bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2025–02–02
63 papers selected by
Gavin McStay, Liverpool John Moores University
  1. The E3-ligase Siah2 activates mitochondrial quality control in neurons to maintain energy metabolism during ischemic brain tolerance.
  2. Glucose-6-phosphate dehydrogenase regulates mitophagy by maintaining PINK1 stability.
  3. Isovitexin targets SIRT3 to prevent steroid-induced osteonecrosis of the femoral head by modulating mitophagy-mediated ferroptosis.
  4. Multiomics reveals that triacylglycerol mobilization helps drive recovery from mitochondrial stress.
  5. A novel strategy for the protective effect of ginsenoside Rg1 against ovarian reserve decline by the PINK1 pathway.
  6. Recent advancements in the understanding of the alterations in mitochondrial biogenesis in Alzheimer's disease.
  7. Molecular Symphony of Mitophagy: Ubiquitin-Specific Protease-30 as a Maestro for Precision Management of Neurodegenerative Diseases.
  8. The temporal relationship between mitochondrial quality and renal tissue recovery following ischemia-reperfusion injury.
  9. Qiangji Decoction mitigates neuronal damage, synaptic and mitochondrial dysfunction in SAMP8 mice through the regulation of ROCK2/Drp1-mediated mitochondrial dynamics.
  10. Circadian clockwork controls the balance between mitochondrial turnover and dynamics: What is life … without time marking?
  11. Ferroptosis triggers mitochondrial fragmentation via Drp1 activation.
  12. Overexpression of Parkin promotes the protective effect of mitochondrial autophagy on the lung of rats with exertional heatstroke.
  13. VEGFR3 mitigates hypertensive nephropathy by enhancing mitophagy via regulating crotonylation of HSPA1L.
  14. MARCH5 ameliorates aortic valve calcification via RACGAP1-DRP1 pathway associated mitochondrial quality control.
  15. Mitochondrial dynamics: molecular mechanism and implications in endometriosis.
  16. The UCP2/PINK1/LC3b-mediated mitophagy is involved in the protection of NRG1 against myocardial ischemia/reperfusion injury.
  17. Mitochondrial fission and fusion in neurodegenerative diseases:Ca2+ signalling.
  18. Altered mitochondrial unfolded protein response and FGF21 secretion in MASLD progression and the effect of exercise intervention.
  19. Beneficial Effects of the Herbal Medicine Zuo Gui Wan in a Mice Model of Alzheimer's Disease via Drp1-Mediated Inhibition of Mitochondrial Fission and Activation of AMPK/PGC-1α-regulated Mitochondrial Bioenergetics.
  20. Dysregulation of Mitochondrial Homeostasis in Cardiovascular Diseases.
  21. Mitochondrial dysfunction in Alzheimer's disease: a key frontier for future targeted therapies.
  22. A Multi-Omics Analysis of a Mitophagy-Related Signature in Pan-Cancer.
  23. Fucoidan Oligosaccharide Supplementation Relieved Kidney Injury and Modulated Intestinal Homeostasis in D-Galactose-Exposed Rats.
  24. Decrease of NAD+ Inhibits the Apoptosis of OLP T Cells via Inducing Mitochondrial Fission.
  25. Adipose-derived stem cells regulate mitochondrial dynamics to alleviate the aging of HFF-1 cells.
  26. Histone lactylation regulates PRKN-Mediated mitophagy to promote M2 Macrophage polarization in bladder cancer.
  27. Protective Effects of Mdivi-1 on Cognition Disturbance Following Sepsis in Mice via Alleviating Microglia Activation and Polarization.
  28. Autophagy and Mitophagy in Diabetic Kidney Disease-A Literature Review.
  29. Acid triggering highly-efficient release of reactive oxygen species to block mitochondrial-mediated homeostasis maintenance for accelerating cell death.
  30. Targeting enolase 1 reverses bortezomib resistance in multiple myeloma through YWHAZ/Parkin axis.
  31. Sodium butyrate attenuates oxidative stress, apoptosis, and excessive mitophagy in sodium fluoride-induced hepatotoxicity in rats.
  32. Semaglutide administration protects cardiomyocytes in db/db mice via energetic improvement and mitochondrial quality control.
  33. Molecular regulation of mitophagy signaling in tumor microenvironment and its targeting for cancer therapy.
  34. Strawberry anthocyanin pelargonidin-3-glucoside attenuated OA-induced neurotoxicity by activating UPRmt.
  35. FAM43A coordinates mtDNA replication and mitochondrial biogenesis in response to mtDNA depletion.
  36. Placental mitochondrial metabolic adaptation maintains cellular energy balance in pregnancy complicated by gestational hypoxia.
  37. The 40S ribosomal subunit recycling complex modulates mitochondrial dynamics and endoplasmic reticulum - mitochondria tethering at mitochondrial fission/fusion hotspots.
  38. Nonapoptotic role of EGL-1 in exopher production and neuronal health in Caenorhabditis elegans.
  39. M6a demethylase FTO regulates the oxidative stress, mitochondrial biogenesis of cardiomyocytes and PGC-1a stability in myocardial ischemia-reperfusion injury.
  40. PEBP1 amplifies mitochondrial dysfunction-induced integrated stress response.
  41. Aqueous extract of Atractylodes macrocephala Koidz. improves dexamethasone-induced skeletal muscle atrophy in mice by enhancing mitochondrial biological function.
  42. Di Huang Yi Zhi Fang improves cognitive function in APP/PS1 mice by inducing neuronal mitochondrial autophagy through the PINK1-parkin pathway.
  43. Ginsenoside-Re-rich ethanol extract of Panax ginseng berry enhances healthspan extension via mitostasis and NAD metabolism.
  44. sVEGFR3 alleviates myocardial ischemia/reperfusion injury through regulating mitochondrial homeostasis and immune cell infiltration.
  45. Astragali Radix-Notoginseng Radix et Rhizoma medicine pair prevents cardiac remodeling by improving mitochondrial dynamic balance.
  46. Electrical homeostasis of the inner mitochondrial membrane potential.
  47. SIRT4 Protects Retina Against Excitotoxic Injury by Promoting OPA1-Mediated Müller Glial Cell Mitochondrial Fusion and GLAST Expression.
  48. Computational Study of the Activation Mechanism of Wild-Type Parkin and Its Clinically Relevant Mutant.
  49. Serine phosphorylation facilitates protein degradation by the human mitochondrial ClpXP protease.
  50. Fasting enhances the efficacy of Sorafenib in breast cancer via mitophagy mediated ROS-driven p53 pathway.
  51. Mechanism of chaperone recruitment and retention on mitochondrial precursors.
  52. The Diurnal Variation in Mitochondrial Gene in Human Type 2 Diabetic Mesenchymal Stem Cell Grafts.
  53. Ginsenoside Rg1 improves hypoxia-induced pulmonary vascular endothelial dysfunction through TXNIP/NLRP3 pathway-modulated mitophagy.
  54. Correction: Docosahexaenoic Acid Alleviates Oxidative Stress-Based Apoptosis Via Improving Mitochondrial Dynamics in Early Brain Injury After Subarachnoid Hemorrhage.
  55. Mitigating PM2.5 Induced Myocardial Metal Deposition Through Sodium Thiosulfate Resulted in Reduction of Cardiotoxicity and Physiological Recovery From Ischemia-Reperfusion via Mitochondrial Preservation.
  56. Leptin drives glucose metabolism to promote cardiac protection via OPA1-mediated HDAC5 translocation and Glut4 transcription.
  57. T-2 Toxin Nephrotoxicity: Toxic Effects, Mechanisms, Mitigations, and Future Perspectives.
  58. NLRX1 deficiency exacerbates skin inflammation in atopic dermatitis by disrupting mitophagy.
  59. Lactate Promotes Hypoxic Granulosa Cells' Autophagy by Activating the HIF-1α/BNIP3/Beclin-1 Signaling Axis.
  60. Effects of Astragaloside IV and Formononetin on Oxidative Stress and Mitochondrial Biogenesis in Hepatocytes.
  61. Autophagy-Enhancing Properties of Hedyotis diffusa Extracts in HaCaT Keratinocytes: Potential as an Anti-Photoaging Cosmetic Ingredient.
  62. Expression profiling of circular RNAs in sepsis-induced acute gastrointestinal injury: insights into potential biomarkers and mechanisms.
  63. Electric-field induced sleep promotion and lifespan extension in Gaucher's disease model flies.
  1. Cell Death Dis. 2025 Jan 28. 16(1): 52
    The E3-ligase Siah2 activates mitochondrial quality control in neurons to maintain energy metabolism during ischemic brain tolerance.
    Maria Josè Sisalli, Elena D'Apolito, Ornella Cuomo, Giovanna Lombardi, Michele Tufano, Lucio Annunziato, Antonella Scorziello.
      Mitochondrial quality control is crucial for the homeostasis of the mitochondrial network. The balance between mitophagy and biogenesis is needed to reduce cerebral ischemia-induced cell death. Ischemic preconditioning (IPC) represents an adaptation mechanism of CNS that increases tolerance to lethal cerebral ischemia. It has been demonstrated that hypoxia-induced Seven in absentia Homolog 2 (Siah2) E3-ligase activation influences mitochondrial dynamics promoting the degradation of mitochondrial proteins. Therefore, in the present study, we investigated the role of Siah2 in the IPC-induced neuroprotection in in vitro and in vivo models of IPC. To this aim, cortical neurons were exposed to 30-min oxygen and glucose deprivation (OGD, sublethal insult) followed by 3 h OGD plus reoxygenation (lethal insult). Our results revealed that the mitochondrial depolarization induced by hypoxia activates Siah2 at the mitochondrial level and increases LC3-II protein expression, a marker of mitophagy, an effect counteracted by the reoxygenation phase. By contrast, hypoxia reduced the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), a marker of mitochondrial biogenesis, whereas its expression was increased after reoxygenation thus improving mitochondrial membrane potential, mitochondrial calcium content, and mitochondrial morphology, hence leading to neuroprotection in IPC. Furthermore, Siah2 silencing confirmed these results. Collectively, these findings indicate that the balance between mitophagy and mitochondrial biogenesis, due to the activation of the Siah2-E3-ligase, might play a role in IPC-induced neuroprotection.
    DOI:  https://doi.org/10.1038/s41419-025-07339-z
  2. Life Metab. 2025 Feb;4(1): loae040
    Glucose-6-phosphate dehydrogenase regulates mitophagy by maintaining PINK1 stability.
    Yik-Lam Cho, Hayden Weng Siong Tan, Jicheng Yang, Basil Zheng Mian Kuah, Nicole Si Ying Lim, Naiyang Fu, Boon-Huat Bay, Shuo-Chien Ling, Han-Ming Shen.
      Glucose-6-phosphate dehydrogenase (G6PD) is the rate-limiting enzyme in the pentose phosphate pathway (PPP) in glycolysis. Glucose metabolism is closely implicated in the regulation of mitophagy, a selective form of autophagy for the degradation of damaged mitochondria. The PPP and its key enzymes such as G6PD possess important metabolic functions, including biosynthesis and maintenance of intracellular redox balance, while their implication in mitophagy is largely unknown. Here, via a whole-genome CRISPR-Cas9 screening, we identified that G6PD regulates PINK1 (phosphatase and tensin homolog [PTEN]-induced kinase 1)-Parkin-mediated mitophagy. The function of G6PD in mitophagy was verified via multiple approaches. G6PD deletion significantly inhibited mitophagy, which can be rescued by G6PD reconstitution. Intriguingly, while the catalytic activity of G6PD is required, the known PPP functions per se are not involved in mitophagy regulation. Importantly, we found a portion of G6PD localized at mitochondria where it interacts with PINK1. G6PD deletion resulted in an impairment in PINK1 stabilization and subsequent inhibition of ubiquitin phosphorylation, a key starting point of mitophagy. Finally, we found that G6PD deletion resulted in lower cell viability upon mitochondrial depolarization, indicating the physiological function of G6PD-mediated mitophagy in response to mitochondrial stress. In summary, our study reveals a novel role of G6PD as a key positive regulator in mitophagy, which bridges several important cellular processes, namely glucose metabolism, redox homeostasis, and mitochondrial quality control.
    Keywords:  G6PD; NADPH; PINK1; PPP; ROS; mitophagy
    DOI:  https://doi.org/10.1093/lifemeta/loae040
  3. Bone Res. 2025 Jan 26. 13(1): 18
    Isovitexin targets SIRT3 to prevent steroid-induced osteonecrosis of the femoral head by modulating mitophagy-mediated ferroptosis.
    Yinuo Fan, Zhiwen Chen, Haixing Wang, Mengyu Jiang, Hongduo Lu, Yangwenxiang Wei, Yunhao Hu, Liang Mo, Yuhao Liu, Chi Zhou, Wei He, Zhenqiu Chen.
      The death of osteoblasts induced by glucocorticoid (GC)-mediated oxidative stress plays a crucial role in the development of steroid-induced osteonecrosis of the femoral head (SIONFH). Improving bone formation driven by osteoblasts has shown promising outcomes in the prognosis of SIONFH. Isovitexin has demonstrated antioxidant properties, but its therapeutic effects on GC-induced oxidative stress and SIONFH remain unexplored. In this study, we analyzed clinical samples obtained from SIONFH patients using proteomic and bioinformatic approaches. We found an imbalance in mitochondrial homeostasis and ferroptosis-induced impairment of osteogenic capacity in SIONFH. Subsequently, we investigated the cause-and-effect relationship between mitochondria and ferroptosis, as well as the regulatory role of mitophagy in maintaining mitochondrial homeostasis and controlling ferroptosis. We then identified the critical involvement of SIRT3 in modulating mitochondrial homeostasis and ferroptosis. Furthermore, molecular docking and co-immunoprecipitation confirmed the strong interaction between SIRT3 and BNIP3. Strikingly, restoring SIRT3 expression significantly inhibited pathological mitophagy mediated by the BNIP3/NIX pathway. Additionally, we discovered that Isovitexin, by promoting SIRT3 expression, effectively regulated mitophagy, preserved mitochondrial homeostasis in osteoblasts, suppressed ferroptosis, and restored osteogenic capacity, leading to remarkable improvements in SIONFH. These findings reveal the effects and molecular mechanisms of Isovitexin on SIONFH and highlight the potential of targeting SIRT3 as a promising strategy to suppress mitophagy-mediated ferroptosis in osteoblasts and against SIONFH.
    DOI:  https://doi.org/10.1038/s41413-024-00390-0
  4. Nat Cell Biol. 2025 Jan 24.
    Multiomics reveals that triacylglycerol mobilization helps drive recovery from mitochondrial stress.
      
    DOI:  https://doi.org/10.1038/s41556-024-01603-8
  5. Pharm Biol. 2025 Dec;63(1): 68-81
    A novel strategy for the protective effect of ginsenoside Rg1 against ovarian reserve decline by the PINK1 pathway.
    Pengdi Yang, Meiling Fan, Ying Chen, Dan Yang, Lu Zhai, Baoyu Fu, Lili Zhang, Yanping Wang, Rui Ma, Liwei Sun.
       CONTEXT: The decline in ovarian reserve is a major concern in female reproductive health, often associated with oxidative stress and mitochondrial dysfunction. Although ginsenoside Rg1 is known to modulate mitophagy, its effectiveness in mitigating ovarian reserve decline remains unclear.
    OBJECTIVE: To investigate the role of ginsenoside Rg1 in promoting mitophagy to preserve ovarian reserve.
    MATERIALS AND METHODS: Ovarian reserve function, reproductive capacity, oxidative stress levels, and mitochondrial function were compared between ginsenoside Rg1-treated and untreated naturally aged female Drosophila using behavioral, histological, and molecular biological techniques. The protective effects of ginsenoside Rg1 were analyzed in a Drosophila model of oxidative damage induced by tert-butyl hydroperoxide. Protein expression levels in the PINK1/Parkin pathway were assessed, and molecular docking and PINK1 mutant analyses were conducted to identify potential targets.
    RESULTS: Ginsenoside Rg1 significantly mitigated ovarian reserve decline, enhancing offspring quantity and quality, increasing the levels of ecdysteroids, preventing ovarian atrophy, and elevating germline stem cell numbers in aged Drosophila. Ginsenoside Rg1 improved superoxide dismutase, catalase activity, and gene expression while reducing reactive oxygen species levels. Ginsenoside Rg1 activated the mitophagy pathway by upregulating PINK1, Parkin, and Atg8a and downregulating Ref(2)P. Knockdown of PINK1 in the ovary by RNAi attenuated the protective effects of ginsenoside Rg1. Molecular docking analysis revealed that the ginsenoside Rg1 could bind to the active site of the PINK1 kinase domain.
