bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2025–05–04
71 papers selected by
Gavin McStay, Liverpool John Moores University
  1. Mitofusin-Mediated Mitochondrial Fusion Inhibits Pseudorabies Virus Infection in Porcine Cells.
  2. Attenuated PINK1 autophosphorylation play neuroprotective and anti-seizure roles in neonatal hypoxia.
  3. Retroviral foamy virus gag induces parkin-dependent mitophagy.
  4. Neferine Ameliorates Slow-Transmitting Constipation by Inducing PINK1/Parkin-Mediated Mitophagy in Protective Enteric Glial Cells.
  5. USP14 inhibits mitophagy and promotes tumorigenesis and chemosensitivity through deubiquitinating BAG4 in microsatellite instability-high colorectal cancer.
  6. Programmed mitophagy at the oocyte-to-zygote transition promotes 1 species immortality.
  7. Inherent potential of mitochondria-targeted interventions for chronic neurodegenerative diseases.
  8. Mechanism of Mitophagy to Protect Yak Kidney from Hypoxia-Induced Fibrosis Damage by Regulating Ferroptosis Pathway.
  9. Arctigenin Suppresses Melanoma via Mitophagy Activation In vitro and Enhances Dacarbazine Sensitivity In vivo.
  10. Ibuprofen exposure interferes with the mitochondrial dynamics processes and affects lipid metabolism in the yellowstripe goby (Mugilogobius chulae).
  11. PGAM5 aggravated doxorubicin-induced cardiotoxicity by disturbing mitochondrial dynamics and exacerbating cardiomyocytes apoptosis.
  12. PICK1 overexpression ameliorates endotoxin-induced acute lung injury by regulating mitochondrial quality control via maintaining Nrf-2 stabilization through activating the PI3K/Akt/GSK-3β pathway and disrupting the E3 ubiquitin ligase adapter β-TrCP.
  13. Senegenin ameliorates diabetic encephalopathy via promoting mitophagy and repressing NLRP3 inflammasome activation.
  14. Ginsenoside Re Inhibits NLRP3 Inflammasome Activation in Depressive Mice by Promoting PINK1-Mediated Mitophagy.
  15. Tooth Loss Leads to Cognitive Impairment and Mitochondrial Disturbance in Wistar Rats.
  16. Therapeutic Effects and Molecular Mechanism of Banxia Xiexin Decoction on Intestinal Mucosal Barrier Function in Sepsis.
  17. Targeting mitochondrial dynamics emerges as an effective strategy of cardioprotection against trastuzumab-induced mitochondrial functional aberrations and cardiotoxicity in rats.
  18. Excessive mitochondrial fission and associated extracellular mitochondria mediate cardiac dysfunction in obesity cardiomyopathy.
  19. Sex and region-specific disruption of autophagy and mitophagy in Alzheimer's disease: linking cellular dysfunction to cognitive decline.
  20. TSPO participates in the pathogenesis of diabetic periodontitis related to mitophagy.
  21. Lupeol mitigates spinal cord injury by modulating microglial M1/M2 polarization via Na+/K+-ATPase-mediated mitophagy.
  22. Emodin: an alveolar macrophage protector in acute pancreatitis induced lung injury.
  23. Dendrobine attenuates sepsis-associated acute kidney injury by promoting PINK1/PARKIN-mediated mitophagy.
  24. Astaxanthin supplementation in Arabian racing horses mitigates oxidative stress and inflammation in peripheral blood mononuclear cells through enhanced mitophagy.
  25. Mitochondrial quality control disorder in neurodegenerative disorders: Potential and advantages of traditional Chinese medicines.
  26. Mechanism of lncRNA gadd7 regulating mitofusin 1 expression by recruiting LSD1 to down-regulate H3K9me3 level, and mediating mitophagy in alveolar type II epithelial cell apoptosis in hyperoxia-induced acute lung injury.
  27. Nitric oxide-primed engineered extracellular vesicles restore bioenergetics in acute kidney injury via mitochondrial transfer.
  28. Natural small molecules regulating the mitophagy pathway counteract the pathogenesis of diabetes and chronic complications.
  29. Harnessing Nur77's mitochondrial apoptotic pathway: A promising therapeutic strategy for targeted disease intervention.
  30. Identification of mitophagy-related genes in patients with acute myocardial infarction.
  31. Cynaropicrin Suppresses Cell Proliferation by Inducing Mitophagy through p38 MAPK-Mediated Mitochondrial ROS Generation in Human Hepatocellular Carcinoma Cells.
  32. Genome-wide association analysis identifies APOE as a mitophagy modifier in Lewy body disease.
  33. Combining In Vivo 2-Photon Imaging with Photoactivatable Fluorescent Labeling Shows Low Rates of Mitochondrial Dynamics in Skeletal Muscle.
  34. The role and machine learning analysis of mitochondrial autophagy-related gene expression in lung adenocarcinoma.
  35. Loss of Ovarian Function Prevents Exercise-Induced Activation of Hepatic Mitophagic Flux.
  36. Hydroxytyrosol as a Mitochondrial Homeostasis Regulator: Implications in Metabolic Syndrome and Related Diseases.
  37. Progranulin enhances M2 macrophage polarization and renal fibrosis by modulating autophagy in chronic kidney disease.
  38. Yellow fever virus infection alters mitochondrial network dynamics and trigger IFN-I response via TLR2 pathway.
  39. Puerarin relives inflammation, bone destruction and facilitates osteogenic differentiation in periodontitis by enhancing mitochondrial autophagy via activating mitochondrial Mitofusin 2.
  40. VDAC1 Inhibition Protects Against Noise-Induced Hearing Loss via the PINK1/Parkin Pathway.
  41. l-Carnitine and Acetyl-l-Carnitine Induce Metabolism Alteration and Mitophagy-Related Cell Death in Colorectal Cancer Cells.
  42. S100A9/RAGE pathway regulation of mitophagy and the effect of JianPi LiShi YangGan formula in acute-on-chronic liver failure.
  43. Cathepsin B Regulates Ovarian Reserve Quality and Quantity via Mitophagy by Modulating IGF1R Turnover.
  44. Ceria nanoparticles alleviate myocardial ischemia-reperfusion injury by inhibiting cardiomyocyte apoptosis via alleviating ROS mediated excessive mitochondrial fission.
  45. Gui-Pi-Tang Defers Skeletal Muscle and Cardiac Muscle Aging by Promoting Mitochondrial Remodeling.
  46. Polydatin reactivates mitochondrial bioenergetics and mitophagy while preventing premature senescence by modulating microRNA-155 and its direct targets in human fibroblasts with trisomy 21.
  47. Neutrophil extracellular traps aggravate placental injury in OAPS by facilitating activation of BNIP3 mediated mitophagy.
  48. Correction: HACE1 protects against myocardial ischemia-reperfusion injury via inhibition of mitochondrial fission in mice.
  49. Effects of high-intensity interval training and moderate-intensity continuous training on mitochondrial dynamics in human skeletal muscle.
  50. Effects of Melatonin on H2O2-Induced Oxidative Damage of the Granulosa Cells in Hen Ovarian Follicles.
  51. Comprehensive transcriptomic analysis integrating bulk and single-cell RNA-seq with machine learning to identify and validate mitochondrial unfolded protein response biomarkers in patients with ischemic stroke.
  52. Macrophage ATG16L1 promotes liver regeneration after partial hepatectomy.
  53. Pharmacological targeting of mitophagy via ALT001 improves herpes simplex virus 1 (HSV1)-mediated microglial inflammation and promotes amyloid β phagocytosis by restricting HSV1 infection.
  54. Targeting mitochondrial dysfunction: an innovative strategy for treating renal fibrosis.
  55. Molecular structure and protein function of mitochondrial fusion protein Mfn2 alleviate Alzheimer's disease: exercise assisted regulation.
  56. Replicative Senescence in Mesenchymal Stem Cells: An In Vitro Study on Mitochondrial Dynamics and Metabolic Alterations.
  57. Role of TRPM2 in Oxidative Stress-Mediated Bone Loss in Periodontitis.
  58. Hesperidin mitigated deoxynivalenol-induced liver injury by inhibiting ROS/ P53/ PGC-1α-mediated disruption of mitochondrial dynamics and PANoptosis.
  59. Stroke in Pregnancy Brings Epigenetic Changes in Correlation with Affected Mitochondrial Dynamics and Inflammasome Mediated Apoptosis in Rodents.
  60. An Insight into Neuronal Processing of Ghrelin: Effects of a Bioactive Ghrelin Derivative on Proteolytic Pathways and Mitophagy.
  61. Control of Mitochondrial Quality: A Promising Target for Diabetic Kidney Disease Treatment.
  62. Dual Role of CRABP2 in Colorectal Cancer: Oncogenesis via Nuclear RB1 and Cytoplasmic AFG3L2/SLC25A39 Axis, While Limiting Liver Metastasis through Cytoplasmic AFG3L2/PINK1/Parkin-Mediated Mitophagy.
  63. Nutritional and hormonal regulation of mitochondrial biogenesis drives fat body remodeling for reproductive competence.
  64. 3D Mitochondrial Structure in Aging Human Skeletal Muscle: Insights Into MFN-2-Mediated Changes.
  65. PGC-1α role in rescuing ferroptosis in cerebral ischemia/reperfusion injury through promoting mitochondrial biogenesis and UCP2 expression.
  66. Cytochrome P450 2E1 aggravates DXR-induced myocardial injury through imbalanced mitochondrial OPA1.
  67. Modulation of Lonp1 Activity by Small Compounds.
  68. Vine-inspired zinc-ion modified black phosphorus coating accelerates bone tissue infiltration of 3D printed scaffolds.
  69. SIRTUINS MODULATORS MITIGATE HYPOXIA-INDUCED CELL DEATH DUE TO CHANGES IN HISTONE 3 ACETYLATION, AND MITOCHONDRIAL FUNCTION, DYNAMICS, AND CONTENT.
  70. Vicenin-2 in Suhuang antitussive capsule attenuates mitophagy-dependent ferroptosis via LRP1 for treating post-infectious cough.
  71. Dapagliflozin activates the RAP1B/NRF2/GPX4 signaling and promotes mitochondrial biogenesis to alleviate vascular endothelial ferroptosis.
  1. Vet Sci. 2025 Apr 15. pii: 368. [Epub ahead of print]12(4):
    Mitofusin-Mediated Mitochondrial Fusion Inhibits Pseudorabies Virus Infection in Porcine Cells.
    Xiuhan Xu, Yuan Zhao, Zhenbang Zhu, Wei Wen, Xiangdong Li.
      Background: Mitochondria are highly dynamic organelles that undergo fusion/fission dynamics, and emerging evidence has established that mitochondrial dynamics plays a crucial regulatory role in the process of viral infection. Nevertheless, the function of mitochondria dynamics during pseudorabies (PRV) infection remains uncertain. Methods: Our investigation commenced with examining PRV-induced alterations in mitochondrial dynamics, focusing on morphological changes and the expression levels of fusion/fission proteins. We then restored mitochondrial dynamics through Mfn1 (Mitofusin 1)/Mfn2 (Mitofusin 2) overexpression and mdivi-1 (mitochondrial division inhibitor-1) treatment to assess their impact on PRV replication and mitochondrial damage. Results: We found a downregulation of the mitochondrial fusion proteins Mfn1, Mfn2, and OPA1 (optic atrophy 1), along with the activation of the fission protein Drp-1 (dynamin-related protein 1) upon PRV infection. Restoring the function of mitochondrial fusion inhibited PRV infection. Furthermore, elevated mitochondrial membrane potential (MMP), decreased reactive oxygen species (ROS) levels, and an increased mitochondrial number were observed after overexpressing Mfns or treatment with mdivi-1. Conclusions: PRV infection impairs mitochondrial dynamics by altering mitochondrial fusion and fission proteins, and the promotion of Mfn-mediated mitochondrial fusion inhibits PRV replication.
    Keywords:  mitochondrial dynamics; mitochondrial fusion; mitofusin proteins; pseudorabies virus
    DOI:  https://doi.org/10.3390/vetsci12040368
  2. Sci Rep. 2025 Apr 29. 15(1): 15078
    Attenuated PINK1 autophosphorylation play neuroprotective and anti-seizure roles in neonatal hypoxia.
    Yi Yuan, Xiaoqian Wang, Yaru Cui, Hua Zhou, Wenna Li, Qian Teng, Hongjin Wang, Bohan Sun, Qiaoyun Wang, Hongliu Sun, Jianhua Tang.
      This study investigated the roles and mechanisms of PINK1 activity in neonatal hypoxia-induced seizures with shRNA intervention targeting translocase outer mitochondrial membrane 7 (TOM7), the positive regulator of PINK1 autophosphorylation, or overlapping with the m-AAA protease 1 homolog (OMA1), the negative regulator of PINK1 autophosphorylation. Studies have suggested that in hypoxia-induced neonatal seizures, the phosphorylation level of PINK1 is significantly increased and the mitophagic pathway is activated, accompanied by neuronal damage and learning-memory deficits. Inhibiting PINK1 phosphorylation by reducing TOM7 expression alleviated mitophagy, mitochondrial oxidative stress, neuronal damage and seizures. In contrast, the inhibition of OMA1 expression resulted in a further increase in PINK1 phosphorylation and aggravated hypoxia-induced seizures and neuronal injury. This study implicated PINK1 activity in neonatal hypoxia and suggest that attenuated PINK1 autophosphorylation may have neuroprotective and anti-seizure effects in neonatal hypoxia.
    Keywords:  Mitochondrial oxidative stress; Mitophagy; Neuronal injury; PINK1; Seizure
    DOI:  https://doi.org/10.1038/s41598-025-99915-8
  3. Retrovirology. 2025 May 02. 22(1): 7
    Retroviral foamy virus gag induces parkin-dependent mitophagy.
    Shanshan Wang, Tongtong Du, Jun Yan, Yingcheng Zheng, Yinglian Tang, Juejie Wu, Qian Xu, Shanshan Xu, Luo Liu, Xiong Chen, Song Han, Jun Yin, Biwen Peng, Xiaohua He, Wanhong Liu.
       BACKGROUND: Prototype foamy virus (PFV) is a complex retrovirus that can maintain latent infection for life after viral infection of the host. However, the mechanism of latent infection with PFV remains unclear. Our previous studies have shown that PFV promotes autophagy flux, but whether PFV causes mitophagy remains unclear.
    RESULTS: In this study, we demonstrated that PFV infection damages mitochondria, increases mitochondria reactive oxygen species (mtROS) production, and induces mitophagy in a time-dependent manner. Further investigation revealed that PFV Gag is a crucial protein responsible for triggering mitophagy. The overexpression of Gag leads to mitochondrial damage and stimulates mitophagy in a dose-dependent manner. Additionally, overexpression of Gag activates the PINK1-Parkin signaling pathway, while the knockdown of Parkin inhibits Gag-induced mitophagy. Furthermore, Rab5a was significantly upregulated in cells overexpressed Gag, and the inhibition of Rab5a reversed the effects of Gag-induced mitophagy.
    CONCLUSIONS: Our data suggested that PFV can induce mitophagy and Gag induces Parkin-dependent mitophagy by upregulating Rab5a. These findings not only enhance a better understanding of the foamy virus infection mechanisms but also provide critical insights into novel virus-host cell interactions.
    Keywords:  Gag; Mitophagy; Parkin; Prototype foamy virus; Rab5a
    DOI:  https://doi.org/10.1186/s12977-025-00664-3
  4. J Microbiol Biotechnol. 2025 Apr 27. 35 e2412022
    Neferine Ameliorates Slow-Transmitting Constipation by Inducing PINK1/Parkin-Mediated Mitophagy in Protective Enteric Glial Cells.
    Taiyu Chen, Xiaodong Jiang, Bo Ma, Yu Zhan, Yong Wen, Lifang Mao, Jun Pang, Xuegui Tang.
      The enteric glial cells (EGCs) are the main components of the enteric nervous system (ENS) and contribute to the development of slow transit constipation (STC). In this study, we aimed to explore the effects of neferine (Nef) on EGCs based on PINK1/Parkin-mediated mitophagy. In vivo, 7 days of loperamide feeding was conducted to model STC rats, which were then treated with 2.5, 5, 10 mg/kg/d Nef, and 2 mg/kg/d mosapride for 14 days. In vitro, a CCK-8 assay was performed to detect EGC viability. EGCs were then stimulated by 400 μM H2O2, transfected with si-PINK1, and treated with Nef or mitochondrial division inhibitor 1 (Mdivi-1). Colon tissue was observed by H&E staining, TEM, ELISA (to quantify SOD, MDA, GDNF, and NGF expression), and immunofluorescence (to count the number of mitochondria). In addition, flow cytometry was used to quantify cell apoptosis, ROS, and mitochondrial membrane potential (MMP). Finally, the p62, PINK1, Parkin, and LC3II/I expression levels were measured by western blotting. Nef was shown to significantly improve STC in rats and reduce mucosal epithelial cell loss, inflammatory cell infiltration, and fibrous proliferation. Moreover, Nef reduced ROS and MDA levels while increasing SOD, GDNF, and NGF. Nef treatment also increased the LC3II/I ratio, as well as p62, PINK1, and Parkin expression, which helped mitigate mitochondrial expansion. However, PINK1 silencing shared the same function as Mdivi-1 in the STC+Nef group, inhibiting EGC viability, oxidative stress, and PINK1/Parkin signaling activation. Additionally, mitophagy was exacerbated by si-PINK1 in the STC+Nef group EGCs. In short, Nef ameliorates STC by inducing PINK1/Parkin-mediated mitophagy in EGCs.
    Keywords:  Neferine; PINK1/Parkin signaling pathway; enteric glial cells; mitophagy; slow-transmitting constipation
    DOI:  https://doi.org/10.4014/jmb.2412.12022
  5. Mol Med. 2025 May 02. 31(1): 163
    USP14 inhibits mitophagy and promotes tumorigenesis and chemosensitivity through deubiquitinating BAG4 in microsatellite instability-high colorectal cancer.
    Zhiyong Wang, Cheng Yu, Gengchen Xie, Kaixiong Tao, Zhijie Yin, Qing Lv.
       BACKGROUND: Mitophagy, essential for cellular homeostasis, is involved in eliminating damaged mitochondria and is associated with cancer progression and chemoresistance. The specific impact of mitophagy on microsatellite instability-high (MSI-H) colorectal cancer (CRC) is still under investigation. Ubiquitination, a post-translational modification, is essential for controlling protein stability, localization, and function. This study identifies USP14, a deubiquitinating enzyme, as a key regulator of mitophagy in MSI-H CRC.
    METHODS: A deubiquitinating enzyme (DUBs) siRNA library screening identified USP14 as a key regulator of mitophagy. Tissue samples from patients were analyzed using immunohistochemistry and Western blot. USP14 knockdown cell lines were generated using lentiviral transfection. Protein interactions between USP14 and BAG4 were confirmed by co-immunoprecipitation, while quantitative PCR was used to measure gene expression. Mitochondrial proteins were extracted to analyze mitophagy, and flow cytometry was used to assess apoptosis. Finally, a mouse xenograft model was employed to study USP14's role in tumor growth and oxaliplatin sensitivity.
    RESULTS: Screening reveals that USP14 inhibits mitophagy and CRC (MSI-H) show high USP14 expression which correlates with poor prognosis. Functional analyses reveal that knocking down USP14 reduces tumor growth, and increases sensitivity to oxaliplatin. Mechanically, USP14 inhibits mitophagy by K48-deubiquitinating and stabilizing BAG4 at K403, which prevents the recruitment of Parkin to damaged mitochondria. The significant clinical relevance of USP14, BAG4, and PRKN are proved in tumor tissues.
    CONCLUSIONS: The study highlights the USP14/BAG4/PRKN axis as a critical pathway in CRC (MSI-H), suggesting that targeting USP14 could inhibit tumor progression and improve chemotherapeutic outcomes. These findings underscore the importance of ubiquitination and mitophagy in cancer biology, indicating a potential therapeutic target for MSI-H CRC.
    Keywords:  Colorectal cancer; Mitophagy; Oxaliplatin; Tumorigenesis; USP14
    DOI:  https://doi.org/10.1186/s10020-025-01182-w
  6. Res Sq. 2025 Apr 09. pii: rs.3.rs-6330979. [Epub ahead of print]
    Programmed mitophagy at the oocyte-to-zygote transition promotes 1 species immortality.
    David Sherwood, Siddharthan Balachandar Thendral, Sasha Bacot, Katherine Morton, Qiuyi Chi, Isabel Kenny-Ganzert, Joel Meyer.
