bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2025–03–23
forty-nine papers selected by
Gavin McStay, Liverpool John Moores University
  1. Mitochondrial fission - changing perspectives for future progress.
  2. PPM1D ameliorates Alzheimer's disease by promoting mitophagy.
  3. SIRT3-PINK1-PKM2 axis prevents osteoarthritis via mitochondrial renewal and metabolic switch.
  4. Acute diacylglycerol production activates critical membrane-shaping proteins leading to mitochondrial tubulation and fission.
  5. Mitochondrial quality control in cardiomyocytes: safeguarding the heart against disease and ageing.
  6. [Effect of moxibustion on cognitive function and hippocampal mitochondrial dynamics related proteins in rats with vascular dementia].
  7. Piezo1 deletion mitigates diabetic cardiomyopathy by maintaining mitochondrial dynamics via ERK/Drp1 pathway.
  8. Advances in mitophagy initiation mechanisms.
  9. Olfactory mucosal mesenchymal stem cell-derived exosome Lnc A2M-AS1 ameliorates oxidative stress by regulating TP53INP1-mediated mitochondrial autophagy through interacting with IGF2BP1 in Parkinson's diseases.
  10. 7'-Hydroxyl substituted xanthones from Gentianella acuta revert hepatic steatosis in obese diabetic mice through preserving mitochondrial homeostasis.
  11. α-Amanitin aggravates hepatic injury by activating oxidative stress and mitophagy via peroxiredoxin 6 inhibition.
  12. DNA damage response regulator ATR licenses PINK1-mediated mitophagy.
  13. ZnT6-mediated Zn2+ redistribution: impact on mitochondrial fission and autophagy in H9c2 cells.
  14. Hydrogen sulfide attenuates PM2.5-induced COPD by inhibiting cellular senescence via the Klotho/Parkin-mediated mitophagy signaling pathway.
  15. [Mechanism of the pretreatment with electroacupuncture of "biaoben acupoint combination" for regulating cardiomyocyte mitochondrial fission in the rats of myocardial ischemia-reperfusion injury].
  16. [Molecular Mechanisms of Huangjing Zanyu Capsule in Treating Oligoasthenospermia: A Study Based on AMPK-Mediated Mitophagy].
  17. Mitochondrial FIS1 level in cumulus cells correlates with morphological grades of human cleavage-stage embryos.
  18. Tubeimoside I induces mitophagy by activating the PINK1/Parkin/Mfn2 signaling pathway in acute myeloid leukemia cells.
  19. Mitophagy and immune cell interaction: insights into pathogenesis and potential targets for necrotizing enterocolitis.
  20. Dietary alpha-lipoic acid alleviates heat stress by modulating insulin-like signaling to maintain homeostasis in C. elegans.
  21. TMBIM-2 orchestrates systemic mitochondrial stress response via facilitating Ca2+ oscillations.
  22. BMAL1 attenuates intervertebral disc degeneration by activating the SIRT1/PGC-1α pathway: evidence from vitro studies.
  23. N-acetylserotonin derivative ameliorates hypoxic-ischemic brain damage by promoting PINK1/Parkin-dependent mitophagy to inhibit NLRP3 inflammasome-induced pyroptosis.
  24. Mito-Apocynin Protects Against Kainic Acid-Induced Excitotoxicity by Ameliorating Mitochondrial Impairment.
  25. Umbilical cord mesenchymal stem cells-derived extracellular vesicles improve excessive autophagy of granulosa cells through METTL3.
  26. Protective effects of olive oil against cardiac aging through mitophagy and apoptosis.
  27. Kirenol alleviates cerebral ischemia-reperfusion injury by reducing oxidative stress and ameliorating mitochondrial dysfunction via activating the CK2/AKT pathway.
  28. Piwei Peiyuan Prescription Attenuates the Progression of Chronic Atrophic Gastritis by Eliciting MAPK10-Mediated Mitochondrial Autophagy.
  29. EPIC-1042 alleviates cerebral ischemic/reperfusion injury through TAX1BP1-induced mitophagy.
  30. Single-cell RNA sequencing-guided engineering of mitochondrial therapies for intervertebral disc degeneration by regulating mtDNA/SPARC-STING signaling.
  31. Definition of the human mitochondrial TOM interactome reveals TRABD as new interacting protein.
  32. Advances in Chinese herbal medicine in modulating mitochondria to treat myocardial ischemia-reperfusion injury: a narrative review.
  33. The role of mitochondrial dysfunction in the protective effect of ginger derived extracellular vesicles on hepatic stellate cells against cytotoxicity.
  34. Short-term heat exposure affects thermogenesis and mitophagy in goat brown adipocytes.
  35. β-hydroxybutyrate facilitates mitochondrial-derived vesicle biogenesis and improves mitochondrial functions.
  36. SIRT2 alleviates pre-eclampsia via prompting mitochondrial biogenesis and function.
  37. Ivabradine ameliorates doxorubicin-induced cardiotoxicity through improving mitochondrial function and cardiac calcium homeostasis.
  38. Steroid Constituents of Solidago canadensis alleviate LPS-induced inflammation via AMPK regulated Mitophagy/NLRP3 and NF-κB pathway.
  39. The Mia40 substrate Mix17 exposes its N-terminus to the cytosolic side of the mitochondrial outer membrane.
  40. Correction: Cornuside alleviates cognitive impairments induced by Aβ1-42 through attenuating NLRP3-mediated neurotoxicity by promoting mitophagy.
  41. Identification and validation of mitophagy-related genes in acute myocardial infarction and ischemic cardiomyopathy and study of immune mechanisms across different risk groups.
  42. Bioengineering the metabolic network of CAR T cells with GLP-1 and Urolithin A increases persistence and long-term anti-tumor activity.
  43. Mitochondria: An overview of their origin, genome, architecture, and dynamics.
  44. Reply to: An alternative model for maternal mtDNA inheritance.
  45. Swimming Exercise Pretreatment Attenuates Postoperative Delirium-Like Behavior in Type 2 Diabetic Rats by Enhancing Mitochondrial Biogenesis Through Activation of SIRT2 Deacetylation.
  46. AMPK-dependent Parkin activation suppresses macrophage antigen presentation to promote tumor progression.
  47. Telomere length in offspring is determined by mitochondrial-nuclear communication at fertilization.
  48. Mitofusin 1 Drives Preimplantation Development by Enhancing Chromatin Incorporation of Histone H3.3.
  49. Transgenerational inheritance of mitochondrial hormetic oxidative stress mediated by histone H3K4me3 and H3K27me3 modifications.
  1. J Cell Sci. 2025 May 01. pii: jcs263640. [Epub ahead of print]138(9):
    Mitochondrial fission - changing perspectives for future progress.
    Sukrut C Kamerkar, Ao Liu, Henry N Higgs.
      Mitochondrial fission is important for many aspects of cellular homeostasis, including mitochondrial distribution, stress response, mitophagy, mitochondrially derived vesicle production and metabolic regulation. Several decades of research has revealed much about fission, including identification of a key division protein - the dynamin Drp1 (also known as DNM1L) - receptors for Drp1 on the outer mitochondrial membrane (OMM), including Mff, MiD49 and MiD51 (also known as MIEF2 and MIEF1, respectively) and Fis1, and important Drp1 regulators, including post-translational modifications, actin filaments and the phospholipid cardiolipin. In addition, it is now appreciated that other organelles, including the endoplasmic reticulum, lysosomes and Golgi-derived vesicles, can participate in mitochondrial fission. However, a more holistic understanding of the process is lacking. In this Review, we address three questions that highlight knowledge gaps. First, how do we quantify mitochondrial fission? Second, how does the inner mitochondrial membrane (IMM) divide? Third, how many 'types' of fission exist? We also introduce a model that integrates multiple regulatory factors in mammalian mitochondrial fission. In this model, three possible pathways (cellular stimulation, metabolic switching or mitochondrial dysfunction) independently initiate Drp1 recruitment at the fission site, followed by a shared second step in which Mff mediates subsequent assembly of a contractile Drp1 ring. We conclude by discussing some perplexing issues in fission regulation, including the effects of Drp1 phosphorylation and the multiple Drp1 isoforms.
    Keywords:  Drp1 receptors; Dynamin related protein-1; Inner mitochondrial membrane division; Mitochondrial fission
    DOI:  https://doi.org/10.1242/jcs.263640
  2. Exp Neurol. 2025 Mar 14. pii: S0014-4886(25)00082-2. [Epub ahead of print] 115218
    PPM1D ameliorates Alzheimer's disease by promoting mitophagy.
    Aiming Wang, Fan Zhang, Wenqiang Zhang, Jian Gong, Xiaohong Sun.
      Mitochondrial autophagy (mitophagy) plays an essential role in the maintenance of mitochondrial homeostasis. Defective mitophagy triggered by amyloid beta (Aβ) is linked to neuronal deterioration and neurodegeneration in Alzheimer's disease (AD). However, the molecular mechanism underlying the defective mitophagy in AD is still not fully illustrated. Protein phosphatase Mn2+/Mg2+-dependent 1D (PPM1D) triggers autophagy in mouse embryonic fibroblasts. Downregulated PPM1D in the hippocampus of APP/PS1 mice. This study aims to investigate the role of PPM1D in the progression of AD. Here, APP/PS1 mice were used to mimic AD, and rAAV2 vectors expressing PPM1D were injected into the bilateral hippocampus. In vitro, the mouse hippocampal neuron cell line HT22 was stimulated by Aβ1-42 to trigger neuronal damage. High PPM1D expression alleviated the impairments of spatial cognition and memory in APP/PS1 mice. Additionally, PPM1D enhanced autophagosome formation, lysosomal degradation of impaired mitochondria, amyloid plaque deposition, and neuronal degeneration and apoptosis in the hippocampus of APP/PS1 mice. Similar effects of PPM1D on neuronal apoptosis and mitophagy were observed in Aβ1-42-treated HT22 cells, and the effects could be reversed by the mitophagy inhibitor cyclosporine A. In conclusion, PPM1D facilitates mitophagy to inhibit the progression of AD-like disease. Taken together, the present work uncovers defective mitophagy in AD may be associated with down-regulated PPM1D, and PPM1D may be a potential therapeutic target for AD treatment.
    Keywords:  Alzheimer's disease; Mitophagy; Neuronal damage; Neurotoxicity; PPM1D
    DOI:  https://doi.org/10.1016/j.expneurol.2025.115218
  3. Bone Res. 2025 Mar 14. 13(1): 36
    SIRT3-PINK1-PKM2 axis prevents osteoarthritis via mitochondrial renewal and metabolic switch.
    Yaoge Deng, Mingzhuang Hou, Yubin Wu, Yang Liu, Xiaowei Xia, Chenqi Yu, Jianfeng Yu, Huilin Yang, Yijian Zhang, Xuesong Zhu.
      Maintaining mitochondrial homeostasis is critical for preserving chondrocyte physiological conditions and increasing resistance against osteoarthritis (OA). However, the underlying mechanisms governing mitochondrial self-renewal and energy production remain elusive. In this study, we demonstrated mitochondrial damage and aberrant mitophagy in OA chondrocytes. Genetically overexpressing PTEN-induced putative kinase 1 (PINK1) protects against cartilage degeneration by removing defective mitochondria. PINK1 knockout aggravated cartilage damage due to impaired mitophagy. SIRT3 directly deacetylated PINK1 to promote mitophagy and cartilage anabolism. Specifically, PINK1 phosphorylated PKM2 at the Ser127 site, preserving its active tetrameric form. This inhibited nuclear translocation and the interaction with β-catenin, resulting in a metabolic shift and increased energy production. Finally, a double-knockout mouse model demonstrated the role of the SIRT3-PINK1-PKM2 axis in safeguarding the structural integrity of articular joints and improving motor functions. Overall, this study provides a novel insight into the regulation of mitochondrial renewal and metabolic switches in OA.
    DOI:  https://doi.org/10.1038/s41413-025-00413-4
  4. Nat Commun. 2025 Mar 19. 16(1): 2685
    Acute diacylglycerol production activates critical membrane-shaping proteins leading to mitochondrial tubulation and fission.
    Joshua G Pemberton, Krishnendu Roy, Yeun Ju Kim, Tara D Fischer, Vijay Joshi, Elizabeth Ferrer, Richard J Youle, Thomas J Pucadyil, Tamas Balla.
      Mitochondrial dynamics are orchestrated by protein assemblies that directly remodel membrane structure, however the influence of specific lipids on these processes remains poorly understood. Here, using an inducible heterodimerization system to selectively modulate the lipid composition of the outer mitochondrial membrane (OMM), we show that local production of diacylglycerol (DAG) directly leads to transient tubulation and rapid fragmentation of the mitochondrial network, which are mediated by isoforms of endophilin B (EndoB) and dynamin-related protein 1 (Drp1), respectively. Reconstitution experiments on cardiolipin-containing membrane templates mimicking the planar and constricted OMM topologies reveal that DAG facilitates the membrane binding and remodeling activities of both EndoB and Drp1, thereby independently potentiating membrane tubulation and fission events. EndoB and Drp1 do not directly interact with each other, suggesting that DAG production activates multiple pathways for membrane remodeling in parallel. Together, our data emphasizes the importance of OMM lipid composition in regulating mitochondrial dynamics.
    DOI:  https://doi.org/10.1038/s41467-025-57439-9
  5. Nat Rev Cardiol. 2025 Mar 20.
    Mitochondrial quality control in cardiomyocytes: safeguarding the heart against disease and ageing.
    Rishith Ravindran, Åsa B Gustafsson.
