bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2025–02–23
sixty-nine papers selected by
Gavin McStay, Liverpool John Moores University
  1. The role of mitochondrial biogenesis, mitochondrial dynamics and mitophagy in gastrointestinal tumors.
  2. Diminazine protects against cardiac aging through the improvement of mitophagy and apoptosis in aging rats induced by D-galactose.
  3. E2F1/CDK5/DRP1 axis mediates microglial mitochondrial division and autophagy in the pathogenesis of cerebral ischemia-reperfusion injury.
  4. High intensity interval training alters gene expression linked to mitochondrial biogenesis and dynamics in high fat diet fed rats.
  5. VPS13D mutations affect mitochondrial homeostasis and locomotion in Caenorhabditis elegans.
  6. Mitophagy is required to protect against excessive skeletal muscle atrophy following hindlimb immobilization.
  7. Stress-induced mitochondrial fragmentation in endothelial cells disrupts blood-retinal barrier integrity causing neurodegeneration.
  8. Porcine epidemic diarrhea virus induces mitophagy to inhibit the apoptosis and activation of JAK/STAT1 pathway.
  9. Dexmedetomidine ameliorates hepatic ischemia reperfusion injury via modulating SIRT3 mediated mitochondrial quality control.
  10. Low-Magnitude High-Frequency Vibration Attenuates Sarcopenia by Modulating Mitochondrial Quality Control via Inhibiting miR-378.
  11. Modulating mitochondrial dynamics preserves cognitive performance via ameliorating iron-mediated brain toxicity in iron-overload rats.
  12. A dual-channel fluorescent probe with mitochondria-immobilization: Detecting polarity and viscosity during mitophagy.
  13. TRAF6 integrates innate immune signals to regulate glucose homeostasis via Parkin-dependent and -independent mitophagy.
  14. Loss of an uncharacterized mitochondrial methionine tRNA-synthetase induces mitochondrial unfolded protein response in Caenorhabditis elegans.
  15. Urolithin A Enhances Tight Junction Protein Expression in Endothelial Cells Cultured In Vitro via Pink1-Parkin-Mediated Mitophagy in Irradiated Astrocytes.
  16. NRF-1 promotes FUNDC1-mediated mitophagy as a protective mechanism against hypoxia-induced injury in cardiomyocytes.
  17. SIRT3-Mediated Deacetylation of DRP1K711 Prevents Mitochondrial Dysfunction in Parkinson's Disease.
  18. Mitochondrial alterations and signatures in hepatocellular carcinoma.
  19. MEK5-ERK5 pathway mediates mitophagy by regulating Nur77 to promote tumorigenesis of osteosarcoma cells.
  20. Imbalanced mitochondrial dynamics in human and mouse PD brains.
  21. Curcuma wenyujin extract alleviates cognitive deficits and restrains pyroptosis through PINK1/Parkin mediated autophagy in Alzheimer's disease.
  22. PFOS causes lysosomes-regulated mitochondrial fission through TRPML1-VDAC1 and oligomerization of MCU/ATP5J2.
  23. Chlorogenic acid inhibits Pseudomonas toxin pyocyanin and activates mitochondrial UPR to protect host against pathogen infection.
  24. Mitophagy at the oocyte-to-zygote transition promotes species immortality.
  25. Cornuside alleviates cognitive impairments induced by Aβ1-42 through attenuating NLRP3-mediated neurotoxicity by promoting mitophagy.
  26. Trilobatin, a Naturally Occurring GPR158 Ligand, Alleviates Depressive-like Behavior by Promoting Mitophagy.
  27. Pyruvate kinase M2 modulates mitochondrial dynamics and EMT in alveolar epithelial cells during sepsis-associated pulmonary fibrosis.
  28. SIRT1 Alleviates Oxidative Stress-Induced Mitochondrial Dysfunction and Mitochondria-Associated Membrane Dysregulation in Stress Urinary Incontinence.
  29. α-asarone activates mitophagy to relieve diabetic encephalopathy via inhibiting apoptosis and oxidative stress.
  30. Increased Matrix Stiffness Promotes Slow Muscle Fibre Regeneration After Skeletal Muscle Injury.
  31. Empagliflozin attenuates renal damage in diabetic nephropathy by modulating mitochondrial quality control via Prdx3-PINK1 pathway.
  32. Polysaccharide alleviates neurodegeneration and behavioral deficit by enhancing mitochondrial autophagy in chronic methamphetamine mice.
  33. Overexpression of hnRNPK and inhibition of cytoplasmic translocation ameliorate lipid disorders in doxorubicin cardiotoxicity via PINK1/Parkin-mediated mitophagy.
  34. Electroacupuncture enhances the mitophagy of granulosa cells in premature ovarian insufficiency model mice by inactivating the hippo-yes-associated protein/transcriptional co-activator with postsynaptic density protein, drosophila disc large tumor suppressor, and zonula occludens-1 protein binding motif pathway.
  35. Distinct developmental outcomes in DNA repair-deficient FANCC c.67delG mutant and FANCC-/- Mice.
  36. Mdm38/LETM1 couples ion homeostasis and proteostatic mechanisms in the inner mitochondrial membrane.
  37. WIPI1-mediated mitophagy dysfunction in ventricular remodeling associated with long-term diabetes mellitus.
  38. Mitophagy impairment drives microglia activation and results in cognitive deficits in neonatal mice following sevoflurane exposure.
  39. Chaihuang Yishen Granule ameliorates mitochondrial homeostasis by upregulating PRDX5/TFAM axis to inhibit renal fibrosis in CKD.
  40. Corrigendum to "Rg1 improves Alzheimer's disease by regulating mitochondrial dynamics mediated by the AMPK/Drp1 signaling pathway" [J. Ethnopharmacol. 340 (2025) 119285].
  41. Hydroxychloroquine corrects mitochondrial recycling dysfunction in natural killer cells from patients with systemic lupus erythematosus.
  42. 17-beta estradiol prevents cardiac myocyte hypertrophy by regulating mitochondrial E3 ubiquitin ligase 1.
  43. ZLN005, a PGC-1α agonist, delays photoreceptor degeneration by enhancing mitochondrial biogenesis in a murine model of retinitis pigmentosa.
  44. Hypoxia induces ferroptotic cell death mediated by activation of the inner mitochondrial membrane fission protein MTP18/Drp1 in invertebrates.
  45. Evaluation of GFM1 mutations pathogenicity through in silico tools, RNA sequencing and mitophagy pahtway in GFM1 knockout cells.
  46. Alda-1 mediates cell senescence and counteracts bone loss in weightlessness through regulating mitophagy.
  47. MitoQ alleviates H2O2-induced mitochondrial dysfunction in keratinocytes through the Nrf2/PINK1 pathway.
  48. Olfactory mucosa mesenchymal stem cell-derived exosomes protect against neuroinflammation after subarachnoid hemorrhage by activating mitophagy.
  49. Vitexin enhances mitophagy and improves renal ischemia-reperfusion injury by regulating the p38/MAPK pathway.
  50. Micheliolide attenuates sepsis-induced acute lung injury by suppressing mitochondrial oxidative stress and PFKFB3-driven glycolysis.
  51. Manganese dioxide coupled metal-organic framework as mitophagy regulator alleviates periodontitis through SIRT1-FOXO3-BNIP3 signaling axis.
  52. Correction: Psmb8 inhibits mitochondrial fission and alleviates myocardial ischaemia/reperfusion injury by targeting Drp1 degradation.
  53. Precise targeting of transcriptional co-activators YAP/TAZ annihilates chemoresistant brCSCs by alteration of their mitochondrial homeostasis.
  54. Distinctive autophagy/mitophagy biomarker profiles in frontotemporal lobar degeneration and Alzheimer's disease.
  55. Dual regulation of mitochondrial fusion by Parkin-PINK1 and OMA1.
  56. Regular exercise alleviates metabolic dysfunction-associated steatohepatitis through rescuing mitochondrial oxidative stress and dysfunction in liver.
  57. Long-term adaptation of lymphoma cell lines to hypoxia is mediated by diverse molecular mechanisms that are targetable with specific inhibitors.
  58. Exploring the therapeutic potential of MOTS-c in age-related macular degeneration: from cellular responses to patient-derived cybrids.
  59. Mitochondrial translation regulates terminal erythroid differentiation by maintaining iron homeostasis.
  60. Putting the brakes on mitochondrial fusion to prevent escape of mitochondrial DNA.
  61. Mitochondrial fission produces a Warburg effect via the oxidative inhibition of prolyl hydroxylase domain-2.
  62. ONC201-Derived Tetrahydropyridopyrimidindiones as Powerful ClpP Protease Activators to Tackle Diffuse Midline Glioma.
  63. How are mitochondrial nucleoids trafficked?
  64. Electroacupuncture alleviates diabetic peripheral neuropathy through modulating mitochondrial biogenesis and suppressing oxidative stress.
  65. Etomidate Induces Mitochondrial Dysfunction in Glioma Cancer Cells by Inhibiting Mitochondrial Biogenesis Mediated by CREB/PGC-1α.
  66. ATF3 Knockdown Exacerbates Astrocyte Activation by Inhibiting Phosphorylation of Drp1 in Ischemic Stroke.
  67. Lon protease 1-mediated metabolic reprogramming promotes the progression of prostate cancer.
  68. Mitochondrial Dysfunction in Diabetes: Shedding Light on a Widespread Oversight.
  69. Melatonin ameliorates Pb-induced mitochondrial homeostasis and ovarian damage through regulating the p38 signaling pathway.
  1. Cancer Cell Int. 2025 Feb 15. 25(1): 46
    The role of mitochondrial biogenesis, mitochondrial dynamics and mitophagy in gastrointestinal tumors.
    Yihong Liu, Hao Wang, Shen Zhang, Na Peng, Shuangshuang Hai, Haibo Zhao, Jingwei Liu, Weixin Liu.
      Gastrointestinal tumors remain the leading causes of cancer-related deaths, and their morbidity and mortality remain high, which imposes a great socio-economic burden globally. Mitochondrial homeostasis depend on proper function and interaction of mitochondrial biogenesis, mitochondrial dynamics (fission and fusion) and mitophagy. Recent studies have demonstrated close implication of mitochondrial homeostasis in gastrointestinal tumorigenesis and development. In this review, we summarized the research progress on gastrointestinal tumors and mitochondrial quality control, as well as the underlying molecular mechanisms. It is anticipated that the comprehensive understanding of mitochondrial homeostasis in gastrointestinal carcinogenesis would benefit the application of mitochondria-targeted therapies for gastrointestinal tumors in future.
    Keywords:  Gastrointestinal tumors; Mitochondrial biogenesis; Mitochondrial dynamics; Mitochondrial quality control; Mitophagy
    DOI:  https://doi.org/10.1186/s12935-025-03685-2
  2. BMC Cardiovasc Disord. 2025 Feb 18. 25(1): 110
    Diminazine protects against cardiac aging through the improvement of mitophagy and apoptosis in aging rats induced by D-galactose.
    Ensiyeh Velayati, Abdolrahman Sarihi, Mohammad Zarei, Alireza Komaki, Fatemeh Ramezani-Aliakbari.
       BACKGROUND: Mitochondrial dysfunction is a main feature of the aged heart. However, there is still no effective treatment against cardiac aging. Diminazine (DIZE) is an anti-infective agent for animals. It is effective against cardiac disorders. The present study aimed to investigate the effects of DIZE on age-related cardiac dysfunction.
    METHODS AND RESULTS: Wistar rats were randomly divided into four groups, with eight rats per group: control rats (CONT), control rats treated with DIZE (CONT + DIZE), aged rats induced by D-galactose (D-GAL), aged rats treated with DIZE (D-GAL + DIZE). Rats received intraperitoneal (IP) injection of D-GAL at 150 mg/kg daily for 8 weeks to induce aging. The aging animals in the D-GAL + DIZE group were treated with subcutaneous injection of DIZE at 15 mg/kg daily for 8 weeks. Heart tissues were harvested to assay molecular parameters. Our results exhibited cardiac hypertrophy and a significant increase in the expression of cardiac BCL2-associated X (Bax) along with a significant decrease in the expression of cardiac Mitofusin 2 (Mfn2), Phosphatase, and tensin homolog (PTEN)-induced putative kinase 1 (PINK1), Dynamin-related protein 1 (Drp1), and B-cell lymphoma 2 (Bcl2) in the aged rats compared with the control animals. DIZE treatment improved cardiac hypertrophy and the expression of genes.
    CONCLUSIONS: Overall, DIZE treatment significantly reversed the downregulation of PINK1, Mfn2, and Drp1. Moreover, DIZE significantly inhibited apoptosis though improving the gene expression of Bax and Bcl-2 in the heart. DIZE is effective in reducing cardiac hypertrophy induced aging through regulating mitochondrial dynamics, mitophagy and apoptosis.
    Keywords:  Aging; Apoptosis; Cardiac hypertrophy; Diminazine; Mitophagy
    DOI:  https://doi.org/10.1186/s12872-025-04572-4
  3. Clin Transl Med. 2025 Feb;15(2): e70197
    E2F1/CDK5/DRP1 axis mediates microglial mitochondrial division and autophagy in the pathogenesis of cerebral ischemia-reperfusion injury.
    Ya-Jing Yuan, Tingting Chen, Yan-Ling Yang, Hao-Nan Han, Li-Ming Xu.
       BACKGROUND: The integrity of brain function is at stake due to cerebral ischemia-reperfusion injury (CIRI), which encompasses mitochondrial dysfunction, autophagy, and neuroinflammation. The role of E2F1 in mediating these processes in microglia during CIRI remains unclear.
    METHODS: A CIRI mouse model was utilized for single-cell RNA transcriptome sequencing of brain tissues. The research comprised diverse gene expression, gene ontology (GO), and the enrichment of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Experimental techniques included oxygen-glucose deprivation (OGD/R) cell models, RT-qPCR, Western Blot, ChIP assays, and microglia-neuron co-cultures.
    RESULTS: A significant aspect highlighted in the study was the involvement of CDK5 in the induction of mitochondrial abnormalities associated with CIRI. Upregulation of E2F1 and CDK5 in post-CIRI microglia was observed. E2F1 facilitated CDK5 transcription, leading to DRP1 phosphorylation, exacerbating neurotoxic effects. Silencing E2F1 improved neurobehavioral outcomes in CIRI mice.
    CONCLUSIONS: Activation of E2F1-mediated CDK5 drives mitochondrial division while inhibiting mitophagy in microglia, triggering inflammation, neuronal apoptosis, and exacerbating CIRI damage. Targeting this pathway could offer novel therapeutic strategies for mitigating CIRI-induced brain injury.
    KEY POINTS: Identification of the E2F1/CDK5/DRP1 Axis in CIRI This study reveals that the E2F1 transcription factor upregulates CDK5 expression, which in turn phosphorylates DRP1, promoting excessive mitochondrial fission and inhibiting mitophagy in microglia. This mechanism plays a critical role in cerebral ischemia-reperfusion injury (CIRI). Mitochondrial Dysfunction and Neuroinflammation The activation of DRP1 leads to mitochondrial fragmentation and excessive ROS accumulation, triggering microglial activation and inflammatory responses, exacerbating neuronal apoptosis and brain injury in CIRI. Therapeutic Potential of E2F1 Silencing Knockdown of E2F1 in microglia effectively reduces mitochondrial damage, restores mitophagy, suppresses inflammation, and improves neurological outcomes in a CIRI mouse model, highlighting a promising therapeutic target for ischemic stroke intervention.
    Keywords:  CDK5; DRP1; E2F1; cerebral ischemia‐reperfusion; microglia; mitochondrial division; mitophagy; single‐cell transcriptome sequencing
    DOI:  https://doi.org/10.1002/ctm2.70197
  4. Sci Rep. 2025 Feb 14. 15(1): 5442
    High intensity interval training alters gene expression linked to mitochondrial biogenesis and dynamics in high fat diet fed rats.
    Mohammad Jahangiri, Shahnaz Shahrbanian, Reza Gharakhanlou.
      A High-Fat Diet (HFD) leads to disruption of mitochondrial biogenesis and dynamics. Exercise training, especially High-Intensity Interval Training (HIIT) increases mitochondrial biogenesis and dynamics. The present study aimed to investigate the effect of a period of HIIT with and without HFD consumption on the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Pgc1-α), Mitofusins-2 (Mfn2), Optic atrophy-1 (Opa1), Dynamin-related protein-1 (Drp1) and mitochondrial Fission protein-1 (Fis1) genes as indicators of mitochondrial biogenesis and dynamics function in the soleus muscle of male Wistar rats. Twenty-four healthy male Wistar rats were randomly divided into four groups: (1) Control, (2) Control + HIIT, (3) HFD, and (4) HFD + HIIT. The HIIT training protocol lasted for 10 weeks with a frequency of 3 sessions per week. The Real-Time Quantitative Reverse Transcription PCR method was used to investigate the gene expression. One-way ANOVA and Fisher's post-hoc analyses were used to examine group differences. HFD consumption caused an increase in weight (P < 0.05), the expression of Drp1 and Fis1 genes (P < 0.001), and a decreased expression of Pgc1-α, Mfn2, and Opa1 genes (P < 0.001). HIIT training increased the expression of PGC1-α (P = 0.009), Mfn2 (P < 0.004), and Opa1 (P < 0.011) genes, while it decreased the expression of Drp1 (P = 0.003) and Fis1 genes (P = 0.027). These findings suggest that HIIT can counteract the negative effects of HFD on mitochondrial function by modulating gene expression related to mitochondrial biogenesis and dynamics.
    Keywords:  Exercise Training; Fission; Fusion; Mitochondrial Biogenesis; Mitochondrial dynamic; Obesity
    DOI:  https://doi.org/10.1038/s41598-025-86767-5
  5. G3 (Bethesda). 2025 Feb 17. pii: jkaf023. [Epub ahead of print]
    VPS13D mutations affect mitochondrial homeostasis and locomotion in Caenorhabditis elegans.
    Xiaomeng Yin, Ruoxi Wang, Andrea Thackeray, Eric H Baehrecke, Mark J Alkema.
      Mitochondria control cellular metabolism, serve as hubs for signaling and organelle communication, and are important for the health and survival of cells. VPS13D encodes a cytoplasmic lipid transfer protein that regulates mitochondrial morphology, mitochondria and endoplasmic reticulum (ER) contact, quality control of mitochondria. VPS13D mutations have been reported in patients displaying ataxic and spastic gait disorders with variable age of onset. Here we used CRISPR/Cas9 gene editing to create VPS13D related-spinocerebellar ataxia-4 (SCAR4) missense mutations and C-terminal deletion in VPS13D's orthologue vps-13D in C. elegans. Consistent with SCAR4 patient movement disorders and mitochondrial dysfunction, vps-13D mutant worms exhibit locomotion defects and abnormal mitochondrial morphology. Importantly, animals with a vps-13D deletion or a N3017I missense mutation exhibited an increase in mitochondrial unfolded protein response (UPRmt). The cellular and behavioral changes caused by VPS13D mutations in C. elegans advance the development of animal models that are needed to study SCAR4 pathogenesis.
    Keywords:   Caenorhabditis elegans ; VPS13D ; vps-13D ; WormBase; mitochondrial homeostasis
    DOI:  https://doi.org/10.1093/g3journal/jkaf023
  6. J Biomed Sci. 2025 Feb 18. 32(1): 29
    Mitophagy is required to protect against excessive skeletal muscle atrophy following hindlimb immobilization.
    Fasih A Rahman, Mackenzie Q Graham, Amanda M Adam, Emma S Juracic, A Russell Tupling, Joe Quadrilatero.
       BACKGROUND: Skeletal muscle atrophy involves significant remodeling of fibers and is characterized by deficits in mitochondrial content and function. These changes are intimately connected to shifts in mitochondrial turnover, encompassing processes such as mitophagy and mitochondrial biogenesis. However, the role of these mitochondrial turnover processes in muscle atrophy remains poorly understood.
    METHODS: We used a novel mitophagy reporter model, mt-Keima mice, to perform hindlimb immobilization and accurately measure mitophagy. A comprehensive set of analyses were conducted to investigate biochemical and molecular changes at the muscle and mitochondrial levels. We also performed image analyses to determine mitophagic flux. To further explore the role of mitophagy in immobilization-induced atrophy, we treated animals with N-acetylcysteine (NAC; 150 mg/kg/day) to modify reactive oxygen species (ROS) signaling and colchicine (0.4 mg/kg/day) to inhibit autophagy.
    RESULTS: Our study revealed that hindlimb immobilization leads to muscle weakness and atrophy of fast-twitch muscle fibers (types IIA, IIX, and IIB), with recovery observed in IIA fibers following remobilization. This atrophy was accompanied by a significant increase in mitophagic flux. Additionally, immobilization induced notable mitochondrial dysfunction, as shown by diminished respiration, increased mitochondrial ROS, and greater whole muscle lipid peroxidation. Treatment of immobilized mice with NAC enhanced mitochondrial respiration and reduced ROS generation but suppressed mitophagic flux and intensified atrophy of type IIX and IIB fibers. Additionally, administration of colchicine to immobilized mice suppressed mitophagic flux, which also exacerbated atrophy of IIX and IIB fibers. Colchicine treatment led to significant reductions in mitochondrial function, accompanied by CASP9 and CASP3 activation.
    CONCLUSION: These findings emphasize the role of mitophagy in limiting excessive muscle atrophy during immobilization. Targeting mitophagy may offer new strategies to preserve muscle function during prolonged periods of immobilization.
    Keywords:  Apoptosis; BNIP3; Disuse atrophy; Mitochondria; Mitophagy; Skeletal muscle
    DOI:  https://doi.org/10.1186/s12929-025-01118-w
  7. bioRxiv. 2025 Jan 31. pii: 2024.12.21.629919. [Epub ahead of print]
    Stress-induced mitochondrial fragmentation in endothelial cells disrupts blood-retinal barrier integrity causing neurodegeneration.
    Jorge L Cueva-Vargas, Nicolas Belforte, Isaac A Vidal-Paredes, Florence Dotigny, Christine Vande Velde, Heberto Quintero, Adriana Di Polo.
      Increased vascular leakage and endothelial cell (EC) dysfunction are major features of neurodegenerative diseases. Here, we investigated the mechanisms leading to EC dysregulation and asked whether altered mitochondrial dynamics in ECs impinge on vascular barrier integrity and neurodegeneration. We show that ocular hypertension, a major risk factor to develop glaucoma, induced mitochondrial fragmentation in retinal capillary ECs accompanied by increased oxidative stress and ultrastructural defects. Analysis of EC mitochondrial components revealed overactivation of dynamin-related protein 1 (DRP1), a central regulator of mitochondrial fission, during glaucomatous damage. Pharmacological inhibition or EC-specific in vivo gene delivery of a dominant negative DRP1 mutant was sufficient to rescue mitochondrial volume, reduce vascular leakage, and increase expression of the tight junction claudin-5 (CLDN5). We further demonstrate that EC-targeted CLDN5 gene augmentation restored blood-retinal-barrier integrity, promoted neuronal survival, and improved light-evoked visual behaviors in glaucomatous mice. Our findings reveal that preserving mitochondrial homeostasis and EC function are valuable strategies to enhance neuroprotection and improve vision in glaucoma.
    DOI:  https://doi.org/10.1101/2024.12.21.629919
  8. Vet Microbiol. 2025 Feb 11. pii: S0378-1135(25)00062-8. [Epub ahead of print]303 110427
    Porcine epidemic diarrhea virus induces mitophagy to inhibit the apoptosis and activation of JAK/STAT1 pathway.
    Xin Li, Yiwan Wu, Jin Peng, Bingjie Li, XiaoLong Li, Zhibin Yan, Gen Li, Yue Zhang, HongLing He, Jun Luo, Xiaofeng Guo.
      Porcine epidemic diarrhea virus (PEDV) infection leads to immunosuppression and clinical symptoms in piglets, including vomiting, watery diarrhea, dehydration, and even death. Mitophagy sustains mitochondrial energy homeostasis and quality through the removal of damaged mitochondria. However, PEDV disrupts mitochondrial homeostasis, which affects cellular energy supply and reproduction. Despite existing research, the mechanisms underlying PEDV pathogenesis and its interaction with the innate immune system remain largely unclear. Therefore, we aimed to clarify the mechanism of PEDV-induced mitophagy and its relationship with apoptosis and Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway after PEDV infection. We infected Vero and IPEC-J2 cells with PEDV. Then, we evaluated mitochondrial morphology, structural proteins of PEDV, reactive oxygen species (ROS) levels, and mitochondrial membrane potential using transmission electron microscopy, confocal laser scanning microscopy, and flow cytometry. We identified mitophagy-related proteins through immunoprecipitation and western blotting. We examined the effects of mitophagy on PEDV proliferation and JAK1-STAT1 signaling via western blotting and indirect immunofluorescence. PEDV infection led to mitochondrial damage and the production of mitophagosome-like vesicles. Subsequently, the PEDV structural N protein initiated mitophagy through ubiquitinating mitofusin 2 (MNF2) via the PINK1/Parkin pathway. Moreover, mitophagy promoted PEDV replication. In the early stage of PEDV infection, PEDV infection inhibits apoptosis by promoting mitophagy. PEDV infection significantly decreased the expression of JAK1, STAT1, interferon regulatory factor 9, and phosphorylated STAT1, inhibiting nuclear translocation and promoting replication. Overall, PINK1/Parkin-mediated mitophagy regulated PEDV-induced apoptosis and JAK/STAT1 expression. These findings provide a scientific basis for elucidating the pathogenic and immune escape mechanisms of PEDV.
    Keywords:  Apoptosis; JAK-STAT1; Mitophagy; Porcine epidemic diarrhea virus
    DOI:  https://doi.org/10.1016/j.vetmic.2025.110427
  9. Sci Rep. 2025 Feb 15. 15(1): 5630
    Dexmedetomidine ameliorates hepatic ischemia reperfusion injury via modulating SIRT3 mediated mitochondrial quality control.
    Xiaqing Ning, Jilang Tang, Xueqin Li, Jiaqi Wang, Fan Zhai, Congcong Jiang, Shixia Zhang.
      Ischaemia-reperfusion (IR) damage is an inevitable adverse effect of liver surgery. Recent research has found that IR damage is involved in severe mitochondrial dysfunction. Mitochondrial biosynthesis and dynamics control mitochondrial mass, distribution, and function. Sirtuin 3 (SIRT3) is widely known for preserving health and functionality of mitochondria. DEX has been proven to alleviate liver damage through antioxidant and anti-apoptotic pathways. But it's unclear how DEX protects mitochondria at this time. In this research, the mechanism behind the protective benefits of DEX was examined using the rat liver IR model and the rat liver cells (BRL-3 A) hypoxia reoxygenation (HR) model. We discovered that DEX treatment restored mitochondrial membrane potential, promoted ATP production, prevented oxidative stress, and decreased apoptosis in BRL-3 A cells. Furthermore, HR damage increased mitochondrial fission while decreasing mitochondrial fusion and biogenesis in BRL-3 A cells, which DEX partially corrected. The benefits of DEX on mitochondrial protection were reversed after addition of SR-18,292. Additionally, DEX showed the ability to enhance SIRT3 expression, and after cells were transfected with SIRT3 siRNA, DEX's effects on mitochondria were partially prevented. Similarly, in the rat model, DEX alleviating liver histopathological injury and oxidative stress. DEX inhibited IR-induced mitochondrial damage through improving ETC complex I- IV activities and ATP content, reducing apoptosis, controlling mitochondrial quality, and upregulating the expression of SIRT3. Additionally, our research shows that DEX's ability to protect the liver against IR damage is mediated by the modulation of mitochondrial quality control. Overall, the modification of SIRT3 activity could be responsible for this outcome.
    Keywords:  Dexmedetomidine; Ischemia-reperfusion; Liver; Mitochondrial biogenesis; Mitochondrial dynamics; SIRT3
    DOI:  https://doi.org/10.1038/s41598-025-90069-1
  10. J Cachexia Sarcopenia Muscle. 2025 Feb;16(1): e13740
    Low-Magnitude High-Frequency Vibration Attenuates Sarcopenia by Modulating Mitochondrial Quality Control via Inhibiting miR-378.
    Yu-Feng Long, Can Cui, Qianjin Wang, Zhen Xu, Simon Kwoon-Ho Chow, Ning Zhang, Ronald Man Yeung Wong, Elvis Chun-Sing Chui, Rebecca Schoenmehl, Christoph Brochhausen, Clinton Rubin, Gang Li, Ling Qin, Da-Zhi Yang, Wing-Hoi Cheung.
       BACKGROUND: Sarcopenia, the age-related decline in muscle mass and muscle strength, significantly contributes to falls, diminished quality of life, and mortality. Although mitochondrial dysfunction is increasingly implicated in sarcopenia, the underlying mechanisms are not fully discovered. Low-magnitude high-frequency vibration (LMHFV), a recommended treatment by the Centers for Disease Control and Prevention (CDC) to reduce fall risk, remains poorly understood of the mechanism on improving skeletal muscle quality. This study aims to investigate whether mitochondrial dysfunction contributes to sarcopenia and evaluate whether LMHFV mitigates sarcopenia by improving mitochondrial homeostasis.
    METHODS: The relationship between mitochondria dysfunction and sarcopenia using senescence accelerated mice prone 8 (SAMP8) model was investigated, assessing muscle and mitochondria. The effects of LMHFV on muscle and mitochondria were evaluated in SAMP8 mice during sarcopenia progression. The role of miR-378 in muscle and mitochondrial homeostasis were evaluated in SAMP8 mice and transgenic over-expressing miR-378 mice (TG mice). The target gene of miR-378 was investigated by dual-luciferase reporter assay in C2C12 cells. Subsequently, we evaluated the effect of LMHFV on miR-378 using both mouse models.
    RESULTS: Reduction in muscle strength was observed from the ages of month 8 to 10 in SAMP8 mice (grip strength decreased 27.1%, p = 0.0263; twitch force decreased 29.1%, p = 0.0178; tetanic force decreased 29.9%, p = 0.011), as well as muscle atrophy (cross-section area: 38.3%, p = 0.0121). Mitochondrial morphological deterioration was noticed from month 6 to 10. Mitochondrial homeostasis, including biogenesis, fusion, fission, mitophagy, and ATP production declined from month 6 to 10. Compared to control group at month 10, knocking down miR-378 in SAMP8 mice mitigated sarcopenia (twitch force increased 44.3%, p = 0.0023; tetanic force increased 51.9%, p = 0.0005), improved mitochondrial morphologies (mitochondrial number increased 1.65-fold, p = 0.0023; mitochondrial density increased 1.65-fold, p = 0.0023; mitochondrial relative area increased 9.05-fold, p = 0.0019) along with improved mitochondrial homeostasis. Over-expressing miR-378 in transgenic mice exacerbated muscle atrophy and mitochondrial deterioration significantly. The dual-luciferase reporter assay in C2C12 cells revealed that miR-378 inhibited PGC-1α directivity. LMHFV was found to mitigate sarcopenia by modulating mitochondrial homeostasis, such as attenuating mitochondrial morphological deterioration and improving mitochondrial biogenesis through increasing PGC-1α via inhibiting miR-378 in skeletal muscle.
    CONCLUSIONS: Our findings indicate that mitochondrial biogenesis, fusion, fission, and mitophagy were compromised during progression of sarcopenia, with mitochondrial deterioration preceding the onset of sarcopenia symptoms. The study also demonstrated that LMHFV could attenuate sarcopenia by modulating mitochondrial quality control through inhibiting miR-378, highlighting its therapeutic potential in the management of age-related muscular degeneration.
    Keywords:  miR‐378; mitochondria; sarcopenia; skeletal muscle; vibration
    DOI:  https://doi.org/10.1002/jcsm.13740
  11. Eur J Pharmacol. 2025 Feb 13. pii: S0014-2999(25)00132-3. [Epub ahead of print]993 177379
    Modulating mitochondrial dynamics preserves cognitive performance via ameliorating iron-mediated brain toxicity in iron-overload rats.
    Jirapas Sripetchwandee, Aphisek Kongkaew, Sirinart Kumfu, Nipon Chattipakorn, Siriporn C Chattipakorn.
      This study aimed to demonstrate the pharmacological efficacy of mitochondrial dynamics modulators, including the fission inhibitor Mdivi-1 and the fusion promoter M1, on parameters in brain and cognitive performance in rats with iron overload condition. Forty male Wistar rats were randomly categorized into two groups to receive either 10% dextrose in normal saline (control, n = 8) or iron dextran (100 mg/kg, Fe group, n = 32) via intraperitoneal injection for six weeks. During the fifth week of injection, rats in the Fe group were further categorized into four groups (n = 8 each) to subcutaneously injected with 1) vehicle (10% DMSO in normal saline), 2) deferoxamine (DFO) (25 mg/kg), 3) Mdivi-1 (1.2 mg/kg), or 4) M1 (2 mg/kg) for further two weeks. Behavioral tests, such as novel object recognition and Morris water maze, were performed post-treatment. Non-heme iron levels in plasma and parameters in the brain, including tight junction-related blood-brain barrier proteins, lipocalin-2, iron levels, ferroptosis, inflammation, mitochondrial function, dynamics, mitophagy, and Alzheimer-like proteins, were assessed. DFO mitigated iron overload condition and brain abnormalities, partially ameliorating cognitive decline. Mdivi-1 and M1 showed superior effects by preventing brain inflammation, LCN2 elevation, and mitochondrial dysfunction, restoring memory function (hippocampal-dependent manner) and spatial cognition (recognition manner). These findings indicate that modulating mitochondrial dynamics via fission inhibitor and fusion promoter could be promising novel pharmacological interventions for the brain in iron overload condition.
    Keywords:  Cognitive decline; Iron-overload; Lipocalin-2; Mitochondrial dynamics; Mitochondrial dynamics modulators
    DOI:  https://doi.org/10.1016/j.ejphar.2025.177379
  12. Biosens Bioelectron. 2025 Feb 07. pii: S0956-5663(25)00120-4. [Epub ahead of print]276 117246
    A dual-channel fluorescent probe with mitochondria-immobilization: Detecting polarity and viscosity during mitophagy.
    Yue Huang, Yang Liu, Chuan Dong, Qi Zan, Feng Feng, Ruibing Wang, Shaomin Shuang.
      Mitophagy is a key pathway for regulating mitochondrial quality and quantity which is essential for the preservation of cellular homeostasis. Mitophagy process may be accompanied by changes of the mitochondrial microenvironments. The multifunctional fluorescent probe is crucial for the precise detection of multiple microenvironments, which is vital for the visualization of mitophagy. Herein, a mitochondria-immobilized fluorescent probe DPP was designed and fabricated to visualize mitophagy by monitoring polarity and viscosity in dual-channel. The DPP is characterized by "D-π-A″ structure, which provides the basis for the intramolecular charge transfer (ICT) and twisted intramolecular charge transfer (TICT) platform, enabling dual-channel responses to polarity and viscosity at emission wavelengths of 487 nm and 656 nm, respectively. The significant wavelength gap (169 nm) between the above channels prevents signal crosstalk. Additionally, the incorporation of 1, 4-dibenzyl chloride grants the probe mitochondrial immobilization capabilities, avoiding the leak of probe due to mitochondrial depolarization during autophagy. The DPP accumulates in mitochondria and monitors polarity and viscosity changes in green and red channels, respectively. Notably, the investigation of the relationship between polarity and viscosity revealed that an increase in viscosity is accompanied by a decrease in polarity. The mitophagy was effectively observed through the induction of DPP by rapamycin, with a particular emphasis on the increase in viscosity and decrease in polarity. Thus, DPP offers a powerful tool for a deeper understanding of the physiological and pathological processes associated with mitophagy and are regulated by various microenvironmental parameters.
    Keywords:  Fluorescent probe; Mitochondria; Polarity; Viscosity
    DOI:  https://doi.org/10.1016/j.bios.2025.117246
  13. bioRxiv. 2025 Feb 01. pii: 2025.01.31.635900. [Epub ahead of print]
    TRAF6 integrates innate immune signals to regulate glucose homeostasis via Parkin-dependent and -independent mitophagy.
    Elena Levi-D'Ancona, Emily M Walker, Jie Zhu, Yamei Deng, Vaibhav Sidarala, Ava M Stendahl, Emma C Reck, Belle A Henry-Kanarek, Anne C Lietzke, Mabelle B Pasmooij, Dre L Hubers, Venkatesha Basrur, Sankar Ghosh, Linsey Stiles, Alexey I Nesvizhskii, Orian S Shirihai, Scott A Soleimanpour.
      Activation of innate immune signaling occurs during the progression of immunometabolic diseases, including type 2 diabetes (T2D), yet the impact of innate immune signaling on glucose homeostasis is controversial. Here, we report that the E3 ubiquitin ligase TRAF6 integrates innate immune signals following diet-induced obesity to promote glucose homeostasis through the induction of mitophagy. Whereas TRAF6 was dispensable for glucose homeostasis and pancreatic β-cell function under basal conditions, TRAF6 was pivotal for insulin secretion, mitochondrial respiration, and increases in mitophagy following metabolic stress in both mouse and human islets. Indeed, TRAF6 was critical for the recruitment and function of machinery within both the ubiquitin-mediated (Parkin-dependent) and receptor-mediated (Parkin-independent) mitophagy pathways upon metabolic stress. Intriguingly, the effect of TRAF6 deficiency on glucose homeostasis and mitophagy was fully reversed by concomitant Parkin deficiency. Thus, our results implicate a role for TRAF6 in the cross-regulation of both ubiquitin- and receptor- mediated mitophagy through the restriction of Parkin. Together, we illustrate that β-cells engage innate immune signaling to adaptively respond to a diabetogenic environment.
    DOI:  https://doi.org/10.1101/2025.01.31.635900
  14. bioRxiv. 2025 Feb 05. pii: 2025.02.03.636310. [Epub ahead of print]
    Loss of an uncharacterized mitochondrial methionine tRNA-synthetase induces mitochondrial unfolded protein response in Caenorhabditis elegans.
    Bharat Vivan Thapa, Mohit Das, James P Held, Maulik R Patel.
      Aminoacyl-tRNA synthetases (aaRSs) are essential for translation, as they charge tRNA molecules with their corresponding amino acids. Alterations in aaRSs can significantly disrupt both cytosolic and mitochondrial translation. Through a forward genetic screen for mitochondrial unfolded protein response (UPR mt ) activators in C. elegans , we identified a missense mutation (P447V) in the previously uncharacterized gene Y105E8A.20, which encodes a dually localized methionine tRNA synthetase (MetRS). Here, we characterize the UPR mt induction by Y105E8A.20, which we call mars-2 , and demonstrate that the P447V allele is a loss-of-function mutation. Furthermore, we show impaired mars-2 activity in the mitochondria triggers UPR mt . This strain provides a valuable tool for studying mitochondrial translation and understanding how aaRSs are involved in mitochondrial homeostasis.
    DOI:  https://doi.org/10.1101/2025.02.03.636310
  15. J Mol Neurosci. 2025 Feb 17. 75(1): 23
    Urolithin A Enhances Tight Junction Protein Expression in Endothelial Cells Cultured In Vitro via Pink1-Parkin-Mediated Mitophagy in Irradiated Astrocytes.
    Gengxin Lu, Junyu Wu, Zhihui Zheng, Zhezhi Deng, Xue Xu, Xintian Li, Xiaoqiu Liang, Weiwei Qi, Shifeng Zhang, Yuemin Qiu, Minping Li, Junjie Guo, Haiwei Huang.
      Radiation brain injury (RBI) is a complication of cranial tumor radiotherapy that significantly impacts patients' quality of life. Astrocyte-secreted vascular endothelial growth factor (VEGF) disrupts the blood-brain barrier (BBB) in RBI. However, further studies are required to elucidate the complex molecular mechanisms involved. Reactive oxygen species (ROS) are closely linked to VEGF pathway regulation, with excessive ROS potentially disrupting this pathway. Mitochondria, the primary ROS-producing organelles, play a crucial role under irradiation. Our findings suggest that irradiation activates astrocytes with altered polarity, generating both cellular and mitochondrial ROS. Concurrently, mitochondrial morphology and function are disrupted, leading to defective mitophagy and an accumulation of damaged mitochondria, which further exacerbates ROS damage. Urolithin A (UA) is a natural activator of mitophagy. We found that UA promoted mitophagy in irradiated astrocytes, reduced cellular and mitochondrial ROS, restored mitochondrial morphology and function, reversed VEGF overexpression, and attenuated the disruption of endothelial tight junction proteins in endothelial cells cultured with irradiated astrocyte supernatants. In conclusion, our study identifies a connection between impaired mitophagy and VEGF overexpression in radiation-induced astrocytes. We also demonstrated UA may serve as a therapeutic strategy for protecting the tight junction protein in RBI by enhancing mitophagy, reducing ROS accumulation, and downregulating VEGF expression.
    Keywords:  Astrocyte; Mitophagy; Radiation-induced brain injury; Urolithin A; VEGF
    DOI:  https://doi.org/10.1007/s12031-024-02302-7
  16. Exp Cell Res. 2025 Feb 18. pii: S0014-4827(25)00068-0. [Epub ahead of print] 114472
    NRF-1 promotes FUNDC1-mediated mitophagy as a protective mechanism against hypoxia-induced injury in cardiomyocytes.
    Junliang Li, Hui Li, Nan Niu, Yazhou Zhu, Siyu Hou, Wei Zhao.
      Hypoxia-induced apoptosis and mitochondrial dysfunction in cardiomyocytes are involved in the mechanisms of heart failure. Our previous studies have confirmed that NRF-1 alleviates hypoxia-induced injury by promoting mitochondrial function and inhibiting apoptosis in cardiomyocytes. However, the mechanism by which NRF-1 attenuates hypoxia-induced injury in cardiomyocytes is still unclear. Mitophagy, a selective autophagy, has recently shown a remarkable correlation with hypoxia-induced cardiomyocyte injury. In this study, we evaluated whether NRF-1 protects cardiomyocytes from hypoxia-induced injury by regulating mitophagy. The findings indicate that hypoxia prevents H9C2 cells from growing, encourages mitochondrial dysfunction, and triggers mitophagy. In addition, promoting mitophagy by rapamycin reduces hypoxia-induced injury in H9C2 cells. Overexpression of NRF-1 in hypoxia-induced H9C2 cells promotes mitophagy and alleviates cell injury, and this effect can be inhibited by 3-MA. Further study found that NRF-1 promotes the expression of FUNDC1 by binding to its promoter region. Knockdown of FUNDC1 in NRF-1 over-expression H9C2 cells inhibited mitophagy and aggravated hypoxia-induced injury. In conclusion, our study suggests that NRF-1 protects against hypoxia-induced injury by regulating FUNDC1-mediated mitophagy in cardiomyocytes.
    Keywords:  FUNDC1; H9c2 cardiomyocytes; Heart failure; NRF-1; hypoxia; mitophagy
    DOI:  https://doi.org/10.1016/j.yexcr.2025.114472
  17. Adv Sci (Weinh). 2025 Feb 20. e2411235
    SIRT3-Mediated Deacetylation of DRP1K711 Prevents Mitochondrial Dysfunction in Parkinson's Disease.
    Ye Xi, Kai Tao, Xiaomin Wen, Dayun Feng, Zifan Mai, Hui Ding, Honghui Mao, Mingming Wang, Qian Yang, Jie Xiang, Jie Zhang, Shengxi Wu.
      Dysregulation of mitochondrial dynamics is a key contributor to the pathogenesis of Parkinson's disease (PD). Aberrant mitochondrial fission induced by dynamin-related protein 1 (DRP1) causes mitochondrial dysfunction in dopaminergic (DA) neurons. However, the mechanism of DRP1 activation and its role in PD progression remain unclear. In this study, Mass spectrometry analysis is performed and identified a significant increased DRP1 acetylation at lysine residue 711 (K711) in the mitochondria under oxidative stress. Enhanced DRP1K711 acetylation facilitated DRP1 oligomerization, thereby exacerbating mitochondrial fragmentation and compromising the mitochondrial function. DRP1K711 acetylation also affects mitochondrial DRP1 recruitment and fission independent of canonical S616 phosphorylation. Further analysis reveals the critical role of sirtuin (SIRT)-3 in deacetylating DRP1K711, thereby regulating mitochondrial dynamics and function. SIRT3 agonists significantly inhibit DRP1K711 acetylation, rescue DA neuronal loss, and improve motor function in a PD mouse model. Conversely, selective knockout of SIRT3 in DA neurons exacerbates DRP1K711 acetylation, leading to increased DA neuronal damage, neuronal death, and worsened motor dysfunction. Notably, this study identifies a novel mechanism involving aberrant SIRT3-mediated DRP1 acetylation at K711 as a key driver of mitochondrial dysfunction and DA neuronal death in PD, revealing a potential target for PD treatment.
    Keywords:  DRP1K711; Parkinson's disease; SIRT3; acetylation; mitochondrial dysfunction; oxidative stress
    DOI:  https://doi.org/10.1002/advs.202411235
  18. Cancer Metastasis Rev. 2025 Feb 18. 44(1): 34
    Mitochondrial alterations and signatures in hepatocellular carcinoma.
    Tsung-Hsien Chen, Shu-Hsien Lin, Ming-Yang Lee, Hsiang-Chen Wang, Kun-Feng Tsai, Chu-Kuang Chou.
      Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer worldwide. Its primary risk factors are chronic liver diseases such as metabolic fatty liver disease, non-alcoholic steatohepatitis, and hepatitis B and C viral infections. These conditions contribute to a specific microenvironment in liver tumors which affects mitochondrial function. Mitochondria are energy producers in cells and are responsible for maintaining normal functions by controlling mitochondrial redox homeostasis, metabolism, bioenergetics, and cell death pathways. HCC involves abnormal mitochondrial functions, such as accumulation of reactive oxygen species, oxidative stress, hypoxia, impairment of the mitochondrial unfolded protein response, irregularities in mitochondrial dynamic fusion/fission mechanisms, and mitophagy. Cell death mechanisms, such as necroptosis, pyroptosis, ferroptosis, and cuproptosis, contribute to hepatocarcinogenesis and play a significant role in chemoresistance. The relationship between mitochondrial dynamics and HCC is thus noteworthy. In this review, we summarize the recent advances in mitochondrial alterations and signatures in HCC and attempt to elucidate its molecular biology. Here, we provide an overview of the mitochondrial processes involved in hepatocarcinogenesis and offer new insights into the molecular pathology of the disease. This may help guide future research focused on improving patient outcomes using innovative therapies.
    Keywords:  Chemoresistance; Hepatocarcinogenesis; Hepatocellular carcinoma; Mitochondria; Mitochondrial dynamics
    DOI:  https://doi.org/10.1007/s10555-025-10251-9
  19. Eur J Med Res. 2025 Feb 19. 30(1): 117
    MEK5-ERK5 pathway mediates mitophagy by regulating Nur77 to promote tumorigenesis of osteosarcoma cells.
    Jianshu Wang, Jinxu Xue, Baijing Ma, Yanqi Zhu, Jing Li, Caiping Tian.
       OBJECTIVES: To investigate the influence of MEK5/ERK5 pathway on mitophagy in osteosarcoma (OS), as well as the involved molecular mechanisms.
    METHODS: The overlapped genes of mitophagy-related genes from MSigDB database and DEGs between metastatic and primary OS groups from GSE32981 were identified. GSVA of mitophagy-related pathways between the metastatic and primary groups were analyzed. The relationships between Nur77 and mitophagy-related pathways, prognosis, immune infiltrating cells, immune response gene sets were investigated. Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and western blotting were utilized to assess the expression levels of MEK5, ERK5, Nur77, PINK1, and Parkin. Cellular behaviors and mitochondrial potential were evaluated via CCK-8, Transwell assay and JC-1 staining.
    RESULTS: Total 4 overlapped genes were obtained as mitophagy-related DEGs, including GABARAPL1, HIF1A, PINK1, and RB1CC1. The activity scores of 3 mitophagy-related pathways exhibited significant differences between metastatic and primary groups. Importantly, Nur77 was significantly negatively correlated with a mitophagy-related pathway (GOBP MITOPHAGY: R = - 0.48, P = 0.02). The Nur77 expression in metastatic group was remarkedly higher than that in the primary group (P < 0.001). Patients with high Nur77 expression had poor prognosis, with AUC values all above 0.615 in predicting 1-, 3-, and 5-year survival. In addition, Nur77 was closely related to numerous immune cells, including activated dendritic cells, activated mast cells and M0 macrophages, and immune response gene sets chemokines and cytokines (all P < 0.05). In addition, MEK5/ERK5 pathway is activated in OS, and Nur77 is overexpressed in OS, and MEK5/ERK pathway promotes Nur77 expression, tumorigenesis and mitochondrial function in U2OS cells. Cytosporone B implement significantly increased the tumorigenesis of U2OS cells in sh-MEK5 group, and inhibited the weaken in mitochondrial membrane potential caused by MEK5 downregulation, and reversed the protein levels of mitophagy markers PINK1 and Parkin in sh-MEK5 group.
    CONCLUSIONS: MEK5-ERK5 pathway mediates mitophagy by regulating Nur77 to promote tumorigenesis of OS cells. These findings offered promising therapeutic targets for OS.
    Keywords:  MEK5–ERK5 pathway; Mitophagy; Nur77; Osteosarcoma
    DOI:  https://doi.org/10.1186/s40001-025-02312-0
  20. bioRxiv. 2025 Jan 28. pii: 2025.01.27.635175. [Epub ahead of print]
    Imbalanced mitochondrial dynamics in human and mouse PD brains.
    Harry J Brown, Rebecca Z Fan, Riley Bell, Said S Salehe, Carlos Martínez Martínez, Yanhao Lai, Kim Tieu.
      Mitochondrial dysfunction is a major pathogenic mechanism in Parkinson's disease (PD). Emerging studies have shown that dysregulation in mitochondrial dynamics (fission/fusion/movement) has a major negative impact on mitochondria - both morphologically and functionally. Partial genetic deletion and pharmacological inhibition of the mitochondrial fission dynamin-related protein 1 (Drp1) have been demonstrated to be beneficial in experimental models of PD. However, the expression of DRP1 (and other fission and fusion genes/proteins) has not been investigated in the brains of Parkinson's patients. Without these data, the question remains whether targeting DRP1 is a valid therapeutic target for PD. To address this gap of knowledge, first, we used post-mortem substantia nigra specimens of Parkinson's patients and controls. Significant increases in the levels of both DNM1L , which encodes DRP1, as well as the DRP1 protein were detected in Parkinson's patients. Immunostaining revealed increased DRP1 expression in dopamine (DA) neurons, astrocytes, and microglia. In addition to DRP1, the levels of other fission and fusion genes/proteins were also altered in Parkinson's patients. To complement these human studies and given the significant role of α-synuclein in PD pathogenesis, we performed time-course studies (3-, 6- and 12-month) using transgenic mice overexpressing human wild-type SNCA under the mouse Thy-1 promoter. As early as 6 months old, we detected an upregulation of Dnm1l and Drp1 in the nigral DA neurons of the SNCA mice as compared to their WT littermates. Furthermore, these mutant animals exhibited more Drp1 phosphorylation at serine 616, which promotes its translocation to mitochondria to induce fragmentation. Together, this study shows an upregulation of DRP1/Drp1 and alterations in other fission/fusion proteins in both human and mouse PD brains, leading to a pro-fission phenotype, providing additional evidence that blocking mitochondrial fission or promoting fusion is a potential therapeutic strategy for PD.
    DOI:  https://doi.org/10.1101/2025.01.27.635175
  21. Phytomedicine. 2025 Feb 07. pii: S0944-7113(25)00123-0. [Epub ahead of print]139 156482
    Curcuma wenyujin extract alleviates cognitive deficits and restrains pyroptosis through PINK1/Parkin mediated autophagy in Alzheimer's disease.
    Yu Qi, Jingwen Zhang, Yuanlong Zhang, Haoyun Zhu, Jiabao Wang, Xiao Xu, Shengjie Jin, Chunlai Wang, Fang Zhang, Min Zhao, Zhigang Wu, Haoru Zhu, Pengcheng Yan.
       BACKGROUND: Pyroptosis and mitophagy have gained significant attention in Alzheimer's disease (AD) treatment. Curcumae Radix (CR), the dried radix of Curcuma wenyujin Y. H. Chen et C. Ling, is a traditional Chinese medicine (TCM) extensively utilized for neurological disorders. Yet, its impact and mechanistic role in AD remain unclear.
    PURPOSE: This study aims to explore the active fraction of CR in AD treatment and its potential mechanisms.
    METHODS: CR extracts were qualitatively analyzed using UHPLC-Triple-TOF/MS. Aβ1-42-induced mice received daily intragastric drug treatments for three weeks. Cognitive abilities of AD model mice were assessed through Y maze, novel object recognition, and eight-arm maze tests. Therapeutic targets of CR extracts were identified using quantitative proteomics. In both in vivo and in vitro settings, effects on pyroptosis and mitophagy were examined by Western blot (WB), immunofluorescence (IF) staining, and ELISA assays.
    RESULTS: The ethyl acetate (EAC) fraction of CR extract exhibited optimal anti-AD effects. CR extracts enhanced memory and cognition in Aβ1-42-induced mice, improved neuronal morphology, and reduced Aβ accumulation in the brain. Proteomics analysis suggested the anti-AD properties of CR might involve inflammation reduction, cell survival enhancement, and mitophagy modulation. CR treatments in both AD mice and Aβ-induced SH-SY5Y cells resulted in reduced pyroptosis, increased LC3 and Beclin1 levels, and activation of the PINK1/Parkin pathway.
    CONCLUSION: The EAC fraction of CR is effective in AD treatment by mitigating pyroptosis, reducing neuroinflammation, and promoting mitophagy, actions facilitated through the PINK1/Parkin pathway.
    Keywords:  Alzheimer's disease; Autophagy; Curcumae Radix; PINK1/Parkin pathway; Pyroptosis
    DOI:  https://doi.org/10.1016/j.phymed.2025.156482
  22. J Hazard Mater. 2025 Feb 20. pii: S0304-3894(25)00599-0. [Epub ahead of print]489 137685
    PFOS causes lysosomes-regulated mitochondrial fission through TRPML1-VDAC1 and oligomerization of MCU/ATP5J2.
    Wei Yang, Yu Li, Ruzhen Feng, Peiyao Liang, Kefan Tian, Lingli Hu, Kejing Wang, Tianming Qiu, Jingyuan Zhang, Xiance Sun, Xiaofeng Yao.
      Perfluorooctane sulfonate (PFOS), a listed persistent organic pollutant, poses risks to human health and is closely linked to chronic metabolic diseases. Although the role of mitochondrial fission in these diseases has garnered attention, whether and how PFOS induces mitochondrial fission remains obscure. Here, we found that PFOS induced mitochondrial fission, as demonstrated by the fragmentation of mitochondria and the upregulation of dynamin-related protein 1 (DRP1), phospho-DRP1 and mitochondrial fission protein 1 (FIS1) in human hepatocytes MIHA and mice liver. Blocking the calcium transfer from lysosomes to mitochondria that was executed by transient receptor potential mucolipin 1 (TRPML1) of lysosomes and voltage-dependent anion channel 1 (VDAC1) of mitochondria, did not affect PFOS-induced mitochondrial fission. In contrast, knockdown of TRPML1 or VDAC1 reversed this process. Knockdown of mitochondrial calcium uniporter (MCU), rather than inhibiting its activity, effectively alleviated PFOS-induced mitochondrial fission. Additionally, PFOS increased MCU oligomers without affecting MCU monomer. Inhibiting autophagy reversed the MCU oligomerization. Further investigation unveiled the interactions of MCU with VDAC1, TRPML1, mitochondrial Fo complex subunit F2 (ATP5J2) and DRP1 in PFOS-exposed mice liver and MIHA cells. We also discovered that knockdown of ATP5J2 alleviated PFOS-induced mitochondrial fission. Ulteriorly, PFOS upregulated ATP5J2 that underwent oligomerization. Knockdown of MCU reversed the increase in ATP5J2. Our study uncovers the presence and molecular basics of lysosomes-regulated mitochondrial fission under PFOS exposure, explains the regulatory pathways on MCU and ATP5J2 oligomerization and their pivotal roles in mitochondrial fission, highlighting the involvement of mitochondrial fission in PFOS-related health risks.
    Keywords:  ATP synthase; Perfluorooctane sulfonate; Toxicity mechanism
    DOI:  https://doi.org/10.1016/j.jhazmat.2025.137685
  23. Sci Rep. 2025 Feb 14. 15(1): 5508
    Chlorogenic acid inhibits Pseudomonas toxin pyocyanin and activates mitochondrial UPR to protect host against pathogen infection.
    Yi Xiao, Linlu Li, Chao Han, Tingyun Huang, Shuangjie Ren, Xiaoqin Wang, Qianlu Xing, Fang Liu.
      Mitochondria are required for protecting host against pathogenic bacteria by activating mitochondrial unfolded protein response (UPRmt). Chlorogenic acid (CGA), a phenolic acid compound of green coffee extracts and tea has been shown to exhibit activities such as antioxidant, antibacterial, hepatoprotective, cardioprotective, anti-inflammatory, neuroprotective, anti-obesity. However, whether CGA regulates innate immunity and the underlying molecular mechanisms remain unknown. In this study, we found that CGA increased resistance to Gram-negative pathogen Pseudomonas aeruginosa PA14 in dose dependent manner. Meanwhile, CGA enhanced innate immunity in Caenorhabditis elegans by reducing intestinal bacterial burden. CGA also inhibited the proliferation of pathogenic bacteria. Importantly, CGA inhibited the production of Pseudomonas toxin pyocyanin (PYO) to protect C. elegans from P. aeruginosa PA14 infection. Furthermore, CGA activated the UPRmt and expression of antibacterial peptide genes to promote innate immunity in C. elegans via transcription factor ATFS-1(activating transcription factor associated with stress-1). Unexpectedly, CGA enhanced innate immunity independently of other known innate immune pathways. Intriguingly, CGA also protected mice from P. aeruginosa PA14 infection and activated UPRmt. Our work revealed a conserved mechanism by which CGA promoted innate immunity and boosted its therapeutic application in the treatment of pathogen infection.
    Keywords:   Caenorhabditis elegans ; Chlorogenic acid; Innate immunity; Mice; Mitochondrial unfolded protein response (UPRmt)
    DOI:  https://doi.org/10.1038/s41598-025-90255-1
  24. bioRxiv. 2025 Feb 03. pii: 2025.02.01.636045. [Epub ahead of print]
    Mitophagy at the oocyte-to-zygote transition promotes species immortality.
    Siddharthan Balachandar Thendral, Sasha Bacot, Katherine S Morton, Qiuyi Chi, Isabel W Kenny-Ganzert, Joel N Meyer, David R Sherwood.
      The quality of inherited mitochondria determines embryonic viability 1 , metabolic health during adulthood and future generation endurance. The oocyte is the source of all zygotic mitochondria 2 , and mitochondrial health is under strict developmental regulation during early oogenesis 3-5 . Yet, fully developed oocytes exhibit the presence of deleterious mitochondrial DNA (mtDNA) 6,7 and mitochondrial dysfunction from high levels of endogenous reactive oxygen species 8 and exogenous toxicants 9 . How fully developed oocytes prevent transmission of damaged mitochondria to the zygotes is unknown. Here we discover that the onset of oocyte-to-zygote transition (OZT) developmentally triggers a robust and rapid mitophagy event that we term mitophagy at OZT (MOZT). We show that MOZT requires mitochondrial fragmentation, activation of the macroautophagy system and the mitophagy receptor FUNDC1, but not the prevalent mitophagy factors PINK1 and BNIP3. Oocytes upregulate expression of FUNDC1 in response to diverse mitochondrial insults, including mtDNA mutations and damage, uncoupling stress, and mitochondrial dysfunction, thereby promoting selection against damaged mitochondria. Loss of MOZT leads to increased inheritance of deleterious mtDNA and impaired bioenergetic health in the progeny, resulting in diminished embryonic viability and the extinction of descendent populations. Our findings reveal FUNDC1-mediated MOZT as a mechanism that preserves mitochondrial health during the mother-to-offspring transmission and promotes species continuity. These results may explain how mature oocytes from many species harboring mutant mtDNA give rise to healthy embryos with reduced deleterious mtDNA.
    DOI:  https://doi.org/10.1101/2025.02.01.636045
  25. Alzheimers Res Ther. 2025 Feb 19. 17(1): 47
    Cornuside alleviates cognitive impairments induced by Aβ1-42 through attenuating NLRP3-mediated neurotoxicity by promoting mitophagy.
    Fulin Zhou, Wenwen Lian, Xiaotang Yuan, Zexing Wang, Congyuan Xia, Yu Yan, Wenping Wang, Zhuohang Tong, Yunchi Cheng, Jiekun Xu, Jun He, Weiku Zhang.
      Alzheimer's disease (AD) is a progressive neurodegenerative disorder in which mitochondrial dysfunction and neuroinflammation play crucial roles in its progression. Our previous studies found that cornuside from Cornus officinalis Sieb.Et Zucc is an anti-AD candidate, however, its underlying mechanism remains unknown. In the present study, AD mice were established by intracerebroventricular injection of Aβ1-42 and treated with cornuside (3, 10, 30 mg/kg) for 2 weeks. Cornuside significantly ameliorated behavioral deficits, protected synaptic plasticity and relieved neuronal damage in Aβ1-42 induced mice. Importantly, cornuside decreased NLRP3 inflammasome activation, characterized by decreased levels of NLRP3, ASC, Caspase-1, GSDMD, and IL-1β. Furthermore, cornuside promoted mitophagy accompanied by decreasing SQSTM1/p62 and promoting LC3B-I transforming into LC3B-II, via Pink1/Parkin signaling instead of FUNDC1 or BNIP3 pathways. In order to investigate the relationship between NLRP3 inflammasome and mitophagy in the neuroprotective mechanism of cornuside, we established an in-vitro model in BV2 cells exposed to LPS and Aβ1-42. And cornuside inhibited NLRP3 inflammasome activation and subsequent cytokine release, also protected neurons from damaging factors in microenvironment of conditional culture. Cornuside improved mitochondrial function by promoting oxidative phosphorylation and glycolysis, decreasing the production of ROS and mitochondrial membrane potential depolarization. Besides, mitophagy was also facilitated with increased colocalization of MitoTracker with LC3B and Parkin, and Pink1/Parkin, FUNDC1 and BNIP3 pathways were all involved in the mechanism of cornuside. By blocking the formation of autophagosomes by 3-MA, the protective effects on mitochondria, the inhibition on NLRP3 inflammasome as well as neuronal protection in conditional culture were eliminated. There is reason to believe that the promotion of mitophagy plays a key role in the NLRP3 inhibition of cornuside. In conclusion, cornuside re-establishes the mitophagy flux which eliminates damaged mitochondria and recovers mitochondrial function, both of them are in favor of inhibiting NLRP3 inflammasome activation, then alleviating neuronal and synaptic damage, and finally improving cognitive function.
    Keywords:  Alzheimer’s disease; Cornuside; Mitophagy; NLRP3; Neuroprotection
    DOI:  https://doi.org/10.1186/s13195-025-01695-w
  26. J Agric Food Chem. 2025 Feb 17.
    Trilobatin, a Naturally Occurring GPR158 Ligand, Alleviates Depressive-like Behavior by Promoting Mitophagy.
    Mu Lin, Dianyou Xie, Yunmei Luo, Lan Dong, Yu Wei, Qihai Gong, Yi Zhun Zhu, Jianmei Gao.
      The G-protein-coupled receptor (GPR158), an orphan receptor, is highly expressed in the medial prefrontal cortex (mPFC) and identified as a novel therapeutic target for depression. Trilobatin is a naturally occurring food additive with potent neuroprotective properties. However, its pharmacological effects and molecular mechanisms against depression remain unknown. Therefore, we explored whether trilobatin alleviates depression by targeting GPR158. Our results indicated that trilobatin alleviated chronic unpredictable mild stress (CUMS)-induced depressive-like behavior in mice. Mitophagy contributed to the antidepressant-like effect of trilobatin, as evidenced by the qRT-PCR array. Furthermore, trilobatin up-regulated autophagy-associated protein expression, restored mitochondrial dynamic balance, and inhibited oxidative stress of mPFC in mice after CUMS insult and in corticosterone-induced primary neuron injury. Intriguingly, trilobatin directly bound to GPR158 and decreased its level of protein expression. GPR158 deficiency attenuated depressive-like behavior through promoting mitophagy, while the antidepressant effect of trilobatin was strengthened in GPR158-deficient mice. Our findings highlight that GPR158-mediated mitophagy acts as a crucial pharmacological target for depression and reveal a new-found pharmacological property of trilobatin: serving as a novel naturally occurring ligand of GPR158 to safeguard from depression by oxidative stress by promoting mitophagy.
    Keywords:  CUMS; GPR158; depression; mitophagy; trilobatin
    DOI:  https://doi.org/10.1021/acs.jafc.4c05431
  27. J Transl Med. 2025 Feb 19. 23(1): 205
    Pyruvate kinase M2 modulates mitochondrial dynamics and EMT in alveolar epithelial cells during sepsis-associated pulmonary fibrosis.
    Jinhua Feng, Xi Huang, Yawen Peng, Wenyu Yang, Xinyi Yang, Ri Tang, Qiaoyi Xu, Yuan Gao, Zhengyu He, Shunpeng Xing, Shuya Mei.
       BACKGROUND: Pulmonary fibrosis (PF) severely impacts both the survival and quality of life of patients with acute respiratory distress syndrome (ARDS) and remains a leading cause of late-stage ARDS-related mortality. The role of epithelial-mesenchymal transition (EMT) in alveolar epithelial cells (AECs) is pivotal in the development of PF.
    METHODS: This study explored the modulation of mitochondrial dynamics and the induction of EMT by pyruvate kinase M2 (PKM2) in AECs, aiming to identify new strategies for the prevention and treatment of sepsis-associated PF.
    RESULTS: The results demonstrated that exposure to LPS increased the levels of PKM2 and the mitochondrial fission marker dynamin-related protein-1 (DRP1), while reducing the levels of the mitochondrial fusion marker mitofusin-2 (MFN2) and the epithelial marker E-cadherin. Moreover, the mesenchymal markers α-SMA and vimentin were upregulated. Treatment with shikonin effectively reversed these alterations, restoring the balance of mitochondrial dynamics, reversing EMT markers, and alleviating the severity of sepsis-associated PF.
    CONCLUSIONS: This study identified PKM2 as a crucial regulator of mitochondrial dynamics and EMT in AECs during sepsis-associated PF. Targeting PKM2 activity offers a promising strategy for developing treatments to mitigate the progression of sepsis-associated PF.
    Keywords:  Epithelial-mesenchymal transition; Mitochondrial dynamics; Pulmonary fibrosis; Pyruvate kinase M2; Sepsis
    DOI:  https://doi.org/10.1186/s12967-025-06199-7
  28. Cell Prolif. 2025 Feb 21. e70009
    SIRT1 Alleviates Oxidative Stress-Induced Mitochondrial Dysfunction and Mitochondria-Associated Membrane Dysregulation in Stress Urinary Incontinence.
    Liying Chen, Jianming Tang, Xiaohu Zuo, Bingshu Li, Cheng Liu, Shasha Hong, Jie Min, Ming Hu, Suting Li, Min Zhou, Mao Chen, Yong He, Ya Xiao, Xiaoyu Huang, Li Hong.
      The pathogenesis of stress urinary incontinence (SUI), a condition common in women, remains to be fully elucidated. This study revealed that the incidence of SUI is associated with mitochondrial homeostasis dysregulation following oxidative stress in the fibrous connective tissue of the pelvic floor. SIRT1 is an essential factor for maintaining mitochondrial homeostasis; however, its potential role and mechanism of action in SUI pathogenesis remain unclear. Both in vitro and in vivo, we observed that oxidative stress reduced SIRT1 expression to inhibit the PGC-1α/NRF1/TFAM and PINK1/Parkin signalling pathways, eliciting impairment of mitochondrial biogenesis and mitophagy in L929 cells and SUI mice. Decreased SIRT1 levels induced endoplasmic reticulum (ER) stress and altered the structure of mitochondria-associated membranes (MAMs), disrupting ER-mitochondrial calcium homeostasis and exacerbting ROS accumulation. SIRT1 activation can restore mitochondrial function and the structure of MAMs and alleviate ER stress in fibroblasts, promoting anterior vaginal wall repair and improving urodynamic parameters in the SUI model. Our findings provide novel insights into the role and associated mechanism of SIRT1 in ameliorating oxidative stress-induced mitochondrial dysfunction in fibroblasts of the anterior vaginal wall and propose SIRT1 as a potential therapeutic target for SUI.
    Keywords:  SIRT1; mitochondrial biogenesis; mitochondria‐associated membranes; mitophagy; stress urinary incontinence
    DOI:  https://doi.org/10.1111/cpr.70009
  29. Metab Brain Dis. 2025 Feb 15. 40(2): 126
    α-asarone activates mitophagy to relieve diabetic encephalopathy via inhibiting apoptosis and oxidative stress.
    Xiao-Dan Yan, Rong-Hua Fan, Yu Wang, Xiao-Xu Duan, Xuan Wei, Lin-Sen Li, Qing Yu.
      Diabetic encephalopathy (DE) is a common complication of diabetes that may result in cognitive impairment. Currently, there is limited effective therapy for DE. Herein, we explored the beneficial effect of α-Asarone on DE and its potential mechanisms. DE was induced in Type 2 diabetes mellitus mice and high-glucose (HG)-exposed PC-12 cells. Cognitive function was evaluated by MWM test. Pathological changes in the brain tissues were observed by HE staining. Cell viability was detected by CCK-8. Apoptosis was assessed by Hoechst 33,342 staining, Annexin V/PI staining and TUNEL. Mitochondrial membrane potential was analyzed by JC-1 probe. ROS production was measured by DCFH-DA staining. Target protein levels were analyzed by Western blotting. Network pharmacology was used to elucidate the beneficial mechanisms of α-Asarone in DE. Our study showed that α-Asarone enhanced cell viability and suppressed apoptosis in HG-stimulated PC-12 cells. Furthermore, α-Asarone relieved HG-induced reduction in mitochondrial membrane potential and ROS overproduction. In addition, mitophagy was triggered by α-Asarone, which was responsible for the inhibitory effect of α-Asarone on apoptosis and oxidative stress. Consistently, the in vivo experiments showed that α-Asarone treatment relieved cognitive dysfunction, apoptosis, and oxidative stress of DE mice via mitophagy induction. However, inhibition of mitophagy by Mdivi-1 counteracted the beneficial action of α-Asarone. Mechanistically, network pharmacology analysis identified 10 key targets of α-Asarone. Molecular docking substantiated a strong affinity of α-Asarone with CASP3, EGFR, NFKB1, and ESR1 proteins. Taken together, α-Asarone protected against mitochondrial dysfunction, oxidative stress and apoptosis via activating mitophagy, thereby alleviating DE. Our findings suggest α-Asarone as a potential drug for DE.
    Keywords:  Apoptosis; Diabetic Encephalopathy; Mitochondrial dysfunction; Mitophagy; Oxidative stress; α-Asarone
    DOI:  https://doi.org/10.1007/s11011-025-01556-3
  30. J Cell Mol Med. 2025 Feb;29(4): e70423
    Increased Matrix Stiffness Promotes Slow Muscle Fibre Regeneration After Skeletal Muscle Injury.
    Dongmei Wang, Jiahong Wu, Zeyu Xu, Jinning Jia, Yimei Lai, Zhihua He.
      The global prevalence of skeletal muscle diseases has progressively escalated in recent years. This study aimed to explore the potential role of matrix stiffness in the repair mechanisms following skeletal muscle injury. We observed an increase in muscle stiffness, a significant rise in the number of type I muscle fibres and a notable elevation in mRNA expression levels of Myh7/2 alongside a decrease in Myh1/4 on day 3 post tibialis anterior muscle injury. To replicate these in vivo changes, C2C12 cells were cultured under high matrix stiffness conditions, and compared to those on low matrix stiffness, the C2C12 cells cultured on high matrix stiffness showed increased expression levels of Myh7/2 mRNA and production levels of MYH7/2, indicating differentiation into slow-twitch muscle fibre types. Furthermore, up-regulation of DRP1 phosphorylation along with elevated F-actin fluorescence intensity and RHOA and ROCK1 production indicates that high matrix stiffness induces cytoskeletal remodelling to regulate mitochondrial fission processes. Our data also revealed up-regulation in mRNA expression level for Actb, phosphorylation level for DRP1, mitochondrial quantity and MYH7/2 production level. Importantly, these effects were effectively reversed by the application of ROCK inhibitor Y-27632, highlighting that targeting cytoskeletal dynamics can modulate myogenic differentiation pathways within C2C12 cells. These findings provide valuable insights into how matrix stiffness influences fibre type transformation during skeletal muscle injury repair while suggesting potential therapeutic targets for intervention.
    Keywords:  RHO/ROCK pathway; cytoskeleton; extracellular matrix; mitochondrial fission; muscle fibre type; stiffness
    DOI:  https://doi.org/10.1111/jcmm.70423
  31. Biochem Pharmacol. 2025 Feb 19. pii: S0006-2952(25)00083-8. [Epub ahead of print] 116821
    Empagliflozin attenuates renal damage in diabetic nephropathy by modulating mitochondrial quality control via Prdx3-PINK1 pathway.
    Canghui Guo, Tao Zhang, Lingyu Du, Ke Yu, Shengnan Zeng, Min Li, Yanqing Chi, Ying Li.
      In clinical practice, sodium-glucose transporter 2 inhibitor (SGLT2i) reduces the composite renal outcomes in patients with diabetic kidney disease (DKD). However, its effect on regulating renal mitochondria remains unclear. Mitochondrial quality control (MQC) has been identified as a key factor in DKD. Peroxiredoxin3 (Prdx3) serves as a primary antioxidant protein in mitochondria. In this study, we investigated the expression of Prdx3 in patients with DKD, diabetic mice and HK-2 cells exposed to high glucose and explored SGLT2i potential mechanism of action. The results also showed that empagliflozin (Empa) treatment improved proteinuria and ameliorated renal pathological damage. We observed that Empa has an impact on the expression of Prdx3 in diabetic mice and HK-2 cells exposed to high glucose, so does the mitochondrial dynamic proteins and mitophagy-related proteins Mfn2, Drp1, PINK1, Parkin, LC3II, and P62. In vitro experiments after transfected with pcDNA3.1(+)-Prdx3 and siPrdx3 the expression of Mfn2, Drp1, PINK1, Parkin, LC3II, and P62 changed. The expression of PINK1 decreased after the knockdown of Prdx3. Furthermore, the knockdown of PINK1 accelerated the MQC damage and weakened the protective effect of Empa. Because Empa has impacts on Prdx3, which plays a protective role by influencing MQC, we investigated the latent impact of Prdx3 deficiency on renal injury and its molecular mechanism in vivo and in vitro in DKD. Herein, we demonstrate that Empa treatment modulates MQC potentially via Prdx3 through interacting with PINK1.
    Keywords:  Diabetic kidney disease; Mitochondrial quality control; Peroxiredoxin3; SGLT2i
    DOI:  https://doi.org/10.1016/j.bcp.2025.116821
  32. Neurotoxicology. 2025 Feb 14. pii: S0161-813X(25)00017-8. [Epub ahead of print]107 53-61
    Polysaccharide alleviates neurodegeneration and behavioral deficit by enhancing mitochondrial autophagy in chronic methamphetamine mice.
    Han Yang, Yuanhe Wang, Shan Liu, Shan Zhang, Yuemeng Chen, Jiuyang Ding, Shunqin Chen, Faze Zhu, Bing Xia, Peng Luo, Yubo Liu.
      Methamphetamine (METH) is a psychostimulant drug widely abused because of its addictive properties.Its impact on the central nervous system is a major area of interest due to its unique ability to cross the blood-brain barrier, facilitated by its dual water and lipid solubility. Studies have indicated that oxidative stress, neuroinflammation, neuronal apoptosis, and mitochondrial dysfunction are primary mechanisms of METH-induced neurotoxicity. Mitophagy, a process regulated by the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) induced kinase 1 (PINK1)/Parkin signaling pathway, has emerged as a critical mechanism for preserving mitochondrial function. Polysaccharides derived from bamboo fungus have shown potential in mitigating neurotoxicity. However, the role of these polysaccharides in ameliorating methamphetamine-induced neurotoxicity remains unclear. This study aimed to investigate whether polysaccharides could alleviate neurodegeneration in a chronic METH mice model and elucidate the underlying mechanisms and elucidate the mechanisms underlying METH-induced neuronal damage.
    Keywords:  Forensic toxicology; Methamphetamine; Mitochondrial autophagy; Neurodegeneration; Polysaccharide
    DOI:  https://doi.org/10.1016/j.neuro.2025.02.004
  33. Free Radic Biol Med. 2025 Feb 19. pii: S0891-5849(25)00096-6. [Epub ahead of print]
    Overexpression of hnRNPK and inhibition of cytoplasmic translocation ameliorate lipid disorders in doxorubicin cardiotoxicity via PINK1/Parkin-mediated mitophagy.
    Qian Xu, Xuehua Wang, Jing Hu, Ya Wang, Shuai Lu, Jingjie Xiong, Han Li, Ni Xiong, YanLing Huang, Yan Wang, Zhaohui Wang.
      Lipid metabolism has been identified as a potential target for the treatment of doxorubicin-induced cardiomyopathy (DIC). Mitochondria, as a central regulator of energy production and utilization, plays a crucial role in this process, and enhancing mitophagy holds promise in mitigating myocardial damage in DIC. However, the relationship between mitophagy and lipid metabolism remains unclear, and the key molecules mediating this connection remain to be elucidated. Among these candidates, heterogeneous nuclear ribonucleoprotein K (hnRNPK) emerges as a potential regulator of mitophagy and metabolism. However, its specific role in DIC remains unclear. In this study, we established chronic DIC models both in vivo and in vitro to assess the relationship between hnRNPK levels, mitophagy, and lipid metabolism, as well as to evaluate the impact of hnRNPK on cardiac function. Our findings revealed that hnRNPK expression is significantly reduced in the hearts and cardiomyocytes of doxorubicin (DOX)-treated mice. Notably, hnRNPK overexpression improves cardiac function and effectively reduces lipid accumulation by enhancing mitophagy. Mechanistically, hnRNPK expression was found to be downregulated in DIC, accompanied by its translocation from the nucleus to the cytoplasm, thereby reducing the transcriptional regulation of PINK1. Overexpression of hnRNPK and inhibition of its cytoplasmic translocation alleviates DOX-induced lipid accumulation by regulating the PINK1/Parkin pathway. These findings underscore a previously unrecognized role of hnRNPK in inhibiting lipid accumulation to prevent DIC.
    Keywords:  Doxorubicin-induced cardiomyopathy; Lipid metabolism; Mitophagy; PINK1/Parkin; Therapeutic target; hnRNPK
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.02.021
  34. J Tradit Chin Med. 2025 Feb;45(1): 13-21
    Electroacupuncture enhances the mitophagy of granulosa cells in premature ovarian insufficiency model mice by inactivating the hippo-yes-associated protein/transcriptional co-activator with postsynaptic density protein, drosophila disc large tumor suppressor, and zonula occludens-1 protein binding motif pathway.
    W U Jiaman, Tang Meng, Luo Yu, Zhu Haimin, Zhao Tianqi, M A Fei, Ning Yan.
       OBJECTIVE: To investigate the potential mechanism of electroacupuncture (EA) in alleviating premature ovarian insufficiency (POI) and to provide a theoretical basis for EA treatment of POI.
    METHODS: For this purpose, a POI mice model was developed by injecting 12 mg/kg busulfan and 120 mg/kg cyclophosphamide intraperitoneally to induce POI. It was then proceeded by EA intervention at Guanyuan (CV4) acupoint on the second day following modeling. Similarly, apoptosis in ovarian granulosa cells was detected by terminal deoxynucleotidyl transferase dUTP nick end labeling staining, while enzyme-linked immunosorbent assay was employed for measuring serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), estrogen (E2), and anti-müllerian hormone (AMH) levels. Moreover, transmission electron microscopy (TEM) was employed for examining mitochondrial morphology, while autophagy and hippo-yes-associated protein/transcriptional co-activator with postsynaptic density protein, drosophila disc large tumor suppressor, and zonula occludens-1 protein binding motif (YAP/TAZ) pathway related protein levels in ovarian tissue were detected via Western blotting.
    RESULTS: Analysis of serum levels of various hormones indicated that serum FSH and LH were reduced in EA compared to the POI group, while E2 and AMH levels were found to be elevated in EA compared to the POI group. The EA was found to inhibit apoptosis in granulosa cells in POI model mice, in addition to improved mito-chondrial damage and significantly improved mitophagy. Pathway analysis revealed that EA was involved in activating the hippo-YAP/TAZ pathway, followed by reversing EA effects on granulosa cell apoptosis and mitophagy with the use of verteporfin, an autophagy and YAP-T-cell factor/enhancer of split and activator of transcription domain family member interaction inhibitor.
    CONCLUSIONS: EA at the Guanyuan (CV4) acupoint protected the granulosa cell by inhibiting cell apoptosis and promoting mitophagy, which was mediated by the Hippo-YAP/TAZ pathway.
    Keywords:  acupuncture; hippo signaling pathway; mitophagy; point CV4 (Guanyuan); primary ovarian insufficiency
    DOI:  https://doi.org/10.19852/j.cnki.jtcm.2025.01.002
  35. Cell Death Differ. 2025 Feb 17.
    Distinct developmental outcomes in DNA repair-deficient FANCC c.67delG mutant and FANCC-/- Mice.
    Swarna Beesetti, Cliff Guy, Shyam Sirasanagandla, Mao Yang, Rhea Jr Sumpter, Heather Sheppard, Stephane Pelletier, Marcin W Wlodarski, Douglas R Green.
      Fanconi Anemia (FA) is an autosomal recessive disorder characterized by diverse clinical manifestations such as aplastic anemia, cancer predisposition, and developmental defects including hypogonadism, microcephaly, organ dysfunction, infertility, hyperpigmentation, microphthalmia, and skeletal defects. In addition to the well-described defects in DNA repair, mitochondrial dysfunction due to defects in mitochondrial autophagy (mitophagy) is also associated with FA, although its contribution to FA phenotypes is unknown. This study focused on the FANCC gene, which, alongside other FA genes, is integral to DNA repair and mitochondrial quality control. In the present study, we created a FANCC mutant mouse model, based on a human mutation (FANCC c.67delG) that is defective in DNA repair but proficient in mitophagy. We found that the FANCC c.67delG mutant mouse model recapitulates some phenotypes observed in FA patients, such as cellular hypersensitivity to DNA cross-linking agents and hematopoietic defects. In contrast, FA phenotypes such as microphthalmia, hypogonadism, and infertility, present in FANCC-deficient mice, were absent in the FANCC c.67delG mice, suggesting that the N-terminal 55 amino acids of FANCC are dispensable for these developmental processes. Furthermore, the FANCC c.67delG mutation preserved mitophagy, and unlike the FANCC null mutation, did not lead to the accumulation of damaged mitochondria in cells or tissues. This study highlights the multifaceted nature of the FANCC protein, with distinct domains responsible for DNA repair and mitophagy. Our results suggest that developmental defects in FA may not solely stem from DNA repair deficiencies but could also involve other functions, such as mitochondrial quality control.
    DOI:  https://doi.org/10.1038/s41418-025-01461-3
  36. bioRxiv. 2025 Jan 30. pii: 2025.01.30.635785. [Epub ahead of print]
    Mdm38/LETM1 couples ion homeostasis and proteostatic mechanisms in the inner mitochondrial membrane.
    Iryna Bohovych, Gabriella Menezes da Silva, Saieeda Fabia Ali, Emma J Bergmeyer, Edward M Germany, Adarsh Mayank, James A Wohlschlegel, Jason C Casler, Muhammad Arifur Rahman, Taras Y Nazarko, Maureen Tarsio, Takuya Shiota, Laura L Lackner, Steven M Claypool, Patricia M Kane, Antoni Barrientos, Oleh Khalimonchuk.
      The mitochondrial inner membrane is among the most protein-dense cellular membranes. Its functional integrity is maintained through a concerted action of several conserved mechanisms that are far from clear. Here, using the baker's yeast model, we functionally characterize Mdm38/LETM1, a disease-related protein implicated in mitochondrial translation and ion homeostasis, although the molecular basis of these connections remains elusive. Our findings reveal a novel role for Mdm38 in maintaining protein homeostasis within the inner membrane. Specifically, we demonstrate that Mdm38 is required for mitochondrial iron homeostasis and for signaling iron bioavailability from mitochondria to vacuoles. These processes are linked to the m- AAA quality control protease, whose unrestrained activity disrupts the assembly and stability of respiratory chain complexes in Mdm38-deficient cells. Our study highlights the central role of Mdm38 in mitochondrial biology and reveals how it couples proteostatic mechanisms to ion homeostasis across subcellular compartments.
    DOI:  https://doi.org/10.1101/2025.01.30.635785
  37. Cell Signal. 2025 Feb 15. pii: S0898-6568(25)00076-2. [Epub ahead of print] 111663
    WIPI1-mediated mitophagy dysfunction in ventricular remodeling associated with long-term diabetes mellitus.
    Daiqi Liu, Lu Zhou, Beizheng Xu, Gary Tse, Qingmiao Shao, Tong Liu.
       BACKGROUND: WIPI1 is a member of the WD-repeat protein family that interacts with phosphoinositides and plays a crucial role in autophagy. This study investigated how WIPI1-mediated mitophagy dysfunction contributes to ventricular remodeling in rat and mouse models of diabetes mellitus.
    METHODS: The study utilized a 32-weeks diabetic animal model to simulate long-term diabetic conditions. AAV9-cTNT-WIPI1 vectors were employed to overexpress WIPI1 in the myocardium. Cardiac function was assessed by echocardiography. Mitochondrial membrane potential was assessed using JC-1 dye. Oxygen consumption rates were quantified using an Oxygraph-O2K high-resolution respirometry.
    RESULTS: Long-term diabetes led to decreased ejection fraction and fractional shortening associated with a marked increase in ventricular fibrosis and elevated expression of fibrotic markers such as collagen type I and periostin. Expression of autophagy markers such as LC3b-II and SQSTM1 was reduced, and colocalization with mitochondria was disrupted, suggesting failures in autophagosome formation and maturation. This impairment was further supported by decreased levels of mitophagy-related proteins (PINK and Parkin), indicating impaired mitophagy. WIPI1 knockdown led to mitochondrial dysfunction, characterized by loss of membrane potential and reduced respiratory capacity.
    CONCLUSION: WIPI1 is essential for proper mitophagy function. Its downregulation produces ventricular remodeling and dysfunction. These findings suggest that targeting WIPI1-mediated pathways could be a potential therapeutic strategy for treating diabetic cardiomyopathy by improving mitochondrial health and mitophagic processes.
    Keywords:  Diabetic cardiomyopathy; Mitochondrial dysfunction; Mitophagy
    DOI:  https://doi.org/10.1016/j.cellsig.2025.111663
  38. Toxicol Lett. 2025 Feb 13. pii: S0378-4274(25)00031-1. [Epub ahead of print]406 20-30
    Mitophagy impairment drives microglia activation and results in cognitive deficits in neonatal mice following sevoflurane exposure.
    Piao Zhang, Rui-Juan Cheng, Qiao-Ling Yang, Yan Gong, Yan Xu, Ling-Min Chen, Li Zhou, Chun-Ling Jiang.
      Sevoflurane exposure induces cognitive deficits in neonatal mice. Mitophagy was closely correlated to sevoflurane inhalation induced neurotoxicity in developing brains. However, the underlying mechanisms have not been fully elucidated. In this study, we attempted to clarify the role of mitophagy in neonatal mice undergoing sevoflurane exposure. BV2 microglial cells were cultured, and mcherry-EGFP-LC3B adenovirus were transfected. The results showed that the fluorescence intensity of GFP was markedly increased after sevoflurane exposure, and rapamycin administration could mitigate this effect. The mitophagy flux test showed that sevoflurane exposure reduced the degree of colocalization between Mito-Traker and Lyso-Traker fluorescent, while which was elevated by rapamycin treatment. The immunofluorescence assay suggested that sevoflurane inhalation resulted in the significant decrease of autolysosome formation, which was sharply enhanced in SEV group after rapamycin treatment. Meanwhile, sevoflurane inhalation shifted microglial M1/M2 phenotypic polarization, and rapamycin administration reversed this status. Moreover, the degree of colocalization among Iba-1, Synaptophysin (Syn) and lysosomal-associated membrane protein 1 (Lamp1) was increased after sevoflurane exposure, and that was reduced following rapamycin treatment. The behavioral performance was worse after sevoflurane inhalation in neonatal mice, and rapamycin treatment effectively improved the cognitive outcome. Collectively, these findings demonstrated that mitophagy impairment induced by sevoflurane exposure promoted microglia M1 phenotypic polarization and enlarged phagocytosis, and resulted in cognitive deficits, while rapamycin administration effectively reversed this tendency.
    Keywords:  Cognitive dysfunction; Microglia; Mitophagy; Sevoflurane
    DOI:  https://doi.org/10.1016/j.toxlet.2025.02.008
  39. Phytomedicine. 2025 Jan 30. pii: S0944-7113(25)00067-4. [Epub ahead of print]139 156426
    Chaihuang Yishen Granule ameliorates mitochondrial homeostasis by upregulating PRDX5/TFAM axis to inhibit renal fibrosis in CKD.
    Ling-Hui Xu, Rui-Zhi Tan, Jing-Yi Lin, Tong Li, Jian Jia, Li-Hua Wu, Rui Wang, Yu-Heng He, Hong-Wei Su, Ping Li, Li Wang.
       BACKGROUND: Chaihuang Yishen Granules (CHYS) has been clinically proven to be effective for the treatment of chronic kidney disease (CKD), yet its underlying molecular mechanisms remain largely unexplored.
    OBJECTIVE: To explore the innovative mechanisms by which CHYS alleviates CKD, focusing on its role in modulating PRDX5/TFAM-mediated mitochondrial homeostasis in renal cells.
    METHODS: In this study, CKD mouse model was established by unilateral ureteral obstruction (UUO) and adenine (Ade) diet. Treatment interventions were administered by gavage with CHYS at doses of 3.8g/kg (low dose) and 7.6g/kg (high dose). The ameliorative effects of CHYS on CKD were evaluated by changes in renal function, kidney tissue structure, renal fibrosis, and mitochondrial dysfunction markers. Tert‑butyl hydroperoxide (t-BHP)-induced oxidative stress in TCMK1 cells was used to simulate CKD renal fibrosis induced by mitochondrial dysfunction in vitro.
    RESULTS: CHYS significantly improves renal function and mitigates fibrosis while restoring mitochondrial homeostasis. Notably, PRDX5 expression, which is markedly reduced in CKD patients and mouse models, is substantially upregulated following CHYS treatment. Meanwhile, we demonstrate that ultrasound microbubble-mediated in situ overexpression of PRDX5 confers considerable renal protection in the UUO model. In vitro data show that CHYS effectively prevents t-BHP-induced mtDNA leakage in renal tubular cells, preserving mitochondrial function and stability, an effect compromised by PRDX5 knockdown. Moreover, our protein binding assays uncover a previously unreported interaction between PRDX5 and TFAM, with TFAM knockdown reversing the mitochondrial functional and fibrotic improvements achieved through PRDX5 overexpression and CHYS intervention.
    CONCLUSION: These findings introduce a pioneering perspective on CHYS's mechanism of action. CHYS enhance TFAM activation through PRDX5 upregulation, counteract ROS-induced mitochondrial damage, and restoring mitochondrial homeostasis, and alleviates the progression of renal fibrosis in CKD, highlighting the innovative therapeutic potential of CHYS in mitochondrial-related renal pathologies.
    Keywords:  Chaihuang Yishen Granule; Chronic kidney disease; Mitochondrial function; PRDX5; ROS; TFAM
    DOI:  https://doi.org/10.1016/j.phymed.2025.156426
  40. J Ethnopharmacol. 2025 Feb 19. pii: S0378-8741(25)00179-5. [Epub ahead of print] 119495
    Corrigendum to "Rg1 improves Alzheimer's disease by regulating mitochondrial dynamics mediated by the AMPK/Drp1 signaling pathway" [J. Ethnopharmacol. 340 (2025) 119285].
    Yini Zhang, Shangzhi Liu, Di Cao, Min Zhao, Haifei Lu, Ping Wang.
      
    DOI:  https://doi.org/10.1016/j.jep.2025.119495
  41. medRxiv. 2025 Jan 28. pii: 2025.01.28.25321013. [Epub ahead of print]
    Hydroxychloroquine corrects mitochondrial recycling dysfunction in natural killer cells from patients with systemic lupus erythematosus.
    Natalia Fluder, Morgane Humbel, Emeline Recazens, Alexis A Jourdain, Camillo Ribi, George C Tsokos, Denis Comte.
       Objectives: Natural Killer (NK) cell dysfunction contributes to systemic lupus erythematosus (SLE) pathogenesis, but the underlying mechanisms remain poorly understood. This study investigates immunometabolic alterations in NK cells from SLE patients and explores therapeutic strategies for their restoration.
    Methods: We characterized mitochondrial structure and function in NK cells from the peripheral blood of SLE patients and healthy controls using flow cytometry, electron microscopy, and proteomics. Key mitophagy-related gene expressions were quantified using qPCR. The ability of hydroxychloroquine (HCQ) to restore mitochondrial recycling and NK cell function were assessed in vitro .
    Results: SLE NK cells displayed accumulated enlarged, hyperpolarized mitochondria with cristae disorganization, and reduced mitophagy. Impaired lysosomal acidification and mtDNA extrusion into the cytosol were also observed. Treatment with HCQ restored mitochondrial recycling, and NK cell effector functions, including cytokine production and cytotoxicity by acidifying lysosomes.
    Conclusions: This study identifies mitochondrial recycling dysfunction as a driver of NK cell abnormalities in SLE patients. HCQ can correct these abnormalities by acidifying the lysosomes and highlights the potential of HCQ to restore NK cell functionality. These findings provide new insights into the immunometabolic mechanisms underlying SLE and suggest avenues for targeted therapeutic interventions.
    WHAT IS KNOWN ON THE TOPIC: ➢ SLE is a complex inflammatory disease characterized by the development of autoreactive cells and a breakdown of self-tolerance (1, 2).➢ Natural Killer (NK) cells, pivotal players in the innate immune system, exhibit reduced numbers, diminished cytotoxicity, and impaired cytokine production in SLE patients (3-5). ➢ Peripheral CD56 dim CD57 + NK cells from SLE patients exhibit increased endogenous apoptosis and higher levels of mitochondrial (mt)ROS, contributing to their altered function (6).
    WHAT THE STUDY ADDS: ➢ This study reveals a full spectrum of immunometabolic alterations in Natural Killer (NK) cells from SLE patients, including hyperpolarized mitochondria accumulation, cristae disorganization and impaired mitophagy. These results identify mitochondrial recycling dysfunction as a central factor in NK cell abnormalities in SLE.➢ It demonstrates for the first time that hydroxychloroquine (HCQ), a standard treatment for SLE, effectively restores mitochondrial recycling in NK cells by modulating lysosomal acidification, reducing cytosolic leakage of mtDNA and enhancing the expression of mitophagy-related genes.➢ These results highlight a new mechanism by which HCQ attenuates immune dysregulation, making it a potential targeted approach for treating the specific dysfunction of NK cells in SLE.
    HOW THIS STUDY MIGHT AFFECT RESEARCH PRACTICE OR POLICY: ➢ Understanding how mitochondrial recycling dysfunction impacts SLE pathogenesis can pave the way for the development of targeted therapies and improved disease management for SLE patients.
    DOI:  https://doi.org/10.1101/2025.01.28.25321013
  42. Cell Death Dis. 2025 Feb 19. 16(1): 111
    17-beta estradiol prevents cardiac myocyte hypertrophy by regulating mitochondrial E3 ubiquitin ligase 1.
    Ximena Calle, Valeria Garrido-Moreno, Brenda Becerra, Mayarling F Troncoso, Juan Francisco Silva-Agüero, Emanuel Guajardo-Correa, Leslye Venegas-Zamora, Erik Lopez-Gallardo, Felipe Muñoz-Córdova, Fernanda Fredericksen, Sebastian Aedo-Cares, Allan Peñaloza-Otárola, Angelica Ortega, Angel Raya, Vinicius Maracaja-Coutinho, Mario Chiong, Valentina Parra, Sergio Lavandero.
      Cardiac hypertrophy is a cellular process characterized by the increased size of cardiomyocytes in response to a high workload or stress. 17-beta estradiol (E2) has cardioprotective and anti-hypertrophic effects by maintaining mitochondrial network and function. MUL1 is a mitochondrial ubiquitin ligase directly involved in the control of mitochondrial fission and mitophagy. Studies from our group and others have previously shown that cardiomyocyte hypertrophy is associated with mitochondrial fission and dysfunction. These findings led us to study in vitro whether E2 regulates MUL1 to prevent cardiac hypertrophy, mitochondrial fission, and dysfunction induced by the catecholamine norepinephrine (NE). Our results showed that NE induces hypertrophy in cultured rat cardiomyocytes. Pre-treatment with E2 (10-100 nM) prevented the NE-dependent increases in cell perimeter and the hypertrophic stress markers ANP and BNP at both the protein and mRNA levels. NE induced the fragmentation of the mitochondrial network and reduced ATP levels, effects that were both prevented by E2. In silico analysis suggested a putative binding site for estrogen receptors on the MUL1 gene promoter. In accordance with this finding, E2 prevented increases in MUL1 mRNA and protein levels induced by NE. Our data also showed that a siRNA MUL1 knockdown counteracted NE-induced cardiomyocyte hypertrophy and mitochondrial dysfunction, mirroring the protective effect triggered by E2. In contrast, a MUL1 adenovirus did not prevent the E2 protection from cardiomyocyte hypertrophy. Further, in vivo analysis in a transgenic mouse model overexpressing MUL1 revealed that only young male mice overexpressed the protein. Consequently, they exhibited increased levels of the hypertrophic marker ANP, an elevated heart weight, and larger cardiomyocyte size. Therefore, our data demonstrate that 17-beta estradiol prevents cardiac myocyte hypertrophy by regulating MUL1.
    DOI:  https://doi.org/10.1038/s41419-025-07389-3
  43. Neuropharmacology. 2025 Feb 12. pii: S0028-3908(25)00067-X. [Epub ahead of print]269 110361
    ZLN005, a PGC-1α agonist, delays photoreceptor degeneration by enhancing mitochondrial biogenesis in a murine model of retinitis pigmentosa.
    Chengyu Hu, Chengda Ren, Yan Wu, Ruoyi Lin, Tianyi Shen, Tingting Li, Donghui Yu, Lei Jiang, Zhongqi Wan, Yunhong Luo, Tu Su, Jing Yu, Yaoyan Qiu.
      Retinitis pigmentosa (RP) is a hereditary neurodegenerative disease characterized by the degeneration of photoreceptors caused by mutations in various genes. Increasing evidence suggests that mitochondrial biogenesis plays a critical role in many neurodegenerative diseases. This study investigated the role of mitochondrial biogenesis in rd1 mice, a widely recognized model of RP. Male C57BL/6 mice and age-matched rd1 mice were used for in vivo experiments, while H2O2 was employed on 661w cells to establish an in vitro model. Our findings revealed that mitochondrial biogenesis and the regulatory PGC-1α/NRF-1/TFAM pathway were significantly downregulated in rd1 mice. Treatment with ZLN005, a PGC-1α agonist, markedly improved visual function in rd1 mice and alleviated thinning of the retinal outer nuclear layer. Additionally, ZLN005 enhanced mitochondrial biogenesis and restored mitochondrial function in photoreceptors. Further analysis in vitro confirmed that ZLN005 rescued photoreceptor degeneration by promoting mitochondrial biogenesis through the PGC-1α/NRF-1/TFAM pathway. In summary, our results highlight the critical role of mitochondrial biogenesis and the PGC-1α/NRF-1/TFAM pathway in the progression of RP. This offers a potential strategy to delay photoreceptor degeneration in RP by maintaining mitochondrial function and could be combined with existing therapies for improving treatment outcomes through synergistic pathways.
    Keywords:  Animal study; Mitochondrial biogenesis; Mitochondrial dysfunction; Retinitis pigmentosa; ZLN005
    DOI:  https://doi.org/10.1016/j.neuropharm.2025.110361
  44. J Biol Chem. 2025 Feb 17. pii: S0021-9258(25)00175-9. [Epub ahead of print] 108326
    Hypoxia induces ferroptotic cell death mediated by activation of the inner mitochondrial membrane fission protein MTP18/Drp1 in invertebrates.
    Jiaqi Liu, Xichao Sun, Yijie Wu, Zhimin Lv, Na Zhou, Chao Bian, Shengming Sun.
      Hypoxia and ischemia damage sensitive organelles such as mitochondria, thus mitochondrial dysfunction contributes to metabolic disorders in crustaceans under hypoxia. The mechanisms associated with ferroptosis in hypoxic disorders have not been determined in crustaceans. In particular, the early molecular events of mitochondrial dynamics in crustaceans require clarification. In this study, two evolutionarily conserved mitochondrial fission proteins, Drp1 and MTP18, were identified in the oriental river prawn (Macrobrachium nipponense). In vitro, ferroptosis-mediated impairment of mitochondrial membrane potential was induced by hypoxia in oriental river prawn hemocytes. In hypoxia-induced hemocytes, activation of Drp1 by increased phosphorylation at S616 was identified. Drp1 mitochondrial translocation also increased, and mitochondrial fusion-related protein expression decreased in vivo. Altered mitochondrial fission-fusion dynamics have been linked to mitochondrial dysfunction, inducing a classic ferroptosis mechanism. Marf overexpression or Drp1 knockdown protected against mitochondrial dysfunction and ferroptotic cell death in vitro. Furthermore, hypoxia-induced mitochondrial fission was verified to be driven by the Drp1/MTP18 interaction. Under hypoxia, MTP18 transcription was increased by the binding of activated HIF-1α to hypoxia response elements (HREs) in its promoter. Conjointly, MTP18 knockdown resulted in less apoptosis and decreased prawn mortality in gill tissue in vitro; suggesting that adaptation to hypoxia involves a vital function of MTP18. In conclusion, we uncovered a conserved role of mitochondrial fission in hypoxia-induced ferroptotic cell death. Therefore, we suggest that specific modulation of MTP18/DRP1-mediated mitochondrial dynamics might be a potential therapeutic strategy in hypoxic stress-induced tissue injury of invertebrates.
    Keywords:  Drp1; ferroptosis; hypoxia; invertebrate; mitochondrial fission
    DOI:  https://doi.org/10.1016/j.jbc.2025.108326
  45. Int J Biol Macromol. 2025 Feb 12. pii: S0141-8130(25)01519-3. [Epub ahead of print] 140970
    Evaluation of GFM1 mutations pathogenicity through in silico tools, RNA sequencing and mitophagy pahtway in GFM1 knockout cells.
    Bashir Ahmad, Dumbuya John Sieh, Ji-Xin Tang, Wen Li, Xiuling Chen, Jun Lu.
      GFM1 is a nuclear gene that plays a role in mitochondrial function. In recent decades, various homozygous and compound heterozygous mutations have been identified, leading to significant health issues in patients and often resulting in early death. There is a few experimental research on this gene, particularly regarding its pathogenicity through in silico methods and RNA sequencing and experimental validation in GFM1 knockout cells. This study aims to explore how high-risk pathogenic variants affect protein stability and function using a comprehensive bioinformatics approach. Analyses with Align-GVGD, PolyPhen-2, MupRo, and SIFT indicated that most variants are likely to be highly pathogenic and destabilize the protein structure. The variants were consistently classified as high-risk by Align-GVGD and were deemed "probably damaging" or "possibly damaging" by PolyPhen-2. MupRo analysis suggested a reduction in protein stability, while SIFT indicated functional impacts for all variants. Further analysis with MetaRNN and structural assessments showed that these variants affect protein size, charge, and hydrophobicity, which may disrupt inter-domain interactions and hinder protein function. Differential gene expression analysis in GFM1 knockout HK2 and 293 T cells revealed significant changes in gene expression, particularly in areas related to translation, mitochondrial function, and cellular responses. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses indicated that the affected genes are linked to neurodegenerative diseases, cancer, and various signaling pathways. GFM1 knockout cells displayed notable pathway changes, including those related to oxidative phosphorylation and neurodegenerative diseases (e.g., Parkinson's, Alzheimer's, Huntington's). Upregulation of mitochondrial electron transport chain components (COX17, NDUFB1, ATP5MC1) suggests a compensatory mechanism in response to impaired mitochondrial function. Disruptions in proteostasis and protein synthesis were highlighted by dysregulated proteasome and ribosomal pathways. Markers of mitophagy, such as increased HSP90 and decreased TOMM20 levels, along with changes in PINK1 protein, emphasize GFM1's involvement in mitophagy. Protein-protein interaction analysis connected GFM1 to key mitophagy proteins (e.g., OPTN, Park2/Parkin). Functional experiments confirmed increased mitophagy, indicating a protective response. These results highlight the negative impact of high-risk pathogenic variants on protein stability and cellular function, shedding light on their potential roles in disease progression. This study offers valuable insights into the pathogenic mechanisms linked to GFM1 mutations, underscoring its critical role in mitochondrial function and cellular balance. The findings highlight the gene's involvement in mitophagy, oxidative phosphorylation, and neurodegenerative pathways, laying the groundwork for future research into therapeutic approaches targeting GFM1-related dysfunctions.
    Keywords:  GFM1; Mutations; Neurodegenerative diseases; Pathogenic variants
    DOI:  https://doi.org/10.1016/j.ijbiomac.2025.140970
  46. Life Sci. 2025 Feb 19. pii: S0024-3205(25)00115-8. [Epub ahead of print] 123482
    Alda-1 mediates cell senescence and counteracts bone loss in weightlessness through regulating mitophagy.
    Jinpeng Wang, Sen Li, Qiao Li, Qiuxin Yan, Yunhao Wang, Xiangyin Zeng, Fan Yang, Siyu Jiang, Manrui Zhang, Yaning Pi, Raza Tahir, Lijun Wei.
       AIMS: Astronauts experience weightlessness-induced bone loss (WIBL) due to an imbalanced bone remodeling process involving bone mesenchymal stem cells (BMSCs), osteoblasts, and osteoclasts. Senescence is an important factor contributes to WIBL. In the current study, the effects of Alda-1 on senescence and WIBL were evaluated.
    MATERIALS AND METHODS: We used the 2D-Rotating Wall Vessel bioreactor and hindlimb suspension rats, the classic cellular and animal models simulating microgravity (SMG). Aging, osteogenic differentiation, osteoclastic differentiation, and lipogenic differentiation were evaluated in the cell and animal models. Differentially expressed proteins in the femurs of rats were further analyzed using bioinformatics analysis. In addition, mitochondrial membrane potential, reactive oxygen species (ROS) production, and mitophagy markers were identified to estimate mitochondrial activity.
    KEY FINDINGS: It was revealed that SMG accelerated senescence including osteoblasts, BMSCs, and inhibited senescence of RAW264.7 cells. SMG suppressed osteogenesis while promoting osteoclastogenesis and adipogenesis during cell senescence and bone loss. Aldehyde dehydrogenase-2 (ALDH2) was negatively related to WIBL. It was mainly enriched in mitochondria and involved in oxidative stress pathways. Finally, it was proved that Alda-1 significantly promoted ALDH2 levels. Alda-1 exhibited a robust protective response against senescence and WIBL by eliminating ROS accumulation, restoring mitophagy, and protecting cells and bone from apoptosis.
    SIGNIFICANCE: Our study indicate that Alda-1 exerts a protective effect against SMG-induced skeletal aging and bone loss through mitophagy. It provides a theoretical basis for advancing therapeutic options against WIBL in space.
    Keywords:  Alda-1; Bone loss; Mitophagy; Senescence; Weightlessness
    DOI:  https://doi.org/10.1016/j.lfs.2025.123482
  47. Biochem Pharmacol. 2025 Feb 18. pii: S0006-2952(25)00073-5. [Epub ahead of print]234 116811
    MitoQ alleviates H2O2-induced mitochondrial dysfunction in keratinocytes through the Nrf2/PINK1 pathway.
    Yan Zhao, Renxue Xiong, Shiyu Jin, Yujie Li, Tingru Dong, Wei Wang, Xiuzu Song, Cuiping Guan.
      Oxidative stress plays a critical role in the pathogenesis of vitiligo by damaging keratinocytes, which disrupts their biological functions and influences the progression of the disease. MitoQ, a mitochondria-specific antioxidant, has the potential to prevent disorders associated with oxidative stress and to exert protective effects specifically on mitochondria. This study investigated the protective effects of MitoQ against oxidative stress in keratinocytes. We observed downregulated expression levels of Nrf2, PINK1, Parkin, and LC3 in vitiligo patients. HaCaT cells were treated with 900 μM H2O2 and/or 50 nM MitoQ, revealing that MitoQ mitigated the downregulation of Nrf2, PINK1, and Parkin; reduced the nuclear translocation of Nrf2; and decreased the level of mitophagy induced by H2O2. Following the knockdown of NFE2L2 or PINK1 in HaCaT cells, we noted an increase in intracellular reactive oxygen species, changes in mitochondrial morphology, a dramatic decrease in the mitochondrial membrane potential, and a significant rise in cell death levels. In comparison to the group without NFE2L2 or PINK1 knockdown, MitoQ treatment failed to alleviate these conditions. These results suggest that MitoQ may regulate the PINK1/Parkin signaling pathway via Nrf2 to counteract mitochondrial oxidative stress induced by H2O2 and protect cells from damage. Therefore, our study offers experimental evidence and insights that may inform the development of therapeutic interventions for vitiligo.
    Keywords:  Keratinocyte; MitoQ; Mitophagy; Oxidative stress; PINK1/Parkin pathway; Vitiligo
    DOI:  https://doi.org/10.1016/j.bcp.2025.116811
  48. Kaohsiung J Med Sci. 2025 Feb 19. e12951
    Olfactory mucosa mesenchymal stem cell-derived exosomes protect against neuroinflammation after subarachnoid hemorrhage by activating mitophagy.
    Jian Wang, Jun Peng, Ling Gao, Jun He, Long Lin, Jia-Meng Li, Ying Xia.
      Subarachnoid hemorrhage (SAH) can lead to significant acute neuroinflammation, with treatment outcomes often being inadequate. Olfactory mucosa mesenchymal stem cells (OM-MSCs) have promising therapeutic potential in nerve regeneration and functional recovery. This investigation sought to elucidate the functional mechanisms through which exosomes derived from OM-MSCs provide protection against neuroinflammation following SAH. Mouse OM-MSCs and their exosomes were isolated and characterized using various techniques, including transmission electron microscopy, immunofluorescence staining, Western blotting, flow cytometry, and nanoparticle tracking analysis. Hemin-induced HT22 cells were subsequently utilized to assess the impact of OM-MSC-derived exosomes on the inflammatory response, apoptosis, and mitophagy through ELISAs, Western blotting, qPCR, flow cytometry, and immunofluorescence staining. The impacts of exosomes on neuroinflammation and neuronal damage in SAH model mice were assessed using qPCR, ELISAs, Western blotting, immunofluorescence staining, and TUNEL staining. Exosomes derived from OM-MSCs had the capacity to reduce the levels of proinflammatory factors (IL-6, IL-1β, and TNF-α) and promote apoptosis in hemin-induced HT22 cells. Exosomes alleviated neuroinflammation and neuronal injury post-SAH, as evidenced by the increase in modified Garcia scores, reduction in the brain water content, decrease in blood-brain barrier permeability, decreases in inflammatory marker levels, and reduction in apoptosis rates. Notably, the protective effects of exosomes derived from OM-MSCs on neuroinflammation and apoptosis, both in vitro and in vivo, were mediated via the activation of mitophagy. These findings provide a fresh perspective for subsequent clinical research in the domain of prevention and treatment strategies.
    Keywords:  exosomes; mitophagy; neuroinflammation; olfactory mucosa mesenchymal stem cells; subarachnoid hemorrhage
    DOI:  https://doi.org/10.1002/kjm2.12951
  49. Ren Fail. 2025 Dec;47(1): 2463572
    Vitexin enhances mitophagy and improves renal ischemia-reperfusion injury by regulating the p38/MAPK pathway.
    Jianan Chen, Chaowei Chen, Chang Lv, Runtao Feng, Weibo Zhong, Yongguang Liu, Song Zhou, Ming Zhao.
      Vitexin (VI) is a naturally occurring flavonoid derived from the leaves and seeds of Vitex, recognized for its strong antioxidant properties. This study aims to explore its effects on renal ischemia-reperfusion injury (IRI) and investigate the underlying mechanisms. We utilized hypoxia-reoxygenation (H/R) models with HK-2 cell lines and renal ischemia-reperfusion (I/R) models in mice, applying vitexin preconditioning to assess its influence on renal IRI. Our findings reveal that vitexin mitigated oxidative stress, decreased cell apoptosis, and reduced the expression of renal damage indicators such as kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL), along with an overall improvement in renal function. To further investigate the mechanism, we used network pharmacology and molecular docking techniques to predict potential vitexin targets in renal IRI. Results from Western blotting and immunofluorescence assays indicate that vitexin may promote mitophagy by suppressing the phosphorylation of the pivotal p38 protein in the p38/MAPK signaling pathway, offering protection against renal IRI. The findings indicate that vitexin could potentially be used as a therapeutic agent to alleviate renal IRI.
    Keywords:  Renal ischemia-reperfusion injury; mitophagy; network pharmacology; vitexin
    DOI:  https://doi.org/10.1080/0886022X.2025.2463572
  50. J Transl Med. 2025 Feb 14. 23(1): 181
    Micheliolide attenuates sepsis-induced acute lung injury by suppressing mitochondrial oxidative stress and PFKFB3-driven glycolysis.
    Wenhan Li, Yuhan Li, Linjie Xiao, Zhanzhan Xie, Jun Peng, Wenhui Huang, Xu Li, Ying Meng.
       BACKGROUND: Sepsis is a potentially fatal condition with a significant risk of death. Acute lung injury (ALI) is a life-threatening complication of sepsis, and the inflammatory response plays a critical role in sepsis-induced ALI. The protective effects of micheliolide (MCL) against renal fibrosis and leukemia have been demonstrated, but the precise underlying mechanisms remain unclear.
    METHODS: In vitro, lipopolysaccharides (LPS) and interferon-gamma (IFN-γ) were used to stimulate RAW264.7 cells and bone marrow-derived macrophages (BMDMs) to investigate the protective effect of MCL on sepsis-induced ALI. Cecal ligation and puncture (CLP) models were constructed in mice to induce ALI in vivo. The expression of inflammatory factors, macrophage polarization markers, and the glycolysis-related enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) were measured in vivo. Mitochondrial function, oxidative stress, and mitochondrial-related proteins were evaluated in vitro.
    RESULTS: MCL inhibited CLP-induced ALI, as evidenced by improvements in proinflammatory factor levels, lung wet/dry ratios, and histopathological findings. In vitro, MCL treatment significantly suppressed LPS + IFN-γ-induced M1-type polarization of RAW264.7 cells and BMDMs, as well as the production of inflammatory factors and oxidative stress. Mechanistic experiments revealed that MCL suppresses PFKFB3-driven glycolysis to reduce inflammation and activates the mitochondrial unfolded protein response (UPRmt) to alleviate mitochondrial stress. However, the therapeutic effect of MCL was diminished when PFKFB3 was overexpressed in cells.
    CONCLUSION: This study is the first to demonstrate that MCL attenuates sepsis-induced ALI by reducing M1-type macrophage polarization. Its therapeutic effect is closely related to the suppression of oxidative stress and PFKFB3-driven glycolysis.
    Keywords:  Acute lung injury; Glycolysis; Macrophage polarization; Oxidative stress; PFKFB3
    DOI:  https://doi.org/10.1186/s12967-024-05906-0
  51. Biomaterials. 2025 Feb 08. pii: S0142-9612(25)00098-5. [Epub ahead of print]319 123179
    Manganese dioxide coupled metal-organic framework as mitophagy regulator alleviates periodontitis through SIRT1-FOXO3-BNIP3 signaling axis.
    Cheng Zhu, Kai Huang, Tiancheng Li, Yixin Li, Yu Jin, Ruomei Li, Zhiyu Zhu, Shengbing Yang, Lunguo Xia, Bing Fang.
      Periodontitis is a prevalent chronic inflammatory disease characterized by alveolar bone resorption. Its progression is closely linked to oxidative stress where reactive oxygen species (ROS) generated by mitochondria exacerbate inflammation in positive feedback loops. Strategies for mitochondrial regulation hold potential for therapeutic advances. Metal-organic frameworks (MOFs) have shown promise as nanozymes for ROS scavenging. However, inability to directly regulate cellular processes to prevent further ROS production from damaged mitochondria during persistent inflammation makes MOFs insufficient in treating periodontitis. This study synthesizes MnO2@UiO-66(Ce) by introducing MnO2 within nanoscale mesoporous UiO-66 type MOFs. MnO2 coupled with Ce clusters in MOF channels, forms a superoxide dismutase/catalase cascade catalytic system. More importantnly, manganese endows the MOFs with bioactive effects which enhances mitophagy, facilitating the removal of damaged mitochondria, thereby restoring long-term cellular homeostasis. The results demonstrate that this synergistic antioxidant solution MnO2@UiO-66 restores mitochondrial homeostasis and osteogenic activity of periodontal ligament cells in vitro and alleviates inflammatory bone resorption in a ligature-induced periodontitis model in vivo. The SIRT1-FOXO3-BNIP3 signaling axis plays a key role in this process. This study may provide a design strategy that combines a highly efficient cascade catalytic system with long-term regulation of cellular homeostasis to combat oxidative stress in chronic inflammation.
    Keywords:  Metal-organic frameworks; Mitophagy; Oxidative stress; Periodontitis
    DOI:  https://doi.org/10.1016/j.biomaterials.2025.123179
  52. Cell Death Dis. 2025 Feb 14. 16(1): 98
    Correction: Psmb8 inhibits mitochondrial fission and alleviates myocardial ischaemia/reperfusion injury by targeting Drp1 degradation.
    Hui-Xiang Su, Luo-Luo Xu, Pang-Bo Li, Hai-Lian Bi, Wen-Xi Jiang, Hui-Hua Li.
      
    DOI:  https://doi.org/10.1038/s41419-025-07408-3
  53. Signal Transduct Target Ther. 2025 Feb 21. 10(1): 61
    Precise targeting of transcriptional co-activators YAP/TAZ annihilates chemoresistant brCSCs by alteration of their mitochondrial homeostasis.
    Priyanka Dey Talukdar, Kunal Pramanik, Priya Gatti, Pritha Mukherjee, Deepshikha Ghosh, Himansu Roy, Marc Germain, Urmi Chatterji.
      Persistence of drug-resistant breast cancer stem cells (brCSCs) after a chemotherapeutic regime correlates with disease recurrence and elevated mortality. Therefore, deciphering mechanisms that dictate their drug-resistant phenotype is imperative for designing targeted and more effective therapeutic strategies. The transcription factor SOX2 has been recognized as a protagonist in brCSC maintenance, and previous studies have confirmed that inhibition of SOX2 purportedly eliminated these brCSCs. However, pharmacological targeting of transcription factors like SOX2 is challenging due to their structural incongruities and intrinsic disorders in their binding interfaces. Therefore, transcriptional co-activators may serve as a feasible alternative for effectively targeting the brCSCs. Incidentally, transcriptional co-activators YAP/TAZ were found to be upregulated in CD44+/CD24-/ALDH+ cells isolated from patient breast tumors and CSC-enriched mammospheres. Interestingly, it was observed that YAP/TAZ exhibited direct physical interaction with SOX2 and silencing YAP/TAZ attenuated SOX2 expression in mammospheres, leading to significantly reduced sphere forming efficiency and cell viability. YAP/TAZ additionally manipulated redox homeostasis and regulated mitochondrial dynamics by restraining the expression of the mitochondrial fission marker, DRP1. Furthermore, YAP/TAZ inhibition induced DRP1 expression and impaired OXPHOS, consequently inducing apoptosis in mammospheres. In order to enhance clinical relevance of the study, an FDA-approved drug verteporfin (VP), was used for pharmacological inhibition of YAP/TAZ. Surprisingly, VP administration was found to reduce tumor-initiating capacity of the mammospheres, concomitant with disrupted mitochondrial homeostasis and significantly reduced brCSC population. Therefore, VP holds immense potential for repurposing and decisively eliminating the chemoresistant brCSCs, offering a potent strategy for managing tumor recurrence effectively.
    DOI:  https://doi.org/10.1038/s41392-025-02133-x
  54. Acta Neuropathol Commun. 2025 Feb 20. 13(1): 37
    Distinctive autophagy/mitophagy biomarker profiles in frontotemporal lobar degeneration and Alzheimer's disease.
    Kateřina Veverová, Alžběta Katonová, Hana Horáková, Jan Laczó, Francesco Angelucci, Jakub Hort, Sofie Lautrup, Evandro Fei Fang, Martin Vyhnálek.
      Maintaining cellular homeostasis by removing damaged and senescent mitochondria, a process termed mitophagy, is crucial in preventing Alzheimer's disease (AD) and represents a promising therapeutic target. Our previous research revealed altered mitophagy biomarkers, such as increased CSF and serum PINK1 and serum BNIP3L and decreased serum TFEB levels, indicating impaired autophagy-lysosomal degradation in the AD continuum. However, the role of autophagy/mitophagy in frontotemporal lobar degeneration (FTLD) remains unclear. This study investigated the biomarkers of autophagy/mitophagy and lysosomal biogenesis (PINK1, ULK1, BNIP3L, and TFEB) in biofluids (CSF and serum) from 308 biomarker-defined individuals across the FTLD continuum (FTLD-dementia, n = 29; FTLD-MCI, n = 33) and compared them with those across the AD continuum (MCI-AD, n = 100; AD-dementia, n = 100) and cognitively unimpaired (CU) controls (n = 46) recruited from Czech Brain Aging Study. Additionally, we compared the mitophagy biomarkers across different FTLD clinical subtypes (frontal, semantic and nonfluent variant) with CU, and explored the association between mitophagy biomarkers and clinical phenotypes of FTLD (biomarkers of tau, biomarkers of neurodegeneration, cognition and ATN profile).Our findings indicated a significantly lower CSF PINK1 and ULK1 levels in FTLD compared to AD, with FTLD dementia showing particularly low CSF PINK1 levels compared to AD-dementia. Conversely, CSF ULK1 levels were higher in FTLD-MCI compared to AD-dementia. Serum analyses revealed lower PINK1 and higher TFEB levels in FTLD dementia compared to AD dementia. This study provides compelling evidence of distinct alterations in autophagy/mitophagy biomarkers between FTLD and AD, indicating that these neurodegenerative diseases may affect the cellular waste disposal system through different pathways. This is the first study to explore mitophagy biomarkers in human CSF and serum in FTLD, opening avenues for further research and potential clinical applications.
    Keywords:  Autophagy; Frontotemporal lobar degeneration; MAPT; Neurocognitive impairment; PINK1, TDP-43, TFEB
    DOI:  https://doi.org/10.1186/s40478-025-01954-9
  55. Nature. 2025 Feb 19.
    Dual regulation of mitochondrial fusion by Parkin-PINK1 and OMA1.
    Tatsuya Yamada, Arisa Ikeda, Daisuke Murata, Hu Wang, Cissy Zhang, Pratik Khare, Yoshihiro Adachi, Fumiya Ito, Pedro M Quirós, Seth Blackshaw, Carlos López-Otín, Thomas Langer, David C Chan, Anne Le, Valina L Dawson, Ted M Dawson, Miho Iijima, Hiromi Sesaki.
      Mitochondrial stress pathways protect mitochondrial health from cellular insults1-8. However, their role under physiological conditions is largely unknown. Here, using 18 single, double and triple whole-body and tissue-specific knockout and mutant mice, along with systematic mitochondrial morphology analysis, untargeted metabolomics and RNA sequencing, we discovered that the synergy between two stress-responsive systems-the ubiquitin E3 ligase Parkin and the metalloprotease OMA1-safeguards mitochondrial structure and genome by mitochondrial fusion, mediated by the outer membrane GTPase MFN1 and the inner membrane GTPase OPA1. Whereas the individual loss of Parkin or OMA1 does not affect mitochondrial integrity, their combined loss results in small body size, low locomotor activity, premature death, mitochondrial abnormalities and innate immune responses. Thus, our data show that Parkin and OMA1 maintain a dual regulatory mechanism that controls mitochondrial fusion at the two membranes, even in the absence of extrinsic stress.
    DOI:  https://doi.org/10.1038/s41586-025-08590-2
  56. Free Radic Biol Med. 2025 Feb 13. pii: S0891-5849(25)00092-9. [Epub ahead of print]230 163-176
    Regular exercise alleviates metabolic dysfunction-associated steatohepatitis through rescuing mitochondrial oxidative stress and dysfunction in liver.
    Baoxuan Lin, Tong Wu, Mohammad Nasb, Zeyun Li, Ning Chen.
      Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by severe mitochondrial dysfunction, associated with the production of mitochondrial reactive oxygen species (mROS). The substantial generation of mROS in the MASH liver, resulting from lipid surplus and electron transport chain (ETC) overload, impairs mitochondrial structure and functionality, thereby contributing to the development of severe hepatic steatosis and inflammation. Regular exercise represents an effective strategy for the treatment of MASH. Understanding the effects of exercise on oxidative stress and mitochondrial function is essential for effective treatment of MASH. This article reviews the pathological alterations in mitochondrial β-oxidation, ETC efficiency and mROS production within MASH liver. Additionally, it discusses how exercise influences the redox state and mitochondrial quality control mechanisms-such as biogenesis, mitophagy, fusion, and fission-within the MASH liver. The article emphasizes the importance of in-depth studies on exercise-induced MASH mitigation through the enhancement of mitochondrial redox balance, quality control, and function. Exploring the relationship between exercise and hepatic mitochondria could provide valuable insights into identifying potential therapeutic targets for MASH.
    Keywords:  MASH; Mitochondrial quality control; Oxidative stress; Reactive oxygen species; Regular exercise
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.02.017
  57. Cell Death Discov. 2025 Feb 18. 11(1): 65
    Long-term adaptation of lymphoma cell lines to hypoxia is mediated by diverse molecular mechanisms that are targetable with specific inhibitors.
    Lenka Daumova, Dmitry Manakov, Jiri Petrak, Dana Sovilj, Matej Behounek, Ladislav Andera, Ondrej Vit, Olga Souckova, Ondrej Havranek, Alex Dolnikova, Nicol Renesova, Liliana Tuskova, Lucie Winkowska, Nardjas Bettazova, Kristyna Kupcova, Marie Hubalek Kalbacova, Miriama Sikorova, Marek Trneny, Pavel Klener.
      A large body of evidence suggests that hypoxia drives aggressive molecular features of malignant cells irrespective of cancer type. Non-Hodgkin lymphomas (NHL) are the most common hematologic malignancies characterized by frequent involvement of diverse hypoxic microenvironments. We studied the impact of long-term deep hypoxia (1% O2) on the biology of lymphoma cells. Only 2 out of 6 tested cell lines (Ramos, and HBL2) survived ≥ 4 weeks under hypoxia. The hypoxia-adapted (HA)b Ramos and HBL2 cells had a decreased proliferation rate accompanied by significant suppression of both oxidative phosphorylation and glycolytic pathways. Transcriptome and proteome analyses revealed marked downregulation of genes and proteins of the mitochondrial respiration complexes I and IV, and mitochondrial ribosomal proteins. Despite the observed suppression of glycolysis, the proteome analysis of both HA cell lines showed upregulation of several proteins involved in the regulation of glucose utilization including the active catalytic component of prolyl-4-hydroxylase P4HA1, an important druggable oncogene. HA cell lines demonstrated increased transcription of key regulators of auto-/mitophagy, e.g., neuritin, BCL2 interacting protein 3 (BNIP3), BNIP3-like protein, and BNIP3 pseudogene. Adaptation to hypoxia was further associated with deregulation of apoptosis, namely upregulation of BCL2L1/BCL-XL, overexpression of BCL2L11/BIM, increased binding of BIM to BCL-XL, and significantly increased sensitivity of both HA cell lines to A1155463, a BCL-XL inhibitor. Finally, in both HA cell lines AKT kinase was hyperphosphorylated and the cells showed increased sensitivity to copanlisib, a pan-PI3K inhibitor. In conclusion, our data report on several shared mechanisms of lymphoma cell adaptation to long-term hypoxia including: 1. Upregulation of proteins responsible for glucose utilization, 2. Degradation of mitochondrial proteins for potential mitochondrial recycling (by mitophagy), and 3. Increased dependence on BCL-XL and PI3K-AKT signaling for survival. In translation, inhibition of glycolysis, BCL-XL, or PI3K-AKT cascade may result in targeted elimination of HA lymphoma cells.
    DOI:  https://doi.org/10.1038/s41420-025-02341-y
  58. Hum Cell. 2025 Feb 17. 38(2): 57
    Exploring the therapeutic potential of MOTS-c in age-related macular degeneration: from cellular responses to patient-derived cybrids.
    Zahra Mohtashami, Kevin Schneider, Reza Azimi, Shari Atilano, Marilyn Chwa, M Cristina Kenney, Mithalesh Kumar Singh.
      Age-related macular degeneration (AMD), the leading cause of irreversible vision loss in the US, is on the rise among the elderly. Uncontrolled mitochondria-derived peptide production from mtDNA disruption and 16S or 12S rRNA damage could worsen AMD. Our previous work has shown that Humanin G possesses cytoprotective effects in retinal pigment epithelial (RPE) cells. However, MOTS-c, a highly efficient mitochondrial peptide, has yet to be evaluated on retinal cell survival. In this study, we show that there are differences in effects between wild-type (wt-) and differentiated ARPE19 cells (diff-ARPE19), implying that the cellular differentiation status may influence how cells respond to MOTS-c. MOTS-c has dose-dependent effects on apoptosis, inflammation, and mitochondrial biogenesis in diff-ARPE19 cells. Lower doses (500 nM) have more significant impacts than 5 µM concentrations. In diff-ARPE19 cells, a lower dose of MOTS-c can reduce the negative impact of hypoxia on cellular survival and gene expression, including apoptosis (CASP3, CASP9), mitochondrial biogenesis (TFAM, PGC-1α), and metabolic sensor (AMPK). However, it had no significant effect on ROS levels or NRF1 expression, regardless of MOTS-c dose. Exposing diff-ARPE19 cells to varied MOTS-c dosages before and after therapy in a chemically induced hypoxic environment yields no extra benefits as compared to MOTS-c treatment alone. MOTS-c had different effects on the expression of genes linked with apoptosis, mitochondrial biogenesis, and antioxidant activity in AMD patients versus age-matched control cybrids. The MOTS-c peptide appears to enhance cellular metabolism and regulate gene expression, which could potentially provide therapeutic benefits in AMD.
    Keywords:  Age-related macular degeneration; Apoptosis; Cybrids; Differentiated ARPE19; Hypoxia; MOTS-c; Mitochondrial biogenesis
    DOI:  https://doi.org/10.1007/s13577-025-01188-w
  59. Sci Adv. 2025 Feb 21. 11(8): eadu3011
    Mitochondrial translation regulates terminal erythroid differentiation by maintaining iron homeostasis.
    Tatsuya Morishima, Md Fakruddin, Yohei Kanamori, Takeshi Masuda, Akiko Ogawa, Yuxin Wang, Vivien A C Schoonenberg, Falk Butter, Yuichiro Arima, Takaaki Akaike, Toshiro Moroishi, Kazuhito Tomizawa, Toshio Suda, Fan-Yan Wei, Hitoshi Takizawa.
      Mitochondrial tRNA taurine modifications mediated by mitochondrial tRNA translation optimization 1 (Mto1) is essential for the mitochondrial protein translation. Mto1 deficiency was shown to induce proteostress in embryonic stem cells. A recent finding that a patient with MTO1 gene mutation showed severe anemia led us to hypothesize that Mto1 dysfunctions may result in defective erythropoiesis. Hematopoietic-specific Mto1 conditional knockout (cKO) mice were embryonic lethal and showed niche-independent defect in erythroblast proliferation and terminal differentiation. Mechanistically, mitochondrial oxidative phosphorylation complexes were severely impaired in the Mto1 cKO fetal liver, and this was followed by cytosolic iron accumulation. Overloaded cytosolic iron promoted heme biosynthesis, which induced an unfolded protein response (UPR) in Mto1 cKO erythroblasts. An iron chelator or UPR inhibitor rescued erythroid terminal differentiation in the Mto1 cKO fetal liver in vitro. This mitochondrial regulation of iron homeostasis revealed the indispensable role of mitochondrial tRNA modification in fetal hematopoiesis.
    DOI:  https://doi.org/10.1126/sciadv.adu3011
  60. Nature. 2025 Feb 19.
    Putting the brakes on mitochondrial fusion to prevent escape of mitochondrial DNA.
    Kate McArthur, Michael T Ryan.
      
    Keywords:  Cell biology
    DOI:  https://doi.org/10.1038/d41586-025-00303-z
  61. Redox Biol. 2025 Feb 04. pii: S2213-2317(25)00042-4. [Epub ahead of print]81 103529
    Mitochondrial fission produces a Warburg effect via the oxidative inhibition of prolyl hydroxylase domain-2.
    Xutong Sun, Manivannan Yegambaram, Qing Lu, Alejandro E Garcia Flores, Marissa D Pokharel, Jamie Soto, Saurabh Aggarwal, Ting Wang, Jeffrey R Fineman, Stephen M Black.
      Excessive mitochondrial fission and a shift to a Warburg phenotype are hallmarks of pulmonary hypertension (PH), although the mechanistic link between these processes remains unclear. We show that in pulmonary arterial endothelial cells (PAEC), Drp1 overexpression induces mitochondrial fission and increases glycolytic ATP production and glycolysis. This is due to mitochondrial reactive oxygen species (mito-ROS)-mediated activation of hypoxia-inducible factor-1α (HIF-1α) signaling, and this is linked to hydrogen peroxide (H2O2)-mediated inhibition of prolyl hydroxylase domain-2 (PHD2) due to its cysteine 326 oxidation and dimerization. Furthermore, these findings are validated in PAEC isolated from a lamb model of PH, which are glycolytic (Shunt PAEC), exhibit increases in both H2O2 and PHD2 dimer levels. The overexpression of catalase reversed the PHD2 dimerization, decreased HIF-1α levels, and attenuated glycolysis in Shunt PAEC. Our data suggest that reducing PHD2 dimerization could be a potential therapeutic target for PH.
    Keywords:  Drp1; HIF-1 alpha; Hydrogen peroxide; Mitochondrial fission; PHD2; ROS; Warburg effect
    DOI:  https://doi.org/10.1016/j.redox.2025.103529
  62. J Med Chem. 2025 Feb 20.
    ONC201-Derived Tetrahydropyridopyrimidindiones as Powerful ClpP Protease Activators to Tackle Diffuse Midline Glioma.
    Morena Miciaccia, Olga Maria Baldelli, Cosimo G Fortuna, Gianfranco Cavallaro, Domenico Armenise, Anselma Liturri, Savina Ferorelli, Denise P Muñoz, Alessandro Bonifazi, Francesca Rizzo, Antonella Cormio, Silvana Filieri, Giuseppe Micalizzi, Paola Dugo, Luigi Mondello, Anna Maria Sardanelli, Francesco Bruni, Paola Loguercio Polosa, Maria Grazia Perrone, Antonio Scilimati.
      Pediatric diffuse intrinsic pontine glioma (DIPG), classified under diffuse midline glioma, is a deadly tumor, with no effective treatments. The human mitochondrial protease hClpP is a potential DIPG therapeutic target, and this study describes the synthesis of two new series of tetrahydropyridopyrimidindiones (THPPDs) as hClpP activators. Among the tested compounds, we have identified 36 (THX6) that shows a strong hClpP activation (EC50 = 1.18 μM) and good cytotoxicity in ONC201-resistant cells (IC50 = 0.13 μM). Studying the oxidation mechanisms on cell membranes, the treatment of DIPG cells with 36 (THX6) causes a change in levels of fatty acids (PUFAs, MUFAs, and SFAs) compared to untreated cells and dysregulates the level of proteins involved in oxidative phosphorylation, biogenesis, and mitophagy that lead to a global collapse of mitochondrial integrity and function suggesting this as the mechanism through which 36 (THX6) accomplishes its antitumor activity in DIPG cell lines.
    DOI:  https://doi.org/10.1021/acs.jmedchem.4c01723
  63. Trends Cell Biol. 2025 Feb 20. pii: S0962-8924(24)00272-1. [Epub ahead of print]
    How are mitochondrial nucleoids trafficked?
    Josefa Macuada, Isidora Molina-Riquelme, Verónica Eisner.
      Mitochondria harbor their own DNA (mtDNA), which codifies essential proteins of the oxidative phosphorylation (OXPHOS) system and locally feeds them to their surrounding inner mitochondrial membrane (IMM), according to the 'sphere of influence' theory. mtDNA is compacted into nucleoids, which are tethered to the IMM and distributed throughout the mitochondrial network. Some nucleoid subpopulations present distinct intramitochondrial positioning during fission and their correct positioning is associated with mtDNA segregation and selective degradation. This opinion article focuses on different mechanisms that could control nucleoid positioning through intramitochondrial trafficking, either by cristae reshaping or by intercompartment-driven mechanisms involving the mitochondrial membranes and extramitochondrial elements. Understanding nucleoid trafficking promises insights into mitochondrial dysfunction in pathologies with mtDNA distribution and segregation issues.
    Keywords:  cristae reshaping; mitochondrial nucleoid; mtDNA inheritance; nucleoid dynamics; sphere of influence
    DOI:  https://doi.org/10.1016/j.tcb.2024.12.007
  64. World J Diabetes. 2025 Feb 15. 16(2): 93130
    Electroacupuncture alleviates diabetic peripheral neuropathy through modulating mitochondrial biogenesis and suppressing oxidative stress.
    Chong-Xi Yuan, Xuan Wang, Yun Liu, Tian-Cheng Xu, Zhi Yu, Bin Xu.
       BACKGROUND: Peripheral neuropathy caused by diabetes is closely related to the vicious cycle of oxidative stress and mitochondrial dysfunction resulting from metabolic abnormalities. The effects mediated by the silent information regulator type 2 homolog-1 (SIRT1)/peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) axis present new opportunities for the treatment of type 2 diabetic peripheral neuropathy (T2DPN), potentially breaking this harmful cycle.
    AIM: To validate the effectiveness of electroacupuncture (EA) in the treatment of T2DPN and investigate its potential mechanism based on the SIRT1/PGC-1α axis.
    METHODS: The effects of EA were evaluated through assessments of metabolic changes, morphological observations, and functional examinations of the sciatic nerve, along with measurements of inflammation and oxidative stress. Proteins related to the SIRT1/PGC-1α axis, involved in the regulation of mitochondrial biogenesis and antioxidative stress, were detected in the sciatic nerve using Western blotting to explain the underlying mechanism. A counterevidence group was created by injecting a SIRT1 inhibitor during EA intervention to support the hypothesis.
    RESULTS: In addition to diabetes-related metabolic changes, T2DPN rats showed significant reductions in pain threshold after 9 weeks, suggesting abnormal peripheral nerve function. EA treatment partially restored metabolic control and reduced nerve damage in T2DPN rats. The SIRT1/PGC-1α axis, which was downregulated in the model group, was upregulated by EA intervention. The endogenous antioxidant system related to the SIRT1/PGC-1α axis, previously inhibited in diabetic rats, was reactivated. A similar trend was observed in inflammatory markers. When SIRT1 was inhibited in diabetic rats, these beneficial effects were abolished.
    CONCLUSION: EA can alleviate the symptoms of T2DNP in experimental rats, and its effects may be related to the mitochondrial biogenesis and endogenous antioxidant system mediated by the SIRT1/PGC-1α axis.
    Keywords:  Electroacupuncture; Mitochondria biogenesis; Oxidative stress; Silent matching type information regulation 2 homolog-1/peroxisome proliferator-activated receptor-gamma coactivator-1α axis; Type 2 diabetic peripheral neuropathy
    DOI:  https://doi.org/10.4239/wjd.v16.i2.93130
  65. Biotechnol Appl Biochem. 2025 Feb 17.
    Etomidate Induces Mitochondrial Dysfunction in Glioma Cancer Cells by Inhibiting Mitochondrial Biogenesis Mediated by CREB/PGC-1α.
    Hailiang Shi, Zhongcheng Cao, Kai Wei.
      Gliomas are one of the most prevalent types of solid tumors in the brain. Imbalances in mitochondrial metabolism have been implicated in the pathological progression of gliomas. Etomidate, an agonist of the γ-aminobutyric acid type A (GABAA) receptor, is widely used in clinical settings. In this study, we report a novel pharmacological function of etomidate in regulating mitochondrial metabolism in glioma cancer cells. U87 glioma tumor cells were treated with etomidate (0.5, 1.0, and 2.0 µg/mL) for 24 h. Quantitative real-time PCR, western blot analysis, mtDNA/nDNA ratio, MitoTracker Red staining, Complex I and IV activity, intracellular ATP levels, and mitochondrial respiration were assessed. First, etomidate exposure inhibited the expression of PGC-1α in U87 glioma tumor cells. Further investigation revealed that etomidate suppressed the expression of Nrf1 and TFAM, the two key executors of mitochondrial biogenesis. Etomidate treatment led to damage in mitochondrial biogenesis by decreasing the mtDNA/nDNA ratio, reducing the protein expression of cytochrome B, and lowering mitochondrial mass. These changes suggest impaired mitochondrial replication and function. Correspondingly, etomidate exposure induced a "loss of mitochondrial function" by diminishing the activities of Complex I and Complex IV, the mitochondrial respiratory rate (MRR), and ATP generation. These effects highlight the detrimental impact of etomidate on the energy metabolism of glioma cells. Mechanistically, etomidate inactivated the transcription factor CREB by reducing its phosphorylation at Ser133. Activation of CREB with the second messenger cAMP restored the expression of PGC-1α, the mtDNA/nDNA ratio, Complex IV activity, summarized mitochondrial respiratory rate (MRR), and ATP production. This suggests that CREB activation may serve as a potential therapeutic strategy to counteract etomidate's inhibitory effects on mitochondrial function in glioma cells. Our results suggest that damage to mitochondrial biogenesis is a key step in the anticancer properties of etomidate in gliomas, and the decrease in PGC-1α and its downstream molecules may be the critical mechanism behind this effect.
    Keywords:  CREB; PGC‐1α; etomidate; gliomas; mitochondrial biogenesis
    DOI:  https://doi.org/10.1002/bab.2722
  66. Biologics. 2025 ;19 15-29
    ATF3 Knockdown Exacerbates Astrocyte Activation by Inhibiting Phosphorylation of Drp1 in Ischemic Stroke.
    Rong Huang, Xiaoyan Huang, Hongmei Yang, Haixuan Wu, Fan Liu, Phei Er Saw, Minghui Cao.
       Introduction: ATF3, a stress-induced transcription factor, has been implicated in the injury processes of various cell types, including neurons. It is recognized as a common marker for neuronal damage following neurotrauma. However, its role in other types of glial cells, particularly astrocytes, in response to ischemic injury remains unclear. Mitochondrial dysfunction is a key factor in the pathogenesis of ischemic stroke, and impaired mitochondrial function in astrocytes is associated with astrocyte activation. This study aimed to explore the relationship between mitochondrial damage and ischemic stroke and to investigate how ATF3 regulates mitochondrial dysfunction and astrocyte activation in the context of ischemic injury.
    Methods: In a transient middle cerebral artery occlusion (tMCAO) mouse model, we knocked down ATF3 and assessed infarct size, motor deficits, astrocyte activation, and mitochondrial damage. In vitro, we used oxygen-glucose deprivation and reoxygenation (OGD-R) to simulate ischemia and evaluated the impact of ATF3 knockdown on astrocyte activation and mitochondrial function.
    Results: ATF3 knockdown exacerbated infarct size, motor deficits, and astrocyte activation in vivo, with increased mitochondrial damage. In vitro, ATF3 depletion worsened mitochondrial dysfunction and astrocyte activation. ATF3 interacted with Drp1 via Akt2, inhibiting mitochondrial fission and protecting astrocytes.
    Conclusion: ATF3 regulates mitochondrial fission and protects astrocytes in ischemic stroke, highlighting its potential as a therapeutic target for stroke recovery.
    Keywords:  AIS; ATF3; Akt2; Drp1; activating transcription factor 3; acute ischemic stroke; astrocytes; dynamics-related protein 1; mitochondrial dysfunction; threonine/serine kinase 2
    DOI:  https://doi.org/10.2147/BTT.S486597
  67. Cell Death Dis. 2025 Feb 19. 16(1): 116
    Lon protease 1-mediated metabolic reprogramming promotes the progression of prostate cancer.
    Mengfei Yao, Xingming Zhang, Tianqi Wu, Tao Feng, Xiaojie Bian, Mierxiati Abudurexiti, Wenfeng Wang, Guohai Shi, Gong-Hong Wei, Qin Zhang, Xiangyun Li, Gang Feng, Leilei Du, Jianhua Wang.
      Lon protease 1 (LONP1) is an ATP-dependent protease located in the mitochondrial matrix and plays a crucial role in regulating mitochondrial proteostasis, metabolism, and cellular stress responses et al. Aberrant LONP1 expression has been found in the progression of various tumors; however, the role and molecular mechanisms of LONP1 in prostate cancer (PCa) remain poorly understood. Here we show that overexpression of LONP1 is closely related to adverse clinic pathological features and poor prognosis in PCa patients. Mechanistically, the findings reveal that LONP1 is implicated in modulating the metabolic switch from oxidative phosphorylation (OXPHOS) to aerobic glycolysis, thereby promoting tumor proliferation, invasion, and metastasis both in vitro and in vivo. Meanwhile, we prove that LONP1 as a protease directly targets mitochondrial pyruvate carrier 1 (MPC1), a key metabolic protein in the process of glycolysis, and enhances its degradation, which in turn suppresses tricarboxylic acid (TCA) cycle and ultimately promotes the progression of PCa. Furthermore, using PCa in cancer-prone mice homozygous for a prostate-targeted conditional Pten knockout and Lonp1 knockin, we integrate transcriptomic and proteomic analyses of prostate tumors, upon which reveals that Lonp1 overexpression results in a significant downregulation of NADH: ubiquinone oxidoreductase activity, consequently impeding the electron transfer process and mitochondrial ATP synthesis, associated with metastasis of PCa. Collectively, our results highlight that metabolic reprogramming induced by LONP1 in PCa is closely coupled with disease progression, suggesting that targeting the LONP1-mediated cascade in the mitochondrial may provide therapeutic potential for PCa disease.
    DOI:  https://doi.org/10.1038/s41419-025-07449-8
  68. Pathophysiology. 2025 Feb 13. pii: 9. [Epub ahead of print]32(1):
    Mitochondrial Dysfunction in Diabetes: Shedding Light on a Widespread Oversight.
    Franklyn Nonso Iheagwam, Amarachi Joy Joseph, Eniola Deborah Adedoyin, Olawumi Toyin Iheagwam, Samuel Akpoyowvare Ejoh.
      Diabetes mellitus represents a complicated metabolic condition marked by ongoing hyperglycemia arising from impaired insulin secretion, inadequate insulin action, or a combination of both. Mitochondrial dysfunction has emerged as a significant contributor to the aetiology of diabetes, affecting various metabolic processes critical for glucose homeostasis. This review aims to elucidate the complex link between mitochondrial dysfunction and diabetes, covering the spectrum of diabetes types, the role of mitochondria in insulin resistance, highlighting pathophysiological mechanisms, mitochondrial DNA damage, and altered mitochondrial biogenesis and dynamics. Additionally, it discusses the clinical implications and complications of mitochondrial dysfunction in diabetes and its complications, diagnostic approaches for assessing mitochondrial function in diabetics, therapeutic strategies, future directions, and research opportunities.
    Keywords:  diabetes mellitus; hyperglycemia; insulin resistance; mitochondrial biogenesis; mitochondrial dynamics; mitochondrial dysfunction
    DOI:  https://doi.org/10.3390/pathophysiology32010009
  69. Ecotoxicol Environ Saf. 2025 Feb 20. pii: S0147-6513(25)00273-8. [Epub ahead of print]292 117937
    Melatonin ameliorates Pb-induced mitochondrial homeostasis and ovarian damage through regulating the p38 signaling pathway.
    Zhuo-Nan Yang, Xin Du, An Wang, Yu-Hang Zhao, Yun-He Xia, Ling-Ge Shi, Si-Min Ding, Xin-Yu Yue, Fen Xing, Dong-Mei Ji, Dan Liang, Zheng-Bao Zha, Chun-Mei Liang, Yun-Xia Cao, Ya-Jing Liu.
      Lead (Pb), a widespread metallic pollutant in the environment, has been found to have detrimental effects on the female reproduction system. Recently, our group discovered a significant correlation between toxic metals and reproductive endocrine diseases. However, there is limited research on the relationship between blood concentration of Pb and the risk of diminished ovarian reserve function (DOR). Melatonin (MT), as a unique antioxidant, has been shown to reduce Pb toxicity both in vivo and in vitro，but the role of MT on follicle development in Pb-exposed female C57BL6 mice, and the underlying mechanisms, have not been clearly identified. In this study, blood Pb level was detected in the DOR patients, and a significant elevation in Pb levels was observed compared to the control group. Subsequently, we investigated the impact of lead acetate trihydrate (0.2 %), an endocrine disruptor of heavy metals, on follicle development in mice. We observed abnormal follicle development induced by lead acetate trihydrate without concurrent follicular apoptosis or excessive autophagy. Furthermore, we found that co-treatment with MT (30 mg/kg) rescued Pb-induced abnormal follicle development. Anti-Müllerian hormone (AMH) is a commonly utilized marker to evaluate ovarian reserve function. Our observation revealed that MT treatment effectively reversed the decrease in AMH levels induced by Pb. Importantly, our results revealed that MT not only protected against the Pb-induced increase of nucleus-encoded proteins, including SDHA, mitofilin and MTCO2, but also rescued Pb-induced the increase of mitochondrial dynamic-related proteins, such as OPA1, MFN and FIS1. In addition, MT protected against the decrease of mitochondrial dynamic-related protein anti-mitochondrial fission factor (MFF) antibody expression and mitochondrial membrane potential level. Finally, MT rescued the Pb-induced inhibition of phosphorylation in the P38 signaling pathway. Conclusively, these findings provide compelling evidence that exposure to Pb influences mitochondrial homeostasis, and MT effectively restores the imbalance between mitochondrial fusion and fission, nucleus-encoded proteins, and improves ovarian reserve function through regulating P38 signaling pathway. These results indicate that targeting the P38 signaling pathway with MT could be a potential therapeutic strategy for treating DOR.
    Keywords:  Lead; Melatonin; Mitochondrial homeostasis; Ovarian reserve function; Signaling pathway
    DOI:  https://doi.org/10.1016/j.ecoenv.2025.117937
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