      The quality of mitochondria inherited from the oocyte determines embryonic viability, metabolic health throughout progeny lifetime, and future generation endurance. High levels of endogenous reactive oxygen species and exogenous toxicants are threats to mitochondrial DNA (mtDNA) in fully developed oocytes. Deleterious mtDNA is commonly detected in developed oocytes, but is absent in embryos, suggesting the existence of a cryptic purifying selection mechanism. Here we discover that in C. elegans, the onset of oocyte-to-zygote transition (OZT) developmentally triggers a rapid mitophagy event. We show that mitophagy at OZT (MOZT) requires mitochondrial fragmentation, the macroautophagy pathway, and the mitophagy receptor FUNDC1, but not the prevalent mitophagy factors PINK1 and BNIP3. Impaired MOZT leads to increased deleterious mtDNA inheritance and decreases embryonic survival. Inherited mtDNA damage accumulates across generations, leading to the extinction of descendent populations. Thus, MOZT represents a strategy that preserves mitochondrial health during the mother-to-offspring transmission and promotes species continuity.
    DOI:  https://doi.org/10.21203/rs.3.rs-6330979/v1
  7. Neural Regen Res. 2025 Apr 29.
    Inherent potential of mitochondria-targeted interventions for chronic neurodegenerative diseases.
    Min Zhou, Min Zheng, Siyao Liang, Maomao Li, Jiarui Ma, Shiyu Zhang, Xinyao Song, Yonglin Hu, Yuhong Lyu, Xingkun Ou, Changwu Yue.
       ABSTRACT: The cure rate for chronic neurodegenerative diseases remains low, creating an urgent need for improved intervention methods. Recent studies have shown that enhancing mitochondrial function can mitigate the effects of these diseases. This paper comprehensively reviews the relationship between mitochondrial dysfunction and chronic neurodegenerative diseases, aiming to uncover the potential use of targeted mitochondrial interventions as viable therapeutic options. We detail five targeted mitochondrial intervention strategies for chronic neurodegenerative diseases that act by promoting mitophagy, inhibiting mitochondrial fission, enhancing mitochondrial biogenesis, applying mitochondria-targeting antioxidants, and transplanting mitochondria. Each method has unique advantages and potential limitations, making them suitable for various therapeutic situations. Therapies that promote mitophagy or inhibit mitochondrial fission could be particularly effective in slowing disease progression, especially in the early stages. In contrast, those that enhance mitochondrial biogenesis and apply mitochondria-targeting antioxidants may offer great benefits during the middle stages of the disease by improving cellular antioxidant capacity and energy metabolism. Mitochondrial transplantation, while still experimental, holds great promise for restoring the function of damaged cells. Future research should focus on exploring the mechanisms and effects of these intervention strategies, particularly regarding their safety and efficacy in clinical settings. Additionally, the development of innovative mitochondria-targeting approaches, such as gene editing and nanotechnology, may provide new solutions for treating chronic neurodegenerative diseases. Implementing combined therapeutic strategies that integrate multiple intervention methods could also enhance treatment outcomes.
    Keywords:  Alzheimer’s disease; Huntington’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; calcium homeostasis; intervention strategy; mitochondria; mitochondrial dysfunction; mitochondrial membrane permeability transition pore; mitophagy; neurodegenerative diseases; oxidative stress; targeted therapy
    DOI:  https://doi.org/10.4103/NRR.NRR-D-24-01507
  8. Biomolecules. 2025 Apr 09. pii: 556. [Epub ahead of print]15(4):
    Mechanism of Mitophagy to Protect Yak Kidney from Hypoxia-Induced Fibrosis Damage by Regulating Ferroptosis Pathway.
    Xuefeng Bai, Hongqin Lu, Rui Ma, Sijiu Yu, Shanshan Yang, Junfeng He, Yan Cui.
      Renal fibrosis is a critical pathological feature of various chronic kidney diseases, with hypoxia being recognized as an important factor in inducing fibrosis. Yaks have long inhabited high-altitude hypoxic environments and do not exhibit fibrotic damage under chronic hypoxia. However, the underlying protective mechanisms remain unclear. This study compared the renal tissue structure and collagen volume between low-altitude cattle and high-altitude yaks, revealing that yaks possess a significantly higher number of renal tubules than cattle, though collagen volume showed no significant difference. Under hypoxic treatment, we observed that chronic hypoxia induced renal fibrosis in cattle, but did not show a significant effect in yaks, suggesting that the hypoxia adaptation mechanisms in yaks may have an anti-fibrotic effect. Further investigation demonstrated a significant upregulation of P-AMPK/AMPK, Parkin, PINK1, LC3Ⅱ/Ⅰ, and BECN1, alongside a downregulation of P-mTOR/mTOR in yak kidneys. Additionally, hypoxia-induced renal tubular epithelial cells (RTECs) showed increased expression of mitophagy-related proteins, mitochondrial membrane depolarization, and an increased number of lysosomes, indicating that hypoxia induces mitophagy. By regulating the mitophagy pathway through drugs, we found that under chronic hypoxia, activation of mitophagy upregulated E-cadherin protein expression while downregulating the expression of Vimentin, α-SMA, Collagen I, and Fibronectin. Simultaneously, there was an increase in SLC7A11, GPX4, and GSH levels, and a decrease in ROS, MDA, and Fe2⁺ accumulation. Inhibition of mitophagy produced opposite effects on protein expression and cellular markers. Further studies identified ferroptosis as a key mechanism promoting renal fibrosis. Moreover, in renal fibrosis models, mitophagy reduced the accumulation of ROS, MDA, and Fe2⁺, thereby alleviating ferroptosis-induced renal fibrosis. These findings suggest that chronic hypoxia protects yaks from hypoxia-induced renal fibrosis by activating mitophagy to inhibit the ferroptosis pathway.
    Keywords:  ferroptosis; hypoxia adaptation; mitophagy; renal fibrosis; yak
    DOI:  https://doi.org/10.3390/biom15040556
  9. Curr Cancer Drug Targets. 2025 Apr 25.
    Arctigenin Suppresses Melanoma via Mitophagy Activation In vitro and Enhances Dacarbazine Sensitivity In vivo.
    Ling Jiang, Yang Lu, Hongyan Zhao, Weiyang He.
       OBJECTIVE: This study aimed to investigate the effect and mechanism of arctigenin (ARG) on the sensitization of dacarbazine (DTIC) via the regulation of mitophagy.
    METHODS: In vitro experiments were conducted to explore the effects of ARG on the biologi-cal behavior of melanoma cells, mitochondrial autophagy mediated by PINK1/Parkin, and the role of reactive oxygen species (ROS)-mitochondrial autophagy in the regulation of the biological behavior of melanoma cells by an ROS quenching agent, a mitochondrial autoph-agy inhibitor, and an activator. The effects of ARG and dacarbazine in nude mice were as-sessed.
    RESULTS: CCK8 assays revealed that ARG inhibited the proliferation of the human melanoma cell lines A375 and SK-MEL-2. The observation of submicroscopic structures demonstrated mitochondrial damage. Flow cytometry further verified that ARG induced apoptosis. West-ern blot analysis revealed that the protein expression levels of cleaved caspase 3 and Bax in-creased, whereas that of Bcl-2 decreased. In addition, ARG increased ROS levels. LC3II/I, PINK1, and Parkin were increased. ARG-induced apoptosis was related to increased mito-chondrial oxidative stress and promoted the occurrence of mitochondrial autophagy. After the addition of the autophagy inhibitor Mdivi-1 or the ROS quencher N-acetylcysteine (NAC), the antiproliferative effect of ARG was markedly attenuated. The expression levels of PINK1, Parkin, LC3II/I, cleaved caspase 3, and Bax were increased, whereas that of Bcl-2 was decreased. The formation of mitochondrial autophagosomes was observed by transmis-sion electron microscopy. ARG inhibited the proliferation and induced the apoptosis of mel-anoma cells in vivo.
    CONCLUSION: Autophagy-mediated cell apoptosis was activated through the PINK1/Parkin pathway by ARG, effectively inhibiting the proliferation of human melanoma cells.
    Keywords:  Arctigenin; antitumor; apoptosis; dacarbazine.; melanoma; mitophagy
    DOI:  https://doi.org/10.2174/0115680096373796250414062644
  10. Aquat Toxicol. 2025 Apr 20. pii: S0166-445X(25)00137-7. [Epub ahead of print]284 107372
    Ibuprofen exposure interferes with the mitochondrial dynamics processes and affects lipid metabolism in the yellowstripe goby (Mugilogobius chulae).
    Huiyu Zhang, Yufei Zhao, Weibo Gong, Chunni Duan, Yuanyuan Xiao, Yimeng Wang, Xiangping Nie.
      Ibuprofen (IBU), a prevalent non-steroidal anti-inflammatory drug (NSAID), is extensively utilized in medical practices. Especially since the popularity of COVID-19, its use has become more widespread, coupled with its low degradation rate and high environmental residues. Thus, more focus is warranted on the possible detrimental impacts on non-target organisms, as well as the underlying mechanisms of toxicity. The present study investigated the relationships and molecular mechanisms between hepatic mitochondrial dynamics processes and lipid metabolism in the yellowstripe goby (Mugilogobius chulae) exposed to IBU at concentrations of 0.5, 5, 50, and 500 μg/L over 7 days. The results showed that IBU exposure inhibited mitochondrial biogenesis and fusion but promoted mitochondrial fission by interfering with the SESN/PGC/ULK signaling pathway, causing an imbalance in mitochondrial dynamics. Thus, high concentration of IBU exposure caused mitochondrial dysfunction and oxidative stress. Molecular biological evidences suggested that IBU caused a decrease in ATP production and lipogenesis, leading to an energetic crisis in M. chulae. Hepatic tissue also showed a significant decrease in relative weight, an increase in mitochondrial damage and adipocyte degeneration. Correspondingly, the exposed organism attempted to mitigate these crises by promoting mitophagy and lipophagy via the Pink-Parkin pathway. Overall, IBU exposure interfered with mitochondrial dynamics processes and caused abnormalities in hepatic lipid metabolism in M. chulae. The present study highlighted the discovery of mitochondrial dynamics imbalance to lipid dysregulation cascade mechanism. We emphasized the negative effects of NSAIDs such as IBU on aquatic non-target organisms at different levels. It provided valuable insights into the ecological risk assessment of IBU in aquatic environments.
    Keywords:  Aquatic toxicology; Autophagy; Ibuprofen; Lipid metabolism; Mitochondria dynamics
    DOI:  https://doi.org/10.1016/j.aquatox.2025.107372
  11. Free Radic Biol Med. 2025 Apr 24. pii: S0891-5849(25)00247-3. [Epub ahead of print]235 95-108
    PGAM5 aggravated doxorubicin-induced cardiotoxicity by disturbing mitochondrial dynamics and exacerbating cardiomyocytes apoptosis.
    Weibin He, Jieying Wang, Wenlong He, Ling Zeng, Ruowen Zhao, Kailun Qiu, Guang Tong, Zhongchan Sun, Pengcheng He.
      Doxorubicin (DOX), a potent chemotherapeutic agent, is widely used for treating malignancies but is limited by its cardiotoxic side effects. Mitochondrial dynamics, encompassing fission and fusion processes, play a pivotal role in maintaining cardiomyocyte function under stress, yet their disruption contributes to DOX-induced cardiotoxicity (DIC). While mitochondrial quality control (MQC) mechanisms are implicated in DIC, the specific molecular players remain unclear. Here, we demonstrate that the mitochondrial phosphatase PGAM5 exacerbates DIC by disturbing mitochondrial dynamics and promoting oxidative stress and apoptosis. We show that DOX induces PGAM5 cleavage via activation of mitochondrial proteases OMA1 and YME1L1. Overexpression of PGAM5 blocks DOX-induced mitochondrial elongation and instead promotes mitochondrial fragmentation by disrupting the balance between fission and fusion, mediated by inducing DRP1 dephosphorylation at Ser637 and exacerbating MFN2 downregulation. In addition, our findings indicate that PGAM5's phosphatase activity, rather than its cleavage, mediates the suppression of DOX-induced mitochondrial elongation. However, PGAM5 overexpression fails to enhance mitophagic clearance of dysfunctional mitochondria. Instead, PGAM5 amplifies DOX-induced oxidative stress and cardiomyocyte apoptosis, without promoting other regulated cell death (RCD) pathways like ferroptosis or pyroptosis. These findings reveal a novel mechanism by which PGAM5 disrupts mitochondrial dynamics and contributes to DIC, highlighting its potential as a therapeutic target for mitigating DOX-induced cardiomyopathy.
    Keywords:  Apoptosis; Cardiotoxicity; Doxorubicin; Mitochondrial dynamics; PGAM5
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.04.037
  12. Int Immunopharmacol. 2025 Apr 25. pii: S1567-5769(25)00675-7. [Epub ahead of print]156 114685
    PICK1 overexpression ameliorates endotoxin-induced acute lung injury by regulating mitochondrial quality control via maintaining Nrf-2 stabilization through activating the PI3K/Akt/GSK-3β pathway and disrupting the E3 ubiquitin ligase adapter β-TrCP.
    Meizi Qian, Yurun Zhu, Wen Lin, Huidan Lian, Yun Xia, Thomas Papadimos, Junlu Wang.
      Mitochondria are important targets for preventing oxidative damage during the progression of sepsis-induced lung injury. Numerous studies have pointed out that maintaining the stabilization of Nrf-2, thereby activating its transcription, may combat pathological inflammation by sustaining the integrity of mitochondrial function. Our previous study found that protein interaction with C-kinase 1 (PICK1) deficiency disrupts the physiological anti-inflammatory mechanism by affecting Nrf-2 transcription. However, whether PICK1 participates in mitochondrial quality control regulation through Nrf-2 has not been explored, and the underlying interaction between PICK1 and Nrf-2 has not been fully elucidated. We found that PICK1 decreased mitochondria-derived ROS, upregulated MnSOD activity in endotoxin-induced acute lung injury mice, improved mitochondrial membrane potential, and restored the damaged structure of mitochondria in LPS-stimulated macrophages. Through in-depth studies, we demonstrated that PICK1 maintains the stability of Nrf-2 by preserving mitochondrial dynamic equilibrium, facilitating mitochondrial biogenesis, and participating in mitophagy by activating the PI3K/AKT/GSK-3β pathway. PICK1 also inhibits the β-TrCP-mediated ubiquitination of Nrf-2. Thus, PICK1 offers an unexplored alternative to current Nrf-2 activators by acting as a Nrf-2 activator that may have therapeutic value against septic inflammation. Our study demonstrated the protective effects of PICK1 overexpression in endotoxin-associated ALI. PICK1 overexpression and the subsequent PI3K/AKT/Nrf-2/HO-1 pathway-dependent and E3 ubiquitin ligase adapter β-TrCP-mediated mitochondrial quality control contribute to lung repair, which offers an unexplored alternative to current Nrf-2 activators by acting as a Nrf-2 activator that may have therapeutic value against septic inflammation.
    Keywords:  Endotoxin-related acute lung injury; Mitochondrial quality control; Nrf-2; PICK1; Β-TrCP
    DOI:  https://doi.org/10.1016/j.intimp.2025.114685
  13. Psychopharmacology (Berl). 2025 Apr 26.
    Senegenin ameliorates diabetic encephalopathy via promoting mitophagy and repressing NLRP3 inflammasome activation.
    Xiao-Dan Yan, Yu Yang, Wan-Ting Zhang, Qing-Quan Kong, Xi-Tong Zheng, Lin-Sen Li, Qing Yu.
       RATIONALE: Diabetic encephalopathy (DE) remains a severe complication of diabetes in central nervous system with limited effective therapy.
    OBJECTIVES: This study investigated the beneficial effect of senegenin on DE and its possible mechanisms.
    METHODS: Type 2 diabetes mellitus mouse model and high-glucose (HG)-stimulated PC-12 cells were used as the in vivo and in vitro DE models. Learning and memory ability was evaluated by MWM test. Pathological changes in the brain tissues were determined by HE staining. Cell viability was detected by CCK-8. Mitochondrial membrane potential was measured by JC-1 probe. Target protein levels were assessed by Western blotting. Nucleotide-binding domain-like receptor protein 3 (NLRP3) expression was observed by immunofluorescent staining.
    RESULTS: Cognitive impairment and obvious pathological changes were found in DE mice, which were effectively attenuated by senegenin treatment. In addition, senegenin induced mitophagy and maintained homeostasis of mitochondrial dynamics to relieve mitochondrial dysfunction. Moreover, NLRP3 inflammation activation induced by DE was inhibited by senegenin. Finally, inhibition of mitophagy counteracted senegenin-mediated inactivation of NLRP3 inflammation and neuroprotection.
    CONCLUSIONS: Senegenin relieved diabetic encephalopathy via inducing mitophagy to inactivate NLRP3 inflammasome. Senegenin might be an effective therapy for treating DE.
    Keywords:  Diabetic encephalopathy; Mitochondrial dysfunction; Mitophagy; NLRP3 inflammation; Senegenin
    DOI:  https://doi.org/10.1007/s00213-025-06796-w
  14. J Agric Food Chem. 2025 Apr 29.
    Ginsenoside Re Inhibits NLRP3 Inflammasome Activation in Depressive Mice by Promoting PINK1-Mediated Mitophagy.
    Shan Liu, Yue Zhang, Hao Zhou, Yating Ma, Fangzhou Huang, Tianyuan Lei, Qingbin Wang, Shangmin Yu.
      Ginsenoside Re (Re) was proved effective in improving depressive-like behaviors. However, the potential antidepressant mechanism of Re remains unrevealed. In this study, we investigated whether PINK1-mediated mitophagy and NLRP3 inflammasomes were linked to the antidepressant mechanism of Re in chronic unpredictable mild stress (CUMS) mice and lipopolysaccharide (LPS)-stimulated astrocytes. RNA sequencing and bioinformatics analyses were performed to discover the targets and pathways associated with Re. PTEN-induced putative kinase 1 (PINK1) knockdown was conducted to clarify the role of PINK1-mediated mitophagy in the antidepressant mechanism of Re. The outcomes showed that Re ameliorated depressive-like behaviors, activated PINK1-mediated mitophagy, and inhibited NLRP3 inflammasome activation. PINK1 knockdown attenuated the antidepressant effect of Re. The promotion of mitophagy and the decline of NLRP3 inflammasome activation caused by Re were reversed by PINK1 knockdown. In conclusion, Re inhibited NLRP3 inflammasome activation by promoting PINK1-mediated mitophagy to exert its antidepressant effect.
    Keywords:  NLRP3 inflammasome; PINK1; depression; ginsenoside Re; mitophagy
    DOI:  https://doi.org/10.1021/acs.jafc.4c09773
  15. Int Dent J. 2025 Apr 30. pii: S0020-6539(25)00108-X. [Epub ahead of print]75(4): 100818
    Tooth Loss Leads to Cognitive Impairment and Mitochondrial Disturbance in Wistar Rats.
    Shixiang Meng, Yunping Lu, Jiangqi Hu, Bin Luo, Xu Sun, Xiaoyu Wang, Qingsong Jiang.
       BACKGROUND: The link between tooth loss and cognitive impairment has become increasingly significant. Recent findings suggest that mitochondrial alteration in hippocampal neurons may mediate this relationship.
    OBJECTIVE: This study aimed to explore the mediating role of mitochondria in the relationship between tooth loss and cognitive function in Wistar rats.
    METHOD: Male Wistar rats (n = 20, 12 weeks old) were randomly divided into tooth extraction (TE) and sham groups. The model was established through upper molar extraction and sham operation respectively. Cognitive evaluations were performed using Morris water maze (MWM) test 8 weeks after the model establishment. Hippocampal neuron morphology was observed. Mitochondrial function was evaluated by ATP level and mitochondrial membrane potential (MMP). Mitophagy assessment involved conducting immunohistochemical and immunofluorescent staining of PTEN-induced kinase 1 (PINK1), Parkin (E3 ubiquitin ligase), translocase of outer mitochondrial membrane 20 (TOMM20), and microtubule-associated protein 1A/1B-light chain 3 (LC3). Additionally, mitophagy protein alterations were analyzed using western blotting.
    RESULTS: Memory impairment in the TE group was obvious 8 weeks after model establishment. Substantial hippocampal mitochondrial dysfunction was observed in the TE group, evidenced by notably decreased ATP production, decreased MMP level, and abnormal mitochondrial morphology in the hippocampus. Diminished mitophagy was detected by immunofluorescent staining, and further confirmed by immunostaining and western blotting, indicating diminished mitophagy marker levels in PINK1 and Parkin, along with decreased LC3II/I ratios and elevated Sequestosome-1 (SQSTM1/P62) levels, highlighting hippocampal mitophagy deficiency following tooth loss.
