bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2025–01–12
sixty papers selected by
Gavin McStay, Liverpool John Moores University
  1. Alpha-Synuclein Effects on Mitochondrial Quality Control in Parkinson's Disease.
  2. New insights into mitochondrial quality control in anthracycline-induced cardiotoxicity: molecular mechanisms, therapeutic targets, and natural products.
  3. Drp1-Dependent Mitochondrial Fission Contributes to Lactic Acid-Induced Chicken Cardiomyocyte Damage.
  4. Deciphering the Power of Resveratrol in Mitophagy: From Molecular Mechanisms to Therapeutic Applications.
  5. Mitochondrial Fragmentation as a Key Driver of Neurodegenerative Disease.
  6. Mitophagy in Doxorubicin-Induced Cardiotoxicity: Insights into Molecular Biology and Novel Therapeutic Strategies.
  7. BNIP3 Downregulation Ameliorates Muscle Atrophy in Cancer Cachexia.
  8. Apelin-13 Ameliorates Sepsis-induced Brain Injury by Activating Phosphatase and Tensin Homolog-induced Putative Kinase 1/Parkin-mediated Mitophagy and Modulating Nucleotide-binding Oligomerization Domain-like Receptor Pyrin Domain-Containing 3-driven Pyroptosis in Rats.
  9. Hepatitis C Virus NS5A Activates Mitophagy Through Cargo Receptor and Phagophore Formation.
  10. Mitochondria- and ER-associated actin are required for mitochondrial fusion.
  11. Sexual Dimorphism of Ethanol-Induced Mitochondrial Dynamics in Purkinje Cells.
  12. Inhibition of Mitochondrial Fission Protein Drp1 Ameliorates Myopathy in the D2-mdx Model of Duchenne Muscular Dystrophy.
  13. Impact of LITAF on Mitophagy and Neuronal Damage in Epilepsy via MCL-1 Ubiquitination.
  14. Rnd3 protects against doxorubicin-induced cardiotoxicity through inhibition of PANoptosis in a Rock1/Drp1/mitochondrial fission-dependent manner.
  15. Yeast Dnm1G178R causes altered organelle dynamics and sheds light on the human DRP1G149R disease mechanism.
  16. Copper doped bioactive glass promotes matrix vesicles-mediated biomineralization via osteoblast mitophagy and mitochondrial dynamics during bone regeneration.
  17. G6PD protects against cerebral ischemia-reperfusion injury by inhibiting excessive mitophagy.
  18. Study on the role of mitophagy and pyroptosis induced by nano-silver in testicular injury.
  19. Optineurin Cooperates With NRF2 to Regulate Tooth Root Morphogenesis by Controlling Mitochondrial Dynamics and Apoptosis.
  20. Bushen-Huoxue-Mingmu-Formula attenuates pressurization-induced retinal ganglion cell damage by reducing mitochondrial autophagy through the inhibition of the Pink1/Parkin pathway.
  21. Mitochondrial YME1L1 governs unoccupied protein translocase channels.
  22. Rnf40 Exacerbates Hypertension-Induced Cerebrovascular Endothelial Barrier Dysfunction by Ubiquitination and Degradation of Parkin.
  23. Apolipoprotein-L Functions in Membrane Remodeling.
  24. Inhibition of PGAM5 hyperactivation reduces neuronal apoptosis in PC12 cells and experimental vascular dementia rats.
  25. The role of clock control of DRP1 activity involved in postoperative cognitive dysfunction.
  26. Triacylglycerol mobilization underpins mitochondrial stress recovery.
  27. TFE3-mediated neuroprotection: Clearance of aggregated α-synuclein and accumulated mitochondria in the AAV-α-synuclein model of Parkinson's disease.
  28. Parkin modulates the hepatocellular carcinoma microenvironment by regulating PD-1/PD-L1 signalling.
  29. Dynamin-Related Protein 1 Orchestrates Inflammatory Responses in Periodontal Macrophages via Interaction With Hexokinase 1.
  30. Metformin Alleviates Doxorubicin-Induced Cardiotoxicity via Preserving Mitochondrial Dynamics Balance and Calcium Homeostasis.
  31. Inhibition of TFAM-Mediated Mitophagy by Oroxylin A Restored Sorafenib Sensitivity Under Hypoxia Conditions in HepG2 Cells.
  32. Identification of a mitophagy-related gene signature for predicting overall survival and response to immunotherapy in rectal cancer.
  33. Histone deacetylase 6 inhibition prevents hypercholesterolemia-induced erectile dysfunction independent of changes in markers of autophagy.
  34. Precursor occupancy controls mitochondrial import channel via proteolysis.
  35. Salidroside Improves Oocyte Competence of Reproductively Old Mice by Enhancing Mitophagy.
  36. The inhibition of PINK1/Drp1-mediated mitophagy by hyperglycemia leads to impaired osteoblastogenesis in diabetes.
  37. Curcumin Improves Hippocampal Cell Bioenergetics, Redox and Inflammatory Markers, and Synaptic Proteins, Regulating Mitochondrial Calcium Homeostasis.
  38. Recombinant Porcine FGF1 Promotes Muscle Stem Cell Proliferation and Mitochondrial Function for Cultured Meat Production.
  39. CDK4 inactivation inhibits apoptosis via mitochondria-ER contact remodeling in triple-negative breast cancer.
  40. eIF2α Phosphorylation-ATF4 Axis-Mediated Transcriptional Reprogramming Mitigates Mitochondrial Impairment During ER Stress.
  41. Consequences of Early Maternal Deprivation on Neuroinflammation and Mitochondrial Dynamics in the Central Nervous System of Male and Female Rats.
  42. Cadmium-Induced Oxidative Damage and the Expression and Function of Mitochondrial Thioredoxin in Phascolosoma esculenta.
  43. Nonreceptor tyrosine kinase ABL1 regulates lysosomal acidification by phosphorylating the ATP6V1B2 subunit of the vacuolar-type H+-ATPase.
  44. KDM4A Silencing Reverses Cisplatin Resistance in Ovarian Cancer Cells by Reducing Mitophagy via SNCA Transcriptional Inactivation.
  45. Novel high-content and open-source image analysis tools for profiling mitochondrial morphology in neurological cell models.
  46. m6A modified pre-miR-503-5p contributes to myogenic differentiation through the activation of mTOR pathway.
  47. A protein interaction map of the myosin Myo2 reveals a role of Alo1 in mitochondrial inheritance in yeast.
  48. Mitochondrial Sorting and Assembly Machinery: Chaperoning a Moonlighting Role?
  49. STZ-induced hyperglycemia differentially influences mitochondrial distribution and morphology in the habenulointerpeduncular circuit.
  50. ANAC044 orchestrates mitochondrial stress signaling to trigger iron-induced stem cell death in root meristems.
  51. Sexual Dimorphism in Migraine. Focus on Mitochondria.
  52. Sesamin alleviates lipid accumulation induced by elaidic acid in L02 cells through TFEB regulated autophagy.
  53. Puerarin pretreatment provides protection against myocardial ischemia/reperfusion injury via inhibiting excessive autophagy and apoptosis by modulation of HES1.
  54. [Cardiotoxicity risk assessment of anticancer drugs by focusing on mitochondrial quality of human iPS cell-derived cardiomyocytes].
  55. The tRF-33/IGF1 Axis Dysregulates Mitochondrial Homeostasis in HER2-Negative Breast Cancer.
  56. Modulatory Effects of Mdivi-1 on OxLDL-Induced Metabolic Alterations, Inflammatory Responses, and Foam Cell Formation in Human Monocytes.
  57. Mitigation of high-fat diet-induced sarcopenia by Toona sinensis fruit extracts via autophagic flux and mitochondrial quality control.
  58. Previous short-term disuse dictates muscle gene expression and physiological adaptations to subsequent resistance exercise.
  59. Long-term mitochondrial and metabolic impairment in lymphocytes of subjects who recovered after severe COVID-19.
  60. Mpox-Induced Metabolic Alterations.
  1. Biomolecules. 2024 Dec 22. pii: 1649. [Epub ahead of print]14(12):
    Alpha-Synuclein Effects on Mitochondrial Quality Control in Parkinson's Disease.
    Lydia Shen, Ulf Dettmer.
      The maintenance of healthy mitochondria is essential for neuronal survival and relies upon mitochondrial quality control pathways involved in mitochondrial biogenesis, mitochondrial dynamics, and mitochondrial autophagy (mitophagy). Mitochondrial dysfunction is critically implicated in Parkinson's disease (PD), a brain disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra. Consequently, impaired mitochondrial quality control may play a key role in PD pathology. This is affirmed by work indicating that genes such as PRKN and PINK1, which participate in multiple mitochondrial processes, harbor PD-associated mutations. Furthermore, mitochondrial complex-I-inhibiting toxins like MPTP and rotenone are known to cause Parkinson-like symptoms. At the heart of PD is alpha-synuclein (αS), a small synaptic protein that misfolds and aggregates to form the disease's hallmark Lewy bodies. The specific mechanisms through which aggregated αS exerts its neurotoxicity are still unknown; however, given the vital role of both αS and mitochondria to PD, an understanding of how αS influences mitochondrial maintenance may be essential to elucidating PD pathogenesis and discovering future therapeutic targets. Here, the current knowledge of the relationship between αS and mitochondrial quality control pathways in PD is reviewed, highlighting recent findings regarding αS effects on mitochondrial biogenesis, dynamics, and autophagy.
    Keywords:  PGC-1α; PINK1/Parkin; Parkinson’s disease; mitochondrial dysfunction; mitochondrial fragmentation; mitophagy; α-synuclein
    DOI:  https://doi.org/10.3390/biom14121649
  2. Int J Biol Sci. 2025 ;21(2): 507-523
    New insights into mitochondrial quality control in anthracycline-induced cardiotoxicity: molecular mechanisms, therapeutic targets, and natural products.
    Weili Li, Yuqin Zhang, Yan Wei, Guanjing Ling, Yawen Zhang, Yilin Li, Shujuan Guo, Nannan Tan, Lin Ma, Wei Li, Qianbin Sun, Wei Wang, Yong Wang.
      Anthracyclines (ANTs) are widely used in cancer therapy, particularly for lymphoma, sarcoma, breast cancer, and childhood leukemia, and have become the cornerstone of chemotherapy for various malignancies. However, it is associated with fatal and dose-dependent cardiovascular complications, especially cardiotoxicity. Mitochondrial quality control mechanisms, encompassing mitophagy, mitochondrial dynamics, and mitochondrial biogenesis, maintain mitochondrial homeostasis in the cardiovascular system. Recent studies have highlighted that mitochondrial quality control mechanisms play considerable roles in ANTs-induced cardiotoxicity (AIC). In addition, natural products targeting mitochondrial quality control mechanisms have emerged as potential therapeutic strategies to alleviate AIC. This review summarizes the types, incidence, prevention, treatment, and pathomechanism of AIC, delves into the molecular mechanisms of mitochondrial quality control in the pathogenesis of AIC, and explores natural products that target these mechanisms, so as to provide potential targets and therapeutic drugs for address the clinical challenges in AIC prevention and treatment, where no effective medicines are available.
    Keywords:  anthracycline; cardiotoxicity; mitochondrial biogenesis; mitochondrial dynamics; mitochondrial quality control; mitophagy; natural products
    DOI:  https://doi.org/10.7150/ijbs.103810
  3. J Biochem Mol Toxicol. 2025 Jan;39(1): e70128
    Drp1-Dependent Mitochondrial Fission Contributes to Lactic Acid-Induced Chicken Cardiomyocyte Damage.
    Dongfang Hu, Yunli Cui, Xueke Hou, Xueying Wang, Zihui Shen, Huiqing Pang, Yaming Ge, Hongmei Ning.
      Enhanced glycolysis and elevated lactic acid (LA) production are observed during sudden death syndrome (SDS) in broilers. However, the mechanism underlying LA-induced cardiomyocyte damage and heart failure in fast-growing broilers remains unclear. In this study, chicken embryo cardiomyocytes (CECs) were cultured and treated with LA to investigate LA-induced CEC injury and its mechanism, aiming to develop strategies to prevent LA-induced SDS in broilers. Results showed that LA inhibited CEC proliferation and contraction whereas inducing apoptosis. Furthermore, LA disrupted mitochondrial ultrastructure, reduced mitochondrial membrane potential, activated mitophagy, and disturbed mitochondrial dynamics. Treatment with Mdivi-1, a selective Drp1 inhibitor, improved CEC viability, restored mitochondrial network integrity, reduced reactive oxygen species production, and inhibited LA-induced apoptosis. These findings suggest that LA-induced cardiomyocyte injury during SDS in broilers is associated with mitochondrial damage and increased mitochondrial fission. The inhibition of mitochondrial hyperfission by Mdivi-1 effectively preserves CEC morphology, structure, and function, playing a critical role in preventing LA-induced damage. This study provides a foundation for strategies to prevent and control SDS in broilers.
    Keywords:  Mdivi‐1; cardiomyocytes damage; lactic acid; mitochondrial dynamics; sudden death syndrome
    DOI:  https://doi.org/10.1002/jbt.70128
  4. Phytother Res. 2025 Jan 04.
    Deciphering the Power of Resveratrol in Mitophagy: From Molecular Mechanisms to Therapeutic Applications.
    Hongmei Liu, Yixuan Song, Huan Wang, Ying Zhou, Min Xu, Jiaxun Xian.
      Resveratrol (RES), a natural polyphenolic compound, has garnered significant attention for its therapeutic potential in various pathological conditions. This review explores how RES modulates mitophagy-the selective autophagic degradation of mitochondria essential for maintaining cellular homeostasis. RES promotes the initiation and execution of mitophagy by enhancing PINK1/Parkin-mediated mitochondrial clearance, reducing reactive oxygen species production, and mitigating apoptosis, thereby preserving mitochondrial integrity. Additionally, RES regulates mitophagy through the activation of key molecular targets such as AMP-activated protein kinase (AMPK), the mechanistic target of rapamycin (mTOR), deacetylases (SIRT1 and SIRT3), and mitochondrial quality control (MQC) pathways, demonstrating substantial therapeutic effects in multiple disease models. We provide a detailed account of the biosynthetic pathways, pharmacokinetics, and metabolic characteristics of RES, focusing on its role in mitophagy modulation and implications for medical applications. Potential adverse effects associated with its clinical use are also discussed. Despite its promising therapeutic properties, the clinical application of RES is limited by issues of bioavailability and pharmacokinetic profiles. Future research should concentrate on enhancing RES bioavailability and developing derivatives that precisely modulate mitophagy, thereby unlocking new avenues for disease therapy.
    Keywords:  AMPK; PINK1/Parkin; SIRT1; disease intervention; mitophagy; resveratrol
    DOI:  https://doi.org/10.1002/ptr.8433
  5. Curr Alzheimer Res. 2025 Jan 08.
    Mitochondrial Fragmentation as a Key Driver of Neurodegenerative Disease.
    Alina Chaplygina, Daria Zhdanova.
      Mitochondrial form and function are intricately linked through dynamic processes of fusion and fission, and disruptions in these processes are key drivers of neurodegenerative diseases, like Alzheimer's. The inability of mitochondria to transition between their dynamic forms is a critical factor in the development of pathological states. In this paper, we focus on the importance of different types of mitochondrial phenotypes in nervous tissue, discussing how mitochondria in Alzheimer's disease are "stuck" in certain patterns and how this pattern maintains itself. Understanding the specific roles and transitions between mitochondrial forms, including tiny, networked, and hyperfused, is crucial in developing new therapies aimed at restoring mitochondrial homeostasis. By targeting these dynamics, we may be able to intervene early in the disease process, offering novel avenues for preventing or treating neurodegeneration.