      Mitochondria are multifunctional organelles that are important for many different cellular processes, including energy production and biosynthesis of fatty acids, haem and iron-sulfur clusters. Mitochondrial dysfunction leads to a disruption in these processes, the generation of excessive reactive oxygen species, and the activation of inflammatory and cell death pathways. The consequences of mitochondrial dysfunction are particularly harmful in energy-demanding organs such as the heart. Loss of terminally differentiated cardiomyocytes leads to cardiac remodelling and a reduced ability to sustain contraction. Therefore, cardiomyocytes rely on multilayered mitochondrial quality control mechanisms to maintain a healthy population of mitochondria. Mitochondrial chaperones protect against protein misfolding and aggregation, and resident proteases eliminate damaged proteins through proteolysis. Irreparably damaged mitochondria can also be degraded through mitochondrial autophagy (mitophagy) or ejected from cells inside vesicles. The accumulation of dysfunctional mitochondria in cardiomyocytes is a hallmark of ageing and cardiovascular disease. This accumulation is driven by impaired mitochondrial quality control mechanisms and contributes to the development of heart failure. Therefore, there is a strong interest in developing therapies that directly target mitochondrial quality control in cardiomyocytes. In this Review, we discuss the current knowledge of the mechanisms involved in regulating mitochondrial quality in cardiomyocytes, how these pathways are altered with age and in disease, and the therapeutic potential of targeting mitochondrial quality control pathways in cardiovascular disease.
    DOI:  https://doi.org/10.1038/s41569-025-01142-1
  6. Zhen Ci Yan Jiu. 2025 Mar 25. pii: 1000-0607(2025)03-0260-10. [Epub ahead of print]50(3): 260-269
    [Effect of moxibustion on cognitive function and hippocampal mitochondrial dynamics related proteins in rats with vascular dementia].
    Qi-Qi Yang, Jun Yang, Min Ye, Ke-Po Wang, Xin-Hua Zhou, Wei-Ran Li, Fei Li.
       OBJECTIVES: To investigate the effect of moxibustion on hippocampal mitochondrial dynamics-related proteins in rats with vascular dementia (VD), so as to reveal the underlying mechanisms of moxibustion in treating VD.
    METHODS: SD rats were randomly divided into sham operation, model, moxibustion and medication groups, with 12 rats in each group. The VD model was prepared using an improved bilateral common carotid artery ligation method. Mild moxibstion was applied to "Shenting" (GV24), "Baihui" (GV20) and "Dazhui" (GV14) for 20 min, once daily for 6 days per week. Rats of the medication group were treated with oral administration of nimodipine (12 mg/kg) once daily. All above interventions were performed for 4 weeks. Learning and memory abilities were assessed using Morris water maze test. Histopathological changes of hippocampus was observed with HE staining. Mitochondrial membrane potential (Δψm) and reactive oxygen species (ROS) levels in hippocampal tissue were measured by flow cytometry. The mRNA and protein expression levels of optic atrophy protein 1 (Opa1), mitochondrial fusion protein 1 (Mfn1), mitochondrial fusion protein 2 (Mfn2), dynamics-related protein 1 (Drp1), fission protein 1 (Fis1), mitochondrial fission factor (Mff) in hippocampus was detected by PCR or Western blot, respectively.
    RESULTS: Compared with the sham operation group, the escape latency was prolonged (P<0.01), the times of crossing the original platform were reduced (P<0.01), the membrane potential of hippocampus, the mRNA and protein expression levels of Opa1, Mfn1 and Mfn2 in hippocampus were decreased (P<0.01, P<0.001) in the model group, while the average fluorescence intensity of ROS was increased, the mRNA and protein expression levels of Drp1, Fis1 and Mff were increased (P<0.001). In comparison with the model group, the escape latency was significantly shortened (P<0.05), the times of crossing the original platform were increased (P<0.05), the membrane potential of the hippocampus, the mRNA and protein expression levels of Opa1, Mfn1 and Mfn2 were increased (P<0.05, P<0.001) in the moxibustion and medication groups, while the average fluorescence intensity of ROS in the hippocampus, the mRNA and protein expression levels of Drp1, Fis1 and Mff were decreased (P<0.001). The average fluorescence intensity of ROS in the moxibustion group was significantly lower than that in the medication group (P<0.001). HE staining showed loose arrangement of neurons, disappearance of partial nucleolus, and necrocytosis after modeling, which were relatively milder in both moxibustion and medication groups.
    CONCLUSIONS: Moxibustion can effectively improve the cognitive function of VD rats, and its mechanism may be related to regulating hippocampal mitochondrial dynamics-related proteins, promoting mitochondrial fusion, inhibiting excessive mitochondrial division, thereby improving the imbalance of mitochondrial dynamics and alleviating mitochondrial dysfunction-related conditions.
    Keywords:  Fusion and fission; Mitochondria; Mitochondrial dynamics; Moxibustion; Vascular dementia
    DOI:  https://doi.org/10.13702/j.1000-0607.20240550
  7. Cardiovasc Diabetol. 2025 Mar 20. 24(1): 127
    Piezo1 deletion mitigates diabetic cardiomyopathy by maintaining mitochondrial dynamics via ERK/Drp1 pathway.
    Weipin Niu, Xin Liu, Bo Deng, Tianying Hong, Cuifen Wang, Yameng Yan, Jiali Liu, Yuehua Jiang, Jing Li.
       OBJECTIVE: Increasing evidence highlights the critical role of Piezo1 in cardiovascular diseases, with its expression upregulated in diabetic heart. However, the involvement of Piezo1 in the pathogenesis of diabetic cardiomyopathy (DCM) remains unclear. This study aims to elucidate the regulatory role of Piezo1 in mitochondrial dynamics within the context of DCM and to investigate the underlying mechanisms.
    METHODS: We constructed cardiac-specific knockout of Piezo1 (Piezo1∆Myh6) mice. Type 1 diabetes was induced using streptozotocin (STZ) injection while type 2 diabetes was established through a high-fat diet combined with STZ. Echocardiography assessed left ventricular function, histological evaluations used HE and Masson staining to examine cardiac pathology in Piezo1fl/fl controls, Piezo1∆Myh6 controls, Piezo1fl/fl diabetic and Piezo1∆Myh6 diabetic mice. Mitochondrial function including oxygen species level, mitochondrial morphology, and respiration rate were also assessed.
    RESULTS: Our findings revealed that Piezo1 expression was upregulated in the myocardium of diabetic mice and in high-glucose-treated cells. Cardiac-specific knockout of Piezo1 improved cardiac dysfunction and ameliorated cardiac fibrosis in diabetic mice. Moreover, Piezo1 deficiency also attenuated mitochondrial impairment. Piezo1fl/fl diabetic mice exhibited increased calpain activity and excessive mitochondrial fission mediated by Drp1 and obvious reduced fusion; however, Piezo1 deficiency restored calpain levels and mitochondrial dysfunction. These observations were also corroborated in H9C2 cells and neonatal mouse cardiomyocytes. Cardiac-specific knockout of Piezo1 increased phosphorylation of Drp1 and ERK1/2 in vivo and in vitro. Piezo1 knockout or treatment with inhibitor improved mitochondrial function.
    CONCLUSIONS: This study provides the first evidence that Piezo1 is elevated in DCM through the modulation of mitochondrial dynamics, which is reversed by Piezo1 deficiency. Thus, Piezo1 inhibition may provide a promising therapeutic strategy for the treatment of DCM.
    Keywords:  Diabetic cardiomyopathy; Drp1; ERK1/2; Mitochondrial dynamics; Piezo1
    DOI:  https://doi.org/10.1186/s12933-025-02625-8
  8. Curr Opin Cell Biol. 2025 Mar 20. pii: S0955-0674(25)00031-6. [Epub ahead of print]94 102493
    Advances in mitophagy initiation mechanisms.
    Catharina Küng, Michael Lazarou, Thanh Ngoc Nguyen.
      Mitophagy is an important lysosomal degradative pathway that removes damaged or unwanted mitochondria to maintain cellular and organismal homeostasis. The mechanisms behind how mitophagy is initiated to form autophagosomes around mitochondria have gained a lot of interest since they can be potentially targeted by mitophagy-inducing therapeutics. Mitophagy initiation can be driven by various autophagy receptors or adaptors that respond to different cellular and mitochondrial stimuli, ranging from mitochondrial damage to metabolic rewiring. This review will cover recent advances in our understanding of how mitophagy is initiated, and by doing so reveal the mechanistic plasticity of how autophagosome formation can begin.
    DOI:  https://doi.org/10.1016/j.ceb.2025.102493
  9. Cell Biol Toxicol. 2025 Mar 20. 41(1): 60
    Olfactory mucosal mesenchymal stem cell-derived exosome Lnc A2M-AS1 ameliorates oxidative stress by regulating TP53INP1-mediated mitochondrial autophagy through interacting with IGF2BP1 in Parkinson's diseases.
    Jiangshan Zhang, Chuang Wang, Guoshuai Yang, Yanhui Zhou, Dan Hou, Ying Xia.
       BACKGROUND: Exosome Lnc A2M-AS1 from olfactory mucosa mesenchymal stem cells (OM-MSCs) can ameliorate oxidative stress by improving mitophagy in cardiomuscular cells; however, it remains unclear whether this effect exists in the brain tissues of patients with Parkinson's disease (PD).
    METHODS: OM-MSC-Exosomes were isolated and verified based on morphology and specific biomarkers. The effects of OM-MSC-Exo on mitochondrial autophagy, oxidative stress, and lncRNA A2M-AS1 were detected in MPP+-treated HT22 cells. The effects of OM-MSC-Exos on mitochondrial autophagy and oxidative stress were detected in an MPTP-induced Parkinson's disease (PD) model in C57BL/6 mice. The interaction between IGF2BP1, A2M-AS1, and TP53INP1 was assessed via RNA pull-down/RNA Immunoprecipitation and RNA stability assays. The effects of lnc A2M-AS1 on IGF2BP1/TP53INP1-mediated mitochondrial autophagy and oxidative stress were verified in MPP+-treated HT22 cells and MPTP-induced PD mouse models.
    RESULTS: Exosomes isolated from olfactory mucosa mesenchymal stem cells were found to be rich in Lnc A2M-AS1. Lnc A2M-AS1 was proved to be able to ameliorate oxidative stress induced by MPP+ in HT22 cells. lncRNA A2M-AS1 regulates oxidative stress by enhancing mitophagy in HT22 cells. In addition, lncRNA A2M-AS1 induced mitophagy through TP53INP1 and mediated TP53INP1 expression by binding to IGF2BP1. Furthermore, OM-MSC-Exo and Lnc A2M-AS1 treatment improved symptoms and ameliorated oxidative stress in MPTP-induced PD mouse models.
    CONCLUSION: Collectively, lncRNA A2M-AS1 from OM-MSC-derived exosomes regulates TP53INP1 expression by targeting IGF2BP1 to induce mitophagy and ameliorate oxidative stress. OM-MSC-derived exosomes could potentially serve as promising candidates for new treatment methods for PD.
    Keywords:  Exosome; Lnc A2M-AS1; Mitophagy; Olfactory Mucosa Mesenchymal Stem Cell; Oxidative Stress; Parkinson’s Disease
    DOI:  https://doi.org/10.1007/s10565-025-10009-7
  10. Biochem Pharmacol. 2025 Mar 19. pii: S0006-2952(25)00140-6. [Epub ahead of print] 116878
    7'-Hydroxyl substituted xanthones from Gentianella acuta revert hepatic steatosis in obese diabetic mice through preserving mitochondrial homeostasis.
    Jian Li, Jiaqi Wu, Qian Chen, Haiyang Yu, Mengyang Liu, Yadong Wang, Yi Zhang, Tao Wang.
      Mitochondrial dysfunction is a key contributor to the development and progression of metabolic dysfunction-associated steatotic liver disease (MASLD). Xanthones, bioactive flavonoids derived from various herbal medicines, are renowned for their anti-inflammatory, antioxidant, and anti-tumor properties. This study aimed to investigate the effects of xanthones isolated from Gentianella acuta on hepatic steatosis and the underlying mechanisms regulating mitochondrial function. We report that a xanthone fraction (400 mg/kg/day) effectively prevented obesity and hepatic steatosis in obese diabetic db/db mice in vivo. In vitro, xanthones inhibited lipid accumulation and mitochondrial dysfunction induced by high glucose (20 mM) and high palmitic acid (200 µM) in HepG2 cells. Mechanistically, norathyriol (NTR), a major in vivo metabolite of Gentianella acuta, inhibited the activity of dynamin-related protein 1 (Drp1), a protein associated with mitochondrial fission, and prevented its translocation from the cytoplasm to the mitochondria by inhibiting the orphan nuclear receptor (Nur77). Additionally, NTR increased the expression of the mitochondrial outer membrane protein FUN14 domain containing 1 (FUNDC1), which stimulated mitophagy to clear damaged or dysfunctional mitochondria under overnutrition conditions. We also discovered that reactive oxygen species (ROS) targeted FUNDC1, leading to mitochondrial damage, but this effect could be reversed by 7'-hydroxyl substituted xanthones. Collectively, 7'-hydroxyl substituted xanthones inhibited mitochondrial fission while promoting mitophagy, ultimately improving mitochondrial and liver function in diabetic hepatic steatosis. The modulation of mitochondrial function by 7'-hydroxyl substituted xanthones presents a novel approach for treating hepatic steatosis, particularly in diabetic conditions.
    Keywords:  FUN14 domain containing 1; Hepatic steatosis; Mitochondrial dysfunction; Nuclear receptor Nur77; Xanthones
    DOI:  https://doi.org/10.1016/j.bcp.2025.116878
  11. Immunol Res. 2025 Mar 19. 73(1): 64
    α-Amanitin aggravates hepatic injury by activating oxidative stress and mitophagy via peroxiredoxin 6 inhibition.
    Zhongfeng Cheng, Kerun Cheng, Yan Tang, Xueqiong Duan, Yangshan Fu, Hongdan Duan, Yong Ye.
