bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2025–06–08
forty-nine papers selected by
Gavin McStay, Liverpool John Moores University
  1. Role of mitochondrial quality control in neurodegenerative disease progression.
  2. Mitochondrial tRNA processing defects reprogram mitochondrial and cellular homeostasis.
  3. The role of mitochondrial dysfunction in the pathogenesis of Alzheimer's disease and future strategies for targeted therapy.
  4. An AI-assisted fluorescence microscopic system for screening mitophagy inducers by simultaneous analysis of mitophagic intermediates.
  5. The developing retina undergoes mitochondrial remodeling via PINK1/PRKN-dependent mitophagy.
  6. Short-Term DMOG treatment rejuvenates senescent mesenchymal stem cells by enhancing mitochondrial function and mitophagy through the HIF-1α/BNIP3 pathway.
  7. Mito-Kaede photoactivation and chase experiment for mitophagy: mitophagy flux response toward various stimulations.
  8. SFXN1 promotes bladder cancer metastasis by restraining PINK1-dependent mitophagy.
  9. PINK1/Parkin-based live-cell quantitative FRET imaging for mitophagy drug screening.
  10. Mitochondrial dynamics reveal potential to facilitate axonal regeneration after spinal cord injury.
  11. Coordination of SLC39A1 and DRP1 facilitates HCC recurrence by impairing mitochondrial quality control.
  12. Artesunate alleviates cerebral ischemia/reperfusion injury by suppressing FUNDC1-mediated excessive mitophagy.
  13. The Neuroprotective Role of Ginsenoside Rg1 Against Cerebral Ischemia-Reperfusion Damage Through Inhibition of Mitophagy via Blocking Mitophagosome-Lysosome Fusion.
  14. Mitophagy-mtROS axis contributes to anti-tuberculosis-induced liver injury through activation of the cGAS-STING pathway in rat hepatocytes.
  15. The clinical impact of mitochondrial autophagy on very late-onset recurrence after catheter ablation for atrial fibrillation.
  16. Parkin-dependent ubiquitination of TAX1BP1 directs efficient autophagic removal of defective mitochondria.
  17. mTOR inhibition triggers mitochondrial fragmentation in cardiomyocytes through proteosome-dependent prohibitin degradation and OPA-1 cleavage.
  18. Chlorogenic acid alleviates intrauterine growth retardation-induced intestinal damage in piglets.
  19. [Molecular mechanism of Siwu Decoction in treating premature ovarian insufficiency based on mitophagy pathway modulated and mediated by estrogen receptor subtype].
  20. Mechanical Stretch-Triggered EGR1 Overexpression Enhances Macrophage M2 Polarization and Drives Mitochondrial Fission.
  21. Mitochondrial Dynamics Through the Lens of Nonlinear Chemical Oscillations: A Theoretical Exploration Inspired by the Belousov-Zhabotinsky Reaction.
  22. CaSun1, a SUN family protein, governs the pathogenicity of Colletotrichum camelliae by recruiting CaAtg8 to promote mitophagy.
  23. Proteomics based discovery of Salvia miltiorrhiza Bunge treating Parkinson's disease through the PINK1/Parkin pathway.
  24. Whey protein hydrolysate alleviated acetaminophen-induced hepatocyte pyroptosis by activating mitophagy.
  25. Resveratrol inhibits autophagy in cardiomyocytes subjected anoxia/reoxygenation injury: involved in VDAC1/PINK1/Parkin pathway.
  26. [Study on mechanism of naringin in alleviating cerebral ischemia/reperfusion injury based on DRP1/LRRK2/MCU axis].
  27. The effect of prolonged G-quadruplex stabilization on the functions of human cells.
  28. Cross-comparison of strains used for mitochondrial imaging in Caenorhabditis elegans during aging.
  29. Lactobacillus johnsonii JJB3 Ameliorates Oxidative Stress-Induced Intestinal Injury and Mitochondrial Damage by Promoting BNIP3L-Mediated Mitophagy.
  30. Melatonin modulates mitochondrial function and inhibits atherosclerosis progression through NRF2 activation and OPA1 inhibition.
  31. 17β-estradiol ameliorates LPS-induced acute lung injury via mediating mitochondrial biogenesis and function in rats.
  32. TREM2 inhibits LPS-induced pyroptosis and inflammation by promoting mitophagy via SYK in BV2 cells.
  33. Practical perspectives on addressing hepatotoxicity during clinical candidate selection.
  34. Corrigendum: Parkin characteristics and blood biomarkers of Parkinson's disease in WPBLC study.
  35. Ginsenoside Rg5 alleviates radiation-induced acute lung vascular endothelium injury by reducing mitochondrial apoptosis via Sirt1.
  36. Ginsenoside Rg1 Downregulates miR-9-5p Expression to Modulate SIRT1-Mediated Mitochondrial Dysfunction and Ameliorate Alzheimer's Disease.
  37. The essential oil from the rhizomes of Stahlianthus involucratus attenuates the progression of vascular aging and atherosclerosis by regulating Nrf2-mediated mitochondrial quality.
  38. MiR221/222 in the conditioned medium of adipose-derived stem cells attenuates particulate matter and high-fat diet-induced cardiac apoptosis.
  39. The impact of exercise on mitochondrial biogenesis in skeletal muscle: A systematic review and meta-analysis of randomized trials.
  40. Interferon-stimulated gene MCL1 inhibits foot-and-mouth disease virus replication by modulating mitochondrial dynamics and autophagy.
  41. A role of arginase-1-expressing myeloid cells in cachexia.
  42. Mitophagy-Related Gene CHDH Predicts Prognosis and Immune Response and Inhibits Proliferation and Migration in vitro and in vivo of Oral Squamous Cell Carcinoma.
  43. The protein interaction of mitochondrial transcription factors A and B2 is associated with 30-day survival in critical COVID-19.
  44. Cadmium targeting MLKL-Drp1 axis to trigger mitochondrial oxidative stress contributes to necroinflammation in rat kidney.
  45. Ertugliflozin induces vasodilation by inhibiting AMPK-mediated mitochondrial fission in vascular smooth muscle cells.
  46. HSF1 remodels mitochondrial biogenesis and function in cancer cells via TIMM17A.
  47. Lon-dependent proteolysis in oxidative stress responses.
  48. Involvement of the PINK1/Parkin signaling pathway in 4-vinylcyclohexene diepoxide-induced ovary toxicity in rats.
  49. Bi-allelic variants in TM2D3 cause a severe syndromic neurodevelopmental disorder associated with endoplasmic reticulum and mitochondrial abnormalities.
  1. Front Cell Neurosci. 2025 ;19 1588645
    Role of mitochondrial quality control in neurodegenerative disease progression.
    Tingting Liu, Weibo Sun, Shuhao Guo, Zhiying Yuan, Minghang Zhu, Jing Lu, Tao Chen, Yuanyuan Qu, Chuwen Feng, Tiansong Yang.
      Neurodegenerative diseases are a diverse group of neurological disorders, in which abnormal mitochondrial function is closely associated with their development and progression. This has generated significant research interest in the field. The proper functioning of mitochondria relies on the dynamic regulation of the mitochondrial quality control system. Key processes such as mitochondrial biogenesis, mitophagy, and mitochondrial dynamics (division/fusion) are essential for maintaining this balance. These processes collectively govern mitochondrial function and homeostasis. Therefore, the mitochondrial quality control system plays a critical role in the onset and progression of neurodegenerative diseases. This article provides a concise overview of the molecular mechanisms involved in mitochondrial biogenesis, mitophagy, and mitochondrial dynamics, explores their interactions, and summarizes current research progress in understanding the mitochondrial quality control system in the context of neurodegenerative diseases.
    Keywords:  Alzheimer’s disease; Huntington’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; mitochondrial quality control
    DOI:  https://doi.org/10.3389/fncel.2025.1588645
  2. J Biol Chem. 2025 Jun 03. pii: S0021-9258(25)02184-2. [Epub ahead of print] 110334
    Mitochondrial tRNA processing defects reprogram mitochondrial and cellular homeostasis.
    Gao Zhu, Yunfan He, Xincheng Li, Yun Xiao, Huisen Zhan, Maoli Duan, Min-Xin Guan.
      Mitochondrial tRNA processing defects have been associated with some clinical presentations including deafness. Especially, a deafness-linked m.7516delA mutation impaired the 5' end processing of RNA precursors and mitochondrial translation. In this study, we investigated the mechanism by m.7516delA mutation induced-deficiencies mitigate organellular and cellular integrity. The m.7516delA mutation downregulated the expression of nucleus encoding subunits and upregulated assemble factors of complex IV and altered the assembly and activities of oxidative phosphorylation (OXPHOS) complexes. The impairment of OXPHOS alleviated mitochondrial quality control processes, including the imbalanced mitochondrial dynamics via increasing fission with abnormal mitochondrial morphology. The m.7516delA mutation upregulated both ubiquitin-dependent and independent mitophagy pathways, evidenced by increasing levels of Parkin, BNIP3, NIX and MFN2-ubiquitination and altering interaction between MFN2 and MUL1 or Parkin, to facilitate the degradation of severely damaged mitochondria. Strikingly, the m.7516delA mutation activated integrated stress response (ISR) pathway, evidenced by upregulation of GCN2, P-GCN2, p-eIF2α, CHOP, ATF4 and elevating the nucleus-location of ATF5 to minimizes the damages in defective mitochondria. Both activation of ISR and PINK1/Parkin mitophagy pathways ameliorate the cell homeostasis via elevating the autophagy process and upregulating apoptotic pathways. Our findings provide new insights into underlying aberrant RNA processing-induced dysfunctions reprogrammed organelles and cellular integrity.
    DOI:  https://doi.org/10.1016/j.jbc.2025.110334
  3. Eur J Med Res. 2025 May 31. 30(1): 434
    The role of mitochondrial dysfunction in the pathogenesis of Alzheimer's disease and future strategies for targeted therapy.
    Xin Li, Ziyang Wu, Xiaying Si, Jing Li, Guode Wu, Manxia Wang.
      Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline, behavioral impairments, and psychiatric comorbidities. The pathogenesis of AD remains incompletely elucidated, despite advances in dominant hypotheses such as the β-amyloid (Aβ) cascade, tauopathy, cholinergic deficiency, and neuroinflammation mechanisms. However, these hypotheses inadequately explain the multifactorial nature of AD, which exposes limitations in our understanding of its mechanisms. Mitochondrial dysfunction is known to play a pivotal role in AD, and since patients exhibit intracellular mitochondrial dysfunction and structural changes in the brain at an early stage, correcting the imbalance of mitochondrial homeostasis and the cytopathological changes caused by it may be a potential target for early treatment of AD. Mitochondrial structural abnormalities accelerate AD pathogenesis. For instance, structural and functional alterations in the mitochondria-associated endoplasmic reticulum membrane (MAM) can disrupt intracellular Ca2⁺ homeostasis and cholesterol metabolism, consequently promoting Aβ accumulation. In addition, the overaccumulation of Aβ and hyperphosphorylated tau proteins can further damage neurons by disrupting mitochondrial integrity and mitophagy, thereby amplifying pathological aggregation and exacerbating neurodegeneration in AD. Furthermore, Aβ deposition and abnormal tau proteins can disrupt mitochondrial dynamics through dysregulation of fission/fusion proteins, leading to excessive mitochondrial fragmentation and subsequent dysfunction. Additionally, hyperphosphorylated tau proteins can impair mitochondrial transport, resulting in axonal dysfunction in AD. This article reviews the biological significance of mitochondrial structural morphology, dynamics, and mitochondrial DNA (mtDNA) instability in AD pathology, emphasizing mitophagy abnormalities as a critical contributor to AD progression. Additionally, mitochondrial biogenesis and proteostasis are critical for maintaining mitochondrial function and integrity. Impairments in these processes have been implicated in the progression of AD, further highlighting the multifaceted role of mitochondrial dysfunction in neurodegeneration. It further discusses the therapeutic potential of mitochondria-targeted strategies for AD drug development.
    Keywords:  Alzheimer’s disease; Mitochondrial dynamics; Mitochondrial quality control; Mitophagy; Therapeutic targets
    DOI:  https://doi.org/10.1186/s40001-025-02699-w
  4. Nat Commun. 2025 Jun 04. 16(1): 5179
    An AI-assisted fluorescence microscopic system for screening mitophagy inducers by simultaneous analysis of mitophagic intermediates.
    Yicheng Wang, Pengfei Song, Heqing Zhou, Pengwei Wang, Yan Li, Zhiyong Shao, Lu Wang, Yan You, Zuhai Lei, Jinhua Yu, Cong Li.
      Mitophagy, the selective autophagic elimination of mitochondria, is essential for maintaining mitochondrial quality and cell homeostasis. Impairment of mitophagy flux, a process involving multiple sequential intermediates, is implicated in the onset of numerous neurodegenerative diseases. Screening mitophagy inducers, particularly understanding their impact on mitophagic intermediates, is crucial for neurodegenerative disease treatment. However, existing techniques do not allow simultaneous visualization of distinct mitophagic intermediates in live cells. Here, we introduce an artificial intelligence-assisted fluorescence microscopic system (AI-FM) that enables the uninterrupted recognition and quantification of key mitophagic intermediates by extracting mitochondrial pH and morphological features. Using AI-FM, we identify a potential mitophagy modulator, Y040-7904, which enhances mitophagy by promoting mitochondria transport to autophagosomes and the fusion of autophagosomes with autolysosomes. Y040-7904 also reduces amyloid-β pathologies in both in vitro and in vivo models of Alzheimer's disease. This work offers an approach for visualizing the entire mitophagy flux, advancing the understanding of mitophagy-related mechanisms and enabling the discovery of mitophagy inducers for neurodegenerative diseases.
    DOI:  https://doi.org/10.1038/s41467-025-60315-1
  5. J Mol Biol. 2025 Jun 03. pii: S0022-2836(25)00329-8. [Epub ahead of print] 169263
    The developing retina undergoes mitochondrial remodeling via PINK1/PRKN-dependent mitophagy.