    Keywords:  Alzheimer's disease.; Mitochondria; fission; fusion; mitochondrial phenotypes; mitophagy
    DOI:  https://doi.org/10.2174/0115672050366194250107050650
  6. Biomolecules. 2024 Dec 17. pii: 1614. [Epub ahead of print]14(12):
    Mitophagy in Doxorubicin-Induced Cardiotoxicity: Insights into Molecular Biology and Novel Therapeutic Strategies.
    Heng Zhang, Saiyang Xie, Wei Deng.
      Doxorubicin is a chemotherapeutic drug utilized for solid tumors and hematologic malignancies, but its clinical application is hampered by life-threatening cardiotoxicity, including cardiac dilation and heart failure. Mitophagy, a cargo-specific form of autophagy, is specifically used to eliminate damaged mitochondria in autophagosomes through hydrolytic degradation following fusion with lysosomes. Recent advances have unveiled a major role for defective mitophagy in the etiology of DOX-induced cardiotoxicity. Moreover, specific interventions targeting this mechanism to preserve mitochondrial function have emerged as potential therapeutic strategies to attenuate DOX-induced cardiotoxicity. However, clinical translation is challenging because of the unclear mechanisms of action and the potential for pharmacological adverse effects. This review aims to offer fresh perspectives on the role of mitophagy in the development of DOX-induced cardiotoxicity and investigate potential therapeutic strategies that focus on this mechanism to improve clinical management.
    Keywords:  cardiotoxicity; doxorubicin; mitochondria; mitophagy; treatment
    DOI:  https://doi.org/10.3390/biom14121614
  7. Cancers (Basel). 2024 Dec 11. pii: 4133. [Epub ahead of print]16(24):
    BNIP3 Downregulation Ameliorates Muscle Atrophy in Cancer Cachexia.
    Claudia Fornelli, Marc Beltrà, Antonio Zorzano, Paola Costelli, David Sebastian, Fabio Penna.
       BACKGROUND AND AIMS: Cancer cachexia is a complex syndrome affecting most cancer patients and is directly responsible for about 20% of cancer-related deaths. Previous studies showed muscle proteolysis hyper-activation and mitophagy induction in tumor-bearing animals. While basal mitophagy is required for maintaining muscle mass and quality, excessive mitophagy promotes uncontrolled protein degradation, muscle loss and impaired function. BNIP3, a key mitophagy-related protein, is significantly increased in the muscles of both mice and human cancer hosts. This study aimed to define the potential of mitigating mitophagy via BNIP3 downregulation in preserving mitochondrial integrity, counteracting skeletal muscle loss in experimental cancer cachexia.
    METHODS: Two in vivo gene delivery methods were performed to knock down muscle BNIP3: electroporation of a BNIP3-specific shRNA expression vector or adenovirus injection.
    RESULTS: The electroporation effectively reduced muscle BNIP3 in healthy mice but was ineffective in C26 tumor-bearing mice. In contrast, adenovirus-mediated BNIP3 knockdown successfully decreased BNIP3 levels also in tumor hosts. Although BNIP3 knockdown did not impact overall on body or muscle mass, it improved muscle fiber size in C26-bearing miceh2, suggesting partial prevention of muscle atrophy. Mitochondrial respiratory chain complexes (OxPhos) and TOM20 protein levels were consistently rescued, indicating improvements in mitochondrial mass, while H2O2 levels were unchanged among the groups, suggesting that BNIP3 downregulation does not impair the endogenous control of oxidative balance.
    CONCLUSIONS: These findings suggest that a fine balance between mitochondrial disposal and biogenesis is fundamental for preserving muscle homeostasis and highlight a potential role for BNIP3 modulation against cancer-induced muscle wasting.
    Keywords:  BNIP3; cancer cachexia; mitochondria; mitophagy; muscle wasting
    DOI:  https://doi.org/10.3390/cancers16244133
  8. J Physiol Investig. 2025 Jan 07.
    Apelin-13 Ameliorates Sepsis-induced Brain Injury by Activating Phosphatase and Tensin Homolog-induced Putative Kinase 1/Parkin-mediated Mitophagy and Modulating Nucleotide-binding Oligomerization Domain-like Receptor Pyrin Domain-Containing 3-driven Pyroptosis in Rats.
    Fan Jiang, Junxia Dong, Yi Han.
       ABSTRACT: Sepsis is a life-threatening condition that often results in severe brain injury, primarily due to excessive inflammation and mitochondrial dysfunction. This study aims to investigate the neuroprotective effects of Apelin-13, a bioactive peptide, in a rat model of sepsis-induced brain injury (SBI). Specifically, we examined the role of Apelin-13 in regulating mitophagy through the phosphatase and tensin homolog-induced putative kinase 1 (PINK1)/Parkin pathway and its impact on nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3) inflammasome-mediated pyroptosis and oxidative stress. A sepsis model was induced in male Sprague-Dawley rats (n = 110, 200-230 g, 12 weeks old) through cecal ligation and puncture (CLP). The septic rats received Apelin-13 (20 μg/kg, intravenously), either alone or combined with mitochondrial division inhibitor-1 (Mdv-1), a mitophagy inhibitor, before undergoing CLP surgery. Survival rates were assessed over a 72-h period, while the cognitive function was evaluated using the Morris water maze over 5 days. Western blotting and immunohistochemistry were utilized to measure the expression levels of NLRP3, cleaved caspase-1, N-terminal fragment of gasdermin D, PINK1, and Parkin in the brains of the rats. In addition, enzyme-linked immunosorbent assays were conducted to evaluate markers of oxidative stress and inflammatory responses in brain samples. Apelin-13 significantly improved survival rates and cognitive function and mitigated brain injury in septic rats. The treatment enhanced PINK1/Parkin-mediated mitophagy and suppressed NLRP3 inflammasome activation, leading to a reduction in pyroptosis, inflammation, and oxidative stress. Inhibition of mitophagy by Mdv-1 significantly reversed the protective effects of Apelin-13 in septic rats. Our findings suggest that Apelin-13 provides neuroprotection in sepsis by modulating mitophagy and inhibiting pyroptosis. These results highlight the potential of Apelin-13 as a therapeutic strategy for SBI.
    DOI:  https://doi.org/10.4103/ejpi.EJPI-D-24-00086
  9. Pathogens. 2024 Dec 23. pii: 1139. [Epub ahead of print]13(12):
    Hepatitis C Virus NS5A Activates Mitophagy Through Cargo Receptor and Phagophore Formation.
    Yuan-Chao Hsiao, Chih-Wei Chang, Chau-Ting Yeh, Po-Yuan Ke.
      Chronic HCV infection is a risk factor for end-stage liver disease, leading to a major burden on public health. Mitophagy is a specific form of selective autophagy that eliminates mitochondria to maintain mitochondrial integrity. HCV NS5A is a multifunctional protein that regulates the HCV life cycle and may induce host mitophagy. However, the molecular mechanism by which HCV NS5A activates mitophagy remains largely unknown. Here, for the first time, we delineate the dynamic process of HCV NS5A-activated PINK1/Parkin-dependent mitophagy. By performing live-cell imaging and CLEM analyses of HCV NS5A-expressing cells, we demonstrate the degradation of mitochondria within autophagic vacuoles, a process that is dependent on Parkin and ubiquitin translocation onto mitochondria and PINK1 stabilization. In addition, the cargo receptors of mitophagy, NDP52 and OPTN, are recruited to the mitochondria and required for HCV NS5A-induced mitophagy. Moreover, ATG5 and DFCP1, which function in autophagosome closure and phagophore formation, are translocated near mitochondria for HCV NS5A-induced mitophagy. Furthermore, autophagy-initiating proteins, including ATG14 and ULK1, are recruited near the mitochondria for HCV NS5A-triggered mitophagy. Together, these findings demonstrate that HCV NS5A may induce PINK1/Parkin-dependent mitophagy through the recognition of mitochondria by cargo receptors and the nascent formation of phagophores close to mitochondria.
    Keywords:  HCV; HCV NS5A; cargo receptor; mitophagy; phagophore
    DOI:  https://doi.org/10.3390/pathogens13121139
  10. Nat Commun. 2025 Jan 07. 16(1): 451
    Mitochondria- and ER-associated actin are required for mitochondrial fusion.
    Priya Gatti, Cara Schiavon, Julien Cicero, Uri Manor, Marc Germain.
      Mitochondria are crucial for cellular metabolism and signalling. Mitochondrial activity is modulated by mitochondrial fission and fusion, which are required to properly balance metabolic functions, transfer material between mitochondria, and remove defective mitochondria. Mitochondrial fission occurs at mitochondria-endoplasmic reticulum (ER) contact sites, and requires the formation of actin filaments that drive mitochondrial constriction and the recruitment of the fission protein DRP1. The role of actin in mitochondrial fusion remains entirely unexplored. Here we show that preventing actin polymerisation on either mitochondria or the ER disrupts both fission and fusion. We show that fusion but not fission is dependent on Arp2/3, whereas both fission and fusion require INF2 formin-dependent actin polymerization. We also show that mitochondria-associated actin marks fusion sites prior to the fusion protein MFN2. Together, our work introduces a method for perturbing organelle-associated actin and demonstrates a previously unknown role for actin in mitochondrial fusion.
    DOI:  https://doi.org/10.1038/s41467-024-55758-x
  11. Int J Mol Sci. 2024 Dec 22. pii: 13714. [Epub ahead of print]25(24):
    Sexual Dimorphism of Ethanol-Induced Mitochondrial Dynamics in Purkinje Cells.
    Rehana Khatoon, Jordan Fick, Abosede Elesinnla, Jaylyn Waddell, Tibor Kristian.
      The cerebellum, a key target of ethanol's toxic effects, is associated with ataxia following alcohol consumption. However, the impact of ethanol on Purkinje cell (PC) mitochondria remains unclear. To investigate how ethanol administration affects mitochondrial dynamics in cerebellar Purkinje cells, we employed a transgenic mouse model expressing mitochondria-targeted yellow fluorescent protein in Purkinje cells (PC-mito-eYFP). Both male and female PC-mito-eYFP mice received an intraperitoneal injection of ethanol or vehicle. One hour after ethanol administration, the animals were perfusion fixed or their cerebellum tissue or isolated mitochondria were collected. Cerebellum sections were analyzed using confocal microscopy to assess changes in mitochondrial length distribution. In vivo superoxide levels were measured using dihydroethidium (DHE), and mitochondrial NAD levels were determined by high-performance liquid chromatography (HPLC). Our findings revealed a sex-dependent response to ethanol administration in mitochondrial size distribution. While male Purkinje cell mitochondria exhibited no significant changes in size, female mitochondria became more fragmented after one hour of ethanol administration. This coincided with elevated phosphorylation of the fission protein Drp1 and increased superoxide production, as measured by DHE fluorescence intensity. Similarly, mitochondrial NAD levels were significantly reduced in female mice, but no changes were observed in males. Our results demonstrate that ethanol induced mitochondrial fragmentation through increased free radical levels, due to reduced NAD and increased p-Drp1, in PC cells of the female cerebellum.
    Keywords:  Purkinje cells; alcohol; cerebellum; free radicals; mitochondria
    DOI:  https://doi.org/10.3390/ijms252413714
  12. bioRxiv. 2024 Dec 26. pii: 2024.12.26.628172. [Epub ahead of print]
    Inhibition of Mitochondrial Fission Protein Drp1 Ameliorates Myopathy in the D2-mdx Model of Duchenne Muscular Dystrophy.
    H Grace Rosen, Nicolas J Berger, Shantel N Hodge, Atsutaro Fujishiro, Jared Lourie, Vrusti Kapadia, Melissa A Linden, Eunbin Jee, Jonghan Kim, Yuho Kim, Kai Zou.
      Although current treatments for Duchenne Muscular Dystrophy (DMD) have proven to be effective in delaying myopathy, there remains a strong need to identify novel targets to develop additional therapies. Mitochondrial dysfunction is an early pathological feature of DMD. A fine balance of mitochondrial dynamics (fission and fusion) is crucial to maintain mitochondrial function and skeletal muscle health. Excessive activation of Dynamin-Related Protein 1 (Drp1)-mediated mitochondrial fission was reported in animal models of DMD. However, whether Drp1-mediated mitochondrial fission is a viable target for treating myopathy in DMD remains unknown. Here, we treated a D2-mdx model of DMD (9-10 weeks old) with Mdivi-1, a selective Drp1 inhibitor, every other day (i.p. injection) for 5 weeks. We demonstrated that Mdivi-1 effectively improved skeletal muscle strength and reduced serum creatine kinase concentration. Mdivi-1 treatment also effectively inhibited mitochondrial fission regulatory protein markers, Drp1(Ser616) phosphorylation and Fis1 in skeletal muscles from D2-mdx mice, which resulted in reduced content of damaged and fragmented mitochondria. Furthermore, Mdivi-1 treatment attenuated lipid peroxidation product, 4-HNE, in skeletal muscle from D2-mdx mice, which was inversely correlated with muscle grip strength. Finally, we revealed that Mdivi-1 treatment downregulated Alpha 1 Type I Collagen (Col1a1) protein expression, a marker of fibrosis, and Interleukin-6 (IL-6) mRNA expression, a marker of inflammation. In summary, these results demonstrate that inhibition of Drp1-mediated mitochondrial fission by Mdivi-1 is effective in improving muscle strength and alleviating muscle damage in D2-mdx mice. These improvements are associated with improved skeletal muscle mitochondrial integrity, leading to attenuated lipid peroxidation.
    DOI:  https://doi.org/10.1101/2024.12.26.628172
  13. CNS Neurosci Ther. 2025 Jan;31(1): e70191
    Impact of LITAF on Mitophagy and Neuronal Damage in Epilepsy via MCL-1 Ubiquitination.
    Fuli Min, Zhaofei Dong, Shuisheng Zhong, Ze Li, Hong Wu, Sai Zhang, Linming Zhang, Tao Zeng.
       OBJECTIVE: This study aims to investigate how the E3 ubiquitin ligase LITAF influences mitochondrial autophagy by modulating MCL-1 ubiquitination, and its role in the development of epilepsy.
    METHODS: Employing single-cell RNA sequencing (scRNA-seq) to analyze brain tissue from epilepsy patients, along with high-throughput transcriptomics, we identified changes in gene expression. This was complemented by in vivo and in vitro experiments, including protein-protein interaction (PPI) network analysis, western blotting, and behavioral assessments in mouse models.
    RESULTS: Neuronal cells in epilepsy patients exhibited significant gene expression alterations, with increased activity in apoptosis-related pathways and decreased activity in neurotransmitter-related pathways. LITAF was identified as a key upregulated factor, inhibiting mitochondrial autophagy by promoting MCL-1 ubiquitination, leading to increased neuronal damage. Knockdown experiments in mouse models further confirmed that LITAF facilitates MCL-1 ubiquitination, aggravating neuronal injury.
    CONCLUSION: Our findings demonstrate that LITAF regulates MCL-1 ubiquitination, significantly impacting mitochondrial autophagy and contributing to neuronal damage in epilepsy. Targeting LITAF and its downstream mechanisms may offer a promising therapeutic strategy for managing epilepsy.