      Mushroom poisoning is mainly caused by α-amanitin (α-AMA), and there is currently no effective drug to treat α-AMA poisoning. Therefore, it is particularly important to find early diagnostic markers for α-AMA injury. Hepatic injury models induced by α-AMA were established both in hepatic cells and mice. The cell viability of human normal hepatic cells after α-AMA treatment was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Liver function parameters was assessed by the Enzyme-Linked Immunosorbent Assay (ELISA). Furthermore, oxidative stress was detected by 2',7'-Dichlorofluorescin Diacetate (DCFH-DA) and Dihydroethidium (DHE) staining. Autophagy- and apoptosis-related proteins were assessed by Western blot and immunofluorescence staining. We applied Hematoxylin and Eosin (H&E), Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and Oil Red O (ORO) staining to observe the degree of cell damage and hepatocyte apoptosis. In addition, mitochondrial membrane potential was also determined by JC-1 immunofluorescence staining and flow cytometry. The results showed that α-AMA decreased cell viability in a dose-dependent manner. In addition, the levels of alanine aminotransferase (ALT), aspartate transaminase (AST) and mitochondrial reactive oxygen species (mtROS) were observed to increase in the α-AMA-treated groups, whereas antioxidants superoxide dismutase (SOD) levels were reduced. Moreover, α-AMA promoted hepatocyte mitophagy and apoptosis, which were alleviated by PRDX6 overexpression. Finally, PRDX6 and Parkin were found to accumulate in mitochondria and α-AMA activated mitophagy by silencing PRDX6. Collectively, our results demonstrated that α-AMA activates oxidative stress and mitophagy by inhibiting the expression of PRDX6, leading to hepatic injury. These findings from both in vitro and in vivo models provide insights into the toxicological mechanisms of α-AMA, underscoring the potential of PRDX6 as a therapeutic target for treating α-AMA-induced hepatotoxicity. HIGHLIGHTS: α-AMA leads to ROS accumulation and activates oxidative stress. α-AMA promotes hepatocyte mitophagy and apoptosis. PRDX6 alleviates α-AMA-induced hepatic injury. PRDX6 mediates mitophagy through Parkin.
    Keywords:  Hepatic injury; PRDX6; Parkin; ROS; α-Amanitin
    DOI:  https://doi.org/10.1007/s12026-025-09619-4
  12. Nucleic Acids Res. 2025 Feb 27. pii: gkaf178. [Epub ahead of print]53(5):
    DNA damage response regulator ATR licenses PINK1-mediated mitophagy.
    Christian Marx, Xiaobing Qing, Yamin Gong, Joanna Kirkpatrick, Kanstantsin Siniuk, Galina V Beznoussenko, Gururaj Rao Kidiyoor, Murat Kirtay, Katrin Buder, Philipp Koch, Martin Westermann, Christopher Bruhn, Eric J Brown, Xingzhi Xu, Marco Foiani, Zhao-Qi Wang.
      Defective DNA damage response (DDR) and mitochondrial dysfunction are a major etiology of tissue impairment and aging. Mitochondrial autophagy (mitophagy) is a mitochondrial quality control (MQC) mechanism to selectively eliminate dysfunctional mitochondria. ATR (ataxia-telangiectasia and Rad3-related) is a key DDR regulator playing a pivotal role in DNA replication stress response and genomic stability. Paradoxically, the human Seckel syndrome caused by ATR mutations exhibits premature aging and neuropathies, suggesting a role of ATR in nonreplicating tissues. Here, we report a previously unknown yet direct role of ATR at mitochondria. We find that ATR and PINK1 (PTEN-induced kinase 1) dock at the mitochondrial translocase TOM/TIM complex, where ATR interacts directly with and thereby stabilizes PINK1. ATR deletion silences mitophagy initiation thereby altering oxidative phosphorylation functionality resulting in reactive oxygen species overproduction that attack cytosolic macromolecules, in both cells and brain tissues, prior to nuclear DNA. This study discloses ATR as an integrated component of the PINK1-mediated MQC program to ensure mitochondrial fitness. Together with its DDR function, ATR safeguards mitochondrial and genomic integrity under physiological and genotoxic conditions.
    DOI:  https://doi.org/10.1093/nar/gkaf178
  13. Mol Cell Biochem. 2025 Mar 14.
    ZnT6-mediated Zn2+ redistribution: impact on mitochondrial fission and autophagy in H9c2 cells.
    Erkan Tuncay, Yusuf Olgar, Leila Aryan, Suatnur Şık, Deniz Billur, Belma Turan.
      Cytosolic free Zn2⁺ level ([Zn2⁺]Cyt) is tightly regulated by Zn2⁺ transporters, under both physiological and pathological conditions. At the cellular level, dysregulated free Zn2⁺ levels have been linked to metabolic and cardiovascular diseases, primarily through their association with various Zn2⁺ transporters. However, the role and localization of ZnT6 in cardiomyocytes remain unclear. Previous studies have shown a significant increase in ZnT6 expression in insulin-resistant cardiomyocytes, suggesting a potential link between ZnT6 dysregulation and cardiac cell dysfunction. Therefore, here, we investigated the impact of ZnT6 overexpression (ZnT6-OE) on cellular Zn2⁺ distribution, mitochondrial dynamics, and autophagy-induced apoptosis in H9c2 cardiomyocytes. Using confocal imaging, biochemical assays, and electron microscopy, we demonstrated the mitochondrial localization of ZnT6 and its role in H9c2 cells. Our findings showed that ZnT6 overexpression led to a significant increase in mitochondrial free Zn2⁺ level ([Zn2⁺]Mit) with a significant reduction in [Zn2⁺]Cyt, which seems to be associated with enhanced numbers of mitochondria and mitochondrial fission process. Specifically, the ZnT6-OE cells exhibited increased dynamin-related protein 1 (DRP1) translocation to mitochondria which is an indication of excessive fission activity. We also determined severe mitochondrial dysfunction in ZnT6-OE cells, such as depolarization in mitochondrial membrane potential, production of excessive reactive oxygen species (ROS), reduced ATP levels, and autophagosome accumulation. Furthermore, these impairments were accompanied by elevated apoptotic markers, indicating autophagy-induced apoptosis. Our findings highlight ZnT6 as a critical regulator of mitochondrial dynamics and function in cardiomyocytes, contributing to disruption Zn2⁺ homeostasis by its overexpression, triggering excessive DRP1-mediated mitochondrial fission and leading to mitochondrial dysfunction, oxidative stress, and apoptotic cell death, suggesting an important impact of ZnT6 dysregulation on cardiomyocyte pathophysiology in metabolic disorders.
    Keywords:  Cardiomyocytes; DRP1; Mitochondria; Zinc; ZnT6
    DOI:  https://doi.org/10.1007/s11010-025-05247-6
  14. Ecotoxicol Environ Saf. 2025 Mar 15. pii: S0147-6513(25)00323-9. [Epub ahead of print]293 117987
    Hydrogen sulfide attenuates PM2.5-induced COPD by inhibiting cellular senescence via the Klotho/Parkin-mediated mitophagy signaling pathway.
    Ying Wang, Guoqing Han, Jin Yang, Lixiang Xue, Yahong Chen.
      Fine particulate matter (PM2.5), an atmospheric pollutant, plays a crucial role in mediating the occurrence of chronic obstructive pulmonary disease (COPD). Hydrogen sulfide (H2S) has shown therapeutic potential in countering COPD, but the underlying mechanisms remain elusive. This study aimed to elucidate the potential mechanisms of H2S in inhibiting cellular senescence and combating the progression of COPD. In this study, mouse and cell models were initially established by pretreating with PM, PM2.5, and NaHS. It was showed that increased expressions of p16, p21, and β-gal positive cells, along with elevated inflammatory and oxidative stress markers and reduced antioxidant markers, could be observed in COPD patients as well as in PM2.5-induced cell and mouse models, correlating with decreased endogenous H2S levels. Pre-treatment with NaHS reversed these effects, enhancing Klotho expression, inhibiting IGF-1R, and activating the Parkin- dependent mitophagy pathway, which significantly mitigated airway inflammation and emphysema. Klotho silencing in BEAS-2B cells exacerbated the PM2.5-induced damage and diminished the protective effects of NaHS, confirming the link between Klotho and the downstream Parkin-dependent mitophagy pathway. Our findings suggest that H2S mitigates PM2.5-induced senescence in airway epithelial cells by modulating the Klotho/IGF-1R/Parkin-dependent mitophagy pathway, thereby alleviating airway inflammation and emphysema. This provides a foundation for devising innovative treatment approaches for COPD and mitigating the health effects of atmospheric pollution.
    Keywords:  Cellular senescence; Chronic obstructive pulmonary disease; Hydrogen sulfide; Klotho; Mitophagy; PM2.5
    DOI:  https://doi.org/10.1016/j.ecoenv.2025.117987
  15. Zhongguo Zhen Jiu. 2025 Mar 12. 45(3): 335-344
    [Mechanism of the pretreatment with electroacupuncture of "biaoben acupoint combination" for regulating cardiomyocyte mitochondrial fission in the rats of myocardial ischemia-reperfusion injury].
    Yanlin Zhang, Song Wu, Qianru Guo, Yuntao Yu, Sunyi Wang, Yuqi Wei, Xiaoman Wan, Zhen Lu, Xiaoru He.
       Objective: To observe the effect of electroacupuncture (EA) pretreatment of "biaoben acupoint combination" on cardiomyocyte mitochondrial fission in the rats with myocardial ischemia-reperfusion injury (MIRI) and explore its mechanism.
    Methods: Fifty male SD rats were randomly divided into a sham-operation group, a model group, an EA pretreatment group, an EA pretreatment + Compound C group and an EA pretreatment+ML385 group, 10 rats in each group. In the EA pretreatment, the EA pretreatment + Compound C group and the EA pretreatment+ML385 group, EA was delivered at bilateral "Neiguan" (PC6), "Zusanli" (ST36) and "Guanyuan" (CV4) for 20 min, with continuous wave and 2 Hz of frequency, 1 mA of current, once daily for consecutive 7 days. On day 8, in the EA pretreatment + Compound C group and the EA pretreatment+ML385 group, 30 min before model preparation, the intraperitoneal injection with Compound C (0.3 mg/kg) and ML385 (30 mg/kg) was administered respectively. Except in the sham-operation group, the ligation of the left anterior descending coronary artery was performed to prepare MIRI rat model in the rest groups. In the sham-operation group, the thread was not ligated. After modeling, the content of reactive oxygen species (ROS) in the ischemic area was measured by flow cytometry, superoxide dismutase (SOD) was detected using xanthine oxidase method, and malondialdelyde (MDA) was detected using thiobarbituric acid (TBA) chromatometry. The morphology of myocardial tissue in the ischemic area was observed with HE staining, and the mitochondria ultrastructure of cardiomyocytes observed under transmission electron microscopy. Using immunofluorescence analysis, the positive expression of mitochondrial fission factor (MFF), mitochondrial fission 1 protein antibody (Fis1) and dynamin-related protein 1 (Drp1) was detected; and with immunohistochemical method used, the protein expression of adenosine monophosphate-activated protein kinase (AMPK), nuclear factor E2-associated factor2 (Nrf2) and Drp1 in the ischemic area was detected.
    Results: Compared with the sham-operation group, the content of ROS and MDA in the myocardial tissue of the ischemic area, and the positive expression of MFF, Fis1 and Drp1 increased in the model group (P<0.01); the content of SOD and the protein expression of AMRK and Nrf2 decreased (P<0.01), and the protein expression of Drp1 elevated (P<0.01). Compared with the model group, the content of ROS and MDA in the myocardial tissue of the ischemic area, and the positive expression of MFF, Fis1 and Drp1 were dropped in the EA pretreatment group (P<0.01); the content of SOD and the protein expression of AMRK and Nrf2 rose (P<0.01), and the protein expression of Drp1 declined (P<0.01); and in the EA pretreatment+Compound C group and the EA pretreatment+ML385 group, the positive expression of MFF, Fis1 and Drp1, and the protein expression of Drp1 were all reduced (P<0.01). When compared with the EA pretreatment + Compound C group and the EA pretreatment+ML385 group, the content of ROS and MDA in the myocardial tissue of the ischemic area, and the positive expression of MFF, Fis1 and Drp1 were dropped in the EA pretreatment group (P<0.01); the content of SOD and the protein expression of AMRK and Nrf2 rose (P<0.01, P<0.05), and the protein expression of Drp1 decreased (P<0.05). In comparison with the model group, the EA pretreatment+Compound C group and the EA pretreatment+ML385 group, the cardiac muscle fiber rupture, cell swelling and mitochondrial disorders were obviously alleviated in the EA pretreatment group. The morphological changes were similar among the model group, the EA pretreatment+Compound C group and the EA pretreatment+ML385 group.
    Conclusion: Electroacupuncture pretreatment of "biaoben acupoint combination" attenuates myocardial injury in MIRI rats, probably through promoting the phosphorylation of AMPK and Nrf2, inhibiting the excessive mitochondrial fission induced by Drp1, and reducing mitochondrial dysfunction caused by mitochondrial fragmentation and vacuolation.
    Keywords:  AMPK; Drp1; Nrf2; biaoben acupoint combination; electroacupuncture; mitochondrial fission; myocardial ischemia-reperfusion injury; pretreatment
    DOI:  https://doi.org/10.13703/j.0255-2930.20240317-k0004
  16. Sichuan Da Xue Xue Bao Yi Xue Ban. 2025 Jan 20. 56(1): 74-82
    [Molecular Mechanisms of Huangjing Zanyu Capsule in Treating Oligoasthenospermia: A Study Based on AMPK-Mediated Mitophagy].