    CONCLUSIONS: Tooth loss leads to mitochondrial disturbance and inhibits PINK1/Parkin-mediated mitophagy in hippocampal neurons, inducing cognitive impairment.
    CLINICAL RELEVANCE: This study reveals mitochondria may mediate the effect of tooth loss on cognitive function, offering a theoretical basis for the prevention of oral health-associated cognitive decline.
    Keywords:  Cognitive Dysfunction; Dental Occlusion; Hippocampus; Mitochondria; Mitophagy; Tooth Loss
    DOI:  https://doi.org/10.1016/j.identj.2025.03.027
  16. Comb Chem High Throughput Screen. 2025 Apr 29.
    Therapeutic Effects and Molecular Mechanism of Banxia Xiexin Decoction on Intestinal Mucosal Barrier Function in Sepsis.
    Wen Dai, Lei Zhou, Hao Hao, Diankui Wang, Feihu Zhang, Peng Wang, Lin Wang, Li Kong.
       AIM: This study aims to investigate therapeutic effects and involved molecular mechanisms of Banxia Xiexin Decoction (BXD) in reducing gastrointestinal complications associated with sepsis.
    BACKGROUND: Sepsis is a common critical illness that threatens patient survival and costs society a lot. This syndrome is a prominent cause of death in ICUs due to its high mortality rate, which exceeds 30% after 28 days and 35.5% after 90 days. Sepsis remains a major medical challenge despite a 20%-30% drop in fatality rates due to a better understanding of its physiological and pathological features and better therapeutic techniques. There is no pharmacological treatment for sepsis, highlighting the need for more study.
    OBJECTIVE: We explored the protecting effects of BXD on intestinal functionality in sepsis by investigating its roles in the regulation of mitochondrial autophagy and mitochondrial functioning in small intestinal epithelial cells, primarily via the PINK1/Parkin signaling pathway.
    METHOD: We established a cell model of Human Intestinal Epithelial Cell (HIEC) injury induced by lipopolysaccharide (LPS) and a cecal ligation and perforation (CLP) sepsis model in Sprague Dawley (SD) rats. The cell model and animal model of sepsis were divided into control groups and different treatment groups that received different doses of BXD. We utilized HIECs with PINK1 knockdown to assess BXD's protective effects on the sepsis intestinal barrier and its regulatory mechanism both on the PINK1/Parkin signaling pathway, exploring both its facilitative and inhibitory effects. ELISA method was used to measure inflammatory markers IL-6, IL-1β, and intestinal injury-related molecules IFABP and DAO. Pathological assessments were performed with H&E staining, and tight junction proteins ZO-1 and Occludin were detected using immunohistochemical staining. Mitochondrial membrane protein TOM20 was detected through immunofluorescence staining. Mitochondrial membrane potential and autophagy were assessed via flow cytometry. The expression levels of PINK1, Park, LC3, and p62 proteins and mRNA, integral to the PINK1/Parkin autophagy pathway, were evaluated using Western Blot and RT-PCR.
    RESULTS: Compared to the control group, BXD therapy significantly lowered serum DAO, IFABP, and DA. The BXD therapy group showed a more significant and sustained drop in IL-6 and IL-1β levels than the control group. The BXD therapy reduced intestinal mucosa damage by lowering DAO and IFABP. BXD also restored tight junction proteins ZO-1 and Occludin, improving intestinal mucosal barrier function. In septic rats, BXD therapy lowered serum IL-6 and IL-1β levels, avoiding inflammation and reducing intestinal damage. BXD enhanced TOM20, which protected intestinal epithelial cell mitochondria against decreasing mitochondrial membrane potential. BXD increased the PINK1/Parkin mitochondrial autophagy pathway at the molecular level. Mitochondrial autophagy can repair mitochondria, reduce oxidative stress, maintain mitochondrial homeostasis, and help intestinal epithelial cells survive and function.
    CONCLUSION: BXD could improve intestinal mucosal damage and systemic inflammation caused by sepsis. BXD mainly promotes the PINK1/Parkin mitophagy pathway by upregulating PINK1 protein.
    Keywords:  PINK1/parkin pathway.; Sepsis; banxia xiexin decoction; gastrointestinal dysfunctions; intestinal epithelial cells; mitochondrial autophagy
    DOI:  https://doi.org/10.2174/0113862073349597250410111941
  17. Eur J Pharmacol. 2025 Apr 25. pii: S0014-2999(25)00439-X. [Epub ahead of print]999 177685
    Targeting mitochondrial dynamics emerges as an effective strategy of cardioprotection against trastuzumab-induced mitochondrial functional aberrations and cardiotoxicity in rats.
    Chayodom Maneechote, Thawatchai Khuanjing, Benjamin Ongnok, Apiwan Arinno, Nanthip Prathumsap, Titikorn Chunchai, Busarin Arunsak, Wichwara Nawara, Siriporn C Chattipakorn, Nipon Chattipakorn.
      Trastuzumab (Trz) is a targeted anticancer therapy that specifically acts on tumors overexpressing the human epidermal growth factor receptor 2 (HER2) protein. Previous research has shown that Trz can induce cardiotoxicity by altering mitochondrial function. While modulating mitochondrial dynamics with Mdivi-1 and M1 has shown cardioprotective effects in various cardiac conditions, their impact on Trz-induced cardiotoxicity in rats remains unclear. In this study, thirty-two male Wistar rats were divided into a control group (CON, n = 8) and a Trz-treated group (4 mg/kg/day, i.p. for 7 days, n = 24). The Trz group was further randomized into subgroups receiving either: 1) vehicle (VEH, 3 % DMSO, i.p., n = 8), 2) the mitochondrial fission inhibitor Mdivi-1 (MDV, 1.2 mg/kg/day, i.p., n = 8), or 3) the mitochondrial fusion promoter M1 (2 mg/kg/day, i.p., n = 8). All interventions began on the first day of Trz administration and continued for 7 days. At the end, cardiac function was then assessed, and heart tissue was collected for biochemical analysis. Trz-treated rats exhibited cardiotoxicity, including cardiac dysfunction and injury, as well as disrupted mitochondrial and autophagic processes, increased inflammation, oxidative stress, apoptosis, ferroptosis, and pyroptosis. Co-administration of either Mdivi-1 or M1 with Trz alleviated these harmful effects, suggesting that modulating mitochondrial dynamics might offer a novel therapeutic strategy to mitigate Trz-induced cardiotoxicity.
    Keywords:  Cardiotoxicity; Chemotherapy; Mitochondrial dynamics; Mitochondrial fission; Mitochondrial fusion; Trastuzumab
    DOI:  https://doi.org/10.1016/j.ejphar.2025.177685
  18. Life Sci. 2025 Apr 24. pii: S0024-3205(25)00293-0. [Epub ahead of print]373 123658
    Excessive mitochondrial fission and associated extracellular mitochondria mediate cardiac dysfunction in obesity cardiomyopathy.
    Sin-Jin Li, Laura H Tetri, Vijith Vijayan, Aly Elezaby, Chun-Hsien Chiang, Ivan Lopez, Nicolai P Ostberg, Timothy T Cornell, Ching-Yi Chen, Bereketeab Haileselassie.
       AIMS: Obesity cardiomyopathy (OCM) is associated with mitochondrial dysfunction caused by altered mitochondrial dynamics. Extracellular mitochondria (exMito) are released following tissue injury under various conditions. While the excessive mitochondrial fission-mediated release of exMito as a mechanism for mitochondrial quality control in several inflammatory disorders, its role in OCM remains unclear. The present work aimed to determine if excessive mitochondrial fission and associated exMito mediate the chronic inflammatory response and cardiac remodeling in OCM.
    MATERIALS AND METHODS: H9c2 cardiomyoblasts were treated with 200 μM palmitate (PA) to induce lipotoxicity. C57BL/6J mice were fed a high-fat diet (HFD) for 12 weeks to induce OCM. P110, a peptide inhibitor of Drp1/Fis1 interaction, was used to evaluate the impact of excessive mitochondrial fission on cardiac mitochondrial function, quality, and quantity of exMito, systemic inflammatory response, and cardiac contractile function in both models of OCM.
    KEY FINDINGS: PA induced excessive mitochondrial fission, increased oxidative stress, decreased ATP level, and damaged exMito release in vitro. Exposure of naïve cardiomyoblasts to exMito isolated from PA treated cells resulted in mitochondrial dysfunction and a pro-inflammatory response. In vivo, HFD induced cardiac mitochondrial and contractile dysfunction, exMito release, and a pro-inflammatory response. Inhibition of Drp1/Fis1 interaction with P110 attenuated the observed effects both in vitro and in vivo.
    SIGNIFICANCE: P110 limited lipid-induced mitochondrial dysfunction and decreased exMito release, subsequently improving the inflammatory state and contractile function in our OCM model. Drp1/Fis1 dependent fission and associated exMito release might serve as a therapeutic target for obesity induced cardiomyopathy.
    Keywords:  Extracellular mitochondria; Fission; Lipotoxicity; Mitochondrial dynamics; Obesity cardiomyopathy; P110
    DOI:  https://doi.org/10.1016/j.lfs.2025.123658
  19. Cell Death Discov. 2025 Apr 26. 11(1): 204
    Sex and region-specific disruption of autophagy and mitophagy in Alzheimer's disease: linking cellular dysfunction to cognitive decline.
    Aida Adlimoghaddam, Fariba Fayazbakhsh, Mohsen Mohammadi, Zeinab Babaei, Amir Barzegar Behrooz, Farhad Tabasi, Teng Guan, Iman Beheshti, Mahmoud Aghaei, Daniel J Klionsky, Benedict C Albensi, Saeid Ghavami.
      Macroautophagy and mitophagy are critical processes in Alzheimer's disease (AD), yet their links to behavioral outcomes, particularly sex-specific differences, are not fully understood. This study investigates autophagic (LC3B-II, SQSTM1) and mitophagic (BNIP3L, BNIP3, BCL2L13) markers in the cortex and hippocampus of male and female 3xTg-AD mice, using western blotting, transmission electron microscopy (TEM), and behavioral tests (novel object recognition and novel object placement). Significant sex-specific differences emerged: female 3xTg-AD mice exhibited autophagosome accumulation due to impaired degradation in the cortex, while males showed fewer autophagosomes, especially in the hippocampus, without significant degradation changes. TEM analyses demonstrated variations in mitochondrial and mitophagosome numbers correlated with memory outcomes. Females had enhanced mitophagy, with higher BNIP3L and BCL2L13 levels, whereas males showed elevated BNIP3 dimers. Cognitive deficits in females correlated with mitochondrial dysfunction in the cortex, while in males, higher LC3B-II levels associated positively with cognitive performance, suggesting protective autophagy effects. Using machine learning, we predicted mitophagosome and mitochondrial numbers based on behavioral data, pioneering a predictive approach to cellular outcomes in AD. These findings underscore the importance of sex-specific regulation of autophagy and mitophagy in AD and support personalized therapeutic approaches targeting these pathways. Integrating machine learning emphasizes its potential to advance neurodegenerative research. Sex-specific differences in autophagy and mitophagy regulation in Alzheimer's disease (AD) are highlighted. Female 3xTg-AD mice show autophagosome accumulation and cognitive deficits, while males exhibit variations in mitophagy markers and behavior.
    DOI:  https://doi.org/10.1038/s41420-025-02490-0
  20. Biochim Biophys Acta Mol Basis Dis. 2025 Apr 23. pii: S0925-4439(25)00214-5. [Epub ahead of print]1871(6): 167866
    TSPO participates in the pathogenesis of diabetic periodontitis related to mitophagy.
    Weiqiu Jin, Daiyu Lu, Wei Wei, Min Wang, Rixin Chen, Fuhua Yan, Yanfen Li.
       OBJECTIVES: Diabetic periodontitis (DP) appears to be the sixth most common complication of diabetes; however, its underlying pathological mechanisms require further explored. Our study investigated the potential function of the translocator protein (TSPO) in the progression of DP, aiming to provide a theoretical foundation for novel treatment strategies.
    METHODS: The ultrastructure and TSPO expression of gingival tissue, collected from healthy individuals, people with periodontitis, and those with DP, were examined. In vivo, a DP model in rats was established using streptozotocin (STZ) and silk ligation. TSPO ligand antagonist PK 11195 was administered as a treatment. Microcomputed tomography (Micro-CT), quantitative real-time polymerase chain reaction (qPCR), histology and immunohistochemistry were employed to assess the destruction, inflammatory and mitophagy in rat periodontal tissues. In in vitro experiments, the inflammatory responses, mitochondrial function, mitophagy and the potential role of TSPO in macrophages were also examined under high-glucose inflammatory conditions, using flow cytometry, fluorescence probes, qPCR, Western blotting and transcription inhibition.
    RESULTS: Mitochondrial damage, mitophagy inhibition and increased TSPO expression were observed in gingivae from patients with DP. PK 11195 facilitated the restoration of mitophagy and alleviated the inflammatory destruction of DP rats. Additionally, the high-glucose inflammatory environment intensified the macrophage inflammatory response, ROS production, and mitochondrial damage. These pathological changes were reduced by TSPO inhibition, which could also upregulate the mitophagy.
    CONCLUSIONS: The inflammation and destruction of periodontal tissue in DP are closely linked to mitophagy associated with TSPO. Immunotherapy targeting TSPO in macrophages could significantly influence the treatment of DP by modulating mitophagy.
    Keywords:  Diabetic periodontitis (DP); Inflammation; Mitophagy; ROS; TSPO
    DOI:  https://doi.org/10.1016/j.bbadis.2025.167866
  21. Cell Immunol. 2025 Apr 19. pii: S0008-8749(25)00040-1. [Epub ahead of print]411-412 104955
    Lupeol mitigates spinal cord injury by modulating microglial M1/M2 polarization via Na+/K+-ATPase-mediated mitophagy.
    Ruyin Liu, Zongjin Yue, Jia'an Dong, Cheng Zhang, Chuanghao Guo, Xinli Wang.
      Spinal cord injury (SCI) often results in severe disability or even death, with inflammation playing a critical role in hindering recovery. Although Lupeol is known for its potent anti-inflammatory properties, its specific role in SCI-induced inflammation remains underexplored. In this study, an in vitro inflammation model was established using LPS-stimulated BV2 microglia. Lupeol treatment effectively counteracted LPS-induced reductions in Na+/K+-ATPase (NKA) activity, suppression of mitophagy, M1 polarization of microglia, release of inflammatory factors, and increased pyroptosis. Mechanistically, Lupeol alleviated microglial inflammation by enhancing mitophagy through the activation of NKA activity. Furthermore, Lupeol upregulated NKA activity and mitophagy by activating the AMPKα2-mTOR-TFEB pathway. In vivo, a mouse model of SCI was established, and Lupeol was administered daily via intraperitoneal injection. Lupeol treatment significantly reduced neuronal loss, promoted microglial polarization from the M1 to the M2 phenotype, attenuated inflammation, and improved motor function recovery in SCI mice. In conclusion, Lupeol promotes mitophagy by enhancing NKA activity via the AMPK-mTOR-TFEB pathway, thereby suppressing the pro-inflammatory phenotype of microglia and mitigating SCI progression.
    Keywords:  Glial activation; Inflammation; Lupeol; Mitophagy; Na(+)/K(+)-ATPase; Spinal cord injury
    DOI:  https://doi.org/10.1016/j.cellimm.2025.104955
  22. Int J Med Sci. 2025 ;22(9): 2075-2087
    Emodin: an alveolar macrophage protector in acute pancreatitis induced lung injury.
    Zhe Chen, Xuanchi Dong, Yongwei Song, Bowen Lan, Yalan Luo, Haiyun Wen, Hailong Chen.
      Background: Emodin (EMO), an anthraquinone derivative from roots and leaves of various plants, has been widely used in many inflammatory diseases. Alveolar macrophages (AMs) play a critical role in maintaining alveolar homeostasis in the lung. However, the comprehensive mechanisms of EMO therapy on AMs during acute pancreatitis-associated lung injury (AP-ALI) have not been reported. Methods: Both in vivo [caerulein/ lipopolysaccharides (LPS)-induced AP-ALI in mice] and in vitro MH-S models were generated to assess the protective features of EMO on mitochondrial damage and mitophagy dysfunction of AMs during AP-ALI progression. Results: First, in vivo, the relative quantity of AMs was significantly decreased with time in AP-ALI mice; however, the mitochondrial flux presented earlier changes than the relative quantity of AMs in our experimental system. EMO pretreatment significantly alleviated the severity of lung injury and improved the damaged alveolar structure, reversing mitochondrial impairment in AMs. Secondly, in vitro, EMO significantly enhanced mitophagy and alleviated mitochondrial damage. Furthermore, the results following mitophagy inhibition by 3-methyladenine (3-MA) demonstrated that the protective effects of EMO were partially achieved by manipulating the mitophagy-mitochondria-alveolar macrophage axis. Conclusion: These data enabled a more comprehensive understanding of the therapeutic effects of EMO in AP-ALI.
    Keywords:  alveolar macrophage; mitochondrial damage; mitochondrial membrane potential; mitophagy dysfunction
    DOI:  https://doi.org/10.7150/ijms.105965
  23. Int Immunopharmacol. 2025 Apr 29. pii: S1567-5769(25)00731-3. [Epub ahead of print]157 114741
    Dendrobine attenuates sepsis-associated acute kidney injury by promoting PINK1/PARKIN-mediated mitophagy.
    Chang Hu, Zhenying Wu, Tianlong Li, Jiachen Qu, Le Li, Bo Hu, Yiming Li, Zhiyong Peng.
      Sepsis-associated acute kidney injury (SA-AKI) is a severe condition with high mortality rates and a lack of specific treatments. Dendrobine (DEN) has shown diverse pharmacological effects across different diseases. Nonetheless, its impact on SA-AKI remains unexplored. This study aimed to investigate DEN's therapeutic potential in SA-AKI and elucidate its mechanism of action. In vivo, SA-AKI models were induced through cecal ligation and puncture or lipopolysaccharide (LPS) administration, while in vitro model was established using LPS-stimulated HK-2 cells. We found that pre-treatment with DEN reduced levels of inflammation-related cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6), and improved kidney function in SA-AKI both in vitro and in vivo. RNA-seq analysis unveiled the critical role of mitophagy in DEN treatment for SA-AKI. We observed an initial increase in mitophagy-related proteins such as PINK1, PARKIN, and LC3B/A, peaking at 8 h post-LPS stimulation, followed by a subsequent decline. Additionally, we demonstrated that DEN upregulated the expression of mitophagy-associated proteins in both in vitro and in vivo SA-AKI models. Notably, we found that carbonyl cyanide 3-chlorophenylhydrazone (CCCP) increased LC3B/A levels in DEN treatment for SA-AKI, whereas Mdivi-1 counteracted the effect of DEN on PINK1, PARKIN, and LC3B/A. These findings demonstrated that DEN enhances mitophagy through the activation of PINK1/PARKIN-mediated pathways, thus mitigating SA-AKI.
    Keywords:  Acute kidney injury; Dendrobine; Mitophagy; Sepsis
    DOI:  https://doi.org/10.1016/j.intimp.2025.114741
  24. Sci Rep. 2025 Apr 26. 15(1): 14633
    Astaxanthin supplementation in Arabian racing horses mitigates oxidative stress and inflammation in peripheral blood mononuclear cells through enhanced mitophagy.
    Beata Giercuszkiewicz-Hecold, David Pajuelo, Zofia Steczkiewicz, Anna Cywinska, Krzysztof Marycz.
      Astaxanthin, a strong antioxidant carotenoid, has shown promising features in mitigating inflammation and oxidative stress and so that has been considered as a supplement for high-performance animals. In this study, we aimed to evaluate the effects of astaxanthin on oxidative stress, inflammation, and mitochondrial health in peripheral blood mononuclear cells (PBMC) isolated from Arabian racehorses. Horse-derived peripheral blood mononuclear cells exposed to hydrogen peroxide (H₂O₂) presented increased reactive oxygen species (ROS) accumulation and overexpression of pro-inflammatory cytokines such as IL-1β, IL-6, IFN-γ, and TNF-α. The addition of astaxanthin to cell culture reduced H₂O₂-induced inflammatory response by decreasing the expression levels of all the tested pro-inflammatory cytokines. Moreover, astaxanthin displayed a potential antioxidant response by increasing the expression of genes related to antioxidative defense, such as NRF1, SOD2, and GPX. Interestingly, PBMCs isolated from the horses orally supplemented with astaxanthin increased the expression of the mitophagy-related genes PINK1 and PARKIN. Moreover, genes related to mitochondrial dynamics and energy production, such as PPARGC1B, NDUFA9, and MRPL24, as well as genes associated with mitochondrial function, structure and dynamics, such as PIGBOS, MRLP24, PUSL1 and TFAM were upregulated in PBMCs isolated from astaxanthin supplemented horses. Altogether, these findings indicate that astaxanthin may be a beneficial dietary supplement for equine health, supporting resilience against oxidative stress and inflammatory challenges, and improving the recovery and performance of racing horses.