    DISCUSSION AND CONCLUSIONS: Ginsenoside Rg1 targets PINK1 to regulate mitophagy, preserving ovarian reserve. These findings suggest the potential of ginsenoside Rg1 as a therapeutic strategy to prevent ovarian reserve decline.
    Keywords:  Ovarian reserve decline; PINK1/Parkin pathway; ginsenoside Rg1; mitophagy; oxidative stress
    DOI:  https://doi.org/10.1080/13880209.2025.2453699
  6. Mol Biol Rep. 2025 Jan 29. 52(1): 173
    Recent advancements in the understanding of the alterations in mitochondrial biogenesis in Alzheimer's disease.
    Shreya Singh, Rakesh Kumar Singh.
      Alzheimer's disease (AD) is a common neurodegenerative disease characterized by progressive memory loss and cognitive decline. The processes underlying the pathophysiology of AD are still not fully understood despite a great deal of research. Since mitochondrial dysfunction affects cellular energy metabolism, oxidative stress, and neuronal survival, it is becoming increasingly clear that it plays a major role in the development of AD. This review summarizes the recent developments of mitochondrial dysfunction in AD, emphasizing mitochondrial biogenesis, dynamics, axonal transport, interactions between endoplasmic reticulum and mitochondria, mitophagy, and mitochondrial proteostasis. It emphasizes how tau and amyloid-beta (Aβ) proteins worsen mitochondrial and synaptic dysfunction by impairing adenosine triphosphate (ATP) synthesis, causing oxidative stress, and upsetting equilibrium. Additionally, important processes controlling mitochondrial activity and their correlation to the brain health are also discussed. One of the promising therapeutic approaches to lessen neurodegeneration and cognitive decline in AD is to improve mitochondrial activity. This study highlights possible directions for creating focused therapies to impede the advancement of AD through incorporating knowledge of mitochondrial biogenesis and its related mechanisms.
    Keywords:  Alzheimer’s disease; Dementia; Mitochondrial biogenesis; Mitophagy
    DOI:  https://doi.org/10.1007/s11033-025-10297-6
  7. CNS Neurosci Ther. 2025 Jan;31(1): e70192
    Molecular Symphony of Mitophagy: Ubiquitin-Specific Protease-30 as a Maestro for Precision Management of Neurodegenerative Diseases.
    Ankit Siwach, Harit Patel, Amit Khairnar, Pathik Parekh.
       INTRODUCTION: Mitochondrial dysfunction stands as a pivotal feature in neurodegenerative disorders, spurring the quest for targeted therapeutic interventions. This review examines Ubiquitin-Specific Protease 30 (USP30) as a master regulator of mitophagy with therapeutic promise in Alzheimer's disease (AD) and Parkinson's disease (PD). USP30's orchestration of mitophagy pathways, encompassing PINK1-dependent and PINK1-independent mechanisms, forms the crux of this exploration.
    METHOD: A systematic literature search was conducted in PubMed, Scopus, and Web of Science, selecting studies that investigated USP's function, inhibitor design, or therapeutic efficacy in AD and PD. Inclusion criteria encompassed mechanistic and preclinical/clinical data, while irrelevant or duplicate references were excluded. Extracted findings were synthesized narratively.
    RESULTS: USP30 modulates interactions with translocase of outer mitochondrial membrane (TOM) 20, mitochondrial E3 ubiquitin protein ligase 1 (MUL1), and Parkin, thus harmonizing mitochondrial quality control. Emerging novel USP30 inhibitors, racemic phenylalanine derivatives, N-cyano pyrrolidine, and notably, benzosulphonamide class compounds, restore mitophagy, and reduce neurodegenerative phenotypes across diverse models with minimal off-target effects. Modulation of other USPs also influences neurodegenerative disease pathways, offering additional therapeutic avenues.
    CONCLUSIONS: In highlighting the nuanced regulation of mitophagy by USP30, this work heralds a shift toward more precise and effective treatments, paving the way for a new era in the clinical management of neurodegenerative disorders.
    Keywords:  Alzheimer's disease; Parkinson's disease; USP13 inhibitors; USP14 inhibitors; USP30 inhibitors; deubiquitinating enzymes; mitophagy; ubiquitin‐specific protease
    DOI:  https://doi.org/10.1111/cns.70192
  8. Heliyon. 2025 Jan 15. 11(1): e41634
    The temporal relationship between mitochondrial quality and renal tissue recovery following ischemia-reperfusion injury.
    Priyanka N Prem, Harish Swaminathan, Gino A Kurian.
       Background: Growing evidence indicates that disruptions in mitochondrial quality management contribute to the development of acute kidney injury (AKI), incomplete or maladaptive kidney repair, and chronic kidney disease. However, the temporal dynamics of mitochondrial quality control alterations in relation to renal injury and its recovery remain poorly understood and are addressed in this manuscript.
    Method: ology: Male Wistar rats (n = 60) were subjected to varying durations of ischemia and reperfusion. Ischemia was instigated by clamping both renal arteries and for reperfusion, the clamps were removed to restore the blood flow. Renal injury, physiological function, mitochondrial assessment, and cellular mediators were analyzed.
    Results: Prolonging ischemia duration reduces bioenergetic function while disrupting the balance of mitochondrial fusion, fission, and mitophagy at the gene expression level while maintaining intact mitochondrial copy number. However, reperfusing a kidney after 45 min of ischemia with varying reperfusion times exacerbates mitochondrial dysfunction and significantly decreases mitochondrial copy number. These declines are particularly evident at 24 h of reperfusion, with some parameters improving by 7 days of reperfusion. Despite these improvements, 7 days of reperfusion did not correlate with renal injury indicators (CrCl- 0.46 ± 0.01, BUN-86.29 ± 4.9, Cr-1.75 ± 0.16) following 45 min of ischemia. Conversely, 15 min of ischemia followed by 7 days of reperfusion restored mitochondrial quality and renal function (CrCl- 7.33 ± 0.59, BUN-43.6 ± 3.16, Cr-0.93 ± 0.14).
    Conclusion: The above findings emphasize that mitochondrial quality control alters with the extent of ischemia and subsequent reperfusion time, impacting not only mitochondrial copy number but also the resilience of mitochondria during tissue repair.
    Keywords:  Mitochondrial bioenergetics; Mitochondrial biogenesis; Mitochondrial dynamics; Mitophagy; Renal ischemia-reperfusion injury
    DOI:  https://doi.org/10.1016/j.heliyon.2025.e41634
  9. J Ethnopharmacol. 2025 Jan 28. pii: S0378-8741(25)00107-2. [Epub ahead of print] 119424
    Qiangji Decoction mitigates neuronal damage, synaptic and mitochondrial dysfunction in SAMP8 mice through the regulation of ROCK2/Drp1-mediated mitochondrial dynamics.
    Bixuan Lai, Dan Wu, Qidan Xiao, Zhengyu Wang, Qixuan Niu, Qingjie Chen, Qinghua Long, Liling He.
       ETHNOPHARMACOLOGICAL RELEVANCE: Qiangji Decoction (QJD), a Chinese medicine, is widely used in Traditional Chinese Medicine to treat amnesia and Alzheimer's disease (AD), showing significant anti-AD effects. However, the precise mechanisms behind these effects are not well understood and require more research.
    AIM OF THE STUDY: This study aims to elucidate the mechanisms by which QJD ameliorates neuronal damage, synaptic dysfunction, and mitochondrial impairment in AD through the regulation of ROCK2/Drp1-mediated mitochondrial dynamics.
    MATERIALS AND METHODS: UPLC-Q-TOF-MS/MS was used to identify active components in QJD extract. The study used SAMP8 mice for AD modeling and SAMR1 mice as controls. Cognitive function in SAMP8 mice was assessed with the Morris Water Maze after following treatment with QJD and the mitochondrial fission inhibitor Mdivi-1. Nissl and FJB staining evaluated QJD's effect on hippocampal injury. Synaptic integrity was examined with Golgi-Cox staining, transmission electron microscopy, and immunofluorescence. Mitochondrial function in hippocampal neurons was assessed using electron microscopy, JC-1 staining, and reagent kits. Western blot analyzed expression of proteins related to mitochondrial fission (ROCK2, Drp1, Fis1, Mff) and fusion (Mfn1, Mfn2, OPA1).
    RESULTS: The analysis of QJD extract via UPLC-Q-TOF-MS/MS led to the identification of 46 active compounds. In SAMP8 mice, administration of QJD resulted in decreased escape latency, increased platform crossings, and extended duration in the target quadrant. Additionally, QJD exhibited neuroprotective effects on the hippocampus of SAMP8 mice, effectively preventing neuronal loss and damage. QJD also facilitated the extension and thickening of dendritic spines, enhanced the ultrastructure of hippocampal synapses, and upregulated synaptic function-related proteins, including PSD95 and SYN1. Furthermore, QJD ameliorated mitochondrial damage, improved mitochondrial membrane potential and ATP content, and reduced ROS expression in hippocampal neurons of SAMP8 mice. These effects were mediated through the downregulation of ROCK2, phosphorylated Drp1 (Ser616), Fis1, and Mff, as well as the upregulation of Mfn1, Mfn2, and OPA1.
    CONCLUSIONS: QJD may reduce neuronal damage, synaptic dysfunction, and mitochondrial impairment in SAMP8 mice by regulating mitochondrial dynamics through the ROCK2/Drp1 pathway.
    Keywords:  Alzheimer's disease; Qiangji Decoction; ROCK2/Drp1 pathway; mitochondrial dynamics; mitochondrial dysfunction; synaptic dysfunction
    DOI:  https://doi.org/10.1016/j.jep.2025.119424
  10. Biochim Biophys Acta Bioenerg. 2025 Jan 27. pii: S0005-2728(25)00008-8. [Epub ahead of print] 149542
    Circadian clockwork controls the balance between mitochondrial turnover and dynamics: What is life … without time marking?
    Olga Cela, Rosella Scrima, Michela Rosiello, Consiglia Pacelli, Claudia Piccoli, Mirko Tamma, Francesca Agriesti, Gianluigi Mazzoccoli, Nazzareno Capitanio.
      Circadian rhythms driven by biological clocks regulate physiological processes in all living organisms by anticipating daily geophysical changes, thus enhancing environmental adaptation. Time-resolved serial multi-omic analyses in vivo, ex vivo, and in synchronized cell cultures have revealed rhythmic changes in the transcriptome, proteome, and metabolome, involving up to 50 % of the mammalian genome. Mitochondrial oxidative metabolism is central to cellular bioenergetics, and many nuclear genes encoding mitochondrial proteins exhibit both circadian and ultradian oscillatory expression. However, studies on mitochondrial DNA (mtDNA) gene expression remain incomplete. Using a well-established in vitro synchronization protocol, we investigated the time-resolved expression of mtDNA genes coding for respiratory chain complex subunits, revealing a rhythmic profile dependent on BMAL1, the master circadian clock transcription factor. Additionally, the expression of genes coding for key mitochondrial biogenesis transcription factors, PGC1a, NRF1, and TFAM, showed BMAL1-dependent circadian oscillations. Notably, LC3-II, involved in mitophagy, displayed a similar in-phase circadian expression, thereby maintaining stable respiratory chain complex levels. Moreover, we found that simultaneous mitochondrial biogenesis and degradation occur in a coordinated manner with cycles in organelle dynamics, leading to rhythmic changes in mitochondrial fission and fusion. This study provides new insights into circadian clock regulation of mitochondrial turnover, emphasizing the importance of temporal regulation in cellular metabolism. Understanding these mechanisms opens potential therapeutic avenues for targeting mitochondrial dysfunctions and related metabolic disorders.
    Keywords:  Circadian clock genes; Mitochondrial DNA; Mitochondrial biogenesis; Mitochondrial dynamics; Mitophagy
    DOI:  https://doi.org/10.1016/j.bbabio.2025.149542
  11. Cell Death Dis. 2025 Jan 25. 16(1): 40
    Ferroptosis triggers mitochondrial fragmentation via Drp1 activation.
    Lohans Pedrera, Laura Prieto Clemente, Alina Dahlhaus, Sara Lotfipour Nasudivar, Sofya Tishina, Daniel Olmo González, Jenny Stroh, Fatma Isil Yapici, Randhwaj Pratap Singh, Nils Grotehans, Thomas Langer, Ana J García-Sáez, Silvia von Karstedt.
      Constitutive mitochondrial dynamics ensure quality control and metabolic fitness of cells, and their dysregulation has been implicated in various human diseases. The large GTPase Dynamin-related protein 1 (Drp1) is intimately involved in mediating constitutive mitochondrial fission and has been implicated in mitochondrial cell death pathways. During ferroptosis, a recently identified type of regulated necrosis driven by excessive lipid peroxidation, mitochondrial fragmentation has been observed. Yet, how this is regulated and whether it is involved in ferroptotic cell death has remained unexplored. Here, we provide evidence that Drp1 is activated upon experimental induction of ferroptosis and promotes cell death execution and mitochondrial fragmentation. Using time-lapse microscopy, we found that ferroptosis induced mitochondrial fragmentation and loss of mitochondrial membrane potential, but not mitochondrial outer membrane permeabilization. Importantly, Drp1 accelerated ferroptotic cell death kinetics. Notably, this function was mediated by the regulation of mitochondrial dynamics, as overexpression of Mitofusin 2 phenocopied the effect of Drp1 deficiency in delaying ferroptosis cell death kinetics. Mechanistically, we found that Drp1 is phosphorylated and activated after induction of ferroptosis and that it translocates to mitochondria. Further activation at mitochondria through the phosphatase PGAM5 promoted ferroptotic cell death. Remarkably, Drp1 depletion delayed mitochondrial and plasma membrane lipid peroxidation. These data provide evidence for a functional role of Drp1 activation and mitochondrial fragmentation in the acceleration of ferroptotic cell death, with important implications for targeting mitochondrial dynamics in diseases associated with ferroptosis.
    DOI:  https://doi.org/10.1038/s41419-024-07312-2
  12. J Intensive Med. 2025 Jan;5(1): 89-99
    Overexpression of Parkin promotes the protective effect of mitochondrial autophagy on the lung of rats with exertional heatstroke.
    Ran Meng, Zhengzhong Sun, Ruxue Chi, Yan Gu, Yuxiang Zhang, Jiaxing Wang.
       Background: The roles of the Pink1/Parkin pathway and mitophagy in lung injury during heat stroke remain unclear. In this study, we investigated the role of Pink1/Parkin-mediated mitophagy in acute lung injury (ALI) in rats with exertional heat stroke (EHS).
    Methods: Sixty Sprague Dawley rats were randomly divided into control (CON), control + Parkin overexpression (CON + Parkin), EHS, and EHS + Parkin overexpression (EHS + Parkin) groups. Parkin was overexpressed by injecting an adeno-associated virus carrying the Parkin gene into the tail vein, and a rat model of EHS was established. Pathological changes in the lung tissue were analyzed using microcomputed tomography (micro-CT), and the lung coefficient and pulmonary capillary permeability were measured. Enzyme-linked immunosorbent assay were used to determine the levels of interleukin-6 (IL-6), IL-1β, and tumor necrosis factor-α, and reactive oxygen species. The morphology of mitochondria in type Ⅱ epithelial cells of lung tissue was observed using transmission electron microscopy; and the apoptosis of lung tissue, the level of mitophagy, and the co-localization of Pink1 and Parkin were determined using immunofluorescence. The expression of Pink1, Parkin, mitofusin-2 (MFN2), phosphatase and tensin homolog (PTEN), PTEN-L, p62, and the autophagy marker microtubule-associated protein 1 light chain 3 (LC3) in rat lung tissue was measured by Western blotting, and the ratio of LC3II/LC3I was calculated.
    Results: Compared with the EHS group, the survival rate of rats in the EHS + Parkin group was significantly higher. Their lung coefficient and pulmonary vascular permeability decreased and the pathological changes were significantly alleviated (P <0.05). Their levels of inflammatory factors and reactive oxygen species were significantly decreased (P <0.05), and the degree of mitochondrial swelling in pulmonary type II epithelial cells was alleviated. The apoptosis of lung tissue was alleviated, the colocalization of Pink1 and Parkin, LC3 and Tom20 was enhanced, and the ratio of LC3-II/LC3-I increased. The expression of Pink1, MFN2, PTEN-L, and p62 decreased, whereas the expression of PTEN was not significantly different from that in the EHS group (P >0.05).
    Conclusion: Pink1/Parkin-mediated mitophagy dysfunction is one of the mechanisms underlying ALI in rats with EHS, and activation of Parkin overexpression-mediated mitophagy can alleviate ALI caused by EHS.
