bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2025–12–21
fifty-five papers selected by
Gavin McStay, Liverpool John Moores University
  1. ZLN005 Alleviates the Dopaminergic Degeneration via PGC-1α-Mediated Mitochondrial Homeostasis in Parkinson's Disease.
  2. Corrigendum to: "Moderate Mechanical Stress Suppresses the IL-1β-Induced Chondrocyte Apoptosis by Regulating Mitochondrial Dynamics".
  3. [The miR-30b/USP14 axis regulates mitophagy via a non-PINK1/Parkin pathway in neuronal oxygen-glucose deprivation/reoxygenation injury].
  4. Mitochondrial Dysfunction Drives Oxidative Stress and Energy Imbalance in a Murine Model of Spondyloarthritis.
  5. VPS13B recruits lipid vesicles to promote mitochondrial fission and quality control.
  6. Pharmacological Activation of Mitophagy Confers Neuroprotective Benefits for Amyotrophic Lateral Sclerosis.
  7. Exploring new benefits of vitamin A: alleviating hypoxia-induced mitochondrial stress and mitophagy in the gills of adult grass carp (Ctenopharyngodon idellus).
  8. Sevoflurane Postconditioning Regulates Mitophagy Through the PINK1/Parkin Pathway to Alleviate Myocardial Microcirculatory Reperfusion Injury.
  9. Ursolic Acid Ameliorates Doxorubicin-induced Cardiotoxicity by Inhibiting DRP1-mediated Excessive Mitochondrial Fission and Oxidative Stress.
  10. Genetic disruption of mitochondrial dynamics and stasis leads to liver injury and tumorigenesis.
  11. Spermidine deficiency induces BNIP3/LC3B-mediated mitophagy in the salivary glands of accelerated aging mice.
  12. Two genomes, one destiny: Mitophagy at the crossroads of inheritance and disease.
  13. MISO regulates mitochondrial dynamics and mtDNA homeostasis by establishing membrane subdomains.
  14. SIRT3/AMPK-Driven Mitophagy Failure Underlies Methylmercury-Induced Neurotoxicity: Evidence from Humans to Cells.
  15. Distinct Roles of Urolithin A and Spermidine in Mitophagy and Autophagy: Implications for Dietary Supplementation.
  16. Pharmacological Inhibition of miR-126 Enhances Venetoclax Activity in Acute Myeloid Leukemia.
  17. Drp1 Interaction with BIP Maintains Mitochondrial Dynamic Equilibrium to Promote Anoikis Resistance and Metastasis in Nasopharyngeal Carcinoma.
  18. CRISPR/Cpf1-mediated editing of PINK1 in induced pluripotent stem cells.
  19. Retraction: Resveratrol improves mitochondrial biogenesis function and activates PGC-1α pathway in a preclinical model of early brain injury following subarachnoid hemorrhage.
  20. Morin, a Natural Flavonoid, Activates the PINK1/Parkin Pathway to Induce Mitophagy, Promote Apoptosis, and Suppress Cancer Stemness in Pancreatic Cancer.
  21. Mechano-metabolic dysregulation in osteoarthritis: Piezo1-mediated mitophagy impairment as a novel therapeutic target.
  22. Unraveling the role of mitochondrial unfolded protein response in colorectal cancer.
  23. Melatonin alleviates atherosclerosis by inhibiting pro-inflammatory differentiation of macrophages via regulating Sirt3-Drp1 mediated mitochondrial fission.
  24. Investigation of Glaucocalyxin A Mechanism in Alleviating Atopic Dermatitis via the HMGB1-RAGE-RhoA/ROCK1-Mediated Mitochondrial Pathway.
  25. Qiang-Xin 1 formula improves cardiac function and alleviates myocardial injury in lipopolysaccharide-induced septic mice by activating calcium/calmodulin-dependent protein kinase I-mediated mitophagy.
  26. Activation of mitophagy antagonizes high uric acid-induced hepatic lipid accumulation.
  27. The microRNA miR-71 suppresses maladaptive UPRmt signaling through both cell-autonomous and cell-non-autonomous mechanisms.
  28. GATA-1-driven TOMM20-mediated mitophagy regulates PDLSCs osteogenesis and enhances periodontal bone regeneration.
  29. Pathogen-induced mitochondrial dysfunction: mechanistic insights, immune crosstalk, and therapeutic opportunities.
  30. Vesicle-mediated mitochondrial clearance presents an actionable metabolic vulnerability in triple-negative breast cancer.
  31. Targeting trophoblast cell mitochondrial dysfunction in preeclampsia via drug repurposing.
  32. Redox switch C674 in SERCA2 triggers Ca2+-calcineurin-MCU-Drp1 cascade and pulmonary vascular remodeling.
  33. Uncovering the muscle clock-mitochondria axis through exercise.
  34. Intestinal γδ T17-IL-17A signaling disrupts hippocampal mitophagy in stress-induced depression and is restored by arketamine.
  35. Hydrogen Gas Alleviates Sepsis-Induced Brain Injury by Improving Mitochondrial Biogenesis Through the Activation of PGC-α in Mice: Erratum.
  36. CAMK1D activates AMPK/PINK1/Parkin-dependent mitophagy to promote enzalutamide resistance in prostate cancer.
  37. Bioenergetic and protein processing imbalances in iPSC-dopamine neurons from individuals with idiopathic Parkinson's disease.
  38. A Tetrahedral DNA Framework-Based Mitochondrial Anchoring System Promotes Diabetic Wound Healing via Mitophagy and Mitostress Regulation.
  39. Mitochondria-derived vesicles serve as reactors in response to stress in cardiomyocytes.
  40. A novel role of Mef2a in mitochondrial homeostasis and muscle regeneration during sarcopenia.
  41. FIP200 regulates plasma B cell differentiation via mitochondrial and heme homeostasis.
  42. ACSS2-mediated acetyl-CoA accumulation promotes mitophagy and tumor growth via increased H3K27ac in HBV-related HCC.
  43. CD4+ T-cell-derived small extracellular vesicles induce the apoptosis of renal tubular epithelial cells in diabetic nephropathy by regulating mitochondrial dynamics.
  44. Mutant CHCHD10 disrupts cytochrome c oxidation and activates mitochondrial retrograde signaling.
  45. Endothelial mitochondrial-derived vesicles (EMDVs) with retinal targeted homing properties dynamically modulate the eIF2α-ATF4-CHOP signaling pathway and efficiently restore mitochondrial homeostasis in diabetic retina.
  46. LncRNA-encoded peptide LRRC75A-AS1-ORF3 suppresses anti-tumor immunity in colorectal cancer through mitophagy-mediated attenuation of cGAS-STING signaling.
  47. Gallic acid attenuates diabetic cardiomyopathy by inhibiting ferroptosis and protecting mitochondria via the TSPO/FTMT pathway.
  48. Cannabidiol attenuates the LPS/D-Galactosamine-induced acute liver injury by inhibiting parkin-mediated ubiquitination of MFN2.
  49. Enoxaparin preserves cellular morphology and modulates mitophagy-associated Parkin-LC3 in acute ischemic rat myocardium.
  50. Mitophagy and Bip-PERK-eIF2α-ATF4 Axis-Mediated ER Stress Mediate Miriplatin-Loaded Liposome's Anti-Colorectal Cancer Action.
  51. Targeting long-chain acylcarnitine accumulation to protect cardiac mitochondrial homeostasis after complete revascularization.
  52. Correction: Novel small molecule derivatives improve survivability in the cellular model of Huntington's disease via improving mitochondrial fusion.
  53. Celastrol induces cardiotoxicity by directly targeting AMOTL2 and inhibiting YAP1/PGC-1α/TFAM-dependent mitochondrial biogenesis.
  54. TMEM65-dependent Ca2+ extrusion safeguards mitochondrial homeostasis.
  55. Telmisartan ameliorates reproductive dysfunction, oxidative stress, and mitochondrial damages induced by fipronil in male rats via regulation of Nrf2/HO-1/PGC-1α/MNF2/DRP1.
  1. Mol Neurobiol. 2025 Dec 16. 63(1): 303
    ZLN005 Alleviates the Dopaminergic Degeneration via PGC-1α-Mediated Mitochondrial Homeostasis in Parkinson's Disease.
    Jasleen Kaur, Saba Naqvi.
      Parkinson's disease (PD) is a neurodegenerative condition marked by significant motor impairments, resulting from extensive loss of dopaminergic neurons and abnormal protein aggregation. One of the early features of PD is disrupted mitochondrial dynamics, which arises from imbalances in cellular energy regulation. Therapeutic strategies that mitigate the mitochondrial dysfunction and enhance mitochondrial performance offer neuroprotection in PD. To delve into the role of mitochondrial function, we employed the synthetic PGC-1α activator ZLN005 to improve PD outcomes. In cellular PD model, we performed western blotting and immunofluorescence assays to assess disease-specific markers, including tyrosine hydroxylase and proteins related to mitochondrial biogenesis and regulation. Mitochondrial function was further evaluated using MitoTracker and ROS detection. We further investigated ZLN005 in a sub-acute MPTP mouse model. Motor performance was assessed, and subsequently, molecular analyses were conducted. Our findings revealed that ZLN005 significantly reduced MPP+/MPTP-induced neurotoxicity, improved motor deficits, and maintained the expression of PGC-1α, tyrosine hydroxylase, and other key mitochondrial markers involved in DNA replication and mitophagy. Notably, proteins that enhance PGC-1α transcription, including SIRT1, were also upregulated. In addition, the expression of mitochondrial fusion proteins increased, a pattern supported by elevated levels of other transcriptional regulators. Imaging and flow cytometry further confirmed that PGC-1α activation improved mitochondrial integrity and reduced oxidative stress. These results provide preliminary insights into the potential therapeutic role of PGC-1α activator in PD. ZLN005 has a neuroprotective effect in PD, which is elaborated by PGC-1α activator regulating the mitochondrial quality control system.
    Keywords:  Mitochondrial biogenesis; Mitophagy; PGC-1α activator; Parkinson’s disease
    DOI:  https://doi.org/10.1007/s12035-025-05612-y
  2. J Cell Physiol. 2025 Dec;240(12): e70125
    Corrigendum to: "Moderate Mechanical Stress Suppresses the IL-1β-Induced Chondrocyte Apoptosis by Regulating Mitochondrial Dynamics".
      
    DOI:  https://doi.org/10.1002/jcp.70125
  3. Zhongguo Dang Dai Er Ke Za Zhi. 2025 Dec 15. pii: 1008-8830(2025)12-1526-09. [Epub ahead of print]27(12): 1526-1534
    [The miR-30b/USP14 axis regulates mitophagy via a non-PINK1/Parkin pathway in neuronal oxygen-glucose deprivation/reoxygenation injury].
    Yu-Hang Bei, Kang Yu, Xia Wang.
       OBJECTIVES: To investigate how miR-30b regulates mitophagy independently of the PINK1/Parkin pathway by targeting ubiquitin specific peptidase 14 (USP14) in neuronal oxygen-glucose deprivation/reoxygenation (OGD/R) injury, and to provide new insights for the treatment of neonatal hypoxic-ischemic encephalopathy.
    METHODS: Fetal rat cortical neurons were isolated and an OGD/R model was established. Experiments were conducted in two parts. In part 1, cells were randomized into control, OGD/R, OGD/R+microRNA (miR)-negative control (NC), OGD/R+miR-30b mimic, OGD/R+miR-30b mimic+oe-NC, and OGD/R+miR-30b mimic+oe-USP14 groups. In part 2, cells were randomized into control, OGD/R, OGD/R+miR-NC, OGD/R+miR-30b mimic, OGD/R+miR-30b mimic+si-NC, OGD/R+miR-30b mimic+si-Parkin, and OGD/R+miR-30b mimic+si-Drp1 (dynamin-related protein 1) groups. miR-30b and USP14 mRNA levels were measured by real-time quantitative PCR. Cell viability was assessed using the CCK-8 assay and cell death by propidium iodide staining. Protein levels of USP14, microtubule-associated protein 1 light chain 3 (LC3) Ⅱ/LC3 Ⅰ, translocase of outer mitochondrial membrane 20 (TOMM20), PINK1, Parkin, and Drp1 were determined by Western blot. MitoTracker Green staining was used to evaluate mitochondrial morphology, and mitochondrial reactive oxygen species (ROS) were measured using the MitoSOX Red probe. AGO2-RNA immunoprecipitation and dual-luciferase reporter assays were performed to validate the targeting relationship between miR-30b and USP14.
    RESULTS: Compared with the OGD/R group, the OGD/R+miR-30b mimic group showed higher cell viability, miR-30b expression, LC3 Ⅱ/LC3 Ⅰ ratio, and Drp1 protein expression (P<0.05), and lower PI positivity, mitochondrial ROS, USP14 mRNA and protein expression, TOMM20 protein expression, mitochondrial fragmentation index, and mitochondrial volume (P<0.05). PINK1 and Parkin protein levels did not differ significantly between these two groups (P>0.05). Compared with the OGD/R+miR-30b mimic+oe-NC group, the OGD/R+miR-30b mimic+oe-USP14 group exhibited reduced cell viability, miR-30b expression, and LC3 Ⅱ/LC3 Ⅰ ratio (P<0.05), and increased PI positivity, mitochondrial ROS, USP14 mRNA and protein expression, TOMM20 protein expression, mitochondrial fragmentation index, and mitochondrial volume (P<0.05). miR-30b was confirmed to target USP14. In addition, no significant differences were observed between the OGD/R+miR-30b mimic+si-NC and OGD/R+miR-30b mimic+si-Parkin groups in LC3 Ⅱ/LC3 Ⅰ ratio, fragmentation index, or average mitochondrial volume (P>0.05). Compared with the OGD/R+miR-30b mimic+si-NC group, the OGD/R+miR-30b mimic+si-Drp1 group showed a decreased LC3 Ⅱ/LC3 Ⅰ ratio and increased fragmentation index and average mitochondrial volume (P<0.05).
    CONCLUSIONS: miR-30b regulates mitophagy by targeting USP14 independently of the PINK1/Parkin pathway, and confers protection against neuronal OGD/R injury.