    Juan Zapata-Muñoz, Juan Ignacio Jiménez-Loygorri, Michael Stumpe, Beatriz Villarejo-Zori, Sandra Alonso-Gil, Petra Terešak, Benan J Mathai, Ian G Ganley, Anne Simonsen, Jörn Dengjel, Patricia Boya.
      Mitophagy, the selective degradation of mitochondria, is essential for retinal ganglion cell (RGC) differentiation and retinal homeostasis. However, the specific mitophagy pathways involved and their temporal dynamics during retinal development and maturation remain poorly understood. Using proteomics analysis of isolated mouse retinas across developmental stages and the mitophagy reporter mouse line, mito-QC, we characterized mitophagy throughout retinogenesis. While mitolysosomes were more prevalent in the mature retina, we observed two distinct mitophagy peaks during embryonic development. The first, independent of PTEN-induced kinase 1 (PINK1) activation, was associated with RGCs. The second, PINK1-dependent peak was triggered after an increase in retinal oxidative stress. This PINK1-dependent, oxidative stress-induced mitophagy pathway is conserved in mice and zebrafish, providing the first evidence of programmed, PINK1-dependent mitophagy during development.
    Keywords:  PINK1; autophagy; development; mitophagy; retina
    DOI:  https://doi.org/10.1016/j.jmb.2025.169263
  6. Stem Cell Res Ther. 2025 Jun 02. 16(1): 274
    Short-Term DMOG treatment rejuvenates senescent mesenchymal stem cells by enhancing mitochondrial function and mitophagy through the HIF-1α/BNIP3 pathway.
    Jiaxin Wen, Lingxian Yi, Lei Chen, Jinhan Xu, Yanmin Zhang, Qiheng Cheng, Hangyu Ping, Huanyu Wang, Feng Shuang, Wei Chai, Tujun Weng.
       BACKGROUND: Mesenchymal stem cells (MSCs) have potential for treating degenerative and immune diseases, but their clinical efficacy is limited by senescence, characterized by mitochondrial dysfunction, impaired mitophagy, and metabolic imbalance. The goal of this study was to investigate the effects of dimethyloxalylglycine (DMOG), a hypoxia-mimetic agent that stabilizes hypoxia-inducible factor 1 alpha (HIF-1α), on rejuvenating senescent MSCs by enhancing mitochondrial function, mitophagy, and metabolic reprogramming.
    METHODS: Two models of MSC senescence were established: oxidative stress-induced senescence using hydrogen peroxide and replicative senescence through serial passaging. Umbilical cord derived MSCs were treated with DMOG for 48 h under normoxic conditions. Mitochondrial function, mitophagy, and metabolism were assessed using assays that measured mitochondrial membrane potential, reactive oxygen species levels, ATP production, and mitophagy. Western blotting and real-time PCR were employed to analyze the expression changes of relevant molecules. RNA sequencing (RNA-seq) was performed to identify key genes and pathways regulated by DMOG. Additionally, to evaluate the therapeutic potential of rejuvenated MSCs, a co-culture system was established, where DMOG-treated senescent MSCs were co-cultured with IL-1β-treated chondrocytes.
    RESULTS: DMOG treatment significantly reduced key senescence markers, including senescence-associated beta-galactosidase, p53, and p21, in both senescence models. DMOG treatment restored mitochondrial morphology and function, improving mitochondrial membrane potential, reducing mitochondrial reactive oxygen species, and enhancing ATP production. DMOG also promoted mitophagy, as evidenced by increased colocalization of mitochondria with lysosomes. RNA-seq analysis revealed that DMOG activated key pathways, including HIF-1 signaling, calcium signaling, and mitophagy-related gene (BNIP3 and BNIP3L). Notably, BNIP3 knockdown greatly abolished DMOG-induced mitophagy and its anti-senescence effects. Furthermore, DMOG treatment improved metabolic flexibility by enhancing both mitochondrial respiration and glycolysis in senescent MSCs. Moreover, DMOG-treated senescent MSCs partially restored their therapeutic efficacy in an osteoarthritis model by improving extracellular matrix regulation in IL-1β-stimulated chondrocytes.
    CONCLUSIONS: Short-term DMOG treatment rejuvenates senescent MSCs by enhancing mitochondrial function, promoting mitophagy via HIF-1α/BNIP3, and improving metabolic reprogramming. DMOG-treated MSCs also showed enhanced therapeutic efficacy in co-culture with IL-1β-treated chondrocytes, suggesting its potential to improve MSC-based therapies in regenerative medicine.
    Keywords:  BNIP3; HIF-1α; Hypoxia-Mimetic agent; Mesenchymal stem cells (MSCs); Mitophagy; Senescence
    DOI:  https://doi.org/10.1186/s13287-025-04422-2
  7. Biotechniques. 2025 May 31. 1-13
    Mito-Kaede photoactivation and chase experiment for mitophagy: mitophagy flux response toward various stimulations.
    Yoh Sugawara, Hiroyuki Morinaga, Jingyuan Chen, Yoshinori Kitagawa, Hiroki Ogata, Asiya Karim, Miu Kikuchi, Maryam Khan, Erica Yasuhara, Takahisa Goto, Joseph A Jeevendra Martyn, Shingo Yasuhara.
      Mitophagy, a crucial mitochondrial quality control system for cellular stress adaptation, is a key focus in pathophysiology and drug discovery. Developing a simple and versatile mitophagy flux assay is vital for advancing our understanding of cellular responses. Addressing a gap in systematic methods, we employ the photoactivatable fluorescent protein mito-Kaede in C2C12 myocytes, demonstrating its remarkable versatility in quantifying mitophagy flux responses under various stimuli, including carbonyl cyanide m-chlorophenyl hydrazone (CCCP), TNF-α, lipopolysaccharide (LPS), and hypoxia. This study underscores the validity and distinctive advantages of the mito-Kaede assay through comparative analysis with conventional assays including Western blotting (WB), potentially providing valuable insights for both mitophagy flux analysis and drug development.
    Keywords:  Autophagy; flux measurement; mito-Kaede; mitochondria; mitophagy; quantitative assay; stimulated response kinetics; time-lapse
    DOI:  https://doi.org/10.1080/07366205.2025.2505357
  8. Oncogene. 2025 Jun 04.
    SFXN1 promotes bladder cancer metastasis by restraining PINK1-dependent mitophagy.
    Baochao Zhang, Guanqun Dong, Xinyue Guo, Hao Li, Wei Chen, Wenli Diao, Qun Lu, Guanghui Xu, Qing Zhang, Meng Ding, Hongqian Guo.
      Sideroflexin 1 (SFXN1), a newly identified mitochondrial serine transporter, exhibits great potential to modulate mitochondrial function and promote tumor development. However, its role in bladder cancer (BLCA) remains unclear. Our study revealed that SFXN1 was enriched in clinical BLCA tissues, and high SFXN1 expression in BLCA was positively associated with the progression and poor prognosis. Further, SFXN1 deficiency remarkably suppressed the proliferation and metastasis of BLCA cells in vitro and in vivo, indicating an oncogenic role of SFXN1 in BLCA. Additionally, our results demonstrated that SFXN1 promotes metastasis through its unknown function of restraining PINK1 (PTEN-induced kinase 1)-dependent mitophagy rather than its classical role as a mitochondrial serine transporter to mediate one-carbon metabolism. Mechanistically, SFXN1 acted as a bridge to promote PINK1 degradation by interacting with PARL (presenilin-associated rhomboid-like protein) and MPP-β (mitochondrial processing peptidase-β), leading to mitophagy arrest. Notably, when mitophagy was restrained by highly-expressed SFXN1, mitochondrial reactive oxygen species were considerably enriched, thus activating TGF-β (transforming growth factor-β)-mediated epithelial-mesenchymal transition and promoting metastasis of BLCA cells. This study highlights SFXN1 as a novel promising therapeutic target for BLCA and identifies a new mitophagic modulator to improve our understanding of an association between mitophagy and BLCA progression. Schematic diagram of the proposed mechanism by which SFXN1 promotes bladder cancer metastasis by restraining PINK1-dependent mitophagy. SFXN1 is upregulated in BLCA tissues, and promotes BLCA metastasis through its unrevealed function of restraining PINK1-dependent mitophagy rather than its classical role as a mitochondrial serine transporter to promote cell proliferation. Specifically, SFXN1 acted as an essential bridging factor to promote PINK1 degradation by interacting with PARL and MPP-β on the IMM, leading to mitophagy arrest and mtROS accumulation, thus activated TGF-β-mediated EMT and promoted BLCA metastasis (This figure was created by Figdraw).
    DOI:  https://doi.org/10.1038/s41388-025-03460-7
  9. FEBS J. 2025 Jun 01.
    PINK1/Parkin-based live-cell quantitative FRET imaging for mitophagy drug screening.
    Beini Sun, Kangrong Deng, Qialing Huang, Lin Cheng, Wei Yao, Zhirui Wu, Xiaoping Wang, Ming Dong, Tongsheng Chen.
      PINK1 (PTEN-induced kinase 1) and Parkin (parkin RBR E3 ubiquitin protein) ligase are important regulators for cells to maintain mitochondrial number and functional homeostasis. Here, we established a PINK1/Parkin-based mitophagy drug evaluation method using quantitative Förster resonance energy transfer (FRET) imaging in living cells. A stable model of carbonyl cyanide 3-chlorophenylhydrazone (CCCP)-induced mitophagy was established, verified by increased colocalization of mitochondria with LC3 aggregates, decreased mitochondrial membrane potential (MMP), and increased intracellular reactive oxygen species (ROS) level. Next, by silencing PINK1 and overexpressing LC3 proteins in MCF-7 cells, it was verified that PINK1 and Parkin significantly promoted CCCP-induced mitophagy, in which CCCP promoted the direct interaction of PINK1 and Parkin. Quantitative FRET imaging analysis for the cells coexpressing CFP-PINK1 and YFP-Parkin was used to assess the action of five drugs [3-methyladenine (3-MA), CCCP, doxorubicin hydrochloride (DOX), metformin (Met), resveratrol (RSV)] on the interaction between PINK1 and Parkin. After 6 h of treatment with these drugs, the CCCP, DOX, Met, and RSV groups showed significantly higher maximum donor-centric FRET efficiency (EDmax) than the control group, suggesting that these four drugs promoted the direct interaction between PINK1 and Parkin. While the 3-MA group showed similar EDmax to the control group, suggesting that 3-MA did not promote direct interaction between PINK1 and Parkin. We also performed these experiments in HeLa cells and obtained the same results, further demonstrating that the PINK1/Parkin-based quantitative FRET drug screening method is a potential tool for mitophagy drug screening in living cells.
    Keywords:  PINK1; Parkin; drug screening; mitophagy; quantitative FRET
    DOI:  https://doi.org/10.1111/febs.70146
  10. J Transl Med. 2025 Jun 02. 23(1): 617
    Mitochondrial dynamics reveal potential to facilitate axonal regeneration after spinal cord injury.
    Kaixuan Wang, Xi Chen, Mengmin Liu, Yunjuan Li, Yihua Zhu, Tiantong Zhou, Weiwei Tao, Yong Ma, Yang Guo, Lining Wang, Yue Hu.
       BACKGROUND: Spinal cord injury (SCI) arises from traumatic damage to the spinal cord, resulting in varying degrees of sensory, motor, and autonomic dysfunction. Mitochondria, as the primary energy-producing organelles within cells, have garnered increasing attention for their critical role in promoting axonal regeneration following SCI.
    AIM OF REVIEW: This review aims to systematically examine the alterations in mitochondrial dynamics post-SCI and to elucidate their influence on axonal regeneration. Furthermore, the review evaluates the current challenges associated with SCI treatment and proposes potential therapeutic strategies for future research.
    KEY SCIENTIFIC CONCEPTS OF REVIEW: The review comprehensively addresses mitochondrial dynamics, with a focus on key processes such as biogenesis, fusion and fission, mitophagy, trafficking, and anchoring. It delves into the molecular mechanisms by which signaling pathways within neurons and glial cells regulate these mitochondrial processes to facilitate axonal regeneration. Additionally, the review identifies existing challenges in SCI treatment and advocates for targeted interventions in mitochondrial dynamics as a promising therapeutic avenue, offering significant potential for advancing future research and treatment of SCI.
    Keywords:  Axonal mitochondria; Axonal regeneration; Dynamics; Spinal cord injury
    DOI:  https://doi.org/10.1186/s12967-025-06611-2
  11. Clin Transl Med. 2025 May;15(5): e70362
    Coordination of SLC39A1 and DRP1 facilitates HCC recurrence by impairing mitochondrial quality control.
    Rui Li, Zhe Wang, Lixin Cheng, Zhiqiang Cheng, Qiong Wu, Fengjuan Chen, Dong Ji, Qingxian Cai, Yijin Wang.
       BACKGROUND: Despite rapid advances in HCC therapy, surgical resection is still the most effective treatment. However, postoperative relapse develops in a large population and the mechanism remains to be explored.
    METHODS: HCC resection samples were retrospectively collected from 12 nonrelapsed and 15 relapsed HCC patients for RNA sequencing. Liver-specific solute carrier family 39 member 1 (SLC39A1) knockout mice were generated by crossing Alb-Cre mice and SLC39A1flox/flox mice. Liver samples were examined for inflammation, fibrosis, proliferation, and apoptosis. Mitochondrial mass, autophagy, ROS, and mitochondrial membrane potential (MMP), were detected. Co-immunoprecipitation and molecular docking were used to identify protein interactions.
    RESULTS: SLC39A1 is highly expressed in relapsed HCC patients and negatively correlated with overall survival. Knockdown of SLC39A1 inhibited cell proliferation by arresting the cell cycle and promoted cell apoptosis, accompanied by suppressing autophagic flux. Mechanistically, SLC39A1 interacts with a member of the dynamin superfamily of GTPases dynamin-related protein 1 (DRP1), followed by facilitating mitochondrial fission and MMP reduction. Inhibition of DRP1 abolished SLC39A1-induced mitochondrial division and MMP depolarization, while overexpression of DRP1 reversed mitochondrial fusion and MMP hyperpolarization in SLC39A1 silenced cells, accompanied by recuperative cell proliferative ability. SLC39A1flox/flox,Alb-Cre mice displayed fewer tumour numbers and less liver damage compared with SLC39A1flox/flox mice. A specific peptide targeting SLC39A1 to disturb the combination of full-length SLC39A1 and DRP1 efficiently suppressed HCC progression.
