR, and western blotting were performed to examine fibrosis, hypertrophy, and mitophagy in the myocardium. Neonatal mouse cardiomyocytes (NMCMs) were cultured in vitro and stimulated with palmitic acid, UBC9 overexpression adenovirus, and small interfering RNA to establish UBC9 overexpression or knockdown NMCMs. Real-time PCR, western blotting, and immunoprecipitation were employed to examine the roles and mechanisms of UBC9 in cardiomyocyte mitophagy.
    RESULTS: The transcription and protein levels of UBC9 were significantly decreased in the myocardium of DCM mice. Cardiomyocyte-specific UBC9 knockout aggravated cardiac dysfunction, myocardial fibrosis, hypertrophy, and impaired mitophagy. Conversely, UBC9 overexpression produced opposite effects. UBC9 protected cardiomyocyte mitophagy independently of SUMOylation. UBC9 exerted protective effects against defective cardiomyocyte mitophagy by directly binding to NEDD4, enhancing RUNX2 ubiquitination and degradation, which in turn increased PSEN2 expression. Moreover, the impact of UBC9 on cardiomyocyte mitophagy was reversed upon PSEN2 knockdown.
    CONCLUSIONS: UBC9 alleviated DCM development through the NEDD4/RUNX2/PSEN2 pathway. These findings offer novel insights into the potential of UBC9 as a therapeutic target for DCM.
    Keywords:  Cardiomyocyte; Mitophagy; PSEN2; UBC9
    DOI:  https://doi.org/10.1016/j.metabol.2025.156264
  27. Theranostics. 2025 ;15(9): 4188-4211
    Activation of FANCC attenuates mitochondrial ROS-driven necroptosis by targeting TBK1-dependent mitophagy in astrocytes after spinal cord injury.
    Mingjie Xia, Chaochen Li, Jiajia Chen, Chunshuai Wu, Jinlong Zhang, Hongxiang Hong, Jiawei Jiang, Guanhua Xu, Zhanyang Qian, Zhiming Cui.
      Rationale: Necroptosis in astrocytes induced by mitochondrial dysfunction following spinal cord injury (SCI) significantly contributes to neuronal functional deficits. Mitophagy plays a crucial role in clearing damaged mitochondria and inhibiting necroptosis. Fanconi anemia complementation group C (FANCC), a member of the Fanconi anemia gene family, exerts a protective role by facilitating mitophagy in immune processes. However, the role of FANCC in SCI-induced astrocytic necroptosis and the underlying mechanisms remain unexplored. Methods: Astrocyte-specific FANCC conditional knockout (Fanccfl/fl-GFAP-Cre) mice, obtained by mating Fanccfl/fl mice with GFAP-Cre mice, served as a model of moderate thoracic spinal cord contusion injuries. Using bulk and single-nucleus RNA sequencing, we investigated the protective role of FANCC in astrocytes after SCI. We assessed necroptosis and mitophagy in astrocytes through quantitative PCR, western blotting, flow cytometry, immunofluorescence, and transmission electron microscopy. Molecular mechanisms were explored via co-immunoprecipitation, proteomics, molecular docking, and confocal imaging. Computer virtual screening identified poliumoside as a FANCC activator. Histopathological staining and functional assessments (gait analysis, Basso Mouse Scale, and hindlimb reflex score) were conducted to evaluate the therapeutic effects of poliumoside on SCI. Results: Astrocytic FANCC deficiency exacerbated necroptosis and mitochondrial damage, leading to severe neurological deficits. Conversely, FANCC overexpression increased PTEN-induced kinase 1-Parkin expression, thereby activating mitophagy and reducing necroptosis. Proteomics revealed FANCC's interaction with a specific peptide of TANK-binding kinase 1 (TBK1), which further promoted mitophagy. Treatment with the FANCC activator poliumoside improved neural pathology and motor function recovery in SCI mice. Conclusion: The current study indicated that FANCC interacts with TBK1 and consequently mediates Parkin translocation, activates mitophagy, and inhibits astrocyte necroptosis. Our findings demonstrate the neuroprotective role and therapeutic potential of FANCC for SCI amelioration.
    Keywords:  FANCC; Mitophagy; Necroptosis; Spinal cord injury; TBK1
    DOI:  https://doi.org/10.7150/thno.109071
  28. Autophagy Rep. 2025 ;pii: 2464376. [Epub ahead of print]4(1):
    The Role of Autophagy in Excitotoxicity, Synaptic Mitochondrial Stress and Neurodegeneration.
    Charleen T Chu.
      Brain and nervous system functions depend upon maintaining the integrity of synaptic structures over the lifetime. Autophagy, a key homeostatic quality control system, plays a central role not only in neuronal development and survival/cell death, but also in regulating synaptic activity and plasticity. Glutamate is the major excitatory neurotransmitter that activates downstream targets, with a key role in learning and memory. However, an excess of glutamatergic stimulation is pathological in stroke, epilepsy and neurodegeneration, triggering excitotoxic cell death or a sublethal process of excitatory mitochondrial calcium toxicity (EMT) that triggers dendritic retraction. Markers of autophagy and mitophagy are often elevated following excitatory neuronal injuries, with the potential to influence cell death or neurodegenerative outcomes of these injuries. Interestingly, leucine-rich repeat kinase 2 (LRRK2) and PTEN-induced kinase 1 (PINK1), two kinases linked to autophagy, mitophagy and Parkinson disease, play important roles in regulating mitochondrial calcium handling, synaptic density and function, and maturation of dendritic spines. Mutations in LRRK2, PINK1, or proteins linked to Alzheimer's disease perturb mitochondrial calcium handling to sensitize neurons to excitatory injury. While autophagy and mitophagy can play both protective and harmful roles, studies in various excitotoxicity and stroke models often implicate autophagy in a pathogenic role. Understanding the role of autophagic degradation in regulating synaptic loss and cell death following excitatory neuronal injuries has important therapeutic implications for both acute and chronic neurological disorders.
    Keywords:  Alzheimer disease; Epilepsy; Glutamate toxicity; Leucine-rich repeat kinase 2; Mitochondrial Na+/Ca2+ exchanger; Mitochondrial calcium uniporter; PTEN-induced kinase 1; Parkinson disease; hypoxia-ischemia; post-synaptic calcium
    DOI:  https://doi.org/10.1080/27694127.2025.2464376
  29. Sci Rep. 2025 Apr 11. 15(1): 12516
    CaMK2A/CREB pathway activation is associated with enhanced mitophagy and neuronal apoptosis in diabetic retinopathy.
    Xiaochun Yang, Yuxin Zhang, Yikun Zhou, Mingzhi Liu, Haiyan Zhao, Yang Yang, Jianyun Su.
      Diabetic retinopathy (DR) is a common complication of diabetes mellitus, characterized by progressive neurodegeneration and vision impairment. The Ca2+/calmodulin-dependent protein kinase II alpha (CaMK2A) and cAMP response element-binding protein (CREB) signaling pathway has been implicated in various neurological disorders. However, its role in DR pathogenesis remains elusive. We established a DR mouse model by streptozotocin administration and performed histological, biochemical, and molecular analyses to investigate the involvement of CaMK2A/CREB signaling and its interplay with mitophagy. Additionally, we employed in vitro high-glucose (HG) treatment in primary mouse retinal ganglion cells to dissect the underlying mechanisms. Pharmacological and genetic modulations were utilized to target CaMK2A/CREB pathway and mitophagy. In the DR model, we observed retinal degeneration, increased apoptosis, and reduced neurotransmitter production, accompanied by enhanced mitophagy and activation of the CaMK2A/CREB pathway. HG induction in retinal ganglion cells recapitulated these findings, and autophagy inhibition partially rescued cell death but failed to suppress CaMK2A/CREB activation, suggesting mitophagy as a downstream consequence. CaMK2A knockdown or CREB phosphorylation inhibition attenuated HG-induced mitophagy, apoptosis, and neurotransmitter depletion, while CREB activation exacerbated these effects. CaMK2A silencing mitigated DR progression, oxidative stress, inflammation, and neuronal loss, akin to dopamine/carbidopa administration in DR mouse model. Our findings reveal the involvement of CaMK2A/CREB signaling activation and enhanced mitophagy in DR, suggesting these pathways may be therapeutically relevant targets for DR management.
    Keywords:  CREB; CaMK2A; Diabetic retinopathy; Mitophagy; Neurodegeneration
    DOI:  https://doi.org/10.1038/s41598-025-97371-y
  30. J Agric Food Chem. 2025 Apr 10.
    Apigenin-Mediated ESCRT-III Activation and Mitophagy Alleviate LPS-Induced Necroptosis in Renal Cells.
    Jiakang Guo, Jin-Ping Hu, Meitong Liu, Yuelin Chen, Shengzhuo Zhang, Shuang Guan.
      Apigenin (API) is a flavonoid widely distributed in vegetables and fruits that exhibits numerous biological functions. Lipopolysaccharide (LPS), a key component of the outer membrane of Gram-negative bacteria, can cause kidney injury when released into the bloodstream. Necroptosis is a form of programmed cell death characterized by the rupture of cell membranes. Excessive occurrence of necroptosis can lead to substantial damage to cells and tissues. In the study, we discovered that API could mitigate LPS-induced kidney injury in mice and alleviate LPS-induced necroptosis in Normal Rat Kidney-52E (NRK-52E) cells by targeting the mitochondrial reactive oxygen species (mtROS)-RIPK3-MLKL pathway. Further mechanistic studies revealed that API could potentially activate the endosomal sorting complexes required for transport-III (ESCRT-III), and activated ESCRT-III could repair cell membrane rupture caused by LPS-induced necroptosis. Simultaneously, we discovered that activated ESCRT-III could promote mitophagy, which facilitates the timely removal of damaged mitochondria and reduces intracellular mtROS levels. In conclusion, our results suggested that API alleviates LPS-induced renal cell necroptosis by activating ESCRT-III-dependent membrane repair and mitophagy. Our study provides new insights into the daily dietary intake of API to alleviate kidney injury caused by LPS.
    Keywords:  ESCRT-III; apigenin; lipopolysaccharide; mitophagy; necroptosis
    DOI:  https://doi.org/10.1021/acs.jafc.5c00627
  31. J Transl Med. 2025 Apr 05. 23(1): 402
    Human neural stem cell-derived exosomes activate PINK1/Parkin pathway to protect against oxidative stress-induced neuronal injury in ischemic stroke.
    Mengke Zhao, Jiayi Wang, Shuaiyu Zhu, Shensen Zhang, Chao Han, Chengcheng Tan, Yubing Huang, Zhaokai Sun, Liang Wang, Jing Liu.
       BACKGROUND: Mitochondria play a critical role in oxidative stress (OS)-induced neuronal injury during ischemic stroke (IS), making them promising therapeutic targets. Mounting evidence underscores the extraordinary therapeutic promise of exosomes derived from human neural stem cells (hNSCs) in the management of central nervous system (CNS) diseases. Nonetheless, the precise mechanisms by which these exosomes target mitochondria to ameliorate the effects of IS remain only partially elucidated. This study investigates the protective effects of hNSC derived exosomes (hNSC-Exos) on neuronal damage.
    METHODS: Using a rat model of middle cerebral artery occlusion (MCAO) in vivo and OS-induced HT22 cells in vitro. Firstly, our research group independently isolated human neural stem cells (hNSCs) and subsequently prepared hNSC-Exos. In vivo, MCAO rats were restored to blood flow perfusion to simulate ischemia-reperfusion injury, and hNSC-Exos were injected through stereotaxic injection into the brain. Subsequently, the protective effects of hNSC-Exos on MCAO rats were evaluated, including histological studies, behavioral assessments. In vivo, H2O2 was used in HT22 cells to simulate the OS environment in MCAO, and then its protective effects on HT22 were evaluated by co-culturing with hNSC-Exos, including immunofluorescence staining, western blotting (WB), quantitative real time PCR (qRT-PCR). In the process of exploring specific mechanisms, we utilized RNA sequencing (RNA-seq) to detect the potential induction of mitophagy in OS-induced HT22 cells. Afterwards, we employed a series of mitochondrial function assessments and autophagy related detection techniques, including measuring mitochondrial membrane potential, reactive oxygen species (ROS) levels, transmission electron microscopy (TEM) imaging, monodansylcadaverine (MDC) staining, and mCherry-GFP-LC3B staining. In addition, we further investigated the regulatory pathway of hNSC-Exos by using autophagy inhibitor mdivi-1 and knocking out PTEN induced kinase 1 (PINK1) in HT22 cells.
