bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2025–05–11
sixty-one papers selected by
Gavin McStay, Liverpool John Moores University
  1. Identification of molecular subtypes and a prognostic risk model based on mitochondrial dynamic related genes in clear cell renal cell carcinoma.
  2. Mechanistic study of modulating mitochondrial fission and fusion to ameliorate neuropathic pain in mice.
  3. A hidden cysteine in Fis1 targeted to prevent excessive mitochondrial fission and dysfunction under oxidative stress.
  4. Kinome screening identifies integrated stress response kinase EIF2AK1/HRI as a negative regulator of PINK1 mitophagy signaling.
  5. SNX10 at the crossroad of endocytosis and piecemeal mitophagy.
  6. Agent-based modeling of neuronal mitochondrial dynamics using intrinsic variables of individual mitochondria.
  7. Krüppel like factor 7 regulates mitochondrial dynamics balance in myocardial infarction.
  8. Chimeric deubiquitinase engineering reveals structural basis for specific inhibition of the mitophagy regulator USP30.
  9. Selenium corrects dysregulated mitophagy and lipophagy in obesity-related acute pancreatitis through the GPX1-Mfn2-PLIN2 axis.
  10. Germline loss diminishes somatic mitochondria but confers preservation of respiratory function during aging and hypothermia.
  11. Parkin mediates the mitochondrial dysfunction through mRpL18.
  12. Adaptations in mitochondrial quality control and interactions with innate immune signaling within skeletal muscle: A narrative review.
  13. ANXA2 regulates mitochondrial function and cellular senescence of PDLCs via AKT/eNOS signaling pathway under high glucose conditions.
  14. Poldip2 Aggravates inflammation in diabetic retinopathy by impairing mitophagy via the AMPK/ULK1/Pink1 pathway.
  15. Impaired Mitochondrial Biogenesis Inhibits Epithelial-Mesenchymal Transition in Villi of PCOS Patients.
  16. Valine acts as an early biomarker and exacerbates pathological cardiac hypertrophy by impairing mitochondrial quality control.
  17. Targeting mitochondrial fission for the treatment of myocardial infarction.
  18. Inhibiting mitochondrial excessive fission alleviates the neuronal damage in Parkinson's disease via regulating PGC-1α mediated mitochondrial biogenesis.
  19. The role of mitochondrial mRNA translation in cellular communication.
  20. Urolithin-A supplementation alleviates sepsis-induced acute lung injury by reducing mitochondrial dysfunction and modulating macrophage polarization.
  21. Furin inhibits HSCs activation and ameliorates liver fibrosis by regulating PTEN-L/PINK1/parkin mediated mitophagy in mouse.
  22. Mitochondrial Dysfunction in Cardiac Diseases: Insights into Pathophysiology and Clinical Outcomes.
  23. Sestrin2 is a central regulator of mitochondrial stress responses in disease and aging.
  24. Wireless, battery-free vagal electrical stimulation: A novel approach to inhibit cardiac hypertrophy via H3K18 lactylation mediated mitophagy.
  25. Phase separation in mitochondrial fate and mitochondrial diseases.
  26. FB1 causes barrier damage to vascular endothelial cells through ferroptosis by a PINK1/Parkin mediated mitophagy-dependent mechanism.
  27. Clerodendranthus spicatus-Cordyceps cicadae regulates mitophagy and protects renal tubular epithelial cells from hyperuricemic nephropathy.
  28. Glabridin Alleviates Metabolic Disorders in Diet-Induced Diabetic Mice.
  29. Lactoferrin Alleviates LPS-Induced Oxidative Stress and Necroptosis in Liver by Promoting Mitophagy.
  30. Metformin restores mitochondrial bioenergetics and redox homeostasis through modulation of mitochondrial biogenesis and dynamics in patient derived cultured fibroblasts and an animal model of molybdenum cofactor deficiency.
  31. LRRC4 Deficiency Drives Premature Ovarian Insufficiency by Disrupting Metabolic Homeostasis in Granulosa Cells.
  32. MiR-125a-5p in MSC-derived small extracellular vesicles alleviates Müller cells injury in diabetic retinopathy by modulating mitophagy via PTP1B pathway.
  33. Corrigendum to "Altered mitochondrial unfolded protein response and protein quality control promote oxidative distress in down syndrome brain" [Free Radic. Biol. Med. 227 (2025) 80-93].
  34. Benfotiamine, a Lipid-Soluble Derivative of Vitamin B1, Ameliorates the Carbohydrate Overload-Induced Mitochondrial Dysfunction in Fish Megalobrama amblycephala by Triggering the ULK1-Mediated Mitophagy.
  35. From Skeletal Muscle to Myocardium: Molecular Mechanisms of Exercise-Induced Irisin Regulation of Cardiac Fibrosis.
  36. Mechanism of SMYD2 promoting stemness maintenance of bladder cancer stem cells by regulating PYCR1 expression and PINK1/Parkin mitophagy pathway.
  37. PINK1-dependent NFKB signaling contributes to amyloid pathology in Alzheimer disease.
  38. Dual-responsive nanoparticles targeting ACE-II senescence for therapeutic mitigation of acute lung injury.
  39. METTL3-dependent m6A modification of GHR mRNA regulates mitochondrial function through mitochondrial biogenesis during myoblast differentiation.
  40. CXCL9 is a dual‑role biomarker in colorectal cancer linked to mitophagy and modulated by ALKBH5.
  41. Mitochondrial viscosity, oxidative stress and autophagy responsive fluorescent Zn(II) complex for monitoring non-alcoholic fatty liver disease.
  42. Cadmium and Lead Induce Mitochondrial Dysfunction in Ovarian Theca Cells: Mechanisms of Oxidative Stress and Bioenergetic Collapse.
  43. Binding of collagen I to integrins alleviates UVB-caused mitochondrial disorders in human keratinocytes HaCaT through enhancement of F-actin polymerization.
  44. SARM1 loss protects retinal ganglion cells in a mouse model of Autosomal Dominant Optic Atrophy.
  45. NDP52 and its emerging role in pathogenesis.
  46. TJ0113-induced mitophagy in acute liver failure detected by Raman microspectroscopy.
  47. MSCs in Acute Kidney Injury Treatment: Modulating Mitochondrial Function and Inhibiting Pyroptosis via PGC-1α.
  48. Cigarette smoke induces endoplasmic reticulum stress-associated mucus hypersecretion via orosomucoid 1-like protein 3 in airway epithelia.
  49. Jujuboside A improves insomnia by maintaining mitochondrial homeostasis in prefrontal neurons.
  50. Mitochondrial GCN5L1 coordinates with YME1L and MICOS to remodel mitochondrial cristae in white adipocytes and modulate obesity.
  51. MG53 deficiency mediated skeletal muscle dysfunction in chronic obstructive pulmonary disease via impairing mitochondrial fission.
  52. Methylmercury Chloride Exposure Affects Oocyte Maturation Through AMPK/mTOR-Mediated Mitochondrial Autophagy.
  53. miR142 silencing alleviates retinal inflammation by impairing mitochondrial function and reprogramming metabolism of CD4+ T cells via targeting MTFR1.
  54. PINK1 affects mitochondrial oxidative phosphorylation by regulating MFN2 to alleviate diabetic kidney disease.
  55. Multi-omics integration reveals Vha68-3 as a testicular aging-specific factor that coordinates spermatid elongation through mitochondrial metabolic homeostasis.
  56. Unveiling the intercompartmental signaling axis: Mitochondrial to ER Stress Response (MERSR) and its impact on proteostasis.
  57. Carvacrol Protects IPEC-J2 Cells from Oxidative Stress by Suppressing Autophagy.
  58. Tubular specific glutathione peroxidase 3 deletion exacerbates kidney damage in IRI-AKI mice.
  59. Metformin aggravates pancreatitis by regulating the release of oxidised mitochondrial DNA via the frataxin (FXN)/ninjurin 1 (NINJ1) signalling pathway.
  60. Taurochenodeoxycholic acid activates autophagy and suppresses inflammatory responses in microglia of MPTP-induced Parkinson's disease mice via AMPK/mTOR, AKT/NFκB and Pink1/Parkin signaling pathways mediated by Takeda G protein-coupled receptor 5.
  61. SETDB1 decline promotes the resistance to sorafenib via DRP1 phosphorylation-mediated mitochondrial dysfunction in HepG2 cells.
  1. Biochem Biophys Res Commun. 2025 Apr 27. pii: S0006-291X(25)00625-4. [Epub ahead of print]767 151911
    Identification of molecular subtypes and a prognostic risk model based on mitochondrial dynamic related genes in clear cell renal cell carcinoma.
    Kaibo Yang, Kun Yang, Zitong Lei, Kunjin Wu, Jing Li, Qiuting Peng, Chang Liu, Kai Qu, Ting Lin.
       BACKGROUND: Clear cell renal cell carcinoma (ccRCC) represents the most prevalent histological subtype and primary contributor to unfavorable prognosis in renal cancer. While mitochondrial dynamics serve as a critical quality control mechanism linked to tumor malignancy, their clinical significance and specific mechanisms in ccRCC remain poorly understood.
    METHODS: Consnsuclusterplus was used to consensus clustering and molecular subtype screening, Kaplan-Meier analysis was used to analyze survival in different subtypes. PINK1 expression was detected by westernblot, and CCK8 is used to detect cell activity. Immunofluorescence staining of LC3 for evaluating mitochondrial autophagy levels.
    RESULTS: In this study, we classified 534 ccRCC samples, identified from the UCSC XENA database, into A and B clusters based on 42 mitochondrial dynamic related genes. Cluster A demonstrated superior survival outcomes compared to cluster B. Subsequent analysis revealed significant inter-cluster differences in gene expression profiles, mutational spectra, and immune infiltration patterns. We established a mitochondrial dynamics-related prognostic model incorporating PINK1, NIPSNAP1, and MTFR2, with mitophagy-associated genes represented by PINK1 showing particular prognostic significance in ccRCC. Gene Ontology (GO) analysis indicated significant enrichment of mitophagy pathways in cluster A. Functional investigations demonstrated that PINK1-overexpressing cells exhibited increased sensitivity to sunitinib (lower IC50 values), whereas PINK1 knockdown conferred therapeutic resistance. Western blot and immunofluorescence analyses confirmed elevated mitophagy levels in PINK1-overexpressing cells under sunitinib treatment, contrasting with diminished mitophagy in PINK1-deficient cells.
    CONCLUSIONS: Our findings advance the understanding of mitochondrial dynamics in ccRCC progression, demonstrating that PINK1-mediated enhancement of mitophagy critically potentiates the anti-tumor effects of sunitinib in ccRCC.
    Keywords:  Clear cell renal cell carcinoma; Mitochondrial dynamic; Molecular subtypes; PINK1
    DOI:  https://doi.org/10.1016/j.bbrc.2025.151911
  2. Sci Rep. 2025 May 04. 15(1): 15571
    Mechanistic study of modulating mitochondrial fission and fusion to ameliorate neuropathic pain in mice.
    Liu Xie, Jing Cao, Yiran Xu, Qingqing Yang, Wanting Chang, Linna Song, Yanyan Sun.
      The emergence of neuropathic pain is significantly influenced by the impairment of mitochondrial processes. Ensuring the stability of mitochondrial activity requires a delicate equilibrium between the processes of mitochondrial fission and fusion. However, the specific alterations in mitochondrial activity across different models of neuropathic pain and the underlying mechanisms remain largely unclear. We developed a persistent compression injury (CCI) model targeting the sciatic nerve in mice. CCI induced pain like behaviors in mice, which were associated with increased levels of dynamin related protein 1 (Drp1) and decreased expression of the fusion protein OPA1 and an increase in the percentage of DRG nerve cell mitochondria in the fission form, and a decrease in percentage in the fusion form. Ultrastructural analysis showed that mitochondria in CCI mice were smaller in perimeter and area, adopting a more circular shape. Overexpression of OPA1 mediated by AAV attenuated pain hypersensitivity, lowered oxidative stress, and expanded mitochondrial circumference and area. Mdivi-1 treatment reduced pain, whereas blocking fusion with MYLS22 augmented pain and oxidative stress and further led to increased mitochondrial fragmentation. Our results illustrate that Mitochondria in DRG nerve cell are highly sensitive to neuropathic pain. Modulating mitochondrial fission and fusion through targeted gene overexpression and pharmacological inhibitors restores mitochondrial dynamics, reduces oxidative stress, and alleviates neuropathic pain in mice. These findings position mitochondrial dynamics as promising therapeutic targets for pain management.
    Keywords:  DRG; Fission and fusion; Mitochondrial; Neuropathic pain; Oxidative stress
    DOI:  https://doi.org/10.1038/s41598-025-99300-5
  3. Nat Commun. 2025 May 06. 16(1): 4187
    A hidden cysteine in Fis1 targeted to prevent excessive mitochondrial fission and dysfunction under oxidative stress.
    Suman Pokhrel, Gwangbeom Heo, Irimpan Mathews, Shun Yokoi, Tsutomu Matsui, Ayori Mitsutake, Soichi Wakatsuki, Daria Mochly-Rosen.
      Fis1-mediated mitochondrial localization of Drp1 and excessive mitochondrial fission occur in human pathologies associated with oxidative stress. However, it is not known how Fis1 detects oxidative stress and what structural changes in Fis1 enable mitochondrial recruitment of Drp1. We find that conformational change involving α1 helix in Fis1 exposes its only cysteine, Cys41. In the presence of oxidative stress, the exposed Cys41 in activated Fis1 forms a disulfide bridge and the Fis1 covalent homodimers cause increased mitochondrial fission through increased Drp1 recruitment to mitochondria. Our discovery of a small molecule, SP11, that binds only to activated Fis1 by engaging Cys41, and data from genetically engineered cell lines lacking Cys41 strongly suggest a role of Fis1 homodimerization in Drp1 recruitment to mitochondria and excessive mitochondrial fission. The structure of activated Fis1-SP11 complex further confirms these insights related to Cys41 being the sensor for oxidative stress. Importantly, SP11 preserves mitochondrial integrity and function in cells during oxidative stress and thus may serve as a candidate molecule for the development of treatment for diseases with underlying Fis1-mediated mitochondrial fragmentation and dysfunction.
    DOI:  https://doi.org/10.1038/s41467-025-59434-6
  4. Sci Adv. 2025 May 09. 11(19): eadn2528
    Kinome screening identifies integrated stress response kinase EIF2AK1/HRI as a negative regulator of PINK1 mitophagy signaling.
    Pawan K Singh, Shalini Agarwal, Ilaria Volpi, Léa P Wilhelm, Giada Becchi, Andrew Keenlyside, Thomas Macartney, Rachel Toth, Adrien Rousseau, Glenn R Masson, Ian G Ganley, Miratul M K Muqit.
      Loss-of-function mutations in the PINK1 kinase lead to early-onset Parkinson's disease (PD). PINK1 is activated by mitochondrial damage to phosphorylate ubiquitin and Parkin, triggering mitophagy. PINK1 also indirectly phosphorylates Rab GTPases, such as Rab8A. Using an siRNA library targeting human Ser/Thr kinases in HeLa cells, we identified EIF2AK1 [heme-regulated inhibitor (HRI) kinase], a branch of the integrated stress response (ISR), as a negative regulator of PINK1. EIF2AK1 knockdown enhances mitochondrial depolarization-induced PINK1 stabilization and phosphorylation of ubiquitin and Rab8A. These results were confirmed in SK-OV-3, U2OS, and ARPE-19 cells. Knockdown of DELE1, an activator of EIF2AK1, produced similar effects. Notably, the ISR inhibitor ISRIB also enhanced PINK1 activation. In human cells with mito-QC mitophagy reporters, EIF2AK1 knockdown or ISRIB treatment increased PINK1-dependent mitophagy without affecting deferiprone-induced mitophagy. These findings suggest that the DELE1-EIF2AK1 ISR pathway is a negative regulator of PINK1-dependent mitophagy. Further evaluation in PD-relevant models is needed to assess the therapeutic potential of targeting this pathway.
    DOI:  https://doi.org/10.1126/sciadv.adn2528
  5. Autophagy. 2025 May 06. 1-3
    SNX10 at the crossroad of endocytosis and piecemeal mitophagy.