    CONCLUSIONS: Our findings reveal a key role of SLC39A1-DRP1 interaction in HCC progression by disturbing mitochondrial quality control and providing a competitive peptide as a potential anti-tumour therapy.
    KEY POINTS: SLC39A1 correlates with HCC recurrence and HCC mortality. Interaction of SLC39A1 and DRP1 facilitates HCC by regulating mitochondrial quality control. Specific peptide targeting SLC39A1 efficiently prevents HCC progression.
    Keywords:  HCC relapse; cancer therapy; hepatocellular carcinoma; mitochondrial quality control
    DOI:  https://doi.org/10.1002/ctm2.70362
  12. Brain Res Bull. 2025 May 30. pii: S0361-9230(25)00219-9. [Epub ahead of print]228 111407
    Artesunate alleviates cerebral ischemia/reperfusion injury by suppressing FUNDC1-mediated excessive mitophagy.
    Fei Wang, Wenji Zhou, Liqing Huang, Li Sun, Lujun Deng, Liping Li.
      Cerebral ischemia-reperfusion (I/R) injury represents a debilitating neurological disorder with significant morbidity. Artesunate, a water-soluble hemisuccinate derivative, has emerged as a potential therapeutic agent for cerebral I/R injury. Our investigation endeavors to assess the efficacy of artesunate in this context while elucidating its mechanisms of action. We established the middle cerebral artery occlusion/refusion (MACO) rat model and oxygen-glucose deprivation/reperfusion (OGD/R)-stimulated PC12 cells model. Mitophagy was analyzed by transmission electron microscope, mitochondrial membrane potential detection, western blotting, and real-time quantitative polymerase chain reaction (RT-qPCR). The underlying mechanism was investigated by cell viability, flow cytometry, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. The results suggested that artesunate inhibited apoptosis and excessive mitophagy. Mechanically, artesunate regulated FUN14 domain containing 1 (FUNDC1)-mediated mitophagy via the AMPK (AMP-activated protein kinase)-mTOR (mechanistic target of rapamycin)-TFEB (transcription factor EB) signaling pathway. Additionally, artemether reduced the infarct size in MCAO rats, inhibited neurological dysfunction, and enhanced memory performance. In summary, our data revealed a novel mechanism whereby artesunate suppresses apoptosis by inhibiting excessive mitophagy. These findings offered a new promising therapy for cerebral I/R injury.
    Keywords:  AMPK/mTOR/TFEB pathway; Artesunate; Cerebral ischemia-reperfusion (I/R) injury; FUNDC1; Mitophagy; Stroke
    DOI:  https://doi.org/10.1016/j.brainresbull.2025.111407
  13. Cell Prolif. 2025 Jun 03. e70071
    The Neuroprotective Role of Ginsenoside Rg1 Against Cerebral Ischemia-Reperfusion Damage Through Inhibition of Mitophagy via Blocking Mitophagosome-Lysosome Fusion.
    Lin Ai, Hangui Ren, Yuan Wang, Mengfan Liu, Yufei Qiu, Jiling Feng, Rongchen Dai, Wang Fu, Yongpeng Wang, Zhichao Xi, Hongxi Xu, Feng Wang.
      Ginsenoside Rg1 has shown promise in ameliorating cerebral ischemia-reperfusion injury (CIRI). However, its precise molecular mechanisms remain unclear. In this study, an in vitro CIRI model was established using SH-SY5Y and SK-N-AS neuronal cell lines subjected to oxygen-glucose deprivation followed by reoxygenation (OGD/R). For the in vivo model, C57BL/6J mice underwent middle cerebral artery occlusion and subsequent reperfusion (MCAO/R). The protective effects of Rg1 against OGD/R injury were analysed using the CCK-8 assay and the PI exclusion method. The in vivo neuroprotective effects of Rg1 against CIRI were evaluated using various assessments, including brain blood flow, neurological deficits, behavioural tests, TTC, H&E, Nissl and TUNEL staining. Mitophagy was assessed by detecting mitophagy-initiating proteins via Western blotting, transmission electron microscopy, immunohistochemistry and immunofluorescence staining. Additionally, mitochondrial function was assessed by ATP measurement, the JC-1 assay and MitoSOX-based flow cytometry. Our results show that Rg1 significantly mitigated cell death caused by OGD/R and substantially enhanced cell viability in vitro. Moreover, Rg1 alleviated OGD/R-induced mitochondrial dysfunction, as indicated by preserved mitochondrial membrane potential and decreased mitochondrial ROS levels. Mitophagy was induced after OGD treatment, which was subsequently inhibited by Rg1 during reperfusion. Mechanistically, Rg1 disrupted the fusion of mitophagosomes with lysosomes rather than inhibiting mitophagy initiation, leading to an accumulation of mitochondrial proteins and mitophagy-initiating proteins. Notably, prolonged inhibition of mitophagy by Rg1 did not induce cytotoxicity or exacerbate mitochondrial dysfunction. Furthermore, administration of Rg1 in MCAO/R mice significantly improved brain blood reperfusion, reduced infarct volume, improved neurological deficits, preserved brain tissue integrity and decreased neuronal apoptosis. Consistent with the in vitro observations, Rg1 upregulated mitophagy-related protein expression in MCAO/R mouse brain tissues, indicating potential inhibition of mitophagy. In conclusion, our study reveals that Rg1 significantly alleviates CIRI at least partially by suppressing mitophagy, specifically by impeding the fusion of mitophagosomes with lysosomes.
    Keywords:  cerebral ischemia–reperfusion injury; ginsenoside Rg1; ischemic stroke; mitophagosome‐lysosome fusion; mitophagy
    DOI:  https://doi.org/10.1111/cpr.70071
  14. Int Immunopharmacol. 2025 May 30. pii: S1567-5769(25)00974-9. [Epub ahead of print]160 114984
    Mitophagy-mtROS axis contributes to anti-tuberculosis-induced liver injury through activation of the cGAS-STING pathway in rat hepatocytes.
    Wenyan Chen, Chenjunlei Luo, He Zhou, Zhenhui Liu, Junfei Huang, Yining Liu, Mingdan You, Guanghong Yang.
      Tuberculosis (TB) remains a major worldwide healthcare issue, with anti-TB drugs playing a pivotal role in its treatment. However, the emergence of anti-TB drug-induced liver injury (ATB-DILI) poses a considerable challenge, undermining treatment efficacy and patient survival. This study investigates the underlying mechanisms of ATB-DILI, focusing on reactive oxygen species (ROS), mitophagy, lysosomal function, and the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling pathway. A rat hepatocyte model treated with standard anti-TB drugs was established to assess liver inflammation, oxidative stress biomarkers, mitochondrial function, and mitophagy processes. The results indicate that anti-TB drug administration induced significant inflammatory injury, characterized by elevated IL-6 and reduced IL-4 and IL-10 levels. ROS overproduction predominantly originates in the mitochondrial level, consequently resulting in oxidative stress and impaired mitochondrial function. A noticeable decline in both the oxygen consumption rate and ATP production is indicative of this phenomenon. Although mitophagy was activated, impaired lysosomal function hindered mitophagic flux, leading to the buildup of damaged mitochondria and ROS. Pharmacological intervention with mitoTEMPO alleviated mitochondrial dysfunction, while clioquinol restored lysosomal function and improved mitophagy. Additionally, the cGAS-STING signaling pathway was found to regulate inflammation in ATB-DILI, with both mitoTEMPO and clioquinol alleviating its effects. These findings elucidate the crucial impact of lysosome-mediated mitophagy dysfunction and mitochondrial ROS in ATB-DILI, highlighting potential therapeutic targets to enhance liver protection during anti-TB treatment.
    Keywords:  Anti-tuberculosis drugs; Liver injury; Lysosomal dysfunction; Mitophagy; Reactive oxygen species; cGAS-STING
    DOI:  https://doi.org/10.1016/j.intimp.2025.114984
  15. Eur Heart J Open. 2025 May;5(3): oeaf058
    The clinical impact of mitochondrial autophagy on very late-onset recurrence after catheter ablation for atrial fibrillation.
    Keisuke Uchida, Naoya Kataoka, Teruhiko Imamura, Takahisa Koi, Koichiro Kinugawa.
       Aims: The mechanisms underlying very late-onset atrial fibrillation (AF) recurrence, defined as occurring more than 1 year after catheter ablation, are hypothesized to differ from those responsible for recurrence within the first year; however, this remains uncertain.
    Methods and results: Two investigations were conducted in patients undergoing AF ablation. First, non-targeted metabolome analysis was performed in 10 patients with very late-onset recurrence and 10 without recurrence. Second, based on metabolomic findings implicating autophagy, serum levels of the autophagy-related proteins Parkin, a marker of mitophagy, and ATG5, an indicator of bulk autophagy, were measured using ELISA. Associations between these variables and very late-onset recurrence were analysed. Among the 203 patients (mean age 70 years, 63% male), 16 experienced very late-onset recurrence during a mean follow-up of 954 days. Metabolome analysis identified 255 peaks (177 cations and 78 anions). Principal component analysis revealed a reduction in γ-glutamyl dipeptides, contributors to mitochondrial autophagy, in the recurrence group. A serum Parkin level below the median was independently associated with very late-onset recurrence (hazard ratio 3.82, 95% confidence interval 1.20-12.13, P = 0.023), after adjustment for left atrial diameter and diabetes mellitus. In contrast, ATG5 levels were not significantly associated. Parkin levels did not predict recurrence within the first year (log-rank P = 0.09).
    Conclusion: Reduced serum Parkin levels were independently associated with very late-onset recurrence following AF ablation, suggesting that impaired mitochondrial autophagy may contribute to the pathogenesis of long-term AF recurrence.
    Keywords:  Atrial fibrillation; Autophagy; Catheter ablation; Mitochondria
    DOI:  https://doi.org/10.1093/ehjopen/oeaf058
  16. bioRxiv. 2025 May 19. pii: 2025.05.16.654474. [Epub ahead of print]
    Parkin-dependent ubiquitination of TAX1BP1 directs efficient autophagic removal of defective mitochondria.
    Anna Lechado-Terradas, Bianca Lemke, Katharina I Zittlau, Boris Macek, Philipp J Kahle.
      In stressed cells, the recessive Parkinson disease (PD) associated gene products PINK1 and parkin mediate the autophagic removal of damaged mitochondria (mitophagy). Upon mitochondrial membrane potential disruption, PINK1 phosphorylation activates the ubiquitin ligase parkin which ubiquitinates various mitochondrial protein substrates. These feed-forward modifications on the mitochondria surface attract ubiquitin-binding autophagy receptors that target ubiquitinated mitochondria to autophagosomes and indirectly contribute to phagophore elongation. Investigating post-translational protein modifications during this process, we detected transient ubiquitination of K549 within the third coiled-coil domain (CC3) of TAX1BP1 in HeLa cells expressing WT but not catalytically inactive parkin. Parkin-dependent ubiquitination did not target TAX1BP1 to proteasomal degradation but was rather indicative of a regulatory modification. In cells with the full complement of autophagy receptors, TAX1BP1 plays only a minor role in mitophagy. However, when expressed as a sole autophagy receptor, both WT and ubiquitination deficient TAX1BP1 were capable of promoting mitophagy, albeit mitochondria degradation was slightly delayed under mutant conditions. Use of the lysosomal inhibitor bafilomycin A indicated classical autophagolysosomal targeting of damaged mitochondria mediated by WT TAX1BP1. However, for the ubiquitination-deficient TAX1BP1, we observed an increased prevalence of enlarged endolysosomal vesicles carrying accumulated TAX1BP1-positive autophagosomes filled with mitochondrial material. Thus, while ubiquitination of the CC3 domain of TAX1BP1 is not essential for complete mitophagy, the lack of CC3 in TAX1BP1 reroutes the degradation flux to a less efficient endolysosmal degradative pathway. Interestingly, the PD gene product VPS35, becomes prominently engaged in this alternative mitophagy pathway.
    DOI:  https://doi.org/10.1101/2025.05.16.654474
  17. Cell Commun Signal. 2025 May 31. 23(1): 256
    mTOR inhibition triggers mitochondrial fragmentation in cardiomyocytes through proteosome-dependent prohibitin degradation and OPA-1 cleavage.
    Hugo E Verdejo, Valentina Parra, Andrea Del Campo, Cesar Vasquez-Trincado, Damian Gatica, Camila Lopez-Crisosto, Jovan Kuzmicic, Leslye Venegas-Zamora, Ursula Zuñiga-Cuevas, Mayarling F Troncoso, Rodrigo Troncoso, Beverly A Rothermel, Mario Chiong, E Dale Abel, Sergio Lavandero.
       INTRODUCTION: Cardiac mitochondrial function is intricately regulated by various processes, ultimately impacting metabolic performance. Additionally, protein turnover is crucial for sustained metabolic homeostasis in cardiomyocytes.
    OBJECTIVE: Here, we studied the role of mTOR in OPA-1 cleavage and its consequent effects on mitochondrial dynamics and energetics in cardiomyocytes.
    RESULTS: Cultured rat cardiomyocytes treated with rapamycin for 6-24 h showed a significant reduction in phosphorylation of p70S6K, indicative of sustained inhibition of mTOR. Structural and functional analysis revealed increased mitochondrial fragmentation and impaired bioenergetics characterized by decreases in ROS production, oxygen consumption, and cellular ATP. Depletion of either the mitochondrial protease OMA1 or the mTOR regulator TSC2 by siRNA, coupled with an inducible, cardiomyocyte-specific knockout of mTOR in vivo, suggested that inhibition of mTOR promotes mitochondrial fragmentation through a mechanism involving OMA1 processing of OPA-1. Under homeostatic conditions, OMA1 activity is kept under check through an interaction with microdomains in the inner mitochondrial membrane that requires prohibitin proteins (PHB). Loss of these microdomains releases OMA1 to cleave its substrates. We found that rapamycin both increased ubiquitination of PHB1 and decreased its abundance, suggesting proteasomal degradation. Consistent with this, the proteasome inhibitor MG-132 maintained OPA-1 content in rapamycin-treated cardiomyocytes. Using pharmacological activation and inhibition of AMPK our data supports the hypothesis that this mTOR-PHB1-OMA-OPA-1 pathway impacts mitochondrial morphology under stress conditions, where it mediates dynamic changes in metabolic status.