    RESULTS: Administration of hNSC-Exos significantly ameliorated brain tissue damage and enhanced behavioral outcomes in MCAO rats. This treatment led to a reduction in brain tissue apoptosis and facilitated the normalization of impaired neurogenesis and neuroplasticity. Notably, the application of hNSC-Exos in vitro resulted in an upregulation of mitophagy in HT22 cells, thereby remedying mitochondrial dysfunction. We demonstrate that hNSC-Exos activate mitophagy via the PINK1/Parkin pathway, improving mitochondrial function and reducing neuronal apoptosis.
    CONCLUSIONS: These findings suggest that hNSC-Exos alleviate OS-induced neuronal damage by regulating the PINK1/Parkin pathway. These reveals a novel role of stem cell-derived mitochondrial therapy in promoting neuroprotection and suggest their potential as a therapeutic approach for OS-associated CNS diseases, including IS.
    Keywords:  Exosomes; Human neural stem cells; Ischemic stroke; Mitophagy; Neuroprotection; Oxidative stress; PINK1/Parkin pathway
    DOI:  https://doi.org/10.1186/s12967-025-06283-y
  32. Eur J Pharmacol. 2025 Apr 04. pii: S0014-2999(25)00346-2. [Epub ahead of print] 177592
    Dipeptidyl Peptidase 3 Induces Myocardial Ischemia-Reperfusion Injury by Mediating Mitophagy and the Intrinsic Apoptotic Pathway.
    Xiao Wang, Yaofeng Xie, Hongjiao Du, Cheng Chang, Chunyang Tian, Yuyao Yin, Xiaodong Li, Yilong Pan.
       BACKGROUND: Dipeptidyl peptidase 3 (DPP3) is a zinc-dependent hydrolase that is regarded as a "myocardial inhibitor". However, the role of DPP3 in myocardial ischemia-reperfusion injury (MIRI) remain to be investigated. The present study aimed to investigate the potential role of DPP3 in MIRI and elucidate the underlying mechanisms.
    METHODS: The AC16 cardiomyocyte cell line was used to investigate the interactions between DPP3 and its protein interactors, and assess its effects on the apoptosis of cardiomyocytes following oxygen glucose deprivation/reperfusion (OGD/R) treatment in vitro. An animal model of ischemia/reperfusion (I/R) injury was established using C57BL/6J mice for in vivo analyses. The role of DPP3 and the underlying mechanisms were investigated both in vitro and in vivo following DPP3 knockdown and overexpression.
    RESULTS: DPP3 interacted with Parkinson's disease protein 7 (Park7), and DPP3 overexpression altered the expression levels of proteins related to the intrinsic apoptotic pathway and autophagy. This significantly downregulated the mitochondrial expression of cytochrome C, thereby exacerbating mitochondrial injury and increasing the rate of apoptosis following reperfusion. DPP3 knockdown reversed these effects; however, the simultaneous knockdown of DPP3 and Park7 did not confer the beneficial effects observed with DPP3 knockdown alone. DPP3 knockdown alleviated the extent of myocardial injury and improved cardiac function in the mouse model of I/R injury.
    CONCLUSIONS: The study demonstrated that DPP3 mediates mitophagy and apoptosis in MIRI through its interaction with Park7. These findings have important implications, suggesting that targeting DPP3 and its associated signaling pathways may serve as a potential therapeutic strategy, and that the downregulation of DPP3 can potentially alleviate MIRI.
    Keywords:  Dipeptidyl peptidase 3; Parkinson’s disease protein 7; apoptosis; mitophagy; myocardial ischemia-reperfusion injury
    DOI:  https://doi.org/10.1016/j.ejphar.2025.177592
  33. FASEB J. 2025 Apr 15. 39(7): e70497
    Novel in vivo models of autosomal optic atrophy reveal conserved pathological changes in neuronal mitochondrial structure and function.
    Elin L Strachan, Eugene T Dillon, Mairéad Sullivan, Jeffrey C Glennon, Amandine Peyrel, Jérôme Sarniguet, Kevin Dubois, Benjamin Delprat, Breandán N Kennedy, Niamh C O'Sullivan.
      Autosomal optic atrophy (AOA) is a form of hereditary optic neuropathy characterized by the irreversible and progressive degermation of the retinal ganglion cells. Most cases of AOA are associated with a single dominant mutation in OPA1, which encodes a protein required for fusion of the inner mitochondrial membrane. It is unclear how loss of OPA1 leads to neuronal death, and despite ubiquitous expression appears to disproportionately affect the RGCs. This study introduces two novel in vivo models of OPA1-mediated AOA, including the first developmentally viable vertebrate Opa1 knockout (KO). These models allow for the study of Opa1 loss in neurons, specifically RGCs. Though survival is significantly reduced in Opa1 deficient zebrafish and Drosophila, both models permit the study of viable larvae. Moreover, zebrafish Opa1 KO larvae show impaired visual function but unchanged locomotor function, indicating that retinal neurons are particularly sensitive to Opa1 loss. Proteomic profiling of both models reveals marked disruption in protein expression associated with mitochondrial function, consistent with an observed decrease in mitochondrial respiratory function. Similarly, mitochondrial fragmentation and disordered cristae organization were observed in neuronal axons in both models highlighting Opa1's highly conserved role in regulating mitochondrial morphology and function in neuronal axons. Importantly, in Opa1 deficient zebrafish, mitochondrial disruption and visual impairment precede degeneration of RGCs. These novel models mimic key features of AOA and provide valuable tools for therapeutic screening. Our findings suggest that therapies enhancing mitochondrial function may offer a potential treatment strategy for AOA.
    Keywords:   Drosophila ; mitochondria; optic atrophy; visual impairment; zebrafish
    DOI:  https://doi.org/10.1096/fj.202403271R
  34. Mitochondrion. 2025 Apr 07. pii: S1567-7249(25)00036-4. [Epub ahead of print] 102039
    Miro1- a key player in β-cell function and mitochondrial dynamics under diabetes mellitus.
    Srikanth Kavyashree, Kannan Harithpriya, Kunka Mohanram Ramkumar.
      Mitochondrial health is crucial for the survival and function of β-cells, preserving glucose homeostasis and effective insulin production. Miro1, a mitochondrial Rho GTPase1 protein, plays an essential role in maintaining thequality of mitochondria by regulating calcium homeostasis and mitophagy. In this review, we aim to explore the dysfunction of Miro1 in type 2 diabetes mellitus (T2DM) and its contribution to impaired Ca2+ signaling, which increases oxidative stress in β-cells. This dysfunction is the hallmark of T2DM pathogenesis, leading to insufficient insulin production and poor glycemic control. Additionally, we discuss the role of Miro1 in modulating insulin secretion and inflammation, highlighting its effect on modulating key signaling cascades in β-cells. Altogether, enhancing Miro1 function and activity could alleviate mitochondrial dysfunction, reducing oxidative stress-mediated damage, and improving pancreatic β-cell survival. Targeting Miro1 by Small molecules or gene-editing approaches could provide effective strategies for restoring cell function and insulin secretion in diabetic individuals. Exploring the deeper knowledge of Miro1 functions and interactions could lead to novel therapeutic advances in T2DM management.
    Keywords:  Diabetes Mellitus; Miro1; Mitochondrial Dynamics; RHOT1; β-cells
    DOI:  https://doi.org/10.1016/j.mito.2025.102039
  35. Mol Cell. 2025 Apr 03. pii: S1097-2765(25)00189-3. [Epub ahead of print]85(7): 1253-1255
    Metabolite tunes MDV pathway to maintain mitochondrial fitness.
    Shiori Sekine, Yusuke Sekine.
      In this issue of Molecular Cell, Tang et al.1 demonstrate that the ketone body β-hydroxybutyrate (BHB) promotes the biogenesis of mitochondrial-derived vesicles (MDVs) via lysine β-hydroxybutyrylation (Kbhb) on SNX9, revealing a way to fine-tune the mitochondrial quality control pathway with metabolites.
    DOI:  https://doi.org/10.1016/j.molcel.2025.02.027
  36. Int Immunopharmacol. 2025 Apr 08. pii: S1567-5769(25)00562-4. [Epub ahead of print]155 114572
    Urolithin A enhances diabetic wound healing: Insights from parkin-mediated mitophagy in endothelial progenitor cells.
    Xia Fang, Zhenxuan Shao, Hongfeng Ding, Haoxiang Xu, Zhuolong Tu, Hui Wang, Dawei Li, Cheng Huang, Chang Jiang.
      Diabetes is often associated with delayed wound healing, where endothelial progenitor cells (EPCs) play a key role in maintaining vascular integrity and promoting angiogenesis. Urolithin A, a metabolite derived from pomegranates, strawberries, and nuts, has demonstrated therapeutic potential in reversing damage in various disease models, indicating its potential in facilitating diabetic wound healing. In this study, we investigated the effects of Urolithin A on mitochondrial dysfunction, apoptosis, and impaired function in EPCs treated with high glucose. Through sequencing and molecular docking analysis, we found that Urolithin A exerts its therapeutic action by upregulating Parkin and activating mitophagy. Furthermore, Urolithin A alleviated delayed wound healing in diabetic rat models. In conclusion, Urolithin A holds promise as a therapeutic agent for improving diabetes-related delayed wound healing by targeting mitochondrial dysfunction and enhancing EPC function.
    Keywords:  Diabetic wound healing; Endothelial progenitor cells; Mitophagy; Urolithin A
    DOI:  https://doi.org/10.1016/j.intimp.2025.114572
  37. J Exp Clin Cancer Res. 2025 Apr 07. 44(1): 114
    Tetrahydrobenzimidazole TMQ0153 targets OPA1 and restores drug sensitivity in AML via ROS-induced mitochondrial metabolic reprogramming.
    Su Jung Park, Claudia Cerella, Jin Mo Kang, Jinyoung Byun, David Kum, Barbora Orlikova-Boyer, Anne Lorant, Michael Schnekenburger, Ali Al-Mourabit, Christo Christov, Juyong Lee, Byung Woo Han, Marc Diederich.
       BACKGROUND: Acute myeloid leukemia (AML) is a highly aggressive cancer with a 5-year survival rate of less than 35%. It is characterized by significant drug resistance and abnormal energy metabolism. Mitochondrial dynamics and metabolism are crucial for AML cell survival. Mitochondrial fusion protein optic atrophy (OPA)1 is upregulated in AML patients with adverse mutations and correlates with poor prognosis.
    METHOD: This study investigated targeting OPA1 with TMQ0153, a tetrahydrobenzimidazole derivative, to disrupt mitochondrial metabolism and dynamics as a novel therapeutic approach to overcome treatment resistance. Effects of TMQ0153 treatment on OPA1 and mitofusin (MFN)2 protein levels, mitochondrial morphology, and function in AML cells. In this study, we examined reactive oxygen species (ROS) production, oxidative phosphorylation (OXPHOS) inhibition, mitochondrial membrane potential (MMP) depolarization, and apoptosis. Additionally, metabolic profiling was conducted to analyze changes in metabolic pathways.
    RESULTS: TMQ0153 treatment significantly reduced OPA1 and mitofusin (MFN)2 protein levels and disrupted the mitochondrial morphology and function in AML cells. This increases ROS production and inhibits OXPHOS, MMP depolarization, and caspase-dependent apoptosis. Metabolic reprogramming was observed, shifting from mitochondrial respiration to glycolysis and impaired respiratory chain activity. Profiling revealed reduced overall metabolism along with changes in the glutathione (GSH)/oxidized glutathione (GSSG) and NAD⁺/NADH redox ratios. TMQ0153 treatment reduces tumor volume and weight in MV4-11 xenografts in vivo. Combination therapies with TMQ0153 and other AML drugs significantly reduced the leukemic burden and prolonged survival in NOD scid gamma (NSG) mice xenografted with U937-luc and MOLM-14-luc cells.
