bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2025–06–01
sixty papers selected by
Gavin McStay, Liverpool John Moores University
  1. Nucleolin alleviates endotoxemia-induced myocardial dysfunction via inhibiting Drp1-mediated mitochondrial fission.
  2. Overexpression of c-Myc triggers p62 aggregation-mediated mitochondrial mitophagy in cabozantinib resistance of hepatocellular carcinoma.
  3. Hyperbaric oxygen therapy attenuates carbon monoxide-induced lung injury by restoring mitochondrial dynamics and suppressing Pink1/Parkin-mediated mitophagy.
  4. Icariin mitigates depressive-like behavior in rats by regulating mitochondrial function.
  5. Review of FUNDC1-mediated mitochondrial autophagy in Alzheimer's disease.
  6. Nur77 inhibits mitochondrial excessive fragmentation through mutated p53 L194F in T47D breast cancer cells.
  7. Imbalanced mitochondrial dynamics in human PD and α-synuclein mouse brains.
  8. Impact of Drp1 Loss on Organelle Interaction, Metabolism, and Inflammation in Mouse Liver.
  9. Different Expression of Nuclear Respiratory Factor 1 (NRF-1) Gene in COVID-19: An Insight into Disease Severity.
  10. Mitophagy Protects Against Cisplatin-Induced Injury in Granulosa Cells.
  11. Lysine acetylation modulates s-OPA1 GTPase activity and oligomerization in mitochondrial membrane remodeling.
  12. Low Fluoride Regulates Macrophage Polarization Through Mitochondrial Autophagy Mediated by PINK1/Parkin Axis.
  13. Mitochondria-Nuclear Crosstalk: Orchestrating mtDNA Maintenance.
  14. Intervention strategies for Parkinson's disease: the role of exercise and mitochondria.
  15. Disruption of cTnT-Mediated Sarcomere-Mitochondrial Communication Results in Dilated Cardiomyopathy.
  16. Reduced Expression of UPRmt Proteins HSP10, HSP60, HTRA2, OMA1, SPG7, and YME1L Is Associated with Accelerated Heart Failure in Humans.
  17. Melatonin Improves Lipid Homeostasis, Mitochondrial Biogenesis, and Antioxidant Defenses in the Liver of Prediabetic Rats.
  18. Targeting mitochondrial quality control for myocardial ischemia-reperfusion injury.
  19. Three-dimensional super-resolution imaging of whole cells using a high numerical aperture oblique-plane microscope.
  20. Vitexin alleviates cerebral ischemia/reperfusion injury by regulating mitophagy via the SIRT1/PINK1/Parkin pathway.
  21. The power of connections: Recent advances in understanding the regulation of mitochondrial dynamics by membrane contact sites.
  22. Hyperoside alleviates zearalenone-induced liver injury by regulating mitochondrial calcium overload mediated excessive autophagy.
  23. Downhill running induced mitophagy in rat soleus muscle via the AMPK pathway.
  24. Activation of the MEK1-CHK2 axis in macrophages by Staphylococcus aureus promotes mitophagy, resulting in a reduction in bactericidal efficacy.
  25. Impaired Mitophagy Contributes to Pyroptosis in Sarcopenic Obesity Zebrafish Skeletal Muscle.
  26. Reduced iron bioavailability drives acute high‑altitude lung injury through HIF1α activation and mitophagy.
  27. Cannabinol (CBN) alleviates age-related cognitive decline by improving synaptic and mitochondrial health.
  28. Dehydrodiisoeugenol alleviates palmitate-induced mitochondrial dysfunction in human vascular smooth muscle cells through the activation of SIRT1-mediated Drp1 deacetylation.
  29. Dl-3-n-Butylphthalide Alleviates Cognitive Impairment in Chronic Cerebral Hypoperfusion: Associations with Mitochondrial Permeability Transition Pore Closure and Suppression of Excessive Mitophagy.
  30. Melatonin mitigates arsenic and fluoride-induced cardiotoxicity in chickens by maintaining mitochondrial homeostasis.
  31. Targeting Ferroptosis via Mitochondria Dynamics in Myocardial Ischemia/Reperfusion Injury.
  32. Mito-TEMPO Mitigates Fibromyalgia Induced by Reserpine in Rats: Orchestration Between SIRT1, Mitochondrial Dynamics, Endoplasmic Reticulum and miRNA-320.
  33. Endoplasmic Reticulum Stress Inhibition Promotes Mitophagy via Miro1 Reduction to Rescue Mitochondrial Dysfunction and Protect Dopamine Neurons in Parkinson's Disease.
  34. Macrophage Notch1 drives septic cardiac dysfunction by impairing mitophagy and promoting NLRP3 activation.
  35. Insertion of mNeonGreen into the variable domain of DRP-1 permits visualization of functional endogenous protein.
  36. Ketogenic diet attenuates microglia-mediated neuroinflammation by inhibiting NLRP3 inflammasome activation via HDAC3 inhibition to activate mitophagy in experimental autoimmune encephalomyelitis.
  37. Lanthanide nanocrystals-based direct triple-state energy converters for mitophagy and ferroptosis-induced antitumor immunoreaction.
  38. Targeting LIF With Cyclovirobuxine D to Suppress Tumor Progression via LIF/p38MAPK/p62-Modulated Mitophagy in Hepatocellular Carcinoma.
  39. PGC-1 alpha regulates mitochondrial biogenesis to promote silica-induced pulmonary fibrosis.
  40. Mitochondrial dysfunction: the hidden catalyst in chronic kidney disease progression.
  41. Marsdenia tenacissima extract accelerates ferroptosis of osteosarcoma cells by upregulating HO-1 and activating mitophagy.
  42. The mitochondrial intermembrane space - a permanently proteostasis-challenged compartment.
  43. Synergistic Impact of Aerobic Exercise and Resveratrol on White Adipose Tissue Browning in Obese Rats: Mechanistic Exploration and Biological Insights.
  44. The Insertion Domain of Mti2 Facilitates the Association of Mitochondrial Initiation Factors with Mitoribosomes in Schizosaccharomyces pombe.
  45. Investigating the mechanism of inositol against paclitaxel chemoresistance on triple-negative breast cancer by using 7T multiparametric MRI and mitochondrial changes.
  46. Contrasting pathophysiological mechanisms of OPA1 mutations in autosomal dominant optic atrophy.
  47. LRRK2-mediated mitochondrial dysfunction in Parkinson's disease.
  48. Neuroprotective effect of folic acid by maintaining DNA stability and mitochondrial homeostasis through the ATM/CHK2/P53/PGC-1α pathway in alcohol-exposed mice.
  49. Ligustrazine nano-drug delivery system ameliorates doxorubicin-mediated myocardial injury via piezo-type mechanosensitive ion channel component 1-prohibitin 2-mediated mitochondrial quality surveillance.
  50. Inhibition of Cathepsin B Ameliorates Murine Cognitive Dysfunction and Neuronal Damage in Ischemic Stroke by Inhibiting Mitochondrial Apoptosis and Drp1-Mediated Mitochondrial Fission.
  51. Mitochondrial calcium homeostasis mediated by estradiol contributes to atrial fibrillation protection.
  52. Myogenic nano-adjuvant for orthopedic-related sarcopenia via mitochondrial homeostasis modulation in macrophage-myosatellite metabolic crosstalk.
  53. Lichong Decoction represses colorectal cancer progression via inhibiting the PINK1/Parkin pathway regulated by Rab27B.
  54. Arginase 1 drives mitochondrial cristae remodeling and PANoptosis in ischemia/hypoxia-induced vascular dysfunction.
  55. Mitochondrial medicine: "from bench to bedside" 3PM-guided concept.
  56. Actin in mitochondrial regulation and mechanometabolic crosstalk.
  57. Membrane ATPases and Mitochondrial Proteins in Fetal Cerebellum After Exposure to L-Glutamate During Gestation.
  58. The AKT-USP15 axis modulates autophagy in MPP+-induced Parkinson's disease model of SN4741 cells.
  59. [Shenqi Buzhong Formula ameliorates mitochondrial dysfunction in a rat model of chronic obstructive pulmonary disease by activating the AMPK/SIRT1/PGC-1α pathway].
  60. Role of mitochondrial homeostasis in female reproductive system aging.
  1. Tissue Cell. 2025 May 18. pii: S0040-8166(25)00244-7. [Epub ahead of print]96 102964
    Nucleolin alleviates endotoxemia-induced myocardial dysfunction via inhibiting Drp1-mediated mitochondrial fission.
    Ludong Yuan, Yuting Tang, Leijing Yin, Xiaofang Lin, Pengfei Liang, Bimei Jiang.
       BACKGROUND: Our previous study found that nucleolin expression exerted anti-cardiac injury effects by promoting mitochondrial biogenesis; however, it could not explain the increase in mitochondrial fragmentation during myocardial injury. Mitochondrial fragmentation is associated with mitochondrial fission, but it is unknown whether nucleolin regulates mitochondrial fission. Therefore, this study aims to investigate the mechanism by which nucleolin regulates mitochondrial fission in endotoxemia-induced myocardial dysfunction.
    METHODS: Nucleolin myocardial-specific knockout mice were used to construct an endotoxemia-induced myocardial dysfunction model. Mitochondrial membrane potential (MMP), ATP production, Mitotracker Red, Transmission Electron Microscope were measured to assess mitochondrial function. Mitochondria were isolated to observe Drp1 translocation to mitochondria. The expression of pGSK-3β-Tyr216, GSK-3β, pDrp1-Ser637, nucleolin and dynamin-related protein 1 (DNM1L, Drp1) were detected using qRT-PCR and western blot.
    RESULTS: Following cecum ligation and puncture (CLP) model, cardiac function was impaired, myocardial mitochondrial function declined, mitochondrial morphology became disorganized and fragmented, nucleolin and Drp1 expression was elevated. Myocardial injury and mitochondrial dysfunction were further exacerbated after nucleolin myocardium-specific knockout. Meanwhile, after cellular-level nucleolin interference, it further led to LPS and TNF-α-induced mitochondrial dysfunction and cardiomyocyte damage. Mechanically, nucleolin interference inhibited Drp1 phosphorylation at Ser637 and promoted Drp1 translocation to mitochondria. Myocardial injury caused by nucleolin knockdown was alleviated by the use of P110, an inhibitor of Drp1 mitochondrial translocation.
    CONCLUSION: Endotoxemia-induced myocardial dysfunction is accompanied by increased mitochondrial fragmentation. Nucleolin alleviates endotoxemia-induced myocardial dysfunction by enhancing Drp1 phosphorylation at Ser637, inhibiting Drp1 translocation to the mitochondria and mitochondrial fission.
    Keywords:  Dynamin-related protein 1 (DNM1L, Drp1); Endotoxemia-induced myocardial dysfunction; Mitochondrial fission; Mitochondrion; Nucleolin
    DOI:  https://doi.org/10.1016/j.tice.2025.102964
  2. Mol Med. 2025 May 27. 31(1): 209
    Overexpression of c-Myc triggers p62 aggregation-mediated mitochondrial mitophagy in cabozantinib resistance of hepatocellular carcinoma.
    Kaibo Yang, Xing Zhang, Kun Yang, Sinan Liu, Jingyao Zhang, Yunong Fu, Tong Liu, Kunjin Wu, Jing Li, Chang Liu, Qichao Huang, Kai Qu.
      Resistance to tyrosine kinase inhibitors (TKIs) poses a significant challenge in the treatment of hepatocellular carcinoma (HCC). Although dysregulation of mitochondrial dynamics has been implicated in the aggressive behaviors of various tumors, the specific role and underlying mechanisms by which this dysregulation contributes to cabozantinib resistance in HCC cells remains insufficiently characterized. By investigating mitochondrial dynamics as central regulators of cabozantinib resistance, this work specifically aims to discover actionable targets for restoring drug sensitivity in treatment-refractory HCC cells. We employed transmission electron microscopy (TEM) and confocal microscopy to analyze mitochondrial morphology in HCC cells resistant to TKIs. Additionally, we utilized an oncogene hydrodynamic injection-induced primary liver cancer mouse model to assess the therapeutic efficacy of combining cabozantinib with other pharmacological agents. Our results demonstrated significant increases in mitochondrial fragmentation, p62 aggregation, and mitophagy in cabozantinib-resistant HCC cells, which correlated with overexpression of c-Myc. Notably, inhibiting mitochondrial fission, p62 aggregation, or autophagy effectively reversed the resistance of HCC cells to cabozantinib. Mechanistically, cabozantinib treatment was shown to induce c-Myc expression, which significantly enhanced mitochondrial fragmentation and p62 aggregation, thereby promoting mitophagy. This mitophagic process selectively eliminated damaged mitochondria, reducing cytochrome C-induced apoptosis in cabozantinib-resistant cells. Ultimately, combining cabozantinib with either the autophagy inhibitor chloroquine or the p62 aggregation inhibitor XRK3F2 resulted in improved anticancer efficacy. In conclusion, c-Myc overexpression facilitates p62 aggregation-mediated mitophagy, leading to cabozantinib resistance in HCC cells. Inhibition of autophagy effectively restores cabozantinib sensitivity in HCC.
    Keywords:  C-Myc; Cabozantinib resistance; HCC; Mitophagy; P62 aggregation
    DOI:  https://doi.org/10.1186/s10020-025-01263-w
  3. Environ Pollut. 2025 May 27. pii: S0269-7491(25)00894-2. [Epub ahead of print] 126521
    Hyperbaric oxygen therapy attenuates carbon monoxide-induced lung injury by restoring mitochondrial dynamics and suppressing Pink1/Parkin-mediated mitophagy.
    Tzu-Hao Chen, Chien-Chin Hsu, Ching-Ping Chang, Chien-Cheng Huang, Ying-Jan Wang.
      Carbon monoxide (CO), a major air pollutant from vehicle emissions, industrial combustion, and indoor fuel use, poses significant environmental and public health risks. Although acute carbon monoxide poisoning (COP) is well-documented, the underlying mechanisms driving long-term pulmonary complications following CO exposure remain poorly understood. Hyperbaric oxygen therapy (HBOT) is the standard treatment for COP, primarily for its ability to eliminate carboxyhemoglobin and reduce oxidative stress. However, its role in preventing long-term pulmonary dysfunction through the regulation of mitochondrial quality control requires further investigation. This study aimed to elucidate how mitochondrial dynamics and Pink1/Parkin-mediated mitophagy contribute to CO-induced lung injury and to evaluate the therapeutic potential of HBOT. Epidemiological analysis revealed an association between COP and an increased chronic obstructive pulmonary disease (COPD) risk. In a rat model, CO exposure led to emphysematous lung damage, persistent cytokine storms, and immune dysregulation. CD86+ and CD163+ macrophages and neutrophils were found in both bronchoalveolar lavage fluid and lung parenchyma, coexpressing pro-inflammatory cytokines (e.g., CCL5, CCL20, IL-1β, IL-10, IL-17). Alveolar barrier integrity was disrupted by downregulation of tight junction proteins ZO-1 and claudin-3. In alveolar type II cells, mitochondrial dynamics were impaired (decreased Opa1, increased Drp1), with concurrent activation of Pink1/Parkin-mediated mitophagy, pyroptosis, and apoptosis. These alterations led to alveolar damage and pulmonary dysfunction, including increased airway resistance, compliance, and hyperinflation-hallmarks of COPD-like pathology. Notably, HBOT reversed these changes by restoring mitochondrial homeostasis, suppressing cell death pathways, reducing inflammation, and improving lung function. These findings provide novel insights into the role of mitochondrial dynamics and selective mitophagy in the pathogenesis of CO-induced lung injury. It also underscores the therapeutic potential of HBOT in preventing and controlling long-term pulmonary complications.
    Keywords:  Carbon monoxide; chronic obstructive pulmonary disease; hyperbaric oxygen therapy; lung injury; mitochondrial damage
    DOI:  https://doi.org/10.1016/j.envpol.2025.126521
  4. J Ethnopharmacol. 2025 May 25. pii: S0378-8741(25)00723-8. [Epub ahead of print]350 120036
    Icariin mitigates depressive-like behavior in rats by regulating mitochondrial function.
    Hui Zhao, Sisi Zhang, Zheng Gong, Tu Chen, Huan Guo, Mingge Yang, Lawen Wang, Xin Zhou, Juanping Xie, Hui Li, Yushan Lu, Zhongliang Zhu.
       ETHNOPHARMACOLOGICAL RELEVANCE: Epimedii Folium is a famous traditional Chinese medicine that has been utilized to treat depression, impotency and rheumatism for centuries in China. Icariin (ICA) is the primary flavonoid and quality control ingredient of Epimedii Folium.
    AIMS OF THE STUDY: The objective of this investigation was to clarify the mechanisms through which ICA improved depressive-like behavior in prenatal stress (PS) offspring rats.
    MATERIALS AND METHODS: Male offspring rats subjected to PS were utilized to investigate the antidepressant effect and possible mechanism of ICA. H&E staining, Nissl staining, ELISA, western blot, immunofluorescence staining and molecular docking were carried out in this work.