    Laura Trachsel-Moncho, Benan John Mathai, Chiara Veroni, Anne Simonsen.
      Mitophagy targets damaged or dysfunctional mitochondria for lysosomal degradation. While canonical mitophagy pathways target the whole mitochondria for lysosomal degradation, it has become clear that selected mitochondrial components can be targeted for lysosomal degradation via other pathways, such as piecemeal mitophagy or mitochondria-derived vesicles. In a recent study, we identified the PX domain-containing endosomal protein SNX10 as a negative modulator of piecemeal mitophagy. Endosomal SNX10-positive vesicles dynamically interact with mitochondria and acquire selected mitochondrial proteins upon hypoxia. Zebrafish larvae lacking Snx10 show elevated Cox-IV degradation, increased levels of reactive oxygen species (ROS), and ROS-dependent neuronal death.
    Keywords:  SNX10; endosomal sorting; mitophagy; oxidative stress; zebrafish
    DOI:  https://doi.org/10.1080/15548627.2025.2499641
  6. iScience. 2025 May 16. 28(5): 112390
    Agent-based modeling of neuronal mitochondrial dynamics using intrinsic variables of individual mitochondria.
    Garrett M Fogo, Francisco J Torres Torres, Reagan L Speas, Anthony R Anzell, Thomas H Sanderson.
      Mitochondrial networks undergo remodeling to regulate form and function. The dynamic nature of mitochondria is maintained by the dueling processes of mitochondrial fission and fusion. Dysfunctional mitochondrial dynamics have been linked to debilitating diseases and injuries, suggesting mitochondrial dynamics as a promising therapeutic target. Increasing our understanding of the factors influencing mitochondrial dynamics will help inform therapeutic development. Utilizing live imaging of primary neurons, we analyzed how intrinsic properties of individual mitochondria influence their behavior. We found that size, shape, mitochondrial membrane potential, and protein oxidation predict mitochondrial fission and fusion. We constructed an agent-based model of mitochondrial dynamics, the mitochondrial dynamics simulation (MiDyS). In silico experiments of neuronal ischemia/reperfusion injury and antioxidant treatment illustrate the utility of MiDyS for testing hypothesized mechanisms of injury progression and evaluating therapeutic strategies. We present MiDyS as a framework for leveraging in silico experimentation to inform and improve the design of therapeutic trials.
    Keywords:  Cell biology; Molecular biology; Neuroscience
    DOI:  https://doi.org/10.1016/j.isci.2025.112390
  7. Commun Biol. 2025 May 09. 8(1): 722
    Krüppel like factor 7 regulates mitochondrial dynamics balance in myocardial infarction.
    Cao Wang, Fuxing Zhu, Lan Zhou, Situo Zhang, Ruiqi Wang, Hui Tian, Bosong Zhang, Jiahui Wu, Xiang Xu, Ruixian Jiang, Xiaolu Hou, Jian Liu, Weiming Tian.
      Targeting the balance of mitochondrial fission and fusion can effectively alleviate the cardiac energy supply efficiency, to restore cardiac systolic dysfunction and reduce mortality. We previously found that Klf7 is closely related to cardiac energy metabolism. Here we generated cardiomyocyte-specific Klf7 knockout and overexpression mice that underwent myocardial infarction (MI) surgery. Klf7 expression increased in the ischemic myocardium of mice, and cardiomyocyte-specific knockout Klf7 significantly lowered the mortality of MI-inflicted mice and improved ATP insufficiency in MI. Subsequently, Klf7 overexpression aggravated adverse cardiac remodeling and mitochondrial fission and fusion imbalance after MI. Our results also demonstrated that Klf7 inhibited mitochondrial fusion and promoted mitochondrial fission by targeting prohibitin 2 (Phb2) and mitofusin 2 (Mfn2). Our study revealed a crucial role in upholding the overall balance of mitochondrial fission and fusion during MI. Furthermore, our findings indicated that the Klf7/Mfn2/Phb2 axis holds promise as a potential target for therapeutic interventions of MI.
    DOI:  https://doi.org/10.1038/s42003-025-08139-z
  8. Nat Struct Mol Biol. 2025 May 05.
    Chimeric deubiquitinase engineering reveals structural basis for specific inhibition of the mitophagy regulator USP30.
    Nafizul Haque Kazi, Nikolas Klink, Kai Gallant, Gian-Marvin Kipka, Malte Gersch.
      The mitochondrial deubiquitinase ubiquitin-specific protease (USP) 30 negatively regulates PINK1-parkin-driven mitophagy. Whether enhanced mitochondrial quality control through inhibition of USP30 can protect dopaminergic neurons is currently being explored in a clinical trial for Parkinson's disease. However, the molecular basis for specific inhibition of USP30 by small molecules has remained elusive. Here we report the crystal structure of human USP30 in complex with a specific inhibitor, enabled by chimeric protein engineering. Our study uncovers how the inhibitor extends into a cryptic pocket facilitated by a compound-induced conformation of the USP30 switching loop. Our work underscores the potential of exploring induced pockets and conformational dynamics to obtain deubiquitinase inhibitors and identifies residues facilitating specific inhibition of USP30. More broadly, we delineate a conceptual framework for specific USP deubiquitinase inhibition based on a common ligandability hotspot in the Leu73 ubiquitin binding site and on diverse compound extensions. Collectively, our work establishes a generalizable chimeric protein-engineering strategy to aid deubiquitinase crystallization and enables structure-based drug design with relevance to neurodegeneration.
    DOI:  https://doi.org/10.1038/s41594-025-01534-4
  9. Biochem Biophys Res Commun. 2025 Apr 28. pii: S0006-291X(25)00630-8. [Epub ahead of print]768 151916
    Selenium corrects dysregulated mitophagy and lipophagy in obesity-related acute pancreatitis through the GPX1-Mfn2-PLIN2 axis.
    Peiyu Han, Xiaoyu Ma, Yuqiu Ge, Hongbo Ren, Yu Wu.
      The incidence of acute pancreatitis (AP) has been on the rise in recent years. Obesity, a significant contributor to AP, increases the risk of AP and promotes disease progression, leading to adverse outcomes. Mitophagy and lipophagy are two main types of selective autophagy in AP and obesity, but their contribution to comorbidity in obesity-related AP (OB-AP) remains unknown. This study demonstrated that OB-AP exhibited more severe pancreatic injury than AP in vivo and in vitro. We found that the balance between mitophagy and lipophagy was disrupted, with a significant increase in mitophagy and a corresponding significant decrease in lipophagy. Mechanistically, overexpression of selenoprotein glutathione peroxidase 1 (GPX1) stabilized mitofusin 2 (Mfn2) protein, promoting the interaction between Mfn2 and perilipin 2 (PLIN2), and thereby attenuating excessive mitophagy and increasing lipophagy. Selenium supplementation improved pancreatic autophagy homeostasis in OB-AP through increasing GPX1 expression, thereby reducing disease severity. Notably, OB-AP patients exhibited lower selenium levels than healthy individuals. In conclusion, selenium supplementation enhanced GPX1 expression, corrected the imbalance between mitophagy and lipophagy, and mitigated disease severity in OB-AP through the GPX1-Mfn2-PLIN2 axis, and therefore has therapeutic potential in OB-AP.
    Keywords:  Glutathione peroxidase 1; Lipophagy; Mitophagy; Obesity-related acute pancreatitis; Selenium
    DOI:  https://doi.org/10.1016/j.bbrc.2025.151916
  10. J Biosci. 2025 ;pii: 33. [Epub ahead of print]50
    Germline loss diminishes somatic mitochondria but confers preservation of respiratory function during aging and hypothermia.
    Hye Jin Hwang, Francis R G Amrit, Brandon J Berry, Claudette St Croix, Andrew P Wojtovich, Sruti Shiva, Arjumand Ghazi.
      Reproductive status influences metabolism and health across the lifespan in diverse ways, and mitochondrial function plays a critical role in mediating this relationship. Using the Caenorhabditis elegans germline ablation model, we investigated the impact of germline stem cell (GSC) loss on mitochondrial dynamics and respiratory function. Our results show that GSC loss reduces mitochondrial volume and respiratory function in young adulthood but preserves mitochondrial activity during aging and upon exposure to hypothermic stress, correlating with enhanced survival. We found that the transcription factor NHR-49/PPARα, but not DAF-16/ FOXO3A, was essential for preserving mitochondrial function and hypothermia resistance in these long-lived mutants. Together, these findings reveal the impact of germline signals on somatic mitochondrial health and underscore the intricate relationship between reproductive fitness and organismal health.
  11. J Biol Chem. 2025 May 07. pii: S0021-9258(25)02057-5. [Epub ahead of print] 110208
    Parkin mediates the mitochondrial dysfunction through mRpL18.
    Xiuxiu Ti, Hui Zuo, Guochun Zhao, Yuwei Li, Minghui Du, Liwen Xu, Shengnan Li, Zhaoliang Shan, Yuxue Gao, Guangming Gan, Yan Wang, Qing Zhang.
      Loss of function of parkin leads to the mitochondrial dysfunction, which is closely related to Parkinson's disease. However, the in vivo mechanism is far from clear. One of the dogmas is that impaired Parkin causes dysfunction of mitophagy mediated by Pink1-Parkin axis. The other is that impaired Parkin causes Mfn accumulation which leads to mitochondrial dysfunction. Surprisingly, in Drosophila muscles, as reported, the first dogma is not applicable; for the second dogma, our study suggests that Parkin mediates the mitochondrial dysfunction through modulating mitochondrial morphology, which is determined by synergy of both Marf and mitochondrial protein mRpL18 got from our genome-wide screen, whose RNAi rescues parkin RNAi phenotype. Mechanistically, we found that impaired Parkin upregulated both the transcription and protein levels of mRpL18 dependent on its E3 ligase activity, causing the mRpL18 accumulation outside mitochondria. Consequently, cytosolic accumulated mRpL18 competitively bound Drp1, leading to the reduction of the binding of Drp1 to its receptor Fis1, which finally inhibited the mitochondrial fission and tipped the balance to mitochondrial hyperfusion, thereby affected the mitochondrial function. Taken together, our study suggests that impaired Parkin causes mitochondrial hyperfusion due to two reasons: (1) Parkin defect impairs Pink1-Parkin axis-mediated Marf degradation, which promotes mitochondrial fusion; (2) Parkin defect causes mRpL18 accumulation, which inhibits Drp1/Fis1-mediated mitochondrial fission. These two ways function together to drive Parkin-mediated mitochondrial hyperfusion. Therefore, knockdown of either marf or mRpL18 can prevent mitochondrial hyperfusion, leading to the rescue of Parkin defect-triggered fly wing phenotypes. Overall, our study unveils a new facet of how Parkin regulates mitochondrial morphology to affect mitochondrial function, which provides new insights for the understanding and treatment of Parkinson's disease.
    Keywords:  Drp1; Parkin; Parkinson's disease; mRpL18
    DOI:  https://doi.org/10.1016/j.jbc.2025.110208
  12. J Sport Health Sci. 2025 May 01. pii: S2095-2546(25)00027-4. [Epub ahead of print] 101049
    Adaptations in mitochondrial quality control and interactions with innate immune signaling within skeletal muscle: A narrative review.
    Priyanka Khemraj, Anastasiya Kuznyetsova, David A Hood.
      Skeletal muscle health and function are essential determinants of metabolic health, physical performance, and overall quality of life. The quality of skeletal muscle is heavily dependent on the complex mitochondrial reticulum that contributes toward its unique adaptability. It is now recognized that mitochondrial perturbations can activate various innate immune pathways, such as the nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome complex by propagating inflammatory signaling in response to damage-associated molecular patterns (DAMPs). The NLRP3 inflammasome is a multimeric protein complex and is a prominent regulator of innate immunity and cell death by mediating the activation of caspase-1, pro-inflammatory cytokines interleukin-1β and interleukin-18 and pro-pyroptotic protein gasdermin-D. While several studies have begun to demonstrate the relationship between various mitochondrial DAMPs (mtDAMPs) and NLRP3 inflammasome activation, the influence of various metabolic states on the production of these DAMPs and subsequent inflammatory profile remains poorly understood. This narrative review aimed to address this by highlighting the effects of skeletal muscle use and disuse on mitochondrial quality mechanisms including mitochondrial biogenesis, fusion, fission and mitophagy. Secondly, this review summarized the impact of alterations in mitochondrial quality control mechanisms following muscle denervation, aging, and exercise training in relation to NLRP3 inflammasome activation. By consolidating the current body of literature, this work aimed to further the understanding of innate immune signaling within skeletal muscle, which can highlight areas for future research and therapeutic strategies to regulate NLRP3 inflammasome activation during divergent metabolic conditions.
    Keywords:  Exercise; Innate immune signaling; Mitochondrial quality control; NLRP3 inflammasome; Skeletal muscle disuse
    DOI:  https://doi.org/10.1016/j.jshs.2025.101049
  13. Sci Rep. 2025 May 06. 15(1): 15843
    ANXA2 regulates mitochondrial function and cellular senescence of PDLCs via AKT/eNOS signaling pathway under high glucose conditions.
    Yanlin Huang, Zejing Qiu, Chunhui Jiang, Qian Fang, Jiaye Wang, Mingfang Han, Yizhao Liu, Zehui Li.
      Diabetes mellitus is one of the risk factors for periodontitis. Patients with diabetes mellitus possess higher prevalence of periodontitis, more severe periodontal destruction, yet the underlying mechanisms of action are not yet clear. Annexin A2 (ANXA2) is a calcium-dependent phospholipid-binding protein widely involved in membrane repair, cytokinesis, and endocytosis. In this study, we explore whether ANXA2 is one of the associative links between diabetes and periodontitis and find out its underlying mechanisms. Cellular senescence and mitochondrial functions (ROS, mitochondrial morphology, mitochondrial autophagy) were observed. We observed that ANXA2 expression was down-regulated in Periodontal ligament cells (PDLCs) under high glucose conditions. Furthermore, overexpression of ANXA2 delayed high glucose-induced cellular senescence and mitochondrial dysfunction. β-galactosidase activity and the mRNA levels of the senescence-relative genes(p21,p16) were decreased, mitochondrial fracture and ROS release were reduced, and the expression of mitochondrial autophagy-related proteins (LC3,p62,Parkin) was enhanced. expression was enhanced. Mechanistically, we demonstrated that it can regulate the AKT/eNOS signaling pathway by knockdown and overexpression of ANXA2 which was measured using Western blotting (WB) assay to measure the expression of eNOS, p-eNOS Ser1177, Akt and p-Akt Ser473 proteins in PDLCs. After that, we used AKT and eNOS inhibitors to demonstrate the protective effect of ANXA2 on PDLCs under high glucose conditions. The above results suggest that ANXA2 has an anti-aging protective effect, attenuates high glucose-induced cellular senescence in PDLCs, and maintains mitochondrial homeostasis. Therefore, it would be valuable to further explore its role in the link between diabetes and periodontitis in future experiments.
    Keywords:  Cellular senescence; Diabetes; Mitochondria; Mitophagy; Periodontitis
    DOI:  https://doi.org/10.1038/s41598-025-00950-2
  14. Life Sci. 2025 May 02. pii: S0024-3205(25)00316-9. [Epub ahead of print]373 123681
    Poldip2 Aggravates inflammation in diabetic retinopathy by impairing mitophagy via the AMPK/ULK1/Pink1 pathway.
    Siyu Lin, Zhiyu Ji, Jie Gao, Jiawei Fan, Jingjing Hou, Sha Liu, Chuanxi Wang, Keyang Chen, Liming Tao, Zhengxuan Jiang.
       BACKGROUND AND AIM: Inflammation is a crucial aspect of the pathophysiology of diabetic retinopathy (DR). Polymerase delta-interacting protein 2 (Poldip2) has been linked to inflammation in various disorders, but its role in DR remains unclear. This study aims to elucidate the underlying mechanisms of Poldip2 in DR.
    METHODS: Transmission Electron Microscopy (TEM) revealed significant mitophagy reduction due to the accumulation of damaged mitochondria in the retinas of Streptozotocin (STZ)-induced diabetic Sprague Dawley (SD) rats. In vivo, AAV9-Poldip2-shRNA was administered to STZ-induced DR rats, partially restoring mitophagy. Microglia (BV2) cells cultured in high glucose (HG) conditions exhibited similar behavior. Likewise, BV2 received Poldip2-siRNA treatment to further explore the regulatory mechanism of Poldip2.