    Keywords:  Hypoxic-ischemic encephalopathy; MicroRNA-30b; Mitophagy; Neuron; PINK1/Parkin pathway; Ubiquitin specific peptidase 14
    DOI:  https://doi.org/10.7499/j.issn.1008-8830.2505067
  4. Cell Biochem Funct. 2025 Dec;43(12): e70151
    Mitochondrial Dysfunction Drives Oxidative Stress and Energy Imbalance in a Murine Model of Spondyloarthritis.
    Rodrigo Prieto-Carrasco, Susana Aideé González-Chávez, Eduardo Chaparro-Barrera, Mario Loya-Rivera, Belén Cuevas-López, Fernando E García-Arroyo, Omar Emiliano Aparicio-Trejo, César Pacheco-Tena.
      Joint inflammation and structural damage in spondyloarthritis (SpA) are not fully explained by known immune mechanisms. While mitochondrial dysfunction has been implicated in other rheumatic diseases, such as rheumatoid arthritis and lupus, its role in SpA remains poorly understood. Male DBA/1 mice with spontaneous arthritis (SpAD) and healthy BALB/c mice were compared to assess mitochondrial alterations in joint tissues, isolated mitochondria and cultured fibroblast-like synoviocytes (FLS). Analyses focused on mitochondrial dynamics (fission and fusion) and turnover (biogenesis and mitophagy), bioenergetic function, oxidative stress, and transcriptomic changes associated with mitochondrial function. SpAD induced a coordinated mitochondrial dysfunction in joint tissues characterized by increased fission (Drp1), reduced fusion (Mfn2), and dysregulated turnover processes with elevated mitophagy (PINK1) and biogenesis (PGC-1α). This imbalance led to dysregulation mitochondrial complexes activity, reduced ATP production, and a pronounced increase in oxidative stress. The latter was evidenced by decreased catalase and glutathione peroxidase (Gpx) activity, elevated superoxide dismutase (SOD) activity, and accumulation of 4 hydroxynonenal (4-HNE), highlighting a shift toward a chronic pro-oxidative environment. Similar gene expression changes were observed in cultured FLS. Transcriptomic analysis identified 6,673 differentially expressed genes, including 139 related to mitochondrial function, which reinforces the central role of mitochondrial dysregulation in SpAD pathophysiology. This study is the first to comprehensively characterize mitochondrial dysfunction in a murine model of SpA, identifying it as a potential driver of joint damage. Targeting mitochondrial pathways may offer novel strategies for disease modification in spondyloarthritis.
    Keywords:  DBA/1 mice; mitochondria; mitochondrial dynamics; mitochondrial dysfunction; mitochondrial turnover; oxidative stress; spondyloarthritis
    DOI:  https://doi.org/10.1002/cbf.70151
  5. Nat Commun. 2025 Dec 16.
    VPS13B recruits lipid vesicles to promote mitochondrial fission and quality control.
    Soo-Kyeong Lee, Hyun-Ji Ham, Semin Park, Hye Eun Lee, Ji Young Mun, Deok-Jin Jang, Jin-A Lee.
      Mutations in the gene VPS13B, which encodes a Golgi-associated protein, cause the neurodevelopmental disorder Cohen syndrome, but the protein's function is unclear. Here we show that this protein is essential for mitochondrial morphology and quality control. Cells lacking VPS13B, including neurons derived from Cohen syndrome patients, exhibit abnormally elongated and fused mitochondria with reduced membrane potential and impaired mitophagy. Mechanistically, the protein localizes to Mitofusin 2-positive mitochondria via its C-terminal region and recruits phosphatidylinositol-4-phosphate-rich Golgi vesicles to mitochondrial fission sites. Loss of VPS13B or depletion of phosphatidylinositol-4-phosphate results in incomplete mitochondrial fission despite normal recruitment of Dynamin-related protein 1, indicating that lipid transfer by VPS13B is required for membrane fission. VPS13B links Golgi-derived lipid vesicles to the mitochondrial fission machinery, ensuring proper mitochondrial fission and quality control and potentially explaining the mitochondrial defects in Cohen syndrome.
    DOI:  https://doi.org/10.1038/s41467-025-67445-6
  6. Aging Dis. 2025 Dec 14.
    Pharmacological Activation of Mitophagy Confers Neuroprotective Benefits for Amyotrophic Lateral Sclerosis.
    Sen Huang, Ang Li, Yixia Ling, Xinyu Yang, Jiayu Wang, Jing Yuan, Dajiang Qin, Xiaoli Yao.
      Amyotrophic lateral sclerosis (ALS) is a rare and devastating neurodegenerative disease characterized by the progressive degeneration of motor neurons in the brain and spinal cord, for which no cure currently exists. Previous studies have shown that abnormal mitochondrial homeostasis and defective mitophagy occur in neurodegenerative diseases, including ALS. Here, we provide evidence that PINK1-Parkin-dependent mitophagy is impaired in multiple ALS mouse models, including the SOD1G93A, TDP43A315T, and rNLS8 strains, leading to the accumulation of damaged mitochondria in affected motor neurons. These findings suggest that mitophagy may be a druggable target for ALS treatment. A classical mitophagy agonist, urolithin A (UA) was used in this study. UA-induced mitophagy antagonizes ALS pathologies in the ALS SOD1G93A transgenic C. elegans model in a pink-1 (PTEN-induced kinase 1)- and pdr-1 (Parkinson's disease-related 1)-dependent manner. Furthermore, pharmacological activation of mitophagy by UA improves locomotor behavior, delays motor neuron degeneration and reduces neuroinflammation in ALS SOD1G93A transgenic mice. In conclusion, our results establish impaired mitophagy as a hallmark of ALS motor neuron degeneration and demonstrate that its pharmacological activation offers a neuroprotective strategy with therapeutic potential.
    DOI:  https://doi.org/10.14336/AD.2025.1224
  7. J Anim Sci Biotechnol. 2025 Dec 16. 16(1): 172
    Exploring new benefits of vitamin A: alleviating hypoxia-induced mitochondrial stress and mitophagy in the gills of adult grass carp (Ctenopharyngodon idellus).
    Hua Cheng, Lin Feng, Pei Wu, Yang Liu, Yaobin Ma, Hongmei Ren, Xiaowan Jin, Xiaoqiu Zhou, Weidan Jiang.
       BACKGROUND: Hypoxia is a pervasive challenge in aquaculture that poses a significant threat to aquatic organisms. Since fish cannot synthesize vitamin A endogenously, it must be supplied through diet, and it plays a vital role in supporting fish stress resistance. This study aimed to investigate the protective effects of VA on the gills of adult grass carp (Ctenopharyngodon idella) against hypoxia and to elucidate the underlying mechanisms.
    METHODS: Six experimental diets with graded VA levels (375, 862, 1,614, 2,099, 2,786, and 3,118 IU/kg) were fed to grass carp (initial weight: 726 ± 1.2 g) for 60 d. After the trial, 24 fish per treatment were selected, divided equally into normoxic and hypoxic groups, fasted for 24 h, and then subjected to a 96-h acute hypoxic challenge.
    RESULTS: The results demonstrated that VA supplementation mitigated hypoxia-induced damage in gill tissue, as evidenced by histological examination. Furthermore, VA alleviated oxidative stress, as indicated by reduced levels of lactate (LD), lactate dehydrogenase (LDH), reactive oxygen species (ROS), protein carbonyl (PC), and malondialdehyde (MDA). Further investigations indicated that VA alleviated mitochondrial stress, potentially through suppressing the canonical UPRmt axis while activating both the UPRmt sirtuin axis and the UPRIMS/Erα axis. VA also modulated mitochondrial mass via multiple mechanisms, including the promotion of mitochondrial biogenesis, maintenance of dynamics by stimulating fusion and reducing fission, and inhibition of mitophagy. The suppression of mitophagy likely involved downregulating both the Pink1/Parkin-dependent pathway and the Hif1a-Bnip3 pathway. Taken together, these adaptations suggested an essential role for VA in preserving mitochondrial homeostasis. Based on the quadratic regression analysis of ROS and MDA levels from the hypoxic group, the estimated VA requirements for adult grass carp were 2,013 and 2,056 IU/kg diet, respectively.
    CONCLUSIONS: In summary, this study provided the first evidence that VA conferred protective effects against hypoxia-induced gill damage in grass carp.
    Keywords:  Gills; Grass carp (Ctenopharyngodon idellus); Hypoxic stress; Mitochondrial stress; Mitophagy; Vitamin A
    DOI:  https://doi.org/10.1186/s40104-025-01309-3
  8. Chem Biol Drug Des. 2025 Dec;106(6): e70228
    Sevoflurane Postconditioning Regulates Mitophagy Through the PINK1/Parkin Pathway to Alleviate Myocardial Microcirculatory Reperfusion Injury.
    Yanming Xue, Liqun Jia, Jianzhong Zhang, Shuqin Ni.
      This study investigates whether sevoflurane postconditioning (SpostC) alleviates myocardial microcirculatory reperfusion injury by regulating mitophagy via the PTEN-induced kinase 1 (PINK1)/Parkin pathway. A mouse model of myocardial ischemia/reperfusion (I/R) injury was established. Microvascular perfusion was assessed by immunofluorescence. Protein expression of endothelial nitric oxide synthase (eNOS), phosphorylated eNOS (p-eNOS), endothelin-1 (ET-1), PINK1, Parkin, microtubule-associated protein 1A/1B-light chain 3 (LC3)II/LC3I, and P62 was analyzed by Western blotting (WB). Hematoxylin-eosin and 2,3,5-triphenyltetrazolium chloride (TTC) staining were used to evaluate vascular pathology and infarct size. In vitro, human cardiac microvascular endothelial cells (hCMECs) were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R), with assessments of cell viability (cell counting kit-8), barrier function (FITC-dextran permeability and transendothelial electrical resistance), cytoskeletal integrity (immunofluorescence), and mitophagy markers (WB). SpostC enhanced microvascular perfusion, reduced infarct size, suppressed excessive mitophagy, and restored endothelial function. These protective effects were reversed by either the mitophagy inducer carbonyl cyanide m-chlorophenylhydrazone (CCCP) or PINK1 overexpression. SpostC exerts protective effects on myocardial microcirculatory reperfusion injury by inhibiting the PINK1/Parkin-mediated mitophagy pathway.
    Keywords:  PINK1/Parkin; endothelial dysfunction; mitophagy; myocardial microcirculatory reperfusion injury; sevoflurane postconditioning
    DOI:  https://doi.org/10.1111/cbdd.70228
  9. Eur J Pharmacol. 2025 Dec 16. pii: S0014-2999(25)01236-1. [Epub ahead of print] 178482
    Ursolic Acid Ameliorates Doxorubicin-induced Cardiotoxicity by Inhibiting DRP1-mediated Excessive Mitochondrial Fission and Oxidative Stress.
    Dejian Lin, Xinqing Dai, Mingyue Tang, Ya Wu, Haixia Xu.
       BACKGROUND: Doxorubicin (DOX) is a commonly used chemotherapeutic agent for treating hematologic malignancies and breast cancer. However, its clinical application is limited by severe cardiotoxicity. Recent studies have suggested that mitochondrial dynamics play a central role in the pathogenesis of doxorubicin-induced cardiotoxicity (DIC). This study was designed to evaluate whether ursolic acid (UA) can mitigate DIC and elucidate the underlying mechanisms related to mitochondrial fission and oxidative stress.
    METHODS: A chronic DOX-induced cardiotoxicity model was established via the intraperitoneal administration of DOX (5 mg/kg/week), while ursolic acid was administered intragastrically (50 mg/kg/day). Echocardiography and histological staining were employed to assess the protective effects of ursolic acid on DOX-induced cardiac injury.
    RESULTS: Ursolic acid treatment significantly improved cardiac function following DOX exposure. Immunofluorescence analysis confirmed the amelioration of mitochondrial dysfunction. Western blotting demonstrated that ursolic acid markedly reduced the DOX-induced increase in the level of dynamin-related protein 1 (DRP1) phosphorylated at Ser616 (p-DRP1(S616)), suggesting its role in attenuating excessive mitochondrial fission. Furthermore, co-treatment with Mitochondrial Division Inhibitor 1 (Mdivi-1) further suppressed p-DRP1 (S616) expression, reinforcing the notion that ursolic acid mitigates DIC by inhibiting DRP1-mediated mitochondrial fission and oxidative stress. The upstream mechanism was explored, with evidence suggesting that the C5a-C5a1 receptor axis mediates p-DRP1(S616) phosphorylation. Western blot analysis revealed significant upregulation of the C5a and C5a1 receptors in the DIC model. The C5a1 receptor agonist BM213 abolished the protective effects of ursolic acid, indicating that ursolic acid exerts its cardioprotective effect by inhibiting the C5a-C5aR1-DRP1(S616) pathway.
    CONCLUSION: Ursolic acid confers protection against DOX-induced cardiotoxicity by improving mitochondrial function through the inhibition of DRP1-mediated excessive mitochondrial fission and oxidative stress.
    Keywords:  Mitochondrial fission; Oxidative stress; Ursolic acid; doxorubicin-induced cardiotoxicity; p-DRP1(S616)
    DOI:  https://doi.org/10.1016/j.ejphar.2025.178482
  10. J Clin Invest. 2025 Dec 16. pii: e194441. [Epub ahead of print]
    Genetic disruption of mitochondrial dynamics and stasis leads to liver injury and tumorigenesis.
    Xiaowen Ma, Xiaoli Wei, Mengwei Niu, Chen Zhang, Zheyun Peng, Wanqing Liu, Junrong Yan, Xiaoyang Su, Lichun Ma, Shaolei Lu, Wei Cui, Hiromi Sesaki, Wei-Xing Zong, Hong-Min Ni, Wen-Xing Ding.