    RESULTS: ICA treatment markedly mitigated depressive-like behavior and hippocampal neuronal damage in PS offspring rats. The hippocampal synaptic plasticity of PS offspring rats was impaired, while the abnormal expressions of synaptic plasticity proteins and the synaptic ultrastructure were restored after the administration of ICA. Importantly, ICA treatment improved disrupted mitochondrial dynamics and morphology, thereby reversing the decline in ATP level and mitochondrial membrane potential (MMP) in the hippocampus of PS offspring rats. The reduction of MMP in PS rats further induced the apoptosis of hippocampal neurons, while this trend was markedly reversed after the treatment with ICA. Concurrently, ICA reversed the decrease of mitochondrial biogenesis proteins (SIRT1, PGC-1α, NRF1, and TFAM) and the interaction between SIRT1 and PGC-1α. Further studies found that treatment with ICA notably counteracted the reduction in SIRT1 deacetylase activity and the increase in PGC-1α acetylation level in the hippocampus of PS rats. Additionally, ICA enhanced mitophagy by activating the PINK1/Parkin signaling pathway.
    CONCLUSION: ICA exerted anti-depressive effects in PS offspring rats, partly by improving mitochondrial dynamics, biogenesis, and mitophagy.
    Keywords:  Depression; Icariin; Mitochondrial biogenesis; Mitochondrial dynamics; Mitophagy; Prenatal stress
    DOI:  https://doi.org/10.1016/j.jep.2025.120036
  5. Front Aging Neurosci. 2025 ;17 1544241
    Review of FUNDC1-mediated mitochondrial autophagy in Alzheimer's disease.
    Dandan Shi, Xiaochen Guo, Ziqi Ning, Yaoyao Zhang, Fang Liu, Meixia Liu, Yun Wei.
      Mitochondrial autophagy is a critical quality control mechanism that eliminates dysfunctional mitochondria to maintain cellular homeostasis. Among receptor-dependent mitophagy pathways, FUN14 domain-containing 1 (FUNDC1)-a mitochondrial outer membrane protein harboring an LC3-interacting region (LIR)-plays a central role by directly binding to LC3 under stress conditions, thereby initiating autophagosome encapsulation of damaged organelles. Emerging evidence implicates FUNDC1 dysregulation in neurodegenerative diseases, particularly Alzheimer's disease (AD), where defective mitophagy exacerbates hallmark pathologies including Aβ plaque deposition and hyperphosphorylated Tau-driven neurofibrillary tangles. Despite advances, the molecular interplay between FUNDC1 phosphorylation states (e.g., Ser13/Ser17/Tyr18) and AD progression remains poorly defined. This review systematically examines FUNDC1's dual regulatory role in mitophagy, its mechanistic links to Aβ and Tau pathologies, and the therapeutic potential of targeting FUNDC1-associated kinases (e.g., ULK1, CK2) or downstream effectors (e.g., DRP1, OPA1) to counteract mitochondrial dysfunction in AD. By synthesizing recent preclinical and clinical findings, we aim to bridge the gap between FUNDC1 biology and AD therapeutics, highlighting actionable nodes for drug development.
    Keywords:  Alzheimer’s disease; FUNDC1 signaling pathway; mitochondrial autophagy; neurodegenerative diseases; signaling molecules
    DOI:  https://doi.org/10.3389/fnagi.2025.1544241
  6. Biochem Pharmacol. 2025 May 23. pii: S0006-2952(25)00262-X. [Epub ahead of print] 116999
    Nur77 inhibits mitochondrial excessive fragmentation through mutated p53 L194F in T47D breast cancer cells.
    Xiaohui Chen, Fang Zhang, Huiying Zhou, Fu-Quan Jiang, Ting Deng, Guanghui Wang, Jie Liu, Xinyou Liu, Huaqin Sun, Lijun Cai, Yang Xu.
      Nur77 is an orphan nuclear receptor for which no endogenous ligand has yet been identified. It has been demonstrated that there is aberrant expression or dysfunction of nur77 in breast cancer (BC), however, its role in different types of breast cancer remains contentious. Despite mounting evidence that Nur77 exerts influence over mitochondrial dynamics, including fission, fusion and mitophagy of mitochondria in diverse systems, the role and mechanism of mitochondrial dynamics regulated by Nur77 in tumor cells remain opaque. In the present study, significant differences in Nur77 levels were observed in various BC cell types, particularly in the Luminal A-type cell lines MCF-7 and T47D. Nur77 was more highly expressed in T47D cells with the p53 L194F mutation and significantly promoted the growth of T47D cells. In T47D cells, the knockout of Nur77 unequivocally disrupted mitochondrial function, inducing excessive mitochondrial fragmentation and inactivating mitophagy. Further mechanistic studies demonstrated that only the mutant p53 L194F protein in T47D regulated p-Drp1-S616 in comparison to the wild-type p53 protein in MCF-7 cells. Nur77 up-regulated p53 L194F expression at the transcriptional level and exerted a stronger effect on the interaction of Drp1 with mutant p53 L194F. These results suggest that the Nur77/p53 L194F/ mitofission axis may be involved in the mitochondrial homeostasis of specific types of BC cells to maintain BC cell growth. The discovery of this axis provides an important experimental basis for the fine classification of Luminal A BC and the identification of new therapeutic targets.
    Keywords:  Breast cancer; Drp1; Mitochondrial dynamics; Nur77; P53
    DOI:  https://doi.org/10.1016/j.bcp.2025.116999
  7. Neurobiol Dis. 2025 May 26. pii: S0969-9961(25)00192-5. [Epub ahead of print]212 106976
    Imbalanced mitochondrial dynamics in human PD and α-synuclein mouse brains.
    Harry J Brown, Rebecca Z Fan, Riley Bell, Said S Salehe, Carlos Martínez Martínez, Yanhao Lai, Kim Tieu.
      Emerging studies have shown that dysregulation in mitochondrial dynamics has a major negative impact on mitochondria. Partial genetic and pharmacological inhibition of the mitochondrial fission dynamin-related protein 1 (DRP1) has been demonstrated to be beneficial in models of neurodegenerative disorders, including Parkinson's disease (PD). However, the expression of DRP1 and other mitochondrial fission/fusion mediators have not been investigated in the brains of Parkinson's patients. This information is critical to strengthening mitochondrial dynamics as a potential therapeutic target for PD. We report in this study that significant increases in the levels of both DNM1L, which encodes DRP1, as well as the DRP1 protein were detected in Parkinson's patients. Immunostaining revealed increased DRP1 expression in dopamine (DA) neurons, astrocytes, and microglia. In addition to DRP1, the levels of other fission and fusion genes/proteins were also altered. To complement these human studies and given the significant role of α-synuclein in PD pathogenesis, we performed time-course studies using transgenic mice overexpressing human wild-type SNCA. As early as six months old, we detected an upregulation of DRP1 in the nigral DA neurons of the SNCA mice as compared to their wild-type littermates. Furthermore, these mutant animals exhibited more DRP1 phosphorylation at serine 616, which promotes its translocation to mitochondria to induce fragmentation. Together, this study shows an upregulation of DRP1 and alterations in other fission/fusion proteins in both human and mouse PD brains, leading to a pro-fission phenotype, providing additional evidence that blocking mitochondrial fission or promoting fusion is a potential therapeutic strategy for PD.
    Keywords:  Dynamin-related protein 1; Mitochondrial dynamics; Neurodegeneration; Parkinson's disease; Protein aggregation; α-synuclein
    DOI:  https://doi.org/10.1016/j.nbd.2025.106976
  8. Cells. 2025 05 08. pii: 679. [Epub ahead of print]14(10):
    Impact of Drp1 Loss on Organelle Interaction, Metabolism, and Inflammation in Mouse Liver.
    Lixiang Wang, Seiji Nomura, Nao Hasuzawa, Sadaki Yokota, Ayako Nagayama, Kenji Ashida, Junjiro Rikitake, Yoshinori Moriyama, Masatoshi Nomura, Ken Yamamoto.
      Dynamin-related protein 1 (Drp1) is a crucial player in mitochondrial fission and liver function. The interactions between mitochondria, endoplasmic reticulum (ER), and lipid droplets (LDs) are fundamental for lipid metabolism. This study utilized liver-specific Drp1 knockout (Drp1LiKO) mice to investigate the effects of Drp1 deficiency on organelle interactions, metabolism, and inflammation. Our analysis revealed disrupted interactions between mitochondria and LDs, as well as altered interactions among ER, mitochondria, and LDs in Drp1LiKO mice. Through mass spectrometry and microarray analysis, we identified changes in lipid profiles and perturbed expression of lipid metabolism genes in the livers of Drp1LiKO mice. Further in vitro experiments using primary hepatocytes from Drp1LiKO mice confirmed disturbances in lipid metabolism and increased inflammation. These findings highlight the critical involvement of Drp1 in regulating organelle interactions for efficient lipid metabolism and overall liver health. Targeting Drp1-mediated organelle interactions may offer potential for developing therapies for liver diseases associated with disrupted lipid metabolism.
    Keywords:  dynamin-related protein 1; lipid metabolism; liver inflammation; organelle interaction
    DOI:  https://doi.org/10.3390/cells14100679
  9. Curr Microbiol. 2025 May 30. 82(7): 317
    Different Expression of Nuclear Respiratory Factor 1 (NRF-1) Gene in COVID-19: An Insight into Disease Severity.
    Shahrzad Shoraka, Seyed Reza Mohebbi, Seyed Masoud Hosseini, Asma Moradi, Shabnam Shahrokh, Amir Sadeghi, Mohammad Reza Zali.
      Mitochondrial quality control is carried out through mechanisms such as mitochondrial biogenesis, dynamics, and mitophagy. Recent studies have shown that SARS-CoV-2 can directly modulate mitochondrial biogenesis. Nuclear respiratory factor 1 (NRF-1) is an important mediator of genes involved in mitochondrial biogenesis. A key role of NRF-1 in innate antiviral immunity and a link between innate immunity and mitochondrial quality control has been suggested. This study aims to investigate the NRF-1 levels in COVID-19 patients and compare between asymptomatic and symptomatic cases. Also, the diagnostic values ​​of NRF-1 in SARS-CoV-2 infection have been evaluated based on disease severity subgroups. Buffy coat samples were collected from 37 COVID-19 patients and 33 healthy individuals. The patient group was divided into the following subgroups: asymptomatic (n = 17), mild/moderate (n = 12), and severe (n = 8) based on clinical and laboratory parameters. After RNA extraction and cDNA synthesis, real-time PCR was used to determine relative expression levels of NRF-1. Our results showed that the NRF-1 levels were significantly higher in COVID-19 patients than in healthy individuals. Also, NRF-1 levels were increased in symptomatic, mild/moderate, and severe cases compared to asymptomatic COVID-19 patients. In addition, the results of ROC curve analysis showed that the level of NRF-1 has high discriminative power to differentiate between COVID-19 severity subgroups. NRF-1 mRNA levels are a promising biomarker for the COVID-19 severity. Further understanding of the role of NRF-1 and mitochondrial quality control in disease severity, and outcome of SARS-CoV-2 infection may help in COVID-19 managements.
    DOI:  https://doi.org/10.1007/s00284-025-04296-w
  10. Toxics. 2025 Apr 23. pii: 332. [Epub ahead of print]13(5):
    Mitophagy Protects Against Cisplatin-Induced Injury in Granulosa Cells.
    Sihui Zhu, Mingge Tang, Jiahua Chen, Shuhang Li, Rufeng Xue.
      Cisplatin, a widely used chemotherapeutic agent, is known to induce premature ovarian insufficiency (POI) and infertility in women of reproductive age. Among the contributing factors, cisplatin-induced apoptosis of ovarian granulosa cells is considered a primary driver of ovarian dysfunction; however, the underlying mechanisms remain incompletely understood. In this study, we investigated the cytotoxicity of cisplatin on the granulosa cell line KGN in vitro and explored the associated mechanisms. Our results demonstrate that cisplatin induces KGN cell apoptosis in a dose-dependent manner and impairs mitochondrial function, as evidenced by excessive ROS production, membrane potential collapse, and reduced ATP synthesis. Mitophagy, a key cellular self-protection mechanism that selectively removes damaged mitochondria, was activated following cisplatin treatment, mitigating its detrimental effects on KGN cells. Activation of mitophagy with urolithin A (UA) ameliorated cisplatin-induced mitochondrial dysfunction and apoptosis, whereas inhibition of mitophagy with cyclosporine A (CsA) exacerbated these effects. Furthermore, pretreatment with the clinical drug melatonin significantly enhanced mitophagy, effectively attenuating cisplatin-induced apoptosis in KGN cells. This study proposes a novel therapeutic strategy for patients undergoing tumor chemotherapy, aiming to preserve treatment efficacy while reducing the adverse effects of chemotherapeutic agents on ovarian function, thereby improving patients' quality of life.
    Keywords:  KGN cells; apoptosis; cisplatin; melatonin; mitophagy
    DOI:  https://doi.org/10.3390/toxics13050332
  11. Protein Sci. 2025 Jun;34(6): e70179
    Lysine acetylation modulates s-OPA1 GTPase activity and oligomerization in mitochondrial membrane remodeling.
    Javaid Jabbar, Bakht Afroze, Naomi X Y Ling, Jonathan S Oakhill, Isabelle Rouiller.
      Mitochondrial dynamics are regulated by coordinated fission and fusion events that rely on key proteins and lipids organized spatially within the mitochondria. The dynamin-related GTPase Optic Atrophy 1 (OPA1) is essential for inner mitochondrial membrane fusion and cristae structure maintenance. While post-translational modifications, particularly lysine acetylation, are emerging as critical regulators of mitochondrial protein function, their impact on OPA1 remains poorly characterized. In this study, we explored the effects of lysine acetylation on the short form of OPA1 (s-OPA1) using acetylation and deacetylation mimetic mutations. Through a combination of in silico analyses and functional assays, we identified lysine residues in s-OPA1 that are conserved across species and significantly influence protein stability, GTPase activity, and oligomeric assembly upon acetylation or deacetylation. Our findings reveal that acetylation at K328 and deacetylation at K342 within the G domain enhance the GTPase activity of s-OPA1 upon lipid membrane binding, whereas deacetylation at K772 abolishes membrane binding-induced GTPase activity. Negative-stain transmission electron microscopy indicated that while lysine acetylation does not alter the ability of s-OPA1 to bind and tubulate liposomes, it significantly impacts higher-order filament formation. These findings provide novel insights into how acetylation modulates s-OPA1 function, highlighting a potential mechanism for post-translational regulation of mitochondrial dynamics. Our study contributes to the understanding of how molecular changes influence broader cellular processes, with implications for mitochondrial function and related disorders.
    Keywords:  GTPase activity; OPA1; acetylation; membrane remodeling; oligomeric assembly
    DOI:  https://doi.org/10.1002/pro.70179
  12. Biomolecules. 2025 Apr 30. pii: 647. [Epub ahead of print]15(5):
    Low Fluoride Regulates Macrophage Polarization Through Mitochondrial Autophagy Mediated by PINK1/Parkin Axis.
    Fengyu Xie, Jing Zhou, Bingshu Liu, Lijun Zhao, Cunqi Lv, Qiong Zhang, Lin Yuan, Dianjun Sun, Wei Wei.
      Fluoride exposure has been shown to affect immune cell subsets and immune function, but its impact on macrophage polarization remains unclear. This study investigates the effects of low fluoride exposure on macrophage polarization and its underlying mechanisms through epidemiological surveys, animal experiments, and in vitro cell experiments. In the population-based epidemiological survey, we used mass cytometry to assess the impact of low fluoride exposure (0.570-2.027 mg/L) in the environment on human immune cell populations following the current water improvement and fluoride reduction measures. A rat fluorosis model was established by treating rats with sodium fluoride (NaF) in drinking water at concentrations of 0 mg/L, 5 mg/L, 10 mg/L, 25 mg/L, and 50 mg/L for 90 days., and morphological changes were assessed by hematoxylin-eosin (H&E) staining and transmission electron microscopy in the spleen of rats. Flow cytometry was used to analyze the proportion of macrophage subtypes in the spleen, while Western blot and immunofluorescence were performed to detect the expression of mitochondrial autophagy-related proteins. An M1 macrophage model was constructed in vitro by inducing THP-1 cells, and the effects of fluoride on macrophage-related cell markers and cytokines were assessed using flow cytometry and ELISA, respectively, following intervention with an autophagy inhibitor. Mitochondrial membrane potential and mitochondrial-lysosomal colocalization are analyzed through flow cytometry and confocal microscopy. The study aims to investigate the role of mitophagy in sodium fluoride-induced macrophage polarization. Epidemiological investigations revealed that low fluoride increases the proportion of blood monocytes, as well as the expression levels of CD68 (a macrophage surface marker), CD86 (an M1 macrophage marker), and the inflammatory cytokine IFN-γ in peripheral blood mononuclear cells (PBMCs). In the rats of NaF-treated groups, splenic tissues exhibited inflammatory infiltration, mitochondrial swelling, and increased autophagosome formation. Moreover, low fluoride activated the PINK1/Parkin-mediated mitophagy pathway, promoting an increase in the M2/M1 macrophage ratio. In vitro experiments further confirmed that autophagy inhibitors reversed the NaF-induced increase in the M2/M1 macrophage ratio. This study demonstrates that low fluoride induces inflammatory responses in the body and drives M1 macrophage polarization toward M2 macrophages via mitophagy. These findings highlight the potential immunological risks associated with low fluoride and provide mechanistic insights into the interplay among fluoride, mitophagy, and macrophage polarization.