    RESULTS: In vivo, Poldip2 was significantly elevated alongside VEGFR and SQSTM1/P62, while mitophagy markers were inhibited. Under HG conditions, BV2 secret large amounts of pro-inflammatory factors. Human Retinal Microvascular Endothelial Cells (HRMECs) were significantly affected by these HG-cultured BV2, leading to angiogenesis. Notably, Poldip2 knockdown significantly increased Pink1 by preventing its ubiquitination-mediated degradation, thereby enhancing mitophagy and reducing retinal inflammation.
    CONCLUSION: Our findings suggest that Poldip2 contributes to DR by promoting Pink1 degradation, which inhibits mitophagy and leads to inflammation. Targeting Poldip2 may offer a novel therapeutic strategy for DR.
    Keywords:  Diabetic retinopathy; Mitophagy; Pink1; Poldip2; Ubiquitination
    DOI:  https://doi.org/10.1016/j.lfs.2025.123681
  15. Endocrinology. 2025 Apr 22. pii: bqaf076. [Epub ahead of print]166(6):
    Impaired Mitochondrial Biogenesis Inhibits Epithelial-Mesenchymal Transition in Villi of PCOS Patients.
    Hui-Ying Jie, Lu Luo, Bing Cai, Yan Xu, Yuan Yuan, Yang-Xing Wen, Si-Min Liu, Ji-Fan Tan, Ming-Hui Chen, Can-Quan Zhou, Qing-Yun Mai.
       CONTEXT: Polycystic ovary syndrome (PCOS) is accompanied by impaired mitochondrial biogenesis in the ovary and uterus. Whether impaired mitochondrial biogenesis exhibits in villi of PCOS, and its effect and underlying mechanism remain unclear.
    OBJECTIVE: This work aimed to investigate mitochondrial biogenesis status and effect on villi of PCOS patients.
    METHODS: Placenta RNA-sequencing data of PCOS downloaded from the GEO database was analyzed with Gene Set Enrichment Analysis (GSEA). GSEA results were validated in first-trimester villi of 8 PCOS patients with euploid miscarriage and 22 matched controls. The function and impact of mitochondrial biogenesis on trophoblast cells were investigated using human trophoblast cell lines HTR-8/SVneo and BeWo.
    RESULTS: Mitochondria-related and epithelial-mesenchymal transition (EMT) pathways were enriched in placentas of PCOS. In villi of PCOS patients with euploid miscarriage, reduced mitochondrial DNA copy number (mtDNA CN) and N-cadherin protein level, and an elevated E-cadherin protein level were detected, indicating mitochondrial biogenesis dysfunction and impaired EMT. 5 α-Dihydrotestosterone (DHT) exposure downregulated mtDNA CN via reducing mitochondrial transcription factor A (TFAM) level, a critical transcription factor of mtDNA, in HTR-8/SVneo cells. Decreased expression level of TFAM was observed in villi of PCOS. Knockdown of TFAM significantly impeded EMT, characterized by decreased levels of N-cadherin and vimentin in HTR-8/SVneo cells, and increased level of E-cadherin in BeWo cells. Reduction of reactive oxygen species (ROS) mitigated TFAM knockdown-induced impairment of EMT via increasing nuclear Yes-associated protein level in trophoblast cells.
    CONCLUSION: The villi of PCOS patients with euploid miscarriage exhibited impaired mitochondrial biogenesis. Androgen-induced downregulation of TFAM impeded EMT via ROS/YAP axis in trophoblast cell.
    Keywords:  TFAM; epithelial-mesenchymal transition (EMT); hyperandrogenism; miscarriage; mitochondrial biogenesis; polycystic ovary syndrome (PCOS)
    DOI:  https://doi.org/10.1210/endocr/bqaf076
  16. Atherosclerosis. 2025 Apr 26. pii: S0021-9150(25)00114-5. [Epub ahead of print]405 119216
    Valine acts as an early biomarker and exacerbates pathological cardiac hypertrophy by impairing mitochondrial quality control.
    Hongyu Kuang, Dan Li, Yunlin Chen, Hongmi Zou, Fang Li, Zhiyan Gong, Yuxiang Long, Hao Zhou, Huaan Du, Yuehui Yin.
       OBJECTIVE: Pathological cardiac hypertrophy is an independent risk factor for heart failure (HF). Early identification and timely treatment are crucial for significantly delaying the progression of HF.
    METHODS: Targeted amino acid metabolomics and RNA sequencing (RNA-seq) were combined to explore the underlying mechanism. In vitro, H9c2 cells were stimulated with angiotensin II (Ang II) or were incubated with extra valine after Ang II stimulation. The branched chain alpha-ketoate dehydrogenase kinase (Bckdk) inhibitor 3,6-dichlorobenzo[b]thiophene-2-carboxylic acid (BT2) and rapamycin were utilized to confirm the role of the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway in this process.
    RESULTS: A significant accumulation of valine was detected within hypertrophic hearts from spontaneously hypertensive rats (SHR). When branched chain amino acid (BCAA) degradation was increased by BT2, the most pronounced decrease was observed in the valine level (Δ = 0.185 μmol/g, p < 0.001), and cardiac hypertrophy was ameliorated. The role of imbalanced mitochondrial quality control (MQC), including the suppression of mitophagy and excessive mitochondrial fission, was revealed in myocardial hypertrophy. In vitro, high concentrations of valine exacerbated cardiomyocyte hypertrophy stimulated by Any II, resulting in the accumulation of impaired mitochondria and respiratory chain dysfunction. BT2, rapamycin, and mitochondrial division inhibitor 1 (Mdivi-1) all ameliorated MQC imbalance, mitochondrial damage and oxidative stress in hypertensive models with high valine concentration.
    CONCLUSION: Valine exacerbated pathological cardiac hypertrophy by causing a MQC imbalance, probably as an early biomarker for cardiac hypertrophy under chronic hypertension.
    Keywords:  Branched chain amino acids; Cardiac hypertrophy; Mitophagy; Oxidative stress; Valine
    DOI:  https://doi.org/10.1016/j.atherosclerosis.2025.119216
  17. Eur Heart J. 2025 May 06. pii: ehaf296. [Epub ahead of print]
    Targeting mitochondrial fission for the treatment of myocardial infarction.
    Christopher G R Perry, Gary Sweeney.
      
    DOI:  https://doi.org/10.1093/eurheartj/ehaf296
  18. Exp Neurol. 2025 May 02. pii: S0014-4886(25)00152-9. [Epub ahead of print] 115288
    Inhibiting mitochondrial excessive fission alleviates the neuronal damage in Parkinson's disease via regulating PGC-1α mediated mitochondrial biogenesis.
    Jingwei Ma, Yang Yang, Caixia Zang, Qiuzhu Chen, Yueqi Jiang, Yirong Dong, Jinrong Wang, Ning Zhou, Xing Yang, Fangfang Li, Xiuqi Bao, Dan Zhang.
      Mitochondrial excessive fission is one of representative pathological features and a principal element triggering the neuronal damage in Parkinson's disease (PD). Inhibiting mitochondrial excessive fission benefits the pathology of PD through promoting mitochondrial biogenesis, but the detailed mechanism has not been clarified. In our study, we revealed that inhibiting mitochondrial excessive fission by Mdivi-1, the dynamin related protein 1 (DRP1) inhibitor, increased the expression and nuclear translocation of peroxisome proliferator-activated receptor γ (PPARγ) coactivator 1α (PGC-1α), as well as its downstream transcriptional factors, nuclear respiratory factor 1/2 (NRF1/2) and mitochondrial transcription factor A (TFAM), and therefore promoted mitochondrial biogenesis. Suppression of mitochondrial excessive fission alleviated dopaminergic synaptic injury, neuronal apoptosis and motor dysfunction, while inhibiting PGC-1α attenuated these ameliorative effects in both in-vitro and in-vivo PD models. Mechanistic study showed that inhibiting mitochondrial excessive fission facilitated the expression of PGC-1α, NRF1 and TFAM by activation of Ca2+/calmodulin-dependent serine/threonine kinase II (CaMKII)/cAMP-response element binding protein (CREB) pathway. Inhibiting mitochondrial excessive fission also activated AMP-activated serine/threonine kinase (AMPK)/Sirtuin1 (Sirt1) pathway, and then phosphorylated and deacetylated PGC-1α by post-translational modifications. In conclusion, inhibiting mitochondrial excessive fission could promote mitochondrial biogenesis through activation of PGC-1α and therefore rescue the impaired dopaminergic neurons, which provided evidence for targeting mitochondrial excessive fission for the treatment of PD and new drug developments.
    Keywords:  Mitochondrial biogenesis; Mitochondrial excessive fission; Neuronal apoptosis; PGC-1α; Parkinson's disease; Synaptic damage
    DOI:  https://doi.org/10.1016/j.expneurol.2025.115288
  19. J Cell Sci. 2025 May 01. pii: jcs263753. [Epub ahead of print]138(9):
    The role of mitochondrial mRNA translation in cellular communication.
    Eleonora Zilio, Tim Schlegel, Marta Zaninello, Elena I Rugarli.
      Mitochondria are dynamic and heterogeneous organelles that rewire their network and metabolic functions in response to changing cellular needs. To this end, mitochondria integrate a plethora of incoming signals to influence cell fate and survival. A crucial and highly regulated node of cell-mitochondria communication is the translation of nuclear-encoded mitochondrial mRNAs. By controlling and monitoring the spatio-temporal translation of these mRNAs, cells can rapidly adjust mitochondrial function to meet metabolic demands, optimise ATP production and regulate organelle biogenesis and turnover. In this Review, we focus on how RNA-binding proteins that recognise nuclear-encoded mitochondrial mRNAs acutely modulate the rate of translation in response to nutrient availability. We further discuss the relevance of localised translation of these mRNAs for subsets of mitochondria in polarised cells. Finally, we highlight quality control mechanisms that monitor the translation process at the mitochondrial surface and their connections to mitophagy and stress responses. We propose that these processes collectively contribute to mitochondrial specialisation and signalling function.
    Keywords:  Cell signalling; Mitochondria; RNA-binding proteins; Ribosome quality control; Translation; mRNA
    DOI:  https://doi.org/10.1242/jcs.263753
  20. Mitochondrion. 2025 May 04. pii: S1567-7249(25)00044-3. [Epub ahead of print] 102047
    Urolithin-A supplementation alleviates sepsis-induced acute lung injury by reducing mitochondrial dysfunction and modulating macrophage polarization.
    Mohd Mohsin, Almaz Zaki, Gulnaz Tabassum, Salman Khan, Shakir Ali, Tanveer Ahmad, Mansoor Ali Syed.
      Sepsis is a severe and life-threatening condition marked by excessive inflammation, mitochondrial dysfunction, and epithelial barrier disruption, often leading to Acute Lung Injury (ALI). Mitophagy, a cellular mechanism that removes damaged mitochondria, plays a vital role in maintaining mitochondrial health during sepsis. In this study, we investigated the protective effects of Urolithin-A against ALI and sepsis. In LPS-stimulated RAW264.7 macrophages, Urolithin-A significantly reduced mitochondrial dysfunction, Reactive Oxygen Species (ROS), Nitric Oxide (NO) production, and apoptosis. Additionally, it enhanced mitophagy by upregulating PINK1, Parkin, and LC3-II, which helped preserve mitochondrial function. In vivo, Urolithin-A treatment in mouse models of ALI and sepsis reduced lung injury and inflammation, as shown by improved ALI scores, decreased wet/dry lung weight ratios, and lower levels of inflammatory markers such as iNOS, IL-1β, and MPO. Urolithin-A also improved epithelial barrier integrity and upregulated anti-apoptotic markers, demonstrating its ability to alleviate sepsis-induced lung damage. These findings suggest that Urolithin-A holds significant promise as a therapeutic agent for managing inflammatory lung conditions associated with sepsis.
    Keywords:  Acute Lung injury; Mitochondrial dysfunction; Mitophagy; ROS; Sepsis; Urolithin-A
    DOI:  https://doi.org/10.1016/j.mito.2025.102047
  21. FASEB Bioadv. 2025 May;7(5): e70009
    Furin inhibits HSCs activation and ameliorates liver fibrosis by regulating PTEN-L/PINK1/parkin mediated mitophagy in mouse.
    Yan-Wei Song, Yu-Hua Zhu, Ming-Ze Ma.
      Hepatic Stellate cells (HSCs) play an important role during liver fibrosis progression; more and more evidence indicates that mitophagy greatly regulates HSCs activation. HSCs mitophagy mainly depends on the classical PINK1/Parkin pathway, which can be strongly regulated by phosphatase PTEN-long (PTEN-L). PTEN-L can be cleaved by Furin that leading to functional changes in the tumor regulation process. However, the impact of the interaction between Furin and PTEN-L on HSCs mitophagy remains unclear. Therefore, this study aims to explore the role of Furin in HSCs activation and liver fibrosis and its potential mechanisms. Our results revealed that Furin expression was obviously up-regulated during HSCs activation and mice liver fibrogenesis. We also found that the activation of primary HSCs can be inhibited by Furin treatment in vitro. Besides, functional studies showed that LX-2 cell proliferation and migration were obviously inhibited by Furin treatment. Further studies showed that mitochondrial membrane potential (MMP) was significantly reduced by Furin treatment, and the knockdown of PTEN-L expression caused similar effects. These results demonstrated the role of Furin in promoting HSCs mitophagy but leading to inhibition of HSCs persistent activation. Furthermore, we constructed a liver fibrosis mouse model by CCl4-induced method and found that forced expression of Furin caused alleviation of liver fibrosis in CCl4-induced mice. Our findings provide a new clue for understanding liver fibrogenesis and highlight the therapeutic potential of Furin for hepatic fibrosis.
    Keywords:  Furin; PTEN‐long; hepatic stellate cells; liver fibrosis; mitophagy
    DOI:  https://doi.org/10.1096/fba.2024-00221
  22. Curr Cardiol Rev. 2025 May 06.
    Mitochondrial Dysfunction in Cardiac Diseases: Insights into Pathophysiology and Clinical Outcomes.
    Syed Shadab Ahmad, Javed Akhtar Ansari, Tarique Mahmood Ansari, Syed Mehdi Hasan Zaidi.
      Mitochondrial dysfunction plays a crucial role in the pathogenesis of various cardiac diseases, including heart failure, ischemic cardiomyopathy, and drug-induced cardiotoxicity. Mitochondria are essential for cellular energy production, calcium homeostasis, redox balance, and apoptotic regulation, making their proper function vital for cardiac health. Dysfunctional mitochondria contribute to excessive reactive oxygen species (ROS) production, impaired ATP synthesis, and disruption of mitochondrial dynamics, leading to cardiomyocyte damage and cell death. Emerging research highlights mitochondrial dynamics, including fission, fusion, mitophagy, and biogenesis, as critical determinants of cardiac homeostasis. Perturbations in these processes exacerbate myocardial injury and heart failure progression. Additionally, chemotherapy-induced cardiotoxicity, primarily from anthracyclines, is closely linked to mitochondrial damage, underscoring the need for targeted therapeutic strategies. Pharmacological interventions, such as antioxidants, mitochondrial-targeted drugs, and cardioprotective agents, have shown promise in mitigating mitochondrial dysfunction-related cardiac toxicity. Furthermore, lifestyle modifications, including exercise and dietary interventions, are being explored to enhance mitochondrial resilience in cardiac tissues. Advanced imaging techniques and biomarker-based diagnostics are improving the early detection of mitochondrial dysfunction in cardiac diseases. Emerging therapeutic strategies, such as mitochondrial transplantation, gene therapy, and precision medicine approaches, hold potential for targeted intervention. Despite these advances, challenges remain in translating mitochondrial-targeted therapies into clinical practice due to complexities in mitochondrial regulation and inter-organ communication. Future research should focus on optimizing mitochondrial-targeted interventions, improving diagnostic precision, and exploring novel molecular pathways to mitigate cardiac mitochondrial dysfunction. A comprehensive understanding of mitochondrial pathophysiology in cardiac diseases will pave the way for innovative treatment strategies aimed at preserving cardiac function and reducing the burden of heart failure.