      Mitochondrial fission is mediated by dynamin-related protein 1 (gene name DNM1L) and fusion by mitofusins (MFN1 and MFN2) and optic atrophy 1 (OPA1). The role of mitochondrial dynamics in liver disease and cancer remains poorly understood. We used single, double, and triple liver-specific knockout (KO) mice lacking mitochondrial fission and fusion proteins, along with systematic analyses of mitochondrial morphology, untargeted metabolomics, RNA sequencing, hydrodynamic tail vein injection of oncogenes, and human hepatocellular carcinoma samples. Liver-specific Dnm1l KO (L-Dnm1l) mice showed increased ALT levels and hepatic fibrosis, with spontaneous liver tumors developing by 12 to 18 months of age. L-Mfn1 KO and L-Mfn2 KO mice showed no significant liver damage or tumor development, although a small percentage of double knockout (DKO) mice developed tumors. Triple knockout of Dnm1l, Mfn1, and Mfn2 (TKO) mice experienced significantly reduced liver injury and fibrosis, along with decreased spontaneous and oncogene-induced tumorigenesis. L-Dnm1l KO mice showed increased activation of the cGAS-STING-interferon pathway and pyrimidine metabolism, which were significantly normalized in TKO mice. Deletion of hepatic cGas reduced both basal and oncogene-induced liver injury and tumor development in L-Dnm1l KO mice. These findings indicate that mitochondrial dynamics are crucial for maintaining hepatic pyrimidine metabolism and regulating the cGAS-STING-mediated immune response to prevent liver tumorigenesis.
    Keywords:  Cell biology; Hepatology; Liver cancer
    DOI:  https://doi.org/10.1172/JCI194441
  11. Biochim Biophys Acta Gen Subj. 2025 Dec 16. pii: S0304-4165(25)00142-4. [Epub ahead of print] 130897
    Spermidine deficiency induces BNIP3/LC3B-mediated mitophagy in the salivary glands of accelerated aging mice.
    Nguyen Khanh Toan, Manh Dat Duong, Nguyen Duy Phu, Le Viet Thanh, Sang-Gun Ahn.
      Aging is associated with mitochondrial dysfunction and altered autophagic processes, particularly in secretory organs such as the salivary glands. In this study, we investigated metabolic changes and their interactions with mitophagy in primary salivary gland cells (PSGCs) from klotho-deficient (kl-/-) mice, a model of accelerated aging. We observed a significant reduction in both mitochondrial number and mitochondrial DNA copy number in the PSGCs of kl-/- mice compared with those of wild-type (WT) controls. In contrast, lysosomal abundance was markedly increased in PSGCs from kl-/- mice. Moreover, the expression of the autophagy marker LC3B was significantly upregulated in kl-/- PSGCs, and the expression of the mitophagy markers BNIP3 and NIX increased. Our metabolomic profiling revealed disrupted spermidine biosynthesis in the salivary glands of kl-/- mice. Interestingly, spermidine treatment in kl-/- PSGCs increased the number of mitochondria and suppressed mitophagy, as indicated by the reduced expression of BNIP3 and LC3B. Conversely, in WT PSGCs, spermidine induced the expression of autophagy and mitophagy markers, namely, BNIP3 and LC3B. These findings suggest that accelerated aging in mice impairs mitochondrial homeostasis and alters autophagy/mitophagy pathways in salivary gland cells, potentially through the dysregulation of spermidine metabolism. Our results provide insight into the molecular mechanisms of aging in salivary glands and reveal the potential role of polyamine metabolism in maintaining mitophagy during aging.
    Keywords:  Aging; Mitochondria; Mitophagy; Salivary glands; Spermidine
    DOI:  https://doi.org/10.1016/j.bbagen.2025.130897
  12. Cell Chem Biol. 2025 Dec 18. pii: S2451-9456(25)00390-3. [Epub ahead of print]32(12): 1439-1441
    Two genomes, one destiny: Mitophagy at the crossroads of inheritance and disease.
    Chih-Yao Chung, Kritarth Singh, Brigida R Pinho, Jorge M A Oliveira, Michael R Duchen.
      Mechanisms ensuring mito-nuclear compatibility are poorly understood. In a recent study published in Science,1 Frison et al. found that a mouse mitochondrial DNA (mtDNA) mutation can escape mitochondrial surveillance in embryogenesis by repressing the ubiquitin-proteasome system. Inhibition of USP30 restored ubiquitin-mediated mitophagy and reduced mutant burden, suggesting a potential therapeutic target for mtDNA disorders.
    DOI:  https://doi.org/10.1016/j.chembiol.2025.11.010
  13. Nat Cell Biol. 2025 Dec 15.
    MISO regulates mitochondrial dynamics and mtDNA homeostasis by establishing membrane subdomains.
    Yue Zhang, Yuchen Xia, Xinhui Wang, Yueqin Xia, Shang Wu, Jianshuang Li, Xuan Guo, Qinghua Zhou, Li He.
      Mitochondrial dynamics and mtDNA homeostasis have been linked to specialized mitochondrial subdomains known as small MTFP1-enriched mitochondria (SMEM), though the underlying molecular mechanisms remain unclear. Here we identified MISO (mitochondrial inner membrane subdomain organizer), a conserved protein that regulates both mitochondrial dynamics and SMEM formation in Drosophila and mammalian cells. MISO inhibits fusion by recruiting MTFP1 and promotes fission through FIS1-DRP1. Furthermore, MISO drives SMEM biogenesis and facilitates their peripheral fission that promotes lysosomal degradation of mtDNA. Genetic ablation of MISO abolishes SMEM generation, confirming that MISO is both necessary and sufficient for SMEM formation. Inner mitochondrial membrane stresses, including mtDNA damages, OXPHOS dysfunction and cristae disruption, stabilize the otherwise short-lived MISO protein, thereby triggering SMEM assembly. This process depends on the C-terminal domain of MISO, likely mediated by oligomerization. Together, our findings reveal a molecular pathway through which inner mitochondrial membrane stresses modulate mitochondrial dynamics and mtDNA homeostasis via MISO-orchestrated SMEM organization.
    DOI:  https://doi.org/10.1038/s41556-025-01829-0
  14. Mol Neurobiol. 2025 Dec 13. 63(1): 292
    SIRT3/AMPK-Driven Mitophagy Failure Underlies Methylmercury-Induced Neurotoxicity: Evidence from Humans to Cells.
    Jiahuan Hu, Li Zhang, Fang Chen, Changsong Tian, Aihua Zhang, Wenjuan Wang.
      Methylmercury (MeHg) is a global environmental pollutant notorious for its developmental neurotoxicity. Although many mechanisms of MeHg toxicity have been proposed, the precise molecular pathways remain incompletely understood. This study integrated population and cell models and utilized high-throughput transcriptomic screening of umbilical cord blood (UCB) and neuronal samples to identify differentially expressed genes associated with MeHg exposure. Subsequently, in vitro validation of the key mechanisms was performed. Omics data showed that differentially expressed genes in UCB from MeHg exposure are linked to mitophagy. Additionally, transcriptome sequencing of primary hippocampal neurons revealed the potential effects of MeHg on energy metabolism, indicating a mitochondrial mechanism that requires further investigation. Further in vitro mechanistic studies revealed that SIRT3/AMPK, key mediators of PINK1-dependent mitophagy, were activated by MeHg exposure. Notably, when PC12 cells were exposed to MeHg, SIRT3 was upregulated compensatorily. Our findings support a model in which MeHg-induced SIRT3 upregulation facilitates AMPKα (Thr172) phosphorylation via LKB1, suggesting that this pathway is associated with mitophagy activation, as evidenced by increased Beclin1 expression, LC3II/I conversion, and decreased p62 levels. Mitophagy was initiated as a defense response to remove damaged mitochondria and exogenous toxicants. Nevertheless, such successive cellular responses exacerbated mitochondrial stress, resulting in neuronal damage and synaptic underfeeding. Together, these results offer novel mechanistic insights into how SIRT3/AMPK-mediated mitophagy coordination regulates MeHg-induced neurotoxicity, providing potential therapeutic targets for developmental neurological disorders.
    Keywords:  Heavy metal; Methylmercury; Mitochondria; Neurodevelopmental
    DOI:  https://doi.org/10.1007/s12035-025-05576-z
  15. Nutr Res Rev. 2025 Dec 17. 1-44
    Distinct Roles of Urolithin A and Spermidine in Mitophagy and Autophagy: Implications for Dietary Supplementation.
    Pavel Borsky, Drahomira Holmannova, Ondrej Soukup, Zdenek Fiala, Tereza Maresova, Michaela Hanzlova, Tom Philipp, Lenka Borska.
      The increasing focus on longevity and cellular health has brought into the spotlight two key compounds, urolithin A (UroA) and spermidine, for their promising roles in autophagy and mitophagy. Urolithin A, a natural metabolite derived from ellagitannins, stimulates mitophagy through pathways such as PTEN induced kinase 1 (PINK1)/ Parkin RBR E3 ubiquitin protein ligase (PRKN), leading to improved mitochondrial health and enhanced muscle function. On the other hand, spermidine, a polyamine found in various food sources, induces autophagy by regulating key signaling pathways such as 5' AMP-activated protein kinase (AMPK) and sirtuin 1, thus mitigating age-related cellular decline and promoting cardiovascular and cognitive health. While both UroA and spermidine target cellular maintenance, they affect overlapping as well as distinct signaling pathways. Thus, they do not have completely identical effects, although they overlap in many ways, and offer varying benefits in terms of metabolic function, oxidative stress reduction, and longevity. This review article aims to describe the mechanisms of action of UroA and spermidine not only on the maintenance of cellular health, which is mediated by the induction and maintenance of autophagy and mitophagy, but also on their potential clinical relevance. The analysis presented here suggests that although both compounds are safe and offer substantial health benefits and are involved in both autophagy and mitophagy, the role of UroA in mitophagy places it as a targeted intervention for mitochondrial health, whereas the broader influence of spermidine on autophagy and metabolic regulation may provide more comprehensive anti-aging effects.
    Keywords:  Autophagy; Mitophagy; Spermidine; Supplement; Urolithin A
    DOI:  https://doi.org/10.1017/S0954422425100292
  16. Blood. 2025 Dec 15. pii: blood.2025029875. [Epub ahead of print]
    Pharmacological Inhibition of miR-126 Enhances Venetoclax Activity in Acute Myeloid Leukemia.
    Lianjun Zhang, HyunJun Kang, Melissa Valerio, Dinh Hoa Hoang, Khyatiben V Pathak, Krystine Garcia-Mansfield, Xiyuan Lu, Wancheng Guo, Yu-Hsuan Fu, Xin He, Ying-Chieh Chen, Zhenhua Chen, Lucy Y Ghoda, Ralf Buettner, Zhuo Li, Amanda Blackmon, Ling Li, Bin Zhang, Patrick Pirrotte, Guido Marcucci, Ya-Huei Kuo, Le Xuan Truong Nguyen.
      Leukemic stem cells (LSCs) in acute myeloid leukemia (AML) depend on oxidative phosphorylation (OXPHOS) sustained by fatty acid oxidation (FAO) and mitochondrial fusion (mitofusion). We demonstrate that miR-126 maintains LSC function by promoting BCL-2-dependent FAO, OXPHOS, and mitofusion, whereas its inhibition disrupts mitochondrial metabolism, induces mitochondrial fission (mitofission), and triggers apoptosis. Mechanistically, miR-126 stabilizes BCL-2 via the SPRED1/ERK axis, which upregulates CPT1B (FAO) and NRF2 (antioxidant response) while regulating mitochondrial dynamics through DRP1 phosphorylation (inhibiting mitofission) and MFN1/2 phosphorylation (enhancing mitofusion). miRisten, a CpG-conjugated anti-miR-126 oligonucleotide now in clinical trials (NCT07025564), synergized with venetoclax (VEN) to suppress FAO/OXPHOS, promote mitofission, and impair LSC homeostasis. In vivo, miRisten potentiated the VEN/azacitidine (AZA) regimen, an FDA-approved therapy for older or unfit AML patients, significantly prolonging survival in patient-derived xenograft models. VEN/miRisten combination also reduced LSC burden and restored VEN sensitivity, establishing miR-126 inhibition as a transformative therapeutic strategy in AML.
    DOI:  https://doi.org/10.1182/blood.2025029875
  17. Cancer Res. 2025 Dec 15.
    Drp1 Interaction with BIP Maintains Mitochondrial Dynamic Equilibrium to Promote Anoikis Resistance and Metastasis in Nasopharyngeal Carcinoma.
    Lili Bao, Keying Li, Yue Fan, Zhen Ge, Yang Zeng, Tian Xia, Qicheng Zhang, Si Pan, Wenhui Chen, Haimeng Yin, Bo You.
      Anoikis resistance is a phenomenon wherein cells survive under anchorage-independent conditions, which is critical for cancer cell dissemination and metastasis. To identify strategies to overcome anoikis resistance, we employed a 3D suspension culture model combined with proteomic screening, identifying a relationship between the dynamin-like protein Drp1 and anoikis resistance in nasopharyngeal carcinoma (NPC). Drp1 facilitated the generation of new mitochondria and the removal of damaged ones by regulating fission and mitophagy, thereby enabling tumor cells to overcome anoikis. Furthermore, the interaction of Drp1 and BIP was enhanced during anoikis resistance, which increased formation of mitochondria-associated endoplasmic reticulum membranes (MAMs) to maintain mitochondrial dynamic equilibrium. Mechanistically, CaMKKβ activated the AMPK-MFF-Drp1 and AMPK-mTOR-Drp1 pathways through O-GlcNAcylation modification, thus recruiting Drp1 to MAMs. Notably, the Drp1-BIP complex served as a prognostic indicator for NPC clinical outcome and metastatic risk. Collectively, these results elucidate a mechanism by which Drp1 regulates anoikis resistance through mitochondrial dynamics and provide a feasible treatment strategy for managing NPC.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-0622
  18. Stem Cell Res. 2025 Dec 12. pii: S1873-5061(25)00237-5. [Epub ahead of print]90 103887
    CRISPR/Cpf1-mediated editing of PINK1 in induced pluripotent stem cells.
    Roohallah Ghodrat, Haribaskar Ramachandran, Barbara Hildebrandt, Stephanie Binder, Andrea Rossi, Andreas S Reichert.
      The PTEN induced kinase 1 (PINK1) gene is crucial for mitophagy and mitochondrial quality control. Mutations in the PINK1 gene are associated with several neurological disorders. To decipher the role of PINK1-mediated mitophagy in human induced pluripotent stem cells (hiPSCs) and in their differentiated counterparts, we used CRISPR/Cpf1 and generated a human iPSC line with homozygous out-of-frame deletions by targeting exon 6 of the PINK1 gene. The generated homozygous PINK1 mutant cell line showed normal cell morphology, genomic stability, and expression of classical stem cell markers. Furthermore, the cells can be differentiated efficiently into the three germ layers.