    CONCLUSION: TMQ0153 targets mitochondrial dynamics by inhibiting OPA1, inducing metabolic reprogramming, and triggering apoptosis in AML cells. It enhances the efficacy of existing AML therapies and provides a promising combination treatment approach that exploits mitochondrial vulnerability and metabolic reprogramming to improve treatment outcomes in AML.
    Keywords:  Drug resistance; Glutathione; Glycolysis; Metabolic reprogramming; Monocytic myeloid leukemia; OXPHOS
    DOI:  https://doi.org/10.1186/s13046-025-03372-0
  38. Cell Mol Biol Lett. 2025 Apr 07. 30(1): 42
    Autophagy: a double-edged sword in ischemia-reperfusion injury.
    Lingxuan Tang, Wangzheqi Zhang, Yan Liao, Weijie Wang, Xiaoming Deng, Changli Wang, Wenwen Shi.
      Ischemia-reperfusion (I/R) injury describes the pathological process wherein tissue damage, initially caused by insufficient blood supply (ischemia), is exacerbated upon the restoration of blood flow (reperfusion). This phenomenon can lead to irreversible tissue damage and is commonly observed in contexts such as cardiac surgery and stroke, where blood supply is temporarily obstructed. During ischemic conditions, the anaerobic metabolism of tissues and organs results in compromised enzyme activity. Subsequent reperfusion exacerbates mitochondrial dysfunction, leading to increased oxidative stress and the accumulation of reactive oxygen species (ROS). This cascade ultimately triggers cell death through mechanisms such as autophagy and mitophagy. Autophagy constitutes a crucial catabolic mechanism within eukaryotic cells, facilitating the degradation and recycling of damaged, aged, or superfluous organelles and proteins via the lysosomal pathway. This process is essential for maintaining cellular homeostasis and adapting to diverse stress conditions. As a cellular self-degradation and clearance mechanism, autophagy exhibits a dualistic function: it can confer protection during the initial phases of cellular injury, yet potentially exacerbate damage in the later stages. This paper aims to elucidate the fundamental mechanisms of autophagy in I/R injury, highlighting its dual role in regulation and its effects on both organ-specific and systemic responses. By comprehending the dual mechanisms of autophagy and their implications for organ function, this study seeks to explore the potential for therapeutic interventions through the modulation of autophagy within clinical settings.
    Keywords:  Apoptosis; Autophagy; I/R injury; Mitophagy; Necroptosis
    DOI:  https://doi.org/10.1186/s11658-025-00713-x
  39. J Agric Food Chem. 2025 Apr 08.
    Smaller-Sized Silica Nanoparticles Exacerbated Cardiomyocyte Pyroptosis by Impairing Mitophagy to Activate mtDNA-cGAS-STING Signaling.
    Dongxu Han, Tong Xu, Xiunan Lyu, Ke Li, Shiwen Xu.
      Silica nanoparticles (SiNPs) are a nanometer powder widely used in various consumer products, engineering, the food industry, and medical applications. Environmental SiNPs have attracted attention owing to their exposure to various cardiovascular adverse events. Here, we exposed C57/BL6 mouse and HL-1 cells with different-sized SiNPs (50, 300 nm, and 1 μm) to investigate the underlying mechanism of its cardiovascular toxicity. Mice exposed to three-sized SiNPs showed significant weight loss after 21 days of treatment. Heart weight to tibia length ratio and histopathology staining indicated increased heart volume and cross-sectional area of myocardial fibers in mice exposed to SiNPs. In vivo and in vitro experiments results showed that exposure to SiNPs causes size-dependent mitochondrial damage and initiates mitophagy. Notably, compared to the damage caused by 300 nm and 1 μm SiNPs exposure, 50 nm SiNPs blocked autophagy flux, leading to excessive accumulation of mitochondrial DNA (mtDNA) in the cytoplasm, ultimately exacerbating downstream cGAS-STING pathway-mediated pyroptosis. This study revealed the potential health risks of SiNPs and helped to understand the differences in cytotoxicity caused by SiNPs of different sizes.
    Keywords:  cGAS-STING pathway; cardiotoxicity; mitophagy; pyroptosis; silica nanoparticles (SiNPs)
    DOI:  https://doi.org/10.1021/acs.jafc.5c01316
  40. Exp Hematol Oncol. 2025 Apr 10. 14(1): 56
    Correction: AOH1996 targets mitochondrial dynamics and metabolism in leukemic stem cells via mitochondrial PCNA inhibition.
    HyunJun Kang, Melissa Valerio, Jia Feng, Long Gu, Dinh Hoa Hoang, Amanda Blackmon, Shawn Sharkas, Khyatiben Pathak, Jennifer Jossart, Zhuo Li, Hongyu Zhang, Bin Zhang, Patrick Pirrotte, J Jefferson P Perry, Robert J Hickey, Linda Malkas, Guido Marcucci, Le Xuan Truong Nguyen.
      
    DOI:  https://doi.org/10.1186/s40164-025-00650-7
  41. Free Radic Biol Med. 2025 Apr 04. pii: S0891-5849(25)00208-4. [Epub ahead of print]
    Mitochondrial calcium uniporter regulates human fibroblast-like synoviocytes invasion via altering mitochondrial dynamics and dictates rheumatoid arthritis pathogenesis.
    Lakra Promila, Kabita Sarkar, Shivika Guleria, Adrija Rakshit, Manisha Rathore, Nishakumari C Singh, Shaziya Khan, Manendra Singh Tomar, Veena Ammanathan, Manoj Kumar Barthwal, Jagavelu Kumaravelu, Ashutosh Shrivastava, Kalyan Mitra, Rajdeep Guha, Amita Aggarwal, Amit Lahiri.
      Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease that currently has no cure. Fibroblast-like synoviocytes (FLS), present in the RA synovium, play a pivotal role in RA pathogenesis. Notably, FLS in the RA patients (RA-FLS) exhibit characteristics similar to cancer cells, like enhanced migration, invasiveness, uncontrolled proliferation, resistance to apoptosis, and metabolic reprogramming. RA-FLS invasiveness is linked to radiographic joint damage in the patients, whereas inhibiting the FLS migration mitigates disease pathology. However, the molecular mechanisms underlying the migration and invasion capabilities of RA-FLS are not entirely understood. In this work, we have explored the function of mitochondrial calcium uniporter (MCU) and calcium signaling in FLS invasion. Our findings demonstrate a positive correlation between MCU expression and RA disease score. Interestingly, mitochondrial size was reduced, and peripheral localization was more pronounced in the RA-FLS when compared to the control FLS. Mitochondrial calcium import inhibition in the FLS by specific MCU inhibitor, Ruthenium-360 restored these altered mitochondrial dynamics and reduced the invasive phenotype. Through unbiased transcriptome analysis, we identified that MCU-mediated calcium signaling in RA-FLS leads to the enriched actin cytoskeleton and focal adhesion pathways responsible for the invasion phenotype, which can be effectively suppressed by inhibiting MCU. Additionally, we found that mitochondrial transport facilitator Miro1 binds to MCU in a calcium-dependent manner and regulates MCU-mediated mitochondrial dynamics and RA-FLS invasion. Experiments utilizing mice xenograft model demonstrated that MCU silencing diminishes the migration of RA-FLS toward the sites of inflammation in the immunocompromised SCID mice. Altogether, our findings highlight MCU as a promising therapeutic target to inhibit RA-FLS migration and RA progression.
    Keywords:  Fibroblast-like synoviocytes; Rheumatoid arthritis; calcium; mitochondrial calcium uniporter; mitochondrial dynamics
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.04.008
  42. Mediators Inflamm. 2025 ;2025 3675276
    Mdivi-1 Attenuates Sepsis-Associated Acute Lung Injury by Inhibiting M1 Alveolar Macrophage Polarization and Pyroptosis.
    Xiaoyu Zhang, Hui Fan, Li Su, Yanni Wang, Guozhong Chen.
      Background: Dynamin-related protein 1 (DRP1)-dependent mitochondrial fission is a novel target for mitigating inflammatory diseases. This study aims to explore the effects of the DRP1 inhibitor Mdivi-1 on sepsis-induced acute lung injury (ALI). Methods: C57BL/6 mice were intraperitoneally injected with lipopolysaccharide (LPS) and then treated with or without Mdivi-1 2 h post-injection. RAW264.7 alveolar macrophages were stimulated with LPS and treated with or without NLRP3 inhibitors, Mito-TEMPO, or Mdivi-1. Hematoxylin and eosin (H&E) staining was used to observe pathological changes in lung tissues. The levels of inflammatory cytokines in lung tissue homogenates, serum, and cell culture medium were detected using enzyme-linked immunosorbent assays (ELISA). The mRNA expression of macrophage polarization markers, NLRP3 activation, and phosphorylation status of DRP1 were assessed. Flow cytometry was employed to evaluate the levels of macrophage apoptosis. Immunofluorescence was utilized to detect the levels of in vivo and in vitro macrophage polarization markers. Mitochondrial reactive oxygen species (Mito-ROS) were measured using a Mito-SOX assay kit. Results: Our results suggested that Mdivi-1 reduced lung tissue pathological injury, M1 alveolar macrophage polarization, NLRP3 activation, and DRP1 Ser616 phosphorylation. In vitro, LPS triggered abnormal accumulation of M1 polarization, NLRP3 activation, and excessive increase in Mito-ROS. NLRP3 inhibitors and Mito-TEMPO inhibited M1 alveolar macrophage polarization and pyroptosis-mediated tissue damage. Mito-TEMPO significantly inhibited NLRP3 activation. Furthermore, Mdivi-1 reduced ALI by inhibiting M1 polarization and pyroptosis. The mechanism of Mdivi-1 in reducing M1 alveolar macrophage polarization and pyroptosis may be related to the inhibition of DRP1-mediated mitochondrial fission, thus suppressing the Mito-ROS/NLRP3 pathway. Similar results were observed in vitro by knocking down DRP1. Conclusion: Inhibition of DRP1 by Mdivi-1 alleviates ALI by hindering Mito-ROS/NLRP3-mediated M1 alveolar macrophage polarization and pyroptosis, suggesting that DRP1-dependent mitochondrial fission is a potential therapeutic target for ALI.
    Keywords:  DRP1; M1 alveolar macrophage polarization; Mdivi-1; NLRP3 inflammasome; acute lung injury; pyroptosis
    DOI:  https://doi.org/10.1155/mi/3675276
  43. MicroPubl Biol. 2025 ;2025
    Neopterin extends C. elegans lifespan in an ATFS-1-dependent manner.
    Miina Pitkänen, Geoffray Monteuuis, Christopher B Jackson, Olli Matilainen.
      Neopterin, a byproduct of tetrahydrobiopterin synthesis, is commonly used as a biomarker for immune system activation. In addition to its role in immune responses, neopterin levels are known to increase with age. Its impact on longevity, however, remains unclear. Here, we demonstrate that neopterin supplementation extends lifespan in Caenorhabditis elegans . Additionally, neopterin shows moderate activation of the mitochondrial unfolded protein response (UPR mt ), and that the neopterin-mediated lifespan extension is dependent on ATFS-1 , the primary transcription factor regulating UPR mt . These findings highlight the need for further investigation into the biological functions and health-promoting effects of neopterin.
    DOI:  https://doi.org/10.17912/micropub.biology.001543
  44. Autophagy. 2025 Apr 07.
    BNIP3-mediated mitophagy in macrophages regulates obesity-induced adipose tissue metaflammation.
    Sangseob Kim, Cheoljun Choi, Yeonho Son, Junhyuck Lee, Sungug Joo, Yun-Hee Lee.