    Keywords:  PINK1/Parkin pathway; low fluoride; macrophage polarization; mitophagy; spleen inflammation
    DOI:  https://doi.org/10.3390/biom15050647
  13. Environ Mol Mutagen. 2025 May 26.
    Mitochondria-Nuclear Crosstalk: Orchestrating mtDNA Maintenance.
    Ghazal Darfarin, Janice Pluth.
      The mitochondria (mt) and nucleus engage in a dynamic bidirectional communication to maintain cellular homeostasis, regulating energy production, stress response, and cell fate. Anterograde signaling directs mt function, while retrograde signaling conveys metabolic and stress-related changes from mt to the nucleus. Central to this crosstalk is mitochondrial DNA (mtDNA), which encodes key oxidative phosphorylation components. MtDNA integrity is preserved through quality control mechanisms, including fusion and fission dynamics, mitophagy, and nuclear-encoded DNA repair. Disruption in these pathways contributes to mt dysfunction, oxidative stress, and genetic instability-hallmarks of aging and diseases. Additionally, redox signaling and NAD+ homeostasis integrate mt and nuclear responses, modulating transcriptional programs that support mt biogenesis and stress adaptation. This review explores the molecular mechanisms coordinating mito-nuclear interactions, emphasizing their role in maintaining mtDNA integrity and cellular equilibrium. Understanding these processes provides insights into how mt dysfunction drives aging and disease, paving the way for targeted therapeutic strategies.
    Keywords:  anterograde and retrograde signaling; cellular homeostasis; mitochondrial biogenesis; mitochondrial dynamics; mtDNA maintenance, mitochondrial‐nuclear communication; redox signaling
    DOI:  https://doi.org/10.1002/em.70013
  14. Front Aging Neurosci. 2025 ;17 1519672
    Intervention strategies for Parkinson's disease: the role of exercise and mitochondria.
    Ganggang Xu, Chunlian Ma, Yi Yang.
      Parkinson's disease (PD), a progressive neurodegenerative disorder with complex pathogenic mechanisms, exhibiting rising prevalence alongside global population aging. Its pathological hallmarks include substantial loss of dopaminergic neurons in the substantia nigra pars compacta, leading to motor symptoms (e.g., bradykinesia, rigidity) and non-motor manifestations (e.g., cognitive impairment, sleep disorders). Accumulating evidence underscores mitochondrial dysfunction-encompassing reactive oxygen species (ROS) overproduction, defective mitophagy, and impaired biogenesis-as an important contributor to PD pathogenesis. Exercise, endorsed by leading medical and sports authorities as a non-pharmacological therapeutic strategy. While mitochondrial dysfunction impairs cellular energetics in PD patients, exercise can re-establish mitochondrial homeostasis through multiple pathways: stimulating neuroprotective exerkines, regulating mitochondrial ROS balance, modulating mitochondrial biogenesis and mitophagy, and enhancing brain-derived neurotrophic factor production. Many studies demonstrate that aerobic, resistance, and mind-body exercises demonstrably improve gait stability, postural control, and cognitive function in PD patients. However, standardized exercise prescriptions for PD prevention and treatment remain underutilized in clinical practice. This review synthesizes mitochondrial pathophysiology in PD progression, exercise-mediated regulatory mechanisms, and evidence-based exercise protocols, proposing accessible exercise regimens to support PD management. By integrating molecular insights with practical strategies, this work provides foundational evidence for utilizing exercise as a non-medical intervention against PD.
    Keywords:  PINK1; Parkinson’s disease; dopamine; exercise; mitochondria
    DOI:  https://doi.org/10.3389/fnagi.2025.1519672
  15. Circulation. 2025 May 27.
    Disruption of cTnT-Mediated Sarcomere-Mitochondrial Communication Results in Dilated Cardiomyopathy.
    Lingqun Ye, Junwei Liu, Wei Lei, Baoqiang Ni, Xinglong Han, Yan Zhang, Yong Wang, Kaili Hao, Yuanhui Peng, Hongchun Wu, Miao Yu, Huadong Li, Zhen-Ao Zhao, Zhenya Shen, Jianyi Zhang, Shijun Hu.
       BACKGROUND: Dilated cardiomyopathy (DCM) is substantially influenced by genetic factors. Sarcomere function is intricately associated with other organelles, particularly the reciprocal regulation between sarcomeres and mitochondria. Mitochondrial stress dysregulation is linked to DCM progression, yet mechanisms remain unclear. In this study, we investigated the effects of cTnT (cardiac troponin T) dysregulation on sarcomere-mitochondrial communication in DCM.
    METHODS: Induced pluripotent stem cells (iPSCs) derived from a DCM family cohort were used in this study, and CRISPR-Cas9 genome editing was used to rectify the TNNT2 (c.A553G) sequence variation in iPSCs. A knock-in mouse model harboring the (p.K192E) sequence variation, equivalent to the human cTnT (p.K185E) sequence variation, was subsequently established. The pathological phenotypes were analyzed in iPSC-derived cardiomyocytes, iPSC-derived cardiac organoids, and mice. RNA sequencing, metabolite profiling, and coimmunoprecipitation mass spectrometry were used to elucidate the molecular mechanisms.
    RESULTS: Through whole exome sequencing, we identified a novel pathogenic variant in cTnT (p.K185E) as the causal sequence variation in a familial DCM cohort. In iPSC-derived cardiomyocytes from patients with DCM, we observed sarcomere disarray and mitochondrial fragmentation accompanied by severe mitochondrial dysfunction. The diminished interaction between cTnT (p.K185E) and 14-3-3 proteins resulted in the dissociation of 14-3-3 proteins from sarcomeric structures. The free 14-3-3 proteins aberrantly engaged in the RAS/RAF1 signaling axis, driving aberrant p44/42 kinase activation that culminated in the phosphorylation of mitochondrial fission regulators DRP1 (dynamin-related protein 1) and MFF (mitochondrial fission factor). These observations were replicated in iPSC-derived cardiac organoids. The knock-in mice bearing the orthologous cTnT sequence variation faithfully recapitulated the hallmark features of human DCM, including cardiac dysfunction, ventricular dilatation, sarcomeric disarray, and mitochondrial fragmentation. Mdivi-1, a mitochondrial fission inhibitor, alleviated DCM phenotypes in vivo.
    CONCLUSIONS: Our findings delineate a novel pathogenic mechanism underlying DCM, demonstrating that cTnT (p.K185E) sequence variation disrupts sarcomere-mitochondrial communication by weakening the interaction between cTnT and 14-3-3 proteins, thereby accelerating mitochondrial fragmentation through excessive activation of the 14-3-3 protein-mediated RAS/RAF1-p44/42-DRP1/MFF signaling axis. Therefore, therapeutic targeting of 14-3-3 proteins and p44/42 kinase activity may represent a promising strategy for DCM and other cardiac diseases associated with aberrant mitochondrial dynamics.
    Keywords:  cardiomyopathy, dilated; induced pluripotent stem cells; mitochondria; organoids; sarcomeres
    DOI:  https://doi.org/10.1161/CIRCULATIONAHA.125.071523
  16. Biomedicines. 2025 May 08. pii: 1142. [Epub ahead of print]13(5):
    Reduced Expression of UPRmt Proteins HSP10, HSP60, HTRA2, OMA1, SPG7, and YME1L Is Associated with Accelerated Heart Failure in Humans.
    Petra Bakovic, Vid Mirosevic, Tomo Svagusa, Ana Sepac, Ana Kulic, Davor Milicic, Hrvoje Gasparovic, Igor Rudez, Marjan Urlic, Suncana Sikiric, Sven Seiwerth, Drazen Belina, Matija Bakos, Monika Karija Vlahovic, Rea Taradi, Rado Zic, Ivana Ilic, Borislav Belev, Bosko Skoric, Dora Fabijanovic, Ivo Planinc, Maja Cikes, Filip Sedlic.
      Background/Objectives: The mitochondrial unfolded protein response (UPRmt) is one of the mitochondrial quality control mechanisms that is responsible for reparation and removal of damaged proteins in mitochondria. Methods: Here we investigated the role of the UPRmt in the myocardium of humans with and without heart failure and in the cell culture model. Results: The analysis of myocardial samples by ELISA from patients with ischemic cardiomyopathy (ICM) and dilated cardiomyopathy (DCM), as well as healthy donors, revealed a significantly reduced expression of the UPRmt proteins HSP10, CLPP, LONP1, OMA1, and SPG7 in patients with DCM and ICM. Furthermore, patients with DCM and ICM exhibited elevated levels of myocardial reactive oxygen species (ROS, tested by 4-hydroxynonenal) compared to controls, and a positive correlation between ROS production and mt-HSP70, OMA1, and SPG7 protein expression. The correlation analysis indicated a negative correlation between cardiomyocyte hypertrophy and the expression of several UPRmt genes. The inhibition of four tested UPRmt effector proteins exacerbated the injury of cultured cells under oxidative stress. The patients with ICM, DCM, or both, who showed lower myocardial expression of HSP10, HSP60, HTRA2, OMA1, SPG7, and YME1L, underwent heart transplantation or implantation of a left ventricular assist device earlier in life compared to those with the higher protein expression. Conclusions: In conclusion, our findings indicate that the reduced expression of several UPRmt effector proteins is associated with accelerated heart failure in patients, which, together with other results, indicates that impaired UPRmt may contribute to the pathogenesis of heart failure in humans.
    Keywords:  ROS; UPRmt; cardiomyopathy; heart; mitochondria
    DOI:  https://doi.org/10.3390/biomedicines13051142
  17. Int J Mol Sci. 2025 May 13. pii: 4652. [Epub ahead of print]26(10):
    Melatonin Improves Lipid Homeostasis, Mitochondrial Biogenesis, and Antioxidant Defenses in the Liver of Prediabetic Rats.
    Milena Cremer de Souza, Maria Luisa Gonçalves Agneis, Karoliny Alves das Neves, Matheus Ribas de Almeida, Geórgia da Silva Feltran, Ellen Mayara Souza Cruz, João Paulo Ferreira Schoffen, Luiz Gustavo de Almeida Chuffa, Fábio Rodrigues Ferreira Seiva.
      Type 2 diabetes mellitus represents a major global health burden and is often preceded by a prediabetic state characterized by insulin resistance and metabolic dysfunction. Mitochondrial alterations, oxidative stress, and disturbances in lipid metabolism are central to the prediabetes pathophysiology. Melatonin, a pleiotropic indolamine, is known to regulate metabolic and mitochondrial processes; however, its therapeutic potential in prediabetes remains poorly understood. This study investigated the effects of melatonin on energy metabolism, oxidative stress, and mitochondrial function in a rat model of prediabetes induced by chronic sucrose intake and low-dose streptozotocin administration. Following prediabetes induction, animals were treated with melatonin (20 mg/kg) for four weeks. Biochemical analyses were conducted to evaluate glucose and lipid metabolism, and mitochondrial function was assessed via gene expression, enzymatic activity, and oxidative stress markers. Additionally, hepatic mitochondrial dynamics were examined by quantifying key regulators genes associated with biogenesis, fusion, and fission. Prediabetic animals exhibited dyslipidemia, hepatic lipid accumulation, increased fat depots, and impaired glucose metabolism. Melatonin significantly reduced serum glucose, triglycerides, and total cholesterol levels, while enhancing the hepatic high-density lipoprotein content. It also stimulated β-oxidation by upregulating hydroxyacyl-CoA dehydrogenase and citrate synthase activity. Mitochondrial dysfunction in prediabetic animals was evidenced by the reduced expression of peroxisome proliferator-activated receptor gamma coactivator-1 alpha and mitochondrial transcription factor A, both of which were markedly upregulated by melatonin. The indolamine also modulated mithocondrial dynamics by regulating fusion and fission markers, including mitosuin 1 and 2, optic atrophy protein, and dynamin-related protein. Additionally, melatonin mitigated oxidative stress by enhancing the activity of superoxide dismutase and catalase while reducing lipid peroxidation. These findings highlight melatonin's protective role in prediabetes by improving lipid and energy metabolism, alleviating oxidative stress, and restoring mitochondrial homeostasis. This study provides novel insights into the therapeutic potential of melatonin in addressing metabolic disorders, particularly in mitigating mitochondrial dysfunction associated with prediabetes.
    Keywords:  energy metabolism; melatonin; mitochondrial dynamics; oxidative stress; prediabetes
    DOI:  https://doi.org/10.3390/ijms26104652
  18. Mitochondrion. 2025 May 24. pii: S1567-7249(25)00043-1. [Epub ahead of print]84 102046
    Targeting mitochondrial quality control for myocardial ischemia-reperfusion injury.
    Yuxuan He, Sixu Ren, Chenglin Liu, Xiufen Zheng, Cuilin Zhu.
      Cardiovascular disease (CVD) remains the leading global cause of mortality. Acute myocardial infarction (AMI) refers to acute myocardial ischemia resulting from thrombosis secondary to coronary atherosclerosis, which poses a major threat to human health. Clinically, timely revascularization (reperfusion) represents the basis of clinical treatment for AMI. However, secondary myocardial ischemia-reperfusion injury (MIRI) caused by reperfusion often exacerbates damage, representing a major challenge in clinical practice. Mitochondria represent essential organelles for maintaining cardiac function and cellular bioenergetics in MIRI. In recent years, the role of mitochondrial quality control (MQC) in maintaining cell homeostasis and mediating MIRI has been extensively studied. This review provides a concise overview of MQC mechanisms at the molecular, organelle, and cellular levels and their possible complex regulatory network in MIRI. In addition, potential treatment strategies targeting MQC to mitigate MIRI are summarized, highlighting the gap between current preclinical research and clinical transformation. Overall, this review provides theoretical guidance for further research and clinical translational studies.
    Keywords:  Biogenesis; Clinical translational application; Mitochondria-mediated cell death; Mitochondrial dynamics; Mitochondrial quality control; Mitophagy; Myocardial ischemia–reperfusion injury; Therapeutic agent
    DOI:  https://doi.org/10.1016/j.mito.2025.102046
  19. Opt Lett. 2025 Jun 01. 50(11): 3529-3532
    Three-dimensional super-resolution imaging of whole cells using a high numerical aperture oblique-plane microscope.
    Zhuoli Ding, Xian'ao Zhao, Lei Wang, Shihang Luo, Tianjie Yang, Chunyan Fan, Jing Lu, Shun Xiong, Weixing Li, Tao Xu, Lusheng Gu, Wei Ji.
      We present HOPE-STORM, a high-numerical-aperture oblique-plane microscope enabling whole-cell super-resolution imaging with an effective NA of 1.40. The system is compatible with DNA-PAINT, resolving nuclear pore complex (NPC) structures at 7.5 nm. We demonstrate dual-color super-resolution imaging of intact cells and, for the first time, to our knowledge, quantify the 3D organization of dynamin-related protein 1 (DRP1) complexes at mitochondrial fission sites. Our findings provide structural insights into DRP1 dynamics and mitochondrial fission mechanisms.
    DOI:  https://doi.org/10.1364/OL.550216
  20. Brain Res Bull. 2025 May 27. pii: S0361-9230(25)00216-3. [Epub ahead of print]227 111404
    Vitexin alleviates cerebral ischemia/reperfusion injury by regulating mitophagy via the SIRT1/PINK1/Parkin pathway.
    Chao Chen, Zhenzhong Zhang, Baolin Du, Chenling Lv.
       OBJECTIVE: This study was conducted to elucidate vitexin's protective effects and underlying mechanism in ameliorating cerebral ischemia/reperfusion injury (CIRI) through regulation of mitophagy.
    METHODS: Focal CIRI in mice was induced using the middle cerebral artery occlusion and reperfusion method. 2,3,5-triphenyltetrazolium chloride staining was performed for the evaluation of cerebral infarction. Neurological deficits and brain tissue damage were assessed by neurological deficit scores and hematoxylin-eosin staining, respectively. HT22 cells underwent oxygen-glucose deprivation/reoxygenation (OGD/R) exposure to develop an in vitro model. Prior to OGD/R, we pretreated the HT22 cells with vitexin, the mitophagy inhibitor (Mdivi-1), or the SIRT1 inhibitor (EX-527). Determination of cell viability and apoptosis were carried out through the cell counting kit-8 assay and flow cytometry, respectively. JC-1 fluorescence staining and MitoSOX™ Red staining were respectively performed for assessing mitochondrial membrane potential (MMP) and detecting levels of mitochondrial reactive oxygen species (mtROS). Expression of B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), microtubule-associated protein 1 A/1B-light chain 3 (LC3), sequestosome-1 (p62), PTEN-induced kinase 1 (PINK1), Parkin, as well as silent information regulator two 1 (SIRT1) was determined via Western blot.