    CONCLUSIONS: These data suggest that mTOR inhibition disrupts mitochondrial integrity in cardiomyocytes by promoting the degradation of prohibitins and OPA-1, leading to mitochondrial fragmentation and metabolic dysfunction, particularly under conditions of metabolic stress.
    Keywords:  AMPK; Mitochondrial fusion; OMA1; OPA-1; Prohibitin; Rapamycin; mTOR
    DOI:  https://doi.org/10.1186/s12964-025-02240-w
  18. Nutrition. 2025 Apr 19. pii: S0899-9007(25)00128-5. [Epub ahead of print]138 112810
    Chlorogenic acid alleviates intrauterine growth retardation-induced intestinal damage in piglets.
    Kang Cheng, Jinxiu Yao, Zhihua Song, Hongyue Zhao, Youzheng Zhao, Jin Huang, Jinrong Wang, Yong Zhang.
       OBJECTIVES: Intestinal disorder is a crucial contributor to growth lag, decreased disease resistance and increased perinatal morbidity and mortality in newborns suffering from intrauterine growth retardation (IUGR). This study was conducted to investigate the protective effects of chlorogenic acid (CGA) on IUGR-induced intestinal damage using weaned piglets as a model.
    RESEARCH METHODS & PROCEDURES: In total, 24 normal birth weight weaned piglets and 24 IUGR weaned piglets were fed either a basal diet or a basal diet plus 1 g/kg CGA from 26 to 47 days of age.
    RESULTS: CGA alleviated IUGR-induced villous atrophy, down-regulated tight junction protein mRNA expression, impaired antioxidant capacity, inflammatory response, impaired mitochondrial ATP production and oxidative metabolism in the intestine, and improved mitochondrial fusion and mitophagy-related protein transcriptional expression.
    CONCLUSION: CGA may be a potential nutrient supplement in the alleviation of intestinal damage, and the improvement of growth and disease resistance in IUGR neonates.
    Keywords:  Chlorogenic acid; Intestinal damage; Intrauterine growth retardation; Mitochondrial dynamics; Mitophagy
    DOI:  https://doi.org/10.1016/j.nut.2025.112810
  19. Zhongguo Zhong Yao Za Zhi. 2025 Apr;50(8): 2173-2183
    [Molecular mechanism of Siwu Decoction in treating premature ovarian insufficiency based on mitophagy pathway modulated and mediated by estrogen receptor subtype].
    Si Chen, Ze-Ye Zhang, Nan Cong, Jiao-Jiao Yang, Feng-Ming You, Yao Chen, Ning Wang, Pi-Wen Zhao.
      In this study, we explored the pharmacological effects of Siwu Decoction in treating premature ovarian insufficiency(POI) and its molecular mechanism based on the mitophagy pathway modulated and mediated by estrogen receptor(ER) subtypes. Female Balb/c mice were divided into a control group, model group, as well as high-dose and low-dose groups of Siwu Decoction. The POI mice model was constructed by intraperitoneal injection of cisplatin. The high-dose and low-dose groups of Siwu Decoction were administered intragastrically with Siwu Decoction each day for 14 days. During this period, we monitored the estrous cycle and body weight of the mice and calculated the ovarian index. The morphology of the ovaries was detected by hematoxylin-eosin(HE) staining, and the number of primordial follicles was counted. The apoptosis of the ovarian tissue was detected by TUNEL staining. The expression levels of anti-Müllerian hormone(AMH), apoptosis-associated and mitophagy-associated proteins, ER subtypes, and the expression levels of key proteins of its mediated molecular pathways were detected by Western blot and immunohistochemistry. KGN cells were divided into a control group, model group, Siwu Decoction group, and gene silencing group. The apoptosis model was induced by H_2O_2, and PTEN-induced putative kinase 1(PINK1) gene silencing was induced by siRNA transfection. The Siwu Decoction group and gene silencing group were added to the medium containing Siwu Decoction. Cell viability was detected by CCK-8 assay. Cell senescence was detected by senescence-associated-β-galactosidase. The expression levels of apoptosis-associated and mitophagy-associated proteins were detected by Western blot. The results of in vivo experiments showed that compared with the model group, the mice in the high-dose and low-dose groups of Siwu Decoction significantly recovered the rhythm of the estrous cycle, and the levels of ovarian index, number of primordial follicles, and expression of AMH, representative indexes of ovarian function, were significantly higher, suggesting that the level of ovarian function was significantly improved. The expression levels of the apoptosis-related proteins, cytochrome C(Cyt C), cysteinyl aspartate specific proteinase 3(caspase 3), B-cell lymphoma-2(Bcl-2)-associated X(Bax), and mitophagy-associated indicator(Beclin 1) were significantly decreased, and the expression levels of Bcl-2 was significantly elevated. The positive area of TUNEL was significantly reduced, suggesting that the apoptosis level of the ovaries was significantly reduced. The expression levels of PINK1, Parkin, and sequestosome 1(p62) were significantly reduced, suggesting that the level of ovarian mitophagy was significantly down-regulated. The expression levels of ERα and ERβ were significantly elevated, and the ratio of ERα/ERβ was significantly reduced. The expression levels of key proteins in the pathway, phosphoinositide 3-kinase(PI3K) and protein kinase B(Akt), were significantly reduced, suggesting that the regulation of ER subtypes and the mediation of PI3K/Akt pathway were the key mechanisms. In vitro experiments showed that compared with the model group, the proportion of senescent cells in the Siwu Decoction group was significantly reduced. Cyt C, caspase 3, Beclin 1, Parkin, and p62 were significantly reduced, which was in line with in vivo experimental results. The proportion of senescent cells and the expression level of the above proteins were further significantly reduced after PINK1 silencing. It can be seen that Siwu Decoction can regulate the expression level and proportion of ER subtypes in KGN cells, then mediate the PI3K/Akt pathway to inhibit excessive mitophagy and apoptosis, and exert therapeutic effects of POI.
    Keywords:  KGN cell; Siwu Decoction; apoptosis; estrogen receptor; mitophagy; premature ovarian insufficiency
    DOI:  https://doi.org/10.19540/j.cnki.cjcmm.20241125.401
  20. Exp Cell Res. 2025 May 31. pii: S0014-4827(25)00217-4. [Epub ahead of print] 114621
    Mechanical Stretch-Triggered EGR1 Overexpression Enhances Macrophage M2 Polarization and Drives Mitochondrial Fission.
    Fei Han, Yi Cheng, Xianzhi Xu, Jiayi Yin, Wei-Bing Zhang.
      Orthodontic tooth movement involves a complex interaction between mechanical forces and bone tissue remodeling. As a response to mechanical stimuli, macrophages play an important role in tissue remodeling and potential side effects. In this study, we investigated the molecular mechanism of macrophage polarization under mechanical stimulation, focusing on the dual regulation of EGR1 (Early Growth Response 1) in mitochondrial dynamics and macrophage polarization. In the cyclic stretch stress model of RAW264.7 cells in vitro, we found that mechanical tension promotes the M2 polarization phenotype of macrophages. During the first to second hour of mechanical stretching, the expression of iNOS, ARG-1, and CD163 in cells increased. At the same time, significant changes in macrophage mitochondrial dynamics include enhanced fission behavior and decreased membrane potential. The transcriptome sequencing results indicated that EGR1 was rapidly upregulated after mechanical stimulation and translocated from the cytoplasm to the nucleus. Inhibition of mitochondrial fission or knockdown of EGR1 significantly inhibited tension-induced M2 polarization. Moreover, this process may be associated with the PI3K-Akt signaling pathway. Our research findings reveal new insights into the connection between mechanical forces and macrophage function through EGR1-mediated mitochondrial dynamics. This work provides new perspectives on bone remodeling during orthodontic movement.
    Keywords:  EGR1(Early Growth Response 1); Macrophage polarization; Mechanical stimulation; Mitochondrial dynamics; Orthodontic tooth movement
    DOI:  https://doi.org/10.1016/j.yexcr.2025.114621
  21. bioRxiv. 2025 May 19. pii: 2025.05.15.654228. [Epub ahead of print]
    Mitochondrial Dynamics Through the Lens of Nonlinear Chemical Oscillations: A Theoretical Exploration Inspired by the Belousov-Zhabotinsky Reaction.
    Ayalur Raghu Subbalakshmi, Tamara Mirzapoiazova, Prakash Kulkarni, Ravi Salgia.
      In biology, oscillations are observed across a wide spectrum of processes and systems. Oscillatory systems are typically leveraged to transmit information within cells. However, they can also serve to transmit information between organisms underscoring their fundamental role in regulating transitions, maintaining stability, and responding to environmental stimuli. In this study, we explore mitochondrial fission and fusion dynamics through the framework of the Belousov-Zhabotinsky (BZ) reaction, a hallmark of non-equilibrium system that exhibits periodic changes in reactant concentrations through autocatalysis and feedback regulation. We observed that mitochondrial changes followed an oscillatory dynamic where the fission, fusion and intermediary factors undergo oscillations. Also, by modelling comparison with publicly available datasets of diseased condition before and after therapy, we observed similarities, where under diseased condition there is increased concentration of the fission and fusion factors but upon treatment the concentration of the intermediary factors increase. Also, patient survival data analysis showed that increase in fission and fusion factors correlated with increased deaths but when there is increase in the intermediary factor concentration, we see better patient survival. These results highlight the possibility of targeting mitochondrial dynamics as a potential strategy for therapeutic development for diseases such as cancer where mitochondrial dynamics is dysregulated.
    DOI:  https://doi.org/10.1101/2025.05.15.654228
  22. Hortic Res. 2025 Jul;12(7): uhaf121
    CaSun1, a SUN family protein, governs the pathogenicity of Colletotrichum camelliae by recruiting CaAtg8 to promote mitophagy.
    Shuai Meng, Shufen Chao, Meng Xiong, Longjun Cheng, Yu Sun, Li Wang, Ya Chen, Sadhna Jagernath Jane, Chaoxi Luo, Jie Chen.
      Camellia oleifera, a woody oilseed plant native to China, is highly susceptible to anthracnose, a fungal disease that poses a significant threat to its yield and quality. Mitophagy, a specialized form of autophagy that specifically targets dysfunctional mitochondria, is crucial for cellular homeostasis, stress response, and pathogenesis in fungi. The proteins that potentially participate in mitophagy in Colletotrichum camelliae were identified herein using immunoprecipitation-mass spectrometry (IP-MS) by screening for the potential protein interactors of the core autophagy-related protein, CaAtg8. Among the identified mitochondria-associated proteins, CaSun1 was selected for further investigation. Phenotypic analyses revealed that CaSun1 is a critical regulator of vegetative growth, conidiation, and pathogenicity. CaSun1 localized to the mitochondria, consistent with the conserved function of SUN family proteins. Notably, the findings revealed that CaSun1 was essential for mitophagy and colocalized with CaAtg8 during nitrogen starvation. Functional analyses demonstrated that CaSun1-mediated mitophagy is vital for the growth of invasive hyphae and pathogenicity in C. camelliae. In summary, our findings indicated that CaSun1 mediates mitophagy by facilitating the recruitment of CaAtg8 in C. camelliae, thereby contributing to the establishment of anthracnose. This study provided novel insights into the molecular mechanisms underlying the pathogenesis of fungal infections and identified a potential target for disease control.
    DOI:  https://doi.org/10.1093/hr/uhaf121
  23. J Ethnopharmacol. 2025 May 31. pii: S0378-8741(25)00766-4. [Epub ahead of print]350 120079
    Proteomics based discovery of Salvia miltiorrhiza Bunge treating Parkinson's disease through the PINK1/Parkin pathway.
    Dongchen Xu, Chenyu ShenTu, Chuhong Zong, Weiliang Fu, Jiawei Ling, Ping Shao, Xuesong Liu, Yong Chen, Tengfei Xu.
       ETHNOPHARMACOLOGICAL RELEVANCE: Salvia miltiorrhiza Bunge, a traditional Chinese medicine, has been utilized in the treatment of Parkinson's disease (PD) for thousands of years, as evidenced by its inclusion in ancient formulas such as YangXue XingNao Tang and XingGan ZhenFeng Tang. However, the underlying mechanisms of its therapeutic effects on PD remain unclear.
    AIM OF THE STUDY: This study aims to evaluate the therapeutic effects of Salvia miltiorrhiza Bunge on a rotenone-induced PD rat model and elucidate its mechanism of action.
    METHODS: To explore the efficacy of Salvia miltiorrhiza Bunge extract (SME) in PD, we employed both in vitro and in vivo models using rotenone-induced PC12 cells and rats. Therapeutic effects were assessed through cell viability assays, behavioral tests, and immunohistochemistry. Proteomic analysis and molecular docking experiments were conducted to identify the pathways involved in SME's effects. Immunofluorescence and Western blotting were used to validate the role of mitophagy, while transmission electron microscopy (TEM) provided direct evidence of mitophagy induction by SME.
    RESULTS: Salvia miltiorrhiza Bunge significantly improved motor dysfunction and mitigated dopaminergic neuron degeneration in the substantia nigra of rotenone-exposed rats. Proteomic analysis revealed significant activation of the PINK1/Parkin pathway following SME treatment. Furthermore, molecular experiments confirmed that SME induces mitophagy, which protects PC12 cells from rotenone-induced damage.
    CONCLUSION: This study demonstrates the therapeutic efficacy of Salvia miltiorrhiza Bunge in mitigating PD-related pathologies. Through proteomic and molecular analyses, we identified SME's ability to activate the PINK1/Parkin pathway and promote mitophagy, offering new insights into its mechanism of action in PD.
