bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2025–03–02
63 papers selected by
Gavin McStay, Liverpool John Moores University
  1. SIRT5 modulates mitochondria function via mitophagy and antioxidant mechanisms to facilitate oocyte maturation in mice.
  2. Mitochondrial dynamics and quality control regulate proteostasis in neuronal ischemia-reperfusion.
  3. Phosphorylation of BCL2L13 by PRKAA2/AMPKα2 activates mitophagy in pressure-overloaded heart.
  4. Visualization of mitochondrial molecular dynamics during mitophagy process by label-free surface-enhanced Raman scattering spectroscopy.
  5. The Role of Mitochondrial Quality Control in Liver Diseases: Dawn of a Therapeutic Era.
  6. High Concentration Hydrogen Protects Sepsis-Associated Encephalopathy by Enhancing Pink1/Parkin-Mediated Mitophagy and Inhibiting cGAS-STING-IRF3 Pathway.
  7. Genetic and pharmacological correction of impaired mitophagy in retinal ganglion cells rescues glaucomatous neurodegeneration.
  8. Cleaving PINK1 or PGAM5? Involvement of PARL in Methamphetamine-Induced Excessive Mitophagy and Neuronal Necroptosis.
  9. Mitochondrial dynamic modulators attenuate iron overload-mediated cardiac toxicity via decreased mitochondrial fission, mitophagy/autophagy, and apoptosis in iron-overloaded rats.
  10. Disruption of Mitochondrial Dynamics and Stasis Leads to Liver Injury and Tumorigenesis.
  11. A quinolinyl analog of resveratrol improves neuronal damage after ischemic stroke by promoting Parkin-mediated mitophagy.
  12. TREM2 Alleviates Neuroinflammation by Maintaining Cellular Metabolic Homeostasis and Mitophagy Activity During Early Inflammation.
  13. Allicin alleviates traumatic brain injury-induced neuroinflammation by enhancing PKC-δ-mediated mitophagy.
  14. Cells with Defective Mitophagy Do Not Accumulate Atherogenic LDL-Derived Cholesterol.
  15. DARS2 Promotes Bladder Cancer Progression by Enhancing PINK1-Mediated Mitophagy.
  16. Dexmedetomidine activates mitophagy and protects against pyroptosis in oxygen-glucose deprivation/reperfusion-induced brain damage via PINK1/Parkin pathway activation.
  17. A Novel Prognostic Signature of Mitophagy-Related E3 Ubiquitin Ligases in Breast Cancer.
  18. Semaglutide enhances PINK1/Parkin‑dependent mitophagy in hypoxia/reoxygenation‑induced cardiomyocyte injury.
  19. Cordycepin Ameliorates Kainic Acid-Induced HT22 Cell Neurotoxicity by Activating GPR120-Mediated Mitophagy.
  20. The Role of Placental MFF-Mediated Mitochondrial Fission in Gestational Diabetes Mellitus.
  21. CgVDAC2 participated in haemocyte mitophagy induced by Vibrio splendidus in the Pacific oyster Crassostrea gigas.
  22. Hippocampal mitophagy alterations in MAPT-associated frontotemporal dementia with parkinsonism.
  23. Recent development of mitochondrial metabolism and dysfunction in osteoarthritis.
  24. Histone lactylation stimulated upregulation of PSMD14 alleviates neuron PANoptosis through deubiquitinating PKM/PKM2 to activate PINK1-mediated mitophagy after traumatic brain injury.
  25. Mitochondrial Dysfunction in Neurodegenerative Diseases.
  26. The Curse of the Red Pearl: A Fibroblast-Specific Pearl-Necklace Mitochondrial Phenotype Caused by Phototoxicity.
  27. Rosmarinic acid promotes mitochondrial fission and induces ferroptosis in triple-negative breast cancer cells.
  28. Discovery of a new mitophagy-related gene signature for predicting the outlook and immunotherapy in triple-negative breast cancer.