    Keywords:  Acute lung injury; Exertional heat stroke; Mitophagy; Parkin; Pink1
    DOI:  https://doi.org/10.1016/j.jointm.2024.07.004
  13. Cell Commun Signal. 2025 Jan 28. 23(1): 52
    VEGFR3 mitigates hypertensive nephropathy by enhancing mitophagy via regulating crotonylation of HSPA1L.
    Qiuwen Wu, Jiaxin Fu, Bin Zhu, Wei Meng, Jingyi Ma, Ying Lv, Wenqi Zhao, Fan Wang, Jingjin Liu, Yongshun Wang, Cong Peng, Shuo Zhang.
      Oxidative stress-associated proximal tubular cells (PTCs) damage is an important pathogenesis of hypertensive renal injury. We previously reported the protective effect of VEGFR3 in salt-sensitive hypertension. However, the specific mechanism underlying the role of VEGFR3 in kidney during the overactivation of the renin-angiotensin-aldosterone system remains unclear. In the present study, hypertensive nephropathy was established by angiotensin II (Ang II). We found that VEGFR3 was highly increased in PTCs of Ang II-infused mice. Activation of VEGFR3 mitigated renal dysfunction, pathological damage, and oxidative stress in Ang II-induced hypertensive mice. Moreover, we found that VEGFR3 restored mitophagy deficiency induced by Ang II both in vivo and in vitro to alleviate oxidative stress injury in PTCs. Furthermore, in vitro experiment demonstrated that VEGFR3 improved abnormal mitophagy by enhancing PARKIN mitochondrial translocation. LC-MS/MS and Co-IP assays identified HSPA1L as the interacted protein of VEGFR3, which promoted the mitochondrial translocation of PARKIN. Mechanistically, VEGFR3 disorder domain bound to HSPA1L, and crotonylation modification of HSPA1L at K130 by VEGFR3 was required for mitophagy regulation in the context of Ang II-induced PTCs. Finally, the protective effect of VEGFR3 on mitophagy and oxidative stress were attenuated by transfection K130 (HSPA1L-K130R) mutant plasmid in vivo and in vitro. These findings indicated that VEGFR3 alleviated oxidative stress by promoting PARKIN-dependent mitophagy pathway via regulating HSPA1L crotonylation at K130 site in Ang II-induced PTCs, which provided a mechanistic basis for the therapeutic target in hypertensive renal injury.
    Keywords:  Crotonylation; HSPA1L; Hypertensive nephropathy; Mitophagy; Oxidative stress; VEGFR3
    DOI:  https://doi.org/10.1186/s12964-025-02045-x
  14. Biochim Biophys Acta Mol Cell Res. 2025 Jan 27. pii: S0167-4889(25)00016-3. [Epub ahead of print] 119911
    MARCH5 ameliorates aortic valve calcification via RACGAP1-DRP1 pathway associated mitochondrial quality control.
    Jialiang Zhang, Yaoyu Zhang, Wenhua Lei, Jing Zhou, Yanjiani Xu, Zhou Hao, Yanbiao Liao, Fangyang Huang, Mao Chen.
       BACKGROUND: Mitochondrial E3 ubiquitin ligase (MARCH5) as an important regulator in maintaining mitochondrial function. Our aims were to investigate the role and mechanism of MARCH5 in aortic valve calcification.
    METHODS: Human aortic valves, both calcified and non-calcified, were analyzed for MARCH5 expression using western blot. Mitochondrial fragmentation was observed under transmission electron microscope. Osteogenic differentiation of human aortic valvular interstitial cells (HVICs) was induced with osteoblastic medium (OM), confirmed by western blot and Alizarin red staining. Mitochondrial morphology and oxidative phosphorylation were assessed using MitoTracker and Seahorse, respectively. MARCH5-knockdown and ApoE-knockout mice fed high-fat diet were used to study aortic valve calcification.
    RESULTS: The mitochondrial quality control was impaired in calcified valves, and the level of MARCH5 protein was also decreased in calcified valves. Inhibition of MARCH5 impaired mitochondrial quality control, increased mitochondrial stress and accelerates osteogenic transformation in OM treated HVICs. While, overexpression MARCH5 has the opposite effects. Co-immunoprecipitation, mass spectrometry and molecular docking found MARCH5 interacted Rac GTPase-activating protein 1 (RACGAP1) and promoted its ubiquitination, leading to impaired mitochondrial quality control. Inhibiting RACGAP1 reversed osteogenic transformation induced by MARCH5 silencing in OM treated HVICs. Silencing dynamin-related protein 1 (DRP1) under RACGAP1 inhibition had no additional benefit. In vivo, deficiency of MARCH5 promoted aortic valve calcification, while inhibition RACGAP1 reversed aortic valve calcification in MARCH5 deficiency mice.
    CONCLUSION: Downregulation of MARCH5 promotes RACGAP1 ubiquitination, activating DRP1 and impairing mitochondrial quality control, which contributes to aortic valve calcification. This identifies a potential therapeutic target for aortic valve calcification.
    Keywords:  Aortic valve calcification; DRP1; MARCH5; Mitochondrial quality control; Osteogenic differentiation; RACGAP1
    DOI:  https://doi.org/10.1016/j.bbamcr.2025.119911
  15. Biochimie. 2025 Jan 28. pii: S0300-9084(25)00023-9. [Epub ahead of print]
    Mitochondrial dynamics: molecular mechanism and implications in endometriosis.
    Ylenia Marino, Francesca Inferrera, Tiziana Genovese, Salvatore Cuzzocrea, Roberta Fusco, Rosanna Di Paola.
      Endometriosis affects about 10% of women of reproductive age, leading to a disabling gynecologic condition. Chronic pain, inflammation, and oxidative stress have been identified as the molecular pathways involved in the progression of this disease, although its precise etiology remains uncertain. Although mitochondria are considered crucial organelles for cellular activity, their dysfunction has been linked to the development of this disease. The purpose of this review is to examine the functioning of the mitochondrion in endometriosis: in particular, we focused on the mitochondrial dynamics of biogenesis, fusion, and fission. Since excessive mitochondrial activity is reported to affect cell proliferation, we also considered mitophagy as a mechanism involved in limiting disease development. To better understand mitochondrial activity, we also considered alterations in circadian rhythms, the gut microbiome, and estrogen receptors: indeed, these mechanisms are also involved in the development of endometriosis. In addition, we focused on recent research about the impact of numerous substances on mitochondrial activity; some of them may offer a future breakthrough in endometriosis treatment by acting on mitochondria and inhibiting cell proliferation.
    Keywords:  Endometriosis; Inflammation; Mitochondria; Mitochondrial Dysfunction; Oxidative stress
    DOI:  https://doi.org/10.1016/j.biochi.2025.01.012
  16. Redox Biol. 2025 Jan 23. pii: S2213-2317(25)00024-2. [Epub ahead of print]80 103511
    The UCP2/PINK1/LC3b-mediated mitophagy is involved in the protection of NRG1 against myocardial ischemia/reperfusion injury.
    Xin-Tao Li, Xin-Yue Li, Tian Tian, Wen-He Yang, Shuai-Guo Lyv, Yi Cheng, Kai Su, Xi-Hua Lu, Mu Jin, Fu-Shan Xue.
      Available evidence indicates that neuregulin-1 (NRG-1) can provide a protection against myocardial ischemia/reperfusion (I/R) injury and is involved in various cardioprotective interventions by potential regulation of mitophagy. However, the molecular mechanisms linking NRG-1 and mitophagy remain to be clarified. In this study, both an in vivo myocardial I/R injury model of rats and an in vitro hypoxia/reoxygenation (H/R) model of H9C2 cardiomyocytes were applied to determine whether NRG-1 postconditioning attenuated myocardial I/R injury through the regulation of mitophagy and to explore the underlying mechanisms. In the in vivo experiment, cardioprotective effects of NRG-1 were determined by infarct size, cardiac enzyme and histopathologic examinations. The potential downstream signaling pathways and molecular targets of NRG-1 were screened by the RNA sequencing and the Protein-Protein Interaction Networks. The expression levels of mitochondrial uncoupling protein 2 (UCP2) and mitophagy-related proteins in both the I/R myocardium and H/R cardiomyocytes were measured by immunofluorescence staining and Western blots. The activation of mitophagy was observed with transmission electron microscopy and JC-1 staining. The KEGG and GSEA analyses showed that the mitophagy-related signaling pathways were enriched in the I/R myocardium treated with NRG-1, and UCP2 exhibited a significant correlation between mitophagy and interaction with PINK1. Meanwhile, the treatment with mitophagy inhibitor Mdivi-1 significant eliminated the cardioprotective effects of NRG-1 postconditioning in vivo, and the challenge with UCP2 inhibitor genipin could also attenuate the activating effect of NRG-1 postconditioning on mitophagy. Consistently, the in vitro experiment using H9C2 cardiomyocytes showd that NRG-1 treatment significantly up-regulated the expression levels of UCP2 and mitophagy-related proteins, and activated the mitophagy, whereas the challenge with small interfering RNA-mediated UCP2 knockdown abolished the effects of NRG-1. Thus, it is conclused that NRG-1 postconditioning can produce a protection against the myocardial I/R injury by activating mitophagy through the UCP2/PINK1/LC3B signaling pathway.
    Keywords:  Ischemia/reperfusion injury; Mitophagy; Neuregulin-1; Uncoupling protein 2
    DOI:  https://doi.org/10.1016/j.redox.2025.103511
  17. Mol Cell Neurosci. 2025 Jan 23. pii: S1044-7431(25)00002-8. [Epub ahead of print]132 103992
    Mitochondrial fission and fusion in neurodegenerative diseases:Ca2+ signalling.
    Xuan Liu, Tianjiao Li, Xinya Tu, Mengying Xu, Jianwu Wang.
      Neurodegenerative diseases (NDs) are a group of disorders characterized by the progressive loss of neuronal structure and function. The pathogenesis is intricate and involves a network of interactions among multiple causes and systems. Mitochondria and Ca2+ signaling have long been considered to play important roles in the development of various NDs. Mitochondrial fission and fusion dynamics are important processes of mitochondrial quality control, ensuring the stability of mitochondrial structure and function. Mitochondrial fission and fusion imbalance and Ca2+ signaling disorders can aggravate the disease progression of NDs. In this review, we explore the relationship between mitochondrial dynamics and Ca2+ signaling in AD, PD, ALS, and HD, focusing on the roles of key regulatory proteins (Drp1, Fis1, Mfn1/2, and Opa1) and the association structures between mitochondria and the endoplasmic reticulum (MERCs/MAMs). We provide a detailed analysis of their involvement in the pathogenesis of these four NDs. By integrating these mechanisms, we aim to clarify their contributions to disease progression and offer insights into the development of therapeutic strategies that target mitochondrial dynamics and Ca2+ signaling. We also examine the progress in drug research targeting these pathways, highlighting their potential as therapeutic targets in the treatment of NDs.
    Keywords:  Ca(2+) signaling; Mitochondrial fusion and fission; Mitochondrial-associated membranes (MAMs); Mitochondrial–ER contact sites (MERCs); Neurodegenerative diseases; Potential drugs
    DOI:  https://doi.org/10.1016/j.mcn.2025.103992
  18. Sci Rep. 2025 Jan 29. 15(1): 3686
    Altered mitochondrial unfolded protein response and FGF21 secretion in MASLD progression and the effect of exercise intervention.
    Xinmeng Yuan, Wen Sun, Ye Xu, Mengqi Xiang, Yaran Gao, Wanyu Feng, Hongjian Xiao, Liumei Zhang, Qiang Tang, Jiao Lu, Yuan Zhang.
      A high-calorie diet and lack of exercise are the most important risk factors contributing to metabolic dysfunction-associated steatotic liver disease (MASLD) initiation and progression. The precise molecular mechanisms of mitochondrial function alteration during MASLD development remain to be fully elucidated. In this study, a total of 60 male C57BL/6J mice were maintained on a normal or amylin liver NASH (AMLN) diet for 6 or 10 weeks. Some of the mice were then subjected to voluntary wheel running, while the other mice were fed a normal or AMLN diet until 14 and 18 weeks. The results showed that hepatic lipid deposition and the PERK-eIF2α-ATF4 pathway were significantly increased with prolonged duration of AMLN diet. However, expression of mitochondrial unfolded protein response (UPRmt) genes and mitokine FGF21 secretion were significantly enhanced in the 14-week AMLN diet mice, but were markedly reduced with the excessive lipid deposition induced by longer AMLN diet. Additionally, the exercise intervention acts as a regulator to optimize UPRmt signal transduction and to enhance mitochondrial homeostasis by improving mitochondrial function, reversing the UPRmt activation pattern, and increasing FGF21 secretion, which plays a pivotal role in delaying the occurrence and development of MASLD.
    Keywords:  AMLN diet; Exercise intervention; Hepatic lipid accumulation; MASLD progression; Mitochondrial unfolded protein response
    DOI:  https://doi.org/10.1038/s41598-025-87190-6
  19. J Ethnopharmacol. 2025 Jan 28. pii: S0378-8741(25)00108-4. [Epub ahead of print] 119425
    Beneficial Effects of the Herbal Medicine Zuo Gui Wan in a Mice Model of Alzheimer's Disease via Drp1-Mediated Inhibition of Mitochondrial Fission and Activation of AMPK/PGC-1α-regulated Mitochondrial Bioenergetics.
    Xirui Yan, Yifang Yang, Weiling Huang, Shuping Fu, Bo Cui, Min Chu, Yang Dong, Yinting Peng, Haiyan Song, Jianrong Shi, Qing Liu.
       ETHNOPHARMACOLOGICAL RELEVANCE: Zuo Gui Wan (ZGW) is a well-known traditional Chinese medicine decoction used for approximately 400 years to treat age-related degenerative conditions, including cognitive impairment in older adults, osteoporosis, and general aging. However, the mechanism of action for ZGW remains unclear.
    AIMS OF THE STUDY: This study aims to investigate the efficacy of ZGW in improving cognitive function in Alzheimer's disease (AD) animal models and to explore the underlying mechanisms, presenting a novel perspective in the field.
    MATERIALS AND METHODS: Six-month-old male APP/PS1 mice were divided into three groups that received either metformin (200 mg/kg daily) or ZGW (6 and 12 g/kg daily). High-performance liquid chromatography was conducted for ZGW's quality control. Cognitive function was assessed using the Morris water maze test. Neuronal loss, synaptic plasticity, and β-amyloid (Aβ) deposition were evaluated through Western blot or immunofluorescence staining. The underlying molecular mechanisms were investigated using ELISA, Western blot, qRT-PCR, co-immunoprecipitation assay, ATP assay, and cytochrome c oxidase assay.
    RESULTS: ZGW, administered in both low and high doses, significantly enhanced cognitive performance, notably decreased neuronal loss and Aβ deposition, and reduced levels of Aβ1-40/42. It also inhibited excessive mitochondrial division primarily by suppressing phosphorylated Drp1, especially at high doses of ZGW. Co-immunoprecipitation experiments further confirmed that ZGW inhibited the interaction between Aβ and p-Drp1. Furthermore, similar to the effects of the AMPK activator metformin, ZGW led to a marked increase in the mitochondrial DNA copy number and upregulated the AMPK/PGC-1α/NRF1/TFAM pathway. Improvements in mitochondrial function were evident from the increased ATP production, elevated expression of SOD2, and upregulated cytochrome c oxidase activity. Additionally, the excess byproduct of reactive oxygen species, 4-HNE, decreased in the group treated with ZGW.
    CONCLUSION: This study provides compelling evidence that ZGW improves cognitive impairment in APP/PS1 mice by activating AMPK/PGC-1α-regulated mitochondrial bioenergetics and inhibiting Aβ-induced mitochondrial fragmentation, highlighting its potential as an effective therapeutic strategy for AD.
    Keywords:  AMPK; Alzheimer’s disease; Aβ; Drp1; Metformin; Mitochondrial; Zuo Gui Wan
    DOI:  https://doi.org/10.1016/j.jep.2025.119425
  20. Pharmaceuticals (Basel). 2025 Jan 16. pii: 112. [Epub ahead of print]18(1):
    Dysregulation of Mitochondrial Homeostasis in Cardiovascular Diseases.
    Ricky Patil, Hui Wang, Matthew Kazaleh, Gorav Ailawadi, Morgan Salmon.
      Mitochondria dysfunction plays a central role in the development of vascular diseases as oxidative stress promotes alterations in mitochondrial morphology and function that contribute to disease progression. Redox imbalances can affect normal cellular processes including mitochondrial biogenesis, electrochemical equilibrium, and the regulation of mitochondrial DNA. In this review, we will discuss these imbalances and, in particular, the potential role of mitochondrial fusion, fission, biogenesis, and mitophagy in the context of vascular diseases and how the dysregulation of normal function might contribute to disease progression. We will also discuss potential implications of targeting mitochondrial regulation as therapeutic targets to treat vascular disease formation.