    Keywords:  Mitochondrion; Mitophagy; Parkinson's disease; Proteomics; Salvia miltiorrhiza Bunge
    DOI:  https://doi.org/10.1016/j.jep.2025.120079
  24. J Dairy Sci. 2025 May 30. pii: S0022-0302(25)00399-6. [Epub ahead of print]
    Whey protein hydrolysate alleviated acetaminophen-induced hepatocyte pyroptosis by activating mitophagy.
    Shengzhuo Zhang, Jiakang Guo, Meitong Liu, Yuelin Chen, Xue Shen, Jianfeng Wang, Xuming Deng, Shuang Guan.
      Whey protein is widely recognized as a high-quality protein source, primarily derived from dairy products. This type of protein is valued not only for its remarkable nutritional benefits but also for its substantial antioxidant properties and its capacity to reduce inflammation. Previous studies have demonstrated that whey protein hydrolysate (WPH) is effective in both the prevention and treatment of liver injury caused by acetaminophen (APAP) overdose. Pyroptosis is a form of programmed cell death that significantly contributes to liver damage induced by APAP, and it is associated with increased levels of oxidative stress and inflammation. However, the specific mechanisms by which WPH influences pyroptosis remain not fully understood. The present study observed a significant alleviation of APAP-induced hepatocyte injury by WPH, alongside a reduction in the release of pro-inflammatory factors, specifically interleukin-1β (IL-1β) and interleukin-18 (IL-18). Moreover, the expression levels of pyroptosis-related proteins, including NOD-like receptor family pyrin domain containing 3 (NLRP3), the N-terminal domain of gasdermin D (GSDMD-N), and cleaved caspase-1, were significantly reduced following treatment with WPH. In the subsequent phase of our research, we examined the levels of reactive oxygen species (ROS) and the expression of cathepsin B (CTSB) in hepatocytes. Increased levels of ROS resulted in heightened permeability of lysosomal membranes, which led to the release of CTSB into the cytosol. The liberated CTSB subsequently activated the NLRP3 inflammasome, thereby promoting pyroptosis. Our results revealed that WPH reduced the accumulation of ROS in hepatocytes and inhibited the release of CTSB. In subsequent mechanistic studies, we found that WPH upregulated the expression of Parkin, PTEN-induced putative kinase 1 (PINK1), and microtubule-associated protein 1 light chain 3 β (LC3), while downregulating the expression of P62 to activate mitophagy. We further validated these results by introducing the mitophagy inhibitor Cyclosporin A (CsA). In conclusion, our findings suggest that WPH may enhance the removal of damaged mitochondria through the activation of the mitophagy mechanism. This process may lead to a reduction in intracellular ROS accumulation and mitigate APAP-induced activation of the NLRP3 inflammasome and pyroptosis.
    Keywords:  acetaminophen; mitophagy; pyroptosis; whey protein hydrolysate
    DOI:  https://doi.org/10.3168/jds.2025-26625
  25. Toxicol Appl Pharmacol. 2025 May 29. pii: S0041-008X(25)00197-8. [Epub ahead of print]502 117421
    Resveratrol inhibits autophagy in cardiomyocytes subjected anoxia/reoxygenation injury: involved in VDAC1/PINK1/Parkin pathway.
    Ying Zhou, Yongzhe Huang, Haiyan Liang, Xiaomei Yang, Shulin Zhang, Yinru Huang, Yanping Wan, Hangfei Zhou, An Huang, Yue Chen, Xiao Li, Yian Peng, Zhangping Liao.
      Resveratrol has confirmed effectiveness in alleviating myocardial ischemia/reperfusion(I/R) injury. However, the underlying mechanisms remain unclear. Mitochondrial dysfunction in injured cardiomyocytes activates autophagy, and excessive autophagy during reperfusion implicates aggravated injury. Considering that resveratrol preserves mitochondrial function by down-regulating VDAC1 expression, we speculated that the cardioprotective effect of resveratrol is achieved by mitochondrial regulation, and we wonder whether it is accomplished by ultimately modulating autophagy. Therefore, this study investigated the mechanism of resveratrol against myocardial I/R injury regarding autophagy regulation and explored the signal pathway. Herein, we established an anoxia/reoxygenation(A/R) model to simulate myocardial I/R injury in vitro. The expressions of VDAC1, Beclin1, LC3-II/I, Parkin, and PINK1 were detected by Western blot; the LDH activity and mPTP opening were measured by spectrophotometry; the ROS levels and mitochondrial membrane potential (ΔΨm) were examined by flow cytometry; the sublocalisation of Parkin and the autophagic vacuoles (AVs) were observed by laser confocal microscopy. Results suggested that resveratrol attenuated A/R injury by inhibiting autophagy, manifested as lower LDH activity, higher cell viability with decreased LC3-II/LC3-I ratio, down-regulated Beclin1 expression, and reduced number of AVs. In addition, stabilised mitochondrial membrane potential, inhibited ROS production and mPTP opening indicated maintained mitochondrial homeostasis. Compared with the A/R group, resveratrol pretreatment down-regulated the PINK1, Parkin, and VDAC1 expressions, accompanied by decreased colocalization of mitochondria with Parkin, suggesting the involved PINK1/Parkin signal pathway. Transfection with pFLAG-VDAC1 reversed resveratrol-induced mitophagy inhibition and cardioprotection. In conclusion, resveratrol protects cardiomyocytes by inhibiting excessive autophagy induced by the VDAC1/PINK1/Parkin pathway during A/R injury.
    Keywords:  Anoxia/reoxygenation; Autophagy; Cardiomyocytes; Resveratrol; Voltage-dependant anion channel 1
    DOI:  https://doi.org/10.1016/j.taap.2025.117421
  26. Zhongguo Zhong Yao Za Zhi. 2025 May;50(9): 2484-2494
    [Study on mechanism of naringin in alleviating cerebral ischemia/reperfusion injury based on DRP1/LRRK2/MCU axis].
    Kai-Mei Tan, Hong-Yu Zeng, Feng Qiu, Yun Xiang, Zi-Yang Zhou, Da-Hua Wu, Chang Lei, Hong-Qing Zhao, Yu-Hong Wang, Xiu-Li Zhang.
      This study aims to investigate the molecular mechanism by which naringin alleviates cerebral ischemia/reperfusion(CI/R) injury through DRP1/LRRK2/MCU signaling axis. A total of 60 SD rats were randomly divided into the sham group, the model group, the sodium Danshensu group, and low-, medium-, and high-dose(50, 100, and 200 mg·kg~(-1)) naringin groups, with 10 rats in each group. Except for the sham group, a transient middle cerebral artery occlusion/reperfusion(tMCAO/R) model was established in SD rats using the suture method. Longa 5-point scale was used to assess neurological deficits. 2,3,5-Triphenyl tetrazolium chloride(TTC) staining was used to detect the volume percentage of cerebral infarction in rats. Hematoxylin-eosin(HE) staining and Nissl staining were employed to assess neuronal structural alterations and the number of Nissl bodies in cortex, respectively. Western blot was used to determine the protein expression levels of B-cell lymphoma-2 gene(Bcl-2), Bcl-2-associated X protein(Bax), cleaved cysteine-aspartate protease-3(cleaved caspase-3), mitochondrial calcium uniporter(MCU), microtubule-associated protein 1 light chain 3(LC3), and P62. Mitochondrial structure and autophagy in cortical neurons were observed by transmission electron microscopy. Immunofluorescence assay was used to quantify the fluorescence intensities of MCU and mitochondrial calcium ion, as well as the co-localization of dynamin-related protein 1(DRP1) with leucine-rich repeat kinase 2(LRRK2) and translocase of outer mitochondrial membrane 20(TOMM20) with LC3 in cortical mitochondria. The results showed that compared with the model group, naringin significantly decreased the volume percentage of cerebral infarction and neurological deficit score in tMCAO/R rats, alleviated the structural damage and Nissl body loss of cortical neurons in tMCAO/R rats, inhibited autophagosomes in cortical neurons, and increased the average diameter of cortical mitochondria. The Western blot results showed that compared to the sham group, the model group exhibited increased levels of cleaved caspase-3, Bax, MCU, and the LC3Ⅱ/LC3Ⅰ ratio in the cortex and reduced protein levels of Bcl-2 and P62. However, naringin down-regulated the protein expression of cleaved caspase-3, Bax, MCU and the ratio of LC3Ⅱ/LC3Ⅰ ratio and up-regulated the expression of Bcl-2 and P62 proteins in cortical area. In addition, immunofluorescence analysis showed that compared with the model group, naringin and positive drug treatments significantly decreased the fluorescence intensities of MCU and mitochondrial calcium ion. Meanwhile, the co-localization of DRP1 with LRRK2 and TOMM20 with LC3 in cortical mitochondria was also decreased significantly after the intervention. These findings suggest that naringin can alleviate cortical neuronal damage in tMCAO/R rats by inhibiting DRP1/LRRK2/MCU-mediated mitochondrial fragmentation and the resultant excessive mitophagy.
    Keywords:  DRP1/LRRK2/MCU signaling axis; cerebral ischemia/reperfusion; cortex; mitochondrial fragmentation; mitophagy; naringin
    DOI:  https://doi.org/10.19540/j.cnki.cjcmm.20250213.701
  27. Sci Rep. 2025 Jun 04. 15(1): 19699
    The effect of prolonged G-quadruplex stabilization on the functions of human cells.
    Nargis Karatayeva, Lili Hegedus, Arindam Bhattacharjee, Eszter Nemeth, Adam Poti, Lorinc Pongor, Gabor Juhasz, David Szuts, Peter Burkovics.
      Guanine-rich DNA sequences have a propensity to form G-quadruplex structures. These structures play several important biological roles and are potential targets for anticancer drugs. However, no G-quadruplex-stabilizing agent has yet been approved for clinical use. Given that G-quadruplex stabilization is quite promising as a mechanism for novel anticancer therapies, it is crucial to elucidate its effects on healthy human cells. In our study, we modeled a potential human treatment using G4 -stabilizing agents and analyzed their effects on genome integrity, transcriptomic changes, and mitochondrial function focusing on non-cancerous cells to predict potential side effects of such treatments. We found that G-quadruplex stabilization does not compromise genome integrity. However, it can induce persistent alterations in the transcriptomic profile of human cells, including genes encoded on the mitochondrial genome. Notably, certain G-quadruplex-stabilizing agents triggered mitophagy in both human cells and Drosophila melanogaster. In summary, our findings indicate that while G-quadruplex stabilization does not cause genome instability, it may pose potential risks due to its long-term effects on transcription and its ability to induce mitophagy. Therefore, we recommend that all potential drug candidates be thoroughly evaluated for their ability to induce mitophagy and to promote cancer formation in animal models prior to clinical trials.
    Keywords:  G-quadruplex; Genome stability; Mitophagy; PhenDC3
    DOI:  https://doi.org/10.1038/s41598-025-04791-x
  28. Life Sci Alliance. 2025 Aug;pii: e202403189. [Epub ahead of print]8(8):
    Cross-comparison of strains used for mitochondrial imaging in Caenorhabditis elegans during aging.
    Juri Kim, Naibedya Dutta, Matthew Vega, Andrew Bong, Maxim Averbukh, Rebecca Aviles Barahona, Athena Alcala, Jacob T Holmes, Gilberto Garcia, Ryo Higuchi-Sanabria.
      Measurements of mitochondrial morphology are a powerful proxy for assessing mitochondrial health, particularly during aging when organelle dynamics are disrupted. Caenorhabditis elegans provides an ideal system for in vivo mitochondrial imaging, but widely used high-copy transgenic strains can induce artifacts that confound interpretation because of their impact on cellular and organismal health and physiology. Here, we present and validate a suite of C. elegans strains expressing single-copy, matrix-localized GFP in the muscle, intestine, and hypodermis using the MosSCI technology. These strains enable robust, tissue-specific visualization of mitochondrial morphology without the caveats associated with multi-copy reporters. We benchmark their performance against existing models and demonstrate that our mitochondrial reporters are similarly capable of assessing age-associated mitochondrial morphology, while avoiding defects in cellular and physiological health associated with the multi-copy reporters. Furthermore, we assess how aging methods, bacterial diets, and inhibition of fusion and fission machinery impact mitochondrial morphology during aging. Our findings provide a standardized and physiologically relevant platform for studying mitochondrial dynamics during aging in C. elegans.
    DOI:  https://doi.org/10.26508/lsa.202403189
  29. Probiotics Antimicrob Proteins. 2025 Jun 06.
    Lactobacillus johnsonii JJB3 Ameliorates Oxidative Stress-Induced Intestinal Injury and Mitochondrial Damage by Promoting BNIP3L-Mediated Mitophagy.
    Xingmei Liu, Jinge Xin, Ning Sun, Yuhua Qin, Haonan Huang, Benhao Chen, Lixiao Duan, Yanxi Zhou, Dandan Wang, Bo Jing, Yan Zeng, Dong Zeng, Kangcheng Pan, Limin Wei, Yu Lin, Xueqin Ni.
      The intestine is particularly susceptible to oxidative damage given its extensive exposure to environmental toxins, dietary components, and microbial metabolites, which leads to various gastrointestinal and systemic diseases. There is an urgent need for effective and safe therapies to maintain intestinal redox balance. This study aimed to explore whether the pig-native strain Lactobacillus johnsonii JJB3, known for its potential in mitigating oxidative stress, can prevent intestinal oxidative stress and elucidate its underlying mechanisms. Our study found that L. johnsonii JJB3 supernatant (sJJB3) effectively ameliorated hydrogen peroxide (H2O2)-induced oxidative stress in intestinal porcine epithelial cell line-J2 (IPEC-J2), manifested by reduced levels of reactive oxygen species (ROS) and increased levels of catalase and glutathione. RNA sequencing revealed that the mitophagy pathway plays a crucial role in this protective effect. Specifically, sJJB3 treatment further enhanced H2O2-induced upregulation of BNIP3L and LC3B at both mRNA and protein levels, promoting mitophagy. These findings were validated in a mouse model of diquat (DQ)-induced intestinal oxidative stress. sJJB3 supplementation reversed DQ-induced oxidative damage, especially in the jejunum, and increased BNIP3L and LC3B expression. Transmission electron microscopy further confirmed that sJJB3 preserved mitochondrial ultrastructure and supported effective mitophagy. Additionally, 16S rRNA sequencing showed that sJJB3 improved gut microbiota composition. These results provide a new theoretical foundation for the application of sJJB3 in mitigating oxidative stress-related intestinal injury.