    DOI:  https://doi.org/10.1016/j.scr.2025.103887
  19. Front Mol Biosci. 2025 ;12 1751510
    Retraction: Resveratrol improves mitochondrial biogenesis function and activates PGC-1α pathway in a preclinical model of early brain injury following subarachnoid hemorrhage.
    Frontiers Editorial Office
      [This retracts the article DOI: 10.3389/fmolb.2021.620683.].
    DOI:  https://doi.org/10.3389/fmolb.2025.1751510
  20. Phytother Res. 2025 Dec 17.
    Morin, a Natural Flavonoid, Activates the PINK1/Parkin Pathway to Induce Mitophagy, Promote Apoptosis, and Suppress Cancer Stemness in Pancreatic Cancer.
    Vinit Sharma, Mayank Sharma, Ankita Semwal, Ankita Arora, Sakshi Bansal, Namrata Sangwan, Anjali Aggarwal.
      Pancreatic cancer (PC) is among the deadliest malignancies, characterized by poor treatment response. Natural bioactive compounds, such as Morin, a flavonoid, have gained interest as potential therapeutic agents due to their anticancer properties but remain unexplored in PC. This study investigates the anticancer effects of Morin on PC cells, particularly its ability to induce mitophagy via the PINK1/Parkin pathway and modulate mitochondrial function and cancer stemness. PANC-1 cells were treated with Morin, and its impact on tumorigenic potential was evaluated using in vitro assays, including cell viability, colony formation, migration, invasion, and spheroid formation, as well as in vivo studies in a nude mice model. Mitochondrial function and apoptosis were assessed through flow cytometry, gene expression analysis, PCR microarrays, transmission electron microscopy (TEM), immunofluorescence, ELISA, western blotting, and molecular docking. Morin exhibited dose-dependent cytotoxicity, significantly reducing viability, colony formation, migration, and invasion in PC. It downregulated mesenchymal and stemness markers (N-cadherin, SNAI1, ZEB1, SOX2, NANOG, OCT4) while upregulating E-cadherin. Morin disrupted spheroid morphology and decreased ALDH activity, indicating reduced cancer stemness. Additionally, Morin-induced mitochondrial dysfunction, as evidenced by decreased membrane potential, ATP synthase activity, and mitochondrial mass, along with increased mitochondrial superoxide production. Upregulation of mitophagy markers (PINK1, Parkin, pAMPK, LC3A/B) and downregulation of fusion (MFN2) confirmed PINK1-mediated mitophagy. Apoptosis induction was supported by Annexin V/PI staining, TEM, elevated caspase-3/-9 levels, and cytochrome c release. Molecular docking confirmed strong Morin-PINK1 interaction. Morin induces mitophagy, promotes apoptosis, and suppresses cancer invasiveness in PC cells, highlighting its potential as an adjuvant therapeutic agent. Future clinical studies are warranted to evaluate its relevance.
    Keywords:  apoptosis; bioflavonoids; mitochondrial dysfunctions; mitophagy; morin; pancreatic cancer; tumorigenesis
    DOI:  https://doi.org/10.1002/ptr.70149
  21. Inflamm Res. 2025 Dec 18. 75(1): 6
    Mechano-metabolic dysregulation in osteoarthritis: Piezo1-mediated mitophagy impairment as a novel therapeutic target.
    DuJiang Yang, Lin Yang, Wenhhao Yang, Junjie Chen, Shuang Wang, Jiexiang Yang, GuoYou Wang.
      The recent study by Yu et al. (2025) elucidates a critical mechanism linking mechanical stress to mitochondrial dysfunction in osteoarthritis (OA), demonstrating that Piezo1 activation is associated with impaired PINK1/Parkin-mediated mitophagy, leading to chondrocyte injury and cartilage degradation. While this work significantly advances our understanding of OA pathogenesis by integrating biomechanical and bioenergetic perspectives, key aspects require further exploration. Specifically, the downstream signaling mechanisms mediated by calcium influx, the potential role of reactive oxygen species (ROS) and inflammasome activation, and alternative therapeutic strategies beyond Piezo1 inhibition warrant deeper investigation. This commentary highlights these avenues for future research and emphasizes the importance of targeting mitochondrial quality control as a promising approach for OA therapy.
    DOI:  https://doi.org/10.1007/s00011-025-02161-x
  22. Biochem Biophys Rep. 2026 Mar;45 102359
    Unraveling the role of mitochondrial unfolded protein response in colorectal cancer.
    Jihao Shi, Lexi Wu, Chuwen Tian, Haotian Chen.
      Colorectal cancer (CRC) ranks among the most prevalent malignancies globally and is the third leading cause of cancer - related deaths. Despite advancements in diagnosis and treatment, prognosis for CRC patients, especially those with advanced or metastatic disease, remains difficult due to its heterogeneity. Mitochondria, central to cellular activity, and the mitochondrial unfolded protein response (UPRmt), a stress - responsive pathway, are involved in various physiological and pathological processes. Recent studies have emphasized the importance of UPRmt in cancer biology. In this research, we explored the role of UPR - related genes (MRGs) in CRC. Through analyzing transcriptional profiles and clinical data of CRC patients, we identified different molecular subtypes according to MRG expression, which were related to patient prognosis, immune cell infiltration, and drug sensitivity. We also developed a prognostic signature based on key MRGs with strong predictive power for patient survival and treatment response. Additionally, the study of the spatial distribution of MRGs in tumor tissues revealed their heterogeneous expression and potential influence on tumor biology. Overall, our findings clarify the role of UPR in CRC and highlight its potential as a target for personalized cancer therapy.
    Keywords:  Colorectal cancer; Database; Single-cell RNA sequencing; Unfolded protein response
    DOI:  https://doi.org/10.1016/j.bbrep.2025.102359
  23. Int Immunopharmacol. 2025 Dec 12. pii: S1567-5769(25)02008-9. [Epub ahead of print]169 116019
    Melatonin alleviates atherosclerosis by inhibiting pro-inflammatory differentiation of macrophages via regulating Sirt3-Drp1 mediated mitochondrial fission.
    Run Dai, Min-Ming Zheng, Ya-Ni Shi, Ming-Hao Luo, Yu Wang, Hua-Wei Wang, Dan-Qing Yu, Qing-Wei Chen, Ling Lin, Jing-Wei Zhou, Ze-da-Zhong Su.
       BACKGROUND: Pro-inflammatory macrophage function is linked to an increase in mitochondrial fission. Melatonin has a positive impact on atherosclerosis and has a significant effect on the control of mitochondrial fission and fusion. Nevertheless, it is still unclear how melatonin contributes to slowing the advancement of atherosclerosis.
    METHODS: The ApoE-/- mice were fed a 16-week high-fat diet (HFD). 16 weeks were spent on melatonin therapy. After using 3-TYP to suppress Sirt3 function, we were able to measure the vascular tissue's biochemical, inflammatory, and mitochondrial fission characteristics as well as the shape of atherosclerotic plaque. RAW264.7 cells were stimulated by oxidized low-density lipoprotein (oxLDL), pretreated with or without 3-TYP or Melatonin.
    RESULTS: The study found that melatonin treatment decreased the area of atherosclerotic plaque, decreased lipid deposition, suppressed inflammatory cytokine levels, inhibited macrophage pro-inflammatory differentiation, inhibited mitochondrial fragmentation, increased the level of Sirt3, and decreased Drp1 expression in atherosclerosis (AS) mice. However, Sirt3 inhibition abolished the protective affects of melatonin in AS mice. Melatonin therapy upregulated Sirt3 expression in RAW264.7 cells subjected to ox-LDL, blocked Drp1-mediated mitochondrial fission, and reduced inflammatory cytokine levels. On the other hand, melatonin's inhibitory effects on Drp1 expression and mitochondrial fission were lessened by Sirt3 inhibition. Additionally, DRP1 siRNA knockdown inhibited mitochondrial fission and pro-inflammatory differentiation of macrophages induced by ox-LDL.
    CONCLUSION: Melatonin inhibits the growth of atherosclerosis and the pro-inflammatory differentiation of macrophages by blocking the Sirt3-Drp1 pathway, which prevents mitochondria from fission. Melatonin's suppression of mitochondrial fission may be a viable strategy for postponing cardiovascular problems in atherosclerosis patients.
    Keywords:  Atherosclerosis; Inflammation; Macrophage; Melatonin; Mitochondrial fission; Sirt3-Drp1 pathway
    DOI:  https://doi.org/10.1016/j.intimp.2025.116019
  24. FASEB J. 2025 Dec 31. 39(24): e71377
    Investigation of Glaucocalyxin A Mechanism in Alleviating Atopic Dermatitis via the HMGB1-RAGE-RhoA/ROCK1-Mediated Mitochondrial Pathway.
    Kexin Xu, Xinyi Song, Wenyu Jin, Longquan Pi, Yue Du, Li Li, Guanghai Yan, Liangchang Li.
      The high mobility group box-1 protein (HMGB1) is crucial in the inflammatory processes associated with atopic dermatitis (AD). The interaction between HMGB1 and its receptor, the receptor for advanced glycation end products (RAGE), plays a central role in mediating inflammation. Nevertheless, the precise mechanisms through which glaucocalyxin A (GLA) influences AD via the HMGB1-RAGE-RhoA/ROCK1 mitochondrial pathway remain to be elucidated. This study aimed to investigate the role of GLA in AD, explore the regulatory effects of the HMGB1-RAGE-RhoA/ROCK1 mitochondrial pathway on inflammatory responses in AD, and identify potential therapeutic targets for the treatment of AD. GLA significantly reduced the levels of inflammatory cytokines (IL-4, TNF-α, IFN-γ) in DNCB-induced AD models. In TNF-α-induced HaCaT cells, treatment with GLA and HMGB1 knockout restored mitochondrial membrane potential and mtROS levels, attenuated mitochondrial fission, and increased the levels of the fusion proteins MFN1 and MFN2. These findings suggest that GLA promotes mitochondrial dynamics by targeting HMGB1. HMGB1 knockout also led to decreased levels of RAGE, RhoA, and ROCK1 proteins. In r-HMGB1-stimulated HaCaT cells treated with a RAGE-specific blocker (TFA), the expression of HMGB1, RAGE, RhoA, and ROCK1 decreased, while levels of MFN1 and MFN2 increased. Similarly, treatment with the Rho kinase inhibitor (Y-27632) reduced p-Drp1 and increased MFN1 and MFN2 levels, though RAGE expression remained unchanged. HMGB1 knockout significantly reduces inflammatory factors in DNCB-induced AD models. HMGB1 promotes mitochondrial fission and inhibits fusion through the HMGB1-RAGE-RhoA/ROCK1 pathway, exacerbating skin inflammation. GLA alleviates AD by modulating the HMGB1-RAGE-RhoA/ROCK1 mitochondrial axis.
    Keywords:  HMGB1; RAGE; RhoA; atopic dermatitis; glaucocalyxin A
    DOI:  https://doi.org/10.1096/fj.202503063R
  25. J Ethnopharmacol. 2025 Dec 13. pii: S0378-8741(25)01726-X. [Epub ahead of print]358 121033
    Qiang-Xin 1 formula improves cardiac function and alleviates myocardial injury in lipopolysaccharide-induced septic mice by activating calcium/calmodulin-dependent protein kinase I-mediated mitophagy.
    Po Huang, Qian Wang, Ye Zhu, Xiao Hu, Xiaolei Fang, Wenjie Deng, Peng Cao, Shasha He.
       ETHNOPHARMACOLOGICAL RELEVANCE: Qiang-Xin 1 (QX1) is a traditional Chinese herbal formula that has been used for decades in treating heart failure. This study is the first to demonstrate its protective effects against sepsis-induced myocardial injury (SIMI). Furthermore, we identified a novel mechanism of QX1 involving calcium/calmodulin-dependent protein kinase I (CaMK I)-mediated mitophagy.
    AIM OF THE STUDY: This study aimed to investigate whether QX1 alleviates SIMI by modulating CaMK I-mediated mitophagy in lipopolysaccharide (LPS)-induced septic mice and cardiomyocytes.
    MATERIALS AND METHODS: An LPS-induced septic mouse model and HL-1 cardiomyocytes were treated with QX1 or its medicated serum. Cardiac function was assessed via echocardiography, pathological staining and biochemical measurement. CaMK I's role was validated using siRNA/shRNA knockdown or overexpression.
    RESULTS: QX1 improved cardiac function, reduced inflammation, and attenuated mitochondrial damage by restoring N-terminal pro-B-type natriuretic peptide, cardiac troponin I, creatine kinase-MB isoenzyme, interleukin-1 beta, tumor necrosis factor alpha and interleukin 6, as well as reversed aberrant levels of Adenosine triphosphate, mitochondrial DNA and membrane potential in SIMI. Mechanistically, QX1 activated mitophagy by upregulating PINK1, Parkin, and LC3-II/I while reducing P62 in the mitochondrial fraction. mRFP-eGFP-LC3 reporter assay and colocalization of LC3 with Parkin in cardiomyocytes demonstrated the enhanced mitophagic flux. Furthermore, in vivo CaMK I knockdown significantly reduced QX1-mediated improvements in cardiac function and mitochondrial integrity. In vitro, autophagy inhibition or CaMK I silencing largely abolished QX1's benefits.
    CONCLUSION: QX1 protects against SIMI by enhancing CaMK I-dependent mitophagy. These findings highlight QX1's therapeutic potential for sepsis-induced cardiomyopathy. However, these results were obtained from a single standardized batch of QX1, and validation across multiple batches prepared from plants collected under different conditions is necessary to confirm the reproducibility and robustness of these mechanisms.
    Keywords:  CaMK I; Cardiac function; Mitophagy; QX1 formula; Sepsis
    DOI:  https://doi.org/10.1016/j.jep.2025.121033
  26. J Biol Chem. 2025 Dec 12. pii: S0021-9258(25)02906-0. [Epub ahead of print] 111054
    Activation of mitophagy antagonizes high uric acid-induced hepatic lipid accumulation.