      Adipose tissue macrophages (ATMs) are key cellular components that respond to nutritional excess, contributing to obesity-induced inflammation and insulin resistance. However, the mechanisms underlying macrophage polarization and recruitment in adipose tissue during obesity remain unclear. In this study, we investigated mitophagy-dependent metabolic reprogramming in ATMs and identified a crucial role of the mitophagy receptor BNIP3 in regulating macrophage polarization in response to obesity. Mitophagic flux in ATMs increased following 12 weeks of high-fat diet (HFD) feeding, with Bnip3 levels upregulated in a HIF1A dependent manner, without affecting other mitophagy receptors. Macrophage-specific bnip3 knockout reduced HFD-induced adipose tissue inflammation and improved glucose tolerance and insulin sensitivity. Mechanistically, hypoxic conditions in vitro induced HIF1A-BNIP3-mediated mitophagy and glycolytic shift in macrophages. Furthermore, HIF1A-BNIP3 signaling-enhanced lipopolysaccharide-induced pro-inflammatory activation in macrophages. These findings demonstrate that BNIP3-mediated mitophagy regulates the glycolytic shift and pro-inflammatory polarization in macrophages and suggest that BNIP3 could be a therapeutical target for obesity-related metabolic diseases.
    Keywords:  Adipose tissue macrophages; BNIP3; hypoxia; inflammation; metabolic diseases; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2025.2487035
  45. J Inflamm Res. 2025 ;18 4665-4680
    VPS35-Retromer: Multifunctional Roles in Various Biological Processes - A Focus on Neurodegenerative Diseases and Cancer.
    Xiaoyang Fan, Yuqi Xie, Sitong Cao, Li Zhu, Xueting Wang.
      The Vacuolar Protein Sorting 35 (VPS35)-Retromer complex plays a pivotal role in intracellular protein trafficking and recycling. As an integral component of the Retromer complex, VPS35 selectively recognizes and retrogradely transports membrane protein receptors to the trans-Golgi network, thereby preventing the degradation of transmembrane proteins by lysosomes after they have fulfilled their physiological functions, and facilitating their continued activity. VPS35 regulates autophagy, mitophagy, mitochondrial homeostasis, and various other biological processes, including epidermal regeneration, neuronal iron homeostasis, and synaptic function. Studies have shown that mutations or dysfunctions in VPS35 disrupt the normal operation of Retromer, impair neuronal health and survival, and contribute to the onset of neurodegenerative diseases such as Parkinson's and Alzheimer's diseases. Additionally, VPS35 modulates tumor growth and metastasis in cancers such as liver and breast cancer through the regulation of multiple signaling pathways. Targeting VPS35 might be a potential therapy in clinic treatment of neurodegenerative diseases and cancers.
    Keywords:  Alzheimer’s disease; Parkinson’s disease; anemia; autophagy; cancer; endosome-lysosome pathway; mitochondrial homeostasis; retinal ganglion cell degeneration; retromer; vacuolar protein sorting 35
    DOI:  https://doi.org/10.2147/JIR.S510768
  46. bioRxiv. 2025 Mar 25. pii: 2025.03.24.645001. [Epub ahead of print]
    In situ cryo-ET visualization of mitochondrial depolarization and mitophagic engulfment.
    Kevin Rose, Eric Herrmann, Eve Kakudji, Javier Lizarrondo, A Yasemin Celebi, Florian Wilfling, Samantha C Lewis, James H Hurley.
      Defective mitochondrial quality control in response to loss of mitochondrial membrane polarization is implicated in Parkinson's disease by mutations in PINK1 and PRKN . Application of in situ cryo-electron tomography (cryo-ET) made it possible to visualize the consequences of mitochondrial depolarization at higher resolution than heretofore attainable. Parkin-expressing U2OS cells were treated with the depolarizing agents oligomycin and antimycin A (OA), subjected to cryo-FIB milling, and mitochondrial structure was characterized by in situ cryo-ET. Phagophores were visualized in association with mitochondrial fragments. Bridge-like lipid transporter (BLTP) densities potentially corresponding to ATG2A were seen connected to mitophagic phagophores. Mitochondria in OA-treated cells were fragmented and devoid of matrix calcium phosphate crystals. The intermembrane gap of cristae was narrowed and the intermembrane volume reduced, and some fragments were devoid of cristae. A subpopulation of ATP synthases re-localized from cristae to the inner boundary membrane (IBM) apposed to the outer membrane (OMM). The structure of the dome-shaped prohibitin complex, a dodecamer of PHB1-PHB2 dimers, was determined in situ by sub-tomogram averaging in untreated and treated cells and found to exist in open and closed conformations, with the closed conformation is enriched by OA treatment. These findings provide a set of native snapshots of the manifold nano-structural consequences of mitochondrial depolarization and provide a baseline for future in situ dissection of Parkin-dependent mitophagy.
    DOI:  https://doi.org/10.1101/2025.03.24.645001
  47. Biochem Biophys Res Commun. 2025 Apr 01. pii: S0006-291X(25)00449-8. [Epub ahead of print]761 151735
    Exosomal 4EBP1 promotes head and neck cancer progression via regulating mitochondrial fission.
    Iyyannar Madhu, Anbarasu Kannan.
      Head and neck cancer (HNC) is the sixth most common cancer around the globe with raised incidence and mortality. Despite the advancement in diagnostic and therapeutic approaches the burden of HNC has not reduced. Therefore, investigation on key molecular mechanisms that contributes to the progression of HNC is required to identify promising therapeutic targets. Exosomes are nanosized vesicles and recently emerged as a carrier of tumorigenic proteins essential for cancer progression. However, the role of exosomal proteins in HNC progression remains largely unclear. Eukaryotic Initiation Factor 4E-Binding protein 1 (4EBP1) regulates the protein synthesis and plays a crucial role in the progression of different forms of cancer. Our current study revealed that 4EBP1 is carried in human serum exosomes and upregulated in HNC serum exosomes than healthy controls (HC) and we observed that coculturing the 4EBP1 upregulated HNC serum exosomes (HNC Exo) promoted the growth and migration of HEp-2 cells. Further, we examined the underlying mechanism by knockdown of 4EBP1 in HEp-2 cells (4EBP1 KD). Our results showed that knockdown of 4EBP1 have suppressed the migration and progression of cancer cells. Mechanistically, knockdown of 4EBP1 downregulated mitochondrial fission modulators DRP1 and FIS1 and attenuated the migration of HNC cancer cells by suppressing TGFβ and upregulating PTEN. Together our findings suggest that 4EBP1 is upregulated in circulating exosomes and promotes HNC progression via modulating mitochondrial fission and could be a potential therapeutic target for HNC.
    Keywords:  4EBP1; DRP1; Exosomes; FIS1; Head and neck cancer; PTEN; TGFβ
    DOI:  https://doi.org/10.1016/j.bbrc.2025.151735
  48. Toxicology. 2025 Apr 05. pii: S0300-483X(25)00084-8. [Epub ahead of print] 154128
    Atrazine Exposure Induces TDP-43 Protein Translocation: A Potential Mechanism for Prefrontal Cortical Neurodegeneration Induced by Environmental Pollutants.
    Yuan Ma, Kaidong Wang, Yuxuan Jiao, Yujing Li, Rong Hu, Yang Li, Ge Shi, Min Huang.
      Atrazine (ATR) is a widely utilized herbicide that has been demonstrated to exert a multitude of deleterious effects on the environment, particularly with regard to water and soil contamination. Moreover, its disruption of endocrine function and implications for antibiotic resistance underscore the urgent need to prioritize alternative solutions for both ecosystems and human health. Therefore, the objective of this study was to investigate a range of neurotoxic effects associated with atrazine-induced damage in the prefrontal lobe of mice. The results of this study indicate that treatment with ATR in C57BL/6J mice resulted in cognitive-related behavioral deficits, including anxiety and depression, as well as motor impairments. In vivo analyses demonstrated that ATR exposure resulted in a reduction in neuronal synapse density at the microstructural level, while also compromising prefrontal morphological integrity, nociceptor count, and overall neuronal health within the brain. These findings collectively suggest that synaptic deficits are implicated in ATR-induced behavioral abnormalities observed in these mice. Furthermore, our findings revealed that ATR exposure resulted in elevated TDP-43 expression levels that were ectopically localized within the cytoplasm. This alteration led to impaired functionality of mRNP granules and contributed to the development of abnormal synaptic defects. Conversely, TDP-43 has the potential to localize ectopically to mitochondria, where it activates the mitochondrial unfolded protein response (UPRmt), which ultimately results in mitochondrial dysfunction. These findings collectively indicate a strong correlation between TDP-43 dysregulation and the progression of neurodegenerative diseases. Further investigation into the potential neurotoxicity of atrazine may foster heightened awareness, leading to more stringent regulatory measures, research into safer alternatives, and the adoption of sustainable practices, which are essential for safeguarding environmental integrity alongside human health.
    Keywords:  Atrazine，behavioral deficits，TDP-43 subcellular translocation，prefrontal lobe damage，neurotoxicity
    DOI:  https://doi.org/10.1016/j.tox.2025.154128
  49. Front Pharmacol. 2025 ;16 1526653
    Aconiti Lateralis Radix Praeparata ameliorates heart failure via PI3K/AKT/Bnip3 pathway.
    Wenxiu Liu, Xingju Zou, Yang Zheng, Yuan Zhang, Guijuan Cui, Siyu Liu, Chen Sun, Cheng Peng.
       Background: Chronic heart failure (CHF) is one of the leading causes of high mortality worldwide. It is characterized by pathological hypertrophy and poses a major threat to human health. Aconiti Lateralis Radix Praeparata is widely used in ancient China to treat CHF. However, the pathology is obscured, necessitating further exploration.
    Methods: Prospective targets were predicted by network analysis. A transverse aortic constriction (TAC) mice model was subsequently constructed to determine the effects of aqueous extract of Aconiti Lateralis Radix Praeparata (AEA) on CHF. The echocardiography was performed to investigate cardiac function. Histopathological analysis of cardiac tissue was conducted to assess myocardial fibrosis. Nontargeted metabolomics was performed to analyze serum metabolites. The phosphorylation level of PI3K and AKT, and downstream targets such as Bnip3, p62, Atg5, and LC3II were measured by Western blotting. In vitro, norepinephrine (NE) was used to stimulate cardiac hypertrophy. Parameters such as reactive oxygen species levels, mitochondrial membrane potential, ATP concentration, and CK/MB content were detected in H9c2 cells.
    Results: AEA significantly alleviated CHF. Network analysis indicated the participation of AKT in CHF, and was modulated by Aconiti Lateralis Radix Praeparata. In vivo, AEA administration effectively ameliorated cardiac performance, evidenced by the elevation of ejection fraction. Histopathological analysis displayed a diminishment of collagen fiber. Metabolomics analysis showed that several metabolites such as tetrahydroxycorticosterone, decylubiquinone and taurocholic acid were increased in the TAC mice serum. Additionally, the phosphorylation levels of PI3K and AKT, and expression levels of Drp1, Opa1, Bnip3, p62, Atg5 and LC3II were altered in TAC group. In vitro, NE stimulation increased the cell surface area and deteriorated mitochondrial functions in H9c2 cells. However, AEA administration partially reversed such results, and the mechanism was associated with mitophagy.
    Conclusion: This study revealed that AEA improved cardiac function via the PI3K/AKT/Bnip3 pathway.
    Keywords:  Aconiti Lateralis Radix Praeparata; chronic heart failure; metabolomics; network analysis; transverse aortic constriction
    DOI:  https://doi.org/10.3389/fphar.2025.1526653
  50. Anim Biotechnol. 2025 Dec;36(1): 2488068
    Identifying sex-based disparities in porcine mitochondrial function.
    Hao Liu, Wenshu Shi, Xing Zhang, Xinmiao He, Xingbo Zhao.
      In pigs, the effect of sex on production and reproductive traits has been largely reported, however, whether sex exerts its influence through regulating mitochondrial function is still unclear. In this study, we constructed 15 male cells and 15 female fibroblasts derived from 35-day and 50-day fetuses, newborn piglets and 1-year-old pigs to identify the sex effect on mitochondrial functions. Results indicated significant differences on cellular and molecular characteristics between male and female cells, including energy metabolic trait, mitochondrial DNA (mtDNA) replication and transcription, and mRNA expressions of mitochondrial biogenesis genes and mitoprotease genes. Referring to sex, males exhibited significantly higher oxygen consumption rate productions, levels of reactive oxygen species (ROS) and mtDNA copy numbers than those with females in muscle and ear fibroblasts. And the expressions of mtDNA, mitochondrial biogenesis genes (POLG, PPARGC1A, TFAM and TWNK) and XPNPEP3 were higher in males than females in ear fibroblasts derived from 1-year-old adult pigs (EFA cells). While, the cell proliferation and expressions of genes related to ROS metabolism were not influenced by sex. The results highlight the effect of sex on mitochondrial function and gene expression, and provide important data for a comprehensive understanding of the mechanisms underlying sex regulation of energy metabolism-related traits in pigs.