    Keywords:  Astaxanthin; Dietary supplementation; Horses; Inflammation; Mitochondria; Oxidative stress; PBMC
    DOI:  https://doi.org/10.1038/s41598-025-93661-7
  25. J Pharm Anal. 2025 Apr;15(4): 101146
    Mitochondrial quality control disorder in neurodegenerative disorders: Potential and advantages of traditional Chinese medicines.
    Lei Xu, Tao Zhang, Baojie Zhu, Honglin Tao, Yue Liu, Xianfeng Liu, Yi Zhang, Xianli Meng.
      Neurodegenerative disorders (NDDs) are prevalent chronic conditions characterized by progressive synaptic loss and pathological protein alterations. Increasing evidence suggested that mitochondrial quality control (MQC) serves as the key cellular process responsible for clearing misfolded proteins and impaired mitochondria. Herein, we provided a comprehensive analysis of the mechanisms through which MQC mediates the onset and progression of NDDs, emphasizing mitochondrial dynamic stability, the clearance of damaged mitochondria, and the generation of new mitochondria. In addition, traditional Chinese medicines (TCMs) and their active monomers targeting MQC in NDD treatment have been demonstrated. Consequently, we compiled the TCMs that show great potential in the treatment of NDDs by targeting MQC, aiming to offer novel insights and a scientific foundation for the use of MQC stabilizers in NDD prevention and treatment.
    Keywords:  Mitochondrial quality control; Neurodegenerative disorder; Traditional Chinese medicine
    DOI:  https://doi.org/10.1016/j.jpha.2024.101146
  26. Cell Biol Toxicol. 2025 Apr 29. 41(1): 77
    Mechanism of lncRNA gadd7 regulating mitofusin 1 expression by recruiting LSD1 to down-regulate H3K9me3 level, and mediating mitophagy in alveolar type II epithelial cell apoptosis in hyperoxia-induced acute lung injury.
    Guoyue Liu, Guiyang Jia, Yingcong Ren, Cunzhi Yin, Xuan Xiao, Hang Wu, Jun Liu, Miao Chen.
       OBJECTIVE: Hyperoxic exposure induces acute lung injury (ALI). We analyzed the mechanism of long non-coding RNA (lncRNA) growth-arrested DNA damage-inducible gene 7 (gadd7) regulating mitofusin 1 (MFN1) in Hyperoxia-induced ALI (HALI) type II alveolar epithelial cell (AEC II) apoptosis.
    METHODS: The HALI rat model was generated using hyperoxic induction and treated with shRNA-gadd7 and rapamycin (Rapa), with ALI, apoptotic level, total protein concentration and total cell, neutrophil and macrophage counts assessed. The HALI cell model was developed on hyperoxia-induced RLE-6TN cells and processed with oe-MFN1, si-gadd7 and Rapa. Cell viability, apoptosis, TOM20/LC3BII co-localization, mitochondrial membrane potential (MMP), superoxide dismutase activity, malonaldehyde, reactive oxygen species (ROS), tumor necrosis factor-α, interleukin (IL)-10, IL-6, IL-1β, gadd7, MFN1, Cleaved caspase-3, Cleaved poly (ADP-ribose) polymerase, B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X, LC3BI/II, lysine-specific demethylase 1 (LSD1), p62, and H3K9me3 protein levels were measured. gadd7-LSD1 interaction was predicted and verified by RPISeq database, RIP, and RNA pull-down assay.
    RESULTS: In HALI rats, gadd7 was up-regulated in lung tissues, and gadd7 silencing alleviated oxidative stress, ALI and apoptosis. gadd7 knockdown inhibited oxidative stress and apoptosis though MFN1, and mediated mitophagy (evidenced by diminished LC3BII/LC3BI ratio, TOM20/LC3BII co-localization and ROS level, and elevated p62 level and MMP), which were reversed by mitophagy activation. By recruiting LSD1 to down-regulate H3K9me3 level and promote MFN1 expression, gadd7-mediated mitophagy affected ALI and apoptosis in HALI rats.
    CONCLUSION: LncRNA gadd7 regulated MFN1 expression by recruiting LSD1 to down-regulate H3K9me3 level and mediate mitophagy, thereby promoting AEC II apoptosis in HALI.
    Keywords:  Alveolar type II epithelial cells; Apoptosis; Epigenetics; Growth-arrested DNA damage-inducible gene 7; H3K9me3; Hyperoxia-induced acute lung injury; Lysine-specific demethylase 1; Mitofusin 1; Mitophagy
    DOI:  https://doi.org/10.1007/s10565-025-10021-x
  27. Theranostics. 2025 ;15(11): 5499-5517
    Nitric oxide-primed engineered extracellular vesicles restore bioenergetics in acute kidney injury via mitochondrial transfer.
    Fei Peng, Xiaoniao Chen, Lingling Wu, Jiayi He, Zongjin Li, Quan Hong, Qiang Zhao, Meng Qian, Xu Wang, Wanjun Shen, Tingting Qi, Yiyu Huang, Guangyan Cai, Chuyue Zhang, Xiangmei Chen.
      Background: The disruption of mitochondrial homeostasis in acute kidney injury (AKI) is an important factor that drives persistent renal dysfunction. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have shown great therapeutic potential in AKI, but insufficient specificity of targeting the impaired mitochondrial function. Herein, we developed an engineered nitric oxide (NO)-primed MSC-EVs (pEVs) to restore mitochondrial homeostasis for AKI therapy. Methods: A cisplatin-induced AKI model was established to investigate the therapeutic effects of MSC-EVs. Proteomic and Western blot analyses compared mitochondrial cargos and functional assays included mitochondrial complex I activity and Adenosine triphosphate (ATP) quantification. Mitochondrial transfer was tracked using flow cytometry and confocal imaging. Mitochondrial dynamics, oxidative stress, and apoptosis were evaluated through ATP measurement, western blotting and rotenone-mediated respiratory chain inhibition. Results: Our data indicated that pEVs outperformed cEVs in restoring renal function and histopathology. Additionally, a reduction in mitochondria-associated oxidative stress and cell death was observed. Proteomic profiling revealed that NO priming enriched pEVs with mitochondrial complex I components, which directly enhanced their bioenergetic capacity, as evidenced by higher mitochondrial complex I activity and elevated ATP production compared to cEVs. In vivo tracking confirmed targeted delivery of pEV-derived mitochondrial contents to renal tubular cells, reducing mitochondrial reactive oxygen species (ROS) and restoring mitochondrial mass. Crucially, mitochondria-depleted pEVs abolished these therapeutic effects, establishing mitochondrial cargos as the primary therapeutic driver. Furthermore, pEVs activated a pro-survival cascade in recipient cells, showing superior efficacy in promoting mitochondrial biogenesis, dynamics, and mitophagy, thereby restoring renal mitochondrial homeostasis. Conclusion: Our study elucidated a mitochondria-targeted therapeutic strategy enabled by engineered EVs that deliver functional cargo to restore mitochondrial homeostasis. These advances provide transformative potential for AKI and other mitochondrial disorders.
    Keywords:  Acute kidney injury.; Extracellular vesicles; Mesenchymal stem cells; Mitochondrial homeostasis; Nitric oxide
    DOI:  https://doi.org/10.7150/thno.113741
  28. Front Pharmacol. 2025 ;16 1571767
    Natural small molecules regulating the mitophagy pathway counteract the pathogenesis of diabetes and chronic complications.
    Du Ye, Junping Zhu, Siya Su, Yunfeng Yu, Jun Zhang, Yuman Yin, Chuanquan Lin, Xuejiao Xie, Qin Xiang, Rong Yu.
      Diabetes mellitus (DM) is a chronic metabolic disorder marked by sustained hyperglycemia. These disturbances contribute to extensive damage across various tissues and organs, giving rise to severe complications such as vision loss, kidney failure, amputations, and higher morbidity and mortality rates. Furthermore, DM imposes a substantial economic and emotional burden on patients, families, and healthcare systems. Mitophagy, a selective process that targets the clearance of damaged or dysfunctional mitochondria, is pivotal for sustaining cellular homeostasis through mitochondrial turnover and recycling. Emerging evidence indicates that dysfunctional mitophagy acts as a key pathogenic driver in the pathogenesis of DM and its associated complications. Natural small molecules are particularly attractive in this regard, offering advantages such as low toxicity, favorable pharmacokinetic profiles, excellent biocompatibility, and a broad range of biochemical activities. This review systematically evaluates the mechanistic roles of natural small molecules-including ginsenosides, resveratrol, and berberine-in enhancing mitophagy and restoring mitochondrial homeostasis via activation of core signaling pathways (e.g., PINK1/Parkin, BNIP3/NIX, and FUNDC1). These pathways collectively ameliorate pathological hallmarks of DM, such as oxidative stress, chronic inflammation, and insulin resistance. Furthermore, the integration of nanotechnology with these compounds optimizes their bioavailability and tissue-specific targeting, thereby establishing a transformative therapeutic platform for DM management. Current evidence demonstrates that mitophagy modulation by natural small molecules not only offers novel therapeutic strategies for DM and its chronic complications but also advances the mechanistic foundation for future drug development targeting metabolic disorders.
    Keywords:  diabetes mellitus; mitophagy; natural small molecules; review; signaling pathway
    DOI:  https://doi.org/10.3389/fphar.2025.1571767
  29. Biomed Pharmacother. 2025 Apr 25. pii: S0753-3322(25)00285-9. [Epub ahead of print]187 118091
    Harnessing Nur77's mitochondrial apoptotic pathway: A promising therapeutic strategy for targeted disease intervention.
    Ruihai Fu, Dandan Ling, Qiqi Zhang, Aifang Jiang, Haiyan Pang.
      The role of mitochondria in disease development cannot be overlooked, and the targeting of mitochondria for the treatment of disease has emerged as a significant area of research in recent years. Mitochondria are the control center of the intrinsic apoptotic pathway, and their normal functions are finely regulated by a series of complex mechanisms. The nuclear receptor Nur77 is closely related to the functions of the mitochondria and is an active pro-apoptotic member of the nuclear receptor superfamily. The translocation of Nur77 to the mitochondria can promote the conversion of the anti-apoptotic protein Bcl-2 to a pro-apoptotic state, disrupt the balance between mitochondrial fission and fusion, and inhibit mitophagy. These effects lead to irreversible damage to mitochondria and apoptosis, ultimately accelerating the progression of the disease. Here, we review the mechanism and targeted drug development of the mitochondrial apoptosis pathway activated by Nur77 in human diseases, helping to understand the new advances in disease treatment.
    Keywords:  Apoptosis; Bcl-2; Mitochondria; Mitochondrial dynamics; Mitophagy; Nur77
    DOI:  https://doi.org/10.1016/j.biopha.2025.118091
  30. Hereditas. 2025 Apr 26. 162(1): 70
    Identification of mitophagy-related genes in patients with acute myocardial infarction.
    Ju-Ying Li, Hong-Kui Chen, Yi-Hao Huang, Yu-Peng Zhi, Yue-E Li, Kai-Yang Lin, Chun Chen, Yan-Song Guo.
      Mitophagy is involved in acute myocardial infarction (AMI) process. However, the role of mitophagy-related genes (MRGs) in the AMI process is not well illustrated. We identified MRGs involved in AMI by bioinformatics analysis. The external datasets were employed for the validation of the MRGs, alongside the execution of cellular and animal experiments. Forty-five MRGs were detected, and machine learning identified the top four hub genes, namely ALDH2, ACSL1, IL1B, and GABARAPL1. Additionally, an external validation set was used to screen for three diagnostic markers (ACSL1, IL1B, and GABARAPL1) among these hub genes. Immune infiltration analysis revealed changes in the immune microenvironment among patients with AMI. Finally, the significant upregulation of ACSL1, IL1B, and GABARAPL1 in both cellular and animal models was confirmed. The occurrence of mitophagy was observed in the cell model through transmission electron microscopy (TEM). Our study demonstrated that ACSL1, IL1B, and GABARAPL1 possess potential biomarkers for AMI.
    DOI:  https://doi.org/10.1186/s41065-025-00424-5
  31. J Microbiol Biotechnol. 2025 Apr 24. 35 e2501025
    Cynaropicrin Suppresses Cell Proliferation by Inducing Mitophagy through p38 MAPK-Mediated Mitochondrial ROS Generation in Human Hepatocellular Carcinoma Cells.
    Min Yeong Kim, Hyun Hwangbo, Seon Yeong Ji, Da Hye Kim, Shin-Hyung Park, Su Hyun Hong, Gi Young Kim, EunJin Bang, Yung Hyun Choi.
      Cynaropicrin, a sesquiterpene lactone, has diverse pharmacological activities. However, its anticancer activity against hepatocellular carcinoma (HCC) has not been fully elucidated. Here, we investigated the cytotoxic effects of cynaropicrin and examined its mechanism of action in human HCC cells. The results demonstrated that cynaropicrin significantly induced cytotoxicity and autophagy in HCC cells, but not in immortalized non-cancerous hepatocytes, which was related to the generation of mitochondrial reactive oxygen species (mtROS) and induction of mitochondrial membrane potential loss. Under cynaropicrin treatment, the expression of microtubule-associated protein light chain 3, which is involved in the elongation of the phagophore membrane, was upregulated, whereas the expression of Beclin-1 and p62, which are essential for the formation of autophagosomes, was downregulated. In addition, the expression of mitophagy regulators PTEN-induced kinase 1 (PINK1) and Parkin in the mitochondria increased, suggesting the induction of autophagic flux in the mitochondria. However, N-acetyl-l-cysteine, a ROS scavenger, counteracted cynaropicrin-induced effects. Moreover, cynaropicrin increased the phosphorylation of p38 mitogen-activated protein kinase (MAPK), and the p38 MAPK inhibitor, SB203580, specifically attenuated cynaropicrin-induced cytotoxicity and mtROS production. Importantly, SB203580 reversed cynaropicrin-induced expression of PINK1 and Parkin in the mitochondria. Collectively, our findings demonstrate that cynaropicrin exerts cytotoxic effects against HCC cells by inducing mitochondrial autophagy through the activation of the p38 MAPK-ROS pathway, indicating that cynaropicrin could be a potential therapeutic agent for liver cancer treatment.
    Keywords:  Cynaropicrin; hepatocellular carcinoma cells; mitophagy; p38 MAPK; reactive oxygen species
    DOI:  https://doi.org/10.4014/jmb.2501.01025
  32. Alzheimers Dement. 2025 Apr;21(4): e70198
    Genome-wide association analysis identifies APOE as a mitophagy modifier in Lewy body disease.
    Xu Hou, Michael G Heckman, Fabienne C Fiesel, Shunsuke Koga, Alexandra I Soto-Beasley, Jens O Watzlawik, Jing Zhao, Rebecca R Valentino, Patrick W Johnson, Launia J White, Zachary S Quicksall, Joseph S Reddy, Jose Bras, Rita Guerreiro, Na Zhao, Guojun Bu, Dennis W Dickson, Owen A Ross, Wolfdieter Springer.
       INTRODUCTION: Phosphorylated ubiquitin (p-S65-Ub) is generated during PINK1-PRKN mitophagy as a specific marker of mitochondrial damage. Despite the widespread deposition of p-S65-Ub in aged and diseased human brain, the genetic contribution to its accumulation remains unclear.
    METHODS: To identify novel mitophagy regulators, we performed a genome-wide association study using p-S65-Ub level as a quantitative trait in 1012 autopsy-confirmed Lewy body disease (LBD) samples.
    RESULTS: We identified a significant genome-wide association with p-S65-Ub for rs429358 (apolipoprotein E ε4 [APOE4]) and a suggestive association for rs6480922 (ZMIZ1). APOE4 was associated with higher p-S65-Ub levels and greater neuropathological burden. Functional validation in mouse and human induced pluripotent stem cell (iPSC) models confirmed APOE4-mediated mitophagy alterations. Intriguingly, ZMIZ1 rs6480922 was associated with lower p-S65-Ub levels, reduced neuropathological load, and increased brain weight, indicating a potential protective role.
    DISCUSSION: Our findings underscore the importance of mitochondrial quality control in LBD pathogenesis and nominate regulators that may contribute to disease risk or resilience.
    HIGHLIGHTS: p-S65-Ub levels were used as a quantitative marker of mitochondrial damage. A GWAS identified two genetic variants that modify mitophagy in LBD autopsy brain. APOE4 was associated with increased p-S65-Ub accumulation and neuropathology. APOE4 altered mitophagy via pathology-dependent and pathology-independent mechanisms. ZMIZ1 was linked to reduced p-S65-Ub and neuropathology indicative of protection.
    Keywords:  GWAS; PINK1; PRKN; Parkin; Parkinson's disease; ZMIZ1; autophagy; mitochondria; phosphorylated ubiquitin; ubiquitin
    DOI:  https://doi.org/10.1002/alz.70198
  33. Med Sci Sports Exerc. 2025 May 01.
    Combining In Vivo 2-Photon Imaging with Photoactivatable Fluorescent Labeling Shows Low Rates of Mitochondrial Dynamics in Skeletal Muscle.
    Colleen L O'Reilly, Arik Davidyan, Katarzyna Cizio, Stephen M Doidge, Matthew P Bubak, Agnieszka K Borowik, Tommy L Lewis, Benjamin F Miller.
       INTRODUCTION: Mitochondrial dynamics involve two distinct and opposing processes, fusion and fission. Traditionally we assess fusion and fission by snapshots of protein markers at distinct time points or in vitro models to infer outcomes in vivo. Recent technological advancements enable visualization of mitochondrial dynamics in vivo using fluorescent microscopy.
    METHODS: Our study modified this technique to evaluate mitochondrial dynamics in skeletal muscle, comparing young (6mo) and old (24mo) mice in vivo and contrasting this to ex vivo and in vitro models. We hypothesized that in vitro and ex vivo models would have higher rates of dynamics than in vivo models and that young animals would have higher rates than old animals. We electroporated mitochondrial matrix-targeted photo-activatable GFP into the tibialis anterior (TA) of young and old C57Bl6 mice and imaged using multiphoton microscopy. We also measured rates of mitochondrial dynamics using single fibers isolated from the TA of the electroporated mice, as well as C2C12 myotubes transfected with the same plasmids.
    RESULTS: We found that the rates of dynamic events in vivo are slower than previously indicated, with the C2C12 myoblasts having the fastest rates of dynamic events across all models. We also observed that dynamic rates are slower in old animals compared to young animals. Finally, we found that rates of dynamic events were higher in old animals after an acute bout of exercise.
    CONCLUSIONS: Our data demonstrate it is possible to directly measure rates of mitochondrial dynamics in vivo. This technique provides a powerful tool to answer experimental questions about mitochondrial dynamics of skeletal muscle.
    Keywords:  FISSION; FUSION; MITOCHONDRIAL DYNAMICS; SKELETAL MUSCLE
    DOI:  https://doi.org/10.1249/MSS.0000000000003748
  34. Front Immunol. 2025 ;16 1509315
    The role and machine learning analysis of mitochondrial autophagy-related gene expression in lung adenocarcinoma.
    Binyu Wang, Di Liu, Danfei Shi, Xinmin Li, Yong Li.
       Objective: Lung adenocarcinoma (LUAD) continues to be a primary cause of cancer-related mortality globally, highlighting the urgent need for novel insights finto its molecular mechanisms. This study aims to investigate the relationship between gene expression and mitophagy in LUAD, with an emphasis on identifying key biomarkers and elucidating their roles in tumorigenesis and immune cell infiltration.
    Methods: We utilized datasets GSE151101 and GSE203609 from the Gene Expression Omnibus (GEO) database to identify differentially expressed genes (DEGs) associated with lung cancer and mitophagy. DEGs were identified using GEO2R, filtered based on criteria of P < 0.05 and log2 fold change ≥ 1. Subsequently, Weighted Gene Co-expression Network Analysis (WGCNA) was conducted to classify DEGs into modules. Functional annotation of these modules was performed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Gene Set Enrichment Analysis (GSEA) was applied to the most relevant module, designated as the greenyellow module. To identify critical biomarkers, machine learning algorithms including Random Forest, Least Absolute Shrinkage and Selection Operator (LASSO) regression, and Support Vector Machine (SVM) were employed. Validation of the findings was conducted using The Cancer Genome Atlas (TCGA) database, Human Protein Atlas (HPA), quantitative PCR (qPCR), and immune cell infiltration analysis via CIBERSORTx.