    Jiayu Chen, Hairong Zhao, Yuemei Xi, Shanpan Fu, De Xie, Linqian Yu, Qiang Wang, Binyang Chen, Qian Zhang, Mingyan Zhang, Xueling Ye, Mengni Wu, Wanling Que, Shuyi Chen, Yayan Liu, Tetsuya Yamamoto, Hidenori Koyama, Hong Zhao, Jidong Cheng.
      The rising prevalence of hyperuricemia associated with lifestyle changes has been confirmed as an independent risk factor for metabolic dysfunction-associated fatty liver disease (MAFLD). Mitochondria, as central regulators of lipid metabolism, maintain functional homeostasis through mitophagy, the selective removal of damaged or dysfunctional mitochondria. However, whether and how high uric acid (HUA) induces mitophagy and the mechanistic role of mitophagy in hyperuricemia-induced hepatic lipid metabolism disorders remain to be elucidated. Our study demonstrated that HUA induces hepatic fat accumulation and damaging mitochondria in primary mouse hepatocytes. Simultaneously, mitophagy was activated by HUA, evidenced by upregulated expression and phosphorylation of PINK1 and Parkin, enhanced LC3B-I to LC3B-II conversion, and enhanced TOM20-LC3B immunofluorescence co-localization. In urate oxidase gene knockout (Uox-KO) mice (a model of sustained hyperuricemia), we detected significantly elevated expression of mitophagy-related proteins in liver tissues, accompanied by marked lipid accumulation and inflammatory responses. Further studies demonstrated that HUA upregulates CD36 protein expression. CD36 knockdown alleviated lipid accumulation in primary mouse hepatocytes, whereas PINK1 knockdown exacerbated this effect through further CD36 upregulation. Notably, treatment with the mitophagy activator Urolithin A significantly ameliorated hepatic lipid accumulation and inflammation in Uox-KO mice. These findings demonstrate that the PINK1-Parkin-mediated mitophagy activated by HUA serves as a protective mechanism against HUA-induced hepatic fat accumulation. Our results suggest that mitophagy regulation may represent a novel therapeutic target for HUA-induced hepatic fat accumulation.
    Keywords:  CD36; Hepatic lipid accumulation; Hyperuricemia; Mitophagy; PINK1-Parkin pathway
    DOI:  https://doi.org/10.1016/j.jbc.2025.111054
  27. Nat Commun. 2025 Dec 14.
    The microRNA miR-71 suppresses maladaptive UPRmt signaling through both cell-autonomous and cell-non-autonomous mechanisms.
    Ina Kirmes, Grace Ching Ching Hung, Anne Hahn, Chuan-Yang Dai, Daniel Campbell, Arnaud Ahier, Rachel Shin Yie Lee, Alexander Palmer, Steven Zuryn.
      Mitochondria play a central role in metabolism and biosynthesis, but function also as platforms that perceive and communicate environmental and physiological stressors to the nucleus and distal tissues. Systemic mitochondrial signaling is thought to synchronize and amplify stress responses throughout the whole body, but during severe or chronic damage, overactivation of mitochondrial stress pathways may be maladaptive and exacerbate aging and metabolic disorders. Here we uncover a protective micro(mi)RNA response to mtDNA damage in Caenorhabditis elegans that prolongs tissue health and function by interfering with mitochondrial stress signaling. Acting within muscle cells, we show that the miRNA miR-71 is induced during severe mitochondrial damage by the combined activities of DAF-16, HIF-1, and ATFS-1, where it restores sarcomere structure and animal locomotion by directly suppressing the inordinate activation of DVE-1, a key regulator of the mitochondrial unfolded protein response (UPRmt). Indirectly, miR-71 also reduces the levels of multiple neuro- and insulin-like peptides and their secretion machinery, resulting in decreased cell-non-autonomous signaling of mitochondrial stress from muscle to glia cells. miR-71 therefore beneficially coordinates the suppression of both local and systemic mitochondrial stress pathways during severe organelle dysfunction. These findings open the possibility that metabolic disorders could be ameliorated by limiting the overactivation of mitochondrial stress responses through targeted small RNAs.
    DOI:  https://doi.org/10.1038/s41467-025-67198-2
  28. Biochem Biophys Res Commun. 2025 Dec 11. pii: S0006-291X(25)01837-6. [Epub ahead of print]795 153121
    GATA-1-driven TOMM20-mediated mitophagy regulates PDLSCs osteogenesis and enhances periodontal bone regeneration.
    Qi Cai, Zhizen Quan, Xinyu Yang, Chen Li, Yu Chen, Yibo Wei, Yang Zhang, Xiaogang Xu.
      Periodontitis-induced periodontal bone defect is a key clinical challenge, and the osteogenic differentiation of periodontal ligament stem cells (PDLSCs) is critical for bone repair. This study explored the role of the GATA-1-TOMM20-mitophagy axis in PDLSC osteogenic differentiation and periodontal bone repair. In a rat periodontitis model, TOMM20 expression was downregulated, accompanied by reduced bone volume/trabecular thickness (BV/TV/Tb.Th) and increased alveolar bone resorption (ABC-CEJ). TOMM20 overexpression (OE-TOMM20) ameliorated these bone defects, promoted mitophagy (reduced P62, increased LC3b/Beclin1), and enhanced PDLSC osteogenic differentiation (upregulated RUNX2/ALP/OCN, increased alizarin red/ALP staining), which was abolished by the autophagy inhibitor 3-MA. Genecards/JASPAR predicted GATA-1 as a top transcription factor for TOMM20. ChIP-PCR confirmed GATA-1 directly bound the TOMM20 promoter. GATA-1 overexpression upregulated TOMM20, while GATA-1 silencing downregulated it. Functional rescue experiments showed OE-GATA-1-induced mitophagy and PDLSC osteogenesis were reversed by TOMM20 silencing or 3-MA. In conclusion, GATA-1 transcriptionally activates TOMM20 to induce mitophagy, thereby promoting PDLSC osteogenic differentiation and periodontal bone repair, providing a potential therapeutic target for periodontitis.
    Keywords:  GATA-1; Mitophagy; Periodontal ligament stem cells; Periodontitis; TOMM20
    DOI:  https://doi.org/10.1016/j.bbrc.2025.153121
  29. Front Cell Infect Microbiol. 2025 ;15 1714998
    Pathogen-induced mitochondrial dysfunction: mechanistic insights, immune crosstalk, and therapeutic opportunities.
    Yang Yang, Yuanyuan Zeng, Zeyi Liu, Jian-An Huang.
      Mitochondria have emerged as multifunctional organelles central to cellular metabolism, innate immunity, and cell fate determination. Increasing evidence demonstrates that pathogens-including viruses, bacteria, fungi, and parasites-target mitochondria to modulate host immune responses and metabolic reprogramming. Disruption of mitochondrial dynamics, excessive reactive oxygen species (ROS) generation, mitochondrial DNA (mtDNA) release, and altered mitophagy represent key hallmarks of pathogen-induced mitochondrial dysfunction. These processes not only compromise cellular bioenergetics but also influence immune signaling cascades, such as cGAS-STING and NLRP3 inflammasome pathways, thereby shaping infection outcomes. This review synthesizes the latest findings on how distinct pathogen classes orchestrate mitochondrial damage and explores their implications for infection biology and immune regulation. Furthermore, we highlight emerging mitochondria-targeted therapeutic strategies and future research directions aimed at mitigating infection-induced mitochondrial pathology.
    Keywords:  host defense; infection; mitochondria; mitochondrial dynamics; pathogens
    DOI:  https://doi.org/10.3389/fcimb.2025.1714998
  30. Cell Rep Med. 2025 Dec 16. pii: S2666-3791(25)00551-8. [Epub ahead of print]6(12): 102478
    Vesicle-mediated mitochondrial clearance presents an actionable metabolic vulnerability in triple-negative breast cancer.
    Jody Vykoukal, Yihui Chen, Mingxin Zuo, Riccardo Ballarò, Monica J Hong, Hansini Krishna, Daniela B Rodriquez-Perera, Hiroyuki Katayama, Ehsan Irajizad, Ranran Wu, Ricardo A León-Letelier, Jennifer B Dennison, Angelica M Gutierrez, Adriana Paulucci-Holthauzen, Timothy C Thompson, Leona Rusling, Yining Cai, Fu Chung Hsiao, Soyoung Park, Banu Arun, Samir Hanash, Johannes F Fahrmann.
      Selective autophagy of mitochondria is known to promote cancer cell survival and progression, including in triple-negative breast cancer (TNBC). Here, we apply an integrated multi-omics approach together with functional experimental analyses to investigate metabolic adaptations that support mitochondrial quality control in TNBC. We detail a mitochondrial quality control mechanism, complementary to mitophagy, that is enabled by a program of heightened extracellular sphingomyelin salvaging in TNBC coupled with extracellular vesicle-mediated intracellular clearance of mitochondrial damage. Targeting of this onco-metabolic pathway via repurposing of eliglustat, a selective small molecule inhibitor of glucosylceramide synthase, results in ceramide-mediated compensatory mitophagy and cancer cell death in vitro and attenuates tumor growth and prolongs overall survival at clinically achievable doses in orthotopic syngeneic mouse models of TNBC as well as in human cell line-derived xenograft models. Our study defines an unexplored mechanism of aberrant sphingolipid metabolism that underlies an actionable metabolic vulnerability for anti-cancer treatment.
    Keywords:  autophagy; eliglustat; extracellular vesicles; glucosylceramide synthase; mitochondria; sphingolipids; triple-negative breast cancer
    DOI:  https://doi.org/10.1016/j.xcrm.2025.102478
  31. Chem Biol Interact. 2025 Dec 15. pii: S0009-2797(25)00513-7. [Epub ahead of print] 111883
    Targeting trophoblast cell mitochondrial dysfunction in preeclampsia via drug repurposing.
    Dinara Afrose, Sofía Alfonso-Sánchez, Ashleigh Philp, Philip M Hansbro, Qian Peter Su, Lana McClements.
      Preeclampsia is a multifactorial pregnancy disorder characterized by the new onset of hypertension and organ damage. Mitochondrial dysfunction is central to preeclampsia pathogenesis leading to placental dysfunction and oxidative stress. This study aims to elucidate the mechanisms of mitochondrial dysfunction in first-trimester trophoblast cells and to assess the therapeutic potential of aspirin, metformin, resveratrol, and a FKBPL-based peptide (AD-01) as a strategy to improve trophoblast mitochondrial health. A 2D in vitro model using the first trimester ACH-3Ps trophoblasts were developed to mimic preeclamptic conditions, including hypoxia-inducible factor (HIF)-1α activation (DMOG, 100 μM), mitochondrial dysfunction (Rho-6G, 1 μg/mL), and inflammation (TNF-α, 10 ng/ml). Cells were treated for 48 hours with metformin (0.5 mM), resveratrol (15 μM), AD-01 (100 nM), or aspirin (0.5 mM). Mitochondrial dynamics were assessed by immunofluorescence staining, the Seahorse XF Mito Stress Test, and RT-qPCR for key genes expression regulating mitochondrial fusion (mfn1), fission (dnm1l), and autophagy (atg5, map1lc3b). Preeclampsia-mimicking stimuli significantly altered mitochondrial networks by reducing mitochondrial size (p<0.0001), increasing circularity (p<0.0001), and decreasing mitochondrial number per cell (p<0.0001). Metformin notably restored mitochondrial architecture under inflammatory stress, normalized mfn1 (p=0.04) and atg5 expression (p<0.001), and improved cellular bioenergetics. Aspirin improved mitochondrial morphology under hypoxic conditions and reduced oxygen consumption (p<0.01). Resveratrol and AD-01 showed context-dependent protective effects, including reduced basal respiration (p=0.03). These findings demonstrate that hypoxia, inflammation, and mitochondrial dysfunction contribute to mitochondrial pathology in preeclampsia and highlight aspirin, metformin, resveratrol, and AD-01 as promising targeted therapies. Tailored interventions may improve mitochondrial health and pregnancy outcomes in women with preeclampsia.
    Keywords:  Autophagy; Mitochondrial dynamics; Mitochondrial dysfunction; Preeclampsia; Trophoblasts
    DOI:  https://doi.org/10.1016/j.cbi.2025.111883
  32. Free Radic Biol Med. 2025 Dec 16. pii: S0891-5849(25)01439-X. [Epub ahead of print]244 380-394
    Redox switch C674 in SERCA2 triggers Ca2+-calcineurin-MCU-Drp1 cascade and pulmonary vascular remodeling.
    Hui Chen, Yi-Xiang Qiu, Yu-Fei Xie, Xun Chen, Ying-Ying Xiang, Hai-Long Zhang, Wei-Min Yu, Ping-Ping Hu, Lang-Tao Wang, Fu-Hua Wu, Xiao-Yong Tong.
      Pulmonary arterial smooth muscle cell (PASMC) phenotypic switching from a contractile to a proliferative state is a central driver of pulmonary vascular remodeling in pulmonary hypertension (PH). Mitochondrial fragmentation is a key metabolic hallmark of this switch, yet the molecular trigger initiating fragmentation remains undefined. We hypothesized that oxidative dysfunction of sarcoplasmic/endoplasmic-reticulum Ca2+-ATPase 2 (SERCA2) at its redox-sensitive C674 residue governs mitochondrial dynamics in PASMCs. Primary PASMCs were isolated from wild-type (WT) mice and from SERCA2 C674S mutant knock-in (SKI) mice that phenocopy irreversible oxidation of SERCA2 under PH-relevant oxidative stress. Mitochondrial morphology, Ca2+ levels, and membrane potential (ΔΨm) were assessed using Mito-Tracker Red CMXRos, Rhod-2 AM, and Rhodamine 123, respectively. Protein expression was analyzed by Western blot. In vivo experiments employed SKI mice treated with either the dynamin-related protein 1 (Drp1) inhibitor Mdivi-1 or AAV6-mediated SERCA2b gene transfer. SKI PASMCs exhibited extensive mitochondrial fragmentation and upregulated pro-fission proteins, accompanied by downregulated fusion proteins. SERCA2 dysfunction causes mitochondrial Ca2+ overload and ΔΨm loss by upregulating the mitochondrial calcium uniporter (MCU). Chelation of intracellular Ca2+, inhibition of calcineurin, MCU, or Drp1 restored mitochondrial integrity and inhibited PASMC phenotypic switch. In SKI mice, Drp1 inhibition or SERCA2b overexpression attenuated pulmonary vascular remodeling. In conclusion, oxidative disruption of SERCA2-C674 initiates a Ca2+/calcineurin-MCU-Drp1 cascade resulting in mitochondrial fragmentation and PASMC phenotypic switch. Targeting SERCA2b restoration, balancing MCU and mitochondrial Ca2+, or Drp1 blockade offers complementary therapeutic strategies for PH by disrupting this pathogenic axis.