    Yuan Gao, Yiyang Guo, Mohan Wu, Yanfei Zheng.
       Objective: To investigate the molecular mechanism of Huangjing Zanyu Capsule (HJZY), a new class-Ⅲ traditional Chinese medicine for the treatment of male infertility developed by Wang Qi, an academician of the Chinese Academy of Engineering, based on AMPK-mediated mitophagy in the treatment of oligoasthenospermia.
    Methods: Acrolein (ACR) was used to treat GC-2spd(ts) mouse spermatocytes to establish a cell model of oligoasthenospermia. The optimal ACR concentration and exposure time for subsequent modeling were determined by CCK8 cell viability assay. After successful modeling, the cells were cultured in complete medium containing different concentrations of HJZY. Then, cell viability was assessed by CCK8 assay after 24 hours, and the subsequent treatment concentration was determined based on the cell viability. After the GC-2spd cells adhered to the wall, they were divided into a normal control (NC) group, a modeling group, and an ACR + HJZY treatment group. The effect of HJZY on mitophagy was observed by confocal fluorescence microscopy. The three groups of cells were transfected with siRNA-NC and siRNA-AMPK, respectively, and divided into six groups, including siRNA-NC + control, siRNA-NC + ACR, siRNA-NC + ACR + HJZY, siRNA-AMPK + control, siRNA-AMPK + ACR, and siRNA-AMPK + ACR + HJZY groups. Western blot was performed to validate the regulatory effect of HJZY on mitophagy-related proteins, such as p-AMPK, LC3B, P62, PINK1, Parkin, TBK1, and ULK1, which were all proteins mediated by AMPK.
    Results: Through the cell viability assay, 34 μmol/L was selected as the the modeling concentration of ACR, and 20 minutes was selected as the modeling time The treatment concentration of HJZY was 160 μmol/L. Confocal fluorescence microscopy showed that HJZY had, to a certain degree, a positive regulatory effect on the mitochondrial membrane potential of damaged spermatogenic cells. The mitochondrial membrane potential of the model group decreased significantly compared with that of the NC group. After exposure to treatment, the cell membrane potential of the ACR + HJZY treatment group increased compared with that of the model group, and the difference was statistically significant (P < 0.05). Western blot results showed that the expression levels of p-AMPK/AMPK and PINK1 proteins in the siRNA-NC + ACR group were significantly lower than those in the siRNA-NC + control group (P < 0.001). The level of Parkin protein in the siRNA-NC + ACR group was lower than that in the siRNA-NC + control group, but the difference was not statistically significant. After the administration of HJZY, the levels of these 3 proteins increased, and those in the siRNA-NC + ACR + HJZY group were higher than those in the siRNA-NC + ACR group (P < 0.001). The expression levels of LC3B, P62, TBK1, and ULK1 proteins in the siRNA-NC + ACR group were higher than those in the siRNA-NC + control group (P < 0.01), and those in the siRNA-NC + ACR + HJZY group were lower than those in the siRNA-NC + ACR group (P < 0.05). After transfection with the gene-silencing siRNA-AMPK, the expression levels of p-AMPK/AMPK, PINK1, and Parkin proteins in the siRNA-AMPK + ACR group were lower than those in the siRNA-AMPK + control group (P < 0.01). After the administration of HJZY, there was no significant difference in the levels of these three proteins between the siRNA-AMPK + ACR + HJZY group and the siRNA-AMPK + ACR group. The expression level of LC3B protein in the siRNA-AMPK + ACR + HJZY group was still lower than that in the siRNA-AMPK + ACR group (P < 0.01). There was no significant difference in the levels of P62, TBK1, and ULK1 proteins between the siRNA-AMPK + ACR + HJZY group and the siRNA-AMPK + ACR group. Compared with the siRNA-NC + control group, the siRNA-AMPK + control group showed significantly decreased expression levels of p-AMPK/AMPK, ULK1, and TBK1 proteins (P < 0.001), decreased expression of PINK1 protein (P < 0.05), and increased expression of P62 protein (P < 0.001). Compared with the siRNA-NC + ACR group, the siRNA-AMPK + ACR group showed decreased expression of TBK1 protein (P < 0.001), decreased expression of LC3B protein (P < 0.01), and decreased expression of ULK1 protein (P < 0.05). The expression levels of PINK1 and Parkin proteins in the siRNA-AMPK + ACR group were lower than those in the siRNA-NC + ACR group, but the difference was not statistically significant. Compared with the siRNA-NC + ACR + HJZY group, the siRNA-AMPK + ACR + HJZY group showed decreased expression of p-AMPK/AMPK, PINK1, and Parkin proteins (P < 0.05), decreased expression of LC3B protein (P < 0.01), and increased expression of P62 protein (P < 0.001). There was no significant difference in the levels of TBK1 and ULK1 proteins between the siRNA-AMPK + ACR + HJZY group and the siRNA-NC + ACR + HJZY group.
    Conclusion: HJZY may exert its therapeutic effect on oligoasthenospermia by regulating AMPK-mediated mitophagy.
    Keywords:  AMPK; Male infertility; Mitophagy; Oligoasthenospermia; Western blot
    DOI:  https://doi.org/10.12182/20250160504
  17. J Assist Reprod Genet. 2025 Mar 17.
    Mitochondrial FIS1 level in cumulus cells correlates with morphological grades of human cleavage-stage embryos.
    Yizhen Sima, Sanbao Shi, Zhunyuan Min, Yuning Chen, Yongning Lu, Hongying Sha, Suying Liu.
       PURPOSE: Advanced-age women have a lower good-quality embryo rate (GQER) compared to young women. However, GQER varies widely within the same age group, suggesting that factors beyond age influence embryo quality. Mitochondria regulate cellular metabolism through dynamic fission and fusion alterations. Specifically, cumulus cell (CC) mitochondria regulate not only the metabolism of CCs but also of adjacent oocytes. This study aims to investigate the relationship between CC mitochondrial dynamics and oocyte developmental potential post-fertilization.
    METHODS: CCs were collected from 183 women aged 25-45 undergoing single sperm intracytoplasmic injection-embryo transfer treatments. Samples were stratified by age into young (< 35) and advanced age (≥ 35) groups. Each group was further subdivided into high and low subgroups based on day 3 GQER. Mitochondrial morphology, dynamics, fission-fusion gene expression, and mitochondrial functions were compared among groups and subgroups.
    RESULTS: Consistent with the literature, data analysis from our laboratory revealed significant variances in GQER among individuals of the same age group. Morphological analysis suggested a negative correlation between GQER and mitochondrial length in CCs (P < 0.0001, r = - 0.38). Live-cell imaging showed that both fission and fusion frequencies of CC mitochondria in the advanced-age group were lower than those in the young group (P = 0.009, P = 0.01). Additionally, within the advanced-age group, CC mitochondria from the low GQER subgroup exhibited lower fission frequency and fission-fusion ratios compared to the high GQER subgroup (P = 0.04, P = 0.01). Consequently, GQER positively correlated with mitochondrial fission-fusion ratio in CCs (P = 0.01, r = 0.44). Notably, there were no significant differences in the expression of mitochondrial fusion-related proteins (OPA1, MFN1, and MFN2) between the advanced-age and young groups or among the subgroups. However, levels of fission proteins, including FIS1 and MFF, were significantly lower in the advanced-age group compared to the young group and in the low GQER subgroup compared to their high GQER counterparts. qPCR results further indicated that fis1 and mff mRNA levels in CCs were positively correlated with GQER (P < 0.0001, r = 0.55; P = 0.0025, r = 0.41). The CCs from the low GQER subgroup exhibit a higher level of mitochondrial dysfunction.
    CONCLUSIONS: Mitochondrial morphology, fission-fusion balance, and fission-fusion gene expression in CCs influence early embryonic development, independent of age. Of these factors, the FIS1 level shows the most robust correlation with GQER.
    Keywords:  Cumulus cells; Maternal age; Mitochondrial dynamics; Preimplantation embryonic development
    DOI:  https://doi.org/10.1007/s10815-025-03431-7
  18. Transl Oncol. 2025 Mar 19. pii: S1936-5233(25)00086-5. [Epub ahead of print]55 102355
    Tubeimoside I induces mitophagy by activating the PINK1/Parkin/Mfn2 signaling pathway in acute myeloid leukemia cells.
    Jing Xu, Fanggang Ren, Jinjuan Wang, Jianbing Liu, Xiaohua Cui, Jianqing Hao, Wanfang Yang, Yaofang Zhang, Dongmin Cao, Li Li, Hongwei Wang.
      Acute myeloid leukemia (AML) is the most prevalent kind of acute leukemia in adults. Despite the availability of new targeted therapies, AML remains connected with a poor prognosis and decreased rate of survival. Tubeimoside I (TBMS1), a critical compound extracted from Bolbostemma paniculatum, has demonstrated potential anticancer effects in lung and colorectal cancers. Nevertheless, the TBMS1 anticancer pathway against AML is still elusive. This study aimed to explore the potential role of TBMS1 in anti-AML and its molecular mechanism. In vitro, TBMS1 treatment suppressed AML cells proliferation, induced apoptosis, and mitochondrial damage, and elevated ROS levels. Network pharmacological analysis suggested, and subsequent studies confirmed, that TBMS1 induced mitophagy in AML cells by modulating the PINK1/Parkin/Mfnh2 signaling pathway, an effect that was effectively reversed following PINK1 knockdown. In vivo, TBMS1 treatment suppressed the proliferation of AML cells after 21 days, improved the survival rates of nude mice, and showed no evident organ toxicity. These evidences suggest that TBMS1 may have significant therapeutic potential in treating AML.
    Keywords:  Acute myeloid leukemia; Mitophagy; PINK1/Parkin/Mfn2 signaling pathway; Tubeimoside I
    DOI:  https://doi.org/10.1016/j.tranon.2025.102355
  19. Transl Pediatr. 2025 Feb 28. 14(2): 171-186
    Mitophagy and immune cell interaction: insights into pathogenesis and potential targets for necrotizing enterocolitis.
    Xinyun Jin, Wenqiang Sun, Yihui Li, Xueping Zhu.
       Background: Neonatal necrotizing enterocolitis (NEC) is a fatal disease in early life characterized by an inflammatory response or even necrosis of the bowel wall. NEC is one of the leading causes of preterm infant mortality. The pathogenesis of NEC is intricate and involves mitochondrial damage to intestinal cells and infiltration of immune cells. However, the specific functions of mitophagy and its association with immune cells in NEC remain unclear. The aim of this study was to explore the pivotal roles of mitophagy and the immune microenvironment in NEC and their potential interactions.
    Methods: Microarray data (GSE46619) associated with NEC were obtained from the Gene Expression Omnibus (GEO) at the National Center for Biotechnology Information (NCBI). Differentially expressed genes (DEGs) were screened by GEO2R. Mitophagy gene data were downloaded from the Pathway Unification database and subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Consequently, mitophagy-related differentially expressed genes (MRDEGs) were obtained. To identify hub MRDEGs that are closely associated with NEC, we used CytoHubba, Molecular Complex Detection (MCODE) and Comparative Toxicogenomics Database (CTD) scores. Cytoscape and miRWalk databases were used to predict the transcription factors (TFs) and target microRNAs (miRNAs) of hub MRDEGs, respectively, and a regulatory network was established. The ImmuCellAI was used to analyze the pattern of immune infiltration, and the Spearman correlation was used to investigate the relationship between the hub MRDEGs and the abundance of infiltrating immune cells. Finally, the expression levels of the hub MRDEGs were verified by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting in NEC animal model.
    Results: A total of 14 up-regulated and 22 down-regulated MRDEGs were identified, these genes exhibited enrichment in mitophagy, and inflammation-related pathways. Furthermore, 13 hub MRDEGs closely related to NEC were identified. The increased presence of immune cells such as neutrophils, M1 macrophages, and activated mast cells were observed while adaptive immune cells including B cells and various T-cell subsets exhibited reduced infiltration. Furthermore, up-regulated MRDEGs were positively correlated with the proinflammatory immune cell infiltration, and the down-regulated MRDEGs were positively correlated with the anti-inflammatory immune cell infiltration. In vivo experiments demonstrated that the expressions of four genes Hif-1a, Acsl4, Pck2, and Aifm1 were consistent with the bioinformatics analysis results.
    Conclusions: The potential interplay of mitophagy and immune cells is crucial in the onset and progression of NEC. This perspective opens the door for deeper investigations into NEC pathogenesis, presenting a possible target for disease intervention.
    Keywords:  Necrotizing enterocolitis (NEC); bioinformatics analysis; immune infiltration; mitophagy
    DOI:  https://doi.org/10.21037/tp-24-441
  20. Food Funct. 2025 Mar 17.
    Dietary alpha-lipoic acid alleviates heat stress by modulating insulin-like signaling to maintain homeostasis in C. elegans.
    Longnong You, Zirui Huang, Wenyuan He, Lizhu Zhang, Haiyang Yu, Yaoyong Zeng, Yan Huang, Shaoxiao Zeng, Lingjun Zheng.
      Prolonged exposure to high temperatures can cause oxidative stress in the body, negatively impacting human health. Alpha-lipoic acid (ALA) is a naturally occurring antioxidant prevalent in both plant and animal foods, exhibiting bioactivity comparable to that of vitamins. Although its roles in antioxidant defense and metabolic regulation have been extensively studied, its potential to mitigate heat stress in organisms is less explored and deserves further study. Our research demonstrates that ALA significantly improves the survival rates of Caenorhabditis elegans under heat stress. ALA achieves this by activating heat shock factor 1 (HSF-1) and promoting mitochondrial fission and mitophagy through the transcription factor HLH-30. These processes help alleviate oxidative damage from heat stress, maintain mitochondrial function, and stabilize cellular energy metabolism. Furthermore, the activation of HSF-1 and enhanced mitophagy by dietary ALA depend on the insulin-like signaling peptide 19 (INS-19), suggesting that ALA may target the insulin-like signaling pathway to combat heat stress and maintain homeostasis. These findings indicate that ALA could serve as a valuable dietary supplement for enhancing heat stress resistance in organisms and may inspire the development of novel food ingredients with protective properties against thermal challenges.