    Results: Our analysis identified 11,012 overlapping DEGs between the two datasets. WGCNA revealed 11 modules, with the green-yellow module exhibiting the highest correlation. Functional enrichment analysis highlighted significant associations with FOXM1 signaling pathways and retinoblastoma in cancer. Machine learning algorithms identified COASY, FTSJ1, and MOGS as pivotal genes. These findings were validated using TCGA data, qPCR experiments, which demonstrated high expression levels in LUAD samples. Immunohistochemistry from HPA confirmed consistency between protein levels and RNA-seq data. Furthermore, pan-cancer analysis indicated that these genes are highly expressed across various cancer types. Immune infiltration analysis suggested significant correlations between these genes and specific immune cell populations.
    Conclusion: COASY, FTSJ1 and MOGS have emerged as critical biomarkers in LUAD, potentially influencing tumorigenesis through mitophagy-related mechanisms and immune modulation. These findings provide promising avenues for future research into targeted therapies and diagnostic tools, thereby enhancing LUAD management.
    Keywords:  WGCNA; gene; lung adenocarcinoma; machine learning; mitochondrial autophagy
    DOI:  https://doi.org/10.3389/fimmu.2025.1509315
  35. Am J Physiol Endocrinol Metab. 2025 Apr 28.
    Loss of Ovarian Function Prevents Exercise-Induced Activation of Hepatic Mitophagic Flux.
    Edziu Franczak, Benjamin A Kugler, Sebastian F Salathe, Julie Allen, Mihaela E Sardiu, Colin S McCoin, Andrea L Hevener, E Matthew Morris, John P Thyfault.
      Exercise effectively treats metabolic dysfunction-associated steatotic liver disease (MASLD) by enhancing hepatic mitochondria energy metabolism. However, the efficiency of exercise in treating MASLD in post-menopausal women may be reduced. Previously, we showed acute treadmill exercise activates hepatic mitophagy, the selective degradation of low-functioning mitochondria. Mitophagic flux is differentially regulated in female mice compared to males, possibly by estrogen. Here, we tested if loss of ovarian function via ovariectomy (OVX), which reduces estrogen, drives MASLD and compromised hepatic mitochondrial energetics, would blunt activation of hepatic mitophagy induced by exercise. Following OVX, 12-15-week-old female mice were placed on a low-fat diet (LFD) or high-fat diet (HFD) for 4 weeks to induce MASLD, after which half of the mice performed a single acute bout of treadmill exercise to exhaustion or remained sedentary. Two hours post-exercise, isolated hepatic mitochondria were examined via western blotting and proteomics for accumulation of known mitophagy proteins. After exercise, reduced basal mitophagic flux in LFD-fed OVX was restored to levels found in Sham mice. However, exercise possessed blunted capacity to promote mitochondrial recruitment of DRP1 (regulator of fission) and accumulation mitophagy-associated proteins (E3-ubiquitin ligase, ubiquitin, autophagy adaptor proteins, and autophagosome cargo receptors) in OVX versus sham mice on HFD. Mitochondrial H2O2 production, which putatively activates mitophagy, was elevated following exercise in all conditions except OVX+HFD. In summary, OVX reduces mitophagic flux, blunting the stimulatory effects of exercise on these factors. The impaired regulation of mitophagy following cessation of ovarian function likely contributes to the pathogenesis of MASLD post-menopause.
    Keywords:  Female; Liver; Mitophagy; Proteomics; Steatosis
    DOI:  https://doi.org/10.1152/ajpendo.00107.2025
  36. Antioxidants (Basel). 2025 Mar 27. pii: 398. [Epub ahead of print]14(4):
    Hydroxytyrosol as a Mitochondrial Homeostasis Regulator: Implications in Metabolic Syndrome and Related Diseases.
    Jie Xu, Huanglong Wei, Zhenyu Sun, Wankang Li, Jiangang Long, Jiankang Liu, Zhihui Feng, Ke Cao.
      Hydroxytyrosol (HT), a principal bioactive phytochemical abundant in Mediterranean dietary sources, has emerged as a molecule of significant scientific interest owing to its multifaceted health-promoting properties. Accumulating evidence suggests that HT's therapeutic potential in metabolic disorders extends beyond conventional antioxidant capacity to encompass mitochondrial regulatory networks. This review synthesizes contemporary evidence from our systematic investigations and the existing literature to delineate HT's comprehensive modulatory effects on mitochondrial homeostasis. We systematically summarized the impact of HT on mitochondrial dynamics (fusion/fission equilibrium), biogenesis and energy metabolism, mitophagy, inter-organellar communication with the endoplasmic reticulum, and microbiota-mitochondria crosstalk. Through this multidimensional analysis, we established HT as a mitochondrial homeostasis modulator with potential therapeutic applications in metabolic syndrome (MetS) and its related pathologies including type 2 diabetes mellitus, obesity-related metabolic dysfunction, dyslipidemia, non-alcoholic steatohepatitis, and hypertension-related complications. Moreover, we further discussed translational challenges in HT research, emphasizing the imperative for direct target identification, mitochondrial-targeted delivery system development, and combinatorial therapeutic strategies. Collectively, this review provides a mechanistic framework for advancing HT research and accelerating its clinical implementation in MetS and its related diseases.
    Keywords:  hydroxytyrosol; metabolic syndrome; mitochondria; mitochondrial delivery system; synergistic therapies
    DOI:  https://doi.org/10.3390/antiox14040398
  37. Cell Mol Life Sci. 2025 Apr 28. 82(1): 186
    Progranulin enhances M2 macrophage polarization and renal fibrosis by modulating autophagy in chronic kidney disease.
    Wei-Chao Tu, Yi-Kun He, Da-Wei Wang, Shao-Xiong Ming, Yang Zhao.
       BACKGROUND: Chronic kidney disease (CKD) is a prevalent global health issue characterized by progressive renal dysfunction and fibrosis, often leading to end-stage renal failure. Renal fibrosis, a hallmark of CKD, is driven by complex immune responses, including macrophage polarization and inflammatory signaling pathways. Progranulin (PGRN), a glycoprotein involved in inflammation and tissue repair, has emerged as a key regulator in various fibrotic diseases. However, the precise role of PGRN in macrophage polarization and renal fibrosis in CKD remains unclear and warrants further investigation.
    METHODS: Renal tissue samples from CKD patients and unilateral ureteral obstruction (UUO)-induced mice were analyzed using immunohistochemistry, immunofluorescence, Western blotting, and qRT-PCR to assess fibrosis, macrophage infiltration, and key markers of autophagy and inflammation. Recombinant PGRN (rPGRN) was administered in vivo to assess its effects on renal fibrosis, macrophage polarization, and autophagic flux. To evaluate the role of PGRN, PGRN knockout (PGRN-/-) mice were also utilized. The effects of PGRN on autophagic flux and mitochondrial dynamics were studied using mCherry-GFP-LC3 dual-labeling, and macrophage polarization was analyzed by flow cytometry and cytokine profiling.
    RESULTS: PGRN expression is significantly elevated in CKD patients and UUO mice and is associated with increased macrophage infiltration and renal fibrosis. rPGRN administration in vivo aggravated fibrosis and promoted M2 macrophage polarization. In contrast, PGRN-/- mice showed reduced renal fibrosis, significantly reduced collagen deposition, and reduced expression of pro-fibrotic cytokines. In addition, the mitochondrial function of PGRN-/- renal fibrosis mice was improved, the mtDNA content of mouse kidney tissue was increased, the results of electron microscopy showed that the mitochondrial structure was relatively normal, the mitochondrial biogenesis related genes PGC1α, TOMM20 and Fis1 were up-regulated, and the levels of MFN2 and Drp1 were significantly reduced. In addition, autophagy related gene LC3 was decreased and P62 protein level was increased in PGRN-/- model mice. Mechanically, PGRN interacts with autophagy related proteins ATG5 and ATG12 to regulate autophagy flux through the PI3K-Akt signaling pathway and promote the polarization of M2 macrophages.
    CONCLUSION: PGRN plays a critical role in driving renal fibrosis by regulating macrophage polarization, autophagy, and mitochondrial dynamics. Our findings suggest that PGRN exacerbates CKD progression by promoting M2 macrophage polarization and disrupting autophagic processes, highlighting PGRN as a potential therapeutic target for the treatment of CKD and renal fibrosis.
    Keywords:  Autophagy; Chronic kidney disease; Macrophage polarization; Mitochondrial function; Progranulin; Renal fibrosis
    DOI:  https://doi.org/10.1007/s00018-025-05716-7
  38. Int Immunopharmacol. 2025 Apr 28. pii: S1567-5769(25)00689-7. [Epub ahead of print]157 114699
    Yellow fever virus infection alters mitochondrial network dynamics and trigger IFN-I response via TLR2 pathway.
    Carla Tomatis, Nancy Charo, María F Ferrer, Silvia Aquila, Federico Fuentes, María L Scalise, Mara C A M Aguiar, Gabriel Valdivieso, Eugenio A Carrera Silva, Ricardo M Gómez.
      It has been emphasized that mitochondria play a fundamental role not only in cellular bioenergetics but also in the defense against infections. Here, we investigated mitochondrial network dynamics (MND) and IFN-Iβ signaling response in epithelial A549 cells after yellow fever virus (YFV) infection. We analyze the MND when only some cells are infected at 1 day post-infection (dpi) and after the spread of viral infection, at 3 dpi. Confocal microscopy and MiNA analysis showed that YFV infection leads to a decrease in the number of branches at 3 dpi and an increase in the length of branches at 1 and 3 dpi, suggesting that mitochondrial fission and fusion occur. Consistent with both processes, we found increased transcription of mitofusin 1 and Drp1 and increased colocalization of mitochondria with Drp1 at 3 dpi. In addition, mitochondrial membrane polarization decreased, mtROS production increased, p62 expression decreased, and LC3 expression increased, suggesting an increase in mitophagy flux. We found decreased expression of the IFN inducers RIG-I and MAVS sensors in YFV-infected A549 cells a t 3 dpi. Surprisingly, increased IFN-Iβ levels were observed at transcriptional and protein levels along with IRF7 induction at 1 and 3 dpi. Using the blocking antibody against TLR2, we showed that IFN-Iβ and IL-6 synthesis is maintained by TLR2 signaling. Mechanistically, infection led to activation of the NFκB pathway by degradation of IkBα, and increased phosphorylation of P65 and ERK MAPK signaling. Our results show that YFV infection induces altered MND in epithelial cells and triggers TLR2 signaling.
    Keywords:  A549 cells; IFN-I; Mitochondrial network dynamics; Mitophagy; TLR2; Yellow fever virus
    DOI:  https://doi.org/10.1016/j.intimp.2025.114699
  39. Stem Cell Res Ther. 2025 May 01. 16(1): 218
    Puerarin relives inflammation, bone destruction and facilitates osteogenic differentiation in periodontitis by enhancing mitochondrial autophagy via activating mitochondrial Mitofusin 2.
    Yulan Xiang, Zelu Li, Xin He, Xiaoyang Chu, Chunyan Gao, Jiahao Guo, Yingyi Luan, Kai Yang, Dongliang Zhang.
       PURPOSE: Puerarin (Pue) has recently been reported to have therapeutic effects on periodontitis (PD). However, there is insufficient evidence, and the mechanism involved has not yet been revealed. This work delved to explore the exact therapeutic effects and molecular mechanism of Pue in treating PD.
    METHODS: PD mouse (C57BL/6 N mouse) model constructed by Porphyromonas gingivalis-lipopolysaccharide (Pg-LPS) induction was treated with Pue. Therapeutic efficacy of Pue for PD was examined by a series of experiments. PD cell model was induced by treating human periodontal ligament cells with Pg-LPS. Therapeutic effects of Pue on PD cell model, along with the potential molecular mechanism, were explored by logical experiments. Rescue experiments based on in vitro and in vivo studies were implemented to validate the molecular mechanism of Pue in treating PD.
    RESULTS: In PD mice, Pue treatment relieved inflammation and bone destruction, facilitated osteogenic differentiation and autophagy in periapical tissues. In PD cell model, Pue treatment facilitated osteogenic differentiation and mitochondrial autophagy; suppressed inflammation and mitochondrial reactive oxygen species; maintained mitochondrial membrane potential and mitochondrial kinetic homeostasis; and activated mitochondrial Mitofusin 2 (Mfn2). However, these influences of Pue on PD cell model were eliminated by CsA (mitochondrial autophagy inhibitor). The enhanced mitochondrial autophagy induced by Pue was reversed by Mfn2 silencing. Through in vivo data, Mfn2 knockdown counteracted the therapeutic effects of Pue on PD mice.
    CONCLUSION: Pue exerted therapeutic effects on PD, possibly by enhancing mitochondrial autophagy via activating mitochondrial Mfn2. This might be a cure for PD.
    Keywords:  Inflammation; Mfn2; Mitochondrial autophagy; Periodontitis; Puerarin
    DOI:  https://doi.org/10.1186/s13287-025-04355-w
  40. CNS Neurosci Ther. 2025 Apr;31(4): e70410
    VDAC1 Inhibition Protects Against Noise-Induced Hearing Loss via the PINK1/Parkin Pathway.
    Yuchen Jin, Wenqi Dong, Yumeng Jiang, Lingkang Dong, Zhuangzhuang Li, Dongzhen Yu.
       AIMS: This study examined the effect of 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS), an anion channel blocker of voltage-dependent anion channel 1 (VDAC1), on noise-induced hearing loss (NIHL) and its underlying mechanisms.
    METHODS: Cochlear explants and House Ear Institute-Organ of Corti 1 (HEI-OC1) cells were used to assess the effect of DIDS in vitro. Auditory brainstem responses were used to assess auditory functions in mice. Immunofluorescence staining of myosin 7a and CTBP2 were used to examine hair cells and synaptic ribbons. The accumulation of reactive oxygen species (ROS) was measured by 4-HNE staining. The gene expression changes of cochlea were analyzed using RNA sequencing.
    RESULTS: DIDS reduced the levels of ROS in cochlear explants and attenuated cell death caused by hydrogen peroxide in both cochlear explants and HEI-OC1 cells. In C57BL/6 mice, DIDS reduced ROS generation and tumor necrosis factor-α induced by noise exposure, thereby protecting outer hair cells and inner hair cell synaptic ribbons from noise-induced damage through a mechanism involving the PINK1/Parkin signaling pathway. The preventive effect of DIDS in cochlear explants was eliminated by mitophagy inhibition.
    CONCLUSION: VDAC1 inhibition enhances mitophagy in cochlear hair cells, playing a critical role in defending against oxidative stress and inflammation. Downregulation of VDAC1 may thus be considered a therapeutic strategy for preventing cochlear hair cell damage and reducing NIHL.
    Keywords:  4,4′‐Diisothiocyanostilbene‐2,2′‐disulfonic acid; autophagy; hair cell; noise‐induced hearing loss; reactive oxygen species
    DOI:  https://doi.org/10.1111/cns.70410
  41. Nutrients. 2025 Mar 13. pii: 1010. [Epub ahead of print]17(6):
    l-Carnitine and Acetyl-l-Carnitine Induce Metabolism Alteration and Mitophagy-Related Cell Death in Colorectal Cancer Cells.
    Isabella Donisi, Anna Balestrieri, Vitale Del Vecchio, Giovanna Bifulco, Maria Luisa Balestrieri, Giuseppe Campanile, Nunzia D'Onofrio.
      Background/Objectives: Colorectal cancer (CRC) remains one of the most common and deadly malignancies worldwide, driven by metabolic reprogramming and mitochondrial dysfunction, which support tumor growth and progression. Several studies showed that nutrition is a contributing factor in the prevention and management of CRC. In this context, carnitines, amino acid derivatives abundant in food of animal origin, such as meat and milk, are crucial for mitochondrial function. Recently, l-carnitine and acetyl-l-carnitine have received particular attention due to their antioxidant, anti-inflammatory, and antitumor properties. However, to date, there is no conclusive evidence on the effects of l-carnitine and acetyl-l-carnitine in CRC or the underlying molecular mechanism. Methods: In this study, we investigated in HCT 116 and HT-29 CRC cells the effects of l-carnitine and acetyl-l-carnitine on mitochondrial homeostasis by XF HS Seahorse Bioanalyzer and cell death pathways by flow cytometry and western blot assays. Results: Data showed that l-carnitine and acetyl-l-carnitine reduced cell viability (p < 0.001), modulated cellular bioenergetics, and induced oxidative stress (p < 0.001). These phenomena promoted autophagic flux and the mitophagy process via PINK1 and Parkin modulation after 72 h of treatment. Of note, the combined treatment with l-carnitine and acetyl-l-carnitine showed a synergistic effect and enhanced the effect of single carnitines on tumor cell growth and metabolic dysfunction (p < 0.05). Moreover, exposure to l-carnitine and acetyl-l-carnitine promoted CRC cell apoptosis, suggesting a mechanism involving mitophagy-related cell death. These data were associated with increased SIRT4 expression levels (p < 0.01) and the activation of AMPK signaling (p < 0.01). Conclusions: Overall, the results, by supporting the importance of nutritional factors in CRC management, highlight l-carnitine and acetyl-l-carnitine as promising agents to target CRC metabolic vulnerabilities.
    Keywords:  SIRT4; carnitines; cellular metabolism; colorectal cancer; mitophagy
    DOI:  https://doi.org/10.3390/nu17061010
  42. J Ethnopharmacol. 2025 Apr 26. pii: S0378-8741(25)00571-9. [Epub ahead of print] 119887
    S100A9/RAGE pathway regulation of mitophagy and the effect of JianPi LiShi YangGan formula in acute-on-chronic liver failure.
    Jing Li, Rui Hu, Xingning Liu, Lanfen Peng, Jinyu Yi, Xin Zhong, Qi Huang, Jialing Sun, Wenxing Feng, Wenfeng Ma, Xiaozhou Zhou.
       ETHNOPHARMACOLOGICAL RELEVANCE: Mitophagy regulates cellular homeostasis and liver inflammation; however, it is inhibited in acute-on-chronic liver failure (ACLF), which drives disease progression. The JianPi LiShi YangGan formula (YGF) has the potential to improve inflammatory responses and reduce mortality in patients with ACLF. However, the precise mechanisms underlying these effects remain unknown.
    AIM OF THE STUDY: We investigated the role of S100A9/RAGE signaling in mitophagy and the protective effects of traditional Chinese medicinal compounds on ACLF.
    MATERIALS AND METHODS: An ACLF mouse model was established using carbon tetrachloride, lipopolysaccharide, and d-galactose. Hematoxylin and eosin staining and enzyme-linked immunosorbent assay were employed to evaluate the hepatoprotective effect of YGF in ACLF mice. Mitochondrial damage was assessed using transmission electron microscopy. Protein levels of mitophagy-related indicators were assessed through immunohistochemistry and western blotting, and immunofluorescence staining was performed to observe Lamp2 and COX-IV co-localization.
    RESULTS: The hepatocytes of ACLF mice contained damaged mitochondria, decreased mitophagy-related protein (Pink1, Parkin, and LC3B) expression and activated S100A9/RAGE signaling. Inhibiting S100A9 or RAGE improved liver injury in ACLF mice and enhanced Lamp2-COX-IV co-localization. In alpha mouse liver 12 (AML12) cells overexpressing RAGE, recombinant S100A9 protein inhibited mitophagy induced by 3-chlorocarbonyl benzoyl chloride. YGF reduced mitochondrial damage, increased Pink1, Parkin, and LC3B levels, and enhanced mitophagy while inhibiting S100A9/RAGE activation in the hepatocytes of ACLF mice.
    CONCLUSIONS: This study found that S100A9/RAGE pathway activation impairs mitophagy, and YGF alleviates liver injury by downregulating S100A9 and RAGE signaling, which may be a novel therapeutic strategy for ACLF.
    Keywords:  JianPi LiShi YangGan formula; RAGE; S100A9; acute chronic liver failure; mitophagy
    DOI:  https://doi.org/10.1016/j.jep.2025.119887
  43. Aging Cell. 2025 Apr 28. e70066
    Cathepsin B Regulates Ovarian Reserve Quality and Quantity via Mitophagy by Modulating IGF1R Turnover.
    Aradhana Mohanty, Anjali Kumari, Lava Kumar S, Ajith Kumar, Pravin Birajdar, Rohit Beniwal, Mohd Athar, Kiran Kumar P, H B D Prasada Rao.