    Keywords:  Dynamin-related protein 1; Mitochondrial calcium uniporter; Pulmonary arterial smooth muscle cell; Pulmonary vascular remodeling; SERCA2
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.12.023
  33. Trends Endocrinol Metab. 2025 Dec 17. pii: S1043-2760(25)00245-0. [Epub ahead of print]
    Uncovering the muscle clock-mitochondria axis through exercise.
    Mauricio Castro-Sepulveda.
      Emerging evidence suggests an interplay between the molecular clock and mitochondrial dynamics in skeletal muscle. In this Forum article, we hypothesize that exercise, as a metabolic challenge, provides a powerful physiological model to investigate the clock-mitochondria axis and its regulatory role in muscle function and metabolic health in humans.
    Keywords:  circadian clock; insulin resistance; mitochondrial dynamics; muscle atrophy
    DOI:  https://doi.org/10.1016/j.tem.2025.11.001
  34. J Neuroinflammation. 2025 Dec 18.
    Intestinal γδ T17-IL-17A signaling disrupts hippocampal mitophagy in stress-induced depression and is restored by arketamine.
    Mengqi Han, Bing Xie, Yuan Yu, Dan Xu, Yuan Shi, Meng Xu, Yuming Wu, Yujing Zhang, Xiaoyue Wen, Xin Wang, Zifan Zhen, Xinyu Zhang, Xueqiang Sun, Yin Yuan, You Shang, Shiying Yuan, Kenji Hashimoto, Jiancheng Zhang.
      Chronic stress precipitates depression, yet how gut-immune-brain interactions translate stress into mood pathology remains unclear. We tested the hypothesis that stress-primed small intestinal γδ T cells drive hippocampal mitochondrial dysfunction and depression-like behavior via interleukin-17A (IL-1A). In mice exposed to chronic restraint stress (CRS), we combined behavioral assays (open-field, sucrose-preference, tail-suspension, forced-swim), 16S rRNA profiling, fecal microbiota transplantation, Kaede photoconversion, conditional CD8α deletion in γδ T cells, hippocampal IL-17A overexpression, rapamycin treatment, and administration of the antidepressant arketamine. CRS increased gut and brain permeability, induced gut-microbiota dysbiosis, and promoted migration of small intestinal CD8α⁺ γδ T17 cells to the meninges and brain; γδ T cells were the predominant IL-17A source in the brain. Kaede tracing confirmed an intestinal origin, and CRS-associated microbiota alone transferred γδ T cell trafficking and depression-like behavior to recipients. In the hippocampus, CRS elevated IL-17A and impaired PINK1/Parkin-mediated mitophagy (decreased PINK1, Parkin, Beclin-1, and LC3B-II/I; increased p62), reduced ATP, and produced mitochondrial and synaptic ultrastructural deficits. IL-17A overexpression further worsened mitophagy and behavior, whereas rapamycin restored both. Conditional deletion of CD8α in γδ T cells reduced brain γδ T17 infiltration, lowered hippocampal IL-17A, rescued mitophagy and synapses, and improved behavior. Arketamine normalized dysbiosis and barrier markers, curtailed γδ T cell trafficking, decreased hippocampal IL-17A, restored mitophagy, and alleviated depression-like behavior in both sexes. These findings delineate a stress-responsive microbiota-γδ T cell-IL-17A pathway that compromises hippocampal mitophagy and identify arketamine as a candidate modulator of this axis, nominating mitophagy and γδ T cell trafficking as translational targets.
    Keywords:  Chronic restraint stress; Depression; Gut-brain axis; Ketamine; Mitophagy; γδT cells
    DOI:  https://doi.org/10.1186/s12974-025-03656-4
  35. Shock. 2025 Dec 01. 64(6): 571-572
    Hydrogen Gas Alleviates Sepsis-Induced Brain Injury by Improving Mitochondrial Biogenesis Through the Activation of PGC-α in Mice: Erratum.
    Keliang Xie, Yaoqi Wang, Lijun Yin, Yuzun Wang, Hongguang Chen, Xing Mao, Guolin Wang.
      
    DOI:  https://doi.org/10.1097/SHK.0000000000002779
  36. Cell Death Dis. 2025 Dec 19.
    CAMK1D activates AMPK/PINK1/Parkin-dependent mitophagy to promote enzalutamide resistance in prostate cancer.
    Feifei Sun, Ying Qu, Shuyu Mei, Lin Zhang, Xianhao Shao, Xinpei Wang, Shijia Liu, Meng Wang, Wenyao Liu, Muyi Yang, Jing Hu, Benkang Shi, Lin Gao, Bo Han.
      Although androgen receptor (AR)-targeted therapies, such as enzalutamide, initially improve outcomes of prostate cancer (PCa) patients, resistance inevitably develops, partly driven by prostate cancer stem-like cells (PCSCs). However, the molecular mechanisms linking the maintenance of PCSCs to enzalutamide resistance (ENZR) remain incompletely elucidated. Here, we implicate Ca²⁺/calmodulin-dependent protein kinase 1D (CAMK1D) in PCSC-mediated ENZR. CAMK1D was consistently upregulated in PCa with ENZR and contributed to ENZR by enhancing mitophagy in PCa cells both in vitro and in vivo. Mechanistically, CAMK1D promotes the expansion of PCSCs by enhancing mitophagy through activation of the AMP-activated protein kinase (AMPK)/PINK1 signaling pathway, thereby facilitating cellular adaptation. We revealed that CAMK1D interacts with and phosphorylates AMPK at Thr172, which in turn activates PINK1 to modulate mitophagy, ultimately supporting the expansion of PCSCs under enzalutamide treatment. In a mouse orthotopic PCa model, targeting the CAMK1D/AMPK pathway with the siCAM/HLNP nanoformulation suppresses tumor growth by depleting the PCSCs population, achieving a synergistic effect with enzalutamide therapy. Our findings identify CAMK1D as a key regulator of ENZR that maintains stemness by orchestrating mitophagy, thereby establishing mitophagy as an important nexus between CAMK1D-mediated ENZR and AMPK-driven PCSC enrichment. Therapeutically, we developed a CAMK1D-targeted approach that potently reverses ENZR and improves treatment responses.
    DOI:  https://doi.org/10.1038/s41419-025-08342-0
  37. Neurobiol Dis. 2025 Dec 12. pii: S0969-9961(25)00439-5. [Epub ahead of print] 107222
    Bioenergetic and protein processing imbalances in iPSC-dopamine neurons from individuals with idiopathic Parkinson's disease.
    Kelsey Bernard, Mandi J Corenblum, Paola Tonino, Lalitha Madhavan.
      Patient induced pluripotent stem cell (iPSC)-based models represent a powerful human system to gain insights into the etiopathology of Parkinson's disease (PD). Here, we studied several iPSC-derived dopamine neuron (iPSC-DAN) lines, from individuals with idiopathic PD, which is the most common form of PD. Specifically, using iPSC-DAN differentiated for 50-55 days, we performed an in-depth analysis of different bioenergetic pathways and cellular quality control mechanisms in the cells. Our results showed wide ranging impairments in oxidative phosphorylation (OXPHOS), glycolysis and creatine kinase pathways in the PD dopamine (DA) neurons. Specifically, the PD neurons exhibited reduced oxygen consumption rates (OCR) at baseline and after challenges with mitochondrial inhibitors, as well as decreased glycolytic reserves measured via ECAR. This translated to lower OCR:ECAR ratios signifying more reliance on glycolysis vs OXPHOS in the PD cells. Moreover, a mislocalization of creatine kinase B to mitochondria was seen in the PD cells. These energetic changes occurred alongside the enhanced expression of mitochondrial fission proteins, disrupted mitophagy and oxidative stress. Additionally, the PD neurons contained more monomeric, phosphorylated, and aggregated forms of alpha synuclein and displayed reduced viability. Ultrastructural examination through immuno-electron microscopy showed more alpha synuclein gold particles directly associated with mitochondria and packed into autophagic vesicles. In essence, these data capture a web of key changes, associated with neuronal degeneration, in human iPSC-DAN from persons with idiopathic PD.
    Keywords:  Dopamine neurons; Glycolysis; Human induced pluripotent stem cells; Oxidative phosphorylation; Protein quality control, alpha Synuclein; Sporadic Parkinson's disease
    DOI:  https://doi.org/10.1016/j.nbd.2025.107222
  38. ACS Appl Mater Interfaces. 2025 Dec 17.
    A Tetrahedral DNA Framework-Based Mitochondrial Anchoring System Promotes Diabetic Wound Healing via Mitophagy and Mitostress Regulation.
    Yangxue Yao, Tianxu Zhang, Yibo Li, Geru Zhang, Yang Gao, Yunfeng Lin, Shaojingya Gao, Xiaoxiao Cai.
      The dysfunction of mitochondria is a prominent factor of the inflammatory microenvironment that delays diabetic wound healing. However, existing methods have limitations of inadequate regulation of mitochondrial function. Herein, a tetrahedral DNA framework-based mitochondrial anchoring system was constructed to regulate mitophagy and mitostress in diabetic wounds. This system, which is fabricated based on tetrahedral framework nucleic acids (tFNAs), is covalently linked with Rhodamine 19 to further load resveratrol, realizing the mitochondria-targeted delivery of resveratrol and sustained drug release. It can activate superoxide dismutase (SOD) to effectively scavenge mitochondrial ROS and promote mitophagy to eliminate damaged mitochondria, thus rescuing cell viability under oxidative stress, promoting cell migration, and upregulating angiogenesis and extracellular matrix-related proteins. In a diabetic skin defect model, TRh-RSV markedly accelerates wound healing by enhancing the regeneration of connective tissues and skin appendages and upregulating mitophagy. These effects are mediated through the suppression of mitochondrial oxidative stress and the concomitant modulation of mitophagy. This study highlights the potential of this system not only for the treatment of refractory diabetic wounds but also for other diseases associated with mitochondrial dysfunction.
    Keywords:  diabetic wound healing; mitochondria; mitophagy; mitostress; resveratrol; tetrahedral framework nucleic acids
    DOI:  https://doi.org/10.1021/acsami.5c19661
  39. Cell Commun Signal. 2025 Dec 18.
    Mitochondria-derived vesicles serve as reactors in response to stress in cardiomyocytes.
    Yiqing Zhou, Shi Jia, Yufei Xiong, Lebin Gan, Saifang Yan, Junhui Zhao, Minghong Leng, Fenghe Yang, Mingyang Zhao, Limei Liu, Yangpo Cao, Jingjing Ye, Ming Zheng.
       BACKGROUND: Mitochondria-derived vesicles (MDVs) are a novel type of mitochondrial quality control (MQC) found in different types of cells. Strictly-organized adult cardiomyocytes contain abundant mitochondria; however, the precise characteristics and functions of MDVs in the heart remain unclear.
    METHODS: Rat cardiomyocytes were examined using transmission electron microscopy (TEM) to visualize MDVs. Live-cell imaging with STED microscopy and fluorescent mitochondrial dyes (PK Mito Red and PK Mito Deep Red) was performed to track MDV dynamics in neonatal and adult rat cardiomyocytes. Nanoparticle tracking analysis (NTA) was used to assess the size and quantity of MDVs. MDVs were purified from heart mitochondria, and their protein profile was analyzed by proteomics. RNA sequencing was conducted on neonatal cardiomyocytes treated with MDVs to explore transcriptomic changes.
    RESULTS: MDVs were observed in live rat cardiomyocytes with TEM revealing vesicles 70-150 nm in diameter. MDVs were universally distributed, showed active motility, and colocalized with other intracellular organelles in adult cardiomyocytes. Proteomics analysis showed MDV-associated proteins and found that the respiratory functions of MDVs were preserved in cardiomyocytes. The number of MDVs in cardiomyocytes was found to increase in response to various acute physiological and pathological stimuli. By increasing the number of MDVs in cardiomyocytes with exogenously purified myocardial MDVs and analyzing transcriptomic changes via RNA sequencing, we found that a greater number of MDVs in cardiomyocytes altered genes in stress-related signaling pathways.
    CONCLUSION: MDVs in cardiomyocytes colocalize with other organelles, which might facilitate inter-organelle communication, and serve as reactors in response to stress in adult cardiomyocytes.
    Keywords:  Adult cardiomyocyte; Inter-organelle communication; MDVs; Mitochondrial dynamics; Response to stress
    DOI:  https://doi.org/10.1186/s12964-025-02547-8
  40. Cells Dev. 2025 Dec 11. pii: S2667-2901(25)00070-1. [Epub ahead of print]185 204063
    A novel role of Mef2a in mitochondrial homeostasis and muscle regeneration during sarcopenia.
    Xin Tao, Suhong Zhang, Yue Li, Gongbing Tu, Dianfu Zhang, Liping Yin.
      Sarcopenia, characterized by an age-related decline in skeletal muscle mass and function, is closely associated with mitochondrial dysfunction. This study aimed to explore the role of myocyte enhancer factor 2A (MEF2A) in alleviating sarcopenia, focusing on its regulatory effect on mitochondrial homeostasis. AAV9-MEF2A was administered to 24-month-old male SAMP8 mice, and their endurance capacity and muscle histology were assessed. In vitro, MEF2A was overexpressed in C2C12 cells to examine its impact on myoblast proliferation and differentiation. Chromatin immunoprecipitation (ChIP), luciferase assays, and rescue experiments were conducted to identify downstream targets and validate the MEF2A-regulated signaling pathway. MEF2A overexpression significantly enhanced endurance performance, with a 1.17-fold increase in muscle mass, a 2.4 to 4.9-fold decrease in muscle atrophy markers compared to the AAV9-NC group, and a nearly 2 to 3-fold increase in mitochondrial biogenesis and antioxidant enzyme expression in aged mice. In C2C12 cells, MEF2A stimulated proliferation (1.8 fold increase in EdU-positive cells vs vector group) and differentiation (2 to 3-fold increase in differentiation markers vs vector group) while improving mitochondrial function through 1.5 to 2-fold increases in both OxPhos complex proteins and mitochondrial biogenesis genes compared to vector control. Mechanistically, MEF2A directly activated the PGC-1α/NRF2 axis, as validated by ChIP and reporter assays. Rescue experiments further verified the critical role of this pathway in MEF2A-mediated effects. These findings demonstrate that MEF2A mitigates sarcopenia by improving mitochondrial function and promoting muscle regeneration via activation of the PGC-1α/NRF2 signaling axis. MEF2A represents a promising therapeutic target for combating age-related muscle degeneration.