    Keywords:  Intestinal injury; Intestinal microbiota; Mitophagy; Oxidative stress; Probiotics
    DOI:  https://doi.org/10.1007/s12602-025-10600-8
  30. Int Immunopharmacol. 2025 May 30. pii: S1567-5769(25)00950-6. [Epub ahead of print]160 114960
    Melatonin modulates mitochondrial function and inhibits atherosclerosis progression through NRF2 activation and OPA1 inhibition.
    Chengbo Lu, Quan Lin, Xiaoli Guo, Tan Luo, Han Zhou, Ziteng Cai, Chaonan Peng, Guangyuan Yang, Weiqun Wang.
       BACKGROUND: Atherosclerosis (AS), a major cardiovascular disease, is characterized by chronic inflammation and oxidative stress. Melatonin (MLT) has emerged as a potential therapeutic agent due to its anti-inflammatory and antioxidant properties, although the specific mechanisms underlying its action, especially as far as mitochondrial function in AS is concerned, have yet to be fully elucidated.
    METHODS: In this study, ApoE-/- mice were fed a high-fat diet with or without MLT treatment. Aortic tissues were analyzed using hematoxylin and eosin, Masson staining, qPCR, and immunofluorescence. Oxidized low-density lipoprotein-treated RAW264.7 macrophages were assessed for AS progression, mitochondrial function, and oxidative stress using electron microscopy, Seahorse analysis, and molecular docking.
    RESULTS: MLT treatment significantly reduced atherosclerotic plaque formation, systemic and mitochondrial oxidative stress, and inflammation. MLT treatment was found to enhance mitochondrial function through upregulating the expression of key regulators of mitochondrial biogenesis and the activity of mitochondrial respiratory chain complexes, whereas markers of mitochondrial fusion [for example, optic atrophy protein 1 (OPA1)] were downregulated. Mechanistically, MLT was shown to directly interact with nuclear factor erythroid 2-related factor 2 (NRF2), thereby activating its antioxidant pathway, which in turn regulated mitochondrial function. Additionally, OPA1 was identified as a downstream target of MLT, and its inhibition improved mitochondrial function and reduced inflammation.
    CONCLUSION: This study is the first to elucidate that MLT synergistically ameliorates mitochondrial dysfunction through dual mechanisms-activating the NRF2 antioxidant pathway and suppressing OPA1-mediated mitochondrial fusion-providing novel therapeutic targets for AS.
    Keywords:  Atherosclerosis; Melatonin; Mitochondrial dynamics; NRF2; OPA1
    DOI:  https://doi.org/10.1016/j.intimp.2025.114960
  31. Int Immunopharmacol. 2025 Jun 04. pii: S1567-5769(25)00982-8. [Epub ahead of print]161 114992
    17β-estradiol ameliorates LPS-induced acute lung injury via mediating mitochondrial biogenesis and function in rats.
    Shaocheng Wang, Hao Yang, Zhongwei Yang, Zhankui Wang, Zhenzhen Li.
      Sepsis-induced acute lung injury (ALI), and its severe manifestation, acute respiratory distress syndrome (ARDS), are complex conditions associated with high global mortality. 17β-estradiol (E2), a sex hormone, is implicated in ARDS pathophysiology, but its mechanisms remain unclear. In this study, we explored the role of E2 in sepsis-induced ALI using ovariectomized female Sprague-Dawley rats and A549 cells. Endogenous E2 levels were assessed via the uterus-to-body weight ratio and serum E2 concentrations. Our findings demonstrate that E2 deficiency exacerbates LPS-induced mitochondrial damage, apoptosis, and lung injury, while exogenous E2 reverses these effects. Mechanistically, E2 promotes mitochondrial biogenesis through activation of the PGC-1β/Nrf2/TFAM signaling pathway. These results suggest that exogenous E2 may offer a promising therapeutic approach for ARDS by enhancing mitochondrial function and reducing apoptosis.
    Keywords:  Acute lung injury; Estrogen; Mitochondrial biogenesis
    DOI:  https://doi.org/10.1016/j.intimp.2025.114992
  32. Neurotoxicol Teratol. 2025 May 31. pii: S0892-0362(25)00077-7. [Epub ahead of print]110 107500
    TREM2 inhibits LPS-induced pyroptosis and inflammation by promoting mitophagy via SYK in BV2 cells.
    Wenwen Jiang, Xixin Fan, Hui Wu, Jiankang Song, Chunhe Yang, Zhanzhi Zhao.
      Neuroinflammation is a critical factor in the pathogenesis of postoperative cognitive dysfunction (POCD). Maintaining microglial homeostasis is vital for regulating neuroinflammation, as microglial cell death can trigger an inflammatory response within the central nervous system. The triggering receptor expressed on myeloid cells 2 (TREM2) plays an essential role in supporting cell survival and modulating microglial-driven neuroinflammation. Our previous study indicated that TREM2 overexpression exerts protective effects against neuroinflammation and cognitive deficits in aged mice. However, the precise mechanisms by which TREM2 functions in microglia remain unclear. Consequently, this study aimed to examine the role of TREM2 in lipopolysaccharide (LPS)-induced cell death and neuroinflammation in BV2 cells. This research showed that TREM2 reduces LPS-induced nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3)-mediated pyroptosis and the subsequent release of inflammatory factors through western blot analysis, flow cytometry, and enzyme-linked immunosorbent assay. Recent research has suggested that the loss of spleen tyrosine kinase (SYK), a downstream receptor kinase of TREM2 in microglia, results in exacerbated neuroinflammatory disease. This study further demonstrated that SYK activation via TREM2 treatment exerts neuroprotective effects by mitigating LPS-induced mitochondrial membrane potential damage, facilitating mitophagy, and inhibiting NLRP3-mediated pyroptosis in BV2 cells. Conversely, SYK inhibition by R406 led to microglial cell death and aggravated neuroinflammation, thereby reducing the neuroprotective effects of TREM2. Our findings indicate that TREM2 and SYK mitigate the inflammatory response in LPS-induced BV2 microglia and interfere with pyroptosis by enhancing mitophagy. These findings suggest that TREM2 and SYK may be valuable therapeutic targets for neuroinflammation.
    Keywords:  Inflammation; Mitophagy; Postoperative cognitive dysfunction; Pyroptosis; SYK; TREM2
    DOI:  https://doi.org/10.1016/j.ntt.2025.107500
  33. Expert Opin Drug Metab Toxicol. 2025 Jun 06. 1-3
    Practical perspectives on addressing hepatotoxicity during clinical candidate selection.
    Adrian S Ray.
      
    Keywords:  bile salt efflux pump (BSEP); drug-induced liver injury (DILI); hepatotoxicity; mitochondrial biogenesis; oxidative stress
    DOI:  https://doi.org/10.1080/17425255.2025.2516048
  34. Front Aging Neurosci. 2025 ;17 1621994
    Corrigendum: Parkin characteristics and blood biomarkers of Parkinson's disease in WPBLC study.
    Haijun He, Xi Xiong, Yi Zheng, Jialong Hou, Tao Jiang, Weiwei Quan, Jiani Huang, Jiaxue Xu, Keke Chen, Jingjing Qian, Jinlai Cai, Yao Lu, Mengjia Lian, Chenglong Xie, Ji Luo.
      [This corrects the article DOI: 10.3389/fnagi.2025.1511272.].
    Keywords:  Parkin; Parkinson's diseaseas; bioinformatics; blood biomarkers; mitophagy
    DOI:  https://doi.org/10.3389/fnagi.2025.1621994
  35. J Ginseng Res. 2025 May;49(3): 260-270
    Ginsenoside Rg5 alleviates radiation-induced acute lung vascular endothelium injury by reducing mitochondrial apoptosis via Sirt1.
    Churong Li, Biao Zhao, Jing Xiong, Linjie Li, Dalong Pang, Keith Unger, Mira Jung, Jiahua Lyu, Hao Kuang, Long Liang, Tao Li, Long Chen, Hansong Bai.
       Background: Ginsenoside Rg5 possesses potent anti-oxidative, anti-inflammatory, and cytoprotective properties. This study explored the protective effects of ginsenoside Rg5 on radiation-induced pulmonary microvascular endothelial cells (PMECs) injury and the associated molecular mechanisms.
    Materials and methods: C57BL/6 mice were used for in vivo studies and primary human PMECs (PPMECs) were utilized as in vitro models. Mice with or without ginsenoside Rg5 pretreatment were irradiated by varying doses. Lung tissues were analyzed for histopathological changes and the expression of endothelial markers. In vitro, PPMECs were irradiated with or without ginsenoside Rg5 pretreatment and analyzed for apoptosis, oxidative stress, mitochondrial function, and endothelial barrier integrity.
    Results: Ginsenoside Rg5 pretreatment attenuated radiation-induced acute lung damage, preserved endothelial cell junction integrity, and maintained endothelial barrier function in vivo. In vitro, ginsenoside Rg5 significantly reduced IR-induced oxidative stress, apoptosis, and mitochondrial dysfunction in PPMECs. Ginsenoside Rg5 suppressed radiation-induced Mfn2 acetylation and proteasomal degradation via Sirt1-mediated deacetylation, thereby preserving mitochondrial dynamics and integrity. The protective effects of ginsenoside Rg5 on the integrity of mitochondrial and endothelial tight junction proteins and barrier function were also Sirt1-dependent.
    Conclusions: Ginsenoside Rg5 exerts a protective effect against radiation-induced endothelial injury by modulating mitochondrial dynamics and function, as well as maintaining endothelial barrier integrity, in a Sirt1-dependent manner.
    Keywords:  Endothelial cell injury; Ginsenoside Rg5; Mitochondrial dynamics; Radiation; Sirt1
    DOI:  https://doi.org/10.1016/j.jgr.2025.01.004
  36. Mol Neurobiol. 2025 Jun 06.
    Ginsenoside Rg1 Downregulates miR-9-5p Expression to Modulate SIRT1-Mediated Mitochondrial Dysfunction and Ameliorate Alzheimer's Disease.
    Yunliang Wang, Xiangyun Sun, Biao He, Shaowen Yu.
      This study aimed to investigate the mechanism of ginsenoside Rg1 in Alzheimer's disease (AD) via miR-9-5p/SIRT1-mediated mitochondrial function. The cognitive function of AD mice was assessed by Morris water maze experiment. The histopathological changes in the CA1 region were observed by H&E staining. TUNEL staining combined with the neuronal marker NeuN was used to detect neuronal apoptosis in hippocampal tissues. Aβ1-42 induced HT-22 cells were used as AD in vitro models. MiR-9-5p expression was detected by qRT-PCR, and SIRT1 protein and autophagy-related proteins (LC3B II/I, Beclin-1) levels were measured by western blot. The binding of miR-9-5p with SIRT1 was predicted and validated. Ginsenoside Rg1 treatment in AD mice reduced miR-9-5p expression, increased SIRT1 level, attenuated mitochondrial dysfunction, and effectively improved AD symptoms in mice, while such effect can be either reversed by miR-9-5p agomir or SIRT1 inhibitor (EX527). In vitro, Aβ1-42-induced HT-22 cell activity was reduced, cell death was significantly increased, and mitochondrial dysfunction was progressed, but treatment of HT-22 cells with Aβ1-42 and ginsenoside Rg1 attenuated mitochondrial dysfunction and improved Aβ1-42-induced HT-22 cell damage. Ginsenoside Rg1 ameliorated Aβ1-42-induced HT-22 cell damage by down-regulating miR-9-5p to regulate SIRT1-mediated mitochondrial dysfunction. miR-9-5p negatively regulates SIRT1. Inhibition of mitochondrial autophagy partially reversed the ameliorative effect of ginsenoside Rg1 on mitochondrial dysfunction and cellular damage in HT-22 cells. Ginsenoside Rg1 down-regulates miR-9-5p expression to modulate SIRT1-mediated mitochondrial dysfunction, hereby attenuating Aβ1-42 induced cell injury in HT-22 cells and alleviating AD in mice.
    Keywords:  Alzheimer disease; Ginsenoside Rg1; MiR-9-5p; Mitochondrial autophagy; Mitochondrial dysfunction; SIRT1
    DOI:  https://doi.org/10.1007/s12035-025-05073-3
  37. Front Pharmacol. 2025 ;16 1579333
    The essential oil from the rhizomes of Stahlianthus involucratus attenuates the progression of vascular aging and atherosclerosis by regulating Nrf2-mediated mitochondrial quality.
    Jianmei Li, Zaishang Wang, Yu Wang, Jiaxin Lin, Ning Tang, Chu Zheng, Qin Xu.
       Introduction: Atherosclerosis (AS), characterized by chronic inflammation within the vasculature, is linked to endothelial dysfunction and oxidative stress. The senescence of vascular endothelial cells (VECs) serves as a pathological basis for AS. Stahlianthus involucratus (King ex Baker) Craib ex Loes is a folk medicinal plant commonly used in Guangxi has its rhizome as the active component. In traditional Chinese medicine, it is believed to promote blood circulation, remove blood stasis, stop bleeding, and disperse accumulated blood. Essential oil extracted from Stahlianthus involucratus rhizomes (EOSIR) is a key bioactive component. However, little research has been reported on the effects of EOSIR on cardiovascular disease.
    Methods: Validation techniques, including H&E staining and western blotting, were employed to assess the efficacy of EOSIR in both in vivo and in vitro models of AS.