    RESULTS: Vitexin was found to significantly alleviate CIRI in mice and mitigate HT22 cell injury due to OGD/R exposure, as confirmed by our in vivo and in vitro experiments, accompanied by activation of mitophagy and the SIRT1/PINK1/Parkin pathway. The OGD/R+Vitexin+Mdivi-1 group (versus the OGD/R+Vitexin group) displayed decreased cell viability, increased apoptosis, a reduced Bcl-2/Bax ratio, diminished MMP, elevated mtROS levels, downregulated PINK1, LC3-II, and Parkin expression, and upregulated p62 expression. Similarly, the OGD/R+Vitexin+EX-527 group showed reduced cell viability, increased apoptosis, a decreased Bcl-2/Bax ratio, decreased MMP, elevated mtROS levels, downregulated SIRT1, PINK1, LC3-II, and Parkin expression, and upregulated p62 expression.
    CONCLUSION: Vitexin ameliorates CIRI by activating mitophagy via the SIRT1/PINK1/Parkin pathway.
    Keywords:  CIRI; Mitophagy; SIRT1/PINK1/Parkin pathway; Vitexin
    DOI:  https://doi.org/10.1016/j.brainresbull.2025.111404
  21. Curr Opin Cell Biol. 2025 May 28. pii: S0955-0674(25)00073-0. [Epub ahead of print]95 102535
    The power of connections: Recent advances in understanding the regulation of mitochondrial dynamics by membrane contact sites.
    Jason C Casler, Laura L Lackner.
      The continuous remodeling of the mitochondrial network through fusion, fission, transport, and turnover events, collectively known as mitochondrial dynamics, is essential for the maintenance of mitochondrial metabolic and genomic health. While the primary molecular machines that mediate these processes were discovered decades ago, the regulation of mitochondrial dynamics clearly involves additional factors. A major breakthrough came from the discovery that sites of close apposition between organelles, known as membrane contact sites (MCSs), serve as critical regulators of organelle function. MCSs between mitochondria and the ER are now universally recognized as important regulatory hubs of mitochondrial dynamics. Despite this, there are still many unknowns pertaining to the mechanisms by which MCSs influence mitochondrial dynamics. In this review, we describe recent progress identifying novel protein and lipid components that regulate mitochondrial dynamics and emphasize clear gaps in our understanding of how mitochondrial dynamics are coordinated at MCSs. Finally, we conclude by discussing progress towards defining the highly biomedically relevant, but enigmatic, role of mitochondrial dynamics in the preservation of mitochondrial DNA integrity.
    DOI:  https://doi.org/10.1016/j.ceb.2025.102535
  22. Phytomedicine. 2025 May 19. pii: S0944-7113(25)00518-5. [Epub ahead of print]143 156880
    Hyperoside alleviates zearalenone-induced liver injury by regulating mitochondrial calcium overload mediated excessive autophagy.
    Tianyu Han, Lulu Wang, Yan Jiang, Shanshan Fei, Yiding Liu, Zhijun Liu, Tong Wang, Baiwen Guan, Yu Yang, Guangliang Shi.
       BACKGROUND: Zearalenone (ZEA), one of the most common mycotoxins in moldy plants, can cause ferroptosis in the liver. Hyperoside (Hyp) is mainly derived from Hypericum perforatum and exerts hepatoprotective, neuroprotective, and cardioprotective effects. It is not known whether Hyp alleviates ZEA-induced ferroptosis-related damage AIM: The protective effect of Hyp on ZEA-induced liver injury was studied and its underlying mechanisms were elucidated.
    METHODS: The protective effect of Hyp on ZEA-induced liver injury was determined based on ALT and AST levels and by using H&E staining and transmission electron microscopy. The protective effect of Hyp in attenuating ferroptosis was determined by measuring mitophagy- and ferroptosis-related indices. CETSA and siRNA transfection were used to determine the targeting of Hyp to MCU protein.
    RESULTS: Hyp attenuated ZEA-induced ferroptosis and excessive mitophagy in hepatocytes, and use of Hyp or FUNDC1 knockdown by siRNA decreased ferroptosis in AML12 cells. Furthermore, Hyp attenuated ZEA exposure-induced Gpx4 interaction with FUNDC1 and reversed the recruitment and degradation of glutathione peroxidase 4 to mitochondria. Hyp was found to target MCU protein to attenuate mitochondrial Ca2+ overload and mitophagy induced by upregulated ZEA exposure. MCU knockdown reversed ZEA-induced mitophagy. Hyp also reversed ZEA-induced excessive mitochondrial fission and impairment in mitochondrial function.
    CONCLUSION: Our study demonstrated that Hyp could alleviate ZEA induced ferroptosis by targeting MCU to inhibit mitochondrial Ca2+overloaded mitophagy.Our findings provide evidence for Hyp as an effective treatment in alleviating ferroptosis-related liver injury.
    Keywords:  Autophagy; Ferroptosis; Hepatotoxicity; Hyperoside; Zearalenone
    DOI:  https://doi.org/10.1016/j.phymed.2025.156880
  23. J Physiol Biochem. 2025 May 24.
    Downhill running induced mitophagy in rat soleus muscle via the AMPK pathway.
    Huayu Shang, Ranggui Ma, Shengju Chen, Hao Deng, Mengyu Li, Shiqiao Zheng, He Zhang, Duo Zhang, Tianai Yang, Ying Yang, Zhi Xia.
      Eccentric exercise is known to induce more pronounced muscle damage associated with delayed-onset muscle soreness than concentric exercise. This study aimed to investigate whether AMP-activated protein kinase (AMPK) pathway participates in control of mitophagy in rat skeletal muscle in response to downhill running. Eighty-eight male Sprague-Dawley rats were exercised on a treadmill tilted at 16° decline at 16 m·min- 1 for 90 min, with the soleus muscle sampled at 0 h, 12 h, 24 h, 48 h and 72 h after exercise. The AMPK inhibitor compound C or AMPK activator AICAR or saline was injected intraperitoneally 20 min before exercise. After downhill treadmill running, the skeletal muscle mitochondrial structure appeared to be abnormal and contained mitophagosomes; the expression levels of AMPK phosphorylation, cyclophilin D (CypD), cytochrome C (CytC), mitochondrial FK506-binding protein 8 (FKBP8), microtubule-associated protein 1 light chain 3 (LC3), and the co-localization of FKBP8 with LC3 and mitochondria with dynamin-related protein 1 (Drp1), lysosomal-associated membrane protein 2 (LAMP2) were significantly higher; the expression levels of mechanistic target of rapamycin (mTOR Ser2448) phosphorylation and heat shock protein 60 (HSP60), mitochondrial respiratory complex I (NDUFB8) and complex III (UQCRC2), and adenosine triphosphate (ATP) content were significantly lower than those in the C group. Further study showed that the effect of downhill treadmill running was partly blocked by compound C and strengthened by AICAR. A session of downhill treadmill running activated the AMPK pathway and promoted LC3 co-localizations with mitochondria and FKBP8, and induced mitophagy and mitochondrial damage within rat skeletal muscle.
    Keywords:  AMP-activated protein kinase; Downhill treadmill running; FK506-binding protein 8; Mitophagy; Skeletal muscle
    DOI:  https://doi.org/10.1007/s13105-025-01093-8
  24. Mol Med. 2025 May 29. 31(1): 211
    Activation of the MEK1-CHK2 axis in macrophages by Staphylococcus aureus promotes mitophagy, resulting in a reduction in bactericidal efficacy.
    Xiaohu Wu, Xin Guan, Chubin Cheng, Zhantao Deng, Zeng Li, Yuanchen Ma, Yanjie Xie, Qiujian Zheng.
       BACKGROUND: Macrophages, which serve as the frontline defenders against microbial invasion, paradoxically become accomplices in Staphylococcus aureus (S. aureus)-driven osteomyelitis pathogenesis through poorly defined immunosuppressive mechanisms.
    METHODS: In this study, we established an S. aureus implant-associated femoral infection model treated with MEK1 inhibitors and evaluated the degree of bone destruction and the bacterial load. We subsequently investigated changes in mitochondrial ROS (mtROS) levels, mitophagy activity, phagocytic-killing ability, and CHEK2 mitochondrial translocation in S. aureus-activated bone marrow-derived macrophages (BMDMs) following MEK1 inhibitor treatment. Finally, in vivo experiments involving different inhibitor combinations were conducted to assess mitophagy levels and the therapeutic potential for treating osteomyelitis.
    RESULTS: Pharmacological inhibition of MEK1 significantly attenuated bone degradation and the pathogen burden in murine models of osteomyelitis, indicating its therapeutic potential. Investigations using BMDMs revealed that blockade of the MEK1-ERK1/2 axis increases mtROS levels by suppressing mitophagy, directly linking metabolic reprogramming to increased bactericidal activity. Mechanistically, inactivation of the MEK1-ERK1/2 pathway restores CHEK2 expression, facilitating its translocation from the nucleus to mitochondria to restore mtROS levels by inhibiting mitophagy. Importantly, in vivo studies confirmed that the MEK1-ERK1/2-CHEK2 axis is pivotal for controlling mitophagy-dependent bone pathology and bacterial persistence during S. aureus infection.
    CONCLUSIONS: We identified a self-amplifying pathogenic loop in which S. aureus exploits macrophage MEK1 to hyperactivate ERK1/2, leading to the suppression of CHEK2 expression. This process results in excessive mitophagy and decreased mtROS levels, which impair the bactericidal function and enable uncontrolled osteolytic destruction. These findings redefine MEK1 as a metabolic-immune checkpoint and highlight its druggable vulnerability in osteomyelitis.
    Keywords:   S. aureus ; Bactericidal function; MEK1-CHEK2; Macrophage mitophagy; Osteomyelitis
    DOI:  https://doi.org/10.1186/s10020-025-01274-7
  25. Nutrients. 2025 May 18. pii: 1711. [Epub ahead of print]17(10):
    Impaired Mitophagy Contributes to Pyroptosis in Sarcopenic Obesity Zebrafish Skeletal Muscle.
    Xiangbin Tang, Yunyi Zou, Siyuan Yang, Zhanglin Chen, Zuoqiong Zhou, Xiyang Peng, Changfa Tang.
      Background: Growing evidence suggests that the prevalence of sarcopenic obesity (SOB) is on the rise across the globe. However, the key molecular mechanisms behind this disease have not been clarified. Methods: In this experiment, we fed zebrafish a high-fat diet (HFD) for 16 weeks to induce sarcopenic obesity. Results: After a dietary trial, HFD zebrafish exhibited an obese phenotype with skeletal muscle atrophy and decreased swimming capacity. We demonstrated that mitochondrial content and function were abnormal in SOB zebrafish skeletal muscle. These results may be associated with the impairment of mitophagy regulated by the PTEN-induced putative kinase 1 (PINK1)/Parkin (PRKN) pathway. In addition, we also found that NOD-like receptor protein 3 (NLRP3)/gasdermin D (GSDMD) signaling was activated with the upregulation of NLRP3, GSDMD-NT, and mature-IL1β, which indicated that pyroptosis was induced in SOB zebrafish skeletal muscle. Conclusions: Our study identified that impaired mitophagy and pyroptosis were associated with the pathogenesis of SOB. These results could potentially offer novel therapeutic objectives for the treatment of sarcopenic obesity.
    Keywords:  mitophagy; pyroptosis; sarcopenic obesity; zebrafish
    DOI:  https://doi.org/10.3390/nu17101711
  26. Mol Med Rep. 2025 Aug;pii: 215. [Epub ahead of print]32(2):
    Reduced iron bioavailability drives acute high‑altitude lung injury through HIF1α activation and mitophagy.
    Yumei Geng, Yu Hu, Huijie Wang, Fang Zhang, Ri-Li Ge.
      High‑altitude pulmonary injury, characterized by pulmonary edema and pulmonary hypertension, is mechanistically driven by dysregulated mitophagy, as evidenced by impaired mitochondrial quality control in endothelial cells under hypobaric hypoxia. Iron supplementation for individuals who have ascended rapidly to high altitudes can effectively mitigate the phenomenon of hypoxic pulmonary vasoconstriction; however, the precise role and detailed mechanisms remain to be determined. The present study aimed to explore the role and mechanism of iron in acute hypoxia‑induced lung injury. Sprague‑Dawley rats were initially placed in a hypobaric hypoxia chamber for various durations to determine the optimal time for acute hypoxia‑induced lung injury. The rats were exposed to a hypobaric hypoxia chamber for 3 days, during which they were treated with an iron chelator or iron sucrose. Mean pulmonary artery pressure (mPAP) was measured to assess hypoxic pulmonary vascular response. Furthermore, the degree of lung injury was assessed by calculating the pulmonary wet/dry weight ratio, and via morphological evaluation of lung tissues and the pulmonary vasculature. Immunofluorescence and western blot analysis were performed to assess hypoxia‑inducible factor 1α (HIF1α) expression and mitophagy levels. Edu and Cell Counting Kit 8 assays were conducted to evaluate cell proliferation under acute hypoxia. In addition, immunofluorescence and western blot analysis were performed to evaluate the expression levels of proteins associated with cell apoptosis and mitophagy. The results indicated that mitophagy (LC3B‑II/LC3B‑I expression), pulmonary edema (lung wet/dry weight ratio) and lung injury score were most significant after 3 days of hypoxia. However, mitophagy (LC3B‑II/LC3B‑I ratio) and lung injury scores peaked after 4 weeks of hypoxic conditions. Furthermore, an iron chelator was observed to promote pulmonary edema, elevate mPAP and cause lung injury. Conversely, iron sucrose was shown to attenuate lung injury in acute hypoxia. The mechanistic findings indicated that acute hypoxia induced HIF1α activation and increased mitophagy, which promoted a reduction in proliferation and an increase in the apoptosis of pulmonary artery endothelial cells. Furthermore, the iron chelator promoted, whereas iron sucrose ameliorated, the abnormal alterations in pulmonary artery endothelial cells under acute hypoxia. In conclusion, the present study demonstrated that a reduction in iron bioavailability in acute hypoxia may promote HIF1α activation and increased mitophagy, which in turn has been linked to the development of pulmonary edema, elevated mPAP and lung injury. The administration of iron supplementation may be considered an effective method for the alleviation of the aforementioned abnormalities resulting from acute hypoxia.
    Keywords:  acute hypoxia; high‑altitude lung injury; hypoxia‑inducible factor 1α; iron bioavailability; mitophagy
    DOI:  https://doi.org/10.3892/mmr.2025.13580
  27. Redox Biol. 2025 May 20. pii: S2213-2317(25)00205-8. [Epub ahead of print]84 103692
    Cannabinol (CBN) alleviates age-related cognitive decline by improving synaptic and mitochondrial health.
    Nawab John Dar, Antonio Currais, Taketo Taguchi, Nick Andrews, Pamela Maher.
      Age-related cognitive decline and neurodegenerative diseases, such as Alzheimer's disease, represent major global health challenges, particularly with an aging population. Mitochondrial dysfunction appears to play a central role in the pathophysiology of these conditions by driving redox dysregulation and impairing cellular energy metabolism. Despite extensive research, effective therapeutic options remain limited. Cannabinol (CBN), a cannabinoid previously identified as a potent inhibitor of oxytosis/ferroptosis through mitochondrial modulation, has demonstrated promising neuroprotective effects. In cell culture, CBN targets mitochondria, preserving mitochondrial membrane potential, enhancing antioxidant defenses and regulating bioenergetic processes. However, the in vivo therapeutic potential of CBN, particularly in aging models, has not been thoroughly explored. To address this gap, this study investigated the effects of CBN on age-associated cognitive decline and metabolic dysfunction using the SAMP8 mouse model of accelerated aging. Our results show that CBN significantly improves spatial learning and memory, with more pronounced cognitive benefits observed in female mice. These cognitive improvements are accompanied by sex-specific changes in metabolic parameters, such as enhanced oxygen consumption and energy expenditure. Mechanistically, CBN modulates key regulators of mitochondrial dynamics, including mitofusin 2 (MFN2) and dynamin-related protein 1 (DRP1), while upregulating markers of mitochondrial biogenesis including mitochondrial transcription factor A (TFAM) and translocase of outer mitochondrial membrane 20 (TOM20). Additionally, CBN upregulates key synaptic proteins involved in vesicle trafficking and postsynaptic signaling suggesting that it enhances synaptic function and neurotransmission, further reinforcing its neuroprotective effects. This study provides in vivo evidence supporting CBN's potential to mitigate age-related cognitive and metabolic dysfunction, with notable sex-specific effects, highlighting its promise for neurodegenerative diseases and cognitive decline.
    Keywords:  Age-related cognitive decline; Cannabinol (CBN); Mitochondrial biogenesis; Mitochondrial dysfunction; Neuroprotection; SAMP8 mouse model; Sex-specific effects; Synaptic function
    DOI:  https://doi.org/10.1016/j.redox.2025.103692
  28. Lipids Health Dis. 2025 May 24. 24(1): 187
    Dehydrodiisoeugenol alleviates palmitate-induced mitochondrial dysfunction in human vascular smooth muscle cells through the activation of SIRT1-mediated Drp1 deacetylation.