    DOI:  https://doi.org/10.1039/d4fo05301j
  21. J Cell Biol. 2025 May 05. pii: e202408050. [Epub ahead of print]224(5):
    TMBIM-2 orchestrates systemic mitochondrial stress response via facilitating Ca2+ oscillations.
    Jiasheng Li, Jimeng Cui, Xinyu Li, Di Zhu, Zhenhua Chen, Xiahe Huang, Yingchun Wang, Qingfeng Wu, Ye Tian.
      Neuronal mitochondrial function is critical for orchestrating inter-tissue communication essential for overall fitness. Despite its significance, the molecular mechanism underlying the impact of prolonged mitochondrial stresses on neuronal activity and how they orchestrate metabolism and aging remains elusive. Here, we identified the evolutionarily conserved transmembrane protein XBX-6/TMBIM-2 as a key mediator in the neuronal-to-intestinal mitochondrial unfolded protein response (UPRmt). Our investigations reveal that intrinsic neuronal mitochondrial stress triggers spatiotemporal Ca2+ oscillations in a TMBIM-2-dependent manner through the Ca2+ efflux pump MCA-3. Notably, persistent Ca2+ oscillations at synapses of ADF neurons are critical for facilitating serotonin release and the subsequent activation of the neuronal-to-intestinal UPRmt. TMBIM2 expression diminishes with age; however, its overexpression counteracts the age-related decline in aversive learning behavior and extends the lifespan of Caenorhabditis elegans. These findings underscore the intricate integration of chronic neuronal mitochondrial stress into neurotransmission processes via TMBIM-2-dependent Ca2+ equilibrium, driving metabolic adaptation and behavioral changes for the regulation of aging.
    DOI:  https://doi.org/10.1083/jcb.202408050
  22. Sci Rep. 2025 Mar 20. 15(1): 9651
    BMAL1 attenuates intervertebral disc degeneration by activating the SIRT1/PGC-1α pathway: evidence from vitro studies.
    Peiming Sang, Yanyan Ma, Xie Zhang, Binhui Chen, Fan He, Neng Shen, Jiangang Zhao.
      To explore the potential effects and the corresponding mechanisms of brain and muscle arnt-like protein-1 (BMAL1) on the progression of intervertebral disc degeneration (IVDD) in vitro studies. The expression of BMAL1, SIRT1 and PINK1 were evaluated by the method of siRNA/pcDNA in the immortalized nucleus pulposus (NP) cells. The expression of SIRT1/PGC-1α pathway was assessed. The characteristics of NP cell, containing the activity and density, the level of apoptosis, inflammatory response, reactive oxygen species (ROS), senescence, and mitophagy were evaluated. The overexpression of BMAL1 was achieved with the pcDNA3.1, the expression of SIRT1 and PGC-1α were increased, the inflammatory response, the ROS, the level of apoptosis and senescence were decreased, however, the level of mitophagy, the activity and density of NP cell were enhanced. The BMAL1 inhibites the progression of IVDD by activating the SIRT1/PGC-1α pathway in the vitro studies.
    Keywords:  BMAL1; Intervertebral disc degeneration (IVDD); Mitophagy; SIRT1/PGC-1α
    DOI:  https://doi.org/10.1038/s41598-025-94029-7
  23. Int Immunopharmacol. 2025 Mar 18. pii: S1567-5769(25)00459-X. [Epub ahead of print]153 114469
    N-acetylserotonin derivative ameliorates hypoxic-ischemic brain damage by promoting PINK1/Parkin-dependent mitophagy to inhibit NLRP3 inflammasome-induced pyroptosis.
    Fang Fang, Jiaxin Tang, Jiaqing Geng, Chengzhi Fang, Binghong Zhang.
      Neonatal hypoxic-ischemic brain damage is the main cause of hypoxic-ischemic encephalopathy and cerebral palsy, whose clinical treatment is still limited to therapeutic hypothermia with limited efficacy. N-[2-(5-hydroxy-1H-indol-3-yl) ethyl]-2-oxopiperidine-3-carboxamide (HIOC), a derivative of N-acetylserotonin, has shown neuroprotective properties. This study was conducted to evaluate the neuroprotective and molecular mechanisms of HIOC. We established an in vitro model using Oxygen-glucose deprivation/reoxygenation (OGD/R) in HT22 cells, alongside an in vivo model via the modified Rice-Vannucci method. The results showed that HIOC reduced OGD/R-induced HT22 cell pyroptosis and inhibited NOD-like receptor pyrin domain- containing protein 3 (NLRP3) inflammasome activation. With the addition of the mitophagy inhibitor 3-MA, we demonstrated that HIOC promoted PTEN-induced putative kinase 1 (PINK1)/Parkin-mediated mitophagy to reduce HT22 cell pyroptosis. Mechanistically, HIOC stimulated mitophagy to remove damaged mitochondria. The clearance of injured mitochondria reduced reactive oxygen species generation, which consequently inhibited NLRP3 inflammasome expression. In vivo, HIOC remarkably lessened cerebral blood flow, infarct volume, neuronal injury by activating mitophagy. HIOC activated mitophagy to produce antipyroptosis effects. Together, our finding demonstrated that HIOC improves brain injury by promoting PINK1/Parkin-dependent mitophagy to inhibit NLRP3 inflammasome activation and pyroptosis, suggesting its potential for hypoxic-ischemic brain damage treatment.
    Keywords:  Hypoxic-ischemic brain damage (HIBD); Mitophagy; N-[2-(5-hydroxy-1H-indol-3-yl) ethyl]-2-oxopiperidine-3-carboxamide (HIOC); N-acetylserotonin derivative; Pyroptosis
    DOI:  https://doi.org/10.1016/j.intimp.2025.114469
  24. Mol Neurobiol. 2025 Mar 17.
    Mito-Apocynin Protects Against Kainic Acid-Induced Excitotoxicity by Ameliorating Mitochondrial Impairment.
    Miaomiao Lin, Huanchen Wu, Xiaorui Wan, Na Liu, Yiyue Jiang, Yichao Sheng, Jing Wang, Haidong Xu, Jie Xue, Zhenghong Qin, Yan Wang.
      Neurodegenerative diseases represent significant global health challenges, with rising incidence rates. A substantial body of evidence indicates that excitotoxicity may be a critical target in the context of these diseases. However, effective pharmacological interventions aimed at mitigating excitotoxicity remain elusive. This study aimed to elucidate the neuroprotective effects and mechanisms of the mitochondrion-targeted NOX inhibitor, mito-apocynin, in the context of kainic acid (KA)-induced excitotoxicity. Our findings demonstrate that KA disrupts mitochondrial morphology, leading to impaired energy metabolism and mitochondrial dysfunction. Western blotting experiments revealed that KA compromises mitochondrial quality control. Additionally, Nissl staining and CCK8 assays indicated that mito-apocynin (administered at 75 μg/kg in vivo and 1 μM in vitro) significantly reduced neuronal death resulting from KA-induced excitotoxic damage in both in vivo and in vitro models. Furthermore, mito-apocynin improved neurobehavioral deficits induced by KA and mitigated mitochondrial dysfunction observed in vitro. Notably, mito-apocynin significantly reversed the KA-induced increase in NOX4 levels within the striatal mitochondria, reduced the ratio of phosphorylated DRP1 (Ser616) to total DRP1, and enhanced the expression of PGC-1α, PINK1, and Parkin proteins throughout the total striatum. In summary, mito-apocynin alleviates oxidative stress, preserves normal mitochondrial function and energy metabolism, and promotes mitochondrial quality control by modulating NOX expression in mitochondria, thereby reducing KA-induced excitotoxic damage.
    Keywords:  Excitotoxicity; KA; Mito-apocynin; Mitochondrial dysfunction; NADPH oxidase
    DOI:  https://doi.org/10.1007/s12035-025-04827-3
  25. Am J Physiol Cell Physiol. 2025 Mar 19.
    Umbilical cord mesenchymal stem cells-derived extracellular vesicles improve excessive autophagy of granulosa cells through METTL3.
    Weiqin Zhou, Ju Zhang, Xuanping Lu, Ziwei Zhao, Yujing Weng, Chunrong Zhu.
      Objective: Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder impacting women's fertility. We assessed the effect of umbilical cord mesenchymal stem cell-derived extracellular vesicles (UC-MSC-EVs) on PTEN-induced kinase 1 (PINK1)/Parkin-mediated excessive autophagy of ovarian granulosa cells (GCs) through methyltransferase-like 3 (METTL3). Methods: Human ovarian GC line KGN was cultured and treated with dehydroepiandrosterone (DHEA) and UC-MSC-EVs. Cell apoptosis and viability, autophagy-related protein levels, adenosine triphosphate (ATP) and mitochondrial membrane potential (MMP) level, and microtubule-associated protein 1 light chain 3 beta (LC3B) and translocase of outer mitochondrial membrane 20 (TOMM20) co-localization were assessed by flow cytometry, CCK-8, western blot, kit, and immunofluorescence. PINK1 N6-methyladenosine (m6A) modification, METTL3 levels, and PINK1 mRNA stability were determined by Me-RIP, RT-qPCR and western blot. The PCOS mouse model was established and treated with UC-MSC-EVs. Serum hormone and ovarian tissue autophagy-related protein levels were determined by ELISA. Results: DHEA decreased KGN cell viability and p62 level, increased PINK1, Parkin, LC3BII/I and Beclin-1 protein levels, ATP content, MMP level, TOMM20+LC3B+ cell number and apoptosis, which were partly abrogated by UC-MSC-EVs treatment. PINK1 had m6A modification sites. METTL3 was a PINK1 m6A-modified Writer protein. After DHEA treatment, KGN cells showed elevated METTL3 and PINK1 m6A modification levels and mRNA stability, while UC-MSC-EV treatment caused the opposite results. METTL3 overexpression partly averted UC-MSC-EVs-improved PINK1/Parkin-mediated mitophagy. UC-MSC-EVs curbed PINK1/Parkin-mediated excessive autophagy through METTL3 and improved ovarian function in PCOS mice. Conclusions: UC-MSC-EVs suppressed PINK1/Parkin-mediated mitophagy of ovarian GCs through METTL3, thereby improving PCOS.
    Keywords:  Methyltransferase-like 3; Mitophagy; Ovarian granulosa cells; PINK1/Parkin; Umbilical cord mesenchymal stem cell-derived extracellular vesicles
    DOI:  https://doi.org/10.1152/ajpcell.00785.2024
  26. Vet Res Forum. 2025 ;16(1): 27-33
    Protective effects of olive oil against cardiac aging through mitophagy and apoptosis.
    Siamak Shahidi, Khadijeh Ramezani-Aliakbari, Abdolrahman Sarihi, Ali Heshmati, Elham Shiri, Shiva Nosrati, Sayed Payam Hashemi, Mitra Bahrami, Fatemeh Ramezani-Aliakbari.
      Cardiac mitochondrial dysfunction is an important feature of aged heart. However, there is still no potent agent to ameliorate cardiac function abnormalities in aged hosts. Olive oil (OLO), containing monounsaturated fatty acids, has diverse protective effects on the cardiovascular system, including anti-diabetic, anti-inflammatory, and anti-hypertensive effects. We evaluated the beneficial impacts of OLO against aging-related cardiac dysfunction. Wistar rats were randomly allotted into three groups with eight rats, including control, aged rats receiving D-galactose (D-GAL), and aged rats administrated with D-galactose plus OLO (D-GAL + OLO). Aged animals were received D-GAL at a dose of 150.00 mg kg-1 daily through intra-peritoneal injection for aging induction. The animals in D-GAL + OLO group were co-administrated with oral OLO at a dose of 1.00 mL kg-1 by gavage feeding daily. The administration term was eight weeks. A histological examination of heart tissue was performed. The heart tissues were also harvested to assay the oxidative stress and molecular parameters. The aged animals showed cardiac hypertrophy, increased malondialdehyde level and Bax expression, and reduced mitofusin 2, phosphatase and tensin homologue-induced putative kinase 1, dynamin-related protein 1, and Bcl2 expressions in comparison with the control animals. The OLO treatment ameliorated all these parameters. Overall, OLO could improve cardiac aging through reducing oxidative stress, enhancing genes mediated mitophagy, and improving genes mediated apoptosis in the heart.
    Keywords:  Aging; Apoptosis; Mitophagy; Olive oil; Oxidative stress
    DOI:  https://doi.org/10.30466/vrf.2024.2030624.4304
  27. Free Radic Biol Med. 2025 Mar 14. pii: S0891-5849(25)00172-8. [Epub ahead of print]232 353-366
    Kirenol alleviates cerebral ischemia-reperfusion injury by reducing oxidative stress and ameliorating mitochondrial dysfunction via activating the CK2/AKT pathway.
    Yuqin Zhang, Yonghua Ye, Yi Feng, Xuezhen Li, Lingxuan Chen, Xiaoxue Zou, Guohong Yan, Yaping Chen, Lihong Nan, Wei Xu, Lixia Chen, Hua Li.