    Results: In vivo experiments, EOSIR decreased plaque volume in atherosclerotic vessels of mice. Activation of the Nrf2 signaling pathway by EOSIR alleviated ox-LDL-induced injury in HUVECs, including a reduction in cellular senescence, apoptosis, ROS, and mitochondrial membrane potential, effects that were reversed by Nrf2 silencing. EOSIR also restored mitochondrial morphology in cells and enhanced Nrf2 expression as well as ATP levels in aortic tissue. Both in vivo and in vitro, EOSIR upregulated the Nrf2, NQO1, and HO-1 expression, downregulated Keap1 expression, and improved the mitochondrial-associated protein expression.
    Discussion: These findings suggest that EOSIR may prevent the onset of AS both in vivo and in vitro by modulating the mitochondrial quality control system through the Nrf2 signaling pathway.
    Keywords:  Nrf2 signaling pathway; atherosclerosis; cardiovascular diseases; mitochondria; oxidative stress
    DOI:  https://doi.org/10.3389/fphar.2025.1579333
  38. Stem Cell Res Ther. 2025 Jun 03. 16(1): 285
    MiR221/222 in the conditioned medium of adipose-derived stem cells attenuates particulate matter and high-fat diet-induced cardiac apoptosis.
    Ya-Chun Chen, Chi-Ming Pu, Shu-Rung Lin, Shu-Wha Lin, I-Shing Yu, Ho-Jun Shih, Chiang-Wen Lee, Ming-Hsueh Lee, Yen-Ting Kuo, Yuh-Lien Chen.
       BACKGROUND: Air pollution and obesity are crucial risk factors for cardiovascular disease (CVD), with epidemiological evidence indicating that air pollution exacerbates obesity-induced cardiac damage. Treatment with adipose-derived stem cells (ADSCs) attenuates cardiac damage by releasing paracrine factors. However, the effects of ADSCs on air pollution- and obesity-induced cardiomyocyte apoptosis and the related mechanisms are still unclear.
    METHODS: Palmitic acid (PA) and a high-fat diet (HFD) were used to cause obesity, and particulate matter (PM) was used to simulate air pollution in the study. We studied the impact of conditioned medium from adipose-derived stem cells (ADSC-CM) on the apoptosis of PA + PM-treated H9c2 cells and HFD + PM-treated mouse cardiomyocytes and the underlying mechanisms involved.
    RESULTS: The levels of apoptosis-related proteins (PUMA and cleaved caspase-3) were significantly increased in PA + PM-treated H9c2 cells and HFD + PM-treated mouse cardiomyocytes, whereas the antiapoptotic protein Bcl-2 expression was reduced. However, ADSC-CM treatment effectively reduced the PUMA and cleaved caspase-3 expression but increased the Bcl-2 expression. ADSC-CM significantly reduced PA + PM- and HFD + PM-induced cardiomyocyte apoptosis, as detected by the TUNEL assay. RT-qPCR revealed that PA + PM and HFD + PM significantly reduced miR221/222 levels, whereas ADSC-CM treatment increased miR221/222 levels. Furthermore, knockout (KO) and transgenic (TG) mice were used to demonstrate that miR221/222 in ADSC-CM ameliorated cardiac apoptosis that was induced by HFD + PM treatment. Furthermore, PA + PM treatment increased the reactive oxygen species (ROS) production, which triggered mitochondrial fission and contributed to apoptosis. However, ADSC-CM effectively reduced ROS levels and regulated mitochondrial fission, alleviating cellular apoptosis.
    CONCLUSIONS: Our findings demonstrated that ADSC-CM attenuated PA + PM-induced cardiomyocyte apoptosis by modulating miR221/222 levels and suppressing ROS production.
    Keywords:   miR221/222 ; Conditioned medium from cultured adipose-derived stem cell (ADSC-CM); High-fat diet (HFD); Mitochondrial fission; Palmitic acid (PA); Particulate matter (PM); Reactive oxygen species (ROS)
    DOI:  https://doi.org/10.1186/s13287-025-04381-8
  39. Biomol Concepts. 2025 Jan 01. 16(1):
    The impact of exercise on mitochondrial biogenesis in skeletal muscle: A systematic review and meta-analysis of randomized trials.
    Diana Marisol Abrego-Guandique, Nalia Mercedes Aguilera Rojas, Aldo Chiari, Filippo Luciani, Erika Cione, Roberto Cannataro.
      The interaction between exercise and mitochondrial biogenesis in skeletal muscle is fundamental to human physiology, with important implications for health and athletic performance. While exercise is known to stimulate mitochondrial biogenesis, the effectiveness of varying-intensity exercise remains unclear. This systematic review and meta-analysis aimed to evaluate the impact of physical activity on mitochondrial biogenesis pathways in skeletal muscle and identify key biomolecular markers in healthy individuals. Among these, PGC-1α emerged as the most consistently reported marker. The meta-analysis showed a significant increase in PGC-1α expression following endurance exercise, with a pooled effect size of Hedge's g = 1.17 (95% confidence interval: 0.14-2.19, I 2 = 84.5%), indicating a large effect with substantial heterogeneity. Subgroup analyses revealed that both interval and continuous endurance training produced large effects (Hedge's g = 1.29 and 1.01, respectively), with no significant difference between modalities (p > 0.05). These findings confirm that exercise induces significant molecular and structural mitochondrial adaptations, with responses influenced by exercise type, intensity, and duration. This underscores exercise as a potent stimulus for mitochondrial biogenesis, supporting its role in promoting metabolic health and physical performance.
    Keywords:  PGC1 alpha; endurance; mitochondrial biogenesis; skeletal muscle; strength training
    DOI:  https://doi.org/10.1515/bmc-2025-0055
  40. J Virol. 2025 Jun 04. e0058125
    Interferon-stimulated gene MCL1 inhibits foot-and-mouth disease virus replication by modulating mitochondrial dynamics and autophagy.
    Aishwarya Mogulothu, Danielle Hickman, Sarah Attreed, Paul Azzinaro, Monica Rodriguez-Calzada, Meike Dittmann, Teresa de Los Santos, Steven Szczepanek, Gisselle N Medina.
      Interferons (IFNs) and the IFN-stimulated genes (ISGs) that they induce are effective in reducing the replication of foot and mouth disease virus (FMDV). The use of a high-throughput ISG screen identified the ISG myeloid cell leukemia 1 (MCL1) as an ISG with an antiviral effect against an FMDV replicon system. In this study, we demonstrated that overexpression of MCL1 inhibits FMDV replication by reducing approximately 4 logs of virus titers in porcine cells. We then explored the regulatory pathways associated with MCL1 to determine the specific antiviral mechanisms against FMDV. Our findings indicated that the antiviral mechanism does not involve apoptosis regulation or alterations in cell cycle phase heterogeneity. Analysis of mitochondrial function, through measurement of mitochondrial oxygen consumption rate, demonstrated that overexpression of MCL1 results in increased mitochondrial respiration and ATP production, whereas FMDV infection reduces both processes. Moreover, MCL1 overexpression resulted in elongated mitochondrial morphology, contrasting with the fragmented and punctate morphology observed during FMDV infection. Importantly, these changes in mitochondrial dynamics were independent of MCL1's regulation of mitochondrial calcium flux. We also found that MCL1 overexpression suppresses autophagy, which is known to be necessary for FMDV replication. Our data indicate that MCL1 is a potent antiviral ISG against FMDV and highlight the importance of mitochondrial dynamics and autophagy in FMDV replication.IMPORTANCEIn this study, we have successfully used a high-throughput ISG screening approach to measure the inhibition of FMDV replication using an RNA replicon system for the first time. This screen led to the identification of the potent antiviral effects of a relatively lesser-known ISG called MCL1. Our findings reveal that MCL1 exerts its antiviral functions through the regulation of mitochondrial dynamics and autophagy. Although mitochondrial dynamics are involved in apoptosis, metabolism, redox homeostasis, stress responses, and antiviral signaling, this pathway has not been thoroughly explored in the context of FMDV infection. Further investigation into mitochondrial dynamics may facilitate the development of improved biotherapeutics for FMDV. Additionally, our studies highlight the significance of autophagy, a pathway that is needed by FMDV for replication. Ultimately, a deep understanding of all mechanisms exploited by FMDV may allow for the rational design of novel therapeutics and vaccines to control FMD.
    Keywords:  antiviral agents; autophagy; foot-and-mouth disease virus; interferon-stimulated genes; interferons; mitochondrial metabolism
    DOI:  https://doi.org/10.1128/jvi.00581-25
  41. Cancer Metab. 2025 Jun 05. 13(1): 27
    A role of arginase-1-expressing myeloid cells in cachexia.
    Lamsal Apsana, Andersen Sonja Benedikte, Nonstad Unni, Kurganovs Natalie Jayne, Skipworth Richard Je, Bjørkøy Geir, Pettersen Kristine.
       BACKGROUND: Despite decades of efforts to find successful treatment approaches, cachexia remains a major unmet medical need. This condition, that affects patients with diverse underlying conditions, is characterized by severe muscle loss and is associated with reduced quality of life and limited survival. Search for underlying mechanisms that may guide cachexia treatment has mainly evolved around potential atrophy-inducing roles of inflammatory mediators, and in cancer patients, tumor-derived factors. Recently, a new paradigm emerged as it is becoming evident that specific immune cells inhabit atrophic muscle tissue. Arginase 1 (Arg1) expression is characteristic of these immune cells. Studies of potential contributions of these immune cells to loss of muscle mass and function is in its infancy, and the contribution of ARG1 to these processes remains elusive.
    METHODS: Analyses of RNA sequencing data from murine cachexia models and comprehensive, unbiased open approach proteomics analyses of skeletal myotubes was performed. In vitro techniques were employed to evaluate mitochondrial function and capacity in skeletal muscle cells and cardiomyocytes. Functional bioassays were used to measure autophagy activity. ARG1 level in patients' plasma was evaluated using ELISA, and the association between ARG1 level and patient survival, across multiple types of cancer, was examined using the online database Kaplan-Meier plotter.
    RESULTS: In line with arginine-degrading activity of ARG1, we found signs of arginine restriction in atrophic muscles. In response to arginine restriction, mitochondrial functions and ATP generation was severely compromised in both skeletal muscle cells and in cardiomyocytes. In skeletal muscle cells, arginine restriction enhanced the expression of autophagic proteins, suggesting autophagic degradation of cellular content. Reduction in mitochondria marker TIMM23 supports selective autophagic degradation of mitochondria (mitophagy). In arginine starved cardiomyocytes, mitochondrial dysfunction is accompanied by both increased bulk autophagy and mitophagy. In cancer patients, we found an association between ARG1 expression and accelerated weight loss and reduced survival, further supporting a role of ARG1-producing cells in cachexia pathogenesis.
    CONCLUSION: Together, our findings point to a mechanism for cachexia which depends on expansion of ARG1-expressing myeloid cells, local restriction of arginine, loss of mitochondrial capacity and induced catabolism in skeletal muscle cells and in the heart.
    Keywords:  ARG1; Arginine; Autophagy; Cachexia; Cancer; Mitochondria; Mitophagy; Muscle; Myeloid-derived suppressor cell; Neutrophil
    DOI:  https://doi.org/10.1186/s40170-025-00396-0
  42. J Inflamm Res. 2025 ;18 6831-6851
    Mitophagy-Related Gene CHDH Predicts Prognosis and Immune Response and Inhibits Proliferation and Migration in vitro and in vivo of Oral Squamous Cell Carcinoma.
    Lingke Chen, Zheng Zhou, Lian Guo, Zhongrun He, Wen Luo, Ying Fu, Qiyu Xiao, Bo Liu, Pengxin Huang.
       Background: Oral squamous cell carcinoma (OSCC) is a common head and neck cancer with high morbidity and mortality. Mitophagy is a special type of cellular autophagy that plays an important role in tumors, but its role in OSCC is still unclear.
    Methods: Mitophagy-related genes (MRGs) were obtained from the GeneCards database. Differential expression analysis was used to identify differentially expressed genes (DEGs) in tumor samples and normal samples. Univariate Cox regression was then performed on the DEGs to determine prognostic MRGs, which were used to compare CNV mutation frequencies and construct consensus cluster analysis. Risk models were constructed to evaluate the prognosis and immune status of OSCC patients. Univariate and multivariate Cox regression analyses were performed to determine MRGs that independently predicted OSCC prognosis. The expression levels of genes and their effects on OSCC proliferation, migration, and invasion were further validated by in vitro and in vivo studies.
    Results: We identified 298 DEGs associated with OSCC survival, and 8 genes were used to create a risk model that can accurately predict the prognosis of OSCC patients, which can accurately assess the immune status of patients with different risks. OSCC patients were clustered into 2 subtypes, and there were significant differences between the two subtypes. Drug sensitivity analysis was used to select 72 sensitive drugs for the low-risk group and 9 sensitive drugs for the high-risk group. Choline dehydrogenase (CHDH) was identified as a reliable and independent predictor of OSCC. CHDH overexpression significantly inhibited OSCC cell proliferation, migration, colony formation, and tumor growth.
    Conclusion: This study's prediction model, created using MRGs, may accurately predict the prognosis and immune response of patients with OSCC. CHDH is essential to the development and progression of OSCC and can be a potential target for treating OSCC.
    Keywords:  Choline dehydrogenase (CHDH); immune response; mitophagy; oral squamous cell carcinoma; prognosis; proliferation
    DOI:  https://doi.org/10.2147/JIR.S516427
  43. Front Immunol. 2025 ;16 1445403
    The protein interaction of mitochondrial transcription factors A and B2 is associated with 30-day survival in critical COVID-19.
    Britta Westhus, Patrick Thon, Lars Palmowski, Katharina Rump, Björn Koos, Frederik Wiebel, Birte Dyck, Martin Eisenacher, Barbara Sitek, Stephanie Pfaender, Nina Babel, Moritz Anft, Christian Putensen, Stefan Felix Ehrentraut, Christina Weisheit, Alexander Zarbock, Thilo von Groote, Andrea Witowski, Matthias Unterberg, Hartmuth Nowak, Alexander Wolf, Lars Bergmann, Michael Adamzik, Dominik Ziehe, Tim Rahmel.