    Keywords:  Sex; mitochondrion; oxygen consumption rate; porcine; reactive oxygen species
    DOI:  https://doi.org/10.1080/10495398.2025.2488068
  51. Mol Med Rep. 2025 Jun;pii: 154. [Epub ahead of print]31(6):
    [Retracted] Grooved hydroxyapatite scaffold modulates mitochondria homeostasis and thus promotes osteogenesis in bone mesenchymal stromal cells.
    Chenglong Li, Lu Yang, Xiaohua Ren, Mu Lin, Daonan Shen, You Li, Xiangyu Zhang, Chunhui Liu, Yandong Mu.
      Following the publication of the above paper, it was drawn to the Editor's attention by a concerned reader that certain of the fluorescence microscopy images shown in Fig. 2C on p. 2805 were strikingly similar to data that had appeared previously in other papers written by different authors at different research institutes. In view of the fact that the abovementioned data had already apparently been published prior to its submission to Molecular Medicine Reports, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a satisfactory reply.  The Editor apologizes to the readership for any inconvenience caused. [Molecular Medicine Reports 22: 2801‑2809, 2020; DOI: 10.3892/mmr.2020.11352].
    Keywords:  bone mesenchymal stromal cells; hydroxyapatite scaffold; mitochondrial homeostasis; mitophagy; osteogenesis
    DOI:  https://doi.org/10.3892/mmr.2025.13519
  52. Front Nutr. 2025 ;12 1552890
    Luteolin attenuates LPS-induced damage in IPEC-J2 cells by enhancing mitophagy via AMPK signaling pathway activation.
    Jianyun Yuan, Ke Zhang, Lingling Yang, Xinyi Cheng, Jinyan Chen, Xiaoquan Guo, Huabin Cao, Caiying Zhang, Chenghong Xing, Guoliang Hu, Yu Zhuang.
       Background: Luteolin (LUT), a flavonoid compound widely present in natural plants, has been extensively studied for its diverse biological properties, involving anti-inflammatory,antioxidant, anti-apoptosis and other properties.
    Methods: The aim of this study was to investigate the effect of LUT on lipopolysaccharide (LPS)-induced Intestinal Porcine Epithelial Cell line-J2 (IPEC-J2 cells) damage and its underlying mechanism.
    Results: The experiment showed that LPS treatment induced injury in IPEC-J2 cells, leading to tight junction disruption, ROS accumulation, and cell apoptosis. Remarkably, LUT attenuated LPS-induced IPEC-J2 cells damage by the up-regulation of Zonula Occludens-1(ZO-1), Occludin, and Claudin protein 1 (Claudin-1) protein expression levels.Besides, LUT increased the activities of CAT, and SOD and prevented LPS-induced MDA and ROS production. LUT suppressed Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation in LPS-induced IPEC-J2 cells, reducing (Interleukin-1beta) IL-1β and Interleukin-6 (IL-6) expression. Moreover, LUT attenuated LPS-induced apoptosis in IPEC-J2 cells by up-regulating expression of B-cell lymphoma 2 (Bcl-2) and down-regulating expression of Cysteine-aspartic acid protease 3 (Caspase-3), Cysteine - aspartic acid protease 9 (Caspase-9) and Bcl-2-associated X protein (Bax). Furthermore, LUT upregulated the AMP-activated protein kinase (AMPK)/Unc-51 like autophagy activating kinase (ULK) signaling pathway and Parkin-RBR E3 ubiquitin protein ligase (Parkin)/PTEN induced putative kinase 1 (PINK1)-mediated mitophagy in a dose-dependent manner. When AMPK was knocked down by short-hairpin RNA (shRNA), the protective effects of LUT against LPS-induced IPEC-J2 cell damage were weakened, as evidenced by the accumulation of excessive ROS and impaired mitophagy.
    Conclusion: In summary, LUT exhibits the ability to protect against LPS-induced damage to intestinal tight junctions by enhancing mitophagy through AMPK activation.
    Keywords:  AMPK; IPEC-J2 cells; lipopolysaccharide; luteolin; mitophagy
    DOI:  https://doi.org/10.3389/fnut.2025.1552890
  53. Biol Direct. 2025 Apr 07. 20(1): 47
    Deubiquitination of DNM1L by USP3 triggers the development and metastasis of gallbladder carcinoma.
    Ruopeng Liang, Xiaoxue Zhang, Shitao Wu, Jing Liu, Yunpeng Zhai, Chaojie Lin, Zhenya Wang, Yi Zhang, Hao Chen, Rongtao Zhu.
       BACKGROUND: Patients diagnosed with gallbladder carcinoma (GBC) accompanied by hepatic metastasis exhibit unfavorable prognoses generally. Mitochondrial dysfunction promotes cellular transformation and cancer cell survival implicating its importance in cancer development. Previous studies have indicated that dynamin 1 like (DNM1L) is a key mediator of mitochondrial fission. However, whether DNM1L regulates mitochondrial homeostasis in GBC remains unknown.
    METHODS: The morphological changes of mitochondria were investigated by transmission electron microscopy and mitoTracker red staining. Co-immunoprecipitation assay was performed to detect the interaction of ubiquitin-specific protease-3 (USP3) and DNM1L. The cell-derived xenograft and liver metastasis tumor models were established to validate the function of DNM1L in vivo. The metabolomics data from transcriptomics/metabolomics were analyzed to identify the differentially expressed genes/metabolites of DNM1L in GBC.
    RESULTS: DNM1L exhibited a marked upregulation in clinical GBC tissues compared to the adjacent tissues, and it promoted proliferation, invasiveness, and migration capability of GBC cells by inducing mitochondrial dysfunction. Mice subcutaneously injected with DNM1L overexpression cells exhibited elevated intrahepatic metastatic nodules within their livers. USP3, a deubiquitinating enzyme, was demonstrated to directly interact with DNM1L and it specifically cleaved the K48-linked polyubiquitin chains to deubiquitinate and stabilize DNM1L. By integrating two omics, we found several altered pathways and speculated that DNM1L disturbed DNA synthesis and glycine, serine, threonine, and pyrimidine metabolism pathways.
    CONCLUSION: Our findings suggest that DNM1L is a promising clinical target for GBC treatment and that focusing on DNM1L may provide new insights into GBC strategy.
    Keywords:  DNM1L; Deubiquitination; Gallbladder cancer; Mitochondrial homeostasis; USP3
    DOI:  https://doi.org/10.1186/s13062-025-00637-8
  54. CNS Neurosci Ther. 2025 Apr;31(4): e70349
    Sanshen San Formula Hinders Cognitive Function and Pathology in Alzheimer's Disease Through Potentiating the Function of Synapse.
    Shiquan Chang, Nana Ding, Yalin Li, Ying Li, Ziling Tang, Junping Pan, Li Yan, Jiaxu Chen.
       BACKGROUND: Alzheimer's disease (AD) constitutes a devastating neurodegenerative disorder, manifested by amyloid-β aggregation, phosphorylated tau accumulation, and progressive cognitive deterioration. Current therapeutic interventions remain predominantly symptomatic, underscoring the urgency for more efficacious treatment strategies.
    PURPOSE: This study elucidated the therapeutic potential of Sanshen San (SSS), a traditional Chinese herbal formula encompassing Polygala Radix, Pini Radix in Poria, and Acori Tatarinowii Rhizoma, on cognitive function and AD pathology.
    METHODS: We implemented both acute Aβ1-42-injected mice and 5xFAD transgenic mouse models. The therapeutic efficacy of SSS was assessed through behavioral paradigms including Y-maze, Novel Object Recognition, and Morris Water Maze. Molecular mechanisms were delineated utilizing RNA sequencing, metabolomics analysis, immunofluorescence staining, Golgi-Cox staining, transmission electron microscopy, and Western blotting.
    RESULTS: Chemical analysis unveiled 10 principal bioactive compounds in SSS. The formula substantially ameliorated cognitive performance in both Aβ1-42-injected and 5xFAD mouse models, attenuated Aβ plaque burden, and augmented microglial phagocytosis. SSS safeguarded synaptic integrity, enhanced mitochondrial function, and facilitated autophagy. Transcriptomic and metabolomic analyses demonstrated that SSS predominantly operates by reinstating synaptic transmission and neurotransmitter function, particularly in the dopaminergic system.
    CONCLUSION: SSS efficaciously mitigates AD pathology through potentiating synaptic function, optimizing mitochondrial homeostasis, and restoring neurotransmitter balance, exemplifying a promising multi-target therapeutic strategy for the treatment of AD.
    Keywords:  Alzheimer's disease; Sanshen san formula; Traditional Chinese medicine; autophagy; neuron
    DOI:  https://doi.org/10.1111/cns.70349
  55. Biochim Biophys Acta Mol Cell Res. 2025 Apr 05. pii: S0167-4889(25)00057-6. [Epub ahead of print] 119952
    Browning of inguinal white adipose tissue by the novel lignan (-)-secoisolariciresinol 4-O-methyl ether attenuates diet-induced obesity through mitochondrial and Peroxisomal activation.
    Wenjun Jiao, Woo Yong Park, Yong-Il Kim, Jin-Hyung Kim, Beomsu Kim, Gahee Song, Ja Yeon Park, Se Jin Jung, Hyun Jeong Kwak, Seong-Kyu Choe, Jong-Hyun Lee, Jae-Young Um.
      Studies indicate that the induction and activation of brown and beige adipocytes, which can enhance energy expenditure, may be beneficial for managing obesity and its associated diseases. This study investigated whether a novel lignan (-)-secoisolariciresinol 4-O-methyl ether (S4M) obtained from arctigenin inhibited diet-induced obesity by the browning of white adipose tissue (WAT). S4M treatment inhibited adipogenesis and lipid accumulation in white-induced 3 T3-L1 adipocytes and in zebrafish embryonic development. Moreover, S4M treatment promoted browning in white adipocytes by increasing TOM20, UCP1, and PGC1α protein levels and consequently upregulating the mitochondrial content. S4M treatment significantly promoted mitochondrial fission by increasing the expression of DRP1. Furthermore, it enhanced peroxisome biogenesis and function by inducing PEX13, ACOX1, and catalase. Mdivi-1, a mitochondrial dynamics inhibitor, diminished the browning effect of white adipocytes by the S4M treatment. This study found that S4M treatment inhibited weight gain in high-fat diet-induced obese mice, decreased the weight of WAT, and increased the abundance and function of mitochondria and peroxisomes in inguinal WAT, suggesting that S4M treatment could increase energy expenditure. The results suggest that S4M has potential as a therapeutic agent for combating obesity and its associated metabolic disorders.
    Keywords:  (−)-secoisolariciresinol 4-O-methyl ether; Browning; Mitochondria; Obesity; Peroxisome
    DOI:  https://doi.org/10.1016/j.bbamcr.2025.119952
  56. Reprod Sci. 2025 Apr 11.
    The Regulation of ZAR1 on Apoptosis and Mitophagy in Ovarian Granular Cells and Primary Ovarian Insufficiency (POI) Mice.
    Xiaodong Zhao, Bin Mao, Jianwen Wang, Huabin Wang, Xiaoling Ma, Kehu Yang, Yongxiu Yang.
      Primary ovarian insufficiency (POI) has become a serious problem causing infertility and endocrine disorders in women of child-bearing age. There is an urgent demand for novel drugs or targets to address the apoptosis, autophagy and mitochondria damage associated with ovarian aging. This study focused on the regulation of zygote arrest 1 (ZAR1) in ovarian function and its potential role in POI. We collected clinical samples, established POI cell and mouse models using 4-vinylcyclohexene diepoxide (VCD), and investigated the effects of ZAR1 in KGN cells and POI mice. We found that ZAR1 expression was negatively associated with follicle-stimulating hormone (FSH) in POI women. ZAR1 overexpression inhibited apoptosis activation, cell cycle arrest and mitophagy, but the protection effects can be blocked by autophagy inhibitor. Mice with lower expression of ZAR1 exhibited more severe ovarian damages. These findings indicated that ZAR1 is a novel target for prevention and treatment of ovarian aging.