    Jianjun Zhao, Zhiyun Shu, Xiangjun Li, Wenqing Zhang, Mengze Sun, Wenxiao Song, Hongyuan Cheng, Shaomin Shi.
       OBJECTIVE: Dehydrodiisoeugenol (Deh) has demonstrated positive effects in the prevention and treatment of cardiovascular disease (CVD) caused by lipid overload, but its specific mechanism of action remains poorly understood. The aim of this study was to investigate the possible mechanisms by which Deh modulates the mitochondrial dysfunction induced by palmitate (PA) in vascular smooth muscle cells (VSMCs).
    METHODS: A PA-induced high-fat model of VSMCs was established, and the effect of PA on the VSMCs on function was detected by evaluating the oxidative stress and apoptosis of cells, as well as mitochondrial function. The expression of dynamin-related protein 1 (Drp1) was detected by immunofluorescence and immunoprecipitation. The key targets of Deh for the treatment of mitochondria-related diseases were screened by bioinformatics analysis and molecular docking techniques. Finally, the role of Silent information regulator 1 (SIRT1) in the treatment of PA-induced mitochondrial dysfunction in VSMCs by Deh was explored by administrating Deh as well as SIRT1 activator (CAY10602, CAY) and SIRT1 inhibitor (JGB1741, JGB).
    RESULTS: The results showed that PA concentration-dependently increased oxidative stress and apoptosis in VSMCs, while modulating the acetylation of Drp1, promoting its expression and mitochondrial ectopia, thereby inducing mitochondrial dysfunction. Bioinformatics analysis and molecular docking indicated that SIRT1 may be a key target of Deh for the treatment of mitochondria-related diseases. Follow-up experiments revealed that Deh significantly inhibited PA-induced mitochondrial dysfunction in VSMCs by suppressing acetylation and expression of Drp1 and reducing mitochondrial ectasia, an effect that was achieved by regulating SIRT1.
    CONCLUSION: Deh was able to inhibit Drp1 expression and mitochondrial ectopia by reducing Drp1 acetylation through activation of SIRT1, thereby inhibiting PA-induced mitochondrial dysfunction effects in VSMCs, ameliorating pathological processes, such as cellular oxidative stress and apoptosis, and maintaining stable cellular functions.
    Keywords:  Deacetylation; Dehydrodiisoeugenol; Mitochondrial dysfunction; Palmitate; SIRT1; VSMC
    DOI:  https://doi.org/10.1186/s12944-025-02611-9
  29. ACS Chem Neurosci. 2025 May 29.
    Dl-3-n-Butylphthalide Alleviates Cognitive Impairment in Chronic Cerebral Hypoperfusion: Associations with Mitochondrial Permeability Transition Pore Closure and Suppression of Excessive Mitophagy.
    Yaqiong Li, Junkui Shang, Huiwen Zhang, Yaru Lu, Ying Zhao, Yadan Wang, Xi Yan, Jiewen Zhang.
      Chronic cerebral hypoperfusion (CCH) results in cognitive impairment, with mitochondrial dysfunction identified as a key contributor. The opening of the mitochondrial permeability transition pore (mPTP) is closely associated with mitochondrial dysfunction and excessive mitophagy, particularly under stress conditions. Dl-3-n-Butylphthalide (Dl-NBP) has been shown to ameliorate cognitive impairment caused by CCH. However, whether Dl-NBP exerts its effects by inhibiting mPTP opening and mitigating excessive mitophagy remains unclear. In this study, we established a rat model of CCH through permanent bilateral common carotid artery occlusion (BCCAO) and explored the neuroprotective effects of Dl-NBP and its underlying mechanisms. The neuroprotective effects of Dl-NBP were evaluated using the Morris water maze test, and protein expression levels related to mPTP, apoptosis, and mitophagy were assessed through Western blotting and immunofluorescence. The ultrastructural changes in mitochondrial morphology and mitophagosomes were observed using transmission electron microscopy. We found that CCH led to cognitive impairment in rats, along with increased expression of p53, cytochrome-c, cleaved-Caspase3, LC3II/LC3I, Beclin1, P62, PINK1, and Parkin in the hippocampal tissue. Additionally, CCH caused an accumulation of mitophagosomes in the hippocampal tissue, although it did not affect Cyclophilin D (CypD) expression levels. However, Dl-NBP reversed these changes, except for CypD. Taken together, these findings suggest that Dl-NBP may improve cognitive impairment in CCH rats, potentially through the reduction of hippocampal neuron apoptosis by inhibiting mPTP opening and excessive mitophagy. Dl-NBP may represent a potential therapeutic strategy for treating cognitive impairment associated with CCH.
    Keywords:  Dl-3-n-butylphthalide; chronic cerebral hypoperfusion; mitochondrial permeability transition pore; mitophagy; vascular dementia
    DOI:  https://doi.org/10.1021/acschemneuro.4c00826
  30. Poult Sci. 2025 May 21. pii: S0032-5791(25)00568-1. [Epub ahead of print]104(8): 105325
    Melatonin mitigates arsenic and fluoride-induced cardiotoxicity in chickens by maintaining mitochondrial homeostasis.
    Xiaohong Yuan, Bokai Wen, Xin Hu, Mingyu Yang, Liqun Han, Shengjie Zhao, Jianhai Zhang, Yanqin Ma.
      Co-exposure to geogenic arsenic and fluoride is widely recognized in numerous countries and has been shown to induce severe cardiac injury in both humans and animals. Our previous studies have demonstrated that mitochondria are primary targets of arsenic and fluoride toxicity, as evidenced by alterations in ultrastructure, mitochondrial membrane potential, respiratory chain function, etc. Therefore, targeting mitochondrial homeostasis to develop pharmacological interventions for mitigating arsenic and fluoride-induced cardiotoxicity holds significant promise. Melatonin has emerged as a potent antioxidant and free radical scavenger. In this study, we reveal the substantial therapeutic potential of melatonin in mitigating arsenic and fluoride-induced cardiac injury in chicken models. A total of 72 one-day-old male Hy-Line Brown broilers were randomly allocated into eight groups: Control Group (basal diet), Arsenic Group (36 mg/kg As2O3 in diet), Fluoride Group (400 mg/kg NaF in diet), Arsenic + Fluoride Group (36 mg/kg As2O3 and 400 mg/kg NaF in diet), Melatonin Group (2.5 mg/kg melatonin in diet), Arsenic + Melatonin Group (36 mg/kg As2O3 and 2.5 mg/kg melatonin in diet), Fluoride + Melatonin Group (400 mg/kg NaF and 2.5 mg/kg melatonin in diet), and Arsenic + Fluoride + Melatonin Group (36 mg/kg As2O3, 400 mg/kg NaF, and 2.5 mg/kg melatonin in diet). Following a 23-week intervention with arsenic, fluoride, or their combination, the chickens exhibited significant cardiac damage and myocardial fibrosis. This was evidenced by elevated serum levels of lactate dehydrogenase (LDH), aspartic transaminase (AST), and troponin I (cTn-I), as well as marked changes observed in histopathological examinations. Dietary supplementation with melatonin significantly mitigated these cardiac damages induced by arsenic and fluoride. Mechanistically, we identified that melatonin exerted cardioprotective effects by reducing oxidative stress and apoptosis, and by restoring mitochondrial homeostasis through attenuating pathological mitochondrial fission, enhancing mitochondrial fusion, and promoting mitochondrial biogenesis. Collectively, our findings highlight melatonin as a potent cardioprotective agent against arsenic and fluoride-induced heart injury in chickens.
    Keywords:  Arsenic; Fluoride; Heart; Melatonin; Mitochondrial homeostasis
    DOI:  https://doi.org/10.1016/j.psj.2025.105325
  31. Discov Med. 2025 May;37(196): 816-827
    Targeting Ferroptosis via Mitochondria Dynamics in Myocardial Ischemia/Reperfusion Injury.
    Alfredo Cruz-Gregorio.
      Myocardial infarction remains a significant worldwide public health issue, primarily owing to its mortality and morbidity rates. This condition is due to myocardial ischemia, appearing once the heart's blood flow is obstructed or significantly reduced, causing the death of heart muscle cells. Reperfusion prevents further death of cardiomyocytes, restoring coronary flow. However, the initial lack of coronary blood flow and the subsequent restoration induce ischemia/reperfusion injury (IRI) due to abrupt metabolic and biochemical changes, such as calcium overload, activation of inflammatory cells, and oxidative stress (OS). OS is associated with damage to cellular biomolecules such as proteins, lipids, DNA, or carbohydrates and with organelles such as mitochondria, activating mitochondrial dynamics. These oxidative conditions may also trigger ferroptosis, cell death linked to cellular oxidation. While ferroptosis induction is desirable in certain diseases like cancer, it is not beneficial in situations such as myocardial IRI. Although considerable research has been conducted on ferroptosis in myocardial IRI, the potential impact of reducing ferroptosis via mitochondrial dynamics in IRI remains to be reviewed. Consequently, this review concentrates on mitochondrial dynamics during myocardial ferroptosis in IRI and explores the potential therapy to inhibit myocardial ferroptosis by targeting mitochondrial dynamics to mitigate IRI.
    Keywords:  ferroptosis; ischemia; mitochondrial dynamics; oxidative stress; reperfusion; treatments related to ferroptosis
    DOI:  https://doi.org/10.24976/Discov.Med.202537196.72
  32. Neurochem Res. 2025 May 28. 50(3): 172
    Mito-TEMPO Mitigates Fibromyalgia Induced by Reserpine in Rats: Orchestration Between SIRT1, Mitochondrial Dynamics, Endoplasmic Reticulum and miRNA-320.
    Heba S Zaky, Nermin T El-Said, Amany S Aboutaleb, Albatoul Allam, Mona Mansour, Hebatalla I Ahmed, Somaia A Abdel-Sattar.
      Fibromyalgia (FM) is a chronic disorder that lacks both well-defined underlying causes and effective treatments. Mito-TEMPO (MIT) is a mitochondrial-specific antioxidant that has demonstrated benefits in many cancerous, renal, cardiovascular, and neurodegenerative disorders. However, the therapeutic effect of MIT on FM remains ambiguous. The objective of the current work is to illuminate the use of MIT for FM and its prospective mechanisms. Here, we used the FM rat model induced by three days of subcutaneous reserpine injection (1 mg/kg) and examined the role of MIT on SIRT1 activation and other implicated molecular pathways. Behavioral tests showed that MIT (0.7 mg/kg) can effectively alleviate the locomotor, nociceptive, and depressive-like behaviors in reserpinized rats, an effect that simultaneously reconciles the balance of monoamines in the rat brain. Western blot analysis showed that MIT up-regulates SIRT1 and improves the expression of mitochondrial dynamics proteins (DRP1 and OPA1) and the endoplasmic reticulum protein (CHOP). Furthermore, MIT treatment significantly enhanced the SOD and CAT activities and decreased the brain contents of NF-κB, TNF-α, and BAX, but significantly enriching the Bcl-2 content. Lastly, MIT treatment significantly reduced the genetic expression of miRNA-320 following RES treatment. All the measured parameters showed a significant correlation with SIRT1 expression. Our results suggest that MIT provides antioxidant, anti-apoptotic, and anti-inflammatory impacts on the FM rat model, with proposed mechanisms involved activating the SIRT1 pathway to regulate mitochondrial dynamics, endoplasmic reticulum stress, as well as miRNA-320. Thus, MIT has the potential to be an effectual drug candidate for FM treatment.
    Keywords:  Fibromyalgia; Mito-TEMPO; Mitochondrial dysfunction; Rats; SIRT 1; miRNA
    DOI:  https://doi.org/10.1007/s11064-025-04424-9
  33. Cell Mol Neurobiol. 2025 May 29. 45(1): 53
    Endoplasmic Reticulum Stress Inhibition Promotes Mitophagy via Miro1 Reduction to Rescue Mitochondrial Dysfunction and Protect Dopamine Neurons in Parkinson's Disease.
    Yuqi Wen, Zheng Han, Bao Wang, Chenxi Feng, Xvshen Ding, Yangni Li, Yan Lv, Xuelian Wang, Li Gao.
      Both mitochondrial dysfunction and endoplasmic reticulum stress (ERS) have been implicated in the pathogenesis of Parkinson's disease (PD). However, the underlying regulatory mechanisms between ERS and mitochondrial dysfunction remain unclear. In the present study, we found that an in vitro model of Parkinson's disease (PD) induced by methyl-4-phenylpyridine (MPP+) showed increased intracellular peroxidation, leading to a significant increase in ERS. ER staining and immunofluorescence analysis of ERS-related proteins verified the presence of ERS, whereas transmission electron microscopy (TEM) showed complete depletion of ER. Notably, treatment with 4-phenylbutyric acid (4-PBA) to suppress ERS reduced apoptosis and concurrently reversed the ER micromorphology. Furthermore, 4-PBA alleviated mitochondrial dysfunction, as shown by increased mitochondrial membrane potential (MMP), upregulation of electron transport chain proteins, and restoration of mitochondrial integrity. Further studies revealed that the effect of 4-PBA could be attributed to the modulation of the mitochondrial Rho-GTPase 1 (Miro1)-mitophagy axis. In vivo experiments in Parkinson's disease models demonstrated that inhibiting ERS reduced dopaminergic neuron loss while improving cognitive and motor function. Collectively, these findings indicate that treatments targeting ERS may be potential candidates for treating PD.
    Keywords:  Endoplasmic reticulum stress; Miro1; Mitophagy; Parkinson’s disease
    DOI:  https://doi.org/10.1007/s10571-025-01575-9
  34. Biol Direct. 2025 May 26. 20(1): 65
    Macrophage Notch1 drives septic cardiac dysfunction by impairing mitophagy and promoting NLRP3 activation.
    Yanjun Zheng, Jingrong Lin, Guoqing Wan, Xuefeng Gu, Jian Ma.
       BACKGROUND: Sepsis is a life-threatening condition with limited therapeutic options, characterized as excessive systemic inflammation and multiple organ failure. Macrophages play critical roles in sepsis pathogenesis. Although numerous studies support the critical role of Notch signaling in most inflammatory diseases, the function of Notch1 signaling in macrophages activation and its underlying molecular mechanism during sepsis has not been fully elucidated.
    METHODS: We evaluated Notch1 expression in a lipopolysaccharide (LPS)-induced model of septic cardiac dysfunction. Using macrophage-specific Notch1 knockout mice (NOTCH1ΔMyelo) in conjunction with AAV-F4/80-mediated NICD1 overexpression, we investigated the impact of Notch1 on septic cardiac injury. LPS-stimulated bone marrow-derived macrophages (BMDMs) were analyzed by flow cytometry and ELISA to assess mitochondrial damage and inflammasome activation. Mitophagy flux and related protein levels were quantified, and a mitophagy inhibitor was applied to further delineate Notch1's in vivo role. Downstream targets of Notch1 were identified and validated via ChIP-qPCR and luciferase reporter assays.
    RESULTS: Intraperitoneal injection of LPS markedly impaired cardiac function, increased macrophage infiltration, and elevated Notch1 expression compared with PBS-treated controls. Notch1 expression was inversely correlated with cardiac performance in LPS-treated mice. Notably, macrophage-specific deletion of Notch1 significantly improved cardiac function, whereas NICD1 overexpression worsened LPS-induced cardiac injury. NOTCH1ΔMyelo macrophages showed reduced mitochondrial damage and diminished activation of NLRP3-dependent caspase-1. Moreover, LPS induced mitophagy, an effect that was further enhanced by Notch1 knockout. Mechanistically, ChIP-seq and qPCR analyses revealed that NICD1 upregulates Mst1 transcription. Furthermore, overexpression of Mst1 counteracted the increased mitophagy in Notch1-deficient macrophages, resulting in elevated mitochondrial reactive oxygen species production, inflammatory cytokine secretion, and caspase-1 activation during prolonged LPS stimulation.
    CONCLUSION: Our study uncovers a novel role for Notch1 in exacerbating LPS-induced septic cardiac dysfunction by suppressing mitophagy in macrophages. These findings suggest that targeting Notch1 may offer a promising therapeutic strategy to mitigate sepsis-induced inflammation by restoring proper mitophagy.
    Keywords:  Macrophages; Mitophagy; NLRP3; Notch1; Sepsis
    DOI:  https://doi.org/10.1186/s13062-025-00657-4
  35. MicroPubl Biol. 2025 ;2025
    Insertion of mNeonGreen into the variable domain of DRP-1 permits visualization of functional endogenous protein.
    Eric J Lambie, Barbara Conradt.
      We used CRISPR-Cas9 editing of the genomic drp-1 locus in C. elegans to test whether the mitochondrial fission function of DRP-1 was retained following insertion of mNeonGreen into the variable domain. We found that DRP-1 activity remains largely intact despite this large internal insertion. Furthermore, in living cells, the internally tagged protein is readily detectable as discrete puncta associated with mitochondria, which presumably represent prospective mitochondrial scission sites. The internally tagged DRP-1 protein represents a powerful new tool for real time in vivo analyses of mitochondrial fission and DRP-1 function.