      The quality and quantity of the ovarian reserve are meticulously regulated through various cell death pathways to guarantee the availability of high-quality oocytes for fertilization. While apoptosis is recognized for contributing to maintaining ovarian reserve, the involvement of other cell death pathways remains unclear. Employing chemical genetics and proteomics, this study reveals the crucial involvement of Cathepsin B in maintaining the ovarian reserve. Results indicate that apoptosis and autophagy play pivotal roles, and inhibiting these pathways significantly increases follicle numbers. Proteomics reveals a dynamic shift from apoptosis to autophagy during follicular development, with Cathepsin B emerging as a key player in this transition. Inhibiting Cathepsin B not only mimics the augmented oocyte reserve observed with autophagy inhibition but also upregulated IGF1R and AKT-mTOR pathways without compromising fertility in pre- and postpubertal mice. Further, IGF1R inhibition partially compromised the protective effects of Cathepsin B inhibition on oocyte reserves, suggesting their interdependence. This association is further supported by the finding that Cathepsin B can degrade IGF1R in vitro. Moreover, the increased IGF1R levels enhance the oocyte mitochondrial membrane potential via transcriptional regulation of mitochondrial biogenesis and mitophagy genes. Remarkably, this Cathepsin B-dependent ovarian reserve maintenance mechanism is conserved in higher-order vertebrates. Cumulatively, our study sheds valuable light on the intricate interplay of autophagy, Cathepsin B, and growth factors in ovarian reserve maintenance, offering potential therapeutic strategies to delay ovarian aging and preserve fertility.
    Keywords:  IGF1R; autophagy; cathepsin B; mitophagy; ovarian reserve
    DOI:  https://doi.org/10.1111/acel.70066
  44. Mater Today Bio. 2025 Jun;32 101770
    Ceria nanoparticles alleviate myocardial ischemia-reperfusion injury by inhibiting cardiomyocyte apoptosis via alleviating ROS mediated excessive mitochondrial fission.
    Ying Sun, Jiabao Xu, Ling Zou, Yan Tan, Jie Li, Haoran Xin, Yanli Guo, Weikai Kong, Dingyuan Tian, Xinyu Bao, Xiaoqin Wan, Xiaoxu Li, Zhihui Zhang, Xiaochao Yang, Fang Deng.
      Reperfusion through thrombolytic therapy or primary percutaneous coronary intervention is commonly used to deal with acute myocardial infarction. However, the reperfusion procedure is accompanied by myocardial ischemia-reperfusion injury (MIRI). Currently, there is no therapeutics that can effectively deal with MIRI in clinical practice. Herein, the potential of ceria nanoparticles (CNPs) coated by different ligands in the treatment of rat MIRI is evaluated. The results demonstrate that CNPs can effectively modulate the oxidative stress in the heart tissue through the elimination of reactive oxygen species (ROS) and stimulation of endogenous antioxidant system. The inhibition of oxidative stress results in the reduction of p-Drp1 (Ser 616) which is critical in driving the fission and fragmentation of mitochondria. The improved mitochondrial dynamics saves the cardiomyocytes from apoptosis and reduces the acute injury of left ventricular wall during the MIRI. The ejection function of the left ventricle for both the short-term and long-term MIRI rats is well preserved. We therefore believe based on these results that the administration of CNPs is beneficial in the attenuation of MIRI during the acute stage. These findings provide useful information for the future fabrication of inorganic antioxidant nanomedicine for the treatment of MIRI.
    Keywords:  Ceria nanoparticles; Mitochondria; Myocardial ischemia-reperfusion injury; Oxidative stress; Reactive oxygen species
    DOI:  https://doi.org/10.1016/j.mtbio.2025.101770
  45. Drug Des Devel Ther. 2025 ;19 3059-3076
    Gui-Pi-Tang Defers Skeletal Muscle and Cardiac Muscle Aging by Promoting Mitochondrial Remodeling.
    Changjiu Cai, Manying Wang, Dan Yang, Chenxu Jing, Yingna Li, Hanying Xu, Fangbing Liu, Daqing Zhao.
       Purpose: To determine whether Gui-Pi-Tang (GPT) has protective effects on skeletal muscle and cardiac muscle in aged mice.
    Methods: This study used C57BL6/J mice to establish an in vivo natural aging model, while D-galactose (D-gal)-injured C2C12 and H9c2 cells were employed to create in vitro aging cell models. Hematoxylin and eosin (H&E) staining was used to assess the effect of GPT on skeletal and cardiac muscle in aged mice. Protection against age-induced cellular damage by GPT was assessed in C2C12 and H9c2 cells using β-galactosidase staining. Mitochondrial morphology, structure, and function were analyzed using transmission electron microscopy, Seahorse assays, and ATP content measurements. Potential mechanisms by which GPT regulates mitochondrial homeostasis were examined using Western blot analysis.
    Results: GPT treatment significantly improved the alignment of skeletal muscle fibers, reduced gaps, and increased the cross-sectional area (CSA) of skeletal muscle in aged mice. It also reduced the CSA of cardiac muscle fibers, alleviating cardiomyocyte hypertrophy. Mitochondrial morphology was restored, and GPT reduced D-gal-induced β-galactosidase elevation. Furthermore, GPT protected mitochondrial morphological and structural integrity in the skeletal and cardiac muscles of aged mice and improved mitochondrial respiratory function and ATP levels in D-gal-injured C2C12 and H9c2 cells. GPT treatment increased the levels of mitochondrion-associated proteins PGC-1α, PPARγ, Nrf1, and OPA1 in the skeletal and cardiac muscle of aged mice. Moreover, GPT modulated Drp1 expression, with increases in aged skeletal muscle and decreases in aged cardiac muscle.
    Conclusion: These findings suggest that GPT helps maintain mitochondrial homeostasis by regulating mitochondrial remodeling, thereby alleviating skeletal and cardiac muscle damage in aged mice.
    Keywords:  Gui-Pi-Tang; mitochondrial homeostasis; myocardium; senescence; skeletal muscle
    DOI:  https://doi.org/10.2147/DDDT.S509046
  46. Free Radic Biol Med. 2025 Apr 23. pii: S0891-5849(25)00242-4. [Epub ahead of print]
    Polydatin reactivates mitochondrial bioenergetics and mitophagy while preventing premature senescence by modulating microRNA-155 and its direct targets in human fibroblasts with trisomy 21.
    Daniela Valenti, Daniela Isabel Abbrescia, Flaviana Marzano, Giampietro Ravagnan, Apollonia Tullo, Rosa Anna Vacca.
      Mitochondrial dysfunction and redox dyshomeostasis are considered crucial factors causally linked to the pathogenesis of Down syndrome (DS), a human genetic anomaly currently lacking a cure, associated with neurodevelopmental deficits in children and early onset symptoms of aging in adults. Several natural plant-derived polyphenolic compounds, known for their neurostimulator, antioxidant and anti-inflammatory activities, have been proposed as dietary supplements to manage DS-linked phenotypic alterations. However, the poor bioavailability and rapid metabolism of these compounds have limited conclusive evidence regarding their clinical efficacy in individuals with DS. Polydatin (PLD), a natural polyphenolic glucoside precursor of resveratrol derived from Polygonum cuspidatum, is instead highly bioavailable and resistant to enzymatic oxidation. PLD supplementation has shown many therapeutic efficacies in several human diseases without side effects. In this study, we used fetal trisomy 21 human skin fibroblasts (DS-HSFs) to investigate, from a mechanistic point of view, whether PLD supplementation could prevent or counteract critical cellular alterations linked to both neurodevelopmental deficits and early aging in DS. Our findings demonstrate that PLD reactivates mitochondrial bioenergetics, reduces oxygen radical overproduction and prevents oxidative stress (OS)-induced cellular senescence and DNA damage in DS-HSF. Notably, we identified a novel mechanism of PLD action involving the chromosome-21-encoded microRNA-155 (miR-155) and its direct target genes casitas B-lineage lymphoma (CBL), BAG Cochaperone 5 (BAG5) and mitochondrial transcription factor A (TFAM). These proteins play pivotal roles in regulating mitochondrial bioenergetics, biogenesis and mitophagy. Given that the deregulation of miR-155/CBL axis is also implicated in acute leukemias, which frequently occur in children with DS, PLD emerges as a promising candidate for translational application. Its ability to enhance mitochondrial bioenergetics and address critical DS-associated phenotypic alterations highlights its therapeutic potential.
    Keywords:  BAG Cochaperone 5; Down syndrome; Polydatin supplementation; aging; casitas B-lineage lymphoma; leukemia; miR-155; mitochondrial bioenergetics; mitophagy; oxidative stress; senescence
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.04.032
  47. Free Radic Biol Med. 2025 Apr 24. pii: S0891-5849(25)00248-5. [Epub ahead of print]235 109-123
    Neutrophil extracellular traps aggravate placental injury in OAPS by facilitating activation of BNIP3 mediated mitophagy.
    Chunying Wang, Anna Li, Cancan Zhang, Zexin Yang, Xuan Yang, Weiyi Qi, Tengwei Liu, Meihua Zhang, Xietong Wang.
      Obstetric antiphospholipid syndrome (OAPS) is an autoimmune disease mediated by antiphospholipid antibodies (aPL), characterized by miscarriage, pre-mature birth caused by pre-eclampsia, intrauterine growth restriction, and other pregnancy complications. Neutrophil extracellular traps (NETs) consist of chromatin scaffolds coated with histones, proteases, granules, and cytosolic proteins. Here, we have observed increased levels of NETs in both human OAPS placental tissues and animal models, accompanied by apoptosis increases. In vitro, NETs induce a decrease in trophoblasts proliferation and an increase in apoptosis. In addition, NETs induce oxidative stress and mitochondrial reactive oxygen species (mtROS) production, upregulation of fission-associated mitochondrial proteins coupled with reduced fusion-associated protein levels. It also led to a rise in BNIP3 and autophagy-related protein expressions, along with an increase in autophagosomal numbers. Moreover, mtROS scavenging or knockdown strategies targeting BNIP3 effectively attenuated mitophagic activation alongside trophoblast apoptosis induction. Furthermore, upregulation of BNIP3 expression was evident in placentas from both APS murine models and human OAPS cases. These results suggest that aPL-induced NETs trigger BNIP3-mediated mitophagy, elevate ROS production, induce apoptosis in trophoblasts, and thereby exacerbate placental damage, with implications for our understanding of the pathogenesis of OAPS and devising novel treatment strategies.
    Keywords:  Extracellular traps; Mitophagy; Neutrophil; OAPS; Trophoblast
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.04.038
  48. BMC Cardiovasc Disord. 2025 Apr 26. 25(1): 327
    Correction: HACE1 protects against myocardial ischemia-reperfusion injury via inhibition of mitochondrial fission in mice.
    Bang-Xia Liu, Juan Zheng, Zhan-Wei Tang, Lei Gao, Meng Wang, Ying Sun, Chen Chen, Heng-Chen Yao.
      
    DOI:  https://doi.org/10.1186/s12872-025-04761-1
  49. Front Physiol. 2025 ;16 1554222
    Effects of high-intensity interval training and moderate-intensity continuous training on mitochondrial dynamics in human skeletal muscle.
    Yuqing Li, Wanjun Zhao, Qi Yang.
      Exercise and physical activity confer health advantages, in part, by enhancing skeletal muscle mitochondrial respiratory function. The objective of this study is to analyze the impacts of high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) on the dynamics and functionality of the mitochondrial network within skeletal muscle. 20 young male participants were assigned to either HIIT or MICT group. Initial assessments of exercise-related indicators were conducted, followed by skeletal muscle biopsies from the vastus lateralis before, 1 day after, and 6 weeks post-experiment. We utilized multi-dimensional myofiber imaging to analyze mitochondrial morphology and arrangement, and assessed citrate synthase activity, complex I activity, and dynamics-related mRNA. Both training modalities increased VO2max, Wmax, citrate synthase and complex I activities, mitochondrial content, and volume density, though the changes differed between the two groups. 6 weeks training induced remodeling of the mitochondrial network within skeletal muscle. Before training, the network appeared sparse and punctate. After MICT, it adopted a grid-like structure with partially robust longitudinal connections. In contrast, HIIT resulted in a less obvious grid structure but showed a stronger longitudinally oriented network. Training also increased mRNA expression of mitochondrial fusion proteins and decreased fission protein expression, with these effects being more pronounced in HIIT. Similarly, peroxisome proliferator-activated receptor γ coactivator 1-alpha mRNA expression showed a comparable trend, though the changes differed between 1 day and 6 weeks of training. In conclusion, HIIT and MICT induce distinct mitochondrial adaptation in skeletal muscle, reflected in different network remodeling and molecular pathways. These findings may be due to HIIT's more pronounced effect on mitochondrial dynamics or respiratory function, but the study has only conducted preliminary observational experiments and further evidence is required for confirmation.
    Keywords:  high-intensity interval training; mitochondrial dynamics; mitochondrial network remodeling; moderate-intensity interval training; skeletal muscle
    DOI:  https://doi.org/10.3389/fphys.2025.1554222
  50. Genes (Basel). 2025 Mar 22. pii: 362. [Epub ahead of print]16(4):
    Effects of Melatonin on H2O2-Induced Oxidative Damage of the Granulosa Cells in Hen Ovarian Follicles.
    Sheng Wang, Yu Ou, Shengxiao Cao, Xue Sun, Ning Qin, Simushi Liswaniso, Rifu Xu.
       BACKGROUND: The egg-laying performance of hens is primarily regulated by ovarian follicle growth and development; these follicles are susceptible to oxidative damage caused by excessive reactive oxygen species (ROS). Oxidative damage can lead to follicular atresia and impaired reproductive performance. Melatonin (MT), a known endogenous antioxidant, plays a role in regulating oxidative damage, but its precise mechanisms in mitigating H2O2-induced oxidative damage via mitophagy regulation in granulosa cells remain unclear.
    METHODS: An in vitro oxidative damage model was established by determining the optimal H2O2 concentration using CCK-8 fluorescence quantification. The optimal MT concentration was identified through fluorescence quantification and catalase (CAT) activity assays. The protective effects of MT against H2O2-induced oxidative damage in follicular granulosa cells were investigated using flow cytometry, Western blotting, ELISA, and quantitative fluorescence analysis.
    RESULTS: An in vitro oxidative damage model was established using H2O2-induced granulosa cells, characterized by P53 and LC3-II upregulation and LC3-I and BCL-2 downregulation. The optimal MT concentration for reducing cellular injury was determined. MT co-treatment enhanced CAT, GSH, and SOD activities, decreased LC3-II/LC3-I conversion, and increased P62 expression. Furthermore, MT reduced autophagic vesicle formation and restored mitochondrial membrane potential, demonstrating its protective effect against H2O2-induced oxidative damage.
    CONCLUSIONS: Melatonin alleviates H2O2-induced oxidative damage in chicken follicular granulosa cells by modulating antioxidant defense, autophagy, and mitochondrial function. These findings provide newer insights to our understanding of the regulatory mechanisms underlying the alleviation of the H2O2-induced oxidative damage in granulosa cells during ovarian follicle development in chickens.
    Keywords:  chicken; granulosa cells; melatonin; mitochondrial autophagy; oxidative damage
    DOI:  https://doi.org/10.3390/genes16040362
  51. Front Cell Dev Biol. 2025 ;13 1582252
    Comprehensive transcriptomic analysis integrating bulk and single-cell RNA-seq with machine learning to identify and validate mitochondrial unfolded protein response biomarkers in patients with ischemic stroke.
    Lu Zhang, Lei Yue, Peng Jia, Ziqi Cheng, Jiwen Liu.
       Background: Ischemic stroke (IS) represents a significant contributor to morbidity and mortality globally. The relationship between IS and mitochondrial unfolded protein response (UPRmt) was presently uncertain. This study endeavors to explore the fundamental mechanism of UPRmt in IS by utilizing bioinformatics methods.
    Methods: In GSE58294, differentially expressed genes (DEGs) were obtained, which were overlapped with key module genes of UPRmt -related gene ( UPRmt -RGs) for producing candidate genes. The biomarkers were identified from the candidate genes through machine learning, expression validation, and receiver operating characteristic (ROC) curves. In order to verify the biomarkers, reverse transcription-quantitative PCR (RT-qPCR) experiments were performed on human peripheral blood. Subsequently, a predictive nomogram was created to estimate the likelihood of developing IS. Next, the mechanisms and functions related to the biomarkers were explored by enrichment analysis and immune infiltration. In addition, cells enriched with biomarkers were identified, and the biological processes involved in these cells were analyzed through intercellular communication analysis and virtual knockout experiments.
    Results: MCEMP1, CACNA1E, and CLEC4D were identified as biomarkers and subsequently validated by RT-qPCR. RT-qPCR revealed that CLEC4D is the most sensitive biomarker. The nomogram analysis revealed that these biomarkers possess strong diagnostic value. Immune infiltration analysis indicated that all three biomarkers are strongly correlated with neutrophils. Additionally, in the single-cell transcriptome data, these biomarkers were predominantly enriched in neutrophils. Compared to the sham group, the middle cerebral artery occlusion (MCAO) group exhibited enhanced immune-inflammatory responses. Virtual knockout experiments provide preliminary evidence that CLEC4D functions as a regulatory molecule in neutrophil-mediated inflammation, rather than serving merely as a passive marker.
    Conclusion: CLEC4D was identified as the most sensitive biomarker for IS related to UPRmt -RGs, offering a new reference for IS diagnosis and treatment.
    Keywords:  bioinformation; biomarker; bulk RNA-seq; ischemic stroke; mitochondrial unfolded protein response; neutrophils; single cell; virtual knockout experiments
    DOI:  https://doi.org/10.3389/fcell.2025.1582252
  52. JHEP Rep. 2025 May;7(5): 101330
    Macrophage ATG16L1 promotes liver regeneration after partial hepatectomy.
    Xinyu Zhan, Yan Bai, Qing Zhu, Yiyun Gao, Fan Li, Qingfa Bu, Zeyu Zhu, Zhuqing Rao, Haoming Zhou.
       Background & Aims: Autophagy plays an important role in liver regeneration. However, most studies are limited to hepatocytes, and the function and mechanism of macrophage autophagy in liver regeneration remain unclear. This study investigated the role of the essential autophagy gene encoding autophagy-related 16-like 1 (ATG16L1), which regulates the macrophage phenotype in liver regeneration.
    Methods: We generated FloxP-Atg16l1 (Atg16l1 FL/FL ), Lyz2-Cre Atg16l1 knockout (KO) (Atg16l1 M-KO ), and myeloid-specific Atg16l1-overexpression-knock-in (Atg16l1 OE ) mice. These mice were subjected to 70% partial hepatectomy to demonstrate the role of ATG16L1 in macrophages during liver regeneration.
    Results: ATG16L1 expression was significantly upregulated in macrophages during the early stages of liver regeneration. ATG16L1 deletion in macrophages substantially delayed liver regeneration in mice and caused a marked imbalance in Ly6Chi and Ly6Clo macrophage proportions in the liver. RNA-sequencing analysis revealed that, compared with macrophages isolated from Atg16l1 FL/FL mice, those from Atg16l1 M-KO mice exhibited significant downregulation of genes associated with oxidative phosphorylation and upregulation of proinflammatory gene expression. Mechanistically, ATG16L1 loss impaired mitophagy in macrophages, leading to the accumulation of mitochondrial damage and a metabolic shift that promoted proinflammatory macrophage polarization. ATG16L1 deficiency not only promoted macrophage mitochondrial (mt)DNA release and cyclic GMP-AMP synthase-stimulator of interferon genes (STING) activation, but also suppressed STING degradation. Sustained STING hyperactivation and subsequent increased release of downstream interferons further contributed to the inhibition of liver regeneration. Notably, pharmacological activation or genetic overexpression of ATG16L1 significantly enhanced liver regeneration in mice.
    Conclusions: ATG16L1 has a pivotal role in liver regeneration by affecting the phenotype and function of macrophages. Thus, targeting ATG16L1 in macrophages could present a novel strategy for promoting liver regeneration.
    Impact and implications: The autophagy-related gene ATG16L1 mediates mitophagy, facilitating the clearance of damaged mitochondria in macrophages following partial hepatectomy and maintaining a reparative macrophage phenotype. ATG16L1 deficiency triggers excessive STING activation and inhibits its degradation, thereby suppressing liver regeneration. Thus, targeting ATG16L1 in macrophages could represent a novel strategy to promote liver regeneration.
    Keywords:  IFN; Mitophagy; Oxidative phosphorylation; Proinflammatory; STING; mtDNA
    DOI:  https://doi.org/10.1016/j.jhepr.2025.101330
  53. Theranostics. 2025 ;15(11): 4890-4908
    Pharmacological targeting of mitophagy via ALT001 improves herpes simplex virus 1 (HSV1)-mediated microglial inflammation and promotes amyloid β phagocytosis by restricting HSV1 infection.
    Soo-Jin Oh, Young Yeon Kim, Ruiying Ma, Seok Tae Choi, Se Myeong Choi, Jong Hyun Cho, Ji-Yeun Hur, Yongjin Yoo, Kihoon Han, Hosun Park, Jeanho Yun, Ok Sarah Shin.