      Ischemic stroke represents a predominant cause of morbidity and mortality globally, resulting from abrupt vascular occlusion or rupture, which precipitates considerable neuronal damage. This study aims to shed more light on the specific neuroprotective mechanisms of Kirenol, a bioactive diterpene derived from traditional herbal medicine, with a particular focus on its regulation of mitochondrial dynamics via the CK2/AKT signalling pathway and its impact on the mitochondrial fusion protein Optic atrophy 1 (Opa1). The effects of Kirenol on neuronal viability, mitochondrial function, and pertinent signalling pathways were evaluated by employing a middle cerebral artery occlusion (MCAO) model in rats and subjecting HT22 neuronal cells to oxidative stress. Treatment with Kirenol significantly improved neurological outcomes, augmented Opa1 expression, and restored apoptotic-related protein markers, antioxidative factors, mitochondrial membrane potential, and adenosine triphosphate (ATP) levels (P < 0.01). Mechanistically, Kirenol elevated CK2 levels and phosphorylated AKT while inhibiting CK2/AKT signalling attenuated Kirenol's protective effects on Opa1 expression. Furthermore, silencing Opa1 using siRNA diminished the neuroprotective effects of Kirenol on oxidative stress and apoptosis-related markers, underscoring the critical role of Opa1. In vitro assessments demonstrated that Kirenol effectively mitigated oxidative stress-induced neuronal damage, restoring cell morphology and viability. Kirenol exhibited dose-dependent neuroprotective effects in the MCAO model (P < 0.01). These findings elucidate the neuroprotective role of Kirenol in ischemic stroke through Opa1-mediated mitochondrial fusion and highlight the CK2/AKT pathway as a promising therapeutic target.
    Keywords:  CK2/AKT signalling; Ischemic stroke; Kirenol; Mitochondrial dynamics; Neuroprotection; Opa1
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.03.022
  28. Cell Biol Int. 2025 Mar 18.
    Piwei Peiyuan Prescription Attenuates the Progression of Chronic Atrophic Gastritis by Eliciting MAPK10-Mediated Mitochondrial Autophagy.
    Yi Zhang, Ying Wu, Bei Pei, Qin Sun, Cheng Zhang, Qi Yang, Yueping Jin, Jing Wu, Xuejun Li.
      Piwei Peiyuan (PWPY) prescription is a traditional Chinese medicine prescription and has been efficiently used in the clinics to treat chronic atrophic gastritis (CAG) for many years. However, the mechanism of action underlying PWPY for treating CAG remains elusive. A CAG rat animal and cell model was constructed in this study to explore the action mechanism of PWPY prescription in treating CAG. Here we show that PWPY attenuates the progression of CAG by eliciting MAPK10-mediated mitochondrial autophagy. Experimental model of CAG was introduced using N-methyl-n'-nitro-n-nitroguanidine (MNNG). Our histological analyses reveal that MNNG-induced CAG in rat undergoes classical morphological alterations judged by immunohistochemistry and serum level of PGⅠ, PGⅡ, and G17. Importantly, PWPY treatment prevents the progression of MNNG-induced CAG judged by serum level of PGⅠ, PGⅡ, and G17. Interestingly, PWPY treatment inhibits MAPK10 activity judged by biochemical assays and promotes mitochondrial autophagy judged by electron microscopic analyses. Thus, we conclude that PWPY attenuates the progression of MNNG-induced CAG and prevents precancerous lesions by harnessing MAPK10-elicited mitochondrial autophagy. The MNNG-induced experimental CAG model provides a robust platform for further delineating therapeutic targets underlying PWPY regimen.
    Keywords:  MAPK10; Piwei Peiyuan prescription; chronic atrophic gastritis; mitochondrial autophagy
    DOI:  https://doi.org/10.1002/cbin.70016
  29. Free Radic Biol Med. 2025 Mar 17. pii: S0891-5849(25)00173-X. [Epub ahead of print]232 367-381
    EPIC-1042 alleviates cerebral ischemic/reperfusion injury through TAX1BP1-induced mitophagy.
    Jiasheng Ju, Chunchao Cheng, Longtao Cui, Biao Hong, Qi Zhan, Qixue Wang, Xiaoteng Cui, Dongyuan Su, Yanping Huang, Chunsheng Kang.
      Post ischemia-reperfusion (I/R) injury, an upregulation in Polymerase I and transcript release factor (PTRF) expression is observed. PTRF is implicated in the regulation of various cellular processes within neuronal cells, thereby exacerbating the deleterious effects of I/R injury. EPIC-1042 is a small molecule pharmacological agent that exhibits specificity in binding to PTRF. Therefore, this study aimed to explore whether EPIC-1042 could be used as a treatment for I/R injury. To achieve this goal, we observed brain injury in mice following EPIC-1042 pre-administration, and then transitioned to therapeutic administration. After observing the pre-protective and therapeutic effects of the drug, proteomic analysis revealed that the expression of TAX1BP1 continued to decline in a time-dependent manner, while EPIC-1042 was able to inhibit this decline. However, the function of TAX1BP1 in ischemic stroke is not yet fully understood. Subsequent experiments confirmed that the addition of EPIC-1042 resulted in an enhancement of mitophagy. Silencing the expression of TAX1BP1 abrogated the drug's effects, indicating that EPIC-1042 exerts a protective function by promoting mitophagy via TAX1BP1 mediation. We further investigated the synergistic effects of EPIC-1042 and edaravone by administering the two drugs in combination, observing an enhanced therapeutic efficacy compared to the administration of each drug alone. Subsequently, we optimized the administration protocol for the two drugs by utilizing liposome encapsulation for both drugs. This approach enabled us to achieve significant therapeutic outcomes while reducing both the dosage and frequency of administration, thereby demonstrating the potential for clinical translation of EPIC-1042.
    Keywords:  Edaravone; Ischemia/reperfusion injury; Liposomes; Mitophagy; Reactive oxygen species
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.03.023
  30. Bioact Mater. 2025 Jun;48 564-582
    Single-cell RNA sequencing-guided engineering of mitochondrial therapies for intervertebral disc degeneration by regulating mtDNA/SPARC-STING signaling.
    Guoyu Yang, Chenpeng Dong, Zhaoxi Wu, Peng Wu, Cao Yang, Lanlan Li, Jianxiang Zhang, Xinghuo Wu.
      Intervertebral disc degeneration (IVDD) is a leading cause of discogenic low back pain, contributing significantly to global disability and economic burden. Current treatments provide only short-term pain relief without addressing the underlying pathogenesis. Herein we report engineering of biomimetic therapies for IVDD guided by single-cell RNA-sequencing data from human nucleus pulposus tissues, along with validation using animal models. In-depth analyses revealed the critical role of mitochondrial dysfunction in fibrotic phenotype polarization of nucleus pulposus cells (NPCs) during IVDD progression. Consequently, mitochondrial transplantation was proposed as a novel therapeutic strategy. Transplanted exogeneous mitochondria improved mitochondrial quality control in NPCs under pathological conditions, following endocytosis, separate distribution or fusion with endogenous mitochondria, and transfer to neighboring cells by tunneling nanotubes. Correspondingly, intradiscal mitochondrial transplantation significantly delayed puncture-induced IVDD progression in rats, demonstrating efficacy in maintaining mitochondrial homeostasis and alleviating pathological abnormalities. Furthermore, exogenous mitochondria were engineered with a bioactive, mitochondrial-targeting macromolecule to impart anti-oxidative and anti-inflammatory activities. The obtained multi-bioactive biotherapy exhibited significantly enhanced benefits in IVDD treatment, in terms of reversing IVDD progression and restoring structural integrity through the mtDNA/SPARC-STING signaling pathways. Overall, our engineered mitochondrial therapies hold great promise for treating IVDD and other musculoskeletal diseases linked to mitochondrial dysfunction.
    Keywords:  Biotherapy; Engineered mitochondria; Inflammation; Intervertebral disc degeneration; STING signaling
    DOI:  https://doi.org/10.1016/j.bioactmat.2025.02.036
  31. J Cell Sci. 2025 Mar 19. pii: jcs.263576. [Epub ahead of print]
    Definition of the human mitochondrial TOM interactome reveals TRABD as new interacting protein.
    Metin Özdemir, Silke Oeljeklaus, Schendzielorz Alexander, Marcel Morgenstern, Anusha Valpadashi, Roya Yousefi, Bettina Warscheid, Sven Dennerlein.
      The mitochondrial proteome arises from dual genetic origin. Nuclear-encoded proteins need to be transported across or inserted into two distinguished membranes, and the TOM complex represents the main translocase in the outer mitochondrial membrane. Its composition and regulations have been extensively investigated within yeast cells. However, we have little knowledge of the TOM complex composition within human cells. Here, we have defined the TOM interactome in a comprehensive manner using biochemical approaches to isolate the TOM complex in combination with quantitative mass spectrometry analyses. Within these studies, we defined the pleiotropic nature of the human TOM complex, including new interactors, such as TRABD. Our studies provide a framework to understand the various biogenesis pathways that merge at the TOM complex within human cells.
    Keywords:  Mitochondria; Mitochondrial Biogenesis; Mitochondrial protein import; Mitochondrial quality control; Protein transport; TOM complex
    DOI:  https://doi.org/10.1242/jcs.263576
  32. Cardiovasc Diagn Ther. 2025 Feb 28. 15(1): 207-232
    Advances in Chinese herbal medicine in modulating mitochondria to treat myocardial ischemia-reperfusion injury: a narrative review.
    Yushi Tian, Xiaoyang Hu, Tingyu Zhang, Bojia Li, Qiang Fu, Ji Li.
       Background and Objective: The urgent need to identify pathways that can mitigate myocardial ischemia-reperfusion injury (MIRI) has become a central focus in cardiovascular treatment. Chinese herbal medicine (CHM), renowned for its multi-component, multi-channel, and multi-target therapeutic properties, holds significant promise in the management of MIRI. Mitochondria, as pivotal players in MIRI, have been shown to be effectively modulated by CHM through various mechanisms. The objective of this narrative review is to underscore the critical role of mitochondria in MIRI and to provide an up-to-date overview of the latest research advancements in utilizing CHM to treat MIRI by targeting mitochondrial morphology and function.
    Methods: The PubMed and the China National Knowledge Infrastructure (CNKI) databases were searched using keywords related to MIRI. Relevant English-language articles published from January 2019 to July 2024 were included in this narrative review.
    Key Content and Findings: Mitochondria are intimately linked to MIRI. The mechanisms involve the regulation of mitochondrial biogenesis and energy metabolism, the functionality of the mitochondrial respiratory chain, resistance to oxidative stress-induced damage, the maintenance of mitochondrial homeostasis, the modulation of calcium ion homeostasis, the preservation of mitochondrial membrane potential, the opening of adenosine triphosphate (ATP)-sensitive potassium channels, and the effective control over the opening of the mitochondrial permeability transition pore, all of which contribute to the balance between autophagy and apoptosis in cardiomyocytes. Various effective monomers of CHM, extracts of CHM, compounds, and proprietary Chinese medicine have demonstrated promising therapeutic potential in basic research, among them, tonic and blood-activating CHMs account for the largest proportion.
    Conclusions: The prospect of CHM targeting mitochondria for the treatment of MIRI is promising, yet it necessitates overcoming challenges such as low bioavailability and inadequate mechanistic research. By integrating traditional Chinese medicine theories with modern scientific technologies, it is imperative to delve deeper into and optimize the pharmacodynamics, pharmacokinetics, and clinical applications of these herbs.
    Keywords:  Mitochondria; extracts of Chinese herbal medicine (extracts of CHM); monomers of Chinese herbal medicine (monomers of CHM); myocardial ischemia-reperfusion injury (MIRI)
    DOI:  https://doi.org/10.21037/cdt-24-346
  33. Mol Cell Biochem. 2025 Mar 17.
    The role of mitochondrial dysfunction in the protective effect of ginger derived extracellular vesicles on hepatic stellate cells against cytotoxicity.
    Jing Yang, Yujie Yang, Xiqian Zhang, Yuan Qin, Toshihiro Sato, Shuyun Qing, Yirong Wang, Xiang Ye, Min Xu, Ying Liu, Qin He, Yaxian Zheng.
      Previous studies have shown that ginger-derived extracellular vesicles (Gin-EVs) can alleviate alcohol-induced liver injury. It remained unknown and needs to be further verified that whether the vesicles has therapeutic potential to alleviate the progression of liver fibrosis. Moreover, the relevant mechanisms need to be further studied. Herein, we provide evidence that Gin-EVs effectively interact with human hepatic stellate cells (LX-2), offering protection against carbon tetrachloride (CCL4) or lipopolysaccharides (LPS)-induced liver fibrosis. The treatment with Gin-EVs was observed to mitigate fibrosis and enhance cell viability in LX-2 cells exposed to CCL4 or LPS. Mechanistically, Gin-EVs counteracted mitochondrial dysfunction by restoring mitochondrial dynamics imbalance characterized by enhanced fusion and reduced fission events while promoting mitochondrial biogenesis, thereby potentially preventing fibrotic processes in LX-2 cells. Collectively, the findings highlight the direct cytoprotective effects of Gin-EVs on LX-2 cells and suggest their promising role as a therapeutic option for hepatic fibrosis.
    Keywords:  Gin-EVs; LX-2; Mitochondrial fission; Mitochondrial fusion
    DOI:  https://doi.org/10.1007/s11010-025-05232-z
  34. BMC Genomics. 2025 Mar 19. 26(1): 272
    Short-term heat exposure affects thermogenesis and mitophagy in goat brown adipocytes.
    Yulong Song, Die Li, Duo Su, Tingting Jiang, Longrui Li, Siyuan Zhan, Tao Zhong, Jiazhong Guo, Jiaxue Cao, Li Li, Hongping Zhang, Linjie Wang.
       BACKGROUND: Brown adipose tissue (BAT) has a significant impact in newborn goats on maintaining body temperature through non-shivering thermogenesis in response to cold exposure. However, the roles of heat treatment on BAT thermogenesis are still limited.