    Keywords:  B-aminopropionitrile; aorta; aortic aneurysm; cardiac surgery; elastase; inflammation; mitochondria; murine model
    DOI:  https://doi.org/10.3390/ph18010112
  21. Front Immunol. 2024 ;15 1484373
    Mitochondrial dysfunction in Alzheimer's disease: a key frontier for future targeted therapies.
    Shuguang Wang, Zuning Liao, Qiying Zhang, Xinyuan Han, Changqing Liu, Jin Wang.
      Alzheimer's disease (AD) is the most common neurodegenerative disorder, accounting for approximately 70% of dementia cases worldwide. Patients gradually exhibit cognitive decline, such as memory loss, aphasia, and changes in personality and behavior. Research has shown that mitochondrial dysfunction plays a critical role in the onset and progression of AD. Mitochondrial dysfunction primarily leads to increased oxidative stress, imbalances in mitochondrial dynamics, impaired mitophagy, and mitochondrial genome abnormalities. These mitochondrial abnormalities are closely associated with amyloid-beta and tau protein pathology, collectively accelerating the neurodegenerative process. This review summarizes the role of mitochondria in the development of AD, the latest research progress, and explores the potential of mitochondria-targeted therapeutic strategies for AD. Targeting mitochondria-related pathways may significantly improve the quality of life for AD patients in the future.
    Keywords:  AD; dysfunction; mechanisms; mitochondria; therapeutic targets
    DOI:  https://doi.org/10.3389/fimmu.2024.1484373
  22. Int J Mol Sci. 2025 Jan 07. pii: 448. [Epub ahead of print]26(2):
    A Multi-Omics Analysis of a Mitophagy-Related Signature in Pan-Cancer.
    Nora Agir, Ilias Georgakopoulos-Soares, Apostolos Zaravinos.
      Mitophagy, an essential process within cellular autophagy, has a critical role in regulating key cellular functions such as reproduction, metabolism, and apoptosis. Its involvement in tumor development is complex and influenced by the cellular environment. Here, we conduct a comprehensive analysis of a mitophagy-related gene signature, composed of PRKN, PINK1, MAP1LC3A, SRC, BNIP3L, BECN1, and OPTN, across various cancer types, revealing significant differential expression patterns associated with molecular subtypes, stages, and patient outcomes. Pathway analysis revealed a complex interplay between the expression of the signature and potential effects on the activity of various cancer-related pathways in pan-cancer. Immune infiltration analysis linked the mitophagy signature with certain immune cell types, particularly OPTN with immune infiltration in melanoma. Methylation patterns correlated with gene expression and immune infiltration. Mutation analysis also showed frequent alterations in PRKN (34%), OPTN (21%), PINK1 (28%), and SRC (15%), with implications for the tumor microenvironment. We also found various correlations between the expression of the mitophagy-related genes and sensitivity in different drugs, suggesting that targeting this signature could improve therapy efficacy. Overall, our findings underscore the importance of mitophagy in cancer biology and drug resistance, as well as its potential for informing treatment strategies.
    Keywords:  BECN1; BNIP3L; MAP1LC3; OPTN; PARK2; PINK1; PRKN; SRC; drug resistance; drug sensitivity; mitophagy; multi-omics; pan-cancer
    DOI:  https://doi.org/10.3390/ijms26020448
  23. Nutrients. 2025 Jan 17. pii: 325. [Epub ahead of print]17(2):
    Fucoidan Oligosaccharide Supplementation Relieved Kidney Injury and Modulated Intestinal Homeostasis in D-Galactose-Exposed Rats.
    Jing Shi, Yan Xu, Kening Zhang, Ying Liu, Nan Zhang, Yabin Zhang, Huaqi Zhang, Xi Liang, Meilan Xue.
      Background/Objectives: A fucoidan oligosaccharide (FOS), a potent compound derived from algae, is known for its diverse biological activities, including prebiotic activity, anticancer activity, and antioxidative properties, and has demonstrated supportive therapeutic effects in treating kidney ailments. This study was conducted to explore the protective influence of FOS on kidney damage due to aging induced by D-galactose in Sprague Dawley (SD) rats. Methods: The low-dose FOS group was administered FOS (100 mg/kg) by gavage, and the high-FOS group received FOS (200 mg/kg) by gavage. Results: The findings showed that FOS could effectively mitigate kidney damage and improve the pathological condition of kidney tissues caused by D-gal and enhance kidney function. Intervention with FOS significantly reduced serum creatinine, serum uric acid, and serum urea nitrogen levels, compared to the model group. The protective mechanism of FOS on D-gal-induced kidney injury may be to inhibit oxidative stress and improve impaired mitochondrial function by downregulating the AMPK/ULK1 signaling pathway. FOS could also modulate the expression of mitochondrial autophagy-related proteins (Beclin-1, P62, and LC3II/LC3I), thereby mitigate D-gal-induced excessive mitophagy in the kidney. Furthermore, FOS may protect against kidney injury by preserving intestinal homeostasis. FOS decreased serum lipopolysaccharide levels and enhanced intestinal mucosal barrier function. FOS upregulated the abundances of Bacteroidota, Muribaculaceae, and Lactobacillus, while it decreased the abundances of Firmicutes, NK4A136_group, and Lachnospiraceae_NK4A136_group. FOS supplementation modulated gut microbiota composition, increasing beneficial bacteria and reducing detrimental ones, potentially contributing to improved kidney function. Conclusions: FOS may safeguard against renal injury in D-gal-exposed rats by inhibiting kidney excessive mitophagy, preserving mitochondrial function, and regulating intestinal homeostasis.
    Keywords:  fucoidan oligosaccharide; kidney injury; mitochondrial autophagy
    DOI:  https://doi.org/10.3390/nu17020325
  24. J Inflamm Res. 2025 ;18 1091-1106
    Decrease of NAD+ Inhibits the Apoptosis of OLP T Cells via Inducing Mitochondrial Fission.
    Zhuo-Yu Zhang, Fang Wang, Gang Zhou.
       Purpose: Oral lichen planus (OLP) is a chronic, immune-mediated inflammatory disease involving T cells. Mitochondrial fission plays a crucial role in T cell fate through structural remodeling. Nicotinamide adenine dinucleotide (NAD+) regulates mitochondrial remodeling and function. This study explored the role of NAD+ in modulating mitochondrial fission and apoptosis in T cells under the OLP immune-inflammatory environment.
    Patients and Methods: T cells and plasma were isolated from peripheral blood. Mitochondrial morphology was characterized by transmission electron microscopy and Mito-Tracker staining. OLP plasma-exposed Jurkat T cells were infected with the Drp1 shRNA virus to investigate the role of mitochondrial fission in OLP T cell apoptosis. OLP T cells and OLP plasma-exposed Jurkat T cells were treated with either β-nicotinamide mononucleotide (an NAD+ synthesis precursor) or FK866 (an NAD+ synthesis inhibitor) to assess the effect of NAD+ regulation on mitochondrial remodeling and T cell apoptosis.
    Results: OLP T cells exhibited fragmented mitochondria with elevated dynamin-related protein 1 (Drp1) and reduced mitofusin 2 (Mfn2) expression, accompanied by decreased apoptosis. Drp1 knockdown in OLP plasma-exposed Jurkat T cells increased apoptosis and reduced proliferation. NAD+ levels were reduced in both OLP T cells and OLP plasma-treated Jurkat T cells, leading to enhanced mitochondrial fission, decreased mitochondrial membrane potential (MMP) and respiration function, and reduced apoptosis rate. β-nicotinamide mononucleotide supplementation restored NAD+ levels, suppressed mitochondrial fission, improved MMP, and promoted apoptosis in these cells.
    Conclusion: Reduced NAD+ levels in OLP T cells enhanced mitochondrial fission and contributed to decreased apoptosis. NAD+ supplementation mitigated these effects, suggesting a potential therapeutic strategy for restoring T cell homeostasis in OLP.
    Keywords:  T cells; mitochondria; nicotinamide adenine dinucleotide; oral lichen planus
    DOI:  https://doi.org/10.2147/JIR.S502273
  25. In Vitro Cell Dev Biol Anim. 2025 Jan 27.
    Adipose-derived stem cells regulate mitochondrial dynamics to alleviate the aging of HFF-1 cells.
    Qi Luo, Ling Liu.
      The objective of this study is to explore how adipose-derived stem cells (ASCs) regulate mitochondrial structure and function and the impact of this regulation on slowing cellular senescence. HFF-1 cells were induced by H2O2 to establish a cellular senescence model, and ASCs or Mdivi-1 (mitochondrial fission inhibitor) was added. MTT examined the cell proliferation; flow cytometry detected mitochondrial membrane potential as well as apoptosis and cell cycle; kit measured ATP production; ELISA analyzed the levels of interleukin-6 (IL-6), interleukin 1 beta (IL-1β), tumor necrosis factor alpha-like (TNF-α), glutathione (GSH), malondialdehyde (MDA), and superoxide dismutase (SOD); Western blotting and qRT-PCR detected the expression of protein and mRNA levels; and β-galactosidase staining observed the degree of cellular senescence. Compared to normal HFF-1 cells, senescent HFF-1 cells exhibited weaker proliferative capacity, marked apoptosis, and G0-G1 cell cycle arrest. These cells also showed lower mitochondrial membrane potential and ATP production, higher expression of inflammatory factors, oxidative damage, and increased levels of senescence. Treatment with Mdivi-1 or ASCs enhanced HFF-1 cell proliferation, reduced apoptosis and cell cycle arrest, increased mitochondrial membrane potential and ATP production, decreased the expression of inflammatory factors, and mitigated oxidative stress, thereby reducing the degree of cellular senescence. Concurrent intervention with Mdivi-1 and ASCs further diminishes the impacts of cellular senescence. In conclusion, ASCs regulate mitochondrial dynamics (promoting mitochondrial fusion and inhibiting mitochondrial fission), enhance ATP production, and upregulate mitochondrial membrane potential, thereby alleviating cell cycle arrest, apoptosis, inflammatory responses, and oxidative stress induced by senescence in HFF-1 cells.
    Keywords:  Adipose-derived stem cells; Aging; Cellular senescence; Mitochondrial dynamics
    DOI:  https://doi.org/10.1007/s11626-025-01017-2
  26. Int Immunopharmacol. 2025 Jan 23. pii: S1567-5769(25)00108-0. [Epub ahead of print]148 114119
    Histone lactylation regulates PRKN-Mediated mitophagy to promote M2 Macrophage polarization in bladder cancer.
    Xiaolin Deng, Yuan Huang, Jinge Zhang, Yuwen Chen, Feifan Jiang, Zicai Zhang, Tanghua Li, Lina Hou, Wanlong Tan, Fei Li.
       BACKGROUND: Bladder cancer (BCa), particularly muscle-invasive bladder cancer (MIBC), is associated with poor prognosis, partly because of immune evasion driven by M2 tumor-associated macrophages (TAMs). Understanding the regulatory mechanisms of M2 macrophage polarization via PRKN-mediated mitophagy and histone lactylation (H3K18la) is crucial for improving treatment strategies.
    METHODS: A single-cell atlas from 46 human BCa samples was constructed to identify macrophage subpopulations. Bioinformatics analysis and experimental validation, including ChIP-seq and lactylation modulation assays, were used to investigate the role of PRKN in M2 macrophage polarization and its regulation by H3K18la.
    RESULTS: Single-cell analysis revealed distinct macrophage subpopulations, including M1 and M2 types. PRKN was identified as a critical regulator of mitophagy in M2 macrophages, supporting their immunosuppressive function. Bulk RNA-seq and gene intersection analysis revealed a set of mitophagy-related macrophage polarization genes (Mito_Macro_RGs) enriched in mitophagy and immune pathways. Pseudotime analysis revealed that PRKN was upregulated during the M1-to-M2 transition. siRNA-mediated PRKN knockdown impaired M2 polarization, reducing the expression of CD206 and ARG1. ChIP-seq and histone lactylation modulation confirmed that H3K18la enhanced PRKN expression, promoting mitophagy and M2 polarization and thereby facilitating immune suppression and tumor progression.
    CONCLUSIONS: Histone lactylation regulated PRKN-mediated mitophagy, promoting M2 macrophage polarization and contributing to immune evasion in BCa.
    Keywords:  Bladder cancer; H3K18la; M2 macrophage polarization; Mitophagy; PRKN
    DOI:  https://doi.org/10.1016/j.intimp.2025.114119
  27. CNS Neurosci Ther. 2025 Jan;31(1): e70149
    Protective Effects of Mdivi-1 on Cognition Disturbance Following Sepsis in Mice via Alleviating Microglia Activation and Polarization.
    Chen Hong, Li Wang, Xiaowei Zhou, Liyong Zou, Xinming Xiang, Haoyue Deng, Qinghui Li, Yue Wu, Liangming Liu, Tao Li.
       BACKGROUND: Neuroinflammation is one of the essential pathogeneses of cognitive damage suffering from sepsis-associated encephalopathy (SAE). Lots of evidences showed the microglia presented mitochondrial fragmentation during SAE. This study investigated the protective effects and novel mechanisms of inhibiting microglia mitochondrial fragmentation via mitochondrial division inhibitor 1 (Mdivi-1) on cognitive damage in SAE.
    METHODS: The SAE model was performed by cecal ligation and puncture (CLP), and Mdivi-1 was administrated via intraperitoneal injection. Morris water maze was performed to assess cognitive function. Mitochondrial morphology was observed by electron microscope or MitoTracker staining. The qRT-PCR, immunofluorescence staining, and western blots were used to detect the inflammatory factors and protein content, respectively. Flow cytometry was used to detect the polarization of hippocampal microglia. Bioinformatics analysis was used to verify hypotheses.
    RESULTS: Mdivi-1 administration alleviated sepsis-induced mitochondrial fragmentation, microglia activation, polarization, and cognitive damage. The mechanisms study showed neuroinflammation and oxidative stress were suppressed via NF-κB and Keap1/Nrf2/HO-1 pathways following Mdivi-1 administration; meanwhile, pyroptosis in microglia was reduced, which was associated with enhanced autophagosome formation via p62 elevation following Mdivi-1 administration.
    CONCLUSION: Inhibition of microglia mitochondrial fragmentation is beneficial to SAE cognitive disturbance, the mechanisms are related to alleviating neuroinflammation, oxidative stress, and pyroptosis.
    Keywords:  Mdivi‐1; cognition; mitochondrial fission; pyroptosis; sepsis‐associated encephalopathy
    DOI:  https://doi.org/10.1111/cns.70149
  28. Int J Mol Sci. 2025 Jan 18. pii: 806. [Epub ahead of print]26(2):
    Autophagy and Mitophagy in Diabetic Kidney Disease-A Literature Review.
    Alina Mihaela Stanigut, Liliana Tuta, Camelia Pana, Luana Alexandrescu, Adrian Suceveanu, Nicoleta-Mirela Blebea, Ileana Adela Vacaroiu.
      Autophagy and mitophagy are critical cellular processes that maintain homeostasis by removing damaged organelles and promoting cellular survival under stress conditions. In the context of diabetic kidney disease, these mechanisms play essential roles in mitigating cellular damage. This review provides an in-depth analysis of the recent literature on the relationship between autophagy, mitophagy, and diabetic kidney disease, highlighting the current state of knowledge, existing research gaps, and potential areas for future investigations. Diabetic nephropathy (DN) is traditionally defined as a specific form of kidney disease caused by long-standing diabetes, characterized by the classic histological lesions in the kidney, including mesangial expansion, glomerular basement membrane thickening, nodular glomerulosclerosis (Kimmelstiel-Wilson nodules), and podocyte injury. Clinical markers for DN are albuminuria and the gradual decline in glomerular filtration rate (GFR). Diabetic kidney disease (DKD) is a broader and more inclusive term, for all forms of chronic kidney disease (CKD) in individuals with diabetes, regardless of the underlying pathology. This includes patients who may have diabetes-associated kidney damage without the typical histological findings of diabetic nephropathy. It also accounts for patients with other coexisting kidney diseases (e.g., hypertensive nephrosclerosis, ischemic nephropathy, tubulointerstitial nephropathies), even in the absence of albuminuria, such as a reduction in GFR.
    Keywords:  AMPK-mTOR-Sirt1 pathway; PINK1/Parkin pathway; autophagy; diabetic nephropathy; mitochondrial dysfunction; mitophagy
    DOI:  https://doi.org/10.3390/ijms26020806
  29. Anal Chim Acta. 2025 Feb 22. pii: S0003-2670(25)00039-X. [Epub ahead of print]1340 343645
    Acid triggering highly-efficient release of reactive oxygen species to block mitochondrial-mediated homeostasis maintenance for accelerating cell death.