    DOI:  https://doi.org/10.17912/micropub.biology.001588
  36. Food Funct. 2025 May 27.
    Ketogenic diet attenuates microglia-mediated neuroinflammation by inhibiting NLRP3 inflammasome activation via HDAC3 inhibition to activate mitophagy in experimental autoimmune encephalomyelitis.
    Qianye Zhang, Mingxiao Zheng, Wei Sun, Gabriele Loers, Min Wen, Qingpeng Wang, Xuexing Zheng, Hans-Christian Siebert, Ruiyan Zhang, Ning Zhang.
      The activation of microglia is an important cause of central nervous system (CNS) inflammatory cell infiltration and inflammatory demyelination in multiple sclerosis (MS). NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome-mediated signaling plays a decisive role in microglial activation. Mitophagy is closely related to NLRP3-mediated neuroinflammation. Previous studies have shown that ketogenic diet (KD) suppresses microglial NLRP3 inflammasome activation and exerts mitophagy-stimulating effects, but the specific mechanism remains unclear. The current study examined the mechanism underlying the anti-inflammatory effect of KD on experimental autoimmune encephalomyelitis (EAE). Our data show that KD inhibited demyelination, increased co-staining of the translocase of the outer mitochondrial membrane (TOM20) and microtubule-associated protein 1A/1B-light chain 3 (LC3II), and decreased microglial NLRP3 inflammasome activation and histone deacetylase 3 (HDAC3) in the hippocampus of EAE mice. Further correlation analysis showed that the reduction of HDAC3 was negatively correlated with NLRP3 activation and positively correlated with the induction of mitophagy in KD-fed EAE mice. In BV2 microglial cells, we confirmed that the inhibition of HDAC3 promoted 5' adenosine monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR)/unc-51-like autophagy activating kinase (ULK)1 and PTEN-induced putative kinase 1 (PINK1)/Parkin-meditated mitophagy, which led to the up-regulation of acetylated AMPK, acetylated ULK1 and acetylated Parkin, and subsequently reduced ROS accumulation and inhibited the activation of the NLRP3 inflammasome. In addition, treatment with 3-methyladenine (3-MA), a specific autophagy inhibitor, abolished the anti-inflammatory effect of HDAC3 inhibition in BV2 cells. The study illustrates that KD ameliorates EAE by reducing NLRP3-mediated inflammation in microglial cells via HDAC3 inhibition and enhancement of mitophagy-related protein acetylation.
    DOI:  https://doi.org/10.1039/d5fo00422e
  37. J Control Release. 2025 May 26. pii: S0168-3659(25)00507-3. [Epub ahead of print]384 113887
    Lanthanide nanocrystals-based direct triple-state energy converters for mitophagy and ferroptosis-induced antitumor immunoreaction.
    Qianqian Sun, Yanrong Qian, Junrong Wang, Man Wang, Guanghui Zhao, Guangqiang Wang, Chunxia Li.
      Achieving multiple antitumor efficacy in a single nanostructure is important for the development of photo-functional nanomedicines. In this paper, we report a direct triplet state energy converter (NCPRB) based on lanthanide nanocrystals, which can reduce the loss of near-infrared (NIR) light and improve the efficiency of generating reactive oxygen species (ROS) to induce ferroptosis through the process of direct energy transfer from rare earth ions (Nd3+) to the triplet state of the photosensitive molecule (chlorin e6, Ce6). Experimental results showed that the generated ROS combined with loaded resveratrol (RES) inhibited oxidative phosphorylation (OXPHOS) and electron transport chain (ETC) processes in the mitochondria of tumor cells and induced the onset of mitochondrial autophagy. Meanwhile, RES also down-regulated the expression of recombinant solute carrier family 7 member 11 (SLC7A11) protein, which enhanced the ferroptosis response. Thus, this energy transducer enables efficient photodynamic therapy (PDT)-induced mitophagy and ferroptosis and activates cancer immunotherapy. More importantly, interferon γ (IFN γ) secreted by killer T (CD8+ T) cells could have a positive feedback effect on ferroptosis by down-regulating the expression of SLC7A11, thus forming a "closed loop" of combined therapy. The above findings provide innovative perspectives for the design of photo-functional nanocancer drugs based on lanthanide nanocrystals.
    Keywords:  Activated immunoreaction; Direct triplet energy transfer; Ferroptosis; Lanthanide nanoparticles; Mitophagy
    DOI:  https://doi.org/10.1016/j.jconrel.2025.113887
  38. MedComm (2020). 2025 Jun;6(6): e70227
    Targeting LIF With Cyclovirobuxine D to Suppress Tumor Progression via LIF/p38MAPK/p62-Modulated Mitophagy in Hepatocellular Carcinoma.
    Yingying Shao, Di Lu, Wenke Jin, Sibao Chen, Lifeng Han, Tao Wang, Leilei Fu, Haiyang Yu.
      Leukemia inhibitory factor (LIF) exerts an oncogenic function in several types of cancer, including hepatocellular carcinoma (HCC). However, small-molecule inhibitors of LIF haven't been established. Here, we identified that LIF was remarkably overexpressed in HCC by multi-omics approaches, indicating that inhibition of LIF would be a promising therapeutic strategy. Inhibiting LIF could suppress proliferation and metastasis by activating p38MAPK/p62-modulated mitophagy. Interestingly, we found that the natural small-molecule Cyclovirobuxine-D (CVB-D), was a new inhibitor of cytoplasmic LIF in HCC. We further validated LIF as a potential target of CVB-D through biotin-modified CVB-D-Probe utilizing mass spectrometry. Mechanistically, we showed that CVB-D could bind to LIF at Val145, thereby inducing mitophagy, accompanied by cell cycle arrest and inhibition of invasion and migration. Moreover, we demonstrated that CVB-D had a therapeutic potential by targeting LIF-modulated mitophagy in patient-derived xenograft (PDX) models, which would elucidate LIF as a druggable target and regulatory mechanisms and exploit CVB-D as the novel small-molecule inhibitor of LIF for future HCC drug discovery.
    Keywords:  cyclovirobuxine D (CVB‐D); hepatocellular carcinoma (HCC); leukemia inhibitory factor (LIF); mitophagy; small‐molecule inhibitor
    DOI:  https://doi.org/10.1002/mco2.70227
  39. Toxicol Res (Camb). 2025 Jun;14(3): tfaf070
    PGC-1 alpha regulates mitochondrial biogenesis to promote silica-induced pulmonary fibrosis.
    Xiaoqiang Han, Mei Zhang, Liu Daowei, Lulu Liu, Xin Ma, Yu Xiong, Huifang Yang, Zhihong Liu, Na Zhang.
      Silicosis is an incurable chronic fibrotic lung disease caused by long-term exposure to respirable silica particles. It is characterized by persistent inflammation and progressive fibrosis of lung tissues, which eventually leads to respiratory failure and seriously affects human health. The high incidence and mortality associated with silicosis have made the disease a widespread public health concern. However, its pathogenesis has not been fully elucidated. Mitochondrial biogenesis plays a crucial role under various fibrotic conditions. However, the mechanism of this process in silicosis is still unclear. Therefore, this study aimed to explore the influence of the PGC-1α gene on mitochondrial biogenesis in the development of silicosis. We established in vivo and in vitro silicosis models by exposing rats and rat type-2 alveolar epithelial cells (RLE-6TN) to silica. Our findings revealed alterations in the mitochondrial structure and function, decreased mitochondrial biogenesis, and reduced expression of mtDNA (Mitochondrial DNA) content. By upregulating the PGC-1α gene in RLE-6TN cells, we activated the PGC-1α- NRF1-TFAM signaling pathway, enhancing mitochondrial biogenesis, increasing citrate synthase and mtDNA content, improving mitochondrial function, and mitigating fibrosis. Our results indicate that the regulation of mitochondrial biogenesis can affect silicosis-induced fibrosis, highlighting the significance of reduced mitochondrial biogenesis in the progression of silicosis-induced fibrosis.
    Keywords:  PGC-1α; mitochondrial biogenesis; pulmonary fibrosis; silica; silicosis
    DOI:  https://doi.org/10.1093/toxres/tfaf070
  40. Ren Fail. 2025 Dec;47(1): 2506812
    Mitochondrial dysfunction: the hidden catalyst in chronic kidney disease progression.
    Jinhu Chen, Qiuyuan Zhou, Lianjiu Su, Lihua Ni.
      Chronic kidney disease (CKD) represents a global health epidemic, with approximately one-third of affected individuals ultimately necessitating renal replacement therapy or transplantation. The kidney, characterized by its exceptionally high energy demands, exhibits significant sensitivity to alterations in energy supply and mitochondrial function. In CKD, a compromised capacity for mitochondrial ATP synthesis has been documented. As research advances, the multifaceted roles of mitochondria, extending beyond their traditional functions in oxygen sensing and energy production, are increasingly acknowledged. Empirical studies have demonstrated a strong association between mitochondrial dysfunction and the pathogenesis of fibrosis and cellular apoptosis in CKD. Targeting mitochondrial dysfunction holds substantial therapeutic promise, with emerging insights into its epigenetic regulation in CKD, particularly involving non-coding RNAs and DNA methylation. This article presents a comprehensive review of contemporary research on mitochondrial dysfunction in relation to the onset and progression of CKD. It elucidates the associated molecular mechanisms across various renal cell types and proposes novel research avenues for CKD treatment.
    Keywords:  Chronic kidney disease; cell death; mitochondrial dysfunction; mitophagy; oxidative stress
    DOI:  https://doi.org/10.1080/0886022X.2025.2506812
  41. J Ethnopharmacol. 2025 May 27. pii: S0378-8741(25)00742-1. [Epub ahead of print] 120055
    Marsdenia tenacissima extract accelerates ferroptosis of osteosarcoma cells by upregulating HO-1 and activating mitophagy.
    Danfeng Xiang, Xiangqi Zhang, Xiaochun Xue, Hanlu Liang, Jingjing Meng, Shuai Zhao, Jiao Yang, Yangyun Zhou, Yujie Hu, Lingyan Xu, Meizhi Shi, Jingxian Zhang, Mengyue Wang, Junjun Chen, Yonglong Han.
       ETHNOPHARMACOLOGICAL RELEVANCE: Marsdenia tenacissima extract (MTE) from the stem of the Traditional Chinese herbal medicine of Marsdenia tenacissima (Roxb.) Wight et Arn. has been used as an anticancer remedy for decades.
    AIM OF THE STUDY: To investigate the beneficial effects of MTE in osteosarcoma in vitro and in vivo and its potential mechanisms.
    MATERIAL AND METHODS: Nude mice with ectopic xenograft tumors were treated with MTE of 10mg/kg and 20mg/kg for 2 weeks. Human osteosarcoma (OS) cell lines 143B and MG63 were treated with 40, 60, and 80 mg/mL MTE for 24 h.
    RESULTS: MTE significantly inhibited OS cell proliferation in vitro and in vivo. Specifically, intracellular ferrous ion accumulation is closely related to the upregulation of HO-1 expression levels regulated by MTE. NAC and DFO could restore the effects of MTE on OS cell viability. In addition, the Fe2+ accumulation caused cellular oxidative stress and promoted HO-1 translocation to mitochondria. Correspondingly, the mitochondria were damaged lysosomes were recruited around, and the expression of autophagy-related proteins PINK1 and Parkin was upregulated. Moreover, the autophagy inhibitor 3-MA reversed the effect of MTE on HO-1 and GPX4 protein expression levels in OS cells. In vivo experiments demonstrated that MTE inhibited the growth of xenograft osteosarcoma while increasing the expression of LC3B, HO-1and FTH1, and simultaneously suppressing the level of GPX4 in tumor tissues.
    CONCLUSION: MTE exerts anti-osteosarcoma effects by modulating HO-1 and activating mitophagy, thereby accelerating the ferroptosis.
    Keywords:  Ferroptosis; HO-1; Marsdenia tenacissima extract; Mitophagy; Osteosarcoma
    DOI:  https://doi.org/10.1016/j.jep.2025.120055
  42. Biol Chem. 2025 May 27.
    The mitochondrial intermembrane space - a permanently proteostasis-challenged compartment.
    Matthias Weith, Konstantin Weiss, Dylan Stobbe, Jan Riemer.
      The mitochondrial intermembrane space (IMS) houses proteins essential for redox regulation, protein import, signaling, and energy metabolism. Protein import into the IMS is mediated by dedicated pathways, including the disulfide relay pathway for oxidative folding. In addition, various IMS-traversing import pathways potentially expose unfolded proteins, representing threats to proteostasis. This trafficking of precursors coincides with unique biophysical challenges in the IMS, including a confined volume, elevated temperature, variable pH and high levels of reactive oxygen species. Ultrastructural properties and import supercomplex formation ameliorate these challenges. Nonetheless, IMS proteostasis requires constant maintenance by chaperones, folding catalysts, and proteases to counteract misfolding and aggregation. The IMS plays a key role in stress signaling, where proteostasis disruptions trigger responses including the integrated stress response (ISR) activated by mitochondrial stress (ISRmt) and responses to cytosolic accumulation of mitochondrial protein precursors. This review explores the biology and mechanisms governing IMS proteostasis, presents models, which have been employed to decipher IMS-specific stress responses, and discusses open questions.
    Keywords:  IMS; mitochondria; protein import; proteostasis; stress responses
    DOI:  https://doi.org/10.1515/hsz-2025-0108
  43. Metabolites. 2025 May 16. pii: 331. [Epub ahead of print]15(5):
    Synergistic Impact of Aerobic Exercise and Resveratrol on White Adipose Tissue Browning in Obese Rats: Mechanistic Exploration and Biological Insights.
    Yulong Hu, Yihan Wu, Chunlong Wang, Qiguan Jin, Xianghe Chen.
      Obesity, marked by excessive white adipose tissue (WAT) accumulation, worsens metabolic disorders, and inducing WAT browning is a promising therapy. This study examined the synergistic effects of moderate-intensity aerobic training and resveratrol (RES) on WAT browning and its underlying mechanisms in obese male rats. Methods: Male Sprague Dawley rats were divided into a normal diet control group (n = 8) and a high-fat-diet modeling group (n = 32), with the rats in the latter group being further divided randomly in groups of eight into a high-fat group; a high-fat, exercise group; a high-fat, RES group; and a high-fat, exercise-combined-with-RES group. The rats in the exercise intervention groups underwent moderate-intensity aerobic treadmill exercise for one hour daily, six days a week, while those in the RES groups received a 50 mg/kg/d RES solution via gavage before exercise, once daily, six days a week. Both interventions lasted eight weeks. Results: The combined intervention synergistically suppressed weight gain and visceral fat accumulation. WAT browning was enhanced, evidenced by upregulated UCP1 and CIDEA expression. Mitochondrial biogenesis was activated via the SIRT1-PGC-1α-NRF-1-TFAM pathway, accompanied by elevated mitochondrial enzyme activity and improved lipid mobilization (reduced serum free fatty acids and triglycerides). Conclusions: The combination of aerobic exercise and RES promotes WAT browning and lipolysis by enhancing mitochondrial biogenesis and stimulating mitochondrial thermogenesis through the modulation of the SIRT1-PGC-1α-NRF-1-TFAM pathway.
    Keywords:  aerobic exercise; mitochondrial biogenesis; resveratrol; white fat browning
    DOI:  https://doi.org/10.3390/metabo15050331
  44. Biomolecules. 2025 May 10. pii: 695. [Epub ahead of print]15(5):
    The Insertion Domain of Mti2 Facilitates the Association of Mitochondrial Initiation Factors with Mitoribosomes in Schizosaccharomyces pombe.
    Ying Luo, Jürg Bähler, Ying Huang.
      Translation initiation in mitochondria involves unique mechanisms distinct from those in the cytosol or in bacteria. The Schizosaccharomyces pombe mitochondrial translation initiation factor 2 (Mti2) is the ortholog of human MTIF2, which plays a vital role in synthesizing proteins in mitochondria. Here, we investigate the insertion domain of Mti2, which stabilizes its interaction with the ribosome and is crucial for efficient translation initiation. Our results show that the insertion domain is critical for the proper folding and function of Mti2. The absence of the insertion domain disrupts cell growth and affects the expression of genes encoded by mitochondrial DNA. Additionally, we show that Mti2 physically interacts with the small subunits of mitoribosomes (mtSSU), and deletion of the insertion domain dissociates mitochondrial initiation factors from the mitoribosome, reducing the efficiency of mitochondrial translation. Altogether, these findings highlight the conserved role of the insertion domain in facilitating translation initiation in fission yeast and thus reveal shared principles of mitochondrial translation initiation in both fission yeast and humans.
    Keywords:  fission yeast; insertion domain; mitochondrial translation; translation initiation factor
    DOI:  https://doi.org/10.3390/biom15050695
  45. Breast Cancer Res. 2025 May 28. 27(1): 93
    Investigating the mechanism of inositol against paclitaxel chemoresistance on triple-negative breast cancer by using 7T multiparametric MRI and mitochondrial changes.
    Wentao Xuan, Wangmin Li, Lixin Ke, Yuanyu Shen, Xiaolei Zhang, Yue Chen, Zhiliang Ye, Caiyu Zhuang, Shiyan Xie, Renhua Wu, Yan Lin.