    Keywords:  LPS‐induced TNF‐alpha factor; MCL1; epilepsy; mitochondrial autophagy; neuroprotection; ubiquitination regulation
    DOI:  https://doi.org/10.1111/cns.70191
  14. Cell Death Dis. 2025 Jan 04. 16(1): 2
    Rnd3 protects against doxorubicin-induced cardiotoxicity through inhibition of PANoptosis in a Rock1/Drp1/mitochondrial fission-dependent manner.
    Wen Ge, Xiaohua Zhang, Jie Lin, Yangyang Wang, Xiao Zhang, Yu Duan, Xinchun Dai, Jiye Zhang, Yan Zhang, Mengyuan Jiang, Huanhuan Qiang, Zhijing Zhao, Xuebin Zhang, Dongdong Sun.
      Doxorubicin, a representative drug of the anthracycline class, is widely used in cancer treatment. However, Doxorubicin-induced cardiotoxicity (DIC) presents a significant challenge in its clinical application. Mitochondrial dysfunction plays a central role in DIC, primarily through disrupting mitochondrial dynamics. This study aimed to investigate the impact of Rnd3 (a Rho family GTPase 3) on DIC, with a focus on mitochondrial dynamics. Cardiomyocyte-specific Rnd3 transgenic mice (Rnd3-Tg) and Rnd3LSP/LSP mice (N-Tg) were established for in vivo experiments, and adenoviruses harboring Rnd3 (Ad-Rnd3) or negative control (Ad-Control) were injected in the myocardium for in vitro experiments. The DIC model was established using wild-type, N-Tg, and Rnd3-Tg mice, with subsequent intraperitoneal injection of Dox for 4 weeks. The molecular mechanism was explored through RNA sequencing, immunofluorescence staining, co-immunoprecipitation assay, and protein-protein docking. Dox administration induced significant mitochondrial injury and cardiac dysfunction, which was ameliorated by Rnd3 overexpression. Further, the augmentation of Rnd3 expression mitigated mitochondrial fragmentation which is mediated by dynamin-related protein 1 (Drp1), thereby ameliorating the PANoptosis (pyroptosis, apoptosis, and necroptosis) response induced by Dox. Mechanically, the interaction between Rnd3 and Rho-associated kinase 1 (Rock1) may impede Rock1-induced Drp1 phosphorylation at Ser616, thus inhibiting mitochondrial fission and dysfunction. Interestingly, Rock1 knockdown nullified the effects of Rnd3 on cardiomyocytes PANoptosis, as well as Dox-induced cardiac remodeling and dysfunction elicited by Rnd3. Rnd3 enhances cardiac resilience against DIC by stabilizing mitochondrial dynamics and reducing PANoptosis. Our findings suggest that the Rnd3/Rock1/Drp1 signaling pathway represents a novel target for mitigating DIC, and modulating Rnd3 expression could be a strategic approach to safeguarding cardiac function in patients undergoing Dox treatment. The graphical abstract illustrated the cardioprotective role of Rnd3 in DIC. Rnd3 directly binds to Rock1 in cytoplasm and ameliorates mitochondrial fission by inhibiting Drp1 phosphorylation at ser616, thereby alleviating PANoptosis (apoptosis, pyroptosis, and necroptosis) in DIC.
    DOI:  https://doi.org/10.1038/s41419-024-07322-0
  15. Mitochondrion. 2025 Jan 07. pii: S1567-7249(25)00003-0. [Epub ahead of print] 102006
    Yeast Dnm1G178R causes altered organelle dynamics and sheds light on the human DRP1G149R disease mechanism.
    Ankita Adhikary, Vivian Francis Joseph, Riddhi Banerjee, Shirisha Nagotu.
      Mitochondrial morphology is a result of regulated opposite events called fission and fusion and requires the GTPase, dynamin-related protein 1 (DRP1/Dnm1), or its homologs. A recent clinical report identified a heterozygous missense mutation in the human DRP1 that replaces Glycine (G) 149 with Arginine (R) and results in debilitating conditions in the patient. In this study, we mimicked this mutation in yeast Dnm1 (G178R) and investigated the impact of the pathogenic mutation on the protein's function. We provide evidence that the substitution of G with R in the G3 motif of the GTPase domain, renders the protein non-functional and in a dominant-negative way. The mutation hampers the distribution, localization, and function of the protein. Cells expressing the mutant variant are blocked in mitochondrial fission and exhibit altered peroxisome morphology and number.
    Keywords:  Dynamin-related protein 1; Mitochondria; Mutations; Peroxisome; Yeast
    DOI:  https://doi.org/10.1016/j.mito.2025.102006
  16. Bioact Mater. 2025 Apr;46 195-212
    Copper doped bioactive glass promotes matrix vesicles-mediated biomineralization via osteoblast mitophagy and mitochondrial dynamics during bone regeneration.
    Ziji Ling, Xiao Ge, Chengyu Jin, Zesheng Song, Hang Zhang, Yu Fu, Kai Zheng, Rongyao Xu, Hongbing Jiang.
      Bone defect repair remains a great challenge in the field of orthopedics. Human body essential trace element such as copper is essential for bone regeneration, but how to use it in bone defects and the underlying its mechanisms of promoting bone formation need to be further explored. In this study, by doping copper into mesoporous bioactive glass nanoparticles (Cu-MBGNs), we unveil a previously unidentified role of copper in facilitating osteoblast mitophagy and mitochondrial dynamics, which enhance amorphous calcium phosphate (ACP) release and subsequent biomineralization, ultimately accelerating the process of bone regeneration. Specifically, by constructing conditional knockout mice lacking the autophagy gene Atg5 in osteogenic lineage cells, we first confirmed the role of Cu-MBGNs-promoted bone formation via mediating osteoblast autophagy pathway. Then, the in vitro studies revealed that Cu-MBGNs strengthened mitophagy by inducing ROS production and recruiting PINK1/Parkin, thereby facilitating the efficient release of ACP from mitochondria into matrix vesicles for biomineralization during bone regeneration. Moreover, we found that Cu-MBGNs promoted mitochondrion fission via activating dynamin related protein 1 (Drp1) to reinforce mitophagy pathway. Together, this study highlights the potential of Cu-MBGNs-mediated mitophagy and biomineralization for augmenting bone regeneration, offering a promising avenue for the development of advanced bioactive materials in orthopedic applications.
    Keywords:  Biomineralization; Bone regeneration; Copper; Mesoporous bioactive glass; Mitophagy
    DOI:  https://doi.org/10.1016/j.bioactmat.2024.12.010
  17. Life Sci. 2025 Jan 03. pii: S0024-3205(24)00957-3. [Epub ahead of print]362 123367
    G6PD protects against cerebral ischemia-reperfusion injury by inhibiting excessive mitophagy.
    Yina Li, Yikun Gao, Guixiang Yu, Yingze Ye, Hua Zhu, Jin Wang, Yilin Li, Lei Chen, Lijuan Gu.
       AIMS: Cerebral ischemia-reperfusion injury (CIRI) exacerbates post-stroke brain damage. We aimed to understand the role of glucose-6-phosphate dehydrogenase (G6PD) in CIRI and mitophagy.
    MATERIALS AND METHODS: Lentivirus and small interfering RNA were utilized to suppress G6PD in tissues and cells, leading to the establishment of in vivo and in vitro models of ischemia-reperfusion following middle cerebral artery occlusion (MCAO) and oxygen-glucose deprivation/ reoxygenation (OGD/R). The expression and function of G6PD were investigated through differential gene analysis and weighted correlation network analysis (WGCNA), immunofluorescence, and western blotting (WB).
    KEY FINDINGS: G6PD mRNA levels increased 3 d after MCAO, and G6PD protein expression was elevated in the ischemic penumbra of mice and HT22 cells following OGD/R. G6PD knockdown increased neural deficits, enlarged infarct volume in mice after CIRI, and reduced HT22 cell survival during OGD/R. WGCNA indicated a correlation between G6PD and mitophagy in CIRI. Following G6PD knockdown, the p-DRP1/DRP ratio increased, the PINK1/Parkin pathway was further activated, and TOMM20 expression was downregulated. The mitophagy inhibitor Mdivi-1 reversed these changes, as well as the nerve damage caused by G6PD knockdown, and alleviated mitochondrial damage in the ischemic penumbra.
    SIGNIFICANCE: The role of G6PD in CIRI was revealed and its interaction with mitophagy was explored, providing important insights for understanding the molecular mechanism of CIRI and developing new therapeutic strategies.
    Keywords:  Cerebral ischemia-reperfusion injury; G6PD; Mitophagy; Neurological dysfunction; PINK1/Parkin pathway
    DOI:  https://doi.org/10.1016/j.lfs.2024.123367
  18. Food Chem Toxicol. 2025 Jan 07. pii: S0278-6915(25)00011-0. [Epub ahead of print] 115245
    Study on the role of mitophagy and pyroptosis induced by nano-silver in testicular injury.
    Deyu Zhu, Yingyi Li, Min Liu, Yufen Yang, Jiayu Fu, Liyu Su, Feng Wang, Yuyan Cen, Yanna Zhou, Yan Li.
      Silver nanoparticles(AgNPs)have been widely used in biomedicine and industry. Growing studies have shown that AgNPs can induce sperm motility decrease and spermiogenesis disorders. In this study, animal experiments were used to investigate the role of mitophagy and pyroptosis caused by AgNPs (25.93 nm) in testicular injury. Results showed that AgNPs induced the production of NLRP3, IL-1β and IL-18, activated Caspase-1, increased the expression of GSDMD protein, and activated the PINK1/Parkin signaling pathway, which induced in mitophagy in mice testicle tissue. In summary, AgNPs induced mitophagy and pyroptosis in mice testis at the highest dose, which lead to damage of testis tissue.
    Keywords:  Mitophagy; NLRP3; PINK1/Parkin; Pyroptosis; Silver nanoparticles
    DOI:  https://doi.org/10.1016/j.fct.2025.115245
  19. Cell Prolif. 2025 Jan 06. e13799
    Optineurin Cooperates With NRF2 to Regulate Tooth Root Morphogenesis by Controlling Mitochondrial Dynamics and Apoptosis.
    Haojie Liu, Xinyu Zhang, Xiao Ge, ChingCho Hsu, Yan Wang, Simai Chen, Xingzhi Yan, Rongyao Xu, Junqing Ma, Shuyu Guo.
      Tooth root development is a complex process essential for tooth function, yet the role of root dentin development in tooth morphogenesis is not fully understood. Optineurin (OPTN), linked to bone disorders like Paget's disease of bone (PDB), may affect tooth root development. In this study, we used single-cell sequencing of embryonic day 16.5 (E16.5), postnatal day 1 (P1), and P7 mouse teeth, as well as embryonic and adult human teeth, to show that OPTN is vital for odontoblastic differentiation. In Optn-/- mice, we observed short root deformities and defective dentin, with impaired apical papilla differentiation and increased apoptosis. In vitro OPTN downregulation in stem cells of the apical papilla (SCAPs) exacerbated apoptosis and hindered odontoblastic differentiation. RNA-seq analysis revealed significant differences in mitochondrial dynamics between control and OPTN knockout SCAPs. We discovered that OPTN influences mitochondrial dynamics primarily by promoting fission, leading to odontoblastic differentiation and mineralisation. Mechanistically, OPTN cooperates with NRF2 to regulate mitochondrial fission via DRP1 phosphorylation and affects the transcription of BCL2. Rescue experiments using an activator of NRF2 in ex vivo organ cultures and local gingival injection experiments confirmed these findings. Therefore, we concluded that OPTN, interacting with NRF2, acts as a key regulator of SCAPs mitochondrial dynamics, mineralisation and apoptosis during tooth development. These findings provide fresh insights into the mechanisms underlying tooth root development.
    Keywords:  apoptosis; mitochondrial dynamics; nrf2; optn; tooth development
    DOI:  https://doi.org/10.1111/cpr.13799
  20. Medicine (Baltimore). 2025 Jan 10. 104(2): e41257
    Bushen-Huoxue-Mingmu-Formula attenuates pressurization-induced retinal ganglion cell damage by reducing mitochondrial autophagy through the inhibition of the Pink1/Parkin pathway.
    Wei Wang, Jia Gao, Qianqian Mu, Dan Zhang, Fen Yang, Wubo Cheng.
       BACKGROUND: Bushen-Huoxue-Mingmu-Formula (MMF) has achieved definite clinical efficacy. However, its mechanism is still unclear.
    OBJECTIVE: Investigating the molecular mechanism of MMF to protect retinal ganglion cells (RGCs).
    METHODS: This study developed a pressurization-induced model of damaged RGCs, which were then treated with a serum supplemented with MMF. The effects of MMF on proliferation, apoptosis, adenosine 5'-triphosphate content, and mitochondrial structure of RGCs were investigated, and the underlying molecular mechanism was explored by RNA interference experiment.
    RESULTS: In the pressurization-induced RGC injury model, apoptosis rate increased, cell proliferation decreased, adenosine 5'-triphosphate content reduced, mitochondrial structure was disrupted, BCL2-associated X, cleaved caspase-3, and microtubule-associated proteins light chain 3 II/I protein expression enhanced, B cell lymphoma-2 and p62 protein expression decreased, and the Pink1/Parkin pathway was activated. The stress-induced damage to RGCs was, however, reversible following MMF-mediated inhibition of the Pink1/Parkin pathway. Pink1 short-hairpin RNA downregulated Pink1 expression in RGCs, which led to outcomes that aligned with those observed with MMF intervention.
    CONCLUSIONS: MMF altered the expression of apoptosis- and autophagy-related proteins and possibly inhibited the Pink1/Parkin signaling pathway, which led to reduced pressurization-induced mitochondrial autophagy in RGCs. This preventive effect of MMF on RGCs can be potentially useful to preserve the viability of RGCs.
    DOI:  https://doi.org/10.1097/MD.0000000000041257
  21. Nat Cell Biol. 2025 Jan 07.
    Mitochondrial YME1L1 governs unoccupied protein translocase channels.
    Meng-Chieh Hsu, Hiroki Kinefuchi, Linlin Lei, Reika Kikuchi, Koji Yamano, Richard J Youle.
      Mitochondrial protein import through the outer and inner membranes is key to mitochondrial biogenesis. Recent studies have explored how cells respond when import is impaired by a variety of different insults. Here, we developed a mammalian import blocking system using dihydrofolate reductase fused to the N terminus of the inner membrane protein MIC60. While stabilization of the dihydrofolate reductase domain by methotrexate inhibited endogenous mitochondrial protein import, it neither activated the transcription factor ATF4, nor was affected by ATAD1 expression or by VCP/p97 inhibition. On the other hand, notably, plugging the channel of translocase of the outer membrane) induced YME1L1, an ATP-dependent protease, to eliminate translocase of the inner membrane (TIM23) channel components TIMM17A and TIMM23. The data suggest that unoccupied TIM23 complexes expose a C-terminal degron on TIMM17A to YME1L1 for degradation. Import plugging caused a cell growth defect and loss of YME1L1 exacerbated the growth inhibition, showing the protective effect of YME1L1 activity. YME1L1 seems to play a crucial role in mitochondrial quality control to counteract precursor stalling in the translocase of the outer membrane complex and unoccupied TIM23 channels.
    DOI:  https://doi.org/10.1038/s41556-024-01571-z
  22. CNS Neurosci Ther. 2025 Jan;31(1): e70210
    Rnf40 Exacerbates Hypertension-Induced Cerebrovascular Endothelial Barrier Dysfunction by Ubiquitination and Degradation of Parkin.
    Chengkun Kou, Xu Zhao, Xin Fan, Runmin Sun, Wenting Wang, Miaomiao Qi, Lulu Zhu, Xin Lin, Jing Yu.