    Keywords:  MEF2A; Mitochondrial biogenesis; Myogenic differentiation; PGC-1α/NRF2; Sarcopenia
    DOI:  https://doi.org/10.1016/j.cdev.2025.204063
  41. J Exp Med. 2026 Mar 02. pii: e20250535. [Epub ahead of print]223(3):
    FIP200 regulates plasma B cell differentiation via mitochondrial and heme homeostasis.
    Liling Xu, Maria Bottermann, Paula M Villavicencio, John Warner, Stephanie R Weldon, Zhenfei Xie, Andrew Filby, Xiaotie Liu, Ian G Ganley, Alison E Ringel, Usha Nair, Facundo D Batista.
      Little is known about the role of autophagy in the human humoral immune system. Here, we found that in B cells, genetic ablation of FIP200, a mammalian metabolic sensor that regulates autophagy in response to a range of stimuli, led to diminished humoral immune responses in mice. FIP200-deficient B cells displayed decreased differentiation into plasma cells, as well as mitochondrial dysfunction, alterations in heme biosynthesis, and significant cell death. Notably, the addition of heme was sufficient to rescue plasma cell differentiation of FIP200-deficient B cells. Thus, FIP200 determines B cell fates by controlling mitophagy and metabolic reprogramming.
    DOI:  https://doi.org/10.1084/jem.20250535
  42. Clin Mol Hepatol. 2025 Dec 19.
    ACSS2-mediated acetyl-CoA accumulation promotes mitophagy and tumor growth via increased H3K27ac in HBV-related HCC.
    Shan Li, Jie Hu, Yihan Yan, Xinrui Liu, Xiao Dong, Huijun Liang, Xin Tang, Junji Tao, Rong Zhang, Yuan Hu, Ailong Huang, Kai Wang, Ni Tang.
       Background/Aims: Acetyl coenzyme A (acetyl-CoA) is one of the most essential metabolites in cell metabolism but its function and concentration in hepatocellular carcinoma (HCC) remains elusive and controversial.
    Methods: A comprehensive analysis of acetyl-CoA levels and ACSS2 expression across a range of samples, including patient specimens from both HBV positive and HBV negative HCC individuals, HBV-transgenic mouse HCC models, and multiple cell lines. Furthermore, to evaluate the functional significance of ACSS2 in HBV-related HCC, we implemented both genetic and pharmacological inhibition strategies targeting ACSS2. Molecular mechanism and mitophagy assessment were revealed by CUT &Tag, RNA sequencing, bioinformatic analyses, transmission electron microscopy (TEM) and JC-1 staining.
    Results: Our study revealed a distinct metabolic signature of HBV-related HCC, marked by elevated acetyl-CoA, which was driven by acetyl-CoA synthetase 2 (ACSS2). ACSS2 was upregulated by the carbohydrate response element-binding protein (ChREBP) in HBV-related HCC. Furthermore, ACSS2 improved tumor cell proliferation, an effect that was dependent on its enzymatic activity. Mechanistically, ACSS2-induced acetyl-CoA accumulation activated voltage-dependent anion channels 1 (VDAC1) transcription through increased H3K27ac occupancy, which subsequently promoted mitophagy and HBV-related HCC tumorigenesis. Notably, targeting ACSS2 by depletion or inhibition with a catalytic inhibitor significantly suppressed tumor growth.
    Conclusions: These findings not only illustrate the interplay between metabolic reprogramming, epigenetic modification, and tumorigenesis in the context of HBV infection, but also highlight ACSS2 as a novel metabolic vulnerability in HBV-related HCC. Therefore, targeting ACSS2 could be a novel strategy against HBV-associated HCC.
    Keywords:  Acetyl-CoA; Hepatitis B virus; Histone acetylation; Liver cancer; Mitophagy
    DOI:  https://doi.org/10.3350/cmh.2025.0754
  43. Biochim Biophys Acta Mol Basis Dis. 2025 Dec 15. pii: S0925-4439(25)00481-8. [Epub ahead of print]1872(3): 168131
    CD4+ T-cell-derived small extracellular vesicles induce the apoptosis of renal tubular epithelial cells in diabetic nephropathy by regulating mitochondrial dynamics.
    Qianqian Han, Yutong Zou, Qing Yang, Enrong Ran, Ziyao Li, Fang Liu.
      CD4+ T cells play a critical role in diabetic nephropathy (DN) progression. High-glucose (HG) conditions induce small extracellular vesicle (sEV) cargo loading disorders, but whether CD4+ T cells mediate renal injury via sEVs remains unclear. In vitro, a transformed C3H mouse kidney-1 (TCMK-1)/CD4+ T-cell coculture model revealed that high-glucose (HG) conditions increased CD4+ T-cell-induced lactate dehydrogenase release, reactive oxygen species production, apoptosis of TCMK-1 cells, and mitochondrial dysfunction, as confirmed by enzyme-linked immunosorbent assays, flow cytometry, Western blotting (WB), and transmission electron microscopy (TEM). Notably, compared with those under normal glucose conditions, CD4+ T cells under HG conditions exacerbated these effects more significantly. In vivo, CD4+ T cells were isolated from the blood of C57BL/6J (control) mice and db/db (experimental) mice using magnetic beads, and their sEVs were extracted from the culture medium. These sEVs were injected into corresponding C57BL/6J or db/db mice, with saline-injected mice used as blank controls. Compared with control mice, mice injected with db/db mouse CD4+ T-cell-derived sEVs (both C57BL/6J and db/db recipients) exhibited significant increases in serum creatinine levels and proteinuria, as well as more severe renal pathological injury. TEM, flow cytometry and WB analyses revealed disordered mitochondrial dynamics in renal tubular epithelial cells (RTECs), marked by reduced membrane potential and imbalanced Drp1/Mfn1/Mfn2 expression. Collectively, these findings indicate that CD4+ T cells exacerbate renal injury and disrupt mitochondrial homeostasis in RTECs by releasing sEVs under HG conditions, highlighting the CD4+ T-cell-sEV axis as a potential diagnostic and therapeutic target for DN.
    Keywords:  CD4+ T cells; Diabetic nephropathy; Mitochondrial dynamics; Renal tubular epithelial cells; Small extracellular vesicles (sEVs)
    DOI:  https://doi.org/10.1016/j.bbadis.2025.168131
  44. EMBO Mol Med. 2025 Dec 19.
    Mutant CHCHD10 disrupts cytochrome c oxidation and activates mitochondrial retrograde signaling.
    Márcio Augusto Campos-Ribeiro, Erminia Donnarumma, Hendrik Nolte, Paul Cobine, Elodie Vimont, Dusanka Milenkovic, Juan Diego Hernandez-Camacho, Francina Langa-Vives, Etienne Kornobis, Esthel Pénard, Sonny Yde, Thomas Langer, Véronique Paquis-Flucklinger, Timothy Wai.
      Mutations in CHCHD10, a mitochondrial intermembrane space (IMS) protein implicated in proteostasis and cristae maintenance, cause mitochondrial disease. Knock-in mice modeling the human CHCHD10S59L variant associated with ALS-FTD develop a mitochondrial cardiomyopathy driven by CHCHD10 aggregation and activation of the mitochondrial integrated stress response (mtISR). We show that cardiac dysfunction is associated with dual defects originating at the onset of disease: (1) bioenergetic failure linked to impaired mitochondrial copper homeostasis and cytochrome c oxidation, and (2) maladaptive mtISR signaling via the OMA1-DELE1-HRI axis. Using protease-inactive Oma1E324Q/E324Q knock-in mice, we show that blunting mtISR in Chchd10S55L/+ mice delays cardiomyopathy onset without rescuing CHCHD10 insolubility, cristae defects or OXPHOS impairment. Proteomic profiling of insoluble mitochondrial proteins in Chchd10S55L/+ mice reveals widespread disruptions of mitochondrial proteostasis, including IMS proteins involved in cytochrome c biogenesis. Defective respiration in mutant mitochondria is rescued by the addition of cytochrome c, pinpointing IMS proteostasis disruption as a key pathogenic mechanism. Thus, mutant CHCHD10 insolubility compromises metabolic resilience by impairing bioenergetics and stress adaptation, offering new perspectives for the development of therapeutic targets.
    Keywords:  CHCHD10; Cardiomyopathy; Cytochrome c; Mitochondrial Disease; OMA1
    DOI:  https://doi.org/10.1038/s44321-025-00358-5
  45. J Nanobiotechnology. 2025 Dec 14.
    Endothelial mitochondrial-derived vesicles (EMDVs) with retinal targeted homing properties dynamically modulate the eIF2α-ATF4-CHOP signaling pathway and efficiently restore mitochondrial homeostasis in diabetic retina.
    Siyu Gui, Jie Gao, Tianchang Tao, Peng Wang, Yueyang Xu, Zhihao Huang, Yuyang She, Jiajie Li, Jingwan Su, Zhe Lu, Jianchao Qiao, Song Wang, Xiaodong Sun, Mohan Li.
      
    Keywords:  Blood-retinal barrier; Diabetic retinopathy; Drug delivery; Endothelial mitochondria-derived vesicles; Integrated stress response; Mitochondrial quality control
    DOI:  https://doi.org/10.1186/s12951-025-03929-3
  46. Carcinogenesis. 2025 Dec 18. pii: bgaf092. [Epub ahead of print]
    LncRNA-encoded peptide LRRC75A-AS1-ORF3 suppresses anti-tumor immunity in colorectal cancer through mitophagy-mediated attenuation of cGAS-STING signaling.
    Qi Wu, Zhun Li, Xinxin He, Shuhui Yu, Mengrou Zhang, Hui Mo, Saiqi He, Jianming Li, Wen Ni.
      Long non-coding RNAs (lncRNAs) serve as pivotal regulators of diverse physiological activities through their interactions with different biomolecules, and their aberrant expression frequently contributes to tumorigenesis and malignant progression. Emerging evidence has demonstrated that certain lncRNAs contain open reading frames (ORFs) that can generate useful short peptides, which influence cancer-related physiological and pathological pathways via diverse mechanisms. In this research, we identified that the lncRNA LRRC75A-AS1 encodes a conserved peptide consisting of 102 amino acids, designated as LRRC75A-AS1-ORF3. Notably, this peptide acts independently of the non-coding RNA itself to suppress anti-tumor immune responses and promote colorectal cancer (CRC) progression. Mechanistically, LRRC75A-AS1-ORF3 is localized in the mitochondria, where it induces mitophagy, thereby eliminating cytosolic mitochondrial DNA (mtDNA) and downregulating the cGAS-STING signaling pathway. Our findings reveal a previously uncharacterized mechanism by which LRRC75A-AS1-ORF3 impairs anti-tumor immunity, thereby presenting a novel immunotherapeutic target for CRC treatment.
    Keywords:  Colorectal Cancer; LncRNA-encoded peptide LRRC75A-AS1-ORF3; anti-tumor immunity; cGAS-STING signaling; mitophagy
    DOI:  https://doi.org/10.1093/carcin/bgaf092
  47. Front Pharmacol. 2025 ;16 1661144
    Gallic acid attenuates diabetic cardiomyopathy by inhibiting ferroptosis and protecting mitochondria via the TSPO/FTMT pathway.
    Chenchao Zou, Huaihan Xu, Fajia Hu, Yuxian Yu, Lanxiang Liu, Xiuqi Wang, Zheyu Zhang, Huaxi Zou, Jichun Liu, Huang Huang, Songqing Lai.
       Purpose: Diabetic cardiomyopathy (DCM), which is diabetes mellitus-induced cardiomyopathy, significantly elevates the risk of heart failure and sudden cardiac death. No specific treatments for DCM are currently available. Gallic acid (GA) is a polyhydroxyphenolic compound that has been shown to inhibit ferroptosis and maintain mitochondrial homeostasis, with potential therapeutic effects in various cardiac diseases. However, its specific role and underlying mechanisms in DCM remain unexplored.
    Methods: An in vitro model was established using H9C2 cells pretreated with high glucose plus palmitate, and an in vivo type 2 diabetes mellitus model generated by treating rats with streptozotocin-induced and feeding a high-fat diet. The protective effects of GA and its mechanism of action were evaluated using various methods, including flow cytometry, Western blotting (WB), and transmission electron microscopy. Bioinformatics analysis identified potential target genes for GA's cardioprotection, which were subsequently validated using pAD/TSPO (for overexpression) and pAD/FTMT-shRNA (for silencing) constructs.
    Results: GA treatment decreased PTGS2, lactate dehydrogenase, malondialdehyde, ferrous iron, ROS, and oxidized glutathione disulfide (GSSG) levels and increased cell viability, glutathione (GSH) levels, the GSH/GSSG ratio, and GPX4 protein levels in the injury models. GA markedly attenuated mitochondrial ultrastructural damage and promoted mitochondrial homeostasis. These protective effects were abrogated by TSPO overexpression and FTMT silencing.
    Conclusion: GA was shown to attenuate diabetic cardiomyopathy by inhibiting ferroptosis and protecting mitochondria via the TSPO/FTMT signaling pathway.
    Keywords:  diabetic cardiomyopathy; ferroptosis; mitochondrial homeostasis; phytochemical; reactive oxygen species
    DOI:  https://doi.org/10.3389/fphar.2025.1661144
  48. J Ethnopharmacol. 2025 Dec 17. pii: S0378-8741(25)01760-X. [Epub ahead of print] 121067
    Cannabidiol attenuates the LPS/D-Galactosamine-induced acute liver injury by inhibiting parkin-mediated ubiquitination of MFN2.