       BACKGROUND: The emerging triple-negative breast cancer (TNBC) treatments target mitochondrial fission to combat paclitaxel (PTX) resistance. Inositol's inhibition of this process makes it a potential therapy. Multiparametric MRI provides an early and effective assessment of these innovations.
    OBJECTIVE: To monitor the efficacy of Inositol on PTX-resistant TNBC mice using 7T multiparametric MRI, and to further explore the mechanism of inositol inhibiting PTX chemoresistance in combination with the morphological changes of isolated mitochondria.
    MATERIALS AND METHODS: BALB/c mice aged 6-8 weeks were subcutaneously inoculated with PTX-resistant 4T1 cells and divided into three groups: PTX-treated mice (n = 24), "PTX + Inositol"-treated mice (n = 24) and untreated mice (n = 24). Six mice in each group underwent diffused weighted imaging (DWI) and diffusion kurtosis imaging (DKI) every 7 days after administration. To observe the dynamic changes of inositol within the tumor tissue post-treatment, chemical exchange saturation transfer (CEST) imaging was performed. Six mice in each group were sacrificed on day 0, 7, and 14 respectively for histopathological examination. After a 3-week scanning cycle, the remaining mice in each group were euthanized for histopathological analysis. The therapeutic response of inositol was assessed via Hematoxylin & Eosin (H&E) staining and Ki-67 immunohistochemistry. The effects of inositol on mitochondrial structure and PTX resistance were studied by Western Blot and electron microscopy. One-way analysis of variance, independent samples t-test, paired samples t-test, Kruskal-Wallis, and Spearman rank correlation were used.
    RESULTS: The CEST signal of inositol in tumor tissue was significantly higher after 1 h of inositol administration than before (2.75 ± 0.71% vs. 1.80 ± 0.33%, p < 0.05). On day 21 after treatment, the tumor volume in the PTX + Ins group was smaller than that in the PTX group (191.52 ± 27.98 mm3 vs. 388.98 ± 32.62 mm3, p < 0.001). The MD, MK, and ADC values were correlated significantly with tumor cell density (MD, r = -0.872; MK, r = 0.723; ADC, r = -0.858) and Ki-67 level (MD, r = -0.975; MK, r = 0.680; ADC, r = -0.860). The p-AMPK levels of PTX + Ins group were lower than that of PTX group (0.50 ± 0.06 vs. 0.60 ± 0.05, p = 0.04), and the mitochondrial length was longer than that of PTX group (0.86 ± 0.10 vs. 0.44 ± 0.09, p < 0.001), with a significant correlation to Ki-67 levels (r = -0.853, p < 0.001).
    CONCLUSION: Inositol may counteract PTX resistance in TNBC by disrupting mitochondrial fission, and DWI combined with DKI effectively tracked this effect.
    Keywords:  Inositol; Mitochondrial dynamics; Multiparametric MRI; Paclitaxel resistance; Triple-negative breast cancer
    DOI:  https://doi.org/10.1186/s13058-025-02051-4
  46. Cell Death Discov. 2025 May 30. 11(1): 259
    Contrasting pathophysiological mechanisms of OPA1 mutations in autosomal dominant optic atrophy.
    Shi-Qi Yao, Jia-Jian Liang, Hui Zhou, Shaoying Tan, Yingjie Cao, Chong-Bo Chen, Ciyan Xu, Ruixi Wang, Tai-Ping Li, Fang-Fang Zhao, Yun Wang, Han-Jie He, Dan Zhang, Meng Wang, Lifang Liu, Patrick Yu-Wai-Man, Shihui Wei, Ling-Ping Cen.
      Autosomal dominant optic atrophy (ADOA) caused by mutations in the nuclear-encoded OPA1 gene result in the preferential loss of retinal ganglion cells (RGCs) and progressive optic nerve degeneration. The severity of ADOA can be highly variable. This study compared the pathophysiological consequences of the c.1034 G > A OPA1 missense mutation and the c.1305+2delGT OPA1 deletion. There was a significant correlation between the severity of visual loss and the extent of macular RGC loss as determined by optical coherence tomography imaging. In cells transfected with the c.1034 G > A mutant, the percentage of fragmented mitochondria was greater than 60% with cytochrome c (cyt c) overflow, and significantly elevated levels of reactive oxygen species (ROS) and apoptosis. In contrast, the c.1305+2delGT mutant caused mitochondrial fragmentation in ~ 20% of HeLa cells, resulting in less cyt c overflow and apoptosis. The extent of mitochondrial network fragmentation and apoptosis increased with decreasing WT OPA1 mRNA expression levels. The c.1034 G > A OPA1 missense mutation is likely to induce a dominant-negative effect compared with haploinsufficiency with the c.1305+2delGT OPA1 deletion. These contrasting pathophysiological mechanisms could influence disease severity in ADOA through their differential consequences on mitochondrial structure and function. The small drug molecule Paromomycin was able to rescue the mitochondrial fragmentation induced by the c.1034 G > A mutation, providing proof-of-concept for further therapeutic validation in ADOA.
    DOI:  https://doi.org/10.1038/s41420-025-02442-8
  47. Biochem J. 2025 May 28. pii: BCJ20253062. [Epub ahead of print]482(11):
    LRRK2-mediated mitochondrial dysfunction in Parkinson's disease.
    Silas A Buck, Laurie H Sanders.
      Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor symptoms including tremor, rigidity, and bradykinesia as well as degeneration of dopamine (DA) neurons in the substantia nigra pars compacta (SNc). A minority of PD cases are familial and are caused by a single genetic mutation. One of the most common PD-causing genes is leucine-rich repeat kinase 2 (LRRK2), which causes an autosomal dominant PD that presents very similarly to sporadic PD. Pathogenic mutations in LRRK2 increase its kinase activity, indicated by both LRRK2 autophosphorylation and phosphorylation of its substrates. To date, the mechanism(s) by which elevated LRRK2 kinase activity induces DA neuron degeneration and PD has not been fully elucidated. One potential mechanism may involve the role of LRRK2 on mitochondria, as mitochondrial dysfunction has been linked to PD pathogenesis, and exciting recent evidence has connected PD pathogenic mutations in LRRK2 to multiple aspects of mitochondrial dysfunction associated with the disease. In this review, we discuss the current knowledge implicating LRRK2 in mitochondrial energetics, oxidative stress, genome integrity, fission/fusion, mitophagy, and ion/protein transport in PD, as well as examine the potential role LRRK2 may play in mediating the effects of mitochondrial therapeutics being investigated for treatment of PD.
    Keywords:  LRRK2; Parkinson’s disease; mitochondria; mitochondrial DNA; mitophagy
    DOI:  https://doi.org/10.1042/BCJ20253062
  48. Food Funct. 2025 May 27.
    Neuroprotective effect of folic acid by maintaining DNA stability and mitochondrial homeostasis through the ATM/CHK2/P53/PGC-1α pathway in alcohol-exposed mice.
    Nan Zhang, Huaqi Zhang, Xi Liang, Yan Xu, Guifa Wang, Yixian Bai, Zijian Zhou, Yexin Pu, Yifan Zhou, Meilan Xue, Hui Liang.
      Excessive drinking leads to alcoholic brain injury, which is characterized by neuroinflammation, cognitive decline and motor dysfunction. These pathological features are closely related to chromosomal DNA damage and mitochondrial dysfunction. In this study, we aimed to uncover the neuroprotective effects of folic acid (FA) in mice with alcoholic brain injury. C57BL/6J mice were used to establish the murine model of alcoholic brain injury after 12 weeks of alcohol exposure. FA treatment significantly increased the levels of ATP and mitochondrial DNA (mtDNA) copy number in brain tissues of alcohol-exposed mice, and regulated the imbalance of mitochondrial homeostasis in cortical nerve cells. Furthermore, it could reduce the leakage of mtDNA into the cytoplasm, thereby inhibiting the cGAS/STING/NLRP3 inflammatory pathway and alleviating neuroinflammation. In addition, FA treatment reduced DNA damage in peripheral blood lymphocytes and decreased the expression of 53BP1 and γ-H2AX proteins in brain tissues of alcohol-exposed mice. At the molecular level, FA reduced DNA damage by downregulating the ATM/CHK2/P53 pathway and induced the expression of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), which further inversely enhanced mitochondrial function through positive feedback. Collectively, this study provides experimental evidence that FA protects DNA stability and mitochondrial homeostasis in alcohol-exposed mice by downregulating the ATM/CHK2/P53/PGC-1α signaling pathway.
    DOI:  https://doi.org/10.1039/d5fo00260e
  49. J Nanobiotechnology. 2025 May 27. 23(1): 383
    Ligustrazine nano-drug delivery system ameliorates doxorubicin-mediated myocardial injury via piezo-type mechanosensitive ion channel component 1-prohibitin 2-mediated mitochondrial quality surveillance.
    Junyan Wang, Haowen Zhuang, Chun Li, Ruiqi Cai, Hongshuo Shi, Boxian Pang, Zhijiang Guo, Sang-Bing Ong, Yifeng Nie, Yingzhen Du, Hao Zhou, Xing Chang.
       BACKGROUND: Doxorubicin (DOX) demonstrates significant therapeutic and anticancer efficacy. Nevertheless, it demonstrates significant cardiotoxicity, resulting in permanent cardiac damage. Ligustrazine (LIG) is a bioactive alkaloid derived from the rhizome of the medicinal plant Ligusticum chuanxiong Hort. The alkaloid has exhibited cardioprotective properties. The therapeutic application of LIG is constrained by inadequate water solubility, fast breakdown, and low bioavailability. Nanoparticle drug delivery technologies effectively address these constraints by encapsulating LIG into nanocarriers, significantly enhancing its solubility and bioavailability, hence maximizing its therapeutic efficacy. Consequently, this study employed tetrahedral backbone nucleic acid molecules as LIG carriers. Furthermore, animal models and single-cell sequencing analyses were employed to forecast the mechanisms and targets of pertinent studies. A mouse model genetically modified for the piezo type mechanosensitive ion channel component 1 (PIEZO1), transmembrane BAX inhibitor motif containing 6 (TMBIM6), and prohibitin 2 (PHB2), along with an in vivo and in vitro model of DOX-induced cardiomyopathy (DIC), was established, and a gene-modified cellular system comprising upstream genes and downstream effector targets was constructed. The mechanism of LIG was validated by molecular biology and integrated pharmacology with the implementation of the LIG nano-drug loading method.
    RESULTS: LIG nano-delivery enhanced DOX-induced cardiac dysfunction and mitochondrial impairment by modulating the PHB2Ser91/Ser176 phosphorylation axis through PIEZO1-TMBIM6, and significantly suppressed cardiomyocyte pyroptosis resulting from mitochondrial homeostasis dysregulation. The findings indicate that LIG nano-delivery is a promising therapeutic approach for addressing DIC.
    CONCLUSION: The PHB2Ser91/Ser176 phosphorylation axis regulated by PIEZO1-TMBIM6 is an important target for LIG nano-drug delivery systems to improve mitochondrial damage in DIC.
    Keywords:  Doxorubicin-induced myocardial injury; Ligustrazine; Mitochondrial quality control; Nano-carrier drug delivery; Piezo-type mechanosensitive ion channel component 1; Prohibitin 2
    DOI:  https://doi.org/10.1186/s12951-025-03420-z
  50. Mol Neurobiol. 2025 May 30.
    Inhibition of Cathepsin B Ameliorates Murine Cognitive Dysfunction and Neuronal Damage in Ischemic Stroke by Inhibiting Mitochondrial Apoptosis and Drp1-Mediated Mitochondrial Fission.
    Hongyi Jia, Bingge Zhang, Xiao Han, Pei Yu, Bocheng Xiong, Tiansu Liu, Luchen Shan, Xifei Yang, Qinghua Hou.
      The surviving brain tissue undergoes secondary degeneration long after an ischemic stroke. Cathepsin B plays dual roles as both a scavenger and an executor. Using a mouse model of ischemic stroke, we specifically investigated the mechanism by which inhibiting Cathepsin B with CA074 methyl ester (CA-074Me) during the chronic phase of stroke exerts a protective effect. In the intervention group, CA-074Me (20 μg CA-074Me/1 μl DMSO) was stereotaxically injected in the right ventricle, and, 30 min later, the animals were subjected to develop transient middle cerebral artery occlusion and reperfusion (tMCAO/R) stroke model with modified Longa method. In the model group, 1 μl DMSO was given in the right ventricle instead and the sham-operated group received 1 μl DMSO in the right ventricle without arterial occlusion. We evaluated the effects of inhibition of Cathepsin B on the nervous system after tMCAO/R injury by combined use behavioral tests, neurological deficit scoring, Western blot and other pharmacological methods and explored the underlying mechanism. After tMCAO/R, sustained upregulation and activation of Cathepsin B was noticed in the ipsilateral hippocampus CA1 zone and CA-074Me ameliorated the parallel lysosome-mitochondria damage, decreased apoptosis, improved the cognitive dysfunction, but had no effects on levels of mouse anxiety or depression. Furthermore, CA-074Me reduced neuroinflammation, levels of oxidative stress and mitochondria fission. Inhibition of Cathepsin B alleviates mitochondrial abnormalities in the ipsilateral hippocampus CA1 zone 28 days after tMCAO/R by suppressing Drp-1mediated excessive mitochondrial fission. This, in turn, reduces neuronal apoptosis, ameliorates neuroinflammation, and mitigates oxidative stress and neuronal damage, indicating Cathepsin B may serve as a potential therapeutic target for remote secondary degeneration following acute ischemic stroke.
    Keywords:  Apoptosis; CA-074Me; Cathepsin B; Ischemic stroke; Mitochondrial fission
    DOI:  https://doi.org/10.1007/s12035-025-05094-y
  51. Biochem Biophys Res Commun. 2025 May 20. pii: S0006-291X(25)00764-8. [Epub ahead of print]772 152050
    Mitochondrial calcium homeostasis mediated by estradiol contributes to atrial fibrillation protection.
    Bing Lu, Bingying Huang, Ying Wang, Guizhou Ma, Zhixiong Cai.
       BACKGROUND: Atrial fibrillation (AF) exhibits marked sex disparities, with premenopausal women showing lower incidence than age-matched men. However, the molecular mechanisms underlying estrogen's cardio protective effects remain unclear. Mitochondrial calcium (Ca2+_m) mishandling is a key driver of AF, but it is unknown whether estrogen regulates Ca2+_m homeostasis through Mitochondrial Calcium Uniporter (MCU).
    METHODS: Ovariectomized (OVX) female Sprague-Dawley rats were subjected to atrial pacing-induced AF for evaluation. Cardiac calcium dynamics, mitochondrial membrane potential (ΔΨm), and expression of calcium-regulating proteins (MICU1, NCX, LETM1) were assessed. In vitro, H9C2 cardiomyocytes under electrical stimulation (0.2 V/cm, 24h) were treated with estradiol (500 nM) or subjected to MCU knockdown (CRISPR-Cas9).
    RESULTS: OVX exacerbated AF susceptibility in rats, as evidenced by prolonged AF duration, reduced serum estradiol, and disrupted myocardial calcium homeostasis. OVX-AF hearts exhibited upregulated MICU1, NCX, and LETM1, alongside ΔΨm collapse (JC-1 monomer). Under electrical stimulation, cardiomyocytes displayed calcium homeostasis dysregulation, decreased ΔΨm, elevated ROS levels, along with concurrent downregulation of both MCU and ERβ protein expression, Estradiol supplementation normalized [Ca2+]mt,restored ΔΨm. Strikingly, MCU knockdown abolished estradiol's protective effects, inducing irreversible [Ca2+]mt overload and a surge in reactive oxygen species (ROS).
    CONCLUSIONS: We reveal that estradiol modulates MCU-mediated mitochondrial calcium homeostasis to ameliorate AF-related cellular phenotypes in vitro, implicating the estrogen-MCU axis as a promising intervention target, though its in vivo cardioprotective effects demand additional investigation. Estrogen deficiency disrupts this axis, triggering maladaptive upregulation of MICU1/NCX/LETM1 and calcium-driven remodeling. Targeting ERβ-MCU signaling may offer novel therapeutic strategies for AF, particularly in hypoestrogenic states such as menopause.
    Keywords:  Atrial fibrillation; Estradiol; Estrogen receptor beta; MCU; Mitochondrial calcium homeostasis
    DOI:  https://doi.org/10.1016/j.bbrc.2025.152050
  52. J Nanobiotechnology. 2025 May 28. 23(1): 390
    Myogenic nano-adjuvant for orthopedic-related sarcopenia via mitochondrial homeostasis modulation in macrophage-myosatellite metabolic crosstalk.
    Xudong Zhang, Peng Zhang, Yunliang Zhu, Jiaqing Lou, Peng Wu, Yingjie Wang, Zhengxi Wang, Quan Liu, Baoliang Lu, Qianming Li, Jiawei Mei, Chen Zhu, Wanbo Zhu, Xianzuo Zhang.