       AIMS: We aimed to investigate the role of Rnf40 in hypertension-induced cerebrovascular endothelial barrier dysfunction and cognitive impairment.
    METHODS: We employed microarray data analysis and integrated bioinformatics databases to identify a novel E3 ligase, Rnf40, that targets Parkin. To understand the role of RNF40 in hypertension-induced cerebrovascular endothelial cell damage, we used pAAV-hFLT1-MCS-EGFP-3×Flag-mir30shRnf40 to establish an Rnf40-deficient model in spontaneously hypertensive rats (SHRs). We also evaluated the cerebrovascular endothelial barrier function, cerebral blood flow, and cognitive performance.
    RESULTS: We observed reduced mitophagy in cerebrovascular endothelial cells of SHRs compared with that in Wistar-Kyoto rats. Rnf40 facilitated K48-linked polyubiquitination and degradation of Parkin, thereby inhibiting mitophagy. In the Rnf40-deficient SHR model, knocking down Rnf40 restored mitophagy in cerebrovascular endothelial cells. Additionally, levels of tight junction proteins and cerebrovascular endothelial barrier function improved following Rnf40 downregulation. Rnf40 depletion also improved global cognitive performance and restored cerebral blood flow in SHRs.
    CONCLUSION: Our findings suggest that increased Rnf40 levels exacerbate hypertension-induced cerebrovascular endothelial barrier dysfunction by ubiquitinating Parkin.
    Keywords:  Rnf40; cerebrovascular endothelial barrier; cognition; endothelial cell; hypertension; mitophagy
    DOI:  https://doi.org/10.1111/cns.70210
  23. Cells. 2024 Dec 20. pii: 2115. [Epub ahead of print]13(24):
    Apolipoprotein-L Functions in Membrane Remodeling.
    Etienne Pays.
      The mammalian Apolipoprotein-L families (APOLs) contain several isoforms of membrane-interacting proteins, some of which are involved in the control of membrane dynamics (traffic, fission and fusion). Specifically, human APOL1 and APOL3 appear to control membrane remodeling linked to pathogen infection. Through its association with Non-Muscular Myosin-2A (NM2A), APOL1 controls Golgi-derived trafficking of vesicles carrying the lipid scramblase Autophagy-9A (ATG9A). These vesicles deliver APOL3 together with phosphatidylinositol-4-kinase-B (PI4KB) and activated Stimulator of Interferon Genes (STING) to mitochondrion-endoplasmic reticulum (ER) contact sites (MERCSs) for the induction and completion of mitophagy and apoptosis. Through direct interactions with PI4KB and PI4KB activity controllers (Neuronal Calcium Sensor-1, or NCS1, Calneuron-1, or CALN1, and ADP-Ribosylation Factor-1, or ARF1), APOL3 controls PI(4)P synthesis. PI(4)P is required for different processes linked to infection-induced inflammation: (i) STING activation at the Golgi and subsequent lysosomal degradation for inflammation termination; (ii) mitochondrion fission at MERCSs for induction of mitophagy and apoptosis; and (iii) phagolysosome formation for antigen processing. In addition, APOL3 governs mitophagosome fusion with endolysosomes for mitophagy completion, and the APOL3-like murine APOL7C is involved in phagosome permeabilization linked to antigen cross-presentation in dendritic cells. Similarly, APOL3 can induce the fusion of intracellular bacterial membranes, and a role in membrane fusion can also be proposed for endothelial APOLd1 and adipocyte mAPOL6, which promote angiogenesis and adipogenesis, respectively, under inflammatory conditions. Thus, different APOL isoforms play distinct roles in membrane remodeling associated with inflammation.
    Keywords:  APOL1 nephropathy; APOL1 risk variants; APOL3 antibacterial activity; adipogenesis; angiogenesis; antigen cross-presentation; kidney disease; membrane fission; membrane fusion; mitophagy
    DOI:  https://doi.org/10.3390/cells13242115
  24. Arch Gerontol Geriatr. 2024 Dec 25. pii: S0167-4943(24)00407-2. [Epub ahead of print]131 105732
    Inhibition of PGAM5 hyperactivation reduces neuronal apoptosis in PC12 cells and experimental vascular dementia rats.
    Ding Zhang, Fangcun Li, Chunying Sun, Canrong Chen, Hongling Qin, Xuzhou Wu, Minghe Jiang, Keqing Zhou, Chun Yao, Yueqiang Hu.
       PURPOSE: The incidence of vascular dementia (VaD), as one of the main types of dementia in old age, has been increasing year by year, and exploring its pathogenesis and seeking practical and effective treatment methods are undoubtedly the key to solving this problem. Phosphoglycerate translocase 5 (PGAM5), as a crossroads of multiple signaling pathways, can lead to mitochondrial fission, which in turn triggers the onset and development of necroptosis, and thus PGAM5 may be a novel target for the prevention and treatment of vascular dementia.
    METHODS: Animal model of vascular dementia was established by Two-vessel occlusion (2-VO) method, and cellular model of vascular dementia was established by oxygen glucose deprivation (OGD) method. Neuronal damage was detected in vivo and in vitro in different groups using different concentrations of the PGAM5-specific inhibitor LFHP-1c, and necroptosis and mitochondrial dynamics-related factors were determined.
    RESULTS: In vivo experiments, 10 mg/kg-1 and 20 mg/kg-1 LFHP-1c improved cognitive deficits, reduced neuronal edema and vacuoles, increased the number of nissl bodies, and it could modulate the expression of Caspase family and Bcl-2 family related proteins and mRNAs and ameliorate neuronal damage. Simultaneously, in vitro experiments, 5 μM, 10 μM and 20 μM LFHP-1c increased the activity and migration number of model cells, reduced the number of apoptotic cells, ameliorated the excessive accumulation of intracellular reactive oxygen species, inhibited the over-activation of caspase-family and Bcl-2-family related proteins and mRNAs, and improved the mitochondrial dynamics of the fission and fusion states. Moreover, in vivo and in vitro experiments have shown that LFHP-1c can also upregulate the expression level of BDNF, inhibit the expression content of TNF-α and ROS, regulate the expression of proteins and mRNAs related to the RIPK1/RIPK3/MLKL pathway and mitochondrial dynamics, and reduce neuronal apoptosis.
    CONCLUSIONS: Inhibition of PGAM5 expression level can reduce neuronal damage caused by chronic cerebral ischemia and hypoxia, which mainly prevents necroptosis by targeting the RIPK1/RIPK3/MLKL signaling pathway and regulates the downstream mitochondrial dynamics homeostasis system to prevent excessive mitochondrial fission, thus improving cognition and exerting cerebroprotective effects.
    Keywords:  Mechanism of action; Mitochondrial dynamics; Necroptosis; Neuronal apoptosis; Vascular dementia
    DOI:  https://doi.org/10.1016/j.archger.2024.105732
  25. Exp Neurol. 2025 Jan 07. pii: S0014-4886(25)00004-4. [Epub ahead of print] 115140
    The role of clock control of DRP1 activity involved in postoperative cognitive dysfunction.
    Yin Cui, Zhiying Zheng, Qingyun Zhou, Xue Han, Shuai Liu, Tianjiao Xia, Xiaopin Gu, Yun Zhang.
      Postoperative cognitive dysfunction (POCD) is a prevalent clinical issue following anesthesia and surgery. The onset of POCD, which is closely linked to circadian rhythm disturbance in previous studies, yet the underlying mechanism remains elusive. There is increasing evidence showed that mitochondrial architecture is coordinated by the circadian clock which DRP1 playing a crucial role. Nonetheless, how DRP1's mediation of mitochondrial dynamics influences POCD through circadian rhythm disruption is still unclear. To investigate this, mice were subjected to 6 h of 1.5 % isoflurane anesthesia from Zeitgeber Time ZT 14 to ZT20 to induce POCD. HT-22 cells underwent prolonged exposure to isoflurane in vitro. Cognitive function was assessed using the Y-maze and fear conditioning tests. Q-PCR and Western blot analyses were performed to measure relative protein expression. Mice's gross movement rhythms were continuously monitored using Mini-Mitter. Mitochondrial morphology was examined via Mito-Tracker imaging. ATP and ROS level were measured to evaluate mitochondrial function. Isoflurane anesthesia compromised the clock control of DRP1 activity in the hippocampus. This disruption of DRP1 phosphorylation rhythm impaired circadian ATP production, affected mitochondrial morphology and function, exacerbated circadian rhythm disturbances, and ultimately led to cognitive deficits in mice. Pretreatment with Mdivi-1, a specific DRP1 inhibitor, managed to reconstruct mitochondrial morphology and function, restore circadian ATP production and rhythm, thereby alleviating the cognitive impairment induced by isoflurane anesthesia. This study suggests that circadian DRP1 activity's regulation of mitochondrial energy metabolism in the hippocampus may play a significant role in the pathogenesis of POCD in mice.
    Keywords:  Circadian rhythm; DRP1; Isoflurane; Mitochondria; POCD
    DOI:  https://doi.org/10.1016/j.expneurol.2025.115140
  26. Nat Cell Biol. 2025 Jan 08.
    Triacylglycerol mobilization underpins mitochondrial stress recovery.
    Zakery N Baker, Yunyun Zhu, Rachel M Guerra, Andrew J Smith, Aline Arra, Lia R Serrano, Katherine A Overmyer, Shankar Mukherji, Elizabeth A Craig, Joshua J Coon, David J Pagliarini.
      Mitochondria are central to myriad biochemical processes, and thus even their moderate impairment could have drastic cellular consequences if not rectified. Here, to explore cellular strategies for surmounting mitochondrial stress, we conducted a series of chemical and genetic perturbations to Saccharomyces cerevisiae and analysed the cellular responses using deep multiomic mass spectrometry profiling. We discovered that mobilization of lipid droplet triacylglycerol stores was necessary for strains to mount a successful recovery response. In particular, acyl chains from these stores were liberated by triacylglycerol lipases and used to fuel biosynthesis of the quintessential mitochondrial membrane lipid cardiolipin to support new mitochondrial biogenesis. We demonstrate that a comparable recovery pathway exists in mammalian cells, which fail to recover from doxycycline treatment when lacking the ATGL lipase. Collectively, our work reveals a key component of mitochondrial stress recovery and offers a rich resource for further exploration of the broad cellular responses to mitochondrial dysfunction.
    DOI:  https://doi.org/10.1038/s41556-024-01586-6
  27. Genes Dis. 2025 Mar;12(2): 101429
    TFE3-mediated neuroprotection: Clearance of aggregated α-synuclein and accumulated mitochondria in the AAV-α-synuclein model of Parkinson's disease.
    Xin He, Mulan Chen, Yepeng Fan, Bin Wu, Zhifang Dong.
      Parkinson's disease (PD) is a neurodegenerative disorder characterized by fibrillar neuronal inclusions containing aggregated α-synuclein (α-Syn). While the pathology of PD is multifaceted, the aggregation of α-Syn and mitochondrial dysfunction are well-established hallmarks in its pathogenesis. Recently, TFE3, a transcription factor, has emerged as a regulator of autophagy and metabolic processes. However, it remains unclear whether TFE3 can facilitate the degradation of α-Syn and regulate mitochondrial metabolism specifically in dopaminergic neurons. In this study, we demonstrate that TFE3 overexpression significantly mitigates the loss of dopaminergic neurons and reduces the decline in tyrosine hydroxylase-positive fiber density, thereby restoring motor function in an α-Syn overexpression model of PD. Mechanistically, TFE3 overexpression reversed α-Syn-mediated impairment of autophagy, leading to enhanced α-Syn degradation and reduced aggregation. Additionally, TFE3 overexpression inhibited α-Syn propagation. TFE3 overexpression also reversed the down-regulation of Parkin, promoting the clearance of accumulated mitochondria, and restored the expression of PGC1-α and TFAM, thereby enhancing mitochondrial biogenesis in the adeno-associated virus-α-Syn model. These findings further underscore the neuroprotective role of TFE3 in PD and provide insights into its underlying mechanisms, suggesting TFE3 as a potential therapeutic target for PD.
    Keywords:  Autophagy; Mitochondrial biogenesis; Mitophagy; Parkinson's disease; TFE3; α-synuclein
    DOI:  https://doi.org/10.1016/j.gendis.2024.101429
  28. J Adv Res. 2025 Jan 02. pii: S2090-1232(24)00623-4. [Epub ahead of print]
    Parkin modulates the hepatocellular carcinoma microenvironment by regulating PD-1/PD-L1 signalling.
    Guiqin Ye, Xin Sun, Jiuzhou Li, Maomao Pu, Jianbin Zhang.
       INTRODUCTION: Parkin-mediated mitophagy is essential for clearing damaged mitochondria, and it inhibits tumour development. The role of mitophagy in modulating tumour immunity is becoming clearer, but the underlying mechanism is still poorly understood.
    OBJECTIVE: This study was designed to examine the role of Parkin in the immune microenvironment of liver tumours induced by carbon tetrachloride (CCl4).
    METHODS: Single-cell RNA sequencing analysis, Western blot, immunofluorescence and co-immunoprecipitation were used to verify the mechanism of Parkin affecting the tumour microenvironment by altering the expression of PD-1.
    RESULTS: Our data revealed that Park2-/- mice showed severe liver damage and increased malignancy. Single-cell RNA sequencing analysis of T lymphocytes in liver tumours showed that the number of cytotoxic CD8+ T cells (Gzmb/Ifng/Fasl) was significantly decreased and the number of exhausted CD8+ T cells (Pdcd1/Lag3/Tigit/Havcr2/Ctla4) was significantly increased in Park2-/- mice, indicating the immune suppressive microenvironment. Single-cell RNA sequencing analysis of myeloid-derived cells also displayed the increase of M2-like macrophages in Park2-/- mice. Through quantitative proteomic analysis, it was found that the differential protein expression between the two groups mainly localized in the plasma membrane and extracellular, including PD-1, MHC-Ⅰ molecules etc., and was mainly associated with PD-1 and antigen presentation pathways. It could impair the antitumour immune response with Parkin deficiency. Parkin deficiency leads to the decrease of hepatic mitophagy levels and the formation of an immune suppressive microenvironment, which promotes the tumourigenesis of liver cancer.
    CONCLUSION: As an E3 ubiquitin ligase, Parkin induces the ubiquitination and degradation of PD-1 in liver cancer and could influence antitumour immunity through the PD-1/PD-L1 signalling pathway. Thus, remodeling the tumour microenvironment through the reintroduction of Parkin or enhancement of mitophagy could activate the anti-tumour immune response and improve the immunotherapy efficacy, which may be a promising strategy for the treatment of HCC.
    DOI:  https://doi.org/10.1016/j.jare.2024.12.045
  29. J Clin Periodontol. 2025 Jan 06.
    Dynamin-Related Protein 1 Orchestrates Inflammatory Responses in Periodontal Macrophages via Interaction With Hexokinase 1.
    Yiming Jiang, Zihan Wang, Kaige Zhang, Yue Hu, Dehao Shang, Lulu Jiang, Minghao Huang, Biyao Wang, Xiaomin He, Zhou Wu, Xu Yan, Xinwen Zhang.
       AIM: To explore the potential roles of mitochondrial dysfunction in the initiation of inflammation in periodontal macrophages and to determine the mechanism underlying the involvement of dynamin-related protein 1 (Drp1) in macrophage inflammatory responses through its interaction with hexokinase 1 (HK1).