    RESULTS: This study focused on the effects of short-term heat exposure on goat brown adipocytes. We found that the content of mitochondria and the proteins of UCP1 and PGC1α were increased after 12 h of heat exposure. Additionally, the triglyceride (TG) content was significantly decreased after 1, 2, 6 h of heat exposure. Furthermore, RNA-seq analysis of brown adipocytes after 12 h of heat exposure identified 1091 differentially expressed genes (DEGs). The KEGG enrichment analysis were mainly enriched in thermogenesis, fatty acid metabolism and mitophagy. In addition, we found that the amount of mitophagosomes and expression levels of mitophagy-related protein (LC3BII/LC3BI, BNIP3, and BECN) were elevated after 12 h of heat treatment.
    CONCLUSION: These findings collectively indicate that heat exposure enhances the thermogenic capacity and mitophagy level of goat brown adipocytes. Our study provides evidence that heat exposure facilitates adaptive thermogenesis in goat brown adipocytes.
    Keywords:  Brown adipocytes; Goat; Heat exposure; Lipogenesis; Mitophagy; Thermogenesis
    DOI:  https://doi.org/10.1186/s12864-025-11467-3
  35. Mol Cell. 2025 Mar 14. pii: S1097-2765(25)00183-2. [Epub ahead of print]
    β-hydroxybutyrate facilitates mitochondrial-derived vesicle biogenesis and improves mitochondrial functions.
    Min Tang, Yingfeng Tu, Yanqiu Gong, Qin Yang, Jinrui Wang, Zhenzhen Zhang, Junhong Qin, Shenghui Niu, Jiamin Yi, Zehua Shang, Hongyu Chen, Yingying Tang, Qian Huang, Yanmei Liu, Daniel D Billadeau, Xingguo Liu, Lunzhi Dai, Da Jia.
      Mitochondrial dynamics and metabolites reciprocally influence each other. Mitochondrial-derived vesicles (MDVs) transport damaged mitochondrial components to lysosomes or the extracellular space. While many metabolites are known to modulate mitochondrial dynamics, it is largely unclear whether they are involved in MDV generation. Here, we discovered that the major component of ketone body, β-hydroxybutyrate (BHB), improved mitochondrial functions by facilitating the biogenesis of MDVs. Mechanistically, BHB drove specific lysine β-hydroxybutyrylation (Kbhb) of sorting nexin-9 (SNX9), a key regulator of MDV biogenesis. Kbhb increased SNX9 interaction with inner mitochondrial membrane (IMM)/matrix proteins and promoted the formation of IMM/matrix MDVs. SNX9 Kbhb was not only critical for maintaining mitochondrial homeostasis in cells but also protected mice from alcohol-induced liver injury. Altogether, our research uncovers the fact that metabolites influence the formation of MDVs by directly engaging in post-translational modifications of key protein machineries and establishes a framework for understanding how metabolites regulate mitochondrial functions.
    Keywords:  MDV; PTMs; metabolite; mitochondrial functions
    DOI:  https://doi.org/10.1016/j.molcel.2025.02.022
  36. Life Sci. 2025 Mar 19. pii: S0024-3205(25)00200-0. [Epub ahead of print] 123566
    SIRT2 alleviates pre-eclampsia via prompting mitochondrial biogenesis and function.
    Ruirui Hou, Xiaoyan Yang, Qi Xu, Can Shen, Longbiao Zhang, Binbin Huang, Yuanyuan Yang, Zhen Yu, Zongzhi Yin, Yunxia Cao, Xiaoqing Peng.
       AIMS: Pre-eclampsia (PE) globally impacts 2-8 % of pregnancies and is a leading cause of neonatal and maternal morbidity and mortality. Recent studies found the association between mitochondrial dysfunction and deficient motility of trophoblast cells in PE. Lower expressions of mitochondrial biogenesis related proteins (i.e. PGC1α, NRF1 and TFAM) and SIRT2 have recently been found. However, the regulative role of SIRT2 on the protein expression and acetylation of PGC1α and its influence on trophoblast migration and invasion in PE have never been investigated.
    MATERIALS AND METHODS: The alterations in protein expressions of SIRT2 and PGC1α/NRF1/TFAM were examined in the placenta from pregnant women with and without PE. The role of SIRT2 on mitochondrial biogenesis and mitochondrial morphology/function was explored in trophoblast cell, and the findings were confirmed in the LPS-induced PE mice with adeno-associated virus transfection system.
    KEY FINDINGS: We demonstrated that the lower protein expressions of SIRT2 and PGC1α/NRF1/TFAM and mitochondrial dysfunction in PE patients and mice compared with counterparts. Moreover, overexpression of SIRT2 enhanced the protein expressions of PGC1α and deacetylated PGC1α, and further facilitating mitochondrial function and motility of trophoblast cells. In vivo, overexpression of SIRT2 attenuated the PE-like symptoms and adverse pregnancy outcomes in LPS-induced PE mice via promoting mitochondrial biogenesis.
    SIGNIFICANCE: Above findings suggest that SIRT2 might be a potential interventive target against PE via improving deacetylation of PGC1α and mitochondrial biogenesis and function.
    Keywords:  Mitochondria/pathology; Mitochondrial dynamics; Pre-eclampsia; Sirtuin 2
    DOI:  https://doi.org/10.1016/j.lfs.2025.123566
  37. Biochem Pharmacol. 2025 Mar 18. pii: S0006-2952(25)00143-1. [Epub ahead of print] 116881
    Ivabradine ameliorates doxorubicin-induced cardiotoxicity through improving mitochondrial function and cardiac calcium homeostasis.
    Adivitch Sripusanapan, Chotrawee Piriyakulthorn, Nattayaporn Apaijai, Siriporn C Chattipakorn, Nipon Chattipakorn.
      Doxorubicin (Dox) is a potent anthracycline chemotherapeutic agent. However, its efficacy is limited by its cardiotoxicity, which is driven by excessive oxidative stress, calcium overload, and mitochondrial dysfunction. These mechanisms ultimately result in cardiomyocyte death and cardiac dysfunction. Ivabradine, a hyperpolarization-activated cyclic nucleotide-gated channel blocker, has cardioprotective effects in heart failure and coronary artery disease. However, its potential for mitigating doxorubicin-induced cardiotoxicity (DIC) has not been explored. This study hypothesized that ivabradine reduces cardiac dysfunction in DIC by improving mitochondrial function, restoring calcium homeostasis, and attenuating apoptosis. For in vitro experiments, H9C2 cells were divided into four groups: control, ivabradine (3 μM), Dox (10 μM), and ivabradine co-treated with Dox, with treatments lasting 24 h. Cell viability and mitochondrial function were assessed. For in vivo experiments, male rats (n = 6 per group) were divided into control, ivabradine (10 mg/kg/day, p.o., 30 days), Dox (3 mg/kg, 6 doses), and ivabradine co-treated with Dox. Cardiac function, mitochondrial function, calcium regulatory proteins, and apoptosis were analyzed. Dox reduced cell viability, increased oxidative stress, and decreased ATP levels in vitro. Co-treatment with ivabradine improved cell viability and reduced oxidative stress but did not restore ATP levels. In rats, Dox impaired mitochondrial function, disrupted mitochondrial dynamics and mitophagy, and altered calcium homeostasis, resulting in cardiomyocyte apoptosis and left ventricular dysfunction. Ivabradine co-treatment attenuated these pathological changes and preserved cardiac function. These findings suggest the potential of ivabradine for cardioprotection against DIC.
    Keywords:  Cardiotoxicity; Doxorubicin; Intracellular calcium; Ivabradine; Mitochondria
    DOI:  https://doi.org/10.1016/j.bcp.2025.116881
  38. Eur J Pharmacol. 2025 Mar 18. pii: S0014-2999(25)00266-3. [Epub ahead of print] 177512
    Steroid Constituents of Solidago canadensis alleviate LPS-induced inflammation via AMPK regulated Mitophagy/NLRP3 and NF-κB pathway.
    Wenying Yin, Han Xue, Yongqi Zhang, Rongxian Li, Mengjia Liu, Hongwei Yue, Di Ge, Na Liu.
      Inflammation is a major risk factor for a variety of human diseases, such as sepsis, Inflammatory Bowel Disease (IBD) and also major cardiovascular disease including atherosclerosis. Solidago canadensis is used as a traditional medicine to treat inflammation-related diseases. However, the component with anti-inflammatory activity of Solidago canadensis is not clear. In this study, we aimed to search for new bioactive steroids from Solidago canadensis and investigate their anti-inflammatory activity both in vitro and in vivo. Lipopolysaccharides (LPS)-stimulated RAW264.7 cells, mouse bone marrow-derived macrophages (BMDMs) and peripheral blood mononuclear cells (PBMCs) were used to induce an inflammation response. Compound 10 outperformed other compounds for superior anti-inflammatory activity and significant inhibition of NLR family, pyrin domain containing 3 (NLRP3) inflammasome activation. Mechanistically, compound 10 induced mitophagy by activating AMP-activated protein kinas (AMPK) to suppress NLRP3 inflammasome activation. Inhibiting AMPK by inhibitor BML-275 significantly attenuated compound 10 induced mitophagy and subsequent the NLRP3 inflammasome. Besides, the NF-κB activation, key step in NLRP3 inflammasome priming, was also suppressed by compound 10 via activation of AMPK. In addition, the in vivo experiments showed that compound 10 could alleviate LPS-induced inflammatory and dextran sulfate sodium salt -induced colitis in C57BL/6 mice. Collectively, the present study, for the first time, shows that the steroids compound 10 exhibited anti-inflammatory effect via AMPK/mitophagy/NLRP3 as well as AMPK/NF-κB/NLRP3 signaling pathway, which strongly suggests the therapeutic potential of compound 10 in various inflammatory diseases.
    Keywords:  AMPK; Mitophagy; NLRP3 inflammasome; RAW264.7 cells; Solidago canadensis
    DOI:  https://doi.org/10.1016/j.ejphar.2025.177512
  39. J Cell Sci. 2025 Mar 17. pii: jcs.263661. [Epub ahead of print]
    The Mia40 substrate Mix17 exposes its N-terminus to the cytosolic side of the mitochondrial outer membrane.
    Moritz Resch, Johanna S Frickel, Korbinian Dischinger, Rachel Choo Shen Wen, Kai Hell, Max E Harner.
      Mitochondrial architecture and the contacts between the outer and the inner mitochondrial membrane depend on the mitochondrial contact site and cristae organizing system (MICOS) that is highly conserved from yeast to human. Mutations in the mammalian MICOS subunit Mic14/CHCHD10 have been linked to amyotrophic lateral sclerosis and frontotemporal dementia, indicating the importance of this protein. Mic14/CHCHD10 has a yeast ortholog, Mix17, a protein of unknown function, which has not been shown to interact with MICOS so far. As a first step to elucidate the function of Mix17 and its orthologs, we analyzed its interactions, biogenesis and mitochondrial sublocation. We report that Mix17 is no stable MICOS subunit in yeast. Our data suggest that Mix17 is the first Mia40 substrate in the mitochondrial outer membrane. Unlike all other Mia40 substrates, Mix17 spans the outer membrane and exposes its N-terminus to the cytosol. The insertion of Mix17 is likely to be mediated by its interaction with Tom40, the pore of the TOM complex. Moreover, we show that the exposure of Mix17 to the cytosolic side of the membrane depends on its N-terminus.
    Keywords:  CHCHD10; Mia40; Mic14; Mix17; Protein import; Tom40
    DOI:  https://doi.org/10.1242/jcs.263661
  40. Alzheimers Res Ther. 2025 Mar 19. 17(1): 63
    Correction: Cornuside alleviates cognitive impairments induced by Aβ1-42 through attenuating NLRP3-mediated neurotoxicity by promoting mitophagy.
    Fulin Zhou, Wenwen Lian, Xiaotang Yuan, Zexing Wang, Congyuan Xia, Yu Yan, Wenping Wang, Zhuohang Tong, Yungchi Cheng, Jiekun Xu, Jun He, Weiku Zhang.
      
    DOI:  https://doi.org/10.1186/s13195-025-01715-9
  41. Front Immunol. 2025 ;16 1486961
    Identification and validation of mitophagy-related genes in acute myocardial infarction and ischemic cardiomyopathy and study of immune mechanisms across different risk groups.
    Ying Hao, RuiLin Li, ChengHui Fan, Yang Gao, Xia Hou, Wei Wen, YunLi Shen.
       Introduction: Acute myocardial infarction (AMI) is a critical condition that can lead to ischemic cardiomyopathy (ICM), a subsequent heart failure state characterized by compromised cardiac function.
    Methods: This study investigates the role of mitophagy in the transition from AMI to ICM. We analyzed AMI and ICM datasets from GEO, identifying mitophagy-related differentially expressed genes (MRDEGs) through databases like GeneCards and Molecular Signatures Database, followed by functional enrichment and Protein-Protein Interaction analyses. Logistic regression, Support Vector Machine, and LASSO (Least Absolute Shrinkage and Selection Operator) were employed to pinpoint key MRDEGs and develop diagnostic models, with risk stratification performed using LASSO scores. Subgroup analyses included functional enrichment and immune infiltration analysis, along with protein domain predictions and the integration of regulatory networks involving Transcription Factors, miRNAs, and RNA-Binding Proteins, leading to drug target identification.
    Results: The TGFβ pathway showed significant differences between high- and low-risk groups in AMI and ICM. Notably, in the AMI low-risk group, MRDEGs correlated positively with activated CD4+ T cells and negatively with Type 17 T helper cells, while in the AMI high-risk group, RPS11 showed a positive correlation with natural killer cells. In ICM, MRPS5 demonstrated a negative correlation with activated CD4+ T cells in the low-risk group and with memory B cells, mast cells, and dendritic cells in the high-risk group. The diagnostic accuracy of RPS11 was validated with an area under the curve (AUC) of 0.794 across diverse experimental approaches including blood samples, animal models, and myocardial hypoxia/reoxygenation models.