      The decline in skeletal muscle mass and muscle strength linked to aging, also known as sarcopenia, is strongly associated with disability, traumatic injury, and metabolic disease in patients. Meanwhile, sarcopenia increases the risk of adverse orthopedic perioperative complications including implant dislocation, infection, loosening, and poor wound healing. Mitochondrial dyshomeostasis in the immune-myosatellite metabolic crosstalk is one of the major pathological factors in sarcopenia. To reduce the incidence of orthopedic perioperative complications in patients, we designed and developed a nano-adjuvant based on two-dimensional layer double hydroxide (LDH) for sustained improvement of systemic and orthopedic-related sarcopenia. Construction of MgAlCo-LDH@UA (MACL@UA) nano-adjuvant was performed by introducing cobalt in magnesium-aluminum LDH and further loading urolithin A (UA). The release of magnesium ions and UA promoted myocyte proliferation, angiogenesis and improved mitochondrial homeostasis. Al acted as an immunomodulatory adjuvant to enhance the metabolic crosstalk between macrophages and myosatellite cells, and prompted macrophage-derived glutamine nourishment. Animal experiments confirmed that vaccination with MACL@UA in systemic sarcopenia and intensive orthopedic perioperative vaccination with MACL@UA significantly enhanced quadriceps muscle mass in rats. This nano-adjuvant offers a solution for long-term improvement of sarcopenia and short-term significant reduction of orthopedic perioperative complications in patients, with promising prospects for clinical application and commercial translation.
    Keywords:  Metabolic crosstalk; Mitochondrial homeostasis; Myogenic nano-adjuvant; Orthopedic-related sarcopenia; Systematic sarcopenia
    DOI:  https://doi.org/10.1186/s12951-025-03480-1
  53. J Ethnopharmacol. 2025 May 27. pii: S0378-8741(25)00682-8. [Epub ahead of print] 119997
    Lichong Decoction represses colorectal cancer progression via inhibiting the PINK1/Parkin pathway regulated by Rab27B.
    Yu Dai, Fei Li, Yao Tang, Lingling Sun, Yongpu Liu, Jinyan Zhan, Chuying Zhou, Aimin Li.
       ETHNOPHARMACOLOGICAL RELEVANCE: Lichong Decoction (LCD), a classical herbal formula, has been widely applied in clinical practice. Studies have validated its effectiveness in combating cancer; nevertheless, the exact pathways through which it influences colorectal cancer require further investigation.
    AIM OF THE STUDY: The mechanism of LCD in inhibiting colorectal cancer progression was investigated.
    MATERIALS AND METHODS: BALB/c-nu mice were xenografted with colorectal cancer cells to establish an animal model. The chemical constituents of LCD were characterised using high-performance liquid chromatography. Quantitative real-time PCR was employed to assess the expression levels of Rab27B mRNA. The Cancer Genome Atlas data of patients with colorectal cancer were used for gene clinical correlation analysis. Lentiviral transfection was used to construct stable cell lines. Cell motility was analysed using wound-healing and invasion assays. Pathological changes were observed using haematoxylin and eosin staining. Protein expression was determined using immunohistochemistry and western blotting. The results were statistically analysed using GraphPad Prism 10.1. 2.
    RESULTS: In vivo, LCD treatment led to a substantial decrease in the size of colorectal cancer tumours. Importantly, LCD markedly lowered the expression of Rab27B and proteins related to the PINK1/Parkin pathway in tumour tissues. In vitro, LCD significantly reduced the expression of Rab27B in colorectal cancer cells. Consistent with the results in vivo, the reduction in Rab27B inhibited PINK1/Parkin signalling protein expression and prevented the migration and invasion of colorectal cancer cells.
    CONCLUSIONS: Lichong Decoction inhibits colorectal cancer growth by dampening PINK1/Parkin signalling in colorectal cancer cells through repressing Rab27B.
    Keywords:  Colorectal cancer; Lichong Decoction; PINK1/Parkin signalling pathway; Rab27B
    DOI:  https://doi.org/10.1016/j.jep.2025.119997
  54. Signal Transduct Target Ther. 2025 May 28. 10(1): 167
    Arginase 1 drives mitochondrial cristae remodeling and PANoptosis in ischemia/hypoxia-induced vascular dysfunction.
    Han She, Jie Zheng, Guozhi Zhao, Yunxia Du, Lei Tan, Zhe-Sheng Chen, Yinyu Wu, Yong Li, Yiyan Liu, Yue Sun, Yi Hu, Deyu Zuo, Qingxiang Mao, Liangming Liu, Tao Li.
      Ischemic/hypoxic injury significantly damages vascular function, detrimentally impacting patient outcomes. Changes in mitochondrial structure and function are closely associated with ischemia/hypoxia-induced vascular dysfunction. The mechanism of this process remains elusive. Using rat models of ischemia and hypoxic vascular smooth muscle cells (VSMCs), we combined transmission electron microscopy, super-resolution microscopy, and metabolic analysis to analyze the structure and function change of mitochondrial cristae. Multi-omics approaches revealed arginase 1 (Arg1) upregulation in ischemic VSMCs, confirmed by in vivo and in vitro knockout models showing Arg1's protective effects on mitochondrial cristae, mitochondrial and vascular function, and limited the release of mtDNA. Mechanistically, Arg1 interacting with Mic10 led to mitochondrial cristae remodeling, together with hypoxia-induced VDAC1 lactylation resulting in the opening of MPTP and release of mtDNA of VSMCs. The released mtDNA led to PANoptosis of VSMCs via activation of the cGAS-STING pathway. ChIP-qPCR results demonstrated that lactate-mediated Arg1 up-regulation was due to H3K18la upregulation. VSMCs targeted nano-material PLGA-PEI-siRNA@PM-α-SMA (NP-siArg1) significantly improved vascular dysfunction. This study uncovers a new mechanism of vascular dysfunction following ischemic/hypoxic injury: a damaging positive feedback loop mediated by lactate-regulated Arg1 expression between the nucleus and mitochondria, leading to mitochondria cristae disorder and mtDNA release, culminating in VSMCs PANoptosis. Targeting VSMCs Arg1 inhibition offers a potential therapeutic strategy to alleviate ischemia/hypoxia-induced vascular impairments.
    DOI:  https://doi.org/10.1038/s41392-025-02255-2
  55. EPMA J. 2025 Jun;16(2): 239-264
    Mitochondrial medicine: "from bench to bedside" 3PM-guided concept.
    Qianwen Shao, Marie Louise Ndzie Noah, Olga Golubnitschaja, Xianquan Zhan.
      Mitochondria are the primary sites for aerobic respiration and play a vital role in maintaining physiologic function at the cellular and organismal levels. Physiologic mitochondrial homeostasis, functions, health, and any kind of mitochondrial impairments are associated with systemic effects that are linked to the human health and pathologies. Contextually, mitochondria are acting as a natural vital biosensor in humans controlling status of physical and mental health in a holistic manner. So far, no any disorder is known as happening to humans independently from a compromised mitochondrial health as the cause (primary mitochondrial dysfunction) or a target of collateral damage (secondary mitochondrial injury). This certainty makes mitochondrial medicine be the superior instrument to reach highly ambitious objectives of predictive, preventive, and personalized medicine (PPPM/3PM). 3PM effectively implements the paradigm change from the economically ineffective reactive medical services to a predictive approach, targeted prevention and treatments tailored to individualized patient profiles in primary (protection against health-to-disease transition) and secondary (protection against disease progression) healthcare. Mitochondrial DNA (mtDNA) properties differ significantly from those of nuclear DNA (nDNA). For example, mtDNA as the cell-free DNA molecule is much more stable compared to nDNA, which makes mtDNA be an attractive diagnostic target circulating in human body fluids such as blood and tear fluid. Further, genetic variations in mtDNA contribute to substantial individual differences in disease susceptibility and treatment response. To this end, the current gene editing technologies, such as clustered regularly interspaced short palindromic repeats (CRISPR)/Cas, are still immature in mtDNA modification, and cannot be effectively applied in clinical practice posing a challenge for mtDNA-based therapies. In contrast, comprehensive multiomics technologies offer new insights into mitochondrial homeostasis, health, and functions, which enables to develop more effective multi-level diagnostics and targeted treatment strategies. This review article highlights health- and disease-relevant mitochondrial particularities and assesses involvement of mitochondrial medicine into implementing the 3PM objectives. By discussing the interrelationship between 3PM and mitochondrial medicine, we aim to provide a foundation for advancing early and predictive diagnostics, cost-effective targeted prevention in primary and secondary care, and exemplify personalized treatments creating proof-of-concept approaches for 3PM-guided clinical applications.
    Keywords:  Autophagy and mitophagy; Cancer; Cardio-vascular disease; Chronic Fatigue; Cost-effective tailored treatments; Environment; Health policy; Health-to-disease transition; Individualized patient profile; Metabolic disease; Mitochondrial medicine; Neurodegeneration; Predictive Preventive Personalized Medicine (PPPM / 3PM / 3P medicine); Signaling; Stress; Vital biosensor
    DOI:  https://doi.org/10.1007/s13167-025-00409-4
  56. Curr Opin Cell Biol. 2025 May 26. pii: S0955-0674(25)00077-8. [Epub ahead of print]95 102539
    Actin in mitochondrial regulation and mechanometabolic crosstalk.
    Peng Shi, Yuhan Zhang, Congying Wu.
      Mitochondria undergo dynamic adaptations to cellular energy demands, changing morphology and function, through active interactions with other cellular organelles and the cytoskeletons. With advances in light and electron microscopy, actin probes for live-cell imaging, as well as proximity labeling, subtle and transient actin structures associated with mitochondria have been resolved and examined, which opened a new era for the understanding of architectural and mechanical regulation of organelles and metabolism. Here, we first review the recent findings that elucidate the actin-mitochondrion interactions in regulating mitochondrial dynamics (including fission, fusion and trafficking), and cristae architecture. Further, we discuss the functional consequences accompanying these morphological changes, which link cellular metabolism to the cytoskeleton and mechanotransduction through direct or indirect organelle control. Moreover, we summarize the avant-garde techniques for probing mitochondrion-associated actin, including new ways to visualize mitochondria-actin interaction in the cytosol and within the mitochondria, methods to identify the molecular components mediating actin-mitochondria crosstalk, and techniques for reconstructing the 3D ultrastructure of actin-mitochondrion interaction. Finally, we conclude pressing issues in this exciting field, calling for interdisciplinary efforts in examine actin-mitochondrion interactions at micro and macro levels. The dynamics and structural integrity of mitochondria are essential for energy metabolism and signal transduction, while their abnormalities lead to mitochondrial dysfunction and severe disease. This review aims to provide a comprehensive perspective on the emerging roles of the actin cytoskeleton in shaping mitochondrial morphology, structure, and functions, providing new angles to understand mitochondria-related diseases.
    DOI:  https://doi.org/10.1016/j.ceb.2025.102539
  57. Membranes (Basel). 2025 May 16. pii: 152. [Epub ahead of print]15(5):
    Membrane ATPases and Mitochondrial Proteins in Fetal Cerebellum After Exposure to L-Glutamate During Gestation.
    Adrián Tejero, David Agustín León-Navarro, Mairena Martín.
      L-Glutamate (L-Glu) and its salt derivatives are widely used in the food industry as flavor enhancers. Although the consumption of these compounds is generally considered safe, some studies suggest that chronically consuming L-Glu may be associated with various disorders. In this study, Wistar pregnant rats were treated daily with 1 g/L of L-Glu in their drinking water throughout the gestational period. OPA-1, DRP-1, and mitofusin 2-key proteins involved in mitochondrial fusion and fission-were analyzed by Western blot. The results showed that L-Glu exposure significantly decreased DRP-1 levels, while OPA-1 and mitofusin 2 levels were unaffected. This was accompanied by a notable decrease in mitochondrial complexes III and V. The activities of Mg2+-ATPase and Na+/K+-ATPase were also analyzed in fetal cerebellar plasma membranes. Maternal L-Glu intake significantly increased Mg2+-ATPase activity. Regarding Na+/K+-ATPase, the data showed that L-Glu exposure did not modulate the protein level or its activity. However, a positive interaction with glutamate receptors was observed in both activities, although neither AMPA nor NMDA receptors appeared to be involved. These results suggest that chronic maternal L-Glu intake during gestation modulates Mg2+-ATPase activity and protein markers of mitochondrial dynamics in the fetal cerebellum, which could affect neonatal development.
    Keywords:  L-glutamate; Mg2+-ATPase; mitochondria
    DOI:  https://doi.org/10.3390/membranes15050152
  58. Cell Signal. 2025 May 27. pii: S0898-6568(25)00294-3. [Epub ahead of print] 111879
    The AKT-USP15 axis modulates autophagy in MPP+-induced Parkinson's disease model of SN4741 cells.
    Xian Wu, Yue Wen, Tianyao Bai, Nanfei Yang, Yuyu Yuan, Lingling Xu, Yujie Ma, Peng Su, Wenjing Luo, Wenjun Li.
      In Parkinson's disease (PD), maintaining the balance between protein synthesis and degradation is critical for cellular homeostasis. Ubiquitination, which marks proteins for degradation, and its reverse process deubiquitination, are essential regulators for protein turnover. Recent research implicate that deubiquitinating enzymes involve in PD pathogenesis. Specially, Ubiquitin Specific Protease 15 (USP15) has been shown to antagonize Parkin, an E3 ubiquitin ligase that facilitates mitophagy - the selective clearance of damaged mitochondria.. However, the regulatory mechanisms governing the activity of USP15 in PD remain unclear. Our study revealed a novel regulatory mechanism: USP15 served as a phosphorylation substrate for protein kinase B (AKT). AKT-mediated phosphorylation triggered translocation of USP15 from the nucleus to the cytoplasm, subsequently restoring autophagy levels. These data identified that AKT mediated phosphorylation of USP15 regulated autophagy in MPP+-induced PD models. Collectivelly, our research elucidates the complex interplay among AKT, USP15, and autophagy in PD. These mechanistic insights advance our understanding of potential therapeutic targets to enhance autophagic flux and ameliorate cellular dysfunction in Parkinson's disease.
    Keywords:  AKT; Autophagy; Parkinson's disease; Phosphorylation; USP15
    DOI:  https://doi.org/10.1016/j.cellsig.2025.111879
  59. Nan Fang Yi Ke Da Xue Xue Bao. 2025 May 20. pii: 1673-4254(2025)05-0969-08. [Epub ahead of print]45(5): 969-976
    [Shenqi Buzhong Formula ameliorates mitochondrial dysfunction in a rat model of chronic obstructive pulmonary disease by activating the AMPK/SIRT1/PGC-1α pathway].
    Lu Zhang, Huanzhang Ding, Haoran Xu, Ke Chen, Bowen Xu, Qinjun Yang, Di Wu, Jiabing Tong, Zegeng Li.
       OBJECTIVES: To explore the mechanism of Shenqi Buzhong (SQBZ) Formula for alleviating mitochondrial dysfunction in a rat model of chronic obstructive pulmonary disease (COPD) in light of the AMPK/SIRT1/PGC-1α pathway.
    METHODS: Fifty male SD rat models of COPD, established by intratracheal lipopolysaccharide (LPS) instillation, exposure to cigarette smoke, and gavage of Senna leaf infusion, were randomized into 5 groups (n=10) for treatment with saline (model group), SQBZ Formula at low, moderate and high doses (3.08, 6.16 and 12.32 g/kg, respectively), or aminophylline (0.024 g/kg) by gavage for 4 weeks, with another 10 untreated rats as the control group. Pulmonary function of the rats were tested, and pathologies and ultrastructural changes of the lung tissues were examined using HE staining and transmission electron microscopy. The levels of SOD, ATP, MDA, and mitochondrial membrane potential in the lungs were detected using WST-1, colorimetric assay, TBA, and JC-1 methods. Flow cytometry was used to analyze ROS level in the lung tissues, and the protein expression levels of P-AMPKα, AMPKα, SIRTI, and PGC-1α were detected using Western blotting.
    RESULTS: The rat models of COPD showed significantly decreased lung function, severe histopathological injuries of the lungs, decreased pulmonary levels of SOD activity, ATP and mitochondrial membrane potential, increased levels of MDA and ROS, and decreased pulmonary expressions of P-AMPKα, SIRTI, and PGC-1α proteins. All these changes were significantly alleviated by treatment with SQBZ Formula and aminophylline, and the efficacy was comparable between high-dose SQBZ Formula group and aminophylline group.
    CONCLUSIONS: SQBZ Formula ameliorates mitochondrial dysfunction in COPD rats possibly by activating the AMPK/SIRT1/PGC-1α pathway.
    Keywords:  AMPK/SIRT1/PGC-1α pathway; Shenqi Buzhong Formula; chronic obstructive pulmonary disease; mitochondrial biogenesis; mitochondrial dysfunction
    DOI:  https://doi.org/10.12122/j.issn.1673-4254.2025.05.09
  60. Sci Bull (Beijing). 2025 May 09. pii: S2095-9273(25)00493-1. [Epub ahead of print]
    Role of mitochondrial homeostasis in female reproductive system aging.
    Rusha Yin, Yaqian Li, Yiwei Zhang, Lan Zhu.
      
    DOI:  https://doi.org/10.1016/j.scib.2025.04.067
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