    Zhikun Zhan, Yaojie Jiang, Siyu Chen, Qiyuan Yang, Guanxing Pan, Yiwei Liu, Weipeng Fang, Runzhi Chen, Lan Tang, Cuihong Lin.
       ETHNOPHARMACOLOGICAL RELEVANCE: Acute liver injury (A-LI) is a clinical syndrome that can rapidly progress to acute liver failure, resulting in high mortality and poor prognosis. Cannabis sativa L. is an important herbaceous plant that has been widely used in folk medicine since ancient times. Cannabidiol (CBD) is its most abundant non-psychoactive compound, exhibiting hepatoprotective, anti-inflammatory, and antioxidant properties. However, the protective effect of CBD against A-LI and its mechanism remain unclear.
    OBJECTIVE: This study aimed to investigate the protective effects of CBD on A-LI and elucidate the underlying molecular mechanisms.
    METHODS: In vivo, an A-LI mouse model was induced by LPS/D-GalN. Each group was treated with or without LPS/D-GalN or CBD. H&E staining, alanine aminotransferase (ALT), aspartate aminotransferase (AST) level assay, TUNEL staining, TEM, IF, RT-qPCR, Western blot, Co-IP and adeno-associated virus (AAV) infection were performed. In vitro, RAW264.7 cells were stimulated with LPS. CCK-8, ELISA, MMP, mitochondrial ROS assay, siRNA knockdown and plasmid overexpression were performed.
    RESULTS: CBD (2.5 or 5 mg kg-1) mitigated LPS/D-GalN-induced liver damage, suppressed inflammatory cytokine expression, reduced hepatocellular apoptosis, and inhibited oxidative stress. CBD treatment increased hepatic mitofusin-2 (MFN2) protein while decreasing Parkin-MFN2 binding and MFN2 ubiquitination. In RAW264.7 cells, CBD pretreatment (2.5 or 5 μM) dose-dependently attenuated LPS-induced inflammation, apoptosis, and mitochondrial dysfunction and likewise elevated MFN2 levels while limiting its ubiquitination. MFN2 knockdown abolished CBD's protective effects, whereas MFN2 overexpression restored them. Consistently, AAV-mediated delivery of MFN2-targeting short hairpin RNA reversed the hepatoprotective action of CBD in vivo.
    CONCLUSION: CBD mediates anti-inflammatory and hepatoprotective effects by inhibiting MFN2 degradation through disrupting the interaction between Parkin and MFN2. These results provide molecular evidence for application of CBD in treatment of A-LI and provide references to the drug development for A-LI.
    Keywords:  Acute Liver Injury; Cannabidiol; LPS; Mitofusin-2; Parkin
    DOI:  https://doi.org/10.1016/j.jep.2025.121067
  49. Rev Assoc Med Bras (1992). 2025 ;pii: S0104-42302025001200619. [Epub ahead of print]71(12): e20251136
    Enoxaparin preserves cellular morphology and modulates mitophagy-associated Parkin-LC3 in acute ischemic rat myocardium.
    Fevzi Ayyıldız, Uğur Karagöz, Tünay Kurtoğlu, Pınar Akokay, Çağatay Bilen.
       OBJECTIVE: Despite the longstanding clinical use of low-molecular-weight heparins and their well-characterized mechanisms of action, their effects on mitophagy pathways in acute myocardial ischemia remain incompletely delineated. The aim of this study was to investigate the enoxaparin effect on cardiomyocyte morphology and the immunopositivity of mitophagy-associated Parkin-LC3 proteins in a rat model of acute myocardial ischemia.
    METHODS: Female Wistar albino rats (median weight: 400 g, minimum: 375 g-maximum: 415 g) were divided into sham (n=7), control (n=7), and treatment (n=7) groups. The control group received subcutaneous 0.9% saline (0.2 mL/kg) twice daily for 28 days, followed by the induction of myocardial ischemia. The treatment group was administered subcutaneous enoxaparin sodium (1 mg/kg) twice daily for the same duration before undergoing myocardial ischemia. Myocardial ischemia was induced by occluding the proximal left anterior descending coronary artery using a 6-0 polypropylene suture for 10 min. Morphometric calculations of cardiomyocytes (cell length and diameter) were performed using light microscopy. Immunohistochemical analysis was performed using anti-Parkin and anti-LC3 antibodies, and immunopositive cells were counted.
    RESULTS: Statistically significant differences were found between the groups (p<0.001). Post-hoc analysis revealed significant differences between the control and treatment groups based on cell length, cell diameter, Parkin, and LC3 values (p<0.001, p=0.001, p<0.001, and p=0.001, respectively).
    CONCLUSION: This study demonstrated that enoxaparin preserved cardiomyocyte morphology and reduced the number of Parkin-LC3 immunopositive cells in a model of induced acute ischemic injury in rat myocardium.
    DOI:  https://doi.org/10.1590/1806-9282.20251136
  50. Cell Prolif. 2025 Dec 19. e70153
    Mitophagy and Bip-PERK-eIF2α-ATF4 Axis-Mediated ER Stress Mediate Miriplatin-Loaded Liposome's Anti-Colorectal Cancer Action.
    Cong Zhao, Yuhan Qiu, Xiaowei Wang, Mengyan Wang, Li Liu, Xiaojun Zhao, Zixiang Gao, Rongguang Shao, Guimin Xia, Wuli Zhao.
      LMPt enters the cell mainly through caveolin-mediated endocytosis, and then fuses with endosomes and lysosomes to deliver MPt to mitochondria and the endoplasmic reticulum to induce mitophagy based on the fusion of lysosomes and mitochondria, and endoplasmic reticulum stress and subsequent apoptosis via the Bip-PERK-eIF2α-ATF4 axis to exert an anti-breast cancer effect.
    DOI:  https://doi.org/10.1111/cpr.70153
  51. Cell Rep Med. 2025 Dec 16. pii: S2666-3791(25)00580-4. [Epub ahead of print]6(12): 102507
    Targeting long-chain acylcarnitine accumulation to protect cardiac mitochondrial homeostasis after complete revascularization.
    Rui Lin, Yuyu Li, Shiwei Yang, Hai Gao, Fengjuan Li, Xue Wang, Xin Tan, Zhengkai Wang, Weiyao Chen, Lu Ren, Xiujie Wang, Li Wang, Jun Qin, Wenjie Yin, Jie Du, Yuan Wang.
      Approximately 20% of acute myocardial infarction (AMI) patients with multivessel disease experience adverse outcomes after complete revascularization. We aim to investigate the underlying metabolic mechanism of ischemia-reperfusion injury responsible for abnormal hemodynamic stresses in high-risk patients undergoing complete revascularization. Elevated preoperative serum levels of long-chain acylcarnitine (LCAC) 16:1 are associated with an increased risk of poor prognosis following complete revascularization. Multi-omics analyses reveal that reperfusion injury activates fatty acid degradation, and carnitine palmitoyltransferase 1A (CPT1A) is identified as a key regulator of LCACs in the interaction network in porcine models. In the early stages of reperfusion injury in non-culprit lesions, the release and prolonged elevation of circulating LCACs primarily depend on the activation of endothelial CPT1A through hemodynamic injury, which can be reduced using an inhibitor (etomoxir). Excess LCACs enter cardiomyocytes via the organic cation transporter 2, leading to imbalanced mitochondrial quality control and causing cardiomyocyte death.
    Keywords:  CPT1A; complete revascularization; hemodynamic shear stress; long-chain acylcarnitine metabolism; non-culprit lesion; reperfusion injury
    DOI:  https://doi.org/10.1016/j.xcrm.2025.102507
  52. RSC Med Chem. 2025 Dec 11.
    Correction: Novel small molecule derivatives improve survivability in the cellular model of Huntington's disease via improving mitochondrial fusion.
    Pradeep Kodam, Vaishali Kumar, Paramita Pattanayak, Praharsh Vitta, Tanmay Chatterjee, Shuvadeep Maity.
      [This corrects the article DOI: 10.1039/D5MD00345H.].
    DOI:  https://doi.org/10.1039/d5md90052b
  53. Chem Biol Interact. 2025 Dec 16. pii: S0009-2797(25)00515-0. [Epub ahead of print] 111885
    Celastrol induces cardiotoxicity by directly targeting AMOTL2 and inhibiting YAP1/PGC-1α/TFAM-dependent mitochondrial biogenesis.
    Huiying Shang, Hongbo Cheng, Wei Zhou, Xianglin Tang, Weiye Han, Xiaotong Zhang, Chengrong Xiao, Yehui Gao, Xian Liu, Yue Gao.
      Celastrol is a promising therapeutic candidate for cancers, metabolic diseases, and autoimmune disorders. However, recent studies demonstrated consecutive administration of celastrol at anticancer doses may induce severe heart injuries, which significantly limited its clinical translation. This study aimed to investigate the cellular target and potential mechanism underlying celastrol-induced cardiotoxicity. Consecutive i.p. injection of celastrol for 14 days induces cardiotoxicity in mice, as evidenced by reduced heart-to-body weight ratio, decreased cardiac output and stroke volume, and increased serum cardiac enzymes and proinflammatory cytokine levels in heart tissues. At the cellular level, celastrol triggered mitochondrial dysfunction and promoted cardiomyocyte apoptosis through activation of the mitochondrial pathway, as evidenced by altered B-Cell Lymphoma 2/Bcl-2-Associated X Protein (Bax/Bcl-2) ratio and expression of Cysteinyl aspartate specific proteinase 3 (caspase-3). Mechanistically, we identified Angiomotin-Like Protein 2 (AMOTL2) as a direct cellular target of celastrol using activity-based protein profiling (ABPP). Celastrol-AMOTL2 binding initiated a signaling cascade through Hippo pathway activation, promoting Yes-Associated Protein 1 (YAP1) phosphorylation and subsequent degradation. Knockdown of AMOTL2 by short hairpin RNA attenuated celastrol-induced cardiomyocyte apoptosis by enhancing YAP1 expression and mitochondrial biogenesis. These findings demonstrate that celastrol induces cardiotoxicity by directly targeting AMOTL2 and disrupting YAP1/PGC-1α/TFAM-dependent mitochondrial biogenesis.
    Keywords:  AMOTL2; Cardiotoxicity; Celastrol; Mitochondrial biogenesis; YAP1
    DOI:  https://doi.org/10.1016/j.cbi.2025.111885
  54. Nat Commun. 2025 Dec 17.
    TMEM65-dependent Ca2+ extrusion safeguards mitochondrial homeostasis.
    Massimo Vetralla, Lena Wischhof, Asrat Kahsay, Vanessa Cadenelli, Enzo Scifo, Beijia Xie, Miriana Sbrissa, Maëlle Sandhira Habert, Dan Ehninger, Rosario Rizzuto, Daniele Bano, Diego De Stefani.
      The bidirectional transport of Ca2+ into and out of mitochondria regulates metabolism, signaling, and cell fate. While influx is mediated by the Mitochondrial Calcium Uniporter (MCU) complex, efflux mechanisms are more diversified, involving Na⁺ or H⁺ exchange pathways. We here demonstrate that TMEM65 is a fundamental component of the Ca2+ efflux machinery of mitochondria. Its overexpression specifically enhances Na⁺- and Li⁺-dependent mitochondrial Ca²⁺ extrusion. This effect is inhibited by CGP-37157 and does not depends on NCLX, currently considered the bona fide mitochondrial Na+/Ca2+ exchanger. Its downregulation chronically elevates basal [Ca²⁺]mt and impairs efflux upon stimulation. In Caenorhabditis elegans, deletion of TMEM65 homologs compromises embryonic development under mild thermal stress, causing necrotic lesions that are suppressed by genetic inhibition of MCU-1. These findings highlight a molecular component that may be relevant in pathological settings in which excessive mitochondrial Ca2+ accumulation critically contribute to degenerative pathways.
    DOI:  https://doi.org/10.1038/s41467-025-67647-y
  55. Naunyn Schmiedebergs Arch Pharmacol. 2025 Dec 19.
    Telmisartan ameliorates reproductive dysfunction, oxidative stress, and mitochondrial damages induced by fipronil in male rats via regulation of Nrf2/HO-1/PGC-1α/MNF2/DRP1.
    Alyaa R Salama, Asmaa A Aboushouk, Ali El-Far, Neveen R Ashoura, Aya H Rohiem, Hanan A Edres, Hebatallah M Saad.
      Fipronil (FIP), as a broad-spectrum pesticide, contributes to adverse reproductive effects. Thus, our study aimed to investigate the effect of telmisartan (TEL) as a selective angiotensin 1 receptor (AT1R) blocker on mitochondrial damage induced by FIP intoxication in male rats. Forty healthy male albino rats were allocated into 4 groups (10/ group): the control group, the TEL group received TEL (10 mg/kg b.wt.), the FIP group received FIP (1/10 of the LD50 of 97 mg/kg b.wt.), and the FIP + TEL cotreated group. All treatments were taken orally for 60 days. Before the experiment, in-silico assessments of FIP and TEL were done. FIP administration diminished relative testicular weight, sperm count, and motility, besides significantly increasing sperm abnormalities (p < 0.05). Biochemically, FIP treatment reduced considerably (p < 0.05) serum testosterone, luteinizing hormone (LH), and follicular-stimulating hormone (FSH) levels related to control animals. Furthermore, FIP administration significantly increased testicular malondialdehyde (MDA), pro-inflammatory markers as tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) levels. Also, downregulated the activities of antioxidant markers, Nrf2, HO-1, and PCNA immunostaining. Furthermore, FIP significantly upregulated (p < 0.05) DRP1 and downregulated PGC-1α, MNF2, TFAM, and mtDNA mRNA transcripts. Histopathologically, FIP induced deterioration in seminiferous tubules' histoarchitecture with upregulation in Cosentino's score and downregulation in Johnson's score. On the contrary, TEL effectively restored the testicular function hormones, testicular and epididymal histoarchitecture, antioxidant indices, PGC-1α, and TFAM, with downregulation in MDA levels and DRP1 mRNA transcript. In conclusion, TEL protects the testicular mitochondria against damage from FIP toxicosis by modulating the Nrf2/HO-1/PGC-1α/MNF2/DRP1 expressions.
    Keywords:  DRP1; Fipronil; MNF2; NRF2; Telmisartan
    DOI:  https://doi.org/10.1007/s00210-025-04812-6
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