    Keywords:  Apoptosis; Autophagy; Ovarian granulosa cell; Primary ovarian insufficiency; ZAR1
    DOI:  https://doi.org/10.1007/s43032-025-01857-z
  57. Front Immunol. 2025 ;16 1566287
    Curcumin targets YAP1 to enhance mitochondrial function and autophagy, protecting against UVB-induced photodamage.
    Quan Chen, Wenxin Lin, Yi Tang, Fengmei He, Bihua Liang, Jiaoquan Chen, Huaping Li, Huilan Zhu.
       Background: Ultraviolet B (UVB) radiation is a major environmental factor contributing to skin damage via DNA damage, oxidative stress, inflammation, and collagen degradation. It penetrates the epidermis, disrupts DNA integrity, and generates reactive oxygen species (ROS), activating pro-inflammatory pathways such as NF-κB and AP-1, and inducing matrix metalloproteinases (MMPs). These processes lead to structural skin changes, inflammation, and pigmentation disorders like melasma. Cumulative DNA damage from UVB also drives photocarcinogenesis, with nearly 90% of melanomas associated with UV radiation (UVR). Despite clinical interventions like phototherapy and antioxidants, effective treatments for UVB-induced damage remain limited due to side effects and efficacy issues.
    Methods: This study investigates the protective effects of curcumin on UVB-induced skin damage using a mouse UVB irradiation model and HaCaT cells exposed to UVB in vitro. Skin damage was assessed through histopathological and immunohistochemical analyses. Cellular functional changes were evaluated using assays for cell viability, mitochondrial function, ROS levels, and apoptosis. Transcriptomic analysis was employed to elucidate the molecular mechanisms underlying curcumin's protective effects on HaCaT cells post-UVB exposure. This integrated approach provides a comprehensive understanding of curcumin's molecular-level protection against UVB-induced skin damage.
    Results: Curcumin significantly alleviated UVB-induced skin lesions and inflammation in vivo. In vitro, it mitigated UVB-induced HaCaT cell damage, enhancing viability while reducing apoptosis and ROS levels. Transcriptomic analysis revealed that curcumin upregulated YAP signaling and mitochondrial autophagy while suppressing IL-18 expression.
    Conclusion: Curcumin treatment markedly improved UVB-induced skin lesions and reduced epidermal inflammation and thickness in vivo. In vitro, curcumin intervention alleviated UVB-induced HaCaT cell damage, including reduced viability, increased apoptosis, elevated ROS and DNA damage, and enhanced inflammatory responses. Transcriptomic analysis demonstrated that curcumin upregulated the YAP signaling pathway and mitochondrial autophagy while inhibiting the IL-18 pathway. Further studies revealed that curcumin directly interacts with YAP1, promoting mitochondrial autophagy, an effect blocked by the YAP1 inhibitor Verteporfin. Additionally, curcumin enhances mitochondrial function through YAP1, maintaining mitochondrial integrity and preventing the release of mitochondrial DNA (mtDNA) and mitochondrial ROS (mtROS), thereby suppressing NLRP3/IL-18 pathway activation.
    Keywords:  UVB; YAP1; autophagy; curcumin; mitochondrial; photoprotection; skin damage
    DOI:  https://doi.org/10.3389/fimmu.2025.1566287
  58. Diagn Pathol. 2025 Apr 11. 20(1): 41
    A collaborative immunohistochemical study of Drp1 and cortactin in the epithelial dysplasia and oral squamous cell carcinoma.
    Marina Nader, Samar Soliman, Shaimaa M Yussif, Azza Abbas El-Sissi.
       OBJECTIVES: Oral squamous cell carcinoma (OSCC) accounts for more than 90% of oral malignancies. The poorly understood molecular and cellular mechanisms underlying the pathogenesis of OSCC remain a subject of paramount importance. For epithelial dysplasia, invasion, and metastasis to occur, tumor cells require energy obtained from the mitochondria and phenotypic cellular changes in the actin cytoskeleton. Dynamin-related protein1 (Drp1) is one of the main mitochondrial proteins regulating the mitochondrial dynamics. Cortactin is an actin-binding protein that promotes the actin polymerization and rearrangement. The interplay between both proteins in OSCC remains elusive. The current study aimed to investigate the immunohistochemical (IHC) expression of Drp1 and cortactin in tissues revealing propagating OSCC cases.
    METHODS: The retrospective study was carried out on 35 formalin-fixed paraffin sections of nodal metastasizing OSCC cases selected from the Oncology Centre, Faculty of Medicine, Mansoura University archives from 2018 to 2023. Immunohistochemistry for Drp1 and cortactin was done. The immune reactivity of both proteins was evaluated using computer-assisted digital image analysis. Statistical analysis was performed to identify significant differences and correlations between both markers in tissues associated with progressing OSCC cases using Chi-Square, Monte Carlo, One-Way ANOVA, and Spearman tests. The p-value less than 0.05 was considered statistically significant.
    RESULTS: Drp1 expression was statistically significant to grades of primary OSCC (p = 0.015), while insignificant to grades of epithelial dysplasia (p = 0.123) and metastatic lymph nodes (LNs) (p = 0.212). Statistically significant differences between dysplastic epithelium & primary tumor, dysplastic epithelium & metastatic LNs, and primary tumor and metastatic LNs were observed (p values were 0.014, 0.001, 0.034, respectively). On the other hand, Cortactin expression revealed no statistically significant differences across the three groups. However, statistically significant differences between dysplastic epithelium & primary tumor, dysplastic epithelium & metastatic LNs, and primary tumor and metastatic LNs were found (p values were 0.014, 0.001, 0.034, respectively). Moreover, the Spearman test presented a strong positive correlation between Drp1 and cortactin expression in the studied cases.
    CONCLUSION: Expressions of both Drp1 and cortactin relatively explain their great role in the propagation and the carcinogenesis of OSCC.
    Keywords:  Cortactin; Drp1; IHC; OSCC
    DOI:  https://doi.org/10.1186/s13000-025-01627-0
  59. J Cell Sci. 2025 Apr 11. pii: jcs.263651. [Epub ahead of print]
    NHR-85 modulates mitochondrial and lipid homeostasis to protect against α-synuclein aggregation in C. elegans.
    Dikaia Tsagkari, Maria Markaki, Nektarios Tavernarakis.
      Peroxisome proliferator-activated receptors (PPARs), such as PPARδ, are transcription factors that play a pivotal role in energy and fat metabolism. PPARδ activates genes involved in lipid and glucose metabolism and is expressed in various human tissues, including all brain regions and especially neurons, where it regulates lipid homeostasis and contributes to neuroprotection. However, the precise molecular mechanisms underlying these protective effects remain poorly understood. Here, we identify the Caenorhabditis elegans nuclear hormone receptor NHR-85 as a putative orthologue of human PPARδ. Furthermore, we show that NHR-85 functions as an essential regulator of fat and energy metabolism, with significant impact on mitochondrial homeostasis, at least in part through modulation of mitophagy. Finally, we find that NHR-85 prevents α-synuclein aggregation in a nematode model of Parkinson's disease, suggesting that it may play a protective role in neurodegenerative diseases. Our results indicate that NHR-85 is a functional orthologue of PPARδ and support the use of C. elegans as a powerful in vivo model for dissecting PPARδ-related metabolic and neurodegenerative processes.
    Keywords:  Fat metabolism; Mitochondrial homeostasis; Mitophagy; NHR-85; α-synuclein
    DOI:  https://doi.org/10.1242/jcs.263651
  60. J Biol Chem. 2025 Apr 08. pii: S0021-9258(25)00343-6. [Epub ahead of print] 108494
    HRI protein kinase in cytoplasmic heme sensing and mitochondrial stress response: relevance to hematological and mitochondrial diseases.
    Jane-Jane Chen.
      Most iron in humans is bound in heme used as a prosthetic group for hemoglobin. Heme-regulated inhibitor (HRI) is responsible for coordinating heme availability and protein synthesis. Originally characterized in rabbit reticulocyte lysates, HRI was shown in 1976 to phosphorylate the α-subunit of eIF2, revealing a new molecular mechanism for regulating protein synthesis. Since then, HRI research has mostly been focused on the biochemistry of heme inhibition through direct binding, and heme sensing in balancing heme and globin synthesis to prevent proteotoxicity in erythroid cells. Beyond inhibiting translation of highly translated mRNAs, eIF2α phosphorylation also selectively increases translation of certain poorly translated mRNAs, notably ATF4 mRNA, for reprogramming of gene expression to mitigate stress, known as the integrated stress response (ISR). In recent years, there have been novel mechanistic insights of HRI-ISR in oxidative stress, mitochondrial function and erythroid differentiation during heme deficiency. Furthermore, HRI-ISR is activated upon mitochondrial stress in several cell types, establishing the bifunctional nature of HRI protein. The role of HRI and ISR in cancer development and vulnerability is also emerging. Excitingly, the UBR4 ubiquitin ligase complex has been demonstrated to silence the HRI-ISR by degradation of activated HRI proteins, suggesting additional regulatory processes. Together, these recent advancements indicate that the HRI-ISR mechanistic axis is a target for new therapies for hematological and mitochondrial diseases, as well as oncology. This review covers the historical overview of HRI biology, the biochemical mechanisms of regulating HRI, and the biological impacts of the HRI-ISR pathway in human diseases.
    Keywords:  ATF4; E3 ubiquitin ligase; Erythropoiesis; Heme; Mitochondrial stress; Protein kinase; Protein synthesis; Proteostasis; Stress response; eIF2
    DOI:  https://doi.org/10.1016/j.jbc.2025.108494
  61. J Cell Biol. 2025 May 05. pii: e202410150. [Epub ahead of print]224(5):
    Rab GTPases are evolutionarily conserved signals mediating selective autophagy.
    Pengwei Zhao, Rui Tian, Dandan Song, Qi Zhu, Xianming Ding, Jianqin Zhang, Beibei Cao, Mengyuan Zhang, Yilu Xu, Jie Fang, Jieqiong Tan, Cong Yi, Hongguang Xia, Wei Liu, Wei Zou, Qiming Sun.
      Selective autophagy plays a crucial role in maintaining cellular homeostasis by specifically targeting unwanted cargo labeled with "autophagy cues" signals for autophagic degradation. In this study, we identify Rab GTPases as a class of such autophagy cues signals involved in selective autophagy. Through biochemical and imaging screens, we reveal that human Rab GTPases are common autophagy substrates. Importantly, we confirm the conservation of Rab GTPase autophagic degradation in different model organisms. Rab GTPases translocate to damaged mitochondria, lipid droplets, and invading Salmonella-containing vacuoles (SCVs) to serve as degradation signals. Furthermore, they facilitate mitophagy, lipophagy, and xenophagy, respectively, by recruiting receptors. This interplay between Rab GTPases and receptors may ensure the de novo synthesis of isolation membranes around Rab-GTPase-labeled cargo, thereby mediating selective autophagy. These processes are further influenced by upstream regulators such as LRRK2, GDIs, and RabGGTase. In conclusion, this study unveils a conserved mechanism involving Rab GTPases as autophagy cues signals and proposes a model for the spatiotemporal control of selective autophagy.
    DOI:  https://doi.org/10.1083/jcb.202410150
  62. Obes Res Clin Pract. 2025 Apr 04. pii: S1871-403X(25)00044-4. [Epub ahead of print]
    Excessive dietary fat and fructose enhance hepatic lipogenesis and impair mitochondrial dynamics to cause MASLD in C57BL/6 mice.
    Flávia Maria Silva-Veiga, Carolline Santos Miranda, Daiana A Santana-Oliveira, Aline Fernandes-da-Silva, Carlos A Mandarim-de-Lacerda, Vanessa Souza-Mello.