    Yuxin Yang, Shen Wang, Xingxing Chen, Xuetao Wu, Junjun Wang, Yingcui Bu, Chang Xu, Qiong Zhang, Xiaojiao Zhu, Hongping Zhou.
      A pivotal pathway of photodynamic therapy (PDT) is to prompt mitochondrial damage by reactive oxygen species (ROS) generation, thus leading to cancer cell apoptosis. However, mitochondrial autophagy is induced during such a PDT process, which is a protective mechanism for cancer cell homeostasis, resulting in undermined therapeutic efficacy. Herein, we report a series of meticulously designed donor (D)-π-acceptor (A) photosensitizers (PSs), characterized by the strategic modulation of thiophene π-bridges, which exhibit unparalleled mitochondrial targeting proficiency. Notably, TTBI within this series possesses remarkable ROS generation capability, which can directly trigger mitochondrial depolarization, thus effectively inducing apoptosis in cancer cells. Meanwhile, the damaged mitochondria activate the mitophagy process, which further boosts the ROS generation of the TTBI owing to the acidic environment in the lysosome, ultimately inducing lysosomal membrane permeability (LMP), thereby blocking the protective autophagy route and promoting extra apoptotic cell death. Accordingly, TTBI disrupts the integrity of mitochondrial and lysosome, leveraging a synergistic interplay between cellular compartments to achieve more potent apoptosis. This work provides new insights to overcome the limitation of PDT efficacy imposed by mitochondrial autophagy.
    Keywords:  Boosted ROS generation ability; Mitophagy activation; Organelle integrity; Thiophene π bridge
    DOI:  https://doi.org/10.1016/j.aca.2025.343645
  30. J Biomed Sci. 2025 Jan 20. 32(1): 9
    Targeting enolase 1 reverses bortezomib resistance in multiple myeloma through YWHAZ/Parkin axis.
    Xuejie Gao, Qilin Feng, Qikai Zhang, Yifei Zhang, Chaolu Hu, Li Zhang, Hui Zhang, Guanli Wang, Ke Hu, Mengmeng Ma, Zhuning Wang, Yujie Liu, Dong An, Hongfei Yi, Yu Peng, Xiaosong Wu, Gege Chen, Xinyan Jia, Haiyan Cai, Jumei Shi.
       BACKGROUND: Enolase 1 (ENO1) is a conserved glycolytic enzyme that regulates glycolysis metabolism. However, its role beyond glycolysis in the pathophysiology of multiple myeloma (MM) remains largely elusive. Herein, this study aimed to elucidate the function of ENO1 in MM, particularly its impact on mitophagy under bortezomib-induced apoptosis.
    METHODS: The bone marrow of clinical MM patients and healthy normal donors was used to compare the expression level of ENO1. Using online databases, we conducted an analysis to examine the correlation between ENO1 expression and both clinicopathological characteristics and patient outcomes. To investigate the biological functions of ENO1 in MM and the underlying molecular mechanisms involved, we conducted the following experiment: construction of a subcutaneous graft tumor model, co-immunoprecipitation, western blot, quantitative real-time polymerase chain reaction, immunohistochemistry, flow cytometry, and cell functional assays.
    RESULTS: ENO1 was identified as an unfavorable prognostic factor in MM. ENO1 knockdown suppresses tumorigenicity and causes cell cycle arrest. Inhibition of ENO1-regulated mitophagy sensitizes tumor cells to apoptosis. ENO1 enhanced the stability of the YWHAZ protein by increasing the acetylation of lysine in YWHAZ while antagonizing its ubiquitination, which in turn promoted mitophagy. HDAC6 mediates the deacetylation of YWHAZ by deacetylating the K138 site of YWHAZ. Inhibition of HDAC6 increased YWHAZ acetylation and decreased YWHAZ ubiquitination. Furthermore, combination treatment with bortezomib and pharmaceutical agents targeting ENO1 has synergistic anti-MM effects both in vivo and in vitro.
    CONCLUSION: Our data suggest that ENO1 promotes MM tumorigenesis and progression. ENO1 activates mitophagy by promoting the stability of YWHAZ and inhibits apoptosis and thus, leads to the drug resistance. ENO1-dependent mitophagy promotes MM proliferation and suppresses the level of bortezomib-induced apoptosis. Inhibition of ENO1 may represent a potential strategy to reverse the resistance of MM to bortezomib.
    Keywords:  Chemoresistance; ENO1; Mitophagy; Multiple myeloma; YWHAZ
    DOI:  https://doi.org/10.1186/s12929-024-01101-x
  31. Ecotoxicol Environ Saf. 2025 Jan 29. pii: S0147-6513(25)00157-5. [Epub ahead of print]291 117821
    Sodium butyrate attenuates oxidative stress, apoptosis, and excessive mitophagy in sodium fluoride-induced hepatotoxicity in rats.
    Jing Xia, Xiaolin Zhang, Leiyu Xu, Nan Yan, Zhenxiang Sun, Xiaoxu Duan, Lu Meng, Rong Qi, Fu Ren, Zhengdong Wang.
       AIM: Long-term exposure to excess sodium fluoride (NaF) can cause chronic fluorosis. Liver, the most important detoxification organ, is the most vulnerable to the effects of fluoride. Sodium butyrate (NaB), a short-chain fatty acid produced in the intestinal tract, maintains normal mitochondrial function in vivo and reduces liver inflammation and oxidative stress. This study aims to investigate the protective effect and potential mechanism of NaB on liver injury in fluoride poisoned rats, particularly through the mitophagy pathway.
    METHODS: Rats were randomly divided into four groups of 12 male rats each: control, NaF (100 mg/mL), NaB (1000 mg/kg), and NaF (100 mg/mL)+NaB (1000 mg/kg) group.
    KEY FINDINGS: Changes in the levels of liver enzymes (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) and antioxidant enzymes (superoxide dismutase [SOD], catalase [CAT], and malondialdehyde [MDA]) confirmed NaF-induced liver injury. NaF also changed the levels of autophagy markers (Beclin-1, LC3α/β, P62), and increased the level of apoptosis. The combined use of NaB and NaF significantly ameliorated these indices.
    SIGNIFICANCE: These findings indicate that NaB may provide effective protection against NaF-induced liver injury through its attenuates oxidative stress, apoptosis, and excessive mitophagy mechanisms.
    Keywords:  Fluorosis; Liver; Mitophagy; Sodium butyrate; Sodium fluoride
    DOI:  https://doi.org/10.1016/j.ecoenv.2025.117821
  32. Acta Pharmacol Sin. 2025 Jan 24.
    Semaglutide administration protects cardiomyocytes in db/db mice via energetic improvement and mitochondrial quality control.
    Meng-Yun Tian, Ji-Qin Yang, Jin-Chuan Hu, Shan Lu, Yong Ji.
      Diabetic cardiomyopathy causes end-stage heart failure, resulting in high morbidity and mortality in type 2 diabetes mellitus (T2DM) patients. Long-term treatment targeting metabolism is an emerging field in the treatment of diabetic cardiomyopathy. Semaglutide, an agonist of the glucagon-like peptide 1 receptor, is clinically approved for the treatment of T2DM and provides cardiac benefits in patients. However, the cardioprotective mechanism of semaglutide, especially its direct effects on cardiomyocytes (CMs), is not fully understood. Here, we used 8-week diabetic and obese db/db mice treated with semaglutide (200 μg·kg·d-1, i.p.) to study its direct effect on CMs and the underlying mechanisms. Our results revealed that the consecutive application of semaglutide improved cardiac function. Increased AMPK and ULK1 phosphorylation levels were detected, accompanied by elevated [Ca2+]mito. Seahorse analysis revealed that semaglutide increases ATP production via elevated basal and maximum respiration rates as well as spare respiration capacity in CMs. Transmission electron microscopy revealed improved mitochondrial morphology in the cardiomyocytes of db/db mice. On the other hand, Western blot analysis revealed increased Parkin and LC3 protein expression, indicating mitophagy in CMs. Collectively, our findings demonstrate that semaglutide directly protects CMs from high-glucose damage by promoting AMPK-dependent ATP production as well as ULK1-mediated mitophagy in db/db mice.
    Keywords:   db/db mice; diabetic cardiomyopathy; mitochondrial calcium; mitophagy; semaglutide
    DOI:  https://doi.org/10.1038/s41401-024-01448-9
  33. Cytokine Growth Factor Rev. 2025 Jan 17. pii: S1359-6101(25)00004-8. [Epub ahead of print]
    Molecular regulation of mitophagy signaling in tumor microenvironment and its targeting for cancer therapy.
    Bishnu Prasad Behera, Soumya Ranjan Mishra, Srimanta Patra, Kewal Kumar Mahapatra, Chandra Sekhar Bhol, Debasna Pritimanjari Panigrahi, Prakash Priyadarshi Praharaj, Daniel J Klionsky, Sujit Kumar Bhutia.
      Aberrations emerging in mitochondrial homeostasis are restrained by mitophagy to control mitochondrial integrity, bioenergetics signaling, metabolism, oxidative stress, and apoptosis. The mitophagy-accompanied mitochondrial processes that occur in a dysregulated condition act as drivers for cancer occurrence. In addition, the enigmatic nature of mitophagy in cancer cells modulates the cellular proteome, creating challenges for therapeutic interventions. Several reports found the role of cellular signaling pathways in cancer to modulate mitophagy to mitigate stress, immune checkpoints, energy demand, and cell death. Thus, targeting mitophagy to hinder oncogenic intracellular signaling by promoting apoptosis, in hindsight, might have an edge against cancer. This review highlights the receptors and adaptors, and the involvement of many proteins in mitophagy and their role in oncogenesis. It also provides insight into using mitophagy as a potential target for therapeutic intervention in various cancer types.
    Keywords:  Apoptosis; Bioenergetics; Cancer; Mitophagy; Oxidative stress
    DOI:  https://doi.org/10.1016/j.cytogfr.2025.01.004
  34. Food Funct. 2025 Jan 28.
    Strawberry anthocyanin pelargonidin-3-glucoside attenuated OA-induced neurotoxicity by activating UPRmt.
    Xiao Han, Xinyi Chen, Xiaodong Zheng, Fujie Yan.
      In this study, network pharmacology analysis revealed that strawberry anthocyanins mainly interfered with lipid metabolism and nerve-related signaling pathways. Pelargonidin-3-glucoside (Pg3G), one of the main anthocyanins in strawberry, was screened as the most effective anthocyanin for attenuating excess lipid accumulation. Moreover, Pg3G decreased lipid levels, relieved oxidative stress, and restored abnormal behavioral activities in Caenorhabditis elegans under oleic acid (OA) exposure. Meanwhile, Pg3G increased the expression of HSP-6 and HSP-60 proteins and activated the mitochondrial unfolded protein response (UPRmt), while beneficial effects of Pg3G were impaired in the ubl-5 knockout strain, suggesting that ubl-5 may be a key target for improving OA-induced neurotoxicity. Expressions of neurotransmitter transmission-related genes showed great correlations with genes involved in lipid metabolism and UPRmt, further explaining the underlying mechanism of Pg3G in neuroprotection. Our findings emphasize the key role of UPRmt in alleviating OA-induced neurotoxicity of Pg3G, providing a theoretical basis for the research and development of strawberry anthocyanins as a dietary supplement for lipid reduction and treatment of neurodegenerative diseases.
    DOI:  https://doi.org/10.1039/d4fo04639k
  35. J Cell Biol. 2025 Mar 03. pii: e202311082. [Epub ahead of print]224(3):
    FAM43A coordinates mtDNA replication and mitochondrial biogenesis in response to mtDNA depletion.
    Alva G Sainz, Gladys R Rojas, Alexandra G Moyzis, Matthew P Donnelly, Kailash C Mangalhara, Melissa A Johnson, Pau B Esparza-Moltó, Kym J Grae, Reuben J Shaw, Gerald S Shadel.
      Mitochondrial retrograde signaling (MRS) pathways relay the functional status of mitochondria to elicit homeostatic or adaptive changes in nuclear gene expression. Budding yeast have "intergenomic signaling" pathways that sense the amount of mitochondrial DNA (mtDNA) independently of oxidative phosphorylation (OXPHOS), the primary function of genes encoded by mtDNA. However, MRS pathways that sense the amount of mtDNA in mammalian cells remain poorly understood. We found that mtDNA-depleted IMR90 cells can sustain OXPHOS for a significant amount of time, providing a robust model system to interrogate human intergenomic signaling. We identified FAM43A, a largely uncharacterized protein, as a CHK2-dependent early responder to mtDNA depletion. Depletion of FAM43A activates a mitochondrial biogenesis program, resulting in an increase in mitochondrial mass and mtDNA copy number via CHK2-mediated upregulation of the p53R2 form of ribonucleotide reductase. We propose that FAM43A performs a checkpoint-like function to limit mitochondrial biogenesis and turnover under conditions of mtDNA depletion or replication stress.
    DOI:  https://doi.org/10.1083/jcb.202311082
  36. J Physiol. 2025 Jan 27.
    Placental mitochondrial metabolic adaptation maintains cellular energy balance in pregnancy complicated by gestational hypoxia.
    Wen Tong, Beth J Allison, Kirsty L Brain, Olga V Patey, Youguo Niu, Kimberley J Botting, Sage G Ford, Tess A Garrud, Peter F B Wooding, Qiang Lyu, Lin Zhang, Jin Ma, Alice P Sowton, Katie A O'Brien, Tereza Cindrova-Davies, Hong Wa Yung, Graham J Burton, Andrew J Murray, Dino A Giussani.
      The mechanisms that drive placental dysfunction in pregnancies complicated by hypoxia and fetal growth restriction remain poorly understood. Changes to mitochondrial respiration contribute to cellular dysfunction in conditions of hypoxia and have been implicated in the pathoaetiology of pregnancy complications, such as pre-eclampsia. We used bespoke isobaric hypoxic chambers and a combination of functional, molecular and imaging techniques to study cellular metabolism and mitochondrial dynamics in sheep undergoing hypoxic pregnancy. We show that hypoxic pregnancy in sheep triggers a shift in capacity away from β-oxidation and complex I-mediated respiration, while maintaining total oxidative phosphorylation capacity. There are also complex-specific changes to electron transport chain composition and a switch in mitochondrial dynamics towards fission. Hypoxic placentas show increased activation of the non-canonical mitochondrial unfolded protein response pathway and enhanced insulin like growth factor 2 signalling. Combined, therefore, the data show that the hypoxic placenta undergoes significant metabolic and morphological adaptations to maintain cellular energy balance. Chronic hypoxia during pregnancy in sheep activated placental mitochondrial stress pathways, leading to alterations in mitochondrial respiration, mitochondrial energy metabolism and mitochondrial dynamics, as seen in the placenta of women with pre-eclampsia. KEY POINTS: Hypoxia shifts mitochondrial respiration away from β-oxidation and complex I. Complex-specific changes occur in the electron transport chain composition. Activation of the non-canonical mitochondrial unfolded protein response pathway is heightened in hypoxic placentas. Enhanced insulin like growth factor 2 signalling is observed in hypoxic placentas. Hypoxic placentas undergo significant functional adaptations for energy balance.
    Keywords:  chronic hypoxia; metabolic homeostasis; mitochondrial reactive oxygen species; mitochondrial respiration; non‐canonical mitochondrial unfolded protein response; placental metabolism
    DOI:  https://doi.org/10.1113/JP287897
  37. Nat Commun. 2025 Jan 25. 16(1): 1021
    The 40S ribosomal subunit recycling complex modulates mitochondrial dynamics and endoplasmic reticulum - mitochondria tethering at mitochondrial fission/fusion hotspots.
    Foozhan Tahmasebinia, Yinglu Tang, Rushi Tang, Yi Zhang, Will Bonderer, Maisa de Oliveira, Bretton Laboret, Songjie Chen, Ruiqi Jian, Lihua Jiang, Michael Snyder, Chun-Hong Chen, Yawei Shen, Qing Liu, Boxiang Liu, Zhihao Wu.
      The 40S ribosomal subunit recycling pathway is an integral link in the cellular quality control network, occurring after translational errors have been corrected by the ribosome-associated quality control (RQC) machinery. Despite our understanding of its role, the impact of translation quality control on cellular metabolism remains poorly understood. Here, we reveal a conserved role of the 40S ribosomal subunit recycling (USP10-G3BP1) complex in regulating mitochondrial dynamics and function. The complex binds to fission-fusion proteins located at mitochondrial hotspots, regulating the functional assembly of endoplasmic reticulum-mitochondria contact sites (ERMCSs). Furthermore, it alters the activity of mTORC1/2 pathways, suggesting a link between quality control and energy fluctuations. Effective communication is essential for resolving proteostasis-related stresses. Our study illustrates that the USP10-G3BP1 complex acts as a hub that interacts with various pathways to adapt to environmental stimuli promptly. It advances our molecular understanding of RQC regulation and helps explain the pathogenesis of human proteostasis and mitochondrial dysfunction diseases.