    MATERIALS AND METHODS: Gingival tissues were collected from patients diagnosed with periodontitis or from healthy volunteers. Drp1 tetramer formation and phosphorylation were analysed using western blot. THP-1 macrophages and RAW264.7 cells were stimulated with Porphyromonas gingivalis (Pg) or Pg lipopolysaccharide (Pg LPS), respectively. Alterations in proteins associated with mitochondrial dynamics were scrutinized via western blot. Immunofluorescence was used to evaluate mitochondrial damage and mitochondrial permeability transition pore (mPTP) opening. Western blot was used to examine the inflammatory markers NLRP3, caspase-1, IL-1β and GSDMD. Protein interactions involving Drp1 were verified through immunoprecipitation.
    RESULTS: In periodontitis patient samples, Pg LPS-treated RAW264.7 cells, and Pg-stimulated THP-1 macrophages, over-activated Drp1 was able to drive NLRP3 inflammasome activation and the subsequent release of inflammatory factors. A direct interaction between Drp1 and HK1 was observed, facilitating excessive mPTP opening and subsequent mitochondrial dysfunction.
    CONCLUSION: In the inflammatory milieu of periodontal tissues, Drp1 hyperactivation in the macrophages is implicated in inflammation induction. Modulation of the inflammatory response in periodontal macrophages by Drp1 appears to facilitate mPTP opening.
    Keywords:  dynamin‐related protein 1; hexokinase 1; inflammasome; mitochondrial permeability transition pore; periodontitis
    DOI:  https://doi.org/10.1111/jcpe.14111
  30. Appl Biochem Biotechnol. 2025 Jan 10.
    Metformin Alleviates Doxorubicin-Induced Cardiotoxicity via Preserving Mitochondrial Dynamics Balance and Calcium Homeostasis.
    Nashwa Maghraby, Mona A H El-Baz, Athar M A Hassan, Sary Kh Abd-Elghaffar, Amira S Ahmed, Mahmoud S Sabra.
      Doxorubicin (DOX) is a commonly used chemotherapeutic medication for treating malignancies, although its cardiotoxicity limits its use. There is growing evidence that alteration of the mitochondrial fission/fusion dynamic processes accompanied by excessive reactive oxygen species (ROS) production and alteration of calcium Ca2+ homeostasis are potential underlying mechanisms of DOX-induced cardiotoxicity (DIC). Metformin (Met) is an AMP-activated protein kinase (AMPK) activator that has antioxidant properties and cardioprotective effects. The purpose of the study is to assess Met's possible cardioprotective benefits against DOX-induced cardiotoxicity. The study included 32 adult male rats. They were randomly divided into four groups: administered saline, DOX, Met, or DOX combined with Met respectively. Heart tissues were used for biochemical assays that measured oxidative stress markers, malondialdehyde (MDA), reduced glutathione (GSH), mitochondrial dynamics markers, optic atrophy-1(OPA-1) and dynamin-1-like protein (Drp1), calcineurin and caspase-3. Serum levels of myocardial injury markers, cardiac troponin I (cTn-I), and aspartate aminotransferase (AST), were also measured. The results revealed that DOX intoxication was associated with a significant increase in the levels of serum cTn-I and AST, increased cardiac MDA level, increased cardiac Drp1, calcineurin, and caspase-3 expressions, as well as reduced cardiac GSH level and cardiac OPA-1 expression. On the other hand, Met treatment significantly reduced DIC by decreasing oxidative stress, apoptosis, and improving mitochondrial and calcium balance. Finally, this study shows that Met may be able to protect the heart from damage caused by DOX by working as an antioxidant and anti-apoptotic agent and keeping the balance of calcium and mitochondria.
    Keywords:  Calcineurin; Cardiotoxicity; Doxorubicin; Metformin; Mitochondrial dynamics
    DOI:  https://doi.org/10.1007/s12010-024-05141-9
  31. Pharmaceuticals (Basel). 2024 Dec 20. pii: 1727. [Epub ahead of print]17(12):
    Inhibition of TFAM-Mediated Mitophagy by Oroxylin A Restored Sorafenib Sensitivity Under Hypoxia Conditions in HepG2 Cells.
    Shufan Ji, Xuefen Xu, Yujia Li, Sumin Sun, Qiuyu Fu, Yangling Qiu, Shuqi Wang, Siwei Xia, Feixia Wang, Feng Zhang, Ji Xuan, Shizhong Zheng.
      Background: Liver cancer treatment encounters considerable therapeutic challenges, especially because hypoxic microenvironments markedly reduce sensitivity to chemotherapeutic agents. TFAM (mitochondrial transcription factor A) plays a crucial role in maintaining mitochondrial function. Oroxylin A (OA), a flavonoid with potential therapeutic properties, demonstrated prospects in cancer treatment. However, the mechanism of the sensitizing effect of OA on cancer cells has not been elucidated. Methods: MTT assays were utilized to evaluate a hypoxia-induced resistance model. Plate colony formation assays, TEM, and JC-1 staining were used to examine the effects of siTFAM on proliferation and mitochondrial damage of HepG2 cells. Cox8-EGFP-mCherry plasmid transfection, LysoTracker and MitoTracker colocalization analysis, and WB were conducted to evaluate the influence of OA on mitophagy. The effect of OA on p53 ubiquitination levels was investigated by Co-IP and the CHX chase assay. A mouse xenograft tumor model was utilized to assess the therapeutic effect of OA on HepG2 cells in vivo. Results: OA significantly improved the inhibitory effect of sorafenib by inhibiting mitophagy on HepG2 cells in in vitro and in vivo models. Notably, the molecular docking and thermal shift assays indicated a clear binding of OA and TFAM. Further research revealed that OA suppressed p53 acetylation and promoted its degradation by downregulating TFAM expression, which ultimately inhibited mitophagy in hypoxia. Conclusions: OA has demonstrated the potential to enhance the efficacy of sorafenib treatment for liver cancer, and TFAM may be one of its targets.
    Keywords:  Oroxylin A; TFAM; hypoxia; p53; sensitivity
    DOI:  https://doi.org/10.3390/ph17121727
  32. BMC Cancer. 2025 Jan 06. 25(1): 15
    Identification of a mitophagy-related gene signature for predicting overall survival and response to immunotherapy in rectal cancer.
    Jian Yang, Zhifei Cao, Chengqing Yu, Wenxu Cui, Jian Zhou.
       BACKGROUND: Rectal cancer is a highly heterogeneous gastrointestinal tumor, and the prognosis for patients with treatment-resistant and metastatic rectal cancer remains poor. Mitophagy, a type of selective autophagy that targets mitochondria, plays a role in promoting or inhibiting tumors; however, the importance of mitophagy-related genes (MRGs) in the prognosis and treatment of rectal cancer is unclear.
    METHODS: In this study, we used the differentially expressed genes (DEGs) and MRGs from the TCGA-READ dataset to identify differentially expressed mitophagy-related genes (MRDEGs). The mitophagy scores were then analyzed for differential expression and ROC. Seven module genes were identified using the weighted gene coexpression network analysis (WGCNA) approach and subsequently validated in the merged datasets GSE87211 and GSE90627. The model genes were obtained based on prognostic features, and the subgroups were distinguished by risk score. Gene enrichment, immune infiltration and immunotherapy response were also evaluated. Finally, validation of prognostic gene expression in rectal cancer was carried out using clinical samples, employing Immunohistochemistry (IHC).
    RESULTS: We demonstrated that 22 MRGs were differentially expressed between normal and rectal cancer tissues. A prognostic model for rectal cancer MRGs was constructed using WGCNA and Cox regression, which exhibited good diagnostic performance. In this study, we identified four molecular markers (MYLK, FLNC, MYH11, and NEXN) as potential prognostic biomarkers for rectal cancer for the first time. Moreover, our findings indicate that the risk scores derived from the four MRGs are associated with tumor immunity. To further validate our findings, IHC analyses suggested that the expression of MYH11 in rectal cancer tissues was lower than in nontumorous rectal tissues.
    CONCLUSION: MRGs could predict the prognosis and response to immunotherapy in patients with rectal cancer and might be able to personalize treatment for patients.
    Keywords:  Immunotherapy; Mitophagy; Prognosis; Rectal cancer; Signature
    DOI:  https://doi.org/10.1186/s12885-024-13412-1
  33. Sex Med. 2024 Dec;12(6): qfae096
    Histone deacetylase 6 inhibition prevents hypercholesterolemia-induced erectile dysfunction independent of changes in markers of autophagy.
    Colin M Ihrig, McLane M Montgomery, Yohei Nomura, Mitsunori Nakano, Deepesh Pandey, Justin D La Favor.
       Background: Erectile dysfunction is a condition with a rapidly increasing prevalence globally with a strong correlation to the increase in obesity and cardiovascular disease rates.
    Aim: The aim of the current study is to investigate the potential role of tubacin, a histone deacetylase 6 (HDAC6) inhibitor, in restoring erectile function in a hypercholesterolemia-induced endothelial dysfunction model.
    Methods: Thirty-nine male C57Bl/6 J mice were divided into 3 groups. Two groups were administered an adeno-associated virus encoding for the gain of function of proprotein convertase subtilisin/kexin type 9 (PCSK9) and placed on a high-fat diet (HFD) with 1.25% cholesterol added for 18 weeks in order to induce a prolonged state of hypercholesterolemia. One of the PCSK9 groups received daily intraperitoneal injections of the HDAC6 inhibitor tubacin, while the other 2 groups received daily vehicle injections. Erectile function was assessed through measurement of intracavernosal pressure and mean arterial pressure during cavernous nerve stimulation, as well as assessment of agonist-stimulated ex vivo relaxation of the corpus cavernosum (CC). Western blotting was performed from CC tissue samples.
    Outcomes: Erectile and endothelial functions were assessed, as well as protein markers of mitochondrial dynamics, mitophagy, and autophagy.
    Results: Erectile function was impaired in the HFD + PCSK9 group throughout the entire voltage range of stimulation. However, the HFD + PCSK9 mice that were treated with tubacin experienced significant restoration of erectile function at the medium and high voltages of nerve stimulation. Similarly, ex vivo CC relaxation responses to acetylcholine and the cystathionine γ-lyase (CSE) substrate L-cysteine were reduced in the vehicle-treated HFD + PCSK9 mice, both of which were restored in the HFD + PCSK9 mice treated with tubacin. Corpus-cavernosum protein expression of CSE was significantly elevated in the tubacin-treated HFD + PCSK9 mice relative to both other groups. There were no significant differences observed in any of the protein markers of mitochondrial dynamics, mitophagy, or autophagy investigated.
    Clinical translation: Histone deacetylase 6 inhibition may protect against erectile and endothelial dysfunction associated with hypercholesterolemia.
    Strengths and limitations: This was the first study to investigate HDAC6-specific inhibition for treatment of erectile dysfunction. A study limitation was the exclusive focus on the CC, rather than structure and function of the pre-penile arteries that may develop a substantial atherosclerotic plaque burden under hypercholesterolemic conditions.
    Conclusions: Tubacin may prevent hypercholesterolemia-induced erectile dysfunction through a hydrogen sulfide-related mechanism unrelated to regulation of mitophagy or autophagy.
    Keywords:  H2S; HDAC6; PCSK9; atherosclerosis; cholesterol; cystathionine gamma-lyase; endothelial; mitophagy; sexual health; tubacin
    DOI:  https://doi.org/10.1093/sexmed/qfae096
  34. Nat Cell Biol. 2025 Jan 08.
    Precursor occupancy controls mitochondrial import channel via proteolysis.
      
    DOI:  https://doi.org/10.1038/s41556-024-01575-9
  35. Aging Cell. 2025 Jan 09. e14475
    Salidroside Improves Oocyte Competence of Reproductively Old Mice by Enhancing Mitophagy.
    Jingkai Gu, Renwu Hua, Huayan Wu, Chenxi Guo, Zhuo Hai, Yuan Xiao, William S B Yeung, Kui Liu, Elnur Babayev, Tianren Wang.
      The decline of oocyte quality with advanced maternal age has a detrimental effect on female fertility. However, there is limited knowledge of therapeutic options and their mechanisms to improve oocyte quality in reproductively older women. In this study, we demonstrated that supplementation of salidroside improves the oocyte quality of reproductively old mice. Salidroside improved the maturation, fertilization, and developmental competence of oocytes from reproductively old mice by maintaining the normal spindle/chromosome structure and mitochondrial function. Oocyte transcriptomic and micro-proteomic analysis revealed that salidroside restores oocyte quality by enhancing mitophagy in reproductively old mice. Our studies provide a new theoretical foundation for utilizing salidroside to improve oocyte quality in reproductively old females in the context of natural fertility or assisted reproduction.
    Keywords:  ART; IVF; aging; egg; mitochondria; ovary
    DOI:  https://doi.org/10.1111/acel.14475
  36. iScience. 2025 Jan 17. 28(1): 111519
    The inhibition of PINK1/Drp1-mediated mitophagy by hyperglycemia leads to impaired osteoblastogenesis in diabetes.
    Xiao-Jing Chen, Yu-Ying Yang, Zheng-Can Pan, Jing-Zun Xu, Tao Jiang, Lin-Lin Zhang, Ke-Cheng Zhu, Deng Zhang, Jia-Xi Song, Chun-Xiang Sheng, Li-Hao Sun, Bei Tao, Jian-Min Liu, Hong-Yan Zhao.
      Impaired bone quality and increased fracture risk are cardinal features of the skeleton in diabetes mellitus. Hyperglycemia-induced oxidative stress is proposed as a potential underlying mechanism, but the precise pathogenic mechanism remains incompletely understood. In this investigation, osteoblasts under high glucose exhibited heightened levels of reactive oxygen species, impaired mitochondrial membrane potential, and profound inhibition of late-stage osteoblast differentiation. Further analyses uncovered that high glucose resulted in the downregulation of the PINK1/Drp1 pathway in osteoblasts, consequently leading to impaired mitophagy. Conversely, the upregulation of PINK1/Drp1 pathway activated mitophagy, which restored the differentiation capacity of osteoblasts. Notably, in an STZ-induced diabetic mouse model, BMP9 upregulated the expression of PINK1/Drp1 in the bone tissue, leading to an improvement in bone quality and bone mineral density. These findings suggest that the PINK1/Drp1 pathway might be a potential therapeutic target to enhance osteogenic differentiation and treat diabetic osteoporosis.
    Keywords:  Cell biology; Molecular biology; Physiology
    DOI:  https://doi.org/10.1016/j.isci.2024.111519
  37. Neurotox Res. 2025 Jan 08. 43(1): 3
    Curcumin Improves Hippocampal Cell Bioenergetics, Redox and Inflammatory Markers, and Synaptic Proteins, Regulating Mitochondrial Calcium Homeostasis.
    Claudia Jara, Angie K Torres, Han S Park-Kang, Lisette Sandoval, Claudio Retamal, Alfonso Gonzalez, Micaela Ricca, Sebastián Valenzuela, Michael P Murphy, Nibaldo C Inestrosa, Cheril Tapia-Rojas.