      Rationale: One of the hallmarks of Alzheimer's disease (AD) is the accumulation of dysfunctional mitochondria. Herpes simplex virus type 1 (HSV1) may be a risk factor for the neuropathology linked to amyloid β (Aβ) accumulation. However, the mechanisms underlying HSV1-associated mitochondrial dysfunction in AD remain unclear. ALT001 is a novel drug that ameliorates AD-related cognitive impairment via ULK1/Rab9-mediated alternative mitophagy. In this study, we investigated the effects of ALT001 on the neurodegeneration-related microglial signatures associated with HSV1 infection. Methods: Molecular mechanisms and physiological functions of mitophagy was investigated in HSV1-infected microglia, including primary murine and human embryonic stem cell (ESC)-derived microglia (ES-MG), as well as in a microglia-neuron co-culture system. Microglial gene signatures following HSV1 infection in the presence or absence of ALT001 were analyzed using bulk RNA sequencing, and the effects of ALT001 on microglial phagocytosis and microglia-mediated immune responses were further evaluated by flow cytometry and cytokine profiles. Results: HSV1 infection inhibited PINK1/Parkin-mediated mitophagy via HSV1-encoded protein kinase US3, resulting in mitochondrial dysfunction in both human and mouse microglia. Furthermore, transcriptomic analysis of HSV1-infected microglia revealed an upregulation of distinct microglial genes associated with disease-associated microglia (DAM)-like phenotype and pro-inflammatory activity. Pharmacological targeting of mitophagy using ALT001 prevents mitochondrial damage caused by HSV1 through ULK1/Rab9-mediated pathway. Furthermore, ALT001-induced ULK1/Rab9-dependent mitophagy restricts HSV1 infection by activating interferon-mediated antiviral immunity. Consequently, ALT001 reduces HSV1-triggered neuroinflammation, recovers HSV1-altered microglial phagocytosis for Aβ, and efficiently reverses morphological and molecular abnormalities in HSV1-infected microglia by triggering mitophagy in ES-MG. ALT001 also suppressed HSV1-mediated Aβ accumulation and neurodegeneration in the microglia-neuron co-culture and cerebral organoid model. Conclusions: In this study, we identified a critical molecular link between HSV1 and AD-related microglial dysfunction. Furthermore, our findings provide an evidence that therapeutic targeting of alternative mitophagy via ALT001 effectively interfere with HSV1-induced microglial dysfunction and alleviate neurodegeneration.
    Keywords:  ALT001; Microglia; alternative mitophagy; herpes simplex virus 1 (HSV1); neurodegeneration
    DOI:  https://doi.org/10.7150/thno.105953
  54. Mol Cell Biochem. 2025 Apr 29.
    Targeting mitochondrial dysfunction: an innovative strategy for treating renal fibrosis.
    Yi-Jin Wu, Yan-Rong Yang, Ya-Ling Yan, Han-Yinan Yang, Jun-Rong Du.
      The incidence and hospitalization rate of kidney disease, especially end-stage renal disease, have increased significantly, which seriously endangers the health of patients. Mitochondria are the core organelles of cellular energy metabolism, and their dysfunction can lead to kidney energy supply insufficiency and oxidative stress damage, which has become a global public health problem. Studies have shown that the disturbance of mitochondrial quality control mechanisms, including mitochondrial dynamics, autophagy, oxidative stress regulation and biosynthesis, is closely related to the occurrence and development of renal fibrosis (RF). As a multicellular pathological process, RF involves the injury and shedding of podocytes, the transdifferentiation of renal tubular epithelial cells, the activation of fibroblasts, and the infiltration of macrophages, among which the mitochondrial dysfunction plays an important role. This review systematically elaborates the molecular mechanisms of mitochondrial damage during RF progression, aiming to provide theoretical foundations for developing novel therapeutic strategies to delay RF advancement.
    Keywords:  Chronic kidney disease; Mitochondrial dynamics; Mitochondrial dysfunction; Renal fibrosis; Renal tubular epithelial cells
    DOI:  https://doi.org/10.1007/s11010-025-05297-w
  55. Int J Biol Macromol. 2025 Apr 29. pii: S0141-8130(25)04248-5. [Epub ahead of print] 143696
    Molecular structure and protein function of mitochondrial fusion protein Mfn2 alleviate Alzheimer's disease: exercise assisted regulation.
    Hailei Li.
      Alzheimer's disease is a neurodegenerative disease that affects cognitive function. Recent studies have shown that mitochondrial dysfunction plays an important role in its pathological process. The mitochondrial fusion protein Mfn2 plays a crucial role in maintaining mitochondrial function and cellular health. The aim of this study is to explore the molecular structure of mitochondrial fusion protein Mfn2 and its role in Alzheimer's disease, combined with the effects of exercise assisted regulation, to evaluate its potential in alleviating symptoms. By constructing a brain model of Alzheimer's disease, conducting pathological analysis and molecular dynamics simulations, we aim to explore the relationship between the disease and mitochondrial function. Analyze the molecular structure of Mfn2, study its role in normal and pathological states, and evaluate its impact on Mfn2 and mitochondrial function through exercise intervention. The study demonstrated the typical pathological features of Alzheimer's disease and confirmed the relationship between mitochondrial dysfunction and disease progression. The structural analysis of mitochondrial fusion protein Mfn2 indicates its importance in promoting mitochondrial fusion. Exercise intervention significantly increased the expression of Mfn2 and improved mitochondrial function, further alleviating pathological changes associated with Alzheimer's disease.
    Keywords:  Alzheimer's disease; Mitochondrial fusion protein Mfn2; Molecular structure; Protein action; Sports assisted adjustment
    DOI:  https://doi.org/10.1016/j.ijbiomac.2025.143696
  56. Antioxidants (Basel). 2025 Apr 08. pii: 446. [Epub ahead of print]14(4):
    Replicative Senescence in Mesenchymal Stem Cells: An In Vitro Study on Mitochondrial Dynamics and Metabolic Alterations.
    Beatrice Casorati, Isabella Zafferri, Sara Castiglioni, Jeanette A Maier.
      Mesenchymal stem cells (MSCs) are multipotent progenitors capable of self-renewal and differentiation into various cell lineages, making them essential for tissue repair and regenerative medicine. However, their regenerative potential is constrained by replicative senescence, an irreversible growth arrest that occurs after a finite number of cell divisions. In this study, we serially passaged human bone marrow-derived MSCs (bMSCs) and compared young, pre-senescent, and senescent cells. The onset of senescence was accompanied by progressive alterations in mitochondrial dynamics, leading to a decline in mitochondrial membrane potential, and increased reactive oxygen species (ROS) production, alongside a diminished cellular antioxidant capacity. These mitochondrial defects play a role in metabolic reprogramming in senescent bMSCs. Our findings underscore the intricate interplay between ROS, mitochondrial dysfunction, and replicative senescence, offering valuable insights to guide the development of therapeutic strategies for preserving MSC functionality in aging and MSC-based therapies.
    Keywords:  ROS; mesenchymal stem cells; mitochondria; replicative senescence
    DOI:  https://doi.org/10.3390/antiox14040446
  57. J Dent Res. 2025 May 01. 220345251329330
    Role of TRPM2 in Oxidative Stress-Mediated Bone Loss in Periodontitis.
    Y Jiang, J Chen, S Guo, W Cui, Y Zhou, X Chen, D Wang, X Wang, L Li, Y Xu.
      Oxidative stress has emerged as a critical player in the development and progression of periodontitis. Transient receptor potential melastatin 2 (TRPM2) is a crucial oxidative stress sensor, while its role in periodontitis and its relationship with the oxidative stress microenvironment remains poorly understood. The objective of this research is to unravel the mechanism by which reactive oxygen species (ROS) activate the TRPM2 channel, driving osteoclast differentiation and eventually leading to bone degradation in periodontitis. By doing so, we aim to provide novel insights into the initiation, progress, and potential treatment methodologies for bone loss instigated by periodontitis. In this study, our results revealed significant upregulation of TRPM2 expression in inflamed periodontal tissues and a close alliance with osteoclast differentiation. First, significant upregulation of TRPM2 in periodontitis, with a clear association with osteoclast differentiation, was observed based on the GEO database. In addition, enhanced levels of TRPM2 and oxidative stress markers were evident in samples from both periodontitis patients and the mouse model of periodontitis. Importantly, the ablation of TRPM2 distinctly alleviated alveolar bone resorption in periodontitis-affected mice. In vitro assays concluded that ROS-induced TRPM2 activation fostered osteoclast differentiation and amplification of osteoclast-related genes. Moreover, RNA-seq results illuminated a close alliance of TRPM2 with osteoclast differentiation, oxidative phosphorylation, mitochondrial inner membrane, and mitochondrial protein complexes. Further validation indicated that damaged mitophagy could overproduce ROS to activate TRPM2 as a positive regulator of osteoclast differentiation via the Ca2+/NFATc1 signaling pathway. Finally, we conducted in vivo and in vitro interventions using a TRPM2 inhibitor and found that the inhibition of TRPM2 significantly alleviated bone loss induced by periodontitis. Consequently, our results suggest that TRPM2 plays a crucial role in triggering osteoclast differentiation in periodontitis's oxidative stress microenvironment, signifying a potential therapeutic target for prevention and treatment of bone erosion induced by periodontitis.
    Keywords:  ROS; bone resorption, oxidative phosphorylation; calcium channel; mitophagy; osteoclast differentiation
    DOI:  https://doi.org/10.1177/00220345251329330
  58. Phytomedicine. 2025 Apr 10. pii: S0944-7113(25)00386-1. [Epub ahead of print]142 156747
    Hesperidin mitigated deoxynivalenol-induced liver injury by inhibiting ROS/ P53/ PGC-1α-mediated disruption of mitochondrial dynamics and PANoptosis.
    Xin Wang, Tong Nie, Aqun Li, Jun Ma.
       BACKGROUND: Deoxynivalenol (DON) is a physico-chemically stable food contaminant that is difficult to destroy during food production and culinary processing. Consumption of food contaminated with DON can impair the liver's antioxidant capacity and trigger various forms of programmed cell death. Hesperidin (HDN) is a highly antioxidant flavonoid compound with excellent biological activity and is a potential drug for treating liver damage. While the various pharmacological actions of HDN have been increasingly clarified over time, its protective role and precise mechanisms in mitigating liver damage caused by DON exposure are still largely shrouded in mystery.
    PURPOSE AND METHODS: To investigate the potential of HDN to mitigate DON-induced liver injury and elucidate its specific mechanisms of action, we established both in vitro and in vivo models of DON exposure and administered HDN intervention.
    RESULTS: Our findings revealed that DON exposure triggered oxidative stress in the liver, DNA damage, and P53 pathway activation, resulted in mitochondrial dynamics disorder and dysfunction, and induced PANoptosis in the liver. HDN significantly attenuated these changes. Using COIP, protein-protein molecular docking, and immunofluorescence methods, we discovered that PGC-1α and P53 can connect tightly, regulating the dynamics and function of the mitochondria. In addition, we intervened in vitro using the N-acetyl-l-cysteine, the pifithrin α, and the Mito TEMPO.
    CONCLUSION: The findings demonstrated that HDN attenuated PANoptosis induced through mtROS overproduction by inhibiting ROS/ P53/ PGC-1α-mediated mitochondrial damage, which ameliorated DON-induced liver injury.
    Keywords:  Deoxynivalenol; Hesperidin; Liver; Mitochondrion; PANoptosis
    DOI:  https://doi.org/10.1016/j.phymed.2025.156747
  59. J Am Heart Assoc. 2025 May 02. e039411
    Stroke in Pregnancy Brings Epigenetic Changes in Correlation with Affected Mitochondrial Dynamics and Inflammasome Mediated Apoptosis in Rodents.
    Aishika Datta, Dipali Rahane, Gangadhar Bhurle, Soumya Akundi, Ushmita Mukherjee, Akshada Dubey, Anirban Barik, Gautam Karmarkar, Nikita Malik, Bijoyani Ghosh, Nikita Rana, Anupom Borah, Pallab Bhattacharya.
       BACKGROUND: Pregnancy may be a risk factor for stroke in females. Stroke in pregnancy influences mitochondrial dynamics as well as the inflammatory responses in mothers. However, limited studies are available that report any epigenetic changes in the offspring following a stroke in mothers. In the present study we investigate the effect of stroke in pregnancy as a possible epigenetic modifier correlated with dysfunctional mitochondrial dynamics and exacerbated inflammasome mediated apoptosis in the offsprings.
    METHODS AND RESULTS: Female and male Sprague Dawley rats were housed in the same cage in 1:2 ratio to ensure successful pregnancy. Stroke was induced by middle cerebral artery occlusion at gestational day 17. After delivery of F1 generation, bloods were collected from the dams for hormonal study. Brains were harvested from both dams and F1 generation for biochemical, histological, genetic, molecular, and mitochondrial studies. In the F1 generation of stroke induced dams, an increased mitochondrial fission and decreased mitochondrial fusion were observed as compared with normal dams and their F1 generation. Similarly, enhanced mitochondrial reactive oxygen species and depolarization were also observed in the F1 generation of stroke induced dams. Exacerbated inflammasome signaling and enhanced apoptosis were also evident in this F1 generation. Changes in histone-methylation corresponding to increased inflammation were also observed in this F1 generation.
    CONCLUSIONS: The present study reports the occurrence of epigenetic modifications towards mitochondrial dysfunction and exacerbated inflammasome mediated apoptosis in the F1 generation following a stroke in pregnant dams.
    Keywords:  epigenetics; histone; inflammasome; mitochondria; pregnancy; stroke
    DOI:  https://doi.org/10.1161/JAHA.124.039411
  60. Mol Neurobiol. 2025 Apr 26.
    An Insight into Neuronal Processing of Ghrelin: Effects of a Bioactive Ghrelin Derivative on Proteolytic Pathways and Mitophagy.
    Daniela Lufrano, Chunmei Gong, Valentina Cecarini, Massimiliano Cuccioloni, Laura Bonfili, Chiara Sturaro, Barbara Bettegazzi, Chiara Ruzza, Mario Perelló, Mauro Angeletti, Anna Maria Eleuteri.
      Protein homeostasis (proteostasis) is preserved by an orchestrated network of molecular mechanisms that regulate protein synthesis, folding, and degradation, ensuring cellular integrity and function. Proteostasis declines with age and is related to pathologies such as neurodegenerative diseases and cardiac disorders, which are accompanied by the accumulation of toxic protein aggregates. In this context, therapeutic strategies enhancing the two primary degradative systems involved in the cellular clearance of those abnormal proteins, namely ubiquitin-proteasome system and autophagy-lysosomal pathway, represent a promising approach to counteract the collapse of proteostasis in such pathological conditions. In this work, we explored the processing of ghrelin, a pleiotropic peptide hormone linked to energy metabolism and higher brain functions, which is reported to modulate the protein degradative mechanisms. According to our data, ghrelin is processed by serine hydrolases secreted into the conditioned medium of SH-SY5Y neuroblastoma cell line, commonly used in neurotoxicology and neuroscience research. Ghrelin processing leads to the formation of a shorter peptide (ghrelin(1-11)) that stimulates both the cell proteasome system and autophagy-lysosomal pathway, encompassing the selective autophagy of mitochondria. Our findings suggest that ghrelin processing may contribute to the maintenance of neuronal proteostasis.
    Keywords:  Autophagy; Ghrelin; Mitophagy; Neuronal Processing; Proteasome
    DOI:  https://doi.org/10.1007/s12035-025-04976-5
  61. Kidney Int Rep. 2025 Apr;10(4): 994-1010
    Control of Mitochondrial Quality: A Promising Target for Diabetic Kidney Disease Treatment.
    Qi Li, Jin Shang, Reiko Inagi.
      Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease (ESRD), affecting over 40% of patients with diabetes. DKD progression involves fibrosis and damage to glomerular and tubulointerstitial regions, with mitochondrial dysfunction playing a critical role. Impaired mitochondria lead to reduced adenosine triphosphate (ATP) production, damaged mitochondria accumulation, and increased reactive oxygen species (ROS), contributing to renal deterioration. Maintaining mitochondrial quality control (MQC) is essential for preventing cell death, tissue injury, and kidney failure. Recent clinical trials show that enhancing MQC can alleviate DKD. However, current treatments cannot halt kidney function decline, underscoring the need for new therapeutic strategies. Mitochondrial-targeted drugs show potential; however, challenges remain because of adverse effects and unclear mechanisms. Future research should aim to comprehensively explore therapeutic potential of MQC in DKD. This review highlights the significance of MQC in DKD treatment, emphasizing the need to maintain mitochondrial quality for developing new therapies.
    Keywords:  diabetic kidney disease; diabetic nephrophathy; mitochondria; mitochondrial quality control; organelle network
    DOI:  https://doi.org/10.1016/j.ekir.2024.12.029
  62. Adv Sci (Weinh). 2025 Apr 30. e2500552
    Dual Role of CRABP2 in Colorectal Cancer: Oncogenesis via Nuclear RB1 and Cytoplasmic AFG3L2/SLC25A39 Axis, While Limiting Liver Metastasis through Cytoplasmic AFG3L2/PINK1/Parkin-Mediated Mitophagy.
    Chuanxin Tian, Sheng Yang, Chuan Zhang, Renzhong Zhu, Chen Chen, Xiaowei Wang, Dongsheng Zhang, Qingyang Sun, Hengjie Xu, Hongxu Nie, Yue Zhang, Dongjian Ji, Junwei Tang, Kangpeng Jin, Yueming Sun.
      Colorectal cancer (CRC) progression and metastasis involve numerous regulatory factors. Among these, cellular retinoic acid-binding protein 2 (CRABP2) has been implicated as both a tumor activator and suppressor. Here, it is aimed to clarify the role of CRABP2 in CRC growth and metastasis and explore the underlying molecular mechanisms mediating its cellular functions. Using both in vitro and in vivo models, including a colonocyte-specific CRABP2 conditional knockout mouse model (Crabp2ΔIEC) and a subcutaneous tumorigenesis assay in BALB/c nude mice, it is shown that nuclear CRABP2 enhances tumor growth by interacting with and downregulating the tumor suppressor RB1, whereas cytoplasmic CRABP2 suppresses CRC liver metastasis by interacting with AFG3L2 and promoting mitophagy. In addition, the AFG3L2-SLC25A39 axis is identified as a distinct mechanism by which cytoplasmic CRABP2 increases mitochondrial glutathione stability to promote cell proliferation independent of the nuclear RB1 pathway. Notably, analysis of tissue from CRC patients reveals that CRABP2 protein has distinct prognostic implications and functional roles in the progression and metastasis of CRC dependent on its subcellular localization. Ultimately, by elucidating the role of CRABP2 in CRC, it is aimed to provide new insight into disease pathogenesis and inform the development of therapeutic interventions.
    Keywords:  AFG3L2; CRABP2; PINK1; RB1; cellular retinoic acid–binding proteins; colorectal cancer; liver metastasis; mitophagy
    DOI:  https://doi.org/10.1002/advs.202500552
  63. J Adv Res. 2025 Apr 28. pii: S2090-1232(25)00285-1. [Epub ahead of print]
    Nutritional and hormonal regulation of mitochondrial biogenesis drives fat body remodeling for reproductive competence.
    Yiying Li, Mengyao Lang, Qiongjie He, Yuanyuan Hu, Huanhuan Shi, Siqian Zheng, Zhongxia Wu, Shutang Zhou.
       INTRODUCTION: Insect fat body serves as a central hub for energy mobilization and protein synthesis. During larval metamorphosis, fat body undergoes programmed cell death and tissue disassembly. Following adult eclosion, fat body reconstructs with cell proliferation and becomes competent for large-scale vitellogenin (Vg) synthesis required for the maturation of dozens of eggs.
    OBJECTIVES: This study aims to uncover the molecular mechanisms underlying the remodeling of fat body in acquisition of competence for massive Vg production.
    METHODS: RNA-seq and metabolomics were used for identification of differentially expressed genes and metabolites. RNAi was applied for gene knockdown. Transmission electron microscope, MitoTracker staining, mitochondrial DNA quantification, ATP and citrate synthase assays were employed for examining mitochondrial biogenesis. Dual-luciferase reporter assay and EMSA were performed for transcriptional regulation. qRT-PCR and western blot were performed for measuring Vg synthesis.