    Keywords:  Mitochondrial dysfunction; cardiac toxicity; cardiomyopathy; cardiovascular diseases; disease.; health
    DOI:  https://doi.org/10.2174/011573403X379197250417061904
  23. Ageing Res Rev. 2025 May 02. pii: S1568-1637(25)00108-4. [Epub ahead of print]109 102762
    Sestrin2 is a central regulator of mitochondrial stress responses in disease and aging.
    Ivo F Machado, Carlos M Palmeira, Anabela P Rolo.
      Mitochondria supply most of the energy for cellular functions and coordinate numerous cellular pathways. Their dynamic nature allows them to adjust to stress and cellular metabolic demands, thus ensuring the preservation of cellular homeostasis. Loss of normal mitochondrial function compromises cell survival and has been implicated in the development of many diseases and in aging. Although exposure to continuous or severe stress has adverse effects on cells, mild mitochondrial stress enhances mitochondrial function and potentially extends health span through mitochondrial adaptive responses. Over the past few decades, sestrin2 (SESN2) has emerged as a pivotal regulator of stress responses. For instance, SESN2 responds to genotoxic, oxidative, and metabolic stress, promoting cellular defense against stress-associated damage. Here, we focus on recent findings that establish SESN2 as an orchestrator of mitochondrial stress adaptation, which is supported by its involvement in the integrated stress response, mitochondrial biogenesis, and mitophagy. Additionally, we discuss the integral role of SESN2 in mediating the health benefits of exercise as well as its impact on skeletal muscle, liver and heart injury, and aging.
    Keywords:  Aging; Liver; Mitochondria; Mitohormesis; Muscle; Sestrin2
    DOI:  https://doi.org/10.1016/j.arr.2025.102762
  24. Pharmacol Res. 2025 May 02. pii: S1043-6618(25)00185-9. [Epub ahead of print]216 107760
    Wireless, battery-free vagal electrical stimulation: A novel approach to inhibit cardiac hypertrophy via H3K18 lactylation mediated mitophagy.
    Pilong Shi, Yang Liu, Yuetong Sha, Jiaxin Wang, Jiajun Zhou, Kai Liu, Yonggang Cao, Qianhui Zhang, Xinran Wang, Hongli Sun.
      Electrical stimulation (ES) has been established as a reliable and beneficial approach in therapeutic rehabilitation, exhibiting negligible side effects. Nevertheless, research focusing on the application of ES for cardiac hypertrophy remains limited, as it fails to provide an enduring remedy for chronic diseases. In this investigation, vagal ES, characterized by its wireless, battery-free, and fully implantable nature, was utilized to treat cardiac hypertrophy. The vagus nerve at the stimulation site was carefully embedded within an envelope, sealed securely using multiple bioabsorbable sutures. Subsequently, a cardiac hypertrophy model was induced in rats via abdominal aortic coarctation for four weeks. The findings of this investigation demonstrated that ES markedly attenuated cardiac hypertrophy. Metabolomic analysis revealed a notable reduction in lactate levels within myocardial tissue following ES. Proteomic analysis of myocardial tissues indicated a substantial decrease in the expression of autophagy and mitophagy-related proteins after ES. Additionally, ChIP-seq result revealed a specific binding interaction between H3K18 lactylation (H3K18la) and BCL2 interacting protein 3 (Bnip3), while luciferase reporter assays demonstrated that H3K18la directly governed Bnip3 transcriptional activation, exploring its role in modulating mitophagy. Mechanistically, it was shown that ES reduced lactate accumulation through the upregulation of monocarboxylate transporter 4 (MCT4) by decreasing norepinephrine (NE) levels. Furthermore, ES reversed cardiac hypertrophy by diminishing H3K18la levels, thus inhibiting Bnip3 protein expression. This pathway assists in diminishing cardiac hypertrophy, emphasizing the critical involvement of the afferent vagal pathway in regulating cardiac hypertrophy.
    Keywords:  Bnip3; Cardiac hypertrophy; H3K18 lactylation; Lactate; Mitophagy; Vagal electrical stimulation
    DOI:  https://doi.org/10.1016/j.phrs.2025.107760
  25. Proc Natl Acad Sci U S A. 2025 May 27. 122(21): e2422255122
    Phase separation in mitochondrial fate and mitochondrial diseases.
    Qingyi Chen, Sanqi An, Chuanlong Wang, Yanshuang Zhou, Xingguo Liu, Wenkai Ren.
      Mitochondria are central metabolic organelles that control cell fate and the development of mitochondrial diseases. Traditionally, phase separation directly regulates cell functions by driving RNA, proteins, or other molecules to concentrate into lipid droplets. Recent studies show that phase separation regulates cell functions and diseases through the regulation of subcellular organelles, particularly mitochondria. In fact, phase separation is involved in various mitochondrial activities including nucleoid assembly, autophagy, and mitochondria-related inflammation. Here, we outline the key mechanisms through which phase separation influences mitochondrial activities and the development of mitochondrial diseases. Insights into how phase separation regulates mitochondrial activities and diseases will help us develop interventions for related diseases.
    Keywords:  mitochondrial disease; mitochondrial dynamics; mitophagy; nucleoid assembly; phase separation
    DOI:  https://doi.org/10.1073/pnas.2422255122
  26. Chem Biol Interact. 2025 May 03. pii: S0009-2797(25)00166-8. [Epub ahead of print] 111536
    FB1 causes barrier damage to vascular endothelial cells through ferroptosis by a PINK1/Parkin mediated mitophagy-dependent mechanism.
    Zhang Shuxia, Zhang Ping, Zheng Xiaoyan, Mao Sichao, Xu Xinyi, Kevin Waldron, Wang Chenfeng, Sherin R Rouby, Ahmed H Ghonaim, Chen Xingxiang.
      Fumonisin B1 (FB1) is an environmental mycotoxin produced mainly by fungi of the genus Fusarium. Exposure to FB1 can lead to pulmonary edema in pigs, likely caused by damage to vascular endothelial cells, but the mechanism of FB1-induced damage was unknown. Here, we found that FB1 damages vascular endothelial cells through ferroptosis, marked by iron-dependent membrane lipid peroxidation, and through mitophagy, a selective autophagy that targets mitochondria. FB1 exposure reduced barrier-related gene expression and increased pro-inflammatory factors. Ferroptosis was evidenced by elevated iron, ROS, lipid peroxidation, and ferroptotic markers (TFR, ACSL4), alongside decreased GSH, SLC7A11, and GPX-4 levels in vascular endothelial cells. Importantly, the ferroptosis inhibitor, Ferrostatin-1, reversed the vascular endothelial cells' barrier damage, inflammation, and ferroptosis caused by FB1. FB1-induced mitophagy was demonstrated by detecting decreased mitochondrial membrane potential and increased levels of mitophagy-related proteins. Surprisingly, silencing PINK1 using siRNA not only diminished mitophagy, cellular damage, and inflammatory responses induced by FB1, but also mitigated FB1-induced ferroptosis. In conclusion, this study demonstrates that FB1 causes vascular endothelial cell damage by ferroptosis in a mitophagy-dependent manner. This study thus lays a mechanistic foundation for the study of FB1 causing pulmonary edema in pigs and for exploring options for therapeutic intervention in conditions caused by this mycotoxin, which causes substantial harm to both human and animal health.
    Keywords:  Barrier damage; FB1; Ferroptosis; Mitophagy; Vascular endothelial cells
    DOI:  https://doi.org/10.1016/j.cbi.2025.111536
  27. J Ethnopharmacol. 2025 May 05. pii: S0378-8741(25)00610-5. [Epub ahead of print] 119926
    Clerodendranthus spicatus-Cordyceps cicadae regulates mitophagy and protects renal tubular epithelial cells from hyperuricemic nephropathy.
    Qiaoru Wu, Danyao Lin, Jianting Ouyang, Shouhai Wu, Junjie Lin, En Zhang, Delun Li, Haohao Quan, Xinwen Fu, Xiaowan Wang, Chuang Li, Wei Mao.
       ETHNOPHARMACOLOGICAL RELEVANCE: Clerodendranthus spicatus (CS) and Cordyceps cicadae (CC) are both medicine and food. They have long been used to treat kidney disease, but their mechanisms for treating hyperuricemic nephropathy (HN) are not yet clear.
    AIM: We investigated the effect and mechanism of Clerodendranthus spicatus-Cordyceps cicadae (CS-CC) in HN treatment.
    METHODS: We detected the chemical profiling of CS-CC freeze-dried powder, drug-containing serum and drug-containing intracellular fluid by UHPLC-Q Exactive Orbitrap-HRMS. We explored the effective components as well as underlying mechanisms of CS-CC in HN treatment via network pharmacological analysis. We constructed HN rat models induced by gavaging potassium oxonate and uric acid (UA) for three weeks, and performed biochemical and pathological tests as well as histological observation. The expressions of fibrosis-associated proteins were quantitatively analyzed using immunohistochemistry staining and western blot analysis. For in vitro studies, we measured the metabolic fluxes in UA-treated HK-2 cells using Seahorse XFe24 analyzer and flow cytometric analysis. Mitophagy-associated proteins were evaluated using immunofluorescence co-localization analysis and western blot analysis.
    RESULTS: A total of 14 simultaneous constituents of CS-CC in vivo and in vitro were identified. Network pharmacological analysis highlighted CS-CC regulated mitophagy in HN. CS-CC treatment effectively enhanced renal function and ameliorate renal fibrosis in HN rats. We found PINK1-mediated mitophagy was suppressed in HN, while CS-CC treatment could restore cellular metabolism, activate mitophagy and protect tubular epithelial cells in HN.
    CONCLUSIONS: PINK1-mediated mitophagy was significantly inhibited in HN, whereas CS-CC treatment demonstrated remarkable efficacy in attenuating renal fibrosis and promoting mitophagy to protect tubular epithelial cells in HN.
    Keywords:  Clerodendranthus spicatus; Cordyceps cicadae; fibrosis; hyperuricemic nephropathy; mitophagy; tubular epithelial cells
    DOI:  https://doi.org/10.1016/j.jep.2025.119926
  28. Phytother Res. 2025 May 06.
    Glabridin Alleviates Metabolic Disorders in Diet-Induced Diabetic Mice.
    Xiaoxue Yang, Kaiyi Lai, Jiayu Zhang, Ziyi Chen, Wenwen Ding, Yu Jiang, Ying Liu.
      Glabridin (GLD) is a flavonoid derived from licorice. This study aims to evaluate GLD's therapeutic potential in ameliorating type 2 diabetes mellitus (T2DM) and elucidate its underlying mechanisms of action. A T2DM model was established using male C57BL/6J mice fed a high-fat, high-glucose diet. GLD was administered via intraperitoneal injection at doses of 10, 20, and 30 mg/kg BW, with MET (200 mg/kg BW) as a positive control. Fasting blood glucose levels, glucose tolerance, insulin tolerance, pyruvate tolerance, and serum parameters were analyzed, along with key markers of glycogen synthesis, gluconeogenesis, lipid metabolism, mitochondrial function, and endoplasmic reticulum (ER) stress. GLD significantly lowered blood glucose levels in the diabetic mice. It suppressed gluconeogenesis by inhibiting PEPCK and G6P, while promoting glycogen synthesis by activating GCK and inhibiting GSK-3β. Additionally, GLD enhanced insulin signaling by increasing IRS1 and IRS2 levels and promoting AKT phosphorylation, thereby improving insulin sensitivity. In lipid metabolism, GLD reduced hepatic steatosis and lipid accumulation by downregulating lipogenesis-related genes (SREBP1c, FAS, ACC1, and SCD1) and upregulating lipolysis-related genes (PPARα and LCAD). In energy metabolism, GLD increased mitochondrial membrane potential, reduced reactive oxygen species levels, and enhanced the expression of genes associated with mitophagy (PINK1 and Parkin) and mitochondrial biogenesis (PGC-1α, SIRT1, and TFAM). Moreover, GLD mitigated ER stress by decreasing GRP78 and CHOP levels, suppressing PERK phosphorylation, and inhibiting key stress response genes. GLD improves insulin sensitivity and exerts antidiabetic effects by ameliorating metabolic disorders, supporting its potential as a therapeutic agent for T2DM.
    Keywords:  ER stress; glabridin; glucolipid metabolism; insulin sensitivity; type 2 diabetes mellitus
    DOI:  https://doi.org/10.1002/ptr.8517
  29. J Agric Food Chem. 2025 May 05.
    Lactoferrin Alleviates LPS-Induced Oxidative Stress and Necroptosis in Liver by Promoting Mitophagy.
    Shuang Guan, Shujing Lu, Ranran Zhang, Yuanmeng Wang, Xinyu Yao, Xuming Deng, Jing Lu.
      Lactoferrin (LF) is an important component of dairy products. Studies have shown that LF has a protective effect against liver injury, but the mechanism of action remains incompletely understood. Lipopolysaccharide (LPS), a key component of bacterial endotoxins, can lead to liver injury when exposure is excessive. Necroptosis is a newly identified type of programmed cell death characterized by cell swelling, rupture, and necrosis, and its excessive activation contributes to tissue damage. In this study, we demonstrated that LF alleviates LPS-induced oxidative stress and necroptosis in liver cells by modulating the ROS-RIPK1-RIPK3 pathway. In further mechanistic studies, we discovered that LF promotes mitophagy in liver cells to promptly remove damaged mitochondria caused by LPS, thereby reducing the increase in reactive oxygen species (ROS) levels associated with damaged mitochondria and alleviating oxidative stress and necrosis. To validate our findings, we used mitophagy inhibitor cyclosporin A (CsA) as a negative control, and the results confirmed our findings. These results provide novel strategies and insights into utilizing LF to alleviate LPS-induced liver injury.
    Keywords:  lactoferrin; mitophagy; necroptosis; oxidative stress
    DOI:  https://doi.org/10.1021/acs.jafc.4c12425
  30. Biomed Pharmacother. 2025 May 05. pii: S0753-3322(25)00317-8. [Epub ahead of print]187 118123
    Metformin restores mitochondrial bioenergetics and redox homeostasis through modulation of mitochondrial biogenesis and dynamics in patient derived cultured fibroblasts and an animal model of molybdenum cofactor deficiency.
    Morgana Brondani, Rafael T Ribeiro, Camila V Pinheiro, Christofer I H Hoffmann, Manuela B Marcuzzo, Al-Walid Mohsen, Moacir Wajner, Bianca Seminotti, Jerry Vockley, Guilhian Leipnitz.
      Molybdenum cofactor deficiency (MoCD) is an inborn error of sulfur metabolism caused by inactivating variants in the genes encoding enzymes of the molybdenum cofactor biosynthetic pathway. Patients present with accumulation of sulfite in the brain with secondary mitochondrial bioenergetics and severe neurological manifestations. To investigate the pathophysiology of this disorder, we evaluated mitochondrial and redox homeostasis in fibroblasts derived from a patient with MoCD type A (MOCS1 deficiency) and in an animal model based on the intracerebroventricular administration of sulfite in Wistar rats. Since treatment for MoCD is largely ineffective, we also investigated the effects of metformin, an antidiabetic drug with neuroprotective potential. Reduced basal, maximal, and ATP-linked respiration and reserve respiratory capacity were verified in MOCS1 deficient fibroblasts. The protein content of MFN1/2, OPA1, DRP1, and NRF1 was also reduced, whereas p-DRP1 (Ser 637) was increased. Superoxide levels were elevated in these cells. Metformin treatment reversed these changes. Further, the p-AMPK/T-AMPK protein ratio and the expression of PRKAA1, PPARGC1A, SIRT1, DNM1L, and mitofusin 1 were increased by metformin in the deficient cells. Sulfite administration into rat brain disturbed the antioxidant defenses, and tricarboxylic acid cycle and electron transfer chain function in the striatum, cerebral cortex and cerebellum. Metformin prevented this bioenergetic dysfunction. Our findings show that metformin elicits positive effects in the brain of sulfite-treated rats and in the MOCS1 deficient cell line by modulating mitochondrial biogenesis and fission, identifying potential therapeutic intervention opportunities in MoCD.