    Conclusions: This study underscores the critical role of mitophagy in the transition from AMI to ICM, highlighting RPS11 as a highly significant biomarker with promising diagnostic potential and therapeutic implications.
    Keywords:  acute myocardial infarction; diagnostic model; ischemic cardiomyopathy; machine learning; mitophagy
    DOI:  https://doi.org/10.3389/fimmu.2025.1486961
  42. Cell Rep Med. 2025 Mar 18. pii: S2666-3791(25)00094-1. [Epub ahead of print]6(3): 102021
    Bioengineering the metabolic network of CAR T cells with GLP-1 and Urolithin A increases persistence and long-term anti-tumor activity.
    Areej Akhtar, Md Shakir, Mohammad Sufyan Ansari, Divya, Md Imam Faizan, Varnit Chauhan, Aashi Singh, Ruquaiya Alam, Iqbal Azmi, Sheetal Sharma, Mehak Pracha, Insha Mohi Uddin, Uzma Bashir, Syeda Najidah Shahni, Rituparna Chaudhuri, Sarah Albogami, Rik Ganguly, Shakti Sagar, Vijay Pal Singh, Gaurav Kharya, Amit Kumar Srivastava, Ulaganathan Mabalirajan, Soumya Sinha Roy, Irfan Rahman, Tanveer Ahmad.
      Constant tumor antigen exposure disrupts chimeric antigen receptor (CAR) T cell metabolism, limiting their persistence and anti-tumor efficacy. To address this, we develop metabolically reprogrammed CAR (MCAR) T cells with enhanced autophagy and mitophagy. A compound screening identifies a synergy between GLP-1R agonist (semaglutide [SG]) and Urolithin A (UrA), which activate autophagy through mTOR (mechanistic target of rapamycin) inhibition and mitophagy via Atg4b activation, maintaining mitochondrial metabolism in CAR T cells (MCAR T-1). These changes increase CD8+ T memory cells (Tm), enhancing persistence and anti-tumor activity in vitro and in xenograft models. GLP-1R knockdown in CAR T cells diminishes autophagy/mitophagy induction, confirming its critical role. We further engineer GLP-1-secreting cells (MCAR T-2), which exhibited sustained memory, stemness, and long-term persistence, even under tumor re-challenge. MCAR T-2 cells also reduce cytokine release syndrome (CRS) risks while demonstrating potent anti-tumor effects. This strategy highlights the potential of metabolic reprogramming via targeting autophagy/mitophagy pathways to improve CAR T cell therapy outcomes, ensuring durability and efficacy.
    Keywords:  CAR T cells; GLP-1 peptide; T cell persistence; Urolithin A; anti-tumor activity; autophagy; metabolism; mitochondrial health; mitophagy
    DOI:  https://doi.org/10.1016/j.xcrm.2025.102021
  43. Biochim Biophys Acta Mol Basis Dis. 2025 Mar 19. pii: S0925-4439(25)00148-6. [Epub ahead of print] 167803
    Mitochondria: An overview of their origin, genome, architecture, and dynamics.
    João P Moura, Paulo J Oliveira, Ana M Urbano.
      Mitochondria are traditionally viewed as the powerhouses of most eukaryotic cells, i.e., the main providers of the metabolic energy required to maintain their viability and function. However, the role of these ubiquitous intracellular organelles far extends energy generation, encompassing a large suite of functions, which they can adjust to changing physiological conditions. These functions rely on a sophisticated membrane system and complex molecular machineries, most of which imported from the cytosol through intricate transport systems. In turn, mitochondrial plasticity is rooted on mitochondrial biogenesis, mitophagy, fusion, fission, and movement. Dealing with all these aspects and terminology can be daunting for newcomers to the field of mitochondria, even for those with a background in biological sciences. The aim of the present educational article, which is part of a special issue entitled "Mitochondria in aging, cancer and cell death", is to present these organelles in a simple and concise way. Complex molecular mechanisms are deliberately omitted, as their inclusion would defeat the stated purpose of the article. Also, considering the wide scope of the article, coverage of each topic is necessarily limited, with the reader directed to excellent reviews, in which the different topics are discussed in greater depth than is possible here. In addition, the multiple cell type-specific genotypic and phenotypic differences between mitochondria are largely ignored, focusing instead on the characteristics shared by most of them, with an emphasis on mitochondria from higher eukaryotes. Also ignored are highly degenerate mitochondrion-related organelles, found in various anaerobic microbial eukaryotes lacking canonical mitochondria.
    Keywords:  Educational article; Mitochondrial endosymbiosis; Mitochondrial function; Mitochondrial morphology; Mitochondrial plasticity and dynamics; mtDNA
    DOI:  https://doi.org/10.1016/j.bbadis.2025.167803
  44. Nat Genet. 2025 Mar 20.
    Reply to: An alternative model for maternal mtDNA inheritance.
    William Lee, Angelica Zamudio-Ochoa, Gina Buchel, Petar Podlesniy, Nuria Marti Gutierrez, Aleksei Mikhalchenko, Ramon Trullas, Shoukhrat Mitalipov, Dmitry Temiakov.
      
    DOI:  https://doi.org/10.1038/s41588-025-02150-0
  45. MedComm (2020). 2025 Apr;6(4): e70142
    Swimming Exercise Pretreatment Attenuates Postoperative Delirium-Like Behavior in Type 2 Diabetic Rats by Enhancing Mitochondrial Biogenesis Through Activation of SIRT2 Deacetylation.
    Kaixi Liu, Lei Chen, Xinning Mi, Qian Wang, Yitong Li, Jingshu Hong, Xiaoxiao Wang, Yue Li, Yanan Song, Yi Yuan, Jie Wang, Dengyang Han, Taotao Liu, Ning Yang, Xiangyang Guo, Zhengqian Li.
      Postoperative delirium (POD) is a common postsurgical complication that seriously affects patients' prognosis and imposes a heavy burden on families and society. Type 2 diabetes mellitus (T2DM) is a major risk factor for POD. The susceptibility mechanisms of POD in T2DM individuals and the role of exercise preconditioning remain unclear. Adult rats with and without T2DM were used to assess the promotive effect of diabetes on postoperative delirium-like behavior. The diabetic rats were also subjected to a swimming exercise program before surgery. The potential beneficial effect of exercise preconditioning on postoperative cognition was evaluated by examining neurobehavior, hippocampal neuroinflammation, mitochondrial morphology, and function in diabetic rats. Finally, underlying mechanisms were further analyzed by exploring the role of the sirtuin family in vivo and in vitro. We found that performing tibial fracture surgery resulted in delirium-like behavior and inhibited hippocampal mitochondrial biogenesis in diabetic rats but not in healthy rats. Preoperative swimming exercise was beneficial in attenuating delirium-like behavior, inhibiting neuroinflammation, and improving mitochondrial biogenesis and function. Preoperative swimming exercise achieved these positive effects by upregulating SIRT2-mediated peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) deacetylation and activating mitochondrial biogenesis in T2DM rats.
    Keywords:  SIRT2; Type 2 diabetes mellitus; mitochondrial biogenesis; postoperative delirium; swimming exercise
    DOI:  https://doi.org/10.1002/mco2.70142
  46. Sci Adv. 2025 Mar 21. 11(12): eadn8402
    AMPK-dependent Parkin activation suppresses macrophage antigen presentation to promote tumor progression.
    Xinyu Wang, Yiyi Li, Yan Li, Xiumei Wang, Hongrui Song, Yingzhao Wang, Chunliu Huang, Chengzhou Mao, Lixiang Wang, Cheng Zhong, Di Yu, Zijin Xia, Yongyi Feng, Jingjing Duan, Yujia Liu, Juanjuan Ou, Congzhou Luo, Wenhao Mai, Hai Hong, Weibin Cai, Limin Zheng, Jean-François Trempe, Edward A Fon, Jing Liao, Wei Yi, Jun Chen.
      The constrained cross-talk between myeloid cells and T cells in the tumor immune microenvironment (TIME) restricts cancer immunotherapy efficacy, whereas the underlying mechanism remains elusive. Parkin, an E3 ubiquitin ligase renowned for mitochondrial quality control, has emerged as a regulator of immune response. Here, we show that both systemic and macrophage-specific ablations of Parkin in mice lead to attenuated tumor progression and prolonged mouse survival. By single-cell RNA-seq and flow cytometry, we demonstrate that Parkin deficiency reshapes the TIME through activating both innate and adaptive immunities to control tumor progression and recurrence. Mechanistically, Parkin activation by AMP-activated protein kinase rather than PTEN-induced kinase 1 mediated major histocompatibility complex I down-regulation on macrophages via Autophagy related 5-dependent autophagy. Furthermore, Parkin deletion synergizes with immune checkpoint blockade treatment and Park2-/- signature aids in predicting the prognosis of patients with solid tumor. Our findings uncover Parkin's involvement in suppressing macrophage antigen presentation for coordinating the cross-talk between macrophages and T cells.
    DOI:  https://doi.org/10.1126/sciadv.adn8402
  47. Nat Commun. 2025 Mar 14. 16(1): 2527
    Telomere length in offspring is determined by mitochondrial-nuclear communication at fertilization.
    Yasmyn E Winstanley, Ryan D Rose, Alexander P Sobinoff, Linda L Wu, Deepak Adhikari, Qing-Hua Zhang, Jadon K Wells, Lee H Wong, Hazel H Szeto, Sandra G Piltz, Paul Q Thomas, Mark A Febbraio, John Carroll, Hilda A Pickett, Darryl L Russell, Rebecca L Robker.
      The initial setting of telomere length during early life in each individual has a major influence on lifetime risk of aging-associated diseases; however there is limited knowledge of biological signals that regulate inheritance of telomere length, and whether it is modifiable is not known. We now show that when mitochondrial activity is disrupted in mouse zygotes, via exposure to 20% O2 or rotenone, telomere elongation between the 8-cell and blastocyst stage is impaired, with shorter telomeres apparent in the pluripotent Inner Cell Mass (ICM) and persisting after organogenesis. Identical defects of elevated mtROS in zygotes followed by impaired telomere elongation, occurred with maternal obesity or advanced age. We further demonstrate that telomere elongation during ICM formation is controlled by mitochondrial-nuclear communication at fertilization. Using mitochondrially-targeted therapeutics (BGP-15, MitoQ, SS-31, metformin) we demonstrate that it is possible to modulate the preimplantation telomere resetting process and restore deficiencies in neonatal telomere length.
    DOI:  https://doi.org/10.1038/s41467-025-57794-7
  48. Adv Sci (Weinh). 2025 Mar 16. e2414985
    Mitofusin 1 Drives Preimplantation Development by Enhancing Chromatin Incorporation of Histone H3.3.
    Xiao-Yan Shi, Yu Tian, Yu-Fan Wang, Yi-Ran Zhang, Ying Yin, Qing Tian, Lei Li, Bing-Xin Ma, Ximiao He, Li-Quan Zhou.
      Mitofusin 1 (MFN1) plays a crucial role in mitochondrial fusion and oocyte development. However, its function in preimplantation embryonic development and its potential involvement in epigenetic regulation remain poorly understood. In this study, it is shown that MFN1 interacts with PADI6, a key component of the cytoplasmic lattice in oocytes and early embryos. MFN1 deficiency in mice results in reduced PADI6 levels and decreased expression of translational machinery components, which suppress protein synthesis activity and lower histone H3.3 abundance. These disruptions lead to the failure of male pronucleus formation, aberrant zygotic genome activation, and impaired embryonic development. It is further demonstrated that the MFN1 activator S89 promotes H3.3 incorporation and rescues early development in maternally aged embryos with low MFN1 levels. Additionally, a positive correlation between MFN1 and H3.3 protein levels in early human embryos is observed. Together, these findings provide new insights into MFN1's role in regulating epigenetic reprogramming during preimplantation embryo development.
    Keywords:  H3.3; MFN1; cytoplasmic lattice; preimplantation; zygotic genome activation
    DOI:  https://doi.org/10.1002/advs.202414985
  49. Redox Biol. 2025 Mar 14. pii: S2213-2317(25)00111-9. [Epub ahead of print]82 103598
    Transgenerational inheritance of mitochondrial hormetic oxidative stress mediated by histone H3K4me3 and H3K27me3 modifications.
    Yimin Li, Chongyang Wang, Xiaoxia Fu, Dan Wu, Chenyang He, Wenyu Dai, Xiaoyang Yue, Zhenhuan Luo, Jing Yang, Qin-Li Wan.
      Mitochondrial hormetic oxidative stress (mtHOS) is crucial in physiology and disease; however, its effects on epigenetic inheritance and organism fitness across generations remains elusive. Utilizing the C. elegans as a model, we elucidate that parental exposure to mtHOS not only elicits a lifespan extension in the exposed individuals but also confers this longevity advantage to the progeny through the transgenerational epigenetic inheritance (TEI) mechanism. This transgenerational transmission of lifespan prolongation depends on the activation of the UPRmt and the synergistic action of the transcription factors DAF-16/FOXO and SKN-1/Nrf2. Additionally, the H3K4me3 and H3K27me3 serve as epigenetic mediators, selectively marking and regulating the expression of genes associated with oxidative stress response and longevity determination. Our findings illuminate the mechanisms underlying the implementation and transmission of mtHOS, revealing a sophisticated interplay among oxidative stress response genes and chromatin remodeling that collectively enhances the progeny's adaptive resilience to future challenges.
    Keywords:  Caenorhabditis elegans; Histone modification; Longevity; Mitochondrial hormetic oxidative stress; Transgenerational epigenetic inheritance; UPR(mt)
    DOI:  https://doi.org/10.1016/j.redox.2025.103598
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