    RESULTS: Transcriptomic and metabolomic analyses revealed significant upregulation of genes and metabolites involved in mitochondrial biogenesis in the fat body of adult locusts. PGC-1α was highly expressed in adult fat body. Knockdown of PGC-1α reduced mitochondrial biogenesis, fat body cell number, Vg synthesis and ovarian development. CREBB bound to PGC-1α promoter and activated its transcription. CREBB depletion impaired mitochondrial biogenesis and fat body remodeling. Moreover, loss of TORC1 function suppressed CREBB function and PGC-1α expression, subsequently disrupting mitochondrial biogenesis and fat body remodeling. Juvenile hormone (JH) deprivation also decreased CREBB function and PGC-1α expression, which was reversible with JH treatment. Our results suggest that TORC1 and JH coordinate CREBB-upregulated PGC-1α expression, which promotes mitochondrial biogenesis and fat body remodeling for Vg synthesis and egg production.
    CONCLUSION: The findings provide new insights into the molecular mechanisms of post-metamorphosis fat body development, and highlight the role of JH/TORC1/CREBB/PGC-1α/mitochondrial biogenesis axis in insect reproduction. The data also offer potential targets for insect pest control.
    Keywords:  Cell proliferation; Fat body remodeling; Juvenile hormone; Mitochondria biogenesis; PGC-1α; TORC1
    DOI:  https://doi.org/10.1016/j.jare.2025.04.041
  64. Aging Cell. 2025 Apr 25. e70054
    3D Mitochondrial Structure in Aging Human Skeletal Muscle: Insights Into MFN-2-Mediated Changes.
    Estevão Scudese, Andrea G Marshall, Zer Vue, Vernat Exil, Benjamin I Rodriguez, Mert Demirci, Larry Vang, Edgar Garza López, Kit Neikirk, Bryanna Shao, Han Le, Dominique Stephens, Duane D Hall, Rahmati Rostami, Taylor Rodman, Kinuthia Kabugi, Jian-Qiang Shao, Margaret Mungai, Salma T AshShareef, Innes Hicsasmaz, Sasha Manus, Celestine N Wanjalla, Aaron Whiteside, Revathi Dasari, Clintoria R Williams, Steven M Damo, Jennifer A Gaddy, Brian Glancy, Estélio Henrique Martin Dantas, André Kinder, Ashlesha Kadam, Dhanendra Tomar, Fabiana Scartoni, Matheus Baffi, Melanie R McReynolds, Mark A Phillips, Anthonya Cooper, Sandra A Murray, Anita M Quintana, Nelson Wandira, Okwute M Ochayi, Magdalene Ameka, Annet Kirabo, Sepiso K Masenga, Chanel Harris, Ashton Oliver, Pamela Martin, Amadou Gaye, Olga Korolkova, Vineeta Sharma, Bret C Mobley, Prasanna Katti, Antentor Hinton.
      Age-related skeletal muscle atrophy, known as sarcopenia, is characterized by loss of muscle mass, strength, endurance, and oxidative capacity. Although exercise has been shown to mitigate sarcopenia, the underlying governing mechanisms are poorly understood. Mitochondrial dysfunction is implicated in aging and sarcopenia; however, few studies explore how mitochondrial structure contributes to this dysfunction. In this study, we sought to understand how aging impacts mitochondrial three-dimensional (3D) structure and its regulators in skeletal muscle. We hypothesized that aging leads to remodeling of mitochondrial 3D architecture permissive to dysfunction and is ameliorated by exercise. Using serial block-face scanning electron microscopy (SBF-SEM) and Amira software, mitochondrial 3D reconstructions from patient biopsies were generated and analyzed. Across five human cohorts, we correlate differences in magnetic resonance imaging, mitochondria 3D structure, exercise parameters, and plasma immune markers between young (under 50 years) and old (over 50 years) individuals. We found that mitochondria are less spherical and more complex, indicating age-related declines in contact site capacity. Additionally, aged samples showed a larger volume phenotype in both female and male humans, indicating potential mitochondrial swelling. Concomitantly, muscle area, exercise capacity, and mitochondrial dynamic proteins showed age-related losses. Exercise stimulation restored mitofusin 2 (MFN2), one such of these mitochondrial dynamic proteins, which we show is required for the integrity of mitochondrial structure. Furthermore, we show that this pathway is evolutionarily conserved, as Marf, the MFN2 ortholog in Drosophila, knockdown alters mitochondrial morphology and leads to the downregulation of genes regulating mitochondrial processes. Our results define age-related structural changes in mitochondria and further suggest that exercise may mitigate age-related structural decline through modulation of mitofusin 2.
    Keywords:  3D reconstruction; MFN‐2; aging; exercise; human skeletal muscle; mitochondria
    DOI:  https://doi.org/10.1111/acel.70054
  65. Biochim Biophys Acta Mol Basis Dis. 2025 Apr 26. pii: S0925-4439(25)00222-4. [Epub ahead of print]1871(6): 167874
    PGC-1α role in rescuing ferroptosis in cerebral ischemia/reperfusion injury through promoting mitochondrial biogenesis and UCP2 expression.
    Jiahui Yang, Xiaohua Shi, Ming Ma, Zheng Li, Hongyu Liu, Yang Cui, Zhongxin Xu, Jiaoqi Wang.
      Cerebral ischemia/reperfusion injury (CIRI) is a critical factor leading to adverse outcomes in acute ischemic stroke with reperfusion therapy. The occurrence of CIRI involves several cell death pathways, such as ferroptosis. Peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) a vital role in mitochondrial biogenesis and induces several crucial reactive oxygen species (ROS) detoxifying enzymes. Nonetheless, the role of activated PGC-1α in CIRI is still unclear. In this research, we utilized a PGC-1α agonist (ZLN005) in both in vitro and in vivo models of CIRI and found that ZLN005 ameliorates neurologic deficits, reduces infarct volume, and inhibits neuronal ferroptosis in CIRI. Furthermore, CIRI led to a decrease in neuronal mitochondrial quantity and downregulation of uncoupling protein 2 (UCP2) expression. Treatment with ZLN005 activated PGC-1α, promoted neuronal mitochondrial biogenesis, and upregulated UCP2 expression, thereby reducing mitochondrial oxidative stress. The application of the mitochondria-targeted antioxidant Mito-TEMPO inhibited ferroptosis, while UCP2 silencing induced mitochondrial oxidative stress and weakened ZLN005 inhibitory effect of ferroptosis, confirming the dependency of ferroptosis on mitochondrial oxidative stress in CIRI. According to these findings, targeting PGC-1α may offer an effective therapeutic strategy for CIRI by regulating mitochondrial homeostasis and protecting neurons from ferroptotic damage.
    Keywords:  Cerebral ischemia/reperfusion injury; Ferroptosis; Mitochondrial biogenesis; Mitochondrial oxidative stress; PGC-1α; UCP2
    DOI:  https://doi.org/10.1016/j.bbadis.2025.167874
  66. Cell Commun Signal. 2025 Apr 30. 23(1): 208
    Cytochrome P450 2E1 aggravates DXR-induced myocardial injury through imbalanced mitochondrial OPA1.
    Jiaxin Ma, Yaheng Wang, Huijiao Lv, Yu Lei, Feifei Guan, Wei Dong, He Wang, Lianfeng Zhang, Dan Lu.
       BACKGROUND: Cytochrome P450 2E1 (CYP2E1), a drug metabolism enzyme, is linked to multiple pathophysiological states in the myocardium and may act as a sensor of heart diseases. However, the exact mechanisms of CYP2E1 in myocardial injury, particularly in chemotherapeutic agent-induced myocardial damage such as doxorubicin-induced cardiotoxicity, remain unclear.
    METHODS: Using multiple animal models of cardiomyopathy and heart failure, we observed CYP2E1 expression in myocardial mitochondria. Myocardium-specific CYP2E1 overexpression and knockout rat models were employed to study its effects on myocardial injury, assessed via echocardiography and histopathology. Mechanistic insights were derived from transcriptome analysis, mass spectrometry, co-immunoprecipitation, signal transduction analysis, and molecular biology techniques.
    RESULTS: CYP2E1 overexpression accelerated, while CYP2E1 knockout inhibited, myocardial injury in DXR-induced cardiomyopathy and isoprenaline-induced hypertrophic cardiomyopathy. Mechanistically, CYP2E1 was upregulated specifically in myocardial mitochondria during heart disease. This upregulation resulted in mitochondrial fragmentation and dysfunction under DXR-induced stress. CYP2E1 interacted with optic atrophy 1 (OPA1) in the inner mitochondrial membrane, leading to an imbalance between long and short OPA1 isoforms.
    CONCLUSIONS: CYP2E1 disrupts OPA1-mediated mitochondrial dynamics, causing mitochondrial fragmentation and apoptosis, which aggravate myocardial injury. Targeting CYP2E1 may offer a therapeutic strategy to mitigate myocardial damage, particularly in chemotherapeutic drug-induced cardiotoxicity.
    DOI:  https://doi.org/10.1186/s12964-025-02197-w
  67. Biomolecules. 2025 Apr 09. pii: 553. [Epub ahead of print]15(4):
    Modulation of Lonp1 Activity by Small Compounds.
    Giada Zanini, Giulia Micheloni, Giorgia Sinigaglia, Valentina Selleri, Anna Vittoria Mattioli, Milena Nasi, Ciro Leonardo Pierri, Marcello Pinti.
      The Lon protease homolog 1 (LONP1) is an ATP-dependent mitochondrial protease essential for maintaining proteostasis, bioenergetics, and cellular homeostasis. LONP1 plays a pivotal role in protein quality control, mitochondrial DNA maintenance, and oxidative phosphorylation system (OXPHOS) regulation, particularly under stress conditions. Dysregulation of LONP1 has been implicated in various pathologies, including cancer, metabolic disorders, and reproductive diseases, positioning it as a promising pharmacological target. This review examines compounds that modulate LONP1 activity, categorizing them into inhibitors and activators. Inhibitors such as CDDO and its derivatives selectively target LONP1, impairing mitochondrial proteolysis, inducing protein aggregation, and promoting apoptosis, particularly in cancer cells. Compounds like Obtusilactone A and proteasome inhibitors (e.g., MG262) demonstrate potent cytotoxicity, further expanding the therapeutic landscape. Conversely, LONP1 activators, including Artemisinin derivatives and 84-B10, restore mitochondrial function and protect against conditions such as polycystic ovary syndrome (PCOS) and acute kidney injury (AKI). Future research should focus on improving the specificity, bioavailability, and pharmacokinetics of these modulators. Advances in structural biology and drug discovery will enable the development of novel LONP1-targeted therapies, addressing diseases driven by mitochondrial dysfunction and proteostasis imbalance.
    Keywords:  CDDO; Lon protease; artemisinin; bardoxolone; bortezomib; cancer therapy; proteasome inhibitors; protein quality control; proteostasis
    DOI:  https://doi.org/10.3390/biom15040553
  68. Theranostics. 2025 ;15(11): 5073-5086
    Vine-inspired zinc-ion modified black phosphorus coating accelerates bone tissue infiltration of 3D printed scaffolds.
    Dan Li, Danni Dai, Jianrong Wang, Yan Wang, Yujia Tian, Chao Zhang.
      Rationale: In the reconstruction of diabetic bone defects, 3D-printed scaffolds often encounter the challenge of limited and delayed tissue ingrowth in their central regions, which is critical for successful osseointegration and prognostic outcomes. Hyperglycemia induces endothelial apoptosis and impedes angiogenesis, thus inhibiting osteogenic differentiation of bone marrow stem cells (BMSCs). Methods: Drawing inspiration from the growth pattern of vines, we developed a Zn@BP/Si coating on the 3D-printed titanium scaffold to promote the coupling of angiogenesis and osteogenesis. This coating was achieved by Zn2+-modified black phosphorus (BP), which not only enhances the stability and photothermal properties of BP, but also prevents endothelial apoptosis. The effectiveness of Zn@BP/Si in the reconstruction of diabetic bone defects was investigated in rat model of diabetic femoral defect. Its effect on osteogenesis-angiogenesis coupling has also been explored in BMSCs and HUVECs. Results: Zn@BP/Si regulated mitochondrial dynamics and provided motivation for cell adhesion and migration, just like the climbing of vines. Notably, the regulation of enzymatic activity plays a crucial role in its inhibition of excessive mitochondrial fission. The results demonstrate that the Zn@BP/Si promotes the growth of "vascular vines" and ameliorates the angiogenic and osteogenic inhibition in diabetes. Conclusions: The study reveals the potential of bio-inspired Zn@BP/Si coating in angiogenesis-osteogenesis coupling and the treatment of diabetic bone defects.
    Keywords:  3D printed scaffold; diabetic bone defect, osteogenesis-angiogenesis coupling, mitochondrial dynamics, bio-inspired
    DOI:  https://doi.org/10.7150/thno.113623
  69. Neuropharmacology. 2025 Apr 30. pii: S0028-3908(25)00190-X. [Epub ahead of print] 110484
    SIRTUINS MODULATORS MITIGATE HYPOXIA-INDUCED CELL DEATH DUE TO CHANGES IN HISTONE 3 ACETYLATION, AND MITOCHONDRIAL FUNCTION, DYNAMICS, AND CONTENT.
    Luiz Felipe Souza E Silva, Amanda Siena, Jessica Mayumi Yuzawa, Tatiana Rosado Rosenstock.
      Hypoxia is a key environmental factor linked to neurodevelopmental complications, primarily through its impact on mitochondrial dysfunction. Given that sirtuins regulate mitochondrial and cellular metabolism, we aimed to investigate whether pharmacological modulation of sirtuins could protect neurons from hypoxia-induced mitochondrial dysfunction and cell death. To explore this, primary cortical neurons from male Wistar rats (control) and Spontaneously Hypertensive Rats (a model for neonatal hypoxia and schizophrenia) were exposed to cobalt chloride (CoCl2) to chemically induce hypoxia. Neurons were also treated with Nicotinamide (50 μM), Resveratrol (0.5 μM), and Sirtinol (5 μM) to modulate sirtuin activity. We first assessed histone deacetylation, cell death, mitochondrial calcium retention capacity, mitochondrial membrane potential, and levels of reactive oxygen species (ROS). In addition, we analysed the expression of genes related to mitochondrial metabolism, dynamics, and biogenesis, as well as high-energy compound levels. Our data indicate that both chemical and neonatal hypoxia caused mitochondrial depolarization, reduced calcium retention, increased ROS levels, and elevated Nfe2l2 expression in primary cortical neurons. Hypoxia also led to increased expression of genes associated with mitochondrial biogenesis and fission, as well as reduced ATP levels and elevated pyruvate and lactate levels. Importantly, treatment with sirtuin modulators enhanced neuron viability, likely by further increasing Nfe2l2 expression and reducing ROS production. These modulators also improved metabolic outcomes, including higher ATP levels, and normalized pyruvate and lactate production, as well as mitochondrial fusion gene expression. Collectively, our findings suggest that sirtuin modulators could mitigate hypoxia-induced damage and may represent a potential therapeutic strategy for managing neurodevelopmental disorders.
    Keywords:  Hypoxia; Mitochondrial dysfunction; Schizophrenia and Neurons; Sirtuins
    DOI:  https://doi.org/10.1016/j.neuropharm.2025.110484
  70. J Ethnopharmacol. 2025 Apr 25. pii: S0378-8741(25)00564-1. [Epub ahead of print] 119880
    Vicenin-2 in Suhuang antitussive capsule attenuates mitophagy-dependent ferroptosis via LRP1 for treating post-infectious cough.
    Qimeng Tian, Hong Jiang, Yajun Luan, Jingge Sun, Yihang Sui, Ling Chen, Yongxiang Wang, Ninghua Tan.
       ETHNOPHARMACOLOGICAL RELEVANCE: Suhuang antitussive capsule (SH) is the only clinically approved traditional Chinese patent medicine for the treatment of post-infectious cough (PIC). During the past decade, our lab has conducted intensive researches on SH, including its efficacy and mechanism on PIC, and determined that SH has favorable anti-inflammatory, antitussive, expectorant, and anti-asthmatic pharmacological effects. Recently, we found that vicenin-2 (VIC-2) could be detected in SH and showed activity in vitro primary screening on PIC.
    AIM OF THE STUDY: To investigate the therapeutic effects of VIC-2 on PIC and its potential mechanisms, and want to elucidate VIC-2 as one of the efficacious components of SH.
    MATERIALS AND METHODS: The PIC mouse model was established with lipopolysaccharide (LPS)-induced combined cigarette smoke (CS)-exposed ICR mice, while the in vitro assay was constructed to induce BEAS-2B cells with cigarette smoke extract (CSE). The therapeutic effects of VIC-2 on PIC in vitro and in vivo were assessed by pathological sections, cough assay, immune cell counting, and quantitative-polymerase chain reaction (Q-PCR). The mechanisms of VIC-2 on ferroptosis and mitophagy in PIC were further explored by cell viability assay, Prussian blue staining, lipid peroxidation assessment, confocal laser scanning microscopy, and western blotting. Subsequently, virtual docking, cellular thermal shift assay (CETSA), and drug affinity responsive target stability (DARTS) verified the target relationship between VIC-2 and LDL receptor-related protein 1 (LRP1). In addition, the link between LRP1 and mitophagy-dependent ferroptosis was explored by knocking down LRP1.
    RESULTS: VIC-2 significantly improved lung inflammation, oxidative stress, and airway remodeling in PIC and inhibited mitophagy-dependent ferroptosis, confirming that it is one of the antitussive components of SH for the treatment of PIC. LRP1 is one of the pharmacological targets of VIC-2, in which VIC-2 exerted the above effects through up-regulating LRP1 by influencing the LRP1-Parkin interaction. The blockade of LRP1 reversed the both in vitro and in vivo pharmacological activities of VIC-2. Furthermore, our results showed for the first time that defects in LRP1 lead to ferroptosis.
    CONCLUSION: This study demonstrates that VIC-2 inhibits mitophagy-dependent ferroptosis via LRP1 for the treatment of PIC, constituting one of the antitussive components of SH.
    Keywords:  Ferroptosis; LDL receptor-related protein 1; Mitophagy; Post-infectious cough; Suhuang antitussive capsule; Vicenin-2
    DOI:  https://doi.org/10.1016/j.jep.2025.119880
  71. Cell Signal. 2025 Apr 23. pii: S0898-6568(25)00237-2. [Epub ahead of print]132 111824
    Dapagliflozin activates the RAP1B/NRF2/GPX4 signaling and promotes mitochondrial biogenesis to alleviate vascular endothelial ferroptosis.
    Yi Zhu, Jin Yang, Jia-Li Zhang, Hao Liu, Xue-Jiao Yan, Ji-Yong Ge, Fang-Fang Wang.
      Vascular endothelial ferroptosis is a key mechanism underlying endothelial injury and atherosclerotic plaque formation. Dapagliflozin, an essential medication in the management of heart failure, has been shown to delay atherosclerosis progression. However, the underlying mechanisms remain unclear. This study aimed to elucidate the molecular pathways whereby dapagliflozin inhibits vascular endothelial ferroptosis. We utilized human umbilical vein endothelial cells (HUVECs) to construct a cell model of atherosclerosis combined with ferroptosis. Dapagliflozin significantly decreased the iron and malondialdehyde levels and the release of inflammatory factors in HUVECs treated with oxidized low-density lipoprotein or Erastin but increased the superoxide dismutase activity and the reduced glutathione / oxidized glutathione ratio. Results from transmission electron microscopy indicated that dapagliflozin alleviated the mitochondrial shrinkage and the reduction in the number of cristae in these HUVECs. RNA sequencing revealed that dapagliflozin upregulates RAP1B. In vitro experiments showed that RAP1B upregulates NRF2 and promotes its nuclear translocation, activating the xCT/GPX4 signaling pathway and inhibiting lipid peroxidation. Additionally, dapagliflozin induces mitochondrial biogenesis and enhances oxidative phosphorylation through the RAP1B/NRF2 pathway, reducing iron overload and excessive production of mitochondrial reactive oxygen species, ultimately mitigating ferroptosis. At the animal level, we constructed an atherosclerosis model by using Apoe-/-; Rap1b-/- double-knockout mice. Rap1b knockout blocked the inhibitory effects of dapagliflozin on atherosclerotic plaque formation and ferroptosis activation. We confirmed in vivo that dapagliflozin upregulates GPX4 and key factors of mitochondrial biogenesis via RAP1B, promoting oxidative phosphorylation. When mitochondrial oxidative phosphorylation was pharmacologically inhibited, ferroptosis was reactivated, promoting atherosclerotic plaque formation. In conclusion, this study demonstrated that dapagliflozin activates the RAP1B/NRF2/GPX4 signaling pathway and promotes mitochondrial biogenesis, thereby alleviating vascular endothelial ferroptosis.
    Keywords:  Dapagliflozin; GPX4; Mitochondrial biogenesis; NRF2; RAP1B; Vascular endothelial ferroptosis
    DOI:  https://doi.org/10.1016/j.cellsig.2025.111824
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