  29. Optineurin overexpression ameliorates neurodegeneration through regulating neuroinflammation and mitochondrial quality in a murine model of amyotrophic lateral sclerosis.
  30. Conditional deletion of Pink1 in mesenchymal stem cells suppresses osteogenesis through downregulation of Apoh transcription.
  31. SIRT1 Alleviates Mitochondrial Fission and Necroptosis in Cerebral Ischemia/Reperfusion Injury via SIRT1-RIP1 Signaling Pathway.
  32. PDE4D inhibition ameliorates cardiac hypertrophy and heart failure by activating mitophagy.
  33. Global research trends on the associations between chronic kidney disease and mitochondria: insights from the bibliometric analysis.
  34. Mitochondrial Dysfunction in Neurodegenerative Diseases: Mechanisms and Corresponding Therapeutic Strategies.
  35. Arctigenin derivative TZOA restores mitochondrial homeostasis to combat rhabdovirus infections.
  36. Shenfuyixin Granules enhance mitochondrial autophagy after myocardial infarction by regulating protein deacetylation via the SIRT3/FOXO1 signaling axis.
  37. Pharmacological approaches to enhance mitochondrial biogenesis: focus on PGC-1Α, AMPK, and SIRT1 in cellular health.
  38. Calnexin promotes glioblastoma progression by inducing protective mitophagy through the MEK/ERK/BNIP3 pathway.
  39. Dietary phytosterol supplementation mitigates renal fibrosis via activating mitophagy and modulating the gut microbiota.
  40. TIMP2-Mediated Mitochondrial Fragmentation and Glycolytic Reprogramming Drive Renal Fibrogenesis following Ischemia-Reperfusion Injury.
  41. Eugenol Promotes Apoptosis in Leukemia Cells via Targeting the Mitochondrial Biogenesis PPRC1 Gene.
  42. 3-D Sustained-Release Culture Carrier Alleviates Rat Intervertebral Disc Degeneration by Targeting STING in Transplanted Skeletal Stem Cells.
  43. An Integrated Approach Utilizing Single-Cell and Bulk RNA-Sequencing for the Identification of a Mitophagy-Associated Genes Signature: Implications for Prognostication and Therapeutic Stratification in Prostate Cancer.
  44. Mitochondria in cutaneous health, disease, ageing and rejuvenation-the 3PM-guided mitochondria-centric dermatology.
  45. Transplantation of gastric epithelial mitochondria into human gastric cancer cells inhibits tumor growth and enhances chemosensitivity by reducing cancer stemness and modulating gastric cancer metabolism.
  46. Fibroblast growth factor receptor 3 mutation promotes HSPB6-mediated cuproptosis in hypochondroplasia by impairing chondrocyte autophagy.
  47. Resveratrol-Enhanced Human Neural Stem Cell-Derived Exosomes Mitigate MPP+-Induced Neurotoxicity Through Activation of AMPK and Nrf2 Pathways and Inhibition of the NLRP3 Inflammasome in SH-SY5Y Cells.
  48. MARIGOLD and MitoCIAO, two searchable compendia to visualize and functionalize protein complexes during mitochondrial remodeling.
  49. The involvement of mitochondrial dysfunction during the development of adenomyosis.
  50. The Noncanonical Wnt5a-Ca2+ Pathway Mediates Mitochondrial Dysfunction in the Progression of Diabetic Nephropathy via the Mitochondrial Calcium Uniporter.
  51. Lysosome-Mitochondrial Crosstalk in Cellular Stress and Disease.
  52. Taurine ameliorates deoxynivalenol-induced intestinal injury in piglets: Restoration of mitochondrial function linked to the PGC1α-NRF1/2 axis.
  53. Mitochondrial Quality Control and Melatonin: A Strategy Against Myocardial Injury.
  54. Bioactivity and Neuroprotective Effects of Extra Virgin Olive Oil in a Mouse Model of Cerebral Ischemia: An In Vitro and In Vivo Study.
  55. Pore-Forming Protein LIN-24 