      Mitochondria produces energy through oxidative phosphorylation (OXPHOS), maintaining calcium homeostasis, survival/death cell signaling mechanisms, and redox balance. These mitochondrial functions are especially critical for neurons. The hippocampus is crucial for memory formation in the brain, which is a process with high mitochondrial function demand. Loss of hippocampal function in aging is related to neuronal damage, where mitochondrial impairment is critical. Synaptic and mitochondrial dysfunction are early events in aging; both are regulated reciprocally and contribute to age-associated memory loss together. We previously showed that prolonged treatment with Curcumin or Mitoquinone (MitoQ) improves mitochondrial functions in aged mice, exerting similar neuroprotective effects. Curcumin has been described as an anti-inflammatory and antioxidant compound, and MitoQ is a potent antioxidant directly targeting mitochondria; however, whether Curcumin exerts a direct impact on the mitochondria is unclear. In this work, we study whether Curcumin could have a mechanism similar to MitoQ targeting the mitochondria. We utilized hippocampal slices of 4-6-month-old C57BL6 mice to assess the cellular changes induced by acute Curcumin treatment ex-vivo compared to MitoQ. Our results strongly suggest that both compounds improve the synaptic structure, oxidative state, and energy production in the hippocampus. Nevertheless, Curcumin and MitoQ modify mitochondrial function differently; MitoQ improves the mitochondrial bioenergetics state, reducing ROS production and increasing ATP generation. In contrast, Curcumin reduces mitochondrial calcium levels and prevents calcium overload related to mitochondrial swelling. Thus, Curcumin is described as a new regulator of mitochondrial calcium homeostasis and could be used in pathological events involving calcium deregulation and excitotoxicity, such as aging and neurodegenerative diseases.
    Keywords:  Curcumin; Hippocampus; MitoQ; Mitochondria
    DOI:  https://doi.org/10.1007/s12640-024-00726-y
  38. J Agric Food Chem. 2025 Jan 08.
    Recombinant Porcine FGF1 Promotes Muscle Stem Cell Proliferation and Mitochondrial Function for Cultured Meat Production.
    Qingying Liu, Lianghua Xie, Wei Chen.
      Cultured meat is an emerging technology with the potential to meet future protein demands while addressing the challenges associated with traditional livestock farming. The production of cultured meat requires efficient, animal component-free in vitro systems for muscle stem cell (MuSC) expansion. Fibroblast growth factor 1 (FGF1) is a critical growth factor that regulates the MuSC function. In this study, we established an efficient method for the soluble expression and purification of recombinant porcine FGF1 (rpFGF1) in Escherichia coli, achieving a yield of 48 mg of purified protein per liter of culture. Treatment with rpFGF1 significantly enhanced the proliferation of porcine MuSC under serum-free conditions. Furthermore, rpFGF1 induced mitochondrial fission and mitophagy by activating the ERK-dependent phosphorylation of DRP1 at Ser616, resulting in improved mitochondrial function and proliferation capacity in porcine MuSC. These findings highlight the potential of rpFGF1 in the development of serum-free media for scalable and sustainable cultured meat production.
    Keywords:  cultured meat; fibroblast growth factor 1; mitochondrial fission; porcine muscle stem cell
    DOI:  https://doi.org/10.1021/acs.jafc.4c09215
  39. Nat Commun. 2025 Jan 09. 16(1): 541
    CDK4 inactivation inhibits apoptosis via mitochondria-ER contact remodeling in triple-negative breast cancer.
    Dorian V Ziegler, Kanishka Parashar, Lucia Leal-Esteban, Jaime López-Alcalá, Wilson Castro, Nadège Zanou, Laia Martinez-Carreres, Katharina Huber, Xavier Pascal Berney, María M Malagón, Catherine Roger, Marie-Agnès Berger, Yves Gouriou, Giulia Paone, Hector Gallart-Ayala, George Sflomos, Carlos Ronchi, Julijana Ivanisevic, Cathrin Brisken, Jennifer Rieusset, Melita Irving, Lluis Fajas.
      The energetic demands of proliferating cells during tumorigenesis require close coordination between the cell cycle and metabolism. While CDK4 is known for its role in cell proliferation, its metabolic function in cancer, particularly in triple-negative breast cancer (TNBC), remains unclear. Our study, using genetic and pharmacological approaches, reveals that CDK4 inactivation only modestly impacts TNBC cell proliferation and tumor formation. Notably, CDK4 depletion or long-term CDK4/6 inhibition confers resistance to apoptosis in TNBC cells. Mechanistically, CDK4 enhances mitochondria-endoplasmic reticulum contact (MERCs) formation, promoting mitochondrial fission and ER-mitochondrial calcium signaling, which are crucial for TNBC metabolic flexibility. Phosphoproteomic analysis identified CDK4's role in regulating PKA activity at MERCs. In this work, we highlight CDK4's role in mitochondrial apoptosis inhibition and suggest that targeting MERCs-associated metabolic shifts could enhance TNBC therapy.
    DOI:  https://doi.org/10.1038/s41467-024-55605-z
  40. Mol Cells. 2025 Jan 03. pii: S1016-8478(24)00201-2. [Epub ahead of print] 100176
    eIF2α Phosphorylation-ATF4 Axis-Mediated Transcriptional Reprogramming Mitigates Mitochondrial Impairment During ER Stress.
    Hien Thi Le, Jiyoung Yu, Hee Sung Ahn, Mi-Jeong Kim, In Gyeong Chae, Hyun-Nam Cho, Juhee Kim, Hye-Kyung Park, Hyuk Nam Kwon, Han-Jung Chae, Byoung Heon Kang, Jeong Kon Seo, Kyunggon Kim, Sung Hoon Back.
      Eukaryotic translation initiation factor 2α (eIF2α) phosphorylation, which regulates all three unfolded protein response pathways, helps maintain cellular homeostasis and overcome endoplasmic reticulum (ER) stress through transcriptional and translational reprogramming. However, transcriptional regulation of mitochondrial homeostasis by eIF2α phosphorylation during ER stress is not fully understood. Here, we report that the eIF2α phosphorylation-activating transcription factor 4 (ATF4) axis is required for expression of multiple transcription factors (TFs) including nuclear factor erythroid 2-related factor 2 (Nrf2) and their target genes responsible for mitochondrial homeostasis during ER stress. eIF2α phosphorylation-deficient (A/A) cells displayed dysregulated mitochondrial dynamics and mitochondrial DNA replication, decreased expression of oxidative phosphorylation complex proteins, and impaired mitochondrial functions during ER stress. ATF4 overexpression suppressed impairment of mitochondrial homeostasis in A/A cells during ER stress by promoting expression of downstream TFs and their target genes. Our findings underscore the importance of the eIF2α phosphorylation-ATF4 axis for maintaining mitochondrial homeostasis through transcriptional reprogramming during ER stress.
    Keywords:  ATF4; ER stress; Mitochondrial homeostasis; Nrf2; eIF2α phosphorylation
    DOI:  https://doi.org/10.1016/j.mocell.2024.100176
  41. Biology (Basel). 2024 Dec 04. pii: 1011. [Epub ahead of print]13(12):
    Consequences of Early Maternal Deprivation on Neuroinflammation and Mitochondrial Dynamics in the Central Nervous System of Male and Female Rats.
    Diego San Felipe, Beatriz Martín-Sánchez, Khaoula Zekri-Nechar, Marta Moya, Ricardo Llorente, Jose J Zamorano-León, Eva M Marco, Meritxell López-Gallardo.
      Early life stress (ELS) is associated with an increased risk for neuropsychiatric disorders, and both neuroinflammation and mitochondrial dysfunction seem to be central to mental health. Herein, using an animal model of ELS, a single episode of maternal deprivation (MD, 24 h on pnd 9) extensively documented to elicit behavioural anomalies in male and female Wistar rats, we investigated its consequences in terms of neuroinflammation and mitochondrial dynamics in the prefrontal cortex (PFC) and the hippocampal formation (HCF). MD differentially affected the brain content of cytokines: MD induced a transient increase in pro-inflammatory cytokines (IL-1β and IL-6) in the PFC, as well as in the levels of the anti-inflammatory cytokine IL-10 in the HCF. MD also induced a significant decrease mitochondria citrate synthase activity, but MD did not exert significant changes in mitochondria Complex IV activity, revealing a generalized decrease in mitochondrial density without any change in mitochondrial respiration. In the present study, we demonstrate that MD induces neuroinflammatory processes in specific brain regions. Additional research is needed to better understand the temporal pattern of such changes, their impact on the developing brain, and their participation in the already well-known behavioural consequences of MD.
    Keywords:  citrate synthase; complex IV; cytokines; early life stress (ELS); hippocampal formation; inflammatory processes; mitochondria; neonatal; prefrontal cortex; sex dimorphism
    DOI:  https://doi.org/10.3390/biology13121011
  42. Int J Mol Sci. 2024 Dec 11. pii: 13283. [Epub ahead of print]25(24):
    Cadmium-Induced Oxidative Damage and the Expression and Function of Mitochondrial Thioredoxin in Phascolosoma esculenta.
    Shenwei Gu, Xuebin Zheng, Xinming Gao, Yang Liu, Yiner Chen, Junquan Zhu.
      Phascolosoma esculenta is a unique aquatic invertebrate native to China, whose habitat is highly susceptible to environmental pollution, making it an ideal model for studying aquatic toxicology. Mitochondrial thioredoxin (Trx2), a key component of the Trx system, plays an essential role in scavenging reactive oxygen species (ROS), regulating mitochondrial membrane potential, and preventing ROS-induced oxidative stress and apoptosis. This study investigated the toxicity of cadmium (Cd) on P. esculenta and the role of P. esculenta Trx2 (PeTrx2) in Cd detoxification. The results showed that Cd stress altered the activities of T-SOD and CAT, as well as the contents of GSH and MDA in the intestine. After 96 h of exposure, histological damages such as vacuolization, cell necrosis, and mitophagy were observed. Suggesting that Cd stress caused oxidative damage in P. esculenta. Furthermore, with the prolongation of stress time, the expression level of intestinal PeTrx2 mRNA initially increased and then decreased. The recombinant PeTrx2 (rPeTrx2) protein displayed dose-dependent redox activity and antioxidant capacity and enhanced Cd tolerance of Escherichia coli. After RNA interference (RNAi) with PeTrx2, significant changes in the expression of apoptosis-related genes (Caspase-3, Bax, Bcl-2, and Bcl-XL) were observed. Proving that PeTrx2 rapidly responded to Cd stress and played a vital role in mitigating Cd-induced oxidative stress and apoptosis. Our study demonstrated that PeTrx2 is a key factor for P. esculenta to endure the toxicity of Cd, providing foundational data for further exploration of the molecular mechanisms underlying heavy metal resistance in P. esculenta.
    Keywords:  Phascolosoma esculenta; apoptosis; cadmium; mitochondrial thioredoxin; oxidative stress
    DOI:  https://doi.org/10.3390/ijms252413283
  43. Autophagy. 2025 Jan 11. 1-20
    Nonreceptor tyrosine kinase ABL1 regulates lysosomal acidification by phosphorylating the ATP6V1B2 subunit of the vacuolar-type H+-ATPase.
    Caiwei Song, Qincai Dong, Yi Yao, Yan Cui, Chunmei Zhang, Lijun Lin, Lin Zhu, Yong Hu, Hainan Liu, Yanwen Jin, Ping Li, Xuan Liu, Cheng Cao.
      The vacuolar-type H+-ATPase (V-ATPase) is a proton pump responsible for controlling the intracellular and extracellular pH of cells. Its activity and assembly are tightly controlled by multiple pathways, of which phosphorylation-mediated regulation is poorly understood. In this report, we show that in response to starvation stimuli, the nonreceptor tyrosine kinase ABL1 directly interacts with ATP6V1B2, a subunit of the V1 domain of the V-ATPase, and phosphorylates ATP6V1B2 at Y68. Y68 phosphorylation in ATP6V1B2 facilitates the recruitment of the ATP6V1D subunit into the V1 subcomplex of V-ATPase, therefore potentiating the assembly of the V1 subcomplex with the membrane-embedded V0 subcomplex to form the integrated functional V-ATPase. ABL1 inhibition or depletion impairs V-ATPase assembly and lysosomal acidification, resulting in an increased lysosomal pH, a decreased lysosomal hydrolase activity, and consequently, the suppressed degradation of lumenal cargo during macroautophagy/autophagy. Consistently, the efficient removal of damaged mitochondrial residues during mitophagy is also impeded by ABL1 deficiency. Our findings suggest that ABL1 is a crucial autophagy regulator that maintains the adequate lysosomal acidification required for both physiological conditions and stress responses.Abbreviation: ANOVA: analysis of variance; Baf A1: bafilomycin A1; CCCP: carbonyl cyanide 3-chlorophenylhydrazone; CRK: CRK proto-oncogene, adaptor protein; CTSD: cathepsin D; DMSO: dimethylsulfoxide; EBSS: Earle's balanced salt solution; FITC: fluorescein isothiocyanate; GFP: green fluorescent protein; GST: glutathione S-transferase; LAMP2: lysosomal associated membrane protein 2; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MTORC1: mechanistic target of rapamycin kinase complex 1; PD: Parkinson disease; PLA: proximity ligation assay; RFP: red fluorescent protein; WT: wild-type.
    Keywords:  ABL1; V-ATPase; kinase; lysosome; phosphorylation
    DOI:  https://doi.org/10.1080/15548627.2024.2448913
  44. Curr Mol Med. 2025 Jan 08.
    KDM4A Silencing Reverses Cisplatin Resistance in Ovarian Cancer Cells by Reducing Mitophagy via SNCA Transcriptional Inactivation.
    Yan Xing, Meiya Mao, Tianhong Zhu, Hongyan Shi, Huiqing Ding.
       BACKGROUND: Ovarian cancer is one of the deadliest gynecologic cancers, with chemotherapy resistance as the greatest clinical challenge. Autophagy occurrence is associated with cisplatin (DDP)-resistant ovarian cancer cells. Herein, the role and mechanism of alpha-synuclein (SNCA), the autophagy-related gene, in DDP resistance of ovarian cancer cells are explored.
    METHODS: Differentially expressed genes in DDP resistance of ovarian cancer cells were analyzed by GEO2R tools. DDP-resistant ovarian cancer cells (A2780/DDP) were transfected and treated with 2.5 μg/mL DDP for 72 h, followed by the determination of cell viability, proliferation, apoptosis, and expressions of SNCA, lysine demethylase 4A (KDM4A), histone H3 lysine 9 trimethylation (H3K9me3), and mitophagy-related proteins. The H3K9me3 demethylation of SNCA by KDM4A was confirmed by chromatin immunoprecipitation.
    RESULTS: SNCA and KDM4A were highly expressed in DDP-resistant ovarian cancer cells and their parental cells. KDM4A knockdown diminished expressions of KDM4A and SNCA and elevated H3K9me3 expression and H3K9me3 enrichment on SNCA promoter in A2780/DDP cells. SNCA or KDM4A knockdown inhibited cell viability, proliferation, and levels of LC3-II/LC3-I and Parkin while inducing cell apoptosis and upregulating Cyt-C expression of A2780/DDP cells with/without DDP treatment; however, SNCA overexpression not only did conversely but also reversed the effects of KDM4A knockdown on DDP-treated A2780/DDP cells and vice versa.
    CONCLUSION: Silencing of KDM4A-mediated transcription inactivation of SNCA reduces mitophagy, thus inhibiting the resistance of ovarian cancer cells to cisplatin. KDM4A may be a promising drug target for DDP-resistant ovarian cancer cells.
    Keywords:  Lysine demethylase 4A; alpha-synuclein; cisplatin resistance; histone methylation.; mitophagy; ovarian cancer
    DOI:  https://doi.org/10.2174/0115665240281083241112053145
  45. SLAS Discov. 2025 Jan 06. pii: S2472-5552(25)00001-2. [Epub ahead of print] 100208
    Novel high-content and open-source image analysis tools for profiling mitochondrial morphology in neurological cell models.