    DOI:  https://doi.org/10.1038/s41467-025-56346-3
  38. Proc Natl Acad Sci U S A. 2025 Jan 14. 122(2): e2407909122
    Nonapoptotic role of EGL-1 in exopher production and neuronal health in Caenorhabditis elegans.
    Zheng Wu, Eric A Cardona, Jesse A Cohn, Jonathan T Pierce.
      While traditionally studied for their proapoptotic functions in activating the caspase, research suggests BH3-only proteins also have other roles such as mitochondrial dynamics regulation. Here, we find that EGL-1, the BH3-only protein in Caenorhabditis elegans, promotes the cell-autonomous production of exophers in adult neurons. Exophers are large, micron-scale vesicles that are ejected from the cell and contain cellular components such as mitochondria. EGL-1 facilitates exopher production potentially through regulation of mitochondrial dynamics. Moreover, an endogenous, low level of EGL-1 expression appears to benefit dendritic health. Our findings provide insights into the role of neuronal BH3-only protein in mitochondrial dynamics, downstream exopher production, and ultimately neuronal health.
    Keywords:  BH3-only protein; exopher; mitochondria; neuroprotection
    DOI:  https://doi.org/10.1073/pnas.2407909122
  39. Redox Rep. 2025 Dec;30(1): 2454892
    M6a demethylase FTO regulates the oxidative stress, mitochondrial biogenesis of cardiomyocytes and PGC-1a stability in myocardial ischemia-reperfusion injury.
    Qiong Jiang, Xuehai Chen, Kezeng Gong, Zhe Xu, Lianglong Chen, Feilong Zhang.
       OBJECTIVE: Myocardial ischemia-reperfusion injury (MIRI) is a highly complex disease with high morbidity and mortality. Studying the molecular mechanism of MIRI and discovering new targets are crucial for the future treatment of MIRI.
    METHODS: We constructed the MIRI rat model and hypoxia/reoxygenation (H/R) injury cardiomyocytes model. RT-PCR and Western blot were used to investigate the expression of the fat mass and obesity-associated (FTO) gene. Electrocardiogram, echocardiography, triphenyltetrazolium chloride (TTC) staining and hematoxylin-eosin (HE) staining were used to assess the model and the effect of FTO overexpression. The generation of reactive oxygen species (ROS) and the levels of superoxide dismutase (SOD2), mitochondrial transcription factor (TFAM) and cytochrome c oxidase I (COXI) were detected to assess the oxidative stress and mitochondrial biogenesis. RNA immunoprecipitation (RIP) and RNA pulldown assays were used to identify the interaction of FTO and PGC-1a. The m6A dot blot, methylated RNA immunoprecipitation PCR (MeRIP-PCR) and RNA stability analysis were used to analyze the regulation of methylation of PGC-1a by FTO.
    RESULTS: FTO was downregulated in MIRI rats and H/R induced cardiomyocytes. Overexpression of FTO inhibited ROS level and increased the expression of SOD2, TFAM and COXI in vitro and in vivo. In addition, PGC-1a was identified as a downstream target of FTO. FTO enhanced the stability of PGC-1a mRNA through removing the m6A modification.
    CONCLUSION: Our study revealed the role of FTO regulates the oxidative stress and mitochondrial biogenesis via PGC-1a in MIRI, which may provide a new approach to mitigating MIRI.
    Keywords:  FTO; PGC-1a; mitochondrial biogenesis; myocardial ischemia-reperfusion injury; oxidative stress
    DOI:  https://doi.org/10.1080/13510002.2025.2454892
  40. Elife. 2025 Jan 29. pii: RP102852. [Epub ahead of print]13
    PEBP1 amplifies mitochondrial dysfunction-induced integrated stress response.
    Ling Cheng, Ian Meliala, Yidi Kong, Jingyuan Chen, Christopher G Proud, Mikael Björklund.
      Mitochondrial dysfunction is involved in numerous diseases and the aging process. The integrated stress response (ISR) serves as a critical adaptation mechanism to a variety of stresses, including those originating from mitochondria. By utilizing mass spectrometry-based cellular thermal shift assay (MS-CETSA), we uncovered that phosphatidylethanolamine-binding protein 1 (PEBP1), also known as Raf kinase inhibitory protein (RKIP), is thermally stabilized by stresses which induce mitochondrial ISR. Depletion of PEBP1 impaired mitochondrial ISR activation by reducing eukaryotic translation initiation factor 2α (eIF2α) phosphorylation and subsequent ISR gene expression, which was independent of PEBP1's role in inhibiting the RAF/MEK/ERK pathway. Consistently, overexpression of PEBP1 potentiated ISR activation by heme-regulated inhibitor (HRI) kinase, the principal eIF2α kinase in the mitochondrial ISR pathway. Real-time interaction analysis using luminescence complementation in live cells revealed an interaction between PEBP1 and eIF2α, which was disrupted by eIF2α S51 phosphorylation. These findings suggest a role for PEBP1 in amplifying mitochondrial stress signals, thereby facilitating an effective cellular response to mitochondrial dysfunction. Therefore, PEBP1 may be a potential therapeutic target for diseases associated with mitochondrial dysfunction.
    Keywords:  PEBP1; cell biology; human; integrated stress response; mitochondrial dysfunction
    DOI:  https://doi.org/10.7554/eLife.102852
  41. Exp Gerontol. 2025 Jan 27. pii: S0531-5565(25)00021-X. [Epub ahead of print] 112693
    Aqueous extract of Atractylodes macrocephala Koidz. improves dexamethasone-induced skeletal muscle atrophy in mice by enhancing mitochondrial biological function.
    Mingzhu Ye, Peng Lai, Yajing Fang, Yafeng Li, Fang Wang, Junqi Yu, Yuyu Zhang, Qiaoyi Yang, Jinsen Zhu, Xiaoqin Xie, Ningrong Yang, Tong Peng.
       PURPOSE: The study aims to investigate the therapeutic effects of the aqueous extract of Atractylodes macrocephala Koidz. (AEA) on dexamethasone (Dex) -induced sarcopenia in mice and to explore its possible mechanisms of action.
    METHODS: This study utilized bioinformatics analysis to explore the primary pathogenic mechanisms of age-related sarcopenia and Dex-induced muscle atrophy. In animal experiments, a mouse model of muscle atrophy was established using Dex, and different doses of AEA were administered for treatment. The therapeutic effects of AEA were evaluated through tests of motor ability and histological analysis, and the molecular mechanisms predicted by bioinformatics were verified by measuring the expression levels of related genes.
    RESULTS: Bioinformatics analysis suggests that there may be shared pathogenic mechanisms related to mitochondrial function and structure between age-related sarcopenia and Dex-induced muscle atrophy. Dex significantly reduced the mass, function, and cross-sectional area of muscle fibers in mice, and also induced changes in muscle fiber types. In contrast, AEA significantly ameliorated the aforementioned atrophic effects caused by Dex. The modulation of mitochondrial biogenesis and dynamics may be a crucial mechanism by which AEA exerts its anti-sarcopenia effects.
    CONCLUSION: AEA can significantly alleviate the symptoms of Dex-induced skeletal muscle atrophy in mice by improving mitochondrial function, indicating its potential for clinical application in the prevention and treatment of age-related sarcopenia.
    Keywords:  Atractylodes macrocephala Koidz.; Dexamethasone; Mitochondria; Sarcopenia
    DOI:  https://doi.org/10.1016/j.exger.2025.112693
  42. J Alzheimers Dis. 2025 Jan 28. 13872877241299832
    Di Huang Yi Zhi Fang improves cognitive function in APP/PS1 mice by inducing neuronal mitochondrial autophagy through the PINK1-parkin pathway.
    Limin Zhang, Hongmei An, Rongrong Zhen, Tong Zhang, Minrui Ding, Mengxue Zhang, Yiguo Sun, Chao Gu.
       BACKGROUND: Alzheimer's disease (AD) is an irreversible age-related neurodegenerative condition characterized by the deposition of amyloid-β (Aβ) peptides and neurofibrillary tangles. Di Huang Yi Zhi (DHYZ) formula, a traditional Chinese herbal compound comprising several prescriptions, demonstrates properties that improve cognitive abilities in clinical. Nonetheless, its molecular mechanisms on treating AD through improving neuron cells mitochondria function have not been deeply investigated.
    OBJECTIVE: This study administered DHYZ to APP/PS1 mice to explore its potential therapeutic mechanisms in AD treatment.
    METHODS: APP/PS1 transgenic mice were given DHYZ (L, M, H), donepezil, or distilled water for a consecutive 12-week period. The Morris water maze test was used to assess memory capacity, transmission electron microscopy was used to observe mitochondrial and synaptic structures, immunohistochemistry and western blot detected proteins involved in the mitochondrial autophagy pathway, ELISA measured serum Aβ content, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assessed neuronal cell apoptosis.
    RESULTS: DHYZ demonstrates a notable therapeutic impact on mice with AD, effectively improving cognitive and memory impairments. DHYZ decreases Aβ accumulation in the hippocampus by reducing BACE1 activity and enhancing Aβ clearance through the blood-brain barrier. Additionally, DHYZ significantly suppresses neuronal apoptosis, enhances synaptic structure, and increases synapse numbers, processes strongly linked to the activation of mitochondrial PINK1-Parkin autophagy.
    CONCLUSIONS: DHYZ enhances cognitive function in APP/PS1 mice by stimulating neuronal mitochondrial autophagy through the PINK1-Parkin pathway.
    Keywords:  Alzheimer's disease; Di Huang Yi Zhi; amyloid-β; autophagy; mitochondrial
    DOI:  https://doi.org/10.1177/13872877241299832
  43. J Ginseng Res. 2025 Jan;49(1): 92-102
    Ginsenoside-Re-rich ethanol extract of Panax ginseng berry enhances healthspan extension via mitostasis and NAD metabolism.
    Minjeong Kim, Su Hwan Kim, Juewon Kim, Eun-Ju Jin, Shibo Wei, Yunju Jo, Chang-Myung Oh, Ki-Tae Ha, Jong-Hwa Roh, Wan-Gi Kim, Donghyun Cho, Young Jin Choi, Su Myung Jung, Dongryeol Ryu.
       Background: Ginseng Berry Concentrate (GBC) enhances exercise capacity in mice, but the effects of its key component, ginsenoside Re (G-Re), on aging and mitochondrial function are not well understood. This study investigates the impact of G-Re on mitophagy and its potential to promote healthy aging.
    Methods: Experiments in C2C12 myocytes and HeLa-mitoKeima-PARKIN cells assessed GBC and G-Re's effects on mitophagy, supported by Gene Set Enrichment Analysis. G-Re was identified as the primary component of GBC via high-performance liquid chromatography. The influence of G-Re on lifespan and healthspan was examined in Caenorhabditis elegans, with a focus on mitophagy pathways.
    Results: GBC and G-Re significantly induced mitophagy and enhanced mitochondrial gene expression, improving mitochondrial function. G-Re extended lifespan and healthspan in C. elegans, effects absent in mitophagy-impaired mutants.
    Conclusion: G-Re enhances mitochondrial function and promotes healthy aging through mitophagy, suggesting its potential for mitigating age-related functional declines.
    Keywords:  Ginseng berry; Ginsenoside Re; Healthy aging; Longevity; Mitochondria; Mitophagy
    DOI:  https://doi.org/10.1016/j.jgr.2024.11.002
  44. Apoptosis. 2025 Jan 25.
    sVEGFR3 alleviates myocardial ischemia/reperfusion injury through regulating mitochondrial homeostasis and immune cell infiltration.
    Liqun Shang, Yuanhan Ao, Xiaolin Huang, Huawei Wu, Kangni Feng, Junjie Wang, Yuan Yue, Zhuoming Zhou, Quan Liu, Huayang Li, Guangguo Fu, Kaizheng Liu, Jinyu Pan, Yang Huang, Jiantao Chen, Guangxian Chen, Mengya Liang, Jianping Yao, Suiqing Huang, Jian Hou, Zhongkai Wu.
      Recent studies have suggested that sVEGFR3 is involved in cardiac diseases by regulating lymphangiogenesis; however, results are inconsistent. The aim of this study was to investigate the function and mechanism of sVEGFR3 in myocardial ischemia/reperfusion injury (MI/RI). sVEGFR3 effects were evaluated in vivo in mice subjected to MI/RI, and in vitro using HL-1 cells exposed to oxygen-glucose deprivation/reperfusion. Echocardiography, TTC-Evans blue staining, ELISA, electron microscopy, immunofluorescence, western blotting, and flow cytometry were used to investigate whether sVEGFR3 attenuates I/R injury. Transcriptome sequencing was used to investigate the downstream mechanism of sVEGFR3. Results showed that, in vivo, sVEGFR3 pretreatment reduced cardiac dysfunction, infarct area, and myocardial injury indicators by reducing ROS production, AIF expression, and apoptosis. In vitro, sVEGFR3 restored mitochondrial homeostasis by stabilizing the mitochondrial membrane potential (MMP) and preventing the opening of mitochondrial permeability transition pores (mPTP). And sVEGFR3 inhibits mitochondrial apoptosis through the Ras/MEK/ERK pathway. Furthermore, I/R injury increased the proportion of M1 macrophages and CD4 + T cells in myocardial tissue, as well as serum IFN-γ and TNF-α levels, whereas sVEGFR3 treatment attenuated these effects. sVEGFR3 attenuates MI/RI by regulating mitochondrial homeostasis and immune cell infiltration, and reduces intrinsic ROS-mediated mitochondrial apoptosis via the Ras/MEK/ERK pathway.
    Keywords:  Immune cell infiltration; Mitochondrial homeostasis; Myocardial ischemia/Reperfusion injury; Ras/MEK/ERK pathway; sVEGFR3
    DOI:  https://doi.org/10.1007/s10495-024-02068-8
  45. Chin J Nat Med. 2025 Jan;pii: S1875-5364(25)60806-5. [Epub ahead of print]23(1): 54-63
    Astragali Radix-Notoginseng Radix et Rhizoma medicine pair prevents cardiac remodeling by improving mitochondrial dynamic balance.
    Pingping Lin, Hong Chen, Zekun Cui, Boyang Yu, Junping Kou, Fang Li.
      Astragali Radix (AR) and Notoginseng Radix et Rhizoma (NR) are frequently employed in cardiovascular disease treatment. However, the efficacy of the AR-NR medicine pair (AN) in improving cardiac remodeling and its underlying mechanism remains unclear. This study aimed to evaluate AN's cardioprotective effect and potential mechanism on cardiac remodeling using transverse aortic constriction (TAC) in mice and angiotensin II (Ang II)-induced neonatal rat cardiomyocytes (NRCMs) and fibroblasts in vitro. High-performance liquid chromatography-quadrupole-time of flight tandem mass spectrometry (HPLC-Q-TOF-MS/MS) characterized 23 main components of AN. AN significantly improved cardiac function in the TAC-induced mice. Furthermore, AN considerably reduced the serum levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP), cardiac troponin T (CTn-T), and interleukin-6 (IL-6) and mitigated inflammatory cell infiltration. Post-AN treatment, TAC-induced heart size approached normal. AN decreased cardiomyocyte cross-sectional area and attenuated the upregulation of cardiac hypertrophy marker genes (ANP, BNP, and MYH7) in vivo and in vitro. Concurrently, AN alleviated collagen deposition in TAC-induced mice. AN also reduced the expression of fibrosis-related indicators (COL1A1 and COL3A1) and inhibited the activation of the transforming growth factor-β1 (TGF-β1)/mothers against decapentaplegic homolog 3 (Smad3) pathway. Thus, AN improved TAC-induced cardiac remodeling. Moreover, AN downregulated p-dynamin-related protein (Drp1) (Ser616) expression and upregulated mitogen 2 (MFN-2) and optic atrophy 1 (OPA1) expression in vivo and in vitro, thereby restoring mitochondrial fusion and fission balance. In conclusion, AN improves cardiac remodeling by regulating mitochondrial dynamic balance, providing experimental data for the rational application of Chinese medicine prescriptions with AN as the main component in clinical practice.
    Keywords:  Astragali Radix−Notoginseng Radix et Rhizoma medicine pair; Cardiac fibrosis; Cardiac hypertrophy; Mitochondrial dynamics; Transforming growth factor-β1/Smad3 pathway
    DOI:  https://doi.org/10.1016/S1875-5364(25)60806-5
  46. Phys Biol. 2025 Jan 31. 22(2):
    Electrical homeostasis of the inner mitochondrial membrane potential.
    Peyman Fahimi, Lázaro A M Castanedo, P Thomas Vernier, Chérif F Matta.
      The electric potential across the inner mitochondrial membrane must be maintained within certain bounds for the proper functioning of the cell. A feedback control mechanism for the homeostasis of this membrane potential is proposed whereby an increase in the electric field decreases the rate-limiting steps of the electron transport chain (ETC). An increase in trans-membrane electric field limits the rate of proton pumping to the inter-membrane gap by slowing the ETC reactions and by intrinsically induced electroporation that depolarizes the inner membrane. The proposed feedback mechanism is akin to a Le Chatelier's-type principle of trans-membrane potential feedback control.
    Keywords:  chemiosmotic theory; electrical feedback control in biological systems; mitochondrial biophysics; mitochondrial electric potential; mitochondrial homeostasis
    DOI:  https://doi.org/10.1088/1478-3975/adaa47
  47. Invest Ophthalmol Vis Sci. 2025 Jan 02. 66(1): 62
    SIRT4 Protects Retina Against Excitotoxic Injury by Promoting OPA1-Mediated Müller Glial Cell Mitochondrial Fusion and GLAST Expression.
    Qian Ying, Hongdou Luo, Zhi Xie, Yi Huang, Haijian Hu, Ming Jin, Ke Xu, Yulian Pang, Yuning Song, Xu Zhang.
       Purpose: This study aimed to investigate the role of SIRT4 in retinal protection, specifically its ability to mitigate excitotoxic damage to Müller glial cells through the regulation of mitochondrial dynamics and glutamate transporters (GLASTs).
    Methods: A model of retinal excitatory neurotoxicity was established in mice. Proteins related to mitochondrial dynamics, GLAST, and SIRT4 were analyzed on days 0, 1, 3, and 5 following toxic injury. The influence of SIRT4 on mitochondrial dynamics-related proteins and GLAST was examined by inducing SIRT4 overexpression through intraperitoneal injection of resveratrol or by using SIRT4 knockout (KO) mice. Additionally, the effects of upregulating and downregulating SIRT4 expression in rat Müller glial cell lines (rMC-1) were explored via lentiviral vector transfection to assess changes in mitochondrial morphology and GLAST expression.
    Results: After excitotoxic injury to the mouse retina, the retinal thickness and structure were disrupted, the number of retinal ganglion cells (RGCs) decreased, and Müller glial cells were activated by day 1. The levels of OPA1, GLAST, and SIRT4 proteins peaked on the first day after injury and then gradually decreased, indicating a synchronized dynamic trend. The upregulation of SIRT4 expression promoted OPA1 and GLAST protein expression, thereby alleviating retinal excitotoxic injury. Furthermore, the upregulation of SIRT4 expression promoted mitochondrial fusion and increased GLAST expression in rMC-1 cells, reducing cellular excitotoxic damage. Conversely, downregulation of SIRT4 had the opposite effect.
    Conclusions: SIRT4 plays a significant role in mitigating excitotoxic damage in the retina, modulating Müller glial cell injury by regulating mitochondrial dynamics and glutamate transporter expression, ultimately influencing retinal health.
    DOI:  https://doi.org/10.1167/iovs.66.1.62
  48. ACS Chem Neurosci. 2025 Jan 26.
    Computational Study of the Activation Mechanism of Wild-Type Parkin and Its Clinically Relevant Mutant.
    Zeynep Nur Cinviz, Ozge Sensoy.
      Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder. It impairs the control of movement and balance. Parkin mutations worsen the symptoms in sporadic cases and cause the early onset of the disease. Therefore, recent efforts have focused on the rescue of defective parkin by engineered proteins or small-molecule activators to enhance parkin activation. These attempts require holistic understanding of the multistep activation mechanism and molecular effects of disease-associated mutations. Hereby, we provided a comprehensive analysis of the activation mechanism of parkin and a clinically relevant mutant, parkinS167N, using molecular dynamics simulations based on the following crystal structures: (1) parkin, (2) parkin/pUb (phosphorylated Ubiquitin), (3) pparkin/pUb, and (4) pparkin/pUb/UbcH7-Ub. Each of these represents an individual step in the activation process. We showed that the mutation impacted the dynamics of not only the RING0 domain, where it is localized, but also the RING2, Ubl, and IBR domains. We identified residues participating in the allosteric interaction network involved in parkin activation. Some of them are mutated in PD-associated parkin variants. The RING0 domain provides a binding interface with various proteins, so understanding problems associated with the mutation paves the way to the discovery of effective engineered proteins or small molecules that activate mutant parkin.
    Keywords:  Parkinson's disease; RING0 domain; mitophagy; molecular dynamics; parkin mutation
    DOI:  https://doi.org/10.1021/acschemneuro.4c00630
  49. Proc Natl Acad Sci U S A. 2025 Feb 04. 122(5): e2422447122
    Serine phosphorylation facilitates protein degradation by the human mitochondrial ClpXP protease.
    Yue Feng, Monica M Goncalves, Yulia Jitkova, Alexander F A Keszei, Yongran Yan, Chaitra Sarathy, Jonathan St-Germain, Tristan M G Kenney, Matthew Tcheng, Vincent Trudel, Ross S Mancini, Rahul Upadhyay, Rose Hurren, Marcela Gronda, Matthew Schultz, Kaylen Soriano, Kaitlin Lees, Neil C Pomroy, S Quinn W Currie, Gilbert G Privé, Mark A Reed, Andrei K Yudin, Linda Z Penn, Cheryl H Arrowsmith, Brian Raught, Mohammad T Mazhab-Jafari, Siavash Vahidi, Aaron D Schimmer.
      ClpXP is a two-component mitochondrial matrix protease. The caseinolytic mitochondrial matrix peptidase chaperone subunit X (ClpX) recognizes and translocates protein substrates into the degradation chamber of the caseinolytic protease P (ClpP) for proteolysis. ClpXP degrades damaged respiratory chain proteins and is necessary for cancer cell survival. Despite the critical role of ClpXP in mitochondrial protein quality control, the specific degrons, or modifications that tag substrate proteins for degradation by human ClpXP, are still unknown. We demonstrated that phosphorylated serine (pSer) targets substrates to ClpX and facilitates their degradation by ClpXP in biochemical assays. In contrast, ClpP hyperactivated by the small-molecule drug ONC201 lost the preference for phosphorylated substrates. Hydrogen deuterium exchange mass spectrometry combined with biochemical assays showed that pSer binds the RKL loop of ClpX. ClpX variants with substitutions in the RKL loop failed to recognize phosphorylated substrates. In intact cells, ClpXP also preferentially degraded substrates with pSer. Moreover, ClpX substrates with the pSer were selectively found in aggregated mitochondrial proteins. Our work uncovers a mechanism for substrate recognition by ClpXP, with implications for targeting acute myeloid leukemia and other disorders involving ClpXP dysfunction.
    Keywords:  AAA+ proteases; degron; mitochondrial proteostasis; phosphorylation; protein degradation
    DOI:  https://doi.org/10.1073/pnas.2422447122
  50. Free Radic Biol Med. 2025 Jan 27. pii: S0891-5849(25)00058-9. [Epub ahead of print]229 350-363
    Fasting enhances the efficacy of Sorafenib in breast cancer via mitophagy mediated ROS-driven p53 pathway.
    Ru Li, Yimei Ma, Anqi He, Yamin Pu, Xuanting Wan, Hongbao Sun, Ningyu Wang, Min Luo, Guan Wang, Yong Xia.
      The multi-kinase inhibitor sorafenib has shown potential to inhibit tumor cell growth and intra-tumoral angiogenesis by targeting several kinases, including VEGFR2 and RAF. Abnormal activation of the Ras/Raf/MAPK/ERK kinase cascade and the VEGF pathway is a common feature in breast cancer. However, the efficacy of sorafenib in breast cancer treatment remains limited. Recently, fasting has emerged as a promising non-pharmacological approach to modulate cancer metabolism and enhance the effectiveness of cancer therapies. In this study, we found that fasting significantly enhances the anti-cancer effects of sorafenib monotherapy and its combination with immunotherapy in breast cancer models without causing obvious side effects. This combined treatment effectively inhibits tumor cell proliferation and intra-tumoral angiogenesis. The fasting-induced reduction in peripheral blood glucose levels strongly correlated with enhanced sensitivity to sorafenib. Mechanistically, the combined treatment induced mitophagy, characterized by mitochondrial dysfunction and activation of the PINK1-Parkin pathway. Consequently, increased mitochondrial ROS levels promoted p53 expression, amplifying cell cycle arrest and apoptosis in breast cancer cells. Furthermore, fasting reduced lactate levels within the tumor, and the consequent glucose limitation synergized with sorafenib to activate AMPK, which in turn elevated PD-L1 expression in tumor cells, potentially enhancing their sensitivity to immunotherapy. In summary, our findings demonstrate that fasting and sorafenib, as a rational combination therapy, induce mitophagy, thereby enhancing sorafenib's efficacy in treating breast cancer through the ROS-driven p53 pathway. This study underscores the potential of fasting in breast cancer therapy and provides a foundation for optimizing the clinical application of sorafenib.
    Keywords:  Breast cancer; Fasting; Mitophagy; ROS; mtROS; p53
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.01.047
  51. Mol Biol Cell. 2025 Jan 29. mbcE25010035
    Mechanism of chaperone recruitment and retention on mitochondrial precursors.
    Szymon Juszkiewicz, Sew-Yeu Peak-Chew, Ramanujan S Hegde.
      Nearly all mitochondrial proteins are imported into mitochondria from the cytosol. How nascent mitochondrial precursors acquire and sustain import-competence in the cytosol under normal and stress conditions is incompletely understood. Here, we show that under normal conditions, the Hsc70 and Hsp90 systems interact with and redundantly minimize precursor degradation. During acute import stress, Hsp90 buffers precursor degradation, preserving proteins in an import-competent state until stress resolution. Unexpectedly, buffering by Hsp90 relies critically on a mitochondrial targeting signal (MTS), the absence of which greatly decreases precursor-Hsp90 interaction. Site-specific photo-crosslinking and biochemical reconstitution showed how the MTS directly engages co-chaperones of Hsc70 (St13 and Stip1) and Hsp90 (p23 and Cdc37) to facilitate chaperone retention on the mature domain. Thus, the MTS has a previously unappreciated role in regulating chaperone dynamics on mitochondrial precursors to buffer their degradation and maintain import competence, functions that may facilitate restoration of mitochondrial homeostasis after acute import stress.
    DOI:  https://doi.org/10.1091/mbc.E25-01-0035
  52. Int J Mol Sci. 2025 Jan 16. pii: 719. [Epub ahead of print]26(2):
    The Diurnal Variation in Mitochondrial Gene in Human Type 2 Diabetic Mesenchymal Stem Cell Grafts.
    Michiko Horiguchi, Kenichi Yoshihara, Yoichi Mizukami, Kenji Watanabe, Yuya Tsurudome, Kentaro Ushijima.
      The application of regenerative therapy through stem cell transplantation has emerged as a promising avenue for the treatment of diabetes mellitus (DM). Transplanted tissue homeostasis is affected by disturbances in the clock genes of stem cells. The aim of this study is to investigate the diurnal variation in mitochondrial genes and function after transplantation of adipose-derived mesenchymal stem cells (T2DM-ADSCs) from type 2 diabetic patients into immunodeficient mice. Diurnal variation in mitochondrial genes was assessed by next-generation sequencing. As a result, the diurnal variation in mitochondrial genes showing troughs at ZT10 and ZT22 was observed in the group transplanted with adipose-derived mesenchymal stem cells derived from healthy individuals (N-ADSC). On the other hand, in the group transplanted with T2DM-ADSCs, diurnal variation indicative of troughs was observed at ZT18, with a large phase and amplitude deviation between the two groups. To evaluate the diurnal variation in mitochondrial function, we quantified mitochondrial DNA copy number using the Human mtDNA Monitoring Primer Set, measured mitochondrial membrane potential using JC-1, and evaluated mitophagy staining. The results showed a diurnal variation in mitochondrial DNA copy number, mitophagy, mitochondrial membrane potential, and NF-kB signaling in the N-ADSC transplant group. In contrast, no diurnal variation was observed in T2DM-ADSC transplants. The diurnal variation in mitochondrial function revealed in this study may be a new marker for the efficiency of T2DM-ADSC transplantation.
    Keywords:  NF-kB; diurnal variation; mesenchymal stem cells (MSC); mitochondria; mitophagy; type 2 diabetes mellitus
    DOI:  https://doi.org/10.3390/ijms26020719
  53. J Ginseng Res. 2025 Jan;49(1): 80-91
    Ginsenoside Rg1 improves hypoxia-induced pulmonary vascular endothelial dysfunction through TXNIP/NLRP3 pathway-modulated mitophagy.
    Ru Zhang, Meili Lu, Chenyang Ran, Linchao Niu, Qi Qi, Hongxin Wang.
       Background: Vascular endothelial dysfunction (VED) is one of the main pathogenic events in pulmonary arterial hypertension (PAH). Previous studies have demonstrated that the ginsenoside Rg1 (Rg1) can ameliorate PAH, but the mechanism by which Rg1 affects pulmonary VED in hypoxia-induced PAH remains unclear.
    Methods: Network pharmacology, molecular docking and other experiments were used to explore the mechanisms by which Rg1 affects PAH. A PAH mouse model was established via hypoxia combined with the vascular endothelial growth factor (VEGFR) inhibitor su5416 (SuHx), and a cell model was established via hypoxia. The functions of Rg1 in VED, oxidative stress, inflammation, mitophagy, and TXNIP and NLRP3 expression were examined.
    Results: In hypoxia-induced VED, progressive exacerbation of oxidative stress, inflammation, and mitophagy were observed, and were associated with elevated TXNIP and NLRP3 expression in vivo and in vitro. Rg1 improved hypoxia-induced impaired endothelium-dependent vasodilation and increased nitric oxide (NO) and endothelial NO synthase (eNOS) expression. Rg1, SRI37330 (a TXNIP inhibitor), MCC950 (an NLRP3 inhibitor), and Liensinine (a mitophagy inhibitor) attenuated oxidative stress, inflammation, and mitophagy by reducing the expression of TXNIP and NLRP3 in mice and cells. Furthermore, the combination of SB203580 (a mitophagy agonist) with Rg1 disrupted the protective effect of Rg1 on hypoxia-induced pulmonary artery and human pulmonary artery endothelial cells (HPAECs).
    Conclusion: Rg1 improves hypoxia-induced pulmonary vascular endothelial dysfunction through TXNIP/NLRP3 pathway-modulated oxidative stress, inflammation and mitophagy.
    Keywords:  Ginsenoside Rg1; NLRP3; Pulmonary arterial hypertension; TXNIP; Vascular endothelial dysfunction
    DOI:  https://doi.org/10.1016/j.jgr.2024.10.002
  54. Cell Mol Neurobiol. 2025 Jan 25. 45(1): 16
    Correction: Docosahexaenoic Acid Alleviates Oxidative Stress-Based Apoptosis Via Improving Mitochondrial Dynamics in Early Brain Injury After Subarachnoid Hemorrhage.
    Tongyu Zhang, Pei Wu, John H Zhang, Yuchen Li, Shancai Xu, Chunlei Wang, Ligang Wang, Guang Zhang, Jiaxing Dai, Shiyi Zhu, Yao Liu, Binbing Liu, Cesar Reis, Huaizhang Shi.
      
    DOI:  https://doi.org/10.1007/s10571-025-01530-8
  55. Environ Toxicol. 2025 Jan 28.
    Mitigating PM2.5 Induced Myocardial Metal Deposition Through Sodium Thiosulfate Resulted in Reduction of Cardiotoxicity and Physiological Recovery From Ischemia-Reperfusion via Mitochondrial Preservation.
    Bhavana Sivakumar, Gino A Kurian.
      The cardiovascular risks linked to PM2.5 include calcification in both vasculature and myocardial tissues, leading to structural changes and functional decline. Through the selection of a clinically proven endogenous agent, sodium thiosulfate (STS), capable of addressing PM2.5 related cardiac abnormalities, we not only address the absence of effective solutions to mitigate PM2.5 toxicity, but also provide evidence for the repurposing potential of STS in ameliorating PM2.5 induced cardiac damage. Female Wistar rats were exposed to PM2.5 (250 μg/m3) for 3 h daily for 21 days. STS was administered thrice weekly for 3 weeks during exposure after which the hearts were excised and mounted on a Langendorff apparatus for induction of ischemia-reperfusion injury (IR). STS administration improved cardiac function in PM2.5 exposed rat hearts, accompanied by increased expression of the master regulator gene PGC1-α and increased mitochondrial mass. Moreover, STS restored bioenergetic function and balanced mitochondrial fission-fusion dynamics. The beneficial effects of STS were further evidenced by its ability to scavenge metals, thereby reducing heavy metal deposition in mitochondria and alleviating oxidative stress and inflammation. Furthermore, STS facilitated the clearance of damaged mitochondria through mitophagy. Additionally, STS activated the PI3K/AKT/GSK3ß signaling pathway, providing cardio protection against IR injury in PM2.5-exposed hearts by preserving mitochondrial function. These results underscore the potential therapeutic benefits of STS in mitigating the adverse cardiac effects induced by PM2.5 exposure. The translation of these findings to clinical practice holds promise for the development of targeted interventions aimed at reducing the cardiovascular toxicity associated with PM2.5 exposure.
    Keywords:  PM2.5; mitochondria; myocardial ischemia–reperfusion injury; oxidative stress; sodium thiosulphate
    DOI:  https://doi.org/10.1002/tox.24473
  56. Funct Integr Genomics. 2025 Jan 29. 25(1): 28
    Leptin drives glucose metabolism to promote cardiac protection via OPA1-mediated HDAC5 translocation and Glut4 transcription.
    Fan Yang, Youfu He, Ling Zhao, Jing Huang, Fawang Du, Shui Tian, Yang Zhang, Xinghui Liu, Baolin Chen, Junhua Ge, Zhi Jiang.
      Metabolic reprogramming, the shifting from fatty acid oxidation to glucose utilization, improves cardiac function as heart failure (HF) progresses. Leptin plays an essential role in regulating glucose metabolism. However, the crosstalk between leptin and metabolic reprogramming is poorly understood. We tested the hypothesis that leptin improves cardiac function after myocardial infarction via enhancing glucose metabolism. In the isoproterenol (ISO)-induced heart failure model in vitro, H9c2 cell apoptosis was assessed by the TUNEL and Annexin V/PI staining assay. Leptin-mediated mitochondrial fusion was performed via TEM, and glucose oxidation was explored, as well as the ECAR, OCR, and protein expression of the vital metabolic enzymes. By blocking OPA1 expression or HDAC5 inhibition, the mitochondrial dynamic and glucose metabolic were detected to evaluate the role of OPA1 and HDAC5 in leptin-stimulated glucose metabolism. In the mouse model of HF in vivo, intraperitoneal leptin administration appreciably increased glucose oxidation and preserved cardiac function 56 days after coronary artery ligation. In vitro, we identified the OPA1-dependent HDAC5 nucleus export as a crucial process in boosting glucose utilization by activating MEF2 to upregulate Glut4 expression using the RNA interference technique in H9c2 cells. In vivo, leptin promotes glucose utilization and confers heart functional and survival benefits in chronic ischemic HF. The current study provided a novel insight into the role of leptin in metabolic reprogramming and revealed potential therapeutic targets for chronic HF.
    Keywords:  Cardiomyocytes; Glucose oxidation; HDAC5; Leptin; OPA1
    DOI:  https://doi.org/10.1007/s10142-024-01515-8
  57. J Agric Food Chem. 2025 Jan 27.
    T-2 Toxin Nephrotoxicity: Toxic Effects, Mechanisms, Mitigations, and Future Perspectives.
    Youshuang Wang, Pengli Liu, Jiayan Fan, Shuo Li, Xinyu Zhang, Yanan Li, Xuebing Wang, Cong Zhang, Xu Yang.
      T-2 toxin is a highly toxic fungal toxin that threatens humans and animals' health. As a major detoxifying and metabolic organ, the kidney is also a target of T-2 toxin. This article reviews T-2 toxin nephrotoxicity research progress, covering renal structure and function damage, nephrotoxicity mechanisms, and detoxification methods to future research directions. T-2 toxin damages kidney structure, causing renal dysfunction. The nephrotoxicity mechanism of T-2 toxin involves multiple factors including oxidative stress, endoplasmic reticulum stress, mitophagy, inflammatory responses, and apoptosis, which are intertwined and interdependent. Current detoxification strategies mainly involve reducing T-2 toxin in feedstuff and using antioxidant substances, but both have limits. Future research should focus on renal cells sensitivity to T-2 toxin, exploring key molecules in T-2 toxin's nephrotoxicity, renal injury's impact on other organs, and better detoxification methods. This review aims to guide future research and underpin T-2 toxin-induced nephrotoxicity prevention and treatment.
    Keywords:  T-2 toxin; apoptosis; detoxification; endoplasmic reticulum stress; inflammation; mitophagy; nephrotoxicity; oxidative stress
    DOI:  https://doi.org/10.1021/acs.jafc.4c10015
  58. Clin Immunol. 2025 Jan 28. pii: S1521-6616(25)00017-8. [Epub ahead of print] 110442
    NLRX1 deficiency exacerbates skin inflammation in atopic dermatitis by disrupting mitophagy.
    Lixin Yue, Pei Qiao, Xia Li, Ke Xue, Bingyu Pang, Yaxing Bai, Pu Song, Huanhuan Qu, Hongjiang Qiao, Danni Sun, Xingan Wu, Rongrong Liu, Gang Wang, Erle Dang.
      NLRX1 is an important regulator of inflammatory signaling in innate immune cells. Recent studies indicate NLRX1 activation may be a novel mechanism for inflammatory diseases, however, it has not been explored in atopic dermatitis (AD). Our study aims to investigate the potential role of NLRX1 in the pathogenesis of AD. We observed a significant decrease in NLRX1 expression in AD skin lesions and MC903-indued AD dermatitis. NLRX1 deficiency exacerbated AD inflammation, characterized by increased skin thickness, exacerbated inflammatory infiltration, and compromised skin barrier function. Mechanistically, NLRX1 regulated TSLP expression through Parkin-PINK1-mediated mitophagy in keratinocytes. Furthermore, topical application of NLRX1 agonist alleviated AD progression, including reduced ear thickness, diminished redness, and improved skin barrier function. This study provides novel insights into the regulatory role of NLRX1 in skin inflammation in AD, highlighting the potential therapeutic implications of targeting NLRX1 and mitophagy in AD treatment.
    Keywords:  Atopic dermatitis; Inflammation; Keratinocytes; Mitophagy; NLRX1; Skin
    DOI:  https://doi.org/10.1016/j.clim.2025.110442
  59. Genes (Basel). 2024 Dec 26. pii: 14. [Epub ahead of print]16(1):
    Lactate Promotes Hypoxic Granulosa Cells' Autophagy by Activating the HIF-1α/BNIP3/Beclin-1 Signaling Axis.
    Yitong Pan, Gang Wu, Min Chen, Xiumei Lu, Ming Shen, Hongmin Li, Honglin Liu.
       BACKGROUND/OBJECTIVES: The avascular nature of the follicle creates a hypoxic microenvironment, establishing a niche where granulosa cells (GCs) rely on glycolysis to produce energy in the form of lactate (L-lactate). Autophagy, an evolutionarily conserved stress-response process, involves the formation of autophagosomes to encapsulate intracellular components, delivering them to lysosomes for degradation. This process plays a critical role in maintaining optimal follicular development. However, whether hypoxia regulates autophagy in GCs via lactate remains unclear.
    METHODS: In this study, we investigated lactate-induced autophagy under hypoxia by utilizing glycolysis inhibitors or silencing related genes.
    RESULTS: We observed a significant increase in autophagy in ovarian GCs under hypoxic conditions, indicated by elevated LC3II levels and reduced P62 levels. Suppressing lactate production through glycolytic inhibitors (2-DG and oxamate) or silencing lactate dehydrogenase (LDHA/LDHB) effectively reduced hypoxia-induced autophagy. Further investigation revealed that the HIF1-α/BNIP3/Beclin-1 axis is essential for lactate-induced autophagy under hypoxic conditions. Inhibiting HIF-1α activity using siRNAs or PX-478 downregulated BNIP3 expression and subsequently suppressed autophagy. Similarly, BNIP3 silencing with siRNAs repressed lactate-induced autophagy in hypoxic conditions. Mechanistically, immunoprecipitation experiments showed that BNIP3 disrupted pre-existing Bcl-2/Beclin-1 complexes by competing with Bcl-2 to form Bcl-2/BNIP3 complexes. This interaction released Beclin-1, which subsequently triggered lactate-induced autophagy under hypoxic conditions.
    CONCLUSIONS: These findings unveil a novel mechanism by which hypoxia regulates GC autophagy through lactate production, highlighting its potential role in sustaining follicular development under hypoxic conditions.
    Keywords:  BNIP3; Beclin-1; HIF-1α; granulosa cell; lactate
    DOI:  https://doi.org/10.3390/genes16010014
  60. Int J Mol Sci. 2025 Jan 17. pii: 774. [Epub ahead of print]26(2):
    Effects of Astragaloside IV and Formononetin on Oxidative Stress and Mitochondrial Biogenesis in Hepatocytes.
    Quoc-Anh Tran, Grant Van Tran, Sanel Velic, Hou-Mai Xiong, Jaspreet Kaur, Zuhurr Moosavi, Phuong Nguyen, Nhi Duong, Vy Tran Luu, Gurjot Singh, Tram Bui, Melanie Rose, Linh Ho.
      Over-accumulation of reactive oxygen species (ROS) causes hepatocyte dysfunction and apoptosis that might lead to the progression of liver damage. Sirtuin-3 (SIRT3), the main NAD+-dependent deacetylase located in mitochondria, has a critical role in regulation of mitochondrial function and ROS production as well as in the mitochondrial antioxidant mechanism. This study explores the roles of astragaloside IV (AST-IV) and formononetin (FMR) in connection with SIRT3 for potential antioxidative effects. It was shown that the condition of combined pre- and post-treatment with AST-IV or FMR at all concentrations statistically increased and rescued cell proliferation. ROS levels were not affected by pre-or post-treatment individually with AST-IV or pre-treatment with FMR; however, post-treatment with FMR resulted in significant increases in ROS in all groups. Significant decreases in ROS levels were seen when pre- and post-treatment with AST-IV were combined at 5 and 10 μM, or FMR at 5 and 20 μM. In the condition of combined pre- and post-treatment with 10 μM AST-IV, there was a significant increase in SOD activity, and the transcriptional levels of Sod2, Cat, and GPX1 in all treatment groups, which is indicative of reactive oxygen species detoxification. Furthermore, AST-IV and FMR activated PGC-1α and AMPK as well as SIRT3 expression in AML12 hepatocytes exposed to t-BHP-induced oxidative stress, especially at high concentrations of FMR. This study presents a novel mechanism whereby AST-IV and FMR yield an antioxidant effect through induction of SIRT3 protein expression and activation of an antioxidant mechanism as well as mitochondrial biogenesis and mitochondrial content and potential. The findings suggest these agents can be used as SIRT3 modulators in treating oxidative-injury hepatocytes.
    Keywords:  SIRT3; SIRT3 modulators; astragaloside; formononetin; mitochondrial sirtuins; oxidative injury; oxidative stress; tert-butyl hydrogen peroxide (t-BHP)
    DOI:  https://doi.org/10.3390/ijms26020774
  61. Molecules. 2025 Jan 10. pii: 261. [Epub ahead of print]30(2):
    Autophagy-Enhancing Properties of Hedyotis diffusa Extracts in HaCaT Keratinocytes: Potential as an Anti-Photoaging Cosmetic Ingredient.
    Qiwen Zheng, Xiangji Jin, Trang Thi Minh Nguyen, Eun-Ji Yi, Se-Jig Park, Gyeong-Seon Yi, Su-Jin Yang, Tae-Hoo Yi.
      The decline in autophagy disrupts homeostasis in skin cells, leading to oxidative stress, energy deficiency, and inflammation-all key contributors to skin photoaging. Consequently, activating autophagy has become a focal strategy for delaying skin photoaging. Natural plants are rich in functional molecules and widely used in the development of anti-photoaging cosmetics. Hedyotis diffusa (HD), as a medicinal plant, is renowned for its anti-inflammatory and anticancer properties; however, its effects on skin photoaging remain unclear. This study investigates HD's potential to counteract skin photoaging by restoring mitochondrial autophagy in keratinocytes. We used HPLC to detect the main chemical components in HD and, using a UVB-induced photoaging model in HaCaT keratinocytes, examined the effects of HD on reactive oxygen species (ROS) levels, Ca2+ concentration, mitochondrial membrane potential (MMP), apoptosis, and the cell cycle. Cellular respiration was further evaluated with the Seahorse XFp Analyzer, and RT-PCR and Western blotting were used to analyze the impact of HD on mitochondrial autophagy-related gene expression and signaling pathways. Our findings indicate that HD promotes autophagy by modulating the PI3K/AKT/mTOR and PINK/PARK2 pathways, which stabilizes mitochondrial quality, maintains MMP and Ca2+ balance, and reduces cytochrome c release. These effects relieve cell cycle arrest and prevent apoptosis associated with an increased BAX/BCL-2 ratio. Thus, HD holds promise as an effective anti-photoaging ingredient with potential applications in the development of cosmetic products.
    Keywords:  HaCaT keratinocytes; Hedyotis diffusa; anti-photoaging; autophagy-enhancing
    DOI:  https://doi.org/10.3390/molecules30020261
  62. Cytotechnology. 2025 Apr;77(2): 43
    Expression profiling of circular RNAs in sepsis-induced acute gastrointestinal injury: insights into potential biomarkers and mechanisms.
    Xiaojun Liu, Chenxi Li, Chengying Hong, Yuting Chen, Chuanchuan Nan, Silin Liang, Huaisheng Chen.
      This study aimed to investigate the role of circular RNAs (circRNAs) in sepsis-induced acute gastrointestinal injury (AGI), focusing on their potential as biomarkers and their involvement in disease progression. Peripheral blood samples from 14 patients with sepsis-induced AGI and healthy volunteers were collected. RNA sequencing was performed to profile circRNA and miRNA expression. Differential expression analysis identified key regulatory RNAs. Functional enrichment analysis was conducted to explore biological pathways, and circRNA-miRNA interaction networks were constructed. Significant differences in circRNA and miRNA expression profiles were observed between sepsis-induced AGI patients and healthy controls. Several circRNAs, including hsa_circ_0008381 and hsa_circ_0071375, exhibited stepwise expression increases correlating with AGI severity. Functional enrichment analysis indicated that the host genes of differentially expressed circRNAs are involved in key biological processes like protein ubiquitination, organelle maintenance, and cellular signaling pathways such as mitochondrial biogenesis and lipid metabolism. CircRNA-miRNA interaction networks suggested their role as miRNA sponges, regulating key downstream processes. This study demonstrated the potential of circRNAs as diagnostic biomarkers and therapeutic targets for sepsis-induced AGI. Further research is warranted to validate their clinical utility and unravel their mechanistic roles in AGI progression.
    Keywords:  Acute gastrointestinal injury; Biomarker; RNA sequencing; Sepsis; TGF-β signaling; circRNA; miRNA
    DOI:  https://doi.org/10.1007/s10616-025-00704-y
  63. Biochem Biophys Rep. 2025 Mar;41 101915
    Electric-field induced sleep promotion and lifespan extension in Gaucher's disease model flies.
    Takaki Nedachi, Haruhisa Kawasaki, Eiji Inoue, Takahiro Suzuki, Yuzo Nakagawa-Yagi, Norio Ishida.
      Gaucher's disease (GD) is a genetic disease characterized by a mutation in the metabolic enzyme glucocerebrosidase (GBA1), leading to the accumulation of glucosylceramide in tissues. We previously discovered that a minos-inserted mutation in the GBA1 gene of fruit flies, Drosophila melanogaster, mimics human neuronopathic GD (nGD) characteristics, providing a promising model for studying the molecular mechanisms of the disease. We also reported that extremely low-frequency electric fields (ELF-EFs) promote sleep and extend the lifespan of wild-type flies. In this study, we show that ELF-EFs have health-promoting effects on nGD model flies. Firstly, the total sleep time and sleep episode duration of EF-exposed nGD model flies increased. EFs also extended the lifespans of nGD model flies. Additionally, the expression of the endoplasmic reticulum stress-related gene PERK and autophagy-related gene p62 were elevated after EF exposure. The effects of EF exposure on nGD flies are associated with the change of these genes expression. Our findings suggest that EF exposure may be effective as an additional therapy for nGD.
    Keywords:  Extremely low frequency (ELF); Mitophagy; Neurodegeneration; Parkinson's disease (PD)
    DOI:  https://doi.org/10.1016/j.bbrep.2025.101915
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