       Introduction: Repair of mitochondrial damage seems pivotal for clinical recovery and determining outcome in patients with critical COVID-19. However, reliable biomarkers for non-invasively assessing mitochondrial repair in peripheral blood of critically ill COVID-19 patients are currently lacking. Accordingly, we sought to assess different surrogates of mitochondrial repair in peripheral blood and correlate these measurements with clinical outcome in patients with critical COVID-19.
    Methods: In this prospective multicentric cohort study, 88 critically ill COVID-19 patients were enrolled across three German intensive care units. Gene products of mitochondrial quality control (MFN2, PINK, TFAM, TFB2M) and the mtDNA copy number were measured in peripheral blood mononuclear cells. Furthermore, the protein interactions between TFAM and TFB2M were quantified. Patients were stratified regarding 30-day mortality.
    Results: Transcript levels of the assessed mRNA markers of mitochondrial quality control were not associated with clinical outcome. In contrast, more than 10.7 protein interactions per cell were associated with a 74% 30-day survival (37 out of 50), while 10.7 or fewer protein interactions per cell were associated with a 32% 30-day survival (12 out of 38; p < 0.001). Furthermore, multivariable Cox regression analysis revealed TFAM-TFB2M protein interaction as an independent predictor for 30-day survival (HR: 3.2; 95% CI: 1.6 to 6.5; p < 0.001).
    Discussion: Our findings indicate that TFAM-TFB2M protein interactions, identified as a novel biomarker, are strongly and independently associated with 30-day survival in critical COVID-19. Therefore, our data suggest a significant impact of mitochondrial repair and quality control on clinical outcome in critical COVID-19.
    Keywords:  COVID-19; TFAM; mitochondrial biogenesis; mitochondrial dysfunction; protein interaction; proximity ligation assay
    DOI:  https://doi.org/10.3389/fimmu.2025.1445403
  44. J Adv Res. 2025 Jun 01. pii: S2090-1232(25)00376-5. [Epub ahead of print]
    Cadmium targeting MLKL-Drp1 axis to trigger mitochondrial oxidative stress contributes to necroinflammation in rat kidney.
    Cai-Yu Lian, Wei-Hao Xia, Ming-Cheng Sun, Xue-Mei Wan, Xue-Lei Zhou, Lin Wang.
       INTRODUCTION: Acute kidney injury (AKI) induced by cadmium (Cd) manifests excessive inflammation with no effective therapy. Necroptosis, a novel manner of necrosis that regulates cell death, has been revealed important functions in the inflammation i.e., necro-inflammation.
    OBJECTIVES: Targeting necroptosis may be a potential therapeutic strategy for Cd-induced AKI, but the role of necroptosis in Cd-evoked nephrotoxicity is poorly understood. Thus, in vivo and in vitro studies were performed to clarify this issue.
    METHODS AND RESULTS: Data from RNA-sequencing analysis and its validation showed that necroptosis and NOD-Like Receptor Protein 3 (NLRP3) inflammasome activation were involved in Cd-induced AKI. Further investigations revealed that mixed lineage kinase domain-like protein (MLKL)-dependent necroptosis drove Cd-induced inflammatory cascades in renal tubular epithelial cells, triggering necroinflammation. Significant mitochondrial dysfunction and mitochondrial ROS (mtROS) overproduction due to MLKL activation were observed in this process. Notably, Cd-induced necroinflammation could be attenuated by mitochondria-targeted antioxidant, suggesting the key role of MLKL-dependent mtROS overproduction. Cd exposure triggered MLKL mitochondrial translocation-dependent dynamin-related protein 1 (Drp1) recruitment, driving excessive mitochondrial fragmentation and mtROS overproduction. And the effects were significantly ameliorated by the Drp1 inhibitor. In addition, mitochondrial calcium efflux due to activated MLKL-Drp1 axis impaired mtROS scavenging, further aggravating Cd-induced mtROS accumulation.
    CONCLUSION: These findings reveal that MLKL-Drp1 interaction is involved in Cd-induced necroinflammation via a novel mechanism to disrupt mitochondrial homeostasis, highlighting the therapeutic potential of targeting MLKL-Drp1 axis in Cd-induced nephrotoxicity.
    Keywords:  Cadmium; Inflammation; Mitochondria; Necroptosis; Oxidative stress
    DOI:  https://doi.org/10.1016/j.jare.2025.05.055
  45. Eur J Pharmacol. 2025 May 30. pii: S0014-2999(25)00538-2. [Epub ahead of print]1002 177784
    Ertugliflozin induces vasodilation by inhibiting AMPK-mediated mitochondrial fission in vascular smooth muscle cells.
    Jie Yan, Xiaowen Zhang, Lifeng Feng, Shengzheng Zhang, Han Wei, Wencong Tian, Qiwen Li, Jing Li, Liang Yang, Jie Liu, Yang Xu, Jianlin Cui, Shan Ren, Zhi Qi, Yang Gao.
      Hypertension is a primary risk factor for cardiovascular disease. Recently, Ertugliflozin (Ertu), a new sodium-glucose cotransporter-2 (SGLT2) inhibitor, though primarily approved by the FDA as an antidiabetic agent, has been reported to lower blood pressure. However, whether Ertu directly regulates the contractility of arteries remains unknown. Here, we examined Ertu's effects on vascular function and underlying molecular mechanisms. Isometric tension of arteries was recorded using a multi-wire myograph system. In rat mesenteric arteries, Ertu acutely relaxed vessels constricted by phenylephrine (PE) and high K+ (KPSS), while pretreatment with Ertu inhibited PE- and KPSS- induced vascular constriction. Similar outcomes were observed in the mouse thoracic aorta. Notably, these vasodilatory effects of Ertu are mediated by vascular smooth muscle cells (VSMCs) rather than endothelial cells. Mechanistically, we found that Ertu activated AMP-activated protein kinase (AMPK) signaling pathway in VSMCs and rat thoracic aorta tissues by decreasing ATP levels and the ATP/ADP ratio. Using the AMPK inhibitor Compound C, we observed that Ertu-induced vasodilation was abolished. Furthermore, we found that Compound C reversed Ertu-mediated reductions in cytosolic calcium concentration ([Ca2+]i) and mitochondrial fission, which were accompanied by diminished mitochondrial membrane potential in VSMCs. In conclusion, this study demonstrates for the first time that Ertu inhibits AMPK-mediated mitochondrial fission in VSMCs, leading to vasorelaxation, suggesting its potential as a therapeutic agent for hypertension.
    Keywords:  AMPK; Ertugliflozin; Mitochondrial fission; Smooth muscle cell; Vasodilation
    DOI:  https://doi.org/10.1016/j.ejphar.2025.177784
  46. bioRxiv. 2025 May 14. pii: 2025.05.12.653547. [Epub ahead of print]
    HSF1 remodels mitochondrial biogenesis and function in cancer cells via TIMM17A.
    Ngoc G T Nguyen, Hem Sapkota, Yoko Shibata, Aleksandra Fesiuk, Matthew Antalek, Vibhavari Sail, Daniel J Ansel, David R Amici, Frederick F Peelor, Holly Van Remmen, Benjamin F Miller, Marc L Mendillo, Richard I Morimoto, Jian Li.
      Mitochondria play critical roles in energy production and cellular metabolism. Despite the Warburg effect, mitochondria are crucial for the survival and proliferation of cancer cells. Heat Shock Factor 1 (HSF1), a key transcription factor in the cellular heat shock response, promotes malignancy and metastasis when aberrantly activated. To understand the multifaceted roles of HSF1 in cancer, we performed a genome-wide CRISPR screen to identify epistatic interactors of HSF1 in cancer cell proliferation. The verified interactors of HSF1 include those involved in DNA replication and repair, transcriptional and post-transcriptional gene expression, and mitochondrial functions. Specifically, we found that HSF1 promotes cell proliferation, mitochondrial biogenesis, respiration, and ATP production in a manner dependent on TIMM17A, a subunit of the inner membrane translocase. HSF1 upregulates the steady-state level of the short-lived TIMM17A protein via its direct target genes, HSPD1 and HSPE1, which encode subunits of the mitochondrial chaperonin complex and are responsible for protein refolding once imported into the matrix. The HSF1- HSPD1/HSPE1-TIMM17A axis remodels the mitochondrial proteome to promote mitochondrial translation and energy production, thereby supporting robust cell proliferation. Our work reveals a mechanism by which mitochondria adjust protein uptake according to the folding capacity in the matrix by altering TIM complex composition.
    DOI:  https://doi.org/10.1101/2025.05.12.653547
  47. J Bacteriol. 2025 Jun 06. e0000525
    Lon-dependent proteolysis in oxidative stress responses.
    Kubra Yigit, Peter Chien.
      Accumulation of reactive oxygen species (ROS) induces oxidative stress, leading to substantial damage to cellular macromolecules, necessitating efficient protein quality control mechanisms. The Lon protease, a highly conserved ATP-dependent protease, is thought to play a central role in mitigating oxidative stress by targeting damaged and misfolded proteins for degradation. This review examines the role of Lon in oxidative stress responses, including its role in degrading oxidized proteins, regulating antioxidant pathways, and modulating heme and Fe-S cluster homeostasis. We highlight cases of substrate recognition through structural changes and describe situations where Lon activity is further regulated by redox conditions. By synthesizing studies across a range of organisms, we find that despite the clear importance of Lon for oxidative stress tolerance, universal rules for Lon degradation of damaged proteins during this response remain unclear.
    Keywords:  AAA+ protease; Lon; bacteria; carbonylation; iron homeostasis; mitochondria; oxidative stress; quality control; redox
    DOI:  https://doi.org/10.1128/jb.00005-25
  48. Food Chem Toxicol. 2025 May 31. pii: S0278-6915(25)00340-0. [Epub ahead of print]203 115572
    Involvement of the PINK1/Parkin signaling pathway in 4-vinylcyclohexene diepoxide-induced ovary toxicity in rats.
    Yue Che, Xiaozhu Wang, Qian Li, Xiyi Peng, Zhen Liu, Wenhui Xu, Mei Jiang, Ting Wang, Jian Gao, Weiling Wang.
      Exposure to 4-vinylcyclohexene diepoxide (VCD) has been associated to reproductive toxicity, However, the dynamic ovarian function alterations over time in rats and the underlying mechanisms remain unclear. This study investigated the effects of VCD on ovarian function in female Sprague-Dawley (SD) rats on the 25, 60 and 135 days after VCD injection and discovered related mechanisms. Our results showed that VCD had little ovotoxicity on the 25th day, as no significant changes were observed except for the reduction of preantral follicles. However, on the 60th day and 135th day, rats exhibited irregular estrous cycles, abnormal serum sex hormone levels, ovarian morphological damage, decreased primordial and preantral follicles, and increased atretic follicles. We further found that on the 60th and 135th day, VCD might exert ovotoxicity by decreasing antioxidant enzyme levels, inhibiting of the Kelch-like ECH-associated protein 1 (KEAP1)/nuclear factor erythroid 2-related factor 2 (NRF2) and PTEN-induced putative kinase 1 (PINK1)/E3 ubiquitin ligase (Parkin) signaling pathway. Interestingly, on the 25th day, KEAP1/NRF2 and PINK1/Parking signaling pathway were activated. This study provided a wider application in using laboratory rodents as a model of ovarian failure and highlighted that VCD-induced ovotoxicity was linked to the regulation of the KEAP1/NRF2 and PINK1/Parkin signaling pathways.
    Keywords:  4-Vinylcyclohexene diepoxide; Exposure time; Mitophagy; Ovotoxicity; Oxidative stress
    DOI:  https://doi.org/10.1016/j.fct.2025.115572
  49. Am J Hum Genet. 2025 May 26. pii: S0002-9297(25)00184-3. [Epub ahead of print]
    Bi-allelic variants in TM2D3 cause a severe syndromic neurodevelopmental disorder associated with endoplasmic reticulum and mitochondrial abnormalities.
    Claudie Gabillard-Lefort, Caroline Silveira Martinez, Naïg Gueguen, Valérie Desquiret-Dumas, Méline Wery, Louis Legoff, Anne Guimier, Sophie Rondeau, Giulia Barcia, Christine Barnerias, Benjamin Cogne, Thomas Besnard, Elsa Lorino, Jessica Douglas, Olaf Bodamer, Annalisa Vetro, Renzo Guerrini, Simona Balestrini, Valerio Conti, Laura Siri, Arnaud Chevrollier, Céline Bris, Estelle Colin, Vincent Procaccio, Delphine Prunier-Mirebeau, Guy Lenaers, Salim Khiati, Mathilde Nizon, Olivier R Baris.
      We identified via exome sequencing bi-allelic variants in TM2D3 in four affected individuals from four unrelated families with overlapping clinical presentations, including microcephaly, severe global developmental delay with absent speech, autistic features, heart malformation, and dysmorphic facial features. TM2D3 encodes a transmembrane protein present in many tissues, with a higher abundance in the central nervous system, but little is known about its function and cell localization. Here, by using chemical and genetically encoded probes in SNB75 cells, we show that TM2D3 is an endoplasmic reticulum (ER) protein. Further analysis on SNB75 TM2D3-knockout cells as well as skin fibroblasts from affected individuals harboring the recurrent c.503G>A (p.Gly168Asp) allele revealed an impact of TM2D3 on ER-stress response, with dysregulated expression of ATF4, HSPA5, and DDIT3. Transmission electron microscopy highlighted ER swelling as well as unexpected secondary mitochondrial alterations including increased length, cristae width, and ER-mitochondria distance. To gain further insights into the pathomechanisms at play, we performed RNA sequencing from the fibroblasts of the three individuals harboring the p.Gly168Asp variant and four available parents and disclosed 21 differentially expressed genes, including genes coding for extracellular matrix components involved in the migration of neuronal precursors. Altogether, these clinical and experimental data show that bi-allelic TM2D3 variants underlie a severe syndromic neurodevelopmental disorder linked to exacerbated ER-stress sensitivity, secondary mitochondrial alterations, and altered extracellular matrix gene expression.
    Keywords:  ER stress; TM2D3; endoplasmic reticulum; extracellular matrix; microcephaly; mitochondria; mitochondrial dynamics; neurodevelopmental disorder
    DOI:  https://doi.org/10.1016/j.ajhg.2025.05.004
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