    Marcus Y Chin, David A Joy, Madhuja Samaddar, Anil Rana, Johann Chow, Takashi Miyamoto, Meredith Calvert.
      Mitochondria undergo dynamic morphological changes depending on cellular cues, stress, genetic factors, or disease. The structural complexity and disease-relevance of mitochondria have stimulated efforts to generate image analysis tools for describing mitochondrial morphology for therapeutic development. Using high-content analysis, we measured multiple morphological parameters and employed unbiased feature clustering to identify the most robust pair of texture metrics that described mitochondrial state. Here, we introduce a novel image analysis pipeline to enable rapid and accurate profiling of mitochondrial morphology in various cell types and pharmacological perturbations. We applied a high-content adapted implementation of our tool, MitoProfilerHC, to quantify mitochondrial morphology changes in i) a mammalian cell dose response study and ii) compartment-specific drug effects in primary neurons. Next, we expanded the usability of our pipeline by using napari, a Python-powered image analysis tool, to build an open-source version of MitoProfiler and validated its performance and applicability. In conclusion, we introduce MitoProfiler as both a high-content-based and an open-source method to accurately quantify mitochondrial morphology in cells, which we anticipate to greatly facilitate mechanistic discoveries in mitochondrial biology and disease.
    Keywords:  Mitochondria; high-content imaging; high-throughput screening; image analysis; mitochondrial morphology; napari plugin; neurons; open-source
    DOI:  https://doi.org/10.1016/j.slasd.2025.100208
  46. Int J Biol Macromol. 2025 Jan 04. pii: S0141-8130(25)00066-2. [Epub ahead of print]294 139517
    m6A modified pre-miR-503-5p contributes to myogenic differentiation through the activation of mTOR pathway.
    Yalong Su, Kaiping Deng, Zhipeng Liu, Zhen Zhang, Zhilin Liu, Zidi Huang, Yuhao Gao, Ke Gao, Yixuan Fan, Yanli Zhang, Feng Wang.
      The post-transcriptional regulation of epigenetic modification is a hot topic in skeletal muscle development research. Both m6A modifications and miRNAs have been well-established as crucial regulators in skeletal muscle development. However, the interacting regulatory mechanisms between m6A modifications and miRNAs in skeletal muscle development remain unclear. In this study, miRNA sequencing analysis of goat primary myoblasts (GPMs) pre- and post-differentiation revealed that miR-503-5p was upregulated during myogenic differentiation, and its precursor was identified to contain m6A modification sites. Combined analysis of RIP, qRT-PCR and mRNA stability assay showed that Ythdf2 could recognize and bind the m6A site on pre-miR-503-5p, thereby facilitating the maturation of pre-miR-503-5p in an m6A-dependent manner. Moreover, the overexpression of miR-503-5p significantly inhibits the proliferation of GPMs, promotes myogenic differentiation, and enhances mitochondrial biogenesis while activating the mTOR pathway. However, the suppression of mTOR activity can effectively counteract the accelerated myogenic differentiation induced by miR-503-5p overexpression. Collectively, our results indicate that Ythdf2-dependent m6A modification facilitates the maturation of pre-miR-503-5p, thereby promoting skeletal muscle differentiation through the activation of the mTOR pathway. These insights lay a valuable foundation for further investigation into the complexities of skeletal muscle development and the potential implications of epigenetic regulation in this process.
    Keywords:  MicroRNA maturation; Myogenesis; m6A modification; mTOR pathway; miR-503-5p
    DOI:  https://doi.org/10.1016/j.ijbiomac.2025.139517
  47. J Cell Sci. 2025 Jan 08. pii: jcs.263678. [Epub ahead of print]
    A protein interaction map of the myosin Myo2 reveals a role of Alo1 in mitochondrial inheritance in yeast.
    Xenia Chelius, Nathalie Rausch, Veronika Bartosch, Maria Klecker, Till Klecker, Benedikt Westermann.
      Budding yeast cells multiply by asymmetric cell division. During this process, the cell organelles are transported by myosin motors along the actin cytoskeleton into the growing bud, while at the same time some organelles must be retained in the mother cell. The ordered partitioning of organelles depends on highly regulated binding of motor proteins to cargo membranes. To search for novel components involved in this process, we performed a protein fragment complementation screen using the cargo binding domain of Myo2, the major organelle transporter in yeast, as a bait and a genome-wide strain collection expressing yeast proteins as prey. One robust hit was Alo1, a poorly characterized D-arabinono-1,4-lactone oxidase located in the mitochondrial outer membrane. We found that mutants lacking Alo1 exhibit defects in mitochondrial morphology and inheritance. During oxidative stress dysfunctional mitochondria are immobilized in the mother in wild type cells. Intriguingly, overexpression of ALO1 restores bud-directed transport of mitochondria under these conditions. We propose that Alo1 supports the recruitment of Myo2 to mitochondria and its activity is particularly important under oxidative stress.
    Keywords:  Mitochondria; Myo2 cargo binding domain; Myosin motor; Organelle inheritance; Oxidative stress; Saccharomyces cerevisiae
    DOI:  https://doi.org/10.1242/jcs.263678
  48. Biochemistry. 2025 Jan 04.
    Mitochondrial Sorting and Assembly Machinery: Chaperoning a Moonlighting Role?
    Roshika Ravi, Deepsikha Routray, Radhakrishnan Mahalakshmi.
      The mitochondrial outer membrane (OMM) β-barrel proteins link the mitochondrion with the cytosol, endoplasmic reticulum, and other cellular membranes, establishing cellular homeostasis. Their active insertion and assembly in the outer mitochondrial membrane is achieved in an energy-independent yet highly effective manner by the Sorting and Assembly Machinery (SAM) of the OMM. The core SAM constituent is the 16-stranded transmembrane β-barrel Sam50. For over two decades, the primary role of Sam50 has been linked to its function as a chaperone in the OMM, wherein it assembles all β-barrels through a lateral gating and β-barrel switching mechanism. Interestingly, recent studies have demonstrated that despite its low copy number, Sam50 performs various diverse functions beyond assembling β-barrels. This includes maintaining cristae morphology, bidirectional lipid shuttling between the ER and mitochondrial inner membrane, import of select proteins, regulation of PINK1-Parkin function, and timed trigger of cell death. Given these multifaceted critical regulatory functions of SAM across all eukaryotes, we now reason that SAM merely moonlights as the hub for β-barrel biogenesis and has indeed evolved a diverse array of primary roles in maintaining mitochondrial function and cellular homeostasis.
    Keywords:  MERCS; Sam50; barrel biogenesis; lipid transport; membrane protein folding; mitochondrial chaperone
    DOI:  https://doi.org/10.1021/acs.biochem.4c00727
  49. Front Cell Neurosci. 2024 ;18 1432887
    STZ-induced hyperglycemia differentially influences mitochondrial distribution and morphology in the habenulointerpeduncular circuit.
    Mohammad Jodeiri Farshbaf, Taelor A Matos, Kristi Niblo, Yacoub Alokam, Jessica L Ables.
       Introduction: Diabetes is a metabolic disorder of glucose homeostasis that is a significant risk factor for neurodegenerative diseases, such as Alzheimer's disease, as well as mood disorders, which often precede neurodegenerative conditions. We examined the medial habenulainterpeduncular nucleus (MHb-IPN), as this circuit plays crucial roles in mood regulation, has been linked to the development of diabetes after smoking, and is rich in cholinergic neurons, which are affected in other brain areas in Alzheimer's disease.
    Methods: This study aimed to investigate the impact of streptozotocin (STZ)-induced hyperglycemia, a type 1 diabetes model, on mitochondrial and lipid homeostasis in 4% paraformaldehyde-fixed sections from the MHb and IPN of C57BL/6 J male mice, using a recently developed automated pipeline for mitochondrial analysis in confocal images. We examined different time points after STZ-induced diabetes onset to determine how the brain responded to chronic hyperglycemia, with the limitation that mitochondria and lipids were not examined with respect to cell type or intracellular location.
    Results: Mitochondrial distribution and morphology differentially responded to hyperglycemia depending on time and brain area. Six weeks after STZ treatment, mitochondria in the ventral MHb and dorsal IPN increased in number and exhibited altered morphology, but no changes were observed in the lateral habenula (LHb) or ventral IPN. Strikingly, mitochondrial numbers returned to normal dynamics at 12 weeks. Both blood glucose level and glycated hemoglobin (HbA1C) correlated with mitochondrial dynamics in ventral MHb, whereas only HbA1C correlated in the IPN. We also examined lipid homeostasis using BODIPY staining for neutral lipids in this model given that diabetes is associated with disrupted lipid homeostasis. BODIPY staining intensity was unchanged in the vMHb of STZ-treated mice but increased in the IPN and VTA and decreased in the LHb at 12 weeks. Interestingly, areas that demonstrated changes in mitochondria had little change in lipid staining and vice versa.
    Discussion: This study is the first to describe the specific impacts of diabetes on mitochondria in the MHb-IPN circuit and suggests that the cholinergic MHb is uniquely sensitive to diabetesinduced hyperglycemia. Further studies are needed to understand the functional and behavioral implications of these findings.
    Keywords:  diabetes; interpeduncular nucleus; lipid; medial habenula; mitochondrial homeostasis
    DOI:  https://doi.org/10.3389/fncel.2024.1432887
  50. Proc Natl Acad Sci U S A. 2025 Jan 07. 122(1): e2411579122
    ANAC044 orchestrates mitochondrial stress signaling to trigger iron-induced stem cell death in root meristems.
    Juanmei Yan, Zhihang Feng, Yihui Xiao, Ming Zhou, Xiaobo Zhao, Xianyong Lin, Weiming Shi, Wolfgang Busch, Baohai Li.
      While iron (Fe) is essential for life and plays important roles for almost all growth related processes, it can trigger cell death in both animals and plants. However, the underlying mechanisms for Fe-induced cell death in plants remain largely unknown. S-nitrosoglutathione reductase (GSNOR) has previously been reported to regulate nitric oxide homeostasis to prevent Fe-induced cell death within root meristems. Here, we found that in the absence of GSNOR, exposure to high Fe treatment results in DNA damage-dependent cell death specifically in vascular stem cells in root meristems within 48 h. Through a series of time-course transcriptomic analyses, we unveil that in the absence of GSNOR, mitochondrial dysfunction emerges as the most prominent response to high Fe treatment. Consistently, the application of mitochondrial respiratory inhibitors leads to stem cell death in root meristems, and pharmacological blockage of the voltage-dependent anion channel that is responsible for the release of mitochondrial-derived molecules into the cytosol or genetic changes that abolish the ANAC017- and ANAC013-mediated mitochondrial retrograde signaling effectively eliminate Fe-induced stem cell death in gsnor root meristems. We further identify the nuclear transcription factor ANAC044 as a mediator of this mitochondrial retrograde signaling. Disruption of ANAC044 completely abolishes the GSNOR-dependent, Fe-induced stem cell death in root meristems, while ectopic expression of ANAC044 causes severe root stem cell death. Collectively, our findings reveal a mechanism responsible for initiating Fe-induced stem cell death in the root meristem, which is the ANAC044-mediated GSNOR-regulated mitochondrial stress signaling pathway.
    Keywords:  ANAC044; iron; mitochondrial retrograde signaling; root meristem; stem cell death
    DOI:  https://doi.org/10.1073/pnas.2411579122
  51. Curr Pain Headache Rep. 2025 Jan 06. 29(1): 11
    Sexual Dimorphism in Migraine. Focus on Mitochondria.
    Michal Fila, Lukasz Przyslo, Marcin Derwich, Elzbieta Pawlowska, Janusz Blasiak.
       PURPOSE OF REVIEW: Migraine prevalence in females is up to 3 times higher than in males and females show higher frequency, longer duration, and increased severity of headache attacks, but the reason for that difference is not known. This narrative review presents the main aspects of sex dimorphism in migraine prevalence and discusses the role of sex-related differences in mitochondrial homeostasis in that dimorphism. The gender dimension is also shortly addressed.
    RECENT FINDINGS: The imbalance between energy production and demand in the brain susceptible to migraine is an important element of migraine pathogenesis. Mitochondria are the main energy source in the brain and mitochondrial impairment is reported in both migraine patients and animal models of human migraine. However, it is not known whether the observed changes are consequences of primary disturbance of mitochondrial homeostasis or are secondary to the migraine-affected hyperexcitable brain. Sex hormones regulate mitochondrial homeostasis, and several reports suggest that the female hormones may act protectively against mitochondrial impairment, contributing to more effective energy production in females, which may be utilized in the mechanisms responsible for migraine progression. Migraine is characterized by several comorbidities that are characterized by sex dimorphism in their prevalence and impairments in mitochondrial functions. Mitochondria may play a major role in sexual dimorphism in migraine through the involvement in energy production, the dependence on sex hormones, and the involvement in sex-dependent comorbidities. Studies on the role of mitochondria in sex dimorphism in migraine may contribute to precise personal therapeutic strategies.
    Keywords:  Gender dimension; Migraine comorbidities; Mitochondria; Sex hormones; Sex-dependence of migraine prevalence
    DOI:  https://doi.org/10.1007/s11916-024-01317-4
  52. Front Nutr. 2024 ;11 1511682
    Sesamin alleviates lipid accumulation induced by elaidic acid in L02 cells through TFEB regulated autophagy.
    Xueli Liang, Tianliang Zhang, Xinyi Cheng, Hang Yuan, Ning Yang, Yanlei Yi, Xiaozhou Li, Fengxiang Zhang, Jinyue Sun, Zhenfeng Li, Xia Wang.
       Introduction: Non-alcoholic fatty liver disease (NAFLD) is a common chronic disease seriously threatening human health, with limited treatment means, however. Sesamin, a common lignan in sesame seed oil, exhibits anti-inflammatory, antioxidant, and anticancer properties. Our previous studies have shown an ameliorative effect of sesamin on lipid accumulation in human hepatocellular carcinoma (HePG2) induced by oleic acid, with its protective effects unclear in the case of 9-trans-C18:1 elaidic acid (9-trans-C18,1).
    Methods: L02 cells, an important tool in scientific researches due to its high proliferation ability, preserved hepatocyte function, and specificity in response to exogenous factors, were incubated with 9-trans-C18:1 to establish an in vitro model of NAFLD in our study. The lipid accumulation in cells and the morphology of mitochondria and autolysosomes were observed by Oil Red O staining and transmission electron microscopy. The effects of sesamin on oxidative stress, apoptosis, mitochondrial function, autophagy as well as related protein levels in L02 cells were also investigated in the presence of 9-trans-C18:1.
    Results: The results showed that sesamin significantly accelerated the autophagy flux of L02 cells induced by 9-trans-C18:1 as well as elevated protein levels of transcription factor EB (TFEB) and its downstream target lysosome-associated membrane protein 1(LAMP1), along with up-regulated levels of TFEB and LAMP1 in the nucleus indicated by Immunofluorescence. In addition, PTEN-induced putative kinase 1 and Parkin mediated mitophagy was activated by sesamin. The direct inhibitor Eltrombopag and indirect inhibitor MHY1485 of TFEB reversed the protective effect of sesamin, suggesting the involvement of autophagy in the lipid-lowering process of sesamin.
    Discussion: This work suggests that sesamin regulates autophagy through TFEB to alleviate lipid accumulation in L02 cells induced by 9-trans-C18:1, providing a potential target for the prevention and treatment of NAFLD.