       OBJECTIVE: Metabolic dysfunction-associated steatotic liver disease (MASLD) affects around 1/3 of the worldwide population, with rising prevalence. Surplus fat and carbohydrate intake are crucial for MASLD onset. This study aimed to elucidate the interference of excess lipids and fructose (32 % as energy each), alone or in combination, on the hepatic energy metabolism of male mice.
    METHODS: Forty male C57BL/6 mice (3 months old) were randomly assigned to receive a control diet (C, 10 % of energy as soybean oil, n = 10), high-fat diet (HF, 32 % of energy as lard and 10 % as soybean oil, n = 10), high-fructose diet (HFRU, 32 % of energy as fructose, and 10 % as soybean oil, n = 10) or a diet rich in lipids and associated fructose (HF-HFRU, 32 % of energy as lard, 10 % as soybean oil, and 32 % of energy as fructose, n = 10) for 12 weeks.
    RESULTS: The increased consumption of saturated fat or fructose, isolated or in association, caused oral glucose intolerance, increased hepatic triacylglycerol and cholesterol, and enhanced the expression of proteins related to hepatic inflammation, lipogenesis, mitochondrial dysfunction, and ER stress, resulting in a marked increase in hepatic steatosis.
    CONCLUSION: Our results showed that high consumption of diets rich in lipids and fructose contributed to the development of MASLD and revealed an intimate relationship between altered mitochondrial dynamics and ER stress. Understanding the molecular pathways that regulate the accumulation of hepatic lipids can lead to promising therapies for MASLD.
    Keywords:  Fructose; Hepatic steatosis; Lipogenesis; MASLD; Mitochondria; Saturated fat
    DOI:  https://doi.org/10.1016/j.orcp.2025.03.007
  63. Nat Metab. 2025 Apr 09.
    The mitochondrial unfolded protein response inhibits pluripotency acquisition and mesenchymal-to-epithelial transition in somatic cell reprogramming.
    Zhongfu Ying, Yanmin Xin, Zihuang Liu, Tianxin Tan, Yile Huang, Yingzhe Ding, Xuejun Hong, Qiuzhi Li, Chong Li, Jingyi Guo, Gaoshen Liu, Qi Meng, Shihe Zhou, Wenxin Li, Yao Yao, Ge Xiang, Linpeng Li, Yi Wu, Yang Liu, Miaohui Mu, Zifeng Ruan, Wenxi Liang, Junwei Wang, Yaofeng Wang, Baojian Liao, Yang Liu, Wuming Wang, Gang Lu, Dajiang Qin, Duanqing Pei, Wai-Yee Chan, Xingguo Liu.
      The mitochondrial unfolded protein response (UPRmt), a mitochondria-to-nucleus retrograde pathway that promotes the maintenance of mitochondrial function in response to stress, plays an important role in promoting lifespan extension in Caenorhabditis elegans1,2. However, its role in mammals, including its contributions to development or cell fate decisions, remains largely unexplored. Here, we show that transient UPRmt activation occurs during somatic reprogramming in mouse embryonic fibroblasts. We observe a c-Myc-dependent, transient decrease in mitochondrial proteolysis, accompanied by UPRmt activation at the early phase of pluripotency acquisition. UPRmt impedes the mesenchymal-to-epithelial transition (MET) through c-Jun, thereby inhibiting pluripotency acquisition. Mechanistically, c-Jun enhances the expression of acetyl-CoA metabolic enzymes and reduces acetyl-CoA levels, thereby affecting levels of H3K9Ac, linking mitochondrial signalling to the epigenetic state of the cell and cell fate decisions. c-Jun also decreases the occupancy of H3K9Ac at MET genes, further inhibiting MET. Our findings reveal the crucial role of mitochondrial UPR-modulated MET in pluripotent stem cell plasticity. Additionally, we demonstrate that the UPRmt promotes cancer cell migration and invasion by enhancing epithelial-to-mesenchymal transition (EMT). Given the crucial role of EMT in tumour metastasis3,4, our findings on the connection between the UPRmt and EMT have important pathological implications and reveal potential targets for tumour treatment.
    DOI:  https://doi.org/10.1038/s42255-025-01261-6
  64. Br J Cancer. 2025 Apr 11.
    Repurposing chlorpromazine for the treatment of triple-negative breast cancer growth and metastasis based on modulation of mitochondria-mediated apoptosis and autophagy/mitophagy.
    Yamin Pu, Fuyan Xu, Anqi He, Ru Li, Xiangxiu Wang, Liang Zhou, Hongbao Sun, Yiwen Zhang, Yong Xia.
       BACKGROUND: Triple-negative breast cancer (TNBC) presents significant challenges due to its aggressive nature and high propensity for brain metastasis, often exhibiting resistance to standard treatments. In this study, we conducted a preliminary screening of potential therapeutic agents and identified chlorpromazine (CPZ) as a promising candidate for treating TNBC and its brain metastases.
    METHODS: The inhibitory activities of CPZ and its combination with several standard treatment drugs were evaluated in preclinical TNBC models. The mechanism of CPZ on TNBC was elucidated using TMT-labeled quantitative proteomics analysis.
    RESULTS: In vivo experiments demonstrated that CPZ robustly suppressed tumor growth and metastasis, particularly in lung and brain models. Importantly, CPZ enhanced the efficacy of standard therapeutic agents such as vinorelbine (NVB) and anti-PD-1 antibody. Mechanistically, CPZ induced G2/M phase arrest and triggered mitochondria-mediated intrinsic apoptosis in TNBC cells. Furthermore, CPZ triggered incomplete autophagy and activated PINK1-Parkin-mediated mitophagy. Inhibiting autophagy/mitophagy augmented CPZ's anticancer effects, indicating these processes may have cell protective roles.
    CONCLUSIONS: Our study highlights the dual function of CPZ in suppressing TNBC growth and metastasis, positioning it as a promising candidate for treating this aggressive cancer. Additionally, targeting autophagy/mitophagy may serve as an effective strategy to enhance anticancer therapies against TNBC.
    DOI:  https://doi.org/10.1038/s41416-025-02992-9
  65. Oncogenesis. 2025 Apr 11. 14(1): 9
    Myeloma mesenchymal stem cells' bioenergetics afford a novel selective therapeutic target.
    Oded Komemi, Elina Orbuch, Osnat Jarchowsky-Dolberg, Yaron Shraga Brin, Shelly Tartakover-Matalon, Metsada Pasmanik-Chor, Michael Lishner, Liat Drucker.
      Bone-marrow mesenchymal stem cells (BM-MSCs) rely on glycolysis, yet their trafficked mitochondria benefit recipient cells' bioenergetics in regenerative and cancerous settings, most relevant to BM-resident multiple myeloma (MM) cells. Fission/fusion dynamics regulate mitochondria function. Proteomics demonstrates excessive mitochondrial processes in BM-MSCs from MM patients compared to normal donors (ND). Thus, we aimed to characterize BM-MSCs (ND, MM) mitochondrial fitness, bioenergetics and dynamics with a focus on therapeutics. MM-MSCs displayed compromised mitochondria evidenced by decreased mitochondrial membrane potential (ΔΨm) and elevated proton leak. This was accompanied by stimulation of stress-coping mechanisms: spare respiratory capacity (SRC), mitochondrial fusion and UPRmt. Interfering with BM-MSCs mitochondrial dynamics equilibrium demonstrated their significance to bioenergetics and fitness according to the source. While ND-MSCs depended on fission, reducing MM-MSCs fusion attenuated glycolysis, OXPHOS and mtROS. Interestingly, optimization of mtROS levels is central to ΔΨm preservation in MM-MSCs only. MM-MSCs also demonstrated STAT3 activation, which regulates their OXPHOS and SRC. Targeting MM-MSC' SRC with Venetoclax diminished their pro-MM support and sensitized co-cultured MM cells to Bortezomib. Overall, MM-MSCs distinct mitochondrial bioenergetics are integral to their robustness. Repurposing Venetoclax as anti-SRC treatment in combination with conventional anti-MM drugs presents a potential selective way to target MM-MSCs conferred drug resistance.
    DOI:  https://doi.org/10.1038/s41389-025-00554-5
  66. Biochem Pharmacol. 2025 Apr 04. pii: S0006-2952(25)00194-7. [Epub ahead of print]237 116932
    Scutellarein ameliorates pulmonary arterial hypertension via sirtuin 1 mediated deacetylation of nicotinamide nucleotide transhydrogenase.
    Heng Tang, Ke Ning, Boji Wu, Xuhong Wang, Jingyu He, Pingping Li, Lina Pan, Jiawen Zhang, Yi He, Shizhu Bian, Xingyu Ma, Jihang Zhang, Chuan Liu, Zhexue Qin, Houyuan Hu.
      Scutellarein (Sc), a natural flavonoid, holds potential for treating pulmonary arterial hypertension (PAH), yet its mechanisms remain unexplored. This study investigated Sc's therapeutic effects and underlying pathways in PAH. In vivo experiments demonstrated that Sc significantly attenuated right ventricular hypertension, pulmonary arterial remodeling, αSMA expression, and vascular inflammation in PAH models. In vitro, Sc suppressed hypoxia-induced proliferation, migration, inflammation, and pyroptosis in human pulmonary artery smooth muscle cells (HPASMCs). Mechanistically, Sc activated the SIRT1/NAD+ axis to restore mitochondrial homeostasis: it upregulated SIRT1 expression and elevated NAD+ levels by promoting SIRT1-mediated deacetylation of nicotinamide nucleotide transhydrogenase (NNT), thereby enhancing NNT activity. Elevated NAD+ further activated SIRT1, forming a self-reinforcing SIRT1/NNT/NAD+ feedback loop that mitigated hypoxia-induced mitochondrial dysfunction. This study identifies Sc as a novel regulator of the SIRT1-dependent NNT deacetylation pathway, which stabilizes NAD+ homeostasis to counteract HPASMCs dysregulation in PAH. These findings highlight Sc's potential as a therapeutic candidate for PAH, offering insights into targeting mitochondrial-metabolic pathways for vascular remodeling diseases.
    Keywords:  Mitochondria; Nicotinamide nucleotide transhydrogenase; Pulmonary arterial hypertension; Pulmonary artery smooth muscle cells; Scutellarein; Sirtuin 1
    DOI:  https://doi.org/10.1016/j.bcp.2025.116932
  67. Phytomedicine. 2025 Apr 01. pii: S0944-7113(25)00354-X. [Epub ahead of print]141 156714
    Bazibushen attenuates fibroblast senescence in silica-induced pulmonary fibrosis via FOXO1/PINK1/Parkin Axis.
    Siyun Zhou, Lan Peng, Yue Wang, Demin Cheng, Ziwei Li, Haojie Xiong, Ting Wang, Yi Liu, Zhenhua Jia, Wenqing Sun, Chunhui Ni.
      Silicosis, an age-related disease, is still a heavy burden on global occupational health. Emerging evidence has revealed that targeting senescent cells may be a promising therapeutic strategy for silicosis. This study was designed to investigate the novel function of Bazibushen (BZBS), a known anti-aging drug, in improving silica-induced lung fibrosis. We first confirmed the accumulation of senescent fibroblasts in the fibrotic regions of silicotic lungs. In both young (6-8 weeks) and aged (12 months) silicotic mice, BZBS exhibited anti-fibrosis and anti-senescence effects. Results of in vitro experiments showed the ability of BZBS to block the expression of p21, fibrotic markers, and senescence-associated secretory phenotype factors. Furthermore, BZBS was observed to attenuate mitochondrial dysfunction in senescent fibroblasts through FOXO1/PINK1/Parkin signaling. Collectively, these results indicated BZBS as a potential anti-fibrosis agent, which exerted its role through maintaining mitochondrial homeostasis in senescent fibroblasts.
    Keywords:  Bazibushen; Cellular senescence; Fibroblasts; Mitochondrial homeostasis; Silicosis
    DOI:  https://doi.org/10.1016/j.phymed.2025.156714
  68. J Hepatol. 2025 Apr 04. pii: S0168-8278(25)00219-3. [Epub ahead of print]
    Cisplatin-induced Disruption of Mitochondrial Divisome Leads to Enhanced Cisplatin Resistance in Cholangiocarcinoma.
    Guo-Yue Lv, Wen-Tao Mu, Yan-Nan Cao, Xiao-Dong Sun, Feng Wei, Kai-Yuan Chai, Bo Huang, Jian-Peng Zhou, Chuan-Lei Wang, Ming-Yue Li, Xiao-Hong Du, Wei Qiu, Meng Wang, Xiao-Ju Shi, Jun-Feng Ye, Xing-Kai Liu, He-Yu Huang, Yu-Guo Chen, Zhao-Ming Gou, Ping Zhang, Ya-Hui Liu, Guang-Yi Wang, Zhong-Qi Fan.
       BACKGROUND & AIMS: Cisplatin (CDDP)-based chemotherapy is the primary treatment for advanced cholangiocarcinoma (CCA), but its clinical efficacy is limited. Mitochondrial divisome (MD) is crucial for regulating mitochondrial division, but their roles in CDDP resistance remain unclear.
    METHODS: Alternations of mitochondrial morphology, expression levels and localization of MD components in CCA under CDDP treatment were evaluated using fluorescence labeling and mitochondrial isolation at cellular and organoid levels. Gene editing and other strategies demonstrated the link between mitochondrial hyperfusion and CDDP resistance. RNA sequencing revealed altered molecular landscapes in CCA cells following CDDP exposure. Mass spectrometry and immunoprecipitation were mainly adopted to explore the mechanisms of actin-binding protein, INF2 (inverted formin-2) degradation. Endoplasmic reticulum (ER)-phagy was characterized using stable transfection of ssRFP-GFP-KDEL. The clinical significance of INF2 was assessed by analyzing tumor samples of 438 CCA patients using tissue microarray. Combination therapy efficacy was validated in cell line and patient-derived xenograft mice models.
    RESULTS: CDDP dramatically damaged various MD components, such as increased F-actin peripheral polymerization, decreased ER colocalization with mitochondria, and INF2 degradation. These events promoted adaptive mitochondrial hyperfusion, paradoxically contributing to CDDP resistance in CCA. INF2 plays a pivotal role in MD-associated CDDP resistance, with its degradation primarily occurring through the proteasome pathway and SEC62-mediated ER-phagy. Inhibiting these pathways increased CDDP sensitivity in CCA, whereas targeting other MD components failed.
    CONCLUSIONS: We proposes a novel feasible treatment strategy to reverse CDDP resistance in CCA through targeting mitochondria morphology. Our study highlights the importance of monitoring dynamic changes at the protein and organelle levels during anticancer treatment, providing robust evidence for functional precision oncology.
    IMPACT AND IMPLICATIONS: This study identifies that high INF2 expression at baseline is associated with poor prognosis in cholangiocarcinoma (CCA) patients. Moreover, cisplatin-induced INF2 degradation via proteasomal and SEC62-mediated ER-phagy is revealed as a key driver of mitochondrial hyperfusion and chemoresistance in CCA. It establishes mitochondrial morphology targeting as a novel strategy to overcome chemotherapy resistance. Furthermore, this study emphasizes the need to focus on dynamic changes in tumor proteins or organelle functions during treatment (functional precise oncology), rather than limiting analysis to static tumor states. Given that inhibition of oncogenes may lead to potential resistance mechanisms, comprehensive preclinical evaluations are essential before clinical application.
    Keywords:  Cisplatin resistance; ER-phagy; INF2; SEC62; cholangiocarcinoma; mitochondrial divisome
    DOI:  https://doi.org/10.1016/j.jhep.2025.03.028
  69. Biochim Biophys Acta Mol Basis Dis. 2025 Apr 02. pii: S0925-4439(25)00169-3. [Epub ahead of print]1871(5): 167824
    Aminolevulinate/iron exposure elicited Nrf-2-mediated cytoprotection in DARS2 deficient fibroblasts with impaired energy and antioxidant metabolisms.
    Wei-Lin Huang, Tuany Eichwald, Alexander Stover, Milad Gazanfari, Philip H Schwartz, Alexandra Latini, Jose E Abdenur.
      Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation (LBSL) is a disorder caused by mutations in the mitochondrial aspartyl-tRNA synthetase gene DARS2, which compromises mitochondrial protein translation. The typical presentation is juvenile in onset with gradually progressive spasticity and ataxia. Only palliative treatment is available for LBSL individuals. Here we showed that the use of the Food and Drug Administration-approved heme precursors, aminolevulinate plus ferrous iron (ALA/Fe), can result in a novel pharmacological treatment that increases energy status in DARS2 deficient cells. The marked mitochondrial and antioxidant deficiencies observed in fibroblasts from two LBSL-affected brothers, harboring intron-2 (c.228-17C > G) and intron-5 (c.492 + 2 T > C) DARS2 mutations, were rescued by ALA/Fe exposure, and the use of dexamethasone, a known Nrf-2 inhibitor, blocked the positive effects of ALA/Fe. Altogether, this study showed that fibroblasts can be used as a biological system to identify potential new treatments for LBSL that can reduce morbidity and mortality, and that the activation of Nrf-2-mediated cytoprotection can be targeted for the treatment of LBSL and other mitochondrial diseases.
    Keywords:  Antioxidant enzymes; Free radicals; Mitochondrial biogenesis; Mitochondrial capacity; Mitochondrial disorders; Respiratory chain complexes
    DOI:  https://doi.org/10.1016/j.bbadis.2025.167824
  70. Front Pharmacol. 2025 ;16 1446574
    Genipin attenuates oxidative damage in periodontal tissues by alleviating mitochondrial dysfunction and abnormal glucose uptake through inhibition of UCP2.
    Yu Deng, Ruobing Fu, Yaqi Shang, Mengting Hu, Xirui Xin, Yubo Hou, Weixian Yu, Xinchan Liu.
       Introduction: Periodontitis is a chronic inflammatory disease closely associated with mitochondrial dysfunction. Uncoupling protein 2 (UCP2), located in the inner membrane of mitochondria, reduces mitochondrial membrane potential (MMP) and adenosine triphosphate (ATP) synthesis by promoting proton leakage across the membrane. This leads to decreased energy metabolism efficiency, impairing cellular glucose uptake, and disrupting intracellular energy balance. Genipin (GP), a recognized UCP2 inhibitor, exhibits anti-inflammatory and antioxidant properties. This study aimed to investigate the specific role of GP in periodontal tissue redox signaling and the potential mechanism of UCP2 in the development of periodontitis.
    Methods: In this study, we constructed a model of H2O2-induced oxidative stress in human periodontal ligament cells (hPDLCs). In vivo, a rat periodontitis model was established to evaluate the effects and mechanisms of GP in alleviating oxidative damage in periodontal tissues and cells.
    Results: Cell experiments showed that GP effectively alleviated H2O2-induced mitochondrial dysfunction and oxidative damage in hPDLCs by inhibiting UCP2 expression and function, restoring cell viability, and reducing cell apoptosis. Additionally, GP intervention increased the expression of glucose transporter 4 (GLUT4), thereby promoting cellular glucose uptake. The results of animal experiments demonstrated that GP intervention reduced alveolar bone resorption and periodontal tissue destruction in rats with periodontitis, inhibited osteoclast differentiation, improved mitochondrial dysfunction in periodontal tissue, promoted GLUT4 expression, and reduced oxidative stress levels and cell apoptosis.
    Discussion: GP regulates oxidative damage in periodontal tissues by maintaining mitochondrial homeostasis, promoting glucose transporter expression, and enhancing glucose uptake, with UCP2 playing a central role.
    Keywords:  UCP2; genipin; glucose uptake; mitochondrial dysfunction; periodontitis
    DOI:  https://doi.org/10.3389/fphar.2025.1446574
  71. Commun Biol. 2025 Apr 09. 8(1): 585
    Regulating Sirtuin 3-mediated mitochondrial dynamics through vanillic acid improves muscle atrophy in cancer-induced cachexia.
    Gahee Song, Jinbong Park, Yunu Jung, Woo Yong Park, Ja Yeon Park, Se Jin Jung, Beomsu Kim, Minji Choi, Sang Hee Kim, Seong-Kyu Choe, Hyun Jeong Kwak, Junhee Lee, Kil Yeon Lee, Kwang Seok Ahn, Jae-Young Um.
      Cancer cachexia is a cancer-associated disease characterized by gradual body weight loss due to pathologic muscle and fat loss, but effective treatments are still lacking. Here, we investigate the possible effect of vanillic acid (VA), known for its antioxidant, anti-inflammatory, and anti-obesity effects, on mitochondria-mediated improvement of cancer cachexia. We utilized cachexia-like models using CT26 colon cancer and dexamethasone. VA improved representative parameters of cancer cachexia including body weight loss and increased serum intereukin-6 levels. VA also attenuated muscle loss in the tibialis anterior and gastrocnemius muscles, inhibited proteolytic markers including muscle RING-finger protein-1 (MURF1) and muscle atrophy F-box (MAFbx) and improved mitochondrial function through alteration of sirtuins 3 (SIRT3) and mitofusin 1 (MFN1). Importantly, silencing the SIRT3 gene abolished the effect of VA, indicating that SIRT3 is important in the mechanism of action of VA. Overall, we suggest using VA as a novel therapeutic agent that can fundamentally treat and recover muscle atrophy in cancer cachexia patients.
    DOI:  https://doi.org/10.1038/s42003-025-07770-0
  72. Signal Transduct Target Ther. 2025 Apr 04. 10(1): 121
    Correction: Small molecule induces mitochondrial fusion for neuroprotection via targeting CK2 without affecting its conventional kinase activity.
    Ke-Wu Zeng, Jing-Kang Wang, Li-Chao Wang, Qiang Guo, Ting-Ting Liu, Fu-Jiang Wang, Na Feng, Xiao-Wen Zhang, Li-Xi Liao, Mei-Mei Zhao, Dan Liu, Yong Jiang, Pengfei Tu.
      
    DOI:  https://doi.org/10.1038/s41392-025-02218-7
  73. Mol Neurobiol. 2025 Apr 08.
    Epigenetics and Mitochondrial Biogenesis: The Role of Sirtuins in HIV Neuropathogenesis.
    James Haorah, Hemavathi Iyappan, Malaroviyam Samikkannu, Karthick Chennakesavan, Jay P McLaughlin, Thangavel Samikkannu.
      Mitochondrial energy deficits play a central role in HIV-associated neurocognitive disorder (HAND). HIV disrupts cellular functions, including epigenetic modifications such as class III histone deacetylation mediated by sirtuins (SIRTs). However, the role of SIRTs in HAND pathogenesis remains unclear. We hypothesize that HIV alters mitochondrial biogenesis and energy homeostasis by modifying SIRT family members 1-7, contributing to HAND progression. To test this hypothesis, we examined postmortem frontal lobe brain tissue from people with HIV (PWH) and HIV-negative controls, focusing on epigenetic alterations in SIRTs 1-7, the energy sensor adenosine monophosphate-activated protein kinase (AMPK), the mitochondrial master regulator peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), and transcription factors such as mitochondrial transcription factor A (TFAM), nuclear respiratory factors 1 and 2 (NRF-1/2), and factors associated with oxidative phosphorylation (OXPHOS). Our analysis revealed a significant increase in AMPK, OXPHOS, and PGC-1α levels, alongside a decrease in TFAM levels in PWH brains compared to uninfected controls. NRF-1 was upregulated in mitochondria but downregulated in the cytoplasm, while NRF-2 exhibited the opposite trend in PWH compared to HIV-negative controls. The epigenetic signatures of SIRTs 1, 2, 3, 4, 6, and 7 were upregulated in PWH, while SIRT5 was downregulated compared to uninfected brain tissues. We exposed primary human astrocyte and microglial cultures to the HIV-1 transactivator of transcription (Tat) protein to identify the cell types involved. These studies confirmed that HIV-induced epigenetic modifications of SIRTs and mitochondrial impairments occurred in both astrocytes and microglia, highlighting the crucial role of SIRTs in HAND pathogenesis.
    Keywords:  Epigenetic modification; HAND; HIV; Mitochondrial biogenesis; Sirtuins
    DOI:  https://doi.org/10.1007/s12035-025-04885-7
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