    Keywords:  Brain; MOCS1 deficient fibroblasts; Metformin; Mitochondrial homeostasis; Molybdenum cofactor deficiency; Sulfite
    DOI:  https://doi.org/10.1016/j.biopha.2025.118123
  31. Adv Sci (Weinh). 2025 May 02. e2417717
    LRRC4 Deficiency Drives Premature Ovarian Insufficiency by Disrupting Metabolic Homeostasis in Granulosa Cells.
    Yujie Shang, Yunjun Li, Di Han, Kun Deng, Wei Gao, Minghua Wu.
      Premature ovarian insufficiency (POI), defined by early loss of ovarian activity before the age of 40 years, is the leading cause of infertility and systematic aging in women, posing a public health challenge worldwide. However, its molecular etiology and therapeutic options are still lacking. Here, leucine-rich repeat containing 4 (LRRC4) is identified as a critical regulator of folliculogenesis expressed in granulosa cells (GCs), which contributes to ovarian reserve maintenance. LRRC4 deficiency triggers defective oocyte maturation and excessive follicular atresia through inhibition of GC differentiation and ultimately leads to POI. Mechanistically, LRRC4 balances mitochondrial fission and fusion to inhibit excessive mitophagy by promoting the K48-linked ubiquitination degradation of Yes-associated protein (YAP), thereby maintaining the metabolic homeostasis of mitochondrial aerobic respiration and glycolysis. Importantly, targeting LRRC4 normalized follicular development and ovarian function in POI model mice. In conclusion, these data reveal the novel pathogenesis of POI and suggest that LRRC4 is a potential target for the diagnosis and treatment of POI.
    Keywords:  granulosa cell; leucine rich repeat containing 4; metabolic homeostasis; mitochondria dynamics; premature ovarian insufficiency
    DOI:  https://doi.org/10.1002/advs.202417717
  32. Cell Death Discov. 2025 May 08. 11(1): 226
    MiR-125a-5p in MSC-derived small extracellular vesicles alleviates Müller cells injury in diabetic retinopathy by modulating mitophagy via PTP1B pathway.
    Cong Liu, Jinjin Xiang, Yueqin Chen, Chang He, Jun Tong, Yinglin Liao, Huangyi Lei, Lingyun Sun, Genhong Yao, Zhenggao Xie.
      Diabetic retinopathy (DR) ranks among the primary causes of adult blindness globally. Oxidative stress and mitochondrial dysfunction play a critical role in the progression of DR. Mounting data indicated that small extracellular vesicles (sEVs) of mesenchymal stem cell (MSC) have the ability to transport bioactive chemicals to target cells, leading to changes in their phenotype. Nevertheless, it remains elusive how MSC-derived sEVs regulate oxidative stress and mitochondrial function in DR. MSC-sEVs was intravitreally injected to streptozotocin (STZ)-treated Sprague-Dawley rats to assess the therapeutic effects on DR. The underlying regulatory mechanism was investigated by coculturing advanced glycation end-products (AGEs)-induced rat Müller cells with/without PTP1B overexpression with MSC-sEVs in vitro, with or without miR-125a-5p suppression. Intravitreal injection of MSC-sEVs improved histological morphology and blood-retinal barrier function, alleviated Müller gliosis, decreased PTP1B expression, redox stress and apoptosis in retina of diabetic rat. MSC-sEVs decreased the accumulation of ROS and improved the structure and function of mitochondria of Müller cells with AGEs treatment. Mechanically, MSC-sEVs activated the mitophagy of AGEs-treated Müller cells, represented by an increased expression of the LC3II/LC3I ratio, TOM20, PINK1 and Parkin along with a decreased expression of P62. Importantly, miR-125a-5p inhibitor abolished the protective effects of MSC-sEVs. Furthermore, the overexpression of PTP1B in Müller cells reduced the effects of MSC-sEVs. These findings suggested that miR-125a-5p of MSC-sEVs alleviates Müller cells injury in DR by modulating PINK1/Parkin-mediated mitophagy via PTP1B pathway.
    DOI:  https://doi.org/10.1038/s41420-025-02439-3
  33. Free Radic Biol Med. 2025 May 05. pii: S0891-5849(25)00271-0. [Epub ahead of print]
    Corrigendum to "Altered mitochondrial unfolded protein response and protein quality control promote oxidative distress in down syndrome brain" [Free Radic. Biol. Med. 227 (2025) 80-93].
    Simona Lanzillotta, Daniel Esteve, Chiara Lanzillotta, Antonella Tramutola, Ana Lloret, Elena Forte, Vito Pesce, Anna Picca, Fabio Di Domenico, Marzia Perluigi, Eugenio Barone.
      
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.04.050
  34. Aquac Nutr. 2025 ;2025 7688386
    Benfotiamine, a Lipid-Soluble Derivative of Vitamin B1, Ameliorates the Carbohydrate Overload-Induced Mitochondrial Dysfunction in Fish Megalobrama amblycephala by Triggering the ULK1-Mediated Mitophagy.
    Ling Zhang, Chaofan He, Zishang Liu, Guangzhen Jiang, Wenbin Liu, Dingdong Zhang, Xiangfei Li.
      Compared with mammals, fish have a limited capability to utilize carbohydrates, thus generally suffering from metabolic disorders when offered carbohydrate-enriched diets. As a synthetic liposoluble derivative of vitamin B1, benfotiamine can alleviate the carbohydrate overload-induced mitochondrial dysfunction in fish, but the potential mechanisms have not been well explored. The present research was performed to unveil the molecular pathways through which benfotiamine benefits the mitochondrial function of a carp species Megalobrama amblycephala, which often exhibits metabolic disturbances. First, a control (C, 30% carbohydrate) group, a high-carbohydrate (HC, 43% carbohydrate) group, and a HC incorporating benfotiamine (1.425 mg/kg) group were conducted, respectively, in a 12-week feeding trial. Then, two in vitro studies were performed by using primary hepatocytes. In the first one, a media treatment, a high-glucose (HG) treatment, and a HG incorporating benfotiamine were designated, respectively. In the second one, a media group, a vehicle group, a HG group, and a HG + BL-918 (the agonist of UNC-51-like kinase 1 [ULK1]) group were adopted, respectively. The results indicated that HC/HG treatment resulted in mitophagy disorder by downregulating the phosphorylation of AMPK and ULK1 and the contents of proteins involved in the PTEN-induced putative kinase protein 1 (PINK1)-Parkin pathway. Mitochondrial dysfunction was also observed, as was indicative of the reduced activities of mitochondrial complex I, III, and SDH. However, benfotiamine treatment increased the contents of P-AMPK, P-ULK1, and the PINK1-Parkin pathway-related proteins as well as mitochondrial complex activities. In conclusion, benfotiamine could trigger the ULK1-mediated mitophagy to ameliorate the carbohydrate overload-induced mitochondrial dysfunction in fish.
    Keywords:  carbohydrate metabolism disturbance; fish culture; mitochondrial dysfunction; mitochondrial nutrients; mitophagy
    DOI:  https://doi.org/10.1155/anu/7688386
  35. Int J Mol Sci. 2025 Apr 10. pii: 3550. [Epub ahead of print]26(8):
    From Skeletal Muscle to Myocardium: Molecular Mechanisms of Exercise-Induced Irisin Regulation of Cardiac Fibrosis.
    Zhao Wang, Lin Li, Meng Yang, Biao Li, Siyuan Hu.
      This study systematically elucidates the regulatory mechanisms and potential therapeutic value of the exercise-induced hormone Irisin in the pathological progression of cardiac fibrosis. Through comprehensive analysis and multidimensional data integration, we constructed a complete regulatory network of Irisin within the cardiovascular system, spanning its secretion, signal transduction, and precise regulatory control. Our findings demonstrate that exercise intervention significantly elevates circulating Irisin levels via the skeletal muscle-peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α)-fibronectin type III domain-containing protein 5 (FNDC5) signaling axis. Irisin establishes a multidimensional molecular barrier against cardiac fibrosis by targeting Sirtuin 1 (Sirt1) activation, inhibiting the transforming growth factor-beta (TGF-β)/Smad3 signaling pathway, and modulating the transcriptional activity of the mitochondrial biogenesis core factors PGC-1α and nuclear respiratory factor 1 (NRF-1). Moreover, the dual regulatory mechanism of the exercise-skeletal muscle-heart axis not only effectively suppresses the aberrant activation of cardiac fibroblasts but also significantly reduces collagen deposition, oxidative stress, and inflammatory infiltration by restoring mitochondrial dynamics balance. Taken together, this study reveals a novel exercise-mediated cardioprotective mechanism at the molecular interaction network level, thereby providing a theoretical basis for the development of non-pharmacological bio-intervention strategies targeting the Irisin signaling pathway and laying a translational foundation for precise exercise prescriptions in cardiovascular diseases.
    Keywords:  Irisin; cardiac fibrosis; cardioprotection; exercise
    DOI:  https://doi.org/10.3390/ijms26083550
  36. Int J Oncol. 2025 May;pii: 41. [Epub ahead of print]66(5):
    Mechanism of SMYD2 promoting stemness maintenance of bladder cancer stem cells by regulating PYCR1 expression and PINK1/Parkin mitophagy pathway.
    Junjie Chen, Shuai Xiao, Xieyu Yan, Yongbao Wei, Wei Song.
      SET and MYND domain‑containing protein 2 (SMYD2), an identified protein‑lysine methyltransferase, is key for bladder cancer (BC) progression. The tumor‑formation capacity and metastatic potential of bladder cancer stem cells (BCSCs) are due to their stemness characteristics. The present study explores the mechanism of SMYD2 in promoting BCSC stemness maintenance by pyrroline‑5‑carboxylate reductase 1 (PYCR1). BC cells were treated with PYCR1, SMYD2 and putative kinase 1 (PINK1) small interfering (si)RNA, pcDNA3.1‑PYCR1 and pcDNA3.1‑SMYD2. Mito‑Tracker Green and light chain‑3B (LC3B) expression, in vitro colony formation ability and tumor stemness were assessed, as well as histone H3 lysine 4 trimethylation (H3K4me3) enrichment and PYCR1, SMYD2, H3K4me3, LC3B II/I, p62, PINK1, Parkin, Nanog and SRY‑box transcription factor 2 (Sox2) expression. A nude mouse xenograft model was used for in vivo verification. PYCR1 mRNA and protein expression were elevated in BCSCs. Following PYCR1 or SMYD2 siRNA treatment, PYCR1, SMYD2 and CD44+CD33+ expression, cancer cell colony formation, number of tumor spheres and Nanog and Sox2 expression were decreased, but pcDNA3.1‑PYCR1 or pcDNA3.1‑SMYD2 transfection enhanced BCSC stemness maintenance. SMYD2 was associated with PYCR1 expression. SMYD2 upregulated PYCR1 expression through H3K4me3, subsequently activating the PINK1/Parkin mitophagy pathway, which supports maintenance of BCSC stemness.
    Keywords:  PINK1/Parkin; SET and MYND domain containing protein 2; bladder cancer; histone H3 lysine 4 trimethylation; mitophagy; pyrroline‑5‑carboxylate reductase 1; stem cell stemness
    DOI:  https://doi.org/10.3892/ijo.2025.5747
  37. Autophagy. 2025 May 04. 1-17
    PINK1-dependent NFKB signaling contributes to amyloid pathology in Alzheimer disease.
    Fang Du, Qing Yu, Gang Hu, Chyuan-Sheng Lin, Shirley ShiDu Yan.
      Mitochondrial dysfunction plays a preponderant role in the development of Alzheimer disease (AD). We have demonstrated that activation of PINK1 (PTEN induced kinase 1)-dependent mitophagy ameliorates amyloid pathology, attenuates mitochondrial and synaptic dysfunction, and improves cognitive function. However, the underlying mechanisms remain largely unknown. Using a newly generated PINK1-AD transgenic mouse model and AD neuronal cell lines, we provide substantial evidence supporting the contribution of PINK1-mediated mitochondrial ROS (reactive oxygen species) and NFKB/NF-κB (nuclear factor kappa B) signaling to altering APP (amyloid beta precursor protein) processing and Aβ metabolism. Enhancing neuronal PINK1 is sufficient to suppress Aβ-induced activation of NFKB signal transduction in PINK1-overexpressed Aβ-AD mice and Aβ-producing neurons. Blocking PINK1-mediated NFKB activation inhibits activities of BACE1 (beta-secretase 1) and γ-secretase, which are key enzymes for cleavage of APP processing to produce Aβ. Conversely, loss or knockdown of PINK1 produces excessive ROS, along with increased phosphorylated NFKB1/p50 and RELA/p65 subunits, APP-related BACE1 and γ-secretase, and Aβ accumulation. Importantly, these detrimental effects were robustly blocked by the addition of scavenging PINK1 Aβ-induced mitochondrial ROS, leading to the suppression of NFKB activation, restoration of normal APP processing, and limitation of Aβ accumulation. Thus, our findings highlight a novel mechanism underlying PINK1-mediated modulation of Aβ metabolism via a ROS-NFKB-APP processing nexus. Activation of PINK1 signaling could be a potential therapeutic avenue for the early stages of AD by combining improving mitochondrial quality control with limiting amyloid pathology in AD.
    Keywords:  APP; Aβ metabolism; NFKB; PINK1; amyloid pathology; reactive oxygen species
    DOI:  https://doi.org/10.1080/15548627.2025.2463322
  38. J Nanobiotechnology. 2025 May 08. 23(1): 339
    Dual-responsive nanoparticles targeting ACE-II senescence for therapeutic mitigation of acute lung injury.
    Linlin Gao, Fushuang Zheng, Zhiling Fu, Wei Wang.
      Acute lung injury (ALI) is a life-threatening condition characterized by severe pulmonary dysfunction, with alveolar type II epithelial cell (ACE-II) senescence playing a pivotal role in its progression. In this study, we developed pH/reactive oxygen species (ROS) dual-responsive nanoparticles (GNPsanti-SP-C) for the targeted delivery of Growth Differentiation Factor 15 (GDF15) to counteract ACE-II senescence. These nanoparticles (NPs) effectively activate the AMP-activated protein kinase (AMPK)/Sirtuin 1 (SIRT1) signaling pathway, inducing the mitochondrial unfolded protein response (UPRmt) and reversing senescence-associated cellular dysfunction. GNPsanti-SP-C were systematically engineered and demonstrated robust pH/ROS sensitivity, efficient GDF15 release, and precise ACE-II targeting. In lipopolysaccharide (LPS)-induced ALI mouse model, GNPsanti-SP-C treatment significantly mitigated lung injury, reduced inflammatory responses, and enhanced pulmonary function, as evidenced by decreased inflammatory markers, lung edema, and improved histopathology. Single-cell transcriptomic and proteomic analyses revealed increased ACE-II cell populations, reduced expression of senescence markers, and upregulation of AMPK/SIRT1 signaling. In vitro studies further demonstrated that UPRmt activation is associated with the NPs' therapeutic effects, suggesting a potential role in their mechanism of action. These findings demonstrate the potential of GDF15-loaded dual-responsive NPs as an innovative strategy to address cellular senescence and alleviate ALI-associated pulmonary damage.
    Keywords:  AMPK/SIRT1 signaling; Acute lung injury; Cellular senescence; GDF15; Mitochondrial unfolded protein response; Nanoparticle therapy
    DOI:  https://doi.org/10.1186/s12951-025-03382-2
  39. Poult Sci. 2025 Apr 25. pii: S0032-5791(25)00458-4. [Epub ahead of print]104(7): 105216
    METTL3-dependent m6A modification of GHR mRNA regulates mitochondrial function through mitochondrial biogenesis during myoblast differentiation.
    Changbin Zhao, Bowen Hu, Zhijun Wang, Ze Zhang, Wen Luo, Hongmei Li, Xiquan Zhang.
      N6-methyl-adenosine (m6A) methylation has recently been shown to play a critical role in muscle development. We recently revealed that local GHR knockdown impairs mitochondrial function by inhibiting mitochondrial biogenesis, thereby repressing myoblast differentiation. And we identified m6A modification peaks in the GHR mRNA of chicken muscle tissue. However, whether m6A modification may regulate GHR mRNA expression to impinge on mitochondrial function through mitochondrial biogenesis during myoblast differentiation is lagging. We first predicted three potential m6A modification sites (GHR-139, GHR-203, GHR-385) on GHR mRNA through SRAMP online prediction website. We then confirmed that GHR-139 is the METTL3-dependent m6A modification site. Further, METTL3-dependent m6A modification down-regulated the GHR mRNA and protein expression, and blunted the GHR mediated GH-GHR-IGFs axis signal transduction during myoblast differentiation. We next revealed that METTL3-dependent m6A modification down-regulated GHR mRNA to inhibit mitochondrial biogenesis and impair mitochondrial function during myoblast differentiation. On the other hand, overexpression of METTL3 alone also proved to inhibit the expression of GHR gene, while suppressing mitochondrial biogenesis and mitochondrial function. In terms of the m6A reader protein, we uncovered that m6A modification might regulate the GHR mRNA expression through three m6A reader proteins hnRNPR, hnRNPA3 and hnRNPM. In conclusion, our data corroborate that METTL3-dependent m6A modification down-regulates GHR mRNA expression to impair mitochondrial function by inhibiting mitochondrial biogenesis during myoblast differentiation.
    Keywords:  GHR; METTL3; Mitochondrial biogenesis; Mitochondrial function; m(6)A
    DOI:  https://doi.org/10.1016/j.psj.2025.105216
  40. Mol Med Rep. 2025 Jul;pii: 188. [Epub ahead of print]32(1):
    CXCL9 is a dual‑role biomarker in colorectal cancer linked to mitophagy and modulated by ALKBH5.
    Geng Hu, Shijun Shen, Mingchao Zhu.
      Colorectal cancer (CRC), the third most prevalent cancer globally, shows a diminished 5‑year survival rate compared with patients at early stages of the disease, underscoring the urgency for early diagnostic biomarker identification. The C‑X‑C motif chemokine ligand (CXCL) family plays a significant role in immune modulation and cancer progression. the present study constructed a prognostic model for CXCL family in CRC and conducted an in‑depth investigation of the hub gene CXCL9 within the model. CXCL9 is highly expressed in CRC while high expression levels of CXCL9 in patients with CRC often indicates an improved prognosis. Through Gene Ontology, Kyoto Encyclopedia of Genes and Genomes and gene set enrichment analysis enrichment analysis, it was discovered that CXCL9 is not only associated with immune modulation but also closely related to pathways that affect the occurrence and development of cancer. CXCL9 is closely related to mitophagy and blocks autophagy flow by altering the expression of autophagy‑related genes. Additionally, it was found that CXCL9 is a downstream gene modified by ALKBH5 and can partially restore the tumor‑suppressive effects induced by the knockdown of ALKBH5. These studies indicated that CXCL9 is a prognostic marker in CRC and plays a dual role in cancer progression: It activates immune responses on one hand and promotes the malignant characteristics of cancer on the other hand.
    Keywords:  C‑X‑C motif chemokine ligand 9; biomarker; colorectal cancer; m6a; mitophagy
    DOI:  https://doi.org/10.3892/mmr.2025.13553
  41. Spectrochim Acta A Mol Biomol Spectrosc. 2025 Apr 29. pii: S1386-1425(25)00625-0. [Epub ahead of print]340 126319
    Mitochondrial viscosity, oxidative stress and autophagy responsive fluorescent Zn(II) complex for monitoring non-alcoholic fatty liver disease.
    Yu Zhang, Ya-Ping Wang, Hui-Li Sun, Xiao-Dong Zhang, Shao-Qi Guan, Mei Pan.
      Accumulating evidence highlights the critical role of dysfunctional mitochondrial quality control in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). However, there is limited information available regarding of viscosity-related cellular metabolic processes of NAFLD. To address this, we developed a novel viscosity-sensitive fluorescent metal Zn(II) complex, LIFM-ZY-1, for monitoring viscosity changes with one-photon (OP) and two-photon (TP) fluorescence. It could effectively track cellular oxidative stress induced by lipotoxicity with viscosity changes, as reflected by viscosity changes in the OP/TP channel. Besides, LIFM-ZY-1 was capable of detecting non-selective mitophagy triggered by starvation in real time and selective mitophagy induced by autophagy drug rapamycin. Moreover, LIFM-ZY-1 successfully monitored the deterioration and therapeutic outcome of NAFLD mice with changing viscosity induced by overeating and autophagy drug empagliflozin. Overall, our findings demonstrated the potential of LIFM-ZY-1 as a valuable tool for real time monitoring NAFLD treatment through viscosity, oxidative stress and autophagy changes, offering valuable insights into the underlying biological processes and potential therapeutic strategies for NAFLD.
    Keywords:  Metabolic processes; NAFLD; TP fluorescence; Viscosity changes; Zinc (II) complex
    DOI:  https://doi.org/10.1016/j.saa.2025.126319
  42. Food Chem Toxicol. 2025 May 07. pii: S0278-6915(25)00299-6. [Epub ahead of print] 115531
    Cadmium and Lead Induce Mitochondrial Dysfunction in Ovarian Theca Cells: Mechanisms of Oxidative Stress and Bioenergetic Collapse.
    Ekramy M Elmorsy, Huda A Al Doghaither, Ayat B Al-Ghafari, Ahmed A Aldarmahi, Ahmed Abdeen, Samah F Ibrahim, Rayan AlBarakati, Saad Amer.
      Heavy metals (HMs), particularly lead (Pb) and cadmium (Cd), are hazardous environmental toxicants with toxic effects on female reproductive health. This study investigated the impact of Pb and Cd on mitochondrial energetics in theca interstitial cells (TICs). At their respective EC50 values (15 μM Pb, 5 μM Cd), both metals induced severe mitochondrial impairment, characterized by diminished ATP production and oxygen consumption rates (OCR) alongside loss of mitochondrial membrane potential (MMP). Additionally, Pb and Cd reduced mitochondrial mass, disrupted mitophagy protein expression, and inhibited activities of respiratory chain complexes, paralleled by downregulation of their subunit-coding genes. Both metals elevated lactate production, indicating a metabolic shift toward glycolysis. Structural alterations included increased mitochondrial swelling, enhanced membrane permeability to H+ and K+ ions, and elevated mitochondrial membrane fluidity (MMF) driven by a higher saturated-to-unsaturated fatty acid ratio. These effects were concentration- and time-dependent. Furthermore, Pb and Cd significantly suppressed progesterone and androstenedione secretion, underscoring endocrine disruption. Collectively, our findings demonstrate that Pb and Cd induce mitochondrial dysfunction in TICs through bioenergetic failure, structural damage, and oxidative stress, providing a mechanistic basis for HM-associated reproductive pathologies. Targeting mitochondrial integrity may offer therapeutic potential for mitigating HM-induced ovarian dysfunction in at-risk populations.
    Keywords:  cytotoxicity; endocrine disruption; heavy metals; mitophagy; reproductive toxicology; steroidogenesis
    DOI:  https://doi.org/10.1016/j.fct.2025.115531
  43. J Photochem Photobiol B. 2025 Apr 28. pii: S1011-1344(25)00073-9. [Epub ahead of print]268 113170
    Binding of collagen I to integrins alleviates UVB-caused mitochondrial disorders in human keratinocytes HaCaT through enhancement of F-actin polymerization.
    Yuying Zhu, Tianyu Ji, Zhao San, Ruiyi Cao, Toshihiko Hayashi, Kazunori Mizuno, Shunji Hattori, Hitomi Fujisaki, Weiwei Liu, Takashi Ikejima.
      Collagen I is one of the major components of the extracellular matrix in human skin, and is frequently used in skin cares and medications. Previously, we revealed that human keratinocytes HaCaT cells grown on collagen I (Col)-coated dishes gain resistance against UVB damages owing to the restored mitophagy. In this study, we further investigate the mechanisms by which collagen I modulates mitophagy. UVB irradiation causes loss of integrin β1 and collapse of F-actin cytoskeleton. Considering the requirement of actin skeleton in various cellular processes, we are curious about the participation of F-actin collapse in UVB damage. Integrin β1, whose activation enhances F-actin assembly, is a potential target for Col in UVB-treated cells. Notably, inhibiting integrin by adding an inhibitor RGDS or siRNA attenuates the effect of Col against UVB damages, confirming the participation of integrin in cell protection. The collapse of F-actin is rescued by Col, accompanying increases in the mRNA of F-actin polymerization-associated proteins and decreases in the mRNA of depolymerization-associated proteins. Inhibiting actin polymerization by using cytochalasin D represses the protective effect of Col, confirming the cytoprotective role of F-actin in UVB-treated cells. Remarkably, mitophagy in UVB-treated cells restored by Col-coating is inhibited by adding cytochalasin D or RGDS, as shown by the decreases of lysosomes, mitochondrial ubiquitin proteins, and co-localization of autophagosomes and mitochondria, resulting in accumulation of damaged mitochondria, which stresses the importance of F-actin and integrin in mitophagy. In summary, integrins and F-actin are required for mitophagy in UVB-irradiated HaCaT cells, and their enhancements by Col-coating facilitate timely elimination of damaged mitochondria caused by UVB, finally contributing to cell survival.
    Keywords:  Apoptosis; Collagen I; F-actin; HaCaT cells; Integrin; UVB
    DOI:  https://doi.org/10.1016/j.jphotobiol.2025.113170
  44. J Clin Invest. 2025 May 09. pii: e191315. [Epub ahead of print]
    SARM1 loss protects retinal ganglion cells in a mouse model of Autosomal Dominant Optic Atrophy.
    Chen Ding, Papa S Ndiaye, Sydney R Campbell, Michelle Y Fry, Jincheng Gong, Sophia R Wienbar, Whitney Gibbs, Philippe Morquette, Luke H Chao, Michael Tri H Do, Thomas Schwarz.
      Autosomal Dominant Optic Atrophy (ADOA), the most prevalent hereditary optic neuropathy, leads to retinal ganglion cell (RGC) degeneration and vision loss. ADOA is primarily caused by mutations in the OPA1 gene, which encodes a conserved GTPase important for mitochondrial inner membrane dynamics. To date, the disease mechanism remains unclear, and no therapies are available. We generated a mouse model carrying the pathogenic Opa1R290Q/+ allele that recapitulated key features of human ADOA, including mitochondrial defects, age-related RGC loss, optic nerve degeneration, and reduced RGC functions. We identified SARM1, a neurodegeneration switch, as a key driver of RGC degeneration in these mice. Sarm1 knockout nearly completely suppressed all the degeneration phenotypes without reversing mitochondrial fragmentation. Additionally, we showed that a portion of SARM1 localized within the mitochondrial intermembrane space (IMS). These findings indicated that SARM1 was activated downstream of mitochondrial dysfunction in ADOA, highlighting it as a promising therapeutic target.
    Keywords:  Cell biology; Mitochondria; Neurodegeneration; Neuroscience; Therapeutics
    DOI:  https://doi.org/10.1172/JCI191315
  45. Cell Death Dis. 2025 May 03. 16(1): 359
    NDP52 and its emerging role in pathogenesis.
    Krenare Bruqi, Flavie Strappazzon.
      Autophagy is a pro-survival process that regulates the degradation and renewal of cellular components, making it a crucial mechanism for cellular homeostasis. There are selective forms of autophagy that are specific to a number of substrates, such as pathogens (bacteria or viruses), protein aggregates or excess/damaged organelles. These processes involve as key players autophagy receptors, that link the cargo to be degraded to the autophagic machinery. Among them, NDP52 (also known as CALCOCO2) has been described to act as a "bridge" between the autophagy machinery and (1) damaged mitochondria in the mitophagy process; (2) pathogens during xenophagy or (3) proteins in the process of aggrephagy. The aim of this review is to summarize the major functions of NDP52, and to highlight the existence of two human NDP52 variants that have been described as risk or protective factors for Crohn's disease or Multiple Sclerosis and Alzheimer's disease patients, respectively. As these three diseases share common pathological features that lead to inflammation, such as mitochondria or gut microbiota dysfunctions, but also pathogenic infections, it seems clear that NDP52 could be a key player at the crossroad by acting indirectly on inflammation, and therefore a potential target for clinical applications and benefits.
    DOI:  https://doi.org/10.1038/s41419-025-07668-z
  46. Redox Biol. 2025 Apr 29. pii: S2213-2317(25)00167-3. [Epub ahead of print]83 103654
    TJ0113-induced mitophagy in acute liver failure detected by Raman microspectroscopy.
    Chunlian Huang, Jiaqi Liao, Xufeng Cen, Changwei Jiao, Sijia Chen, Dong Liu, Hang-Shuai Qu, Jiansheng Zhu, Sailing He.
      Impaired mitophagy underlies the pathophysiology of acute liver failure (ALF) and is closely associated with tissue damage and dysfunction. A novel mitophagy inducer, TJ0113, was used for treatment during ALF pathogenesis. In this study, we used a novel mitophagy inducer, TJ0113, to investigate the effects and mechanisms of TAA-induced ALF mice. The results showed that TJ0113 could enhance mitophagy through Parkin/PINK1 and ATG5 pathways, which in turn attenuated mitochondrial damage, hepatocyte apoptosis, nuclear factor (NF)-κB/NLRP3 signaling activation and inflammatory responses after TAA. Metabolomics results showed that TJ0113 mainly regulated lipid metabolism, amino acid metabolism and nucleotide metabolism in the livers of ALF mice. RNA sequencing (RNA-seq) analysis yielded that TJ0113 was involved in the development of ALF by regulating the P13K/AKT signaling pathway. The key highlight of this work is the use of an aberration-free line-scanning confocal Raman imager (AFLSCRI) to study the molecular changes in blood, liver tissue, gastrocnemius muscle, and mitochondrial extracts in ALF mice after TJ0113 treatment. Compared to the measurement with conventional assays, Raman microspectroscopy (micro-Raman) offers the benefits of being rapid, non-invasive, label-free and real-time. Our results found good agreement between Raman signals and histopathologic findings. The system has good performance with a spatial resolution of 2 μm, a spectral resolution of 4 cm-1 and a fast detection speed improved by 2 orders. Innovations in this test contribute to clinical diagnosis of disease, personalized treatment, effective intraoperative guidance and accurate prognosis. The data may help in the development of a non-invasive clinical device for mitochondrial damage using bedside micro-Raman.
    Keywords:  Aberration-free line-scanning confocal Raman imaging; Acute liver failure; Mitophagy; Point-scan Raman imaging; Raman signal; TJ0113
    DOI:  https://doi.org/10.1016/j.redox.2025.103654
  47. Exp Cell Res. 2025 May 03. pii: S0014-4827(25)00179-X. [Epub ahead of print] 114583
    MSCs in Acute Kidney Injury Treatment: Modulating Mitochondrial Function and Inhibiting Pyroptosis via PGC-1α.
    Yanjun Wang, Yanlin Ding, Haiyun Dong, Tana Wuren, Pengli Luo.
       OBJECTIVE: This study aims to investigate the mechanisms of MSC therapy for acute kidney injury, focusing on the regulation of mitochondrial function and pyroptosis in renal tubular epithelial cells (RTECs).
    METHODS: An in vivo ischemia/reperfusion (I/R) model was used to assess the effects of MSC treatment on mitochondrial membrane potential, mitochondrial function, cell pyroptosis, and PGC-1α expression in RTECs.
    RESULTS: MSCs significantly improved mitochondrial function in RTECs by upregulating PGC-1α expression, regulating mitochondrial fusion and fission proteins, reducing mitochondrial ROS production, and suppressing NLRP3 inflammasome activation. Furthermore, MSC treatment reduced the levels of pyroptotic markers, such as IL-18, and exhibited a marked anti-fibrotic effect in the long-term. These findings suggest that MSCs not only repair acute kidney injury but also offer long-term protection against fibrosis.
    CONCLUSION: MSCs improve the repair of acute kidney injury by modulating mitochondrial function and inhibiting pyroptosis, providing new theoretical support for MSC-based therapies in AKI treatment.
    Keywords:  Acute Kidney Injury; Chronic Kidney Disease; Mesenchymal Stem Cells; Mitochondrial Dynamics; PGC-1α
    DOI:  https://doi.org/10.1016/j.yexcr.2025.114583
  48. Free Radic Res. 2025 May 08. 1-14
    Cigarette smoke induces endoplasmic reticulum stress-associated mucus hypersecretion via orosomucoid 1-like protein 3 in airway epithelia.
    Rui Chen, Yuting Cui, Mary Sau-Man Ip, Judith Choi-Wo Mak.
      Apart from a strong association with childhood-onset asthma, orosomucoid 1-like protein 3 (ORMDL3), an endoplasmic reticulum (ER)-localized transmembrane protein, is also linked with chronic obstructive pulmonary disease (COPD), in which cigarette smoke (CS) is the crucial risk factor. Compared to healthy subjects, COPD patients had elevated ORMDL3 mRNA in well-differentiated primary human bronchial epithelial cells (HBECs). However, its role in COPD remains understudied. We, therefore, hypothesize that ORMDL3 may play an essential role in CS-induced chronic mucus hypersecretion and inflammation via activation of specific unfolded protein response (UPR) pathways under ER stress in primary HBECs. Gene silencing using siRNA for ORMDL3 was performed in submerged culture of primary HBECs before 24-h cigarette smoke medium (CSM) exposure. The mucin, inflammatory and mitochondrial markers, and the activation of the UPR pathways were evaluated. CSM triggered significant induction of ORMDL3 expression at both mRNA and protein level, which was significantly inhibited by silencing ORMDL3. In addition, ORMDL3 knockdown inhibited CSM-induced mucin MUC5AC mRNA and release of inflammatory marker interleukin (IL)-8. Silencing ORMDL3 reduced CSM-induced ER stress via inhibiting the activating transcription factor (ATF)6 and the inositol-requiring enzyme (IRE)1 of the UPR pathways. The involvement of ORMDL3 was demonstrated in mitochondrial dynamics via fusion protein Mfn2 and mitochondrial respiration after CSM stimulation. In conclusion, ORMDL3 is an inducible gene in mediating CS-induced activation of specific ATF6 and IRE1 pathways to regulate mucus hypersecretion and inflammation. Therefore, ORMDL3 may be a promising therapeutic target to treat smoking-associated mucus hypersecretion and inflammation in COPD.
    Keywords:  COPD; ORMDL3; cigarette smoke; mucus hypersecretion; unfolded protein response
    DOI:  https://doi.org/10.1080/10715762.2025.2501019
  49. Brain Res Bull. 2025 May 05. pii: S0361-9230(25)00184-4. [Epub ahead of print]226 111372
    Jujuboside A improves insomnia by maintaining mitochondrial homeostasis in prefrontal neurons.
    Zhen Zhang, Xinyue Che, Tingyu Feng, Juntao Zou, Guangpei Chen, Wenping Guo, Chunmei Ma, Haozhe Yuan, Jingying Chen, Xiaowu Xu.
       OBJECTIVE: Jujuboside A (JB-A) is the major component of Semen Ziziphi Spinosae (SZS), a traditional Chinese herbal medicine used to treat sleep with clinical efficacy. This is the first study to investigate the effects of JB-A on mitochondrial structure and function in the prefrontal cortex of the insomnia model mice.
    METHODS: Young adult C57BL/6 mice were induced to develop insomnia by P-chlorophenylalanine. After 14 d of JB-A treatment via gavage, anxiety level was assessed using the open field and elevated plus maze tests. Next, the mitochondrial metabolic activity and morphological changes in the prefrontal cortex of each group of mice, as well as their effects on mitochondrial membrane potential, oxidative phosphorylation levels, and cytochrome c (Cyt c) content in neurons were measured.
    RESULTS: In our mouse model, JB-A ameliorated anxiety-like behaviors; up-regulated the membrane potential (Δψm) and had a therapeutic effect on the metabolic activity and damaged microscopic structure of mitochondria in the prefrontal cortex; effectively improved mitochondrial function by increasing the expression of Cyt c oxidase I and IV proteins, ATPase activity, and ATP content; and reduced the accumulation of Cyt c in the neuronal cytoplasm while inhibiting mitochondrial permeability transition pore (mPTP) opening.
    CONCLUSIONS: JB-A can improve insomnia by restoring mitochondrial intracellular oxidative phosphorylation, regulating mPTP to maintain mitochondrial homeostasis, and alleviating structural damage, providing a scientific basis for finding new targets for insomnia treatment.
    Keywords:  ATP; Insomnia; Jujuboside A (JB-A); Mitochondria; Mitochondrial membrane potential (Δψm); Oxidative phosphorylation
    DOI:  https://doi.org/10.1016/j.brainresbull.2025.111372
  50. Cell Rep. 2025 May 07. pii: S2211-1247(25)00453-X. [Epub ahead of print]44(5): 115682
    Mitochondrial GCN5L1 coordinates with YME1L and MICOS to remodel mitochondrial cristae in white adipocytes and modulate obesity.
    Juan Xu, Qiqi Zhang, Xinyu Yang, Qiqi Tang, Yitong Han, Jiahui Meng, Jiaqi Zhang, Xin Lu, Danni Wang, Jing Liu, Bo Shan, Xue Bai, Kai Zhang, Longhao Sun, Lingdi Wang, Lu Zhu.
      The relationship between mitochondrial architecture and energy homeostasis in adipose tissues is not well understood. In this study, we utilized GCN5L1-knockout mice in white (AKO) and brown (BKO) adipose tissues to examine mitochondrial homeostasis in adipose tissues. GCN5L1, a regulator of mitochondrial metabolism and dynamics, influences resistance to high-fat-diet-induced obesity in AKO but not BKO mice. This resistance is mediated by an increase in mitochondrial cristae that stabilizes oxidative phosphorylation (OXPHOS) complexes and enhances energy expenditure. Our protein-interactome analysis reveals that GCN5L1 is associated with the mitochondrial crista complex MICOS (MIC13) and the protease YME1L, facilitating the degradation of MICOS and disassembly of cristae during obesity. This interaction results in decreased OXPHOS levels and subsequent adipocyte expansion. Accumulation of GCN5L1 in the mitochondrial intermembrane space is triggered by a high-fat diet. Our findings highlight a regulatory pathway involving YME1L/GCN5L1/MIC13 that remodels mitochondrial cristae in WAT in response to overnutrition-induced obesity.
    Keywords:  CP: Cell biology; CP: Metabolism; MICOS; OXPHOS; YME1L; beige; mitochondria; mitochondrial crista remodeling; white adipose tissue
    DOI:  https://doi.org/10.1016/j.celrep.2025.115682
  51. Redox Biol. 2025 May 03. pii: S2213-2317(25)00176-4. [Epub ahead of print]83 103663
    MG53 deficiency mediated skeletal muscle dysfunction in chronic obstructive pulmonary disease via impairing mitochondrial fission.
    Liwei Liao, Ziwen Zheng, Mingming Deng, Weidong Xu, Qin Zhang, Zilin Wang, Chang Li, Jiaye Li, Yiding Bian, Kai Wang, Jinrui Miao, Ruixia Li, Yan Yin, Xiaoming Zhou, Gang Hou.
       BACKGROUND: Myokine dysregulation and mitochondrial dysfunction are implicated in the pathogenesis of sarcopenia in chronic obstructive pulmonary disease. The objective of this study is to explore the role of myokines and mitochondrial dysfunction in sarcopenia in chronic obstructive pulmonary disease.
    METHODS: We identified mitsugumin 53 and its clinical correlation through an enzyme-linked immunosorbent assay using the plasma samples of patients with chronic obstructive pulmonary disease. The role of mitsugumin 53 was confirmed in mitsugumin 53-knockout mice. The underlying mechanisms were investigated using multi-omics sequencing, live-cell imaging, and histological and molecular experiments. The effectiveness and safety of recombinant mitsugumin 53 in treating cigarette smoke-induced muscle dysfunction were evaluated in vitro and in vivo.
    RESULTS: Plasma mitsugumin 53 levels were decreased in patients with chronic obstructive pulmonary disease and were associated with skeletal muscle dysfunction. Mitsugumin 53 deficiency exacerbated cigarette smoking-induced skeletal muscle atrophy. In muscle cells, mitsugumin 53 co-localized with the mitochondria and regulated mitochondrial fission. As a lipid transporter, mitsugumin 53 directly bound to the mitochondria-specific lipid cardiolipin and participated in maintaining mitochondrial homeostasis and membrane integrity. As an E3-ligase, mitsugumin 53 deletion triggered BCL2L13-mediated mitochondrial fission upon cigarette smoking stimulation. Supplementation with recombinant mitsugumin 53 significantly alleviated cigarette smoking-induced muscle atrophy and rescued mitochondrial dysfunction in vitro and in vivo.
    CONCLUSIONS: Mitsugumin 53 is a vital regulator of sarcopenia in patients with chronic obstructive pulmonary disease. Thus, mitsugumin 53 and mitochondrial fission may be promising therapeutic targets for muscle dysfunction in chronic obstructive pulmonary disease.
    Keywords:  Chronic obstructive pulmonary disease (COPD); Mitochondrial fission; Mitsugumin 53 (MG53); Myokine; Sarcopenia
    DOI:  https://doi.org/10.1016/j.redox.2025.103663
  52. Int J Mol Sci. 2025 Apr 11. pii: 3603. [Epub ahead of print]26(8):
    Methylmercury Chloride Exposure Affects Oocyte Maturation Through AMPK/mTOR-Mediated Mitochondrial Autophagy.
    Shengkui Hou, Caiyu Wang, Xin Ma, Jing Zhao, Jun Wang, Yi Fang, Hongyu Liu, He Ding, Jing Guo, Wenfa Lu.
      Mercury, a prevalent heavy metal, negatively impacts oocyte maturation. However, the exact mechanism by which methylmercury chloride (MMC) affects this process remains elusive. The present study found that MMC administration triggered meiotic failure in oocytes by disrupting cumulus cell expansion, leading to compromised spindle apparatus and altered chromosomal architecture, which are crucial for oocyte development. This disruption is characterized by abnormal microtubule organization and defective chromosome alignment. Additionally, MMC exposure caused oxidative stress-induced apoptosis due to mitochondrial dysfunction, as indicated by decreased mitochondrial membrane potential, mitochondrial content, mitochondrial DNA copy number, and adenosine triphosphate levels. Proteomic analysis identified 97 differentially expressed proteins, including P62, an autophagy marker. Our results confirmed that MMC induced autophagy, particularly through the hyperactivation of the mitochondrial autophagy to remove damaged and normal mitochondria. The mitochondrial reactive oxygen species (ROS) scavenger Mito-TEMPO alleviated oxidative stress and mitochondrial autophagy levels, suggesting that mitochondrial ROS initiates this autophagic response. Notably, MMC activates mitochondrial autophagy via the monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) signal pathway due to mitochondrial dysfunction. In vivo studies in mice revealed that MMC exposure decreased reproductive performance, attributed to excessive mitochondrial autophagy leading to reduced oocyte quality. Overall, these findings demonstrate that MMC exposure impairs oocyte maturation via the hyperactivation of mitochondrial autophagy induced by mitochondrial dysfunction.
    Keywords:  MMC; mitochondrial autophagy; oocyte; oxidative stress
    DOI:  https://doi.org/10.3390/ijms26083603
  53. Int Immunopharmacol. 2025 May 06. pii: S1567-5769(25)00717-9. [Epub ahead of print]157 114727
    miR142 silencing alleviates retinal inflammation by impairing mitochondrial function and reprogramming metabolism of CD4+ T cells via targeting MTFR1.
    Yunwei Hu, Wenjie Zhu, Zhuang Li, Guanyu Chen, Qian Chen, Zuoyi Li, Jun Huang, Haixiang Huang, Yanyan Xie, Minzhen Wang, Xiaoqing Chen, Dan Liang.
       BACKGROUND: Autoimmune uveitis is a sight-threatening inflammatory disease of the retina. MicroRNA-142 (miR-142) has been implicated in its pathogenesis. This study aimed to elucidate the role of miR-142 in uveitis and its underlying mechanisms.
    METHODS: The expression of miR-142-3p was analyzed in peripheral blood mononuclear cells from uveitis patients and in experimental autoimmune uveitis (EAU) models. With EAU induction for 14 days, clinical and histopathological scores were graded to evaluate the retinal inflammation. To investigate the effects of miR-142 deficiency on uveitis development, the miR-142 knockout (miR-142-/-) mouse model was used. The miR-142-/- T cell phenotype and function were characterized using flow cytometry and single-cell sequencing for both in vivo and in vitro experiments. The Seahorse Analyzer, mitochondrial staining and electron microscope analysis were conducted to reveal the mitochondrial function and morphology. And then Luciferase Assays and Western-Blot analysis were used to explore the target of miR-142.
    RESULTS: We found that miR-142-3p was significantly up-regulated in uveitis and that its deletion in mice prevented EAU development. The T cell isolated from miR-142-/- mice lose its uveitogenic nature. T cell lacking miR-142 exhibited reduced numbers and attenuated pathogenicity in uveitis, characterized by decreased proliferation, increased apoptosis, and abnormal differentiation. Single-cell sequencing, energy metabolism analysis and flow cytometry analysis unveiled metabolic reprogramming in miR-142-/- T cells, with a distinct shift toward glycolysis and restrained oxidative phosphorylation. Further investigation revealed mitochondrial fission regulator 1 (MTFR1) as a direct target of miR-142. The over-expressed protein of MTFR1 in CD4+ T cells was found in miR-142-/- mice.
    CONCLUSIONS: Our findings highlight the indispensable role of miR-142 in maintaining T cell mitochondrial function. By modulating MTFR1, miR-142 orchestrates mitochondrial homeostasis, metabolic alterations, apoptosis susceptibility, and proliferation capacity in T cells, thereby influencing susceptibility to autoimmune uveitis.
    Keywords:  Autoimmune uveitis; CD4(+) T cell; Energy metabolism; MicroRNA-142; Mitochondrial fission regulator 1; Mitochondrial function
    DOI:  https://doi.org/10.1016/j.intimp.2025.114727
  54. Int Immunopharmacol. 2025 May 03. pii: S1567-5769(25)00776-3. [Epub ahead of print]157 114786
    PINK1 affects mitochondrial oxidative phosphorylation by regulating MFN2 to alleviate diabetic kidney disease.
    Xiaoyan Pei, Jie Liu, Yu Wei, Yanhui Zhu, Yu Li, Qiong Wang, Langen Zhuang, Guoxi Jin.
       BACKGROUND: Diabetic kidney disease (DKD) is widely recognized as a prevalent and major microvascular complication of diabetes mellitus. Mitofusin 2 (MFN2) has been closely linked to the development of diabetes mellitus, yet its precise role in the pathogenesis of DKD remains uncertain. The objective of our current research was to explore the role of MFN2 in the advanced DKD and its underlying molecular pathway. This research was to examine the involvement and molecular pathways of MFN2 in the advancement of DKD.
    METHODS: In this study, MFN2 was manipulated in high glucose (HG)-treated HK2 cells to investigate its impact on cell proliferation, apoptosis, and mitochondrial oxidative phosphorylation. Models of MFN2 overexpression or silencing were established in db/db mice as a diabetes model. The alterations in kidney morphology, renal fibrosis severity, macrophage polarization, and related inflammatory factors (tumor necrosis factor-α [TNF-α], interleukin-6 [IL-6], and interleukin-1β [IL-1β]) were evaluated. Furthermore, HK2 cells were co-cultivated with M1-type macrophages to examine the impact of MFN2 expression on macrophage polarization. Subsequently, we delved deeper into the upstream mechanisms utilizing the STRING database.
    RESULTS: Our study identified that MFN2 expression was downregulated in HG-treated HK-2 cells. The overexpression of MFN2 resulted in increased HK2 cell proliferation, improved degree of oxidative phosphorylation, and reduced apoptosis. In db/db mice, MFN2 overexpression exerted a protective effect on DKD-induced nephropathy and fibrosis. Notably, MFN2 overexpression influenced macrophage polarization and modulated expression of related inflammatory factors by promoting mitochondrial oxidative phosphorylation. Additionally, STRING database prediction revealed that PTEN-induced kinase 1 (PINK1) regulated MFN2 expression, which was consistent with MFN2 changes in DKD, and this regulation was associated with DKD progression.
    CONCLUSION: The role of MFN2 in maintaining mitochondrial function in DKD may be regulated by PINK1 and provides a new potential therapeutic target for DKD.
    Keywords:  Diabetic kidney disease; MFN2; Mitochondrial oxidative phosphorylation; PINK1
    DOI:  https://doi.org/10.1016/j.intimp.2025.114786
  55. Cell Mol Biol Lett. 2025 May 09. 30(1): 58
    Multi-omics integration reveals Vha68-3 as a testicular aging-specific factor that coordinates spermatid elongation through mitochondrial metabolic homeostasis.
    Jun Yu, Qiuru Huang, Yangbo Fu, Lei He, Cong Shen, Xia Chen, Zhiran Li, Jiaxin Li, Chenyu Wang, Xinda Wang, Binbin Yang, Ziwen Lin, Chen Qiao, Xiaofang Tan, Xiaoqing Yang, Hao Chen, Ying Zheng, Bo Zheng, Fei Sun.
       BACKGROUND: Testicular aging has profound effects on spermatogenesis, sperm function, and the spermatogenic microenvironment, contributing to reduced male fertility. However, the precise molecular mechanisms by which mitochondria influence spermiogenesis during aging still remain largely unclear.
    METHODS: Vha68-3 KO flies were generated using the CRISPR/Cas9 technique. Testicular phenotypes and functions were mainly observed through immunofluorescence staining and transmission electron microscopy. Multi-omics study was mainly conducted through single-cell RNA sequencing and transcriptome-metabolomics association analysis. Vha68-3 binding proteins were identified via liquid chromatography-tandem mass spectrometry. The therapeutic potential of modulating mitochondrial metabolism for testicular aging mainly relied on the dietary intake of related compounds in fruit flies.
    RESULTS: In this study, we identified Vha68-3, a testis-specific subunit of the V-type adenosine triphosphate (ATP) synthase, predominantly localized in the tails of elongated spermatids, as a key age-related regulator of male fertility and spermatid elongation in Drosophila testes. Crucially, Vha68-3 deficiency impaired mitochondrial homeostasis in elongated spermatids during testicular aging. Through a multi-omics approach, including single-cell transcriptomics, protein interaction mapping of Vha68-3, and transcriptome-metabolome integration, we identified pyruvate metabolism as a critical pathway disrupted by Vha68-3 deficiency. Moreover, dietary supplementation with pyruvate (PA), S-lactoylglutathione (SLG), and phosphoenolpyruvate (PEP) effectively alleviated mitochondrial dysfunction and testicular aging linked to Vha68-3 deficiency.
    CONCLUSIONS: Our findings uncover novel mechanisms by which mitochondrial metabolism regulates spermatid elongation and propose potential therapeutic strategies to combat mitochondrial metabolic disorders in aging testes.
    Keywords:  Mitochondrial homeostasis; Multi-omics; Pyruvate metabolism; Spermiogenesis; Testicular aging
    DOI:  https://doi.org/10.1186/s11658-025-00737-3
  56. PLoS Genet. 2025 May 08. 21(5): e1011700
    Unveiling the intercompartmental signaling axis: Mitochondrial to ER Stress Response (MERSR) and its impact on proteostasis.
    Jeson J Li, Nan Xin, Chunxia Yang, Bo G Kim, Larissa A Tavizon, Ruth Hong, Jina Park, Travis I Moore, Rebecca George Tharyan, Adam Antebi, Hyun-Eui Kim.
      Maintaining protein homeostasis is essential for cellular health. Our previous research uncovered a cross-compartmental Mitochondrial to Cytosolic Stress Response, activated by the perturbation of mitochondrial proteostasis, which ultimately results in the improvement of proteostasis in the cytosol. Here, we found that this signaling axis also influences the unfolded protein response of the endoplasmic reticulum (UPRER), suggesting the presence of a Mitochondria to ER Stress Response (MERSR). During MERSR, the IRE1 branch of UPRER is inhibited, introducing a previously unknown regulatory component of MCSR. Moreover, proteostasis is enhanced through the upregulation of the PERK-eIF2α signaling pathway, increasing phosphorylation of eIF2α and improving the ER's ability to handle proteostasis. MERSR activation in both polyglutamine and amyloid-beta peptide-expressing C. elegans disease models also led to improvement in both aggregate burden and overall disease outcome. These findings shed light on the coordination between the mitochondria and the ER in maintaining cellular proteostasis and provide further evidence for the importance of intercompartmental signaling.
    DOI:  https://doi.org/10.1371/journal.pgen.1011700
  57. Int J Mol Sci. 2025 Apr 08. pii: 3495. [Epub ahead of print]26(8):
    Carvacrol Protects IPEC-J2 Cells from Oxidative Stress by Suppressing Autophagy.
    Ming-Chun Hsu, Han-Tsung Wang, Ching-Yi Chen.
      Oxidative stress impairs intestinal function and causes poor growth performance in piglets. Carvacrol is a natural essential oil, and its anti-oxidative and anti-inflammatory activities in the intestines of piglets have been reported in many studies. However, the mechanisms underlying these protective effects against oxidative stress remain unclear. This study aimed to investigate the possible pathway of carvacrol in the porcine intestine under oxidative stress using an in vitro model. Porcine intestinal epithelial cells (IPEC-J2) were treated with carvacrol and hydrogen peroxide (H2O2), an oxidative stress inducer, to investigate the protective mechanisms of carvacrol under oxidative stress. We found that carvacrol ameliorated a H2O2-induced loss of cell viability, apoptosis, and reduced intracellular reactive oxygen species (ROS) and malondialdehyde (MDA) levels. Carvacrol reduced mitochondrial ROS generation and increased citrate synthase activity during oxidative stress. Furthermore, carvacrol attenuated an increase in the autophagy marker LC3II-to-I ratio and reduced the accumulation of lysosomes and autolysosomes induced by H2O2. The increased protein expression of the mitophagy marker PINK1, induced by H2O2, was also reduced by carvacrol treatment. Metformin-activated autophagy diminished the protective effects of carvacrol on cell viability and MDA levels under H2O2 treatment, indicating that autophagy inhibition is necessary for carvacrol-induced protection in IPEC-J2 cells during oxidative stress. In conclusion, this study demonstrated the underlying mechanism that carvacrol exerted its anti-oxidative effects on porcine intestinal epithelial cells by relieving excessive autophagy during weaning stress.
    Keywords:  autophagy; carvacrol; intestinal health; mitochondrial dysfunction; oxidative stress; weaning piglet
    DOI:  https://doi.org/10.3390/ijms26083495
  58. Biochim Biophys Acta Mol Basis Dis. 2025 May 07. pii: S0925-4439(25)00243-1. [Epub ahead of print] 167895
    Tubular specific glutathione peroxidase 3 deletion exacerbates kidney damage in IRI-AKI mice.
    Jinrong He, Xueqin Wu, Jie Qiao, Xian Xie, Yu Wang, Hao Zhang, Wei Zhang.
      Ischemia-reperfusion injury stands as a primary instigator of acute kidney injury (AKI), prominently driven by oxidative stress. Among the critical antioxidant defenses is glutathione peroxidase 3 (GPX3), an enzyme generated by renal tubular epithelial cells. Our prior investigations have unveiled a substantial downregulation of GPX3 in renal tissues gleaned from AKI patients and murine models. This study aims to investigate the role of tubular cell-specific Gpx3 deletion on ischemia-reperfusion injury-induced AKI (IRI-AKI) in a murine model and delineate the potential underlying mechanisms. By generating renal tubular epithelial cell-specific Gpx3 knockout mice and inducing IRI-AKI, we assessed a spectrum of kidney injury indices including renal function, oxidative stress, apoptosis and mitochondrial dynamics. Additionally, we conducted transcriptome sequencing and bioinformatics analyses. The outcomes underscore that the deficiency of GPX3 in tubular cells exacerbates tubular injury, renal dysfunction, oxidative stress, apoptosis, and mitochondrial dynamic disturbances in the context of IRI-AKI. Sequencing and bioinformatics analysis suggest that the Gpx3 deletion predominantly impacts pathways associated with metabolism and inflammation. In conclusion, the tubular cell-specific deficiency of GPX3 exacerbates renal injury by intensifying oxidative stress, fostering mitochondrial impairment, perturbing metabolic processes and fueling inflammation. The targeted restoration of GPX3 in the renal tubular emerges as a potential therapeutic avenue for mitigating IRI-AKI.
    Keywords:  Apoptosis; GPX3; IRI-AKI; Mitochondrial dynamics; Oxidative stress
    DOI:  https://doi.org/10.1016/j.bbadis.2025.167895
  59. Br J Pharmacol. 2025 May 09.
    Metformin aggravates pancreatitis by regulating the release of oxidised mitochondrial DNA via the frataxin (FXN)/ninjurin 1 (NINJ1) signalling pathway.
    Guang Xin, Qilong Zhou, Tao Wang, Chengyu Wan, Xiuxian Yu, Ke Li, Fan Li, Shiyi Li, Yuman Dong, Yilan Wang, Lijuan Feng, Kun Zhang, Ao Wen, Wen Huang.
       BACKGROUND AND PURPOSE: Patients with diabetes are at a higher risk of developing acute pancreatitis compared to those without diabetes. Therefore, it is essential to investigate the effects of metformin, a primary treatment for type 2 diabetes, on the progression of pancreatitis.
    EXPERIMENTAL APPROACH: Network pharmacology was employed to investigate the potential effects of metformin on pancreatitis and to predict its underlying molecular mechanisms. Pharmacological and mechanistic studies of metformin were conducted utilising mtDNA depletion (ρ0) of 266-6 acinar cells, knockout mouse models and experimental models of both acute and chronic pancreatitis. The mitochondrial homeostasis and plasma membrane integrity were examined through phase-contrast microscopy and time-lapse video imaging.
    KEY RESULTS: Network pharmacology analysis revealed that metformin possesses significant potential to modulate the pathogenesis of pancreatitis, likely through its regulation of mitochondrial function and cell membrane morphology. Further, the results revealed that metformin augmented the release of oxidised mitochondrial DNA (Ox-mtDNA) by enhancing NINJ1-mediated plasma membrane rupture, which subsequently ignited a cascade of acinar cell necrosis. Metformin exacerbated mitochondrial iron imbalance by suppressing Frataxin, thereby worsening mitochondrial homeostasis disruption and Ox-mtDNA generation. NINJ1 knockout eliminated the metformin-induced acinar cell necrosis and elevation of Ox-mtDNA levels, and mtDNA depletion reversed the effect of metformin on acinar cell death.
    CONCLUSION AND IMPLICATIONS: Metformin exacerbates both acute and chronic pancreatitis, possibly because of increased release of Ox-mtDNA via modulation of mitochondrial iron homeostasis and NINJ1-mediated plasma membrane rupture, suggesting that extreme caution should be exercised when using metformin in diabetic patients with pancreatitis.
    Keywords:  FXN/NINJ1 signalling; Ox‐mtDNA; metformin; mitochondrial homeostasis; pancreatitis
    DOI:  https://doi.org/10.1111/bph.70065
  60. Free Radic Biol Med. 2025 May 03. pii: S0891-5849(25)00274-6. [Epub ahead of print]
    Taurochenodeoxycholic acid activates autophagy and suppresses inflammatory responses in microglia of MPTP-induced Parkinson's disease mice via AMPK/mTOR, AKT/NFκB and Pink1/Parkin signaling pathways mediated by Takeda G protein-coupled receptor 5.
    Chenyang Ni, Lupeng Wang, Yuyan Bai, Fei Huang, Hailian Shi, Hui Wu, Xiaojun Wu, Jin Huang.
      Parkinson's disease (PD) is a neurodegenerative disease characterized by degeneration and necrosis of dopaminergic neurons in the substantia nigra and decreased dopamine secretion in the striatum. Bile acids are important components of animal bile. In recent years, a variety of hydrophilic bile acids have been reported to have ameliorative effects in neurodegenerative diseases. Taurochenodeoxycholic acid (TCDCA) is one of the components of bile acid. However, whether TCDCA can treat PD and its specific mechanism is unclear. In this study, 1-methyl-4-phenylpyridine (MPTP)-induced PD model mice were constructed to investigate the effects of TCDCA on PD model mice and the impact of microglia-mediated neuroinflammation. Concurrently, in vitro cell experiments utilized the lipopolysaccharide (LPS)-induced BV-2 microglial inflammation model to further investigate the effect and mechanism of TCDCA in inhibiting neuroinflammation. TCDCA effectively improved dyskinesia, attenuated dopaminergic neuronal damage in the substantia nigra and striatum, and inhibited α-Synuclein (α-Syn) expression in the substantia nigra of PD mice. TCDCA significantly inhibited microglia and astrocyte activation in the substantia nigra of PD mice, and decreased the messenger ribonucleic acid (mRNA) and protein expressions of inflammatory factors. In addition, TCDCA was found to inhibit nitric oxide (NO) release and reactive oxygen species (ROS) production in LPS-stimulated BV2 microglia. Furthermore, TCDCA suppressed the production of inflammatory factors, including interleukin (IL)-1β, IL-6, and tumor necrosis factor α (TNF-α), both in vivo and in vitro. Meanwhile, TCDCA significantly promoted Takeda G protein-coupled receptor 5 (TGR5) protein expression and inhibited the phosphorylation of serine/threonine kinase B (AKT), nuclear factor κB (NFκB) and inhibitor of NFκB (IκBα). TCDCA promoted autophagy in vivo and in vitro by increasing adenosine 5'-monophosphate-activated protein kinase (AMPK) phosphorylation, inhibiting mammalian target of rapamycin (mTOR) phosphorylation, increasing LC3II/LC3I and Beclin1 expression, and decreasing P62 expression. Furthermore, TCDCA demonstrated mitochondrial protection by enhancing the expression of PTEN induced putative kinase 1 (Pink1) and Parkin. However, knockdown of TGR5 expression partially counteracted the inhibitory effect of TCDCA on LPS-treated BV-2 cells. Our results manifested that TCDCA activated autophagy and inhibited microglia-mediated neuroinflammation in experimental PD models probably through activation of TGR5 mediated AKT/NFκB, AMPK/mTOR and Pink1/Parkin signaling pathways.
    Keywords:  Parkinson’s Disease; TCDCA; TGR5; microglia; neuroinflammation
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.04.053
  61. Biochem Biophys Res Commun. 2025 May 02. pii: S0006-291X(25)00648-5. [Epub ahead of print]768 151934
    SETDB1 decline promotes the resistance to sorafenib via DRP1 phosphorylation-mediated mitochondrial dysfunction in HepG2 cells.
    Mingjian Fan, Jiahang Wu, Yunjiao Wu, Yi Zhang, Meiqi Song, Tan Wei, Dongbo Zhu, Leiming Jiang, Yuanhui Yu, Lihui Qu, Meng Wang, Zhigang Wang.
      Sorafenib is a widely-adopted kinase inhibitor in anticancer therapy for advanced hepatocellular carcinoma (HCC) and the individualized pharmacological resistance to sorafenib is still an unresolved issue. Whether histone H3K9 methyltransferase SETDB1, which represses chromatin states and promotes various oncogenesis, modulate this process is still elusive. The analysis from both TCGA-LIHC cohort and our clinical HCC patient samples revealed that hepatic SETDB1 expression positively correlates with the prognosis of HCC patients receiving sorafenib therapy. Meanwhile, SETDB1 silencing diminished the cytotoxic effects of sorafenib in hepatoma cells. Mechanistically, SETDB1 knockdown led to mitochondrial dysfunction, including reduced mitochondrial membrane potential, mitochondria superoxide (mSOX), mitochondrial DNA (mtDNA) content, increased fission and DRP1S616 phosphorylation (pDRP1S616) in HepG2 cells. Not only did mSOX fluctuation modulate the sensitivity to sorafenib, but DRP1 activity-silenced counterpart pDRP1S616A inactivation also elevated the susceptibility to sorafenib and the corresponding mSOX and mtDNA content. Finally, pDRP1S616 IHC staining in clinical samples showed that hepatic pDRP1S616 level negatively correlates with the prognosis of HCC patients with sorafenib therapy as well. We first demonstrated that SETDB1 knockdown reduced the susceptibility to sorafenib through enhancing mitochondrial pDRP1S616 in hepatoma cells and hepatic SETDB1 expression might be a potential indicator for clinical HCC sorafenib therapy.
    Keywords:  DRP1; Hepatocellular carcinoma; Mitochondria; SETDB1; Sorafenib
    DOI:  https://doi.org/10.1016/j.bbrc.2025.151934
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