    Keywords:  NAFLD; autophagy; elaidic acid; mitophagy; sesamin
    DOI:  https://doi.org/10.3389/fnut.2024.1511682
  53. Sci Rep. 2025 Jan 04. 15(1): 794
    Puerarin pretreatment provides protection against myocardial ischemia/reperfusion injury via inhibiting excessive autophagy and apoptosis by modulation of HES1.
    Yong Yuan, Songqing Lai, Tie Hu, Fajia Hu, Chenchao Zou, Xiuqi Wang, Ming Fang, Jichun Liu, Huang Huang.
      The study aimed to elucidate the underlying pharmacological mechanism of the traditional Chinese medicine Pue in ameliorating myocardial ischemia-reperfusion injury (MIRI), a critical clinical challenge exacerbated by reperfusion therapy. In vivo MIRI and in vitro anoxia/reoxygenation (A/R) models were constructed. The results demonstrated that Pue pretreatment effectively alleviated MIRI, as manifested by diminishing the levels of serum CK-MB and LDH, mitigating the extent of myocardial infarction and enhancing cardiac functionality. Additionally, Pue significantly alleviated histopathological damage in MIRI-treated myocardium, as evidenced by HE staining and TUNEL assay. In vitro, Pue pretreatment significantly alleviated A/R-induced damage by decreasing LDH levels, increasing cellular activity, inhibiting autophagic lysosomal overactivation, inhibiting oxidative stress (ROS, LIP ROS, MDA), increasing antioxidant defense (SOD, GSH-Px), and increasing P62 protein expression while decreasing LC3II/I ratio. Furthermore, Pue inhibited apoptosis and maintained mitochondrial homeostasis by up-regulating the expression of Hairy and Enhancer of Split-1 (HES1) protein, which was crucial for its cardioprotective effects. Nevertheless, the cardioprotective efficacy of Pue pretreatment was negated via the knockdown of HES1 protein expression via pAD/HES1-shRNA transfection. In conclusion, Pue effectively ameliorated HES1-mediated MIRI-induced autophagy, apoptosis, and mitochondrial dysfunction.
    Keywords:  Apoptosis; Autophagy; HES1; Myocardial ischemia/reperfusion injury; Puerarin
    DOI:  https://doi.org/10.1038/s41598-024-84808-z
  54. Nihon Yakurigaku Zasshi. 2025 ;160(1): 9-12
    [Cardiotoxicity risk assessment of anticancer drugs by focusing on mitochondrial quality of human iPS cell-derived cardiomyocytes].
    Yuri Kato, Yuya Nakamura, Moe Kondo, Yasunari Kanda, Motohiro Nishida.
      Currently, a variety of anticancer agents are used in the treatment of cancer. Since anticancer agents are used continuously over a long time, they carry the risk of side effects. One of the major side effects is cardiac dysfunction. For example, doxorubicin, an anthracycline-type anticancer agent, is clinically restricted because of its dose-dependent cardiotoxicity. Cardiotoxicity includes decreased ejection fraction, arrhythmias, and congestive heart failure, all of which are associated with high mortality rates. Therefore, it is important to assess the risk of cardiotoxicity of anticancer agents in advance. Cardiomyocytes require energy to beat and retain an abundance of mitochondria. We established quantitative measurements of mitochondrial length and respiratory activities using cardiomyocytes. We found that exposure of human iPS cell-derived cardiomyocytes (hiPSC-CMs) to anticancer agents with reported cardiotoxicity enhanced mitochondrial hyperfission and the oxygen consumption rate was significantly reduced. Knockdown of dynamin-related protein 1 (Drp1), mitochondrial fission-accelerating GTP-binding protein, suppressed mitochondrial hyperfission in hiPSC-CMs. This indicates that visualizing mitochondrial functions in hiPSC-CMs will be helpful in assessing the risk of cardiotoxicity caused by anticancer agents and that maintaining mitochondrial quality will become a new strategy to reduce anticancer agents-induced cardiotoxicity. In this review, we present the evaluation of cardiotoxicity targeting mitochondrial quality in anticancer agents, using osimertinib, a non-small cell lung cancer drug, as an example.
    DOI:  https://doi.org/10.1254/fpj.24056
  55. Am J Physiol Cell Physiol. 2025 Jan 10.
    The tRF-33/IGF1 Axis Dysregulates Mitochondrial Homeostasis in HER2-Negative Breast Cancer.
    Yuming Lou, Bifei Fu, Lutong Liu, Jialu Song, Mengying Zhu, Chaoyang Xu.
      Transfer RNA-derived small RNAs (tsRNAs), a recently identified non-coding RNA subset, are mainly classified into tRNA-derived small RNA fragments (tRFs) and tRNA-derived stress-induced RNAs (tiRNAs). tsRNAs dysregulation is frequently observed in numerous cancer types, suggesting involvement in tumorigenesis. However, their functions in breast cancer (BC) remain to be fully understood. Here, it was discovered that tRF-33-MEF91SS2PMFI0Q (tRF-33), derived from mature tRNA-LysTTT, was markedly upregulated in HER2-negative BC cells and tissue samples. tRF-33 stimulated the proliferation, migration, and invasiveness of BC cells in vitro and facilitated tumor progression in vivo. Mechanistically, tRF-33 was found for the first time to bind directly to the 3'-UTR of IGF1, resulting in downregulation of both its mRNA and protein and thus affecting mitochondrial homeostasis and progression of BC. These results demonstrate a novel tsRNA modulatory mechanism and a potential direction for treating HER2-negative BC.
    Keywords:  HER2-negative breast cancer; IGF1; mitochondrial homeostasis; tRF-33-MEF91SS2PMFI0Q (tRF-33); tRNA-derived small RNAs (tsRNAs)
    DOI:  https://doi.org/10.1152/ajpcell.00588.2024
  56. bioRxiv. 2024 Dec 17. pii: 2024.12.12.628145. [Epub ahead of print]
    Modulatory Effects of Mdivi-1 on OxLDL-Induced Metabolic Alterations, Inflammatory Responses, and Foam Cell Formation in Human Monocytes.
    Negin Mosalmanzadeh, Rafael Moura Maurmann, Kierstin Davis, Brenda Landvoigt Schmitt, Liza Makowski, Brandt D Pence.
      Atherosclerosis, a major contributor to cardiovascular disease, involves lipid accumulation and inflammatory processes in arterial walls, with oxidized low-density lipoprotein (OxLDL) playing a central role. OxLDL is increased during aging and stimulates monocyte transformation into foam cells and induces metabolic reprogramming and pro-inflammatory responses, accelerating atherosclerosis progression and contributing to other age-related diseases. This study investigated the effects of Mdivi-1, a mitochondrial fission inhibitor, and S1QEL, a selective complex I-associated reactive oxygen species (ROS) inhibitor, on OxLDL-induced responses in monocytes. Healthy monocytes isolated from participants were treated with OxLDL, with or without Mdivi-1 or S1QEL, and assessed for metabolic shifts, inflammatory cytokine expression, foam cell formation, and ROS production. OxLDL treatment elevated glycolytic activity (ECAR) and expression of pro-inflammatory cytokines IL1B and CXCL8, promoting foam cell formation and mitochondrial ROS (mtROS) production. Mdivi-1 and S1QEL effectively reduced OxLDL-induced glycolytic reprogramming, inflammatory cytokine levels, and foam cell formation while limiting mtROS. These findings suggest that both Mdivi-1 and S1QEL modulate key monocyte responses to OxLDL, providing insights into potential therapeutic approaches for age-related diseases.
    DOI:  https://doi.org/10.1101/2024.12.12.628145
  57. Food Sci Biotechnol. 2025 Jan;34(1): 245-256
    Mitigation of high-fat diet-induced sarcopenia by Toona sinensis fruit extracts via autophagic flux and mitochondrial quality control.
    Yung-Chia Chen, Yin-Ching Chan, Yun-Ching Chang, Hung-Wen Liu, Chung-Che Cheng, Sue-Joan Chang.
      Sarcopenic obesity, encompassing both muscle wasting and obesity, is relevant across individuals. Toona sinensis (TS) has been shown to regulate glucose and lipid metabolisms. However, the efficacy and mechanisms of TS fruit (TSF) in sarcopenic obesity are unclear. This study investigated impacts of TSF extract on skeletal muscle atrophy in C57BL/6 mice fed a high-fat diet (HFD). After 25 weeks of TSF pre-treatment and supplementation, it reversed loss of skeletal muscle mass and grip strength in HFD-fed mice, independent of body weight changes. TSF treatment notably increased the phosphorylation of Akt, mTOR, and P70S6K, while suppressing nuclear localization of NFκB, FoxO1a, and transcription of atrogin-1, MuRF-1, and myostatin expression in HFD-fed muscle. Additionally, TSF influenced autophagic flux and mitochondria quality control, emphasizing its role in balancing protein synthesis and degradation. In conclusion, TSF alleviates HFD-induced sarcopenia via protein turnover, autophagic flux and mitochondria quality control, highlighting its potential therapeutic value for sarcopenic obesity.
    Graphical abstract:
    Supplementary Information: The online version contains supplementary material available at 10.1007/s10068-024-01610-3.
    Keywords:  Autophagy; Mitochondrial quality control; Obesity; Sarcopenia; Toona sinensis fruit
    DOI:  https://doi.org/10.1007/s10068-024-01610-3
  58. J Physiol. 2025 Jan 10.
    Previous short-term disuse dictates muscle gene expression and physiological adaptations to subsequent resistance exercise.
    Martino V Franchi, Julián Candia, Fabio Sarto, Giuseppe Sirago, Giacomo Valli, Matteo Paganini, Lisa Hartnell, Emiliana Giacomello, Luana Toniolo, Elena Monti, Leonardo Nogara, Tatiana Moro, Antonio Paoli, Marta Murgia, Lorenza Brocca, Maria Antonietta Pellegrino, Bruno Grassi, Roberto Bottinelli, Giuseppe De Vito, Luigi Ferrucci, Marco V Narici.
      Short-term unloading experienced following injury or hospitalisation induces muscle atrophy and weakness. The effects of exercise following unloading have been scarcely investigated. We investigated the functional and molecular adaptations to a resistance training (RT) programme following short-term unloading. Eleven males (22.09 ± 2.91 years) underwent 10 days of unilateral lower limb suspension (ULLS) followed by 21 days of knee extensor RT (three times/week). Data collection occurred at Baseline (LS0), after ULLS (LS10) and at active recovery (AR21). Knee extensor maximum voluntary contraction (MVC) was evaluated. Quadriceps volume was estimated by ultrasonography. Muscle fibre cross-sectional area, fibre type distribution, glycogen content and succinate dehydrogenase (SDH) activity were measured from vastus lateralis biopsies. Mitochondrial-related proteins were quantified by western blot and transcriptional responses were assessed by RNA sequencing. Following ULLS, quadriceps volume and MVC decreased significantly (3.7%, P < 0.05; 29.3%, P < 0.001). At AR21 (vs. LS10), MVC was fully restored (42%) and quadriceps volume increased markedly (18.6%, P < 0.001). Glycogen content and whole-body water increased at AR21 (14%, P < 0.001; 3.1%, P < 0.05). We observed a marked increase in fibre type I at AR21 (38%, P < 0.05). SDH immunoreactivity increased significantly after exercise (20%, P < 0.001). Mitochondrial fusion (MFN1, MFN2 and OPA1) and fission (DRP1) proteins were markedly increased by RT, and the most differentially expressed genes belonged to oxidative phosphorylation pathways. In contrast with what is usually observed after RT, oxidative metabolism, slow fibre type and mitochondrial dynamics were enhanced beyond expected. We propose that prior exposure to short-term muscle unloading may drive the nature of molecular adaptations to subsequent RT. KEY POINTS: Short-term unloading is often experienced during recovery from injuries and hospitalisation, leading to loss of muscle mass and strength. Although exercise can be beneficial in mitigating/reversing such alterations during disuse, only a few studies have focused on the effects of exercise following muscle unloading. With an integrative physiological approach, we aimed to elucidate the basic mechanisms of muscle function recovery in response to 21 days of resistance exercise that followed 10 days of unilateral lower limb suspension (ULLS), assessing whether the mechanisms underlying recovery are defined by a specific reversal of those that occurred during disuse. Resistance training was successful in recovering functional and structural muscle properties after 10 days of ULLS, but in contrast with what is usually observed in response to this training modality, oxidative metabolism and slow fibre type were mostly enhanced. We propose that prior exposure to short-term muscle unloading may drive the adaptations to subsequent exercise.
    Keywords:  exercise physiology; gene expression; muscle adaptation; muscle atrophy; muscle physiology; muscle plasticity; resistance training; unloading responses
    DOI:  https://doi.org/10.1113/JP287003
  59. Cell Biol Toxicol. 2025 Jan 10. 41(1): 27
    Long-term mitochondrial and metabolic impairment in lymphocytes of subjects who recovered after severe COVID-19.
    Irene Gómez-Delgado, Andrea R López-Pastor, Adela González-Jiménez, Carlos Ramos-Acosta, Yenitzeh Hernández-Garate, Neus Martínez-Micaelo, Núria Amigó, Laura Espino-Paisán, Eduardo Anguita, Elena Urcelay.
      The underlying mechanisms explaining the differential course of SARS-CoV-2 infection and the potential clinical consequences after COVID-19 resolution have not been fully elucidated. As a dysregulated mitochondrial activity could impair the immune response, we explored long-lasting changes in mitochondrial functionality, circulating cytokine levels, and metabolomic profiles of infected individuals after symptoms resolution, to evaluate whether a complete recovery could be achieved. Results of this pilot study evidenced that different parameters of aerobic respiration in lymphocytes of individuals recuperated from a severe course lagged behind those shown upon mild COVID-19 recovery, in basal conditions and after simulated reinfection, and they also showed altered glycolytic capacity. The severe groups showed trends to enhanced superoxide production in parallel to lower OPA1-S levels. Unbalance of pivotal mitochondrial fusion (MFN2, OPA1) and fission (DRP1, FIS1) proteins was detected, suggesting a disruption in mitochondrial dynamics, as well as a lack of structural integrity in the electron transport chain. In serum, altered cytokine levels of IL-1β, IFN-α2, and IL-27 persisted long after clinical recovery, and growing amounts of the latter after severe infection correlated with lower basal and maximal respiration, ATP production, and glycolytic capacity. Finally, a trend for higher circulating levels of 3-hydroxybutyrate was found in individuals recovered after severe compared to mild course. In summary, long after acute infection, mitochondrial and metabolic changes seem to differ in a situation of full recovery after mild infection versus the one evolving from severe infection.
    Keywords:  COVID-19; Cytokines; Disease severity; Immune system; Metabolomics; Mitochondria; SARS-CoV-2
    DOI:  https://doi.org/10.1007/s10565-024-09976-0
  60. J Cell Mol Med. 2025 Jan;29(1): e70341
    Mpox-Induced Metabolic Alterations.
    Milad Zandi, Fatemeh Sadat Mousavi, Seyyed Mohammed Reza Hashemnia.
      The resurgence of mpox as a global health threat highlights the need to understand its interaction with host cell metabolism. Unlike other well-studied viruses, research on mpox is limited, particularly regarding its impact on cellular processes. In this article, we explore how mpox might manipulate metabolic pathways-such as glycolysis, lipid synthesis and mitochondrial dynamics-to enhance its replication and evade immune responses. By drawing parallels with related poxviruses, we underscore the potential for targeting these metabolic shifts as novel therapeutic strategies. Understanding these interactions is crucial for developing effective treatments against mpox.
    DOI:  https://doi.org/10.1111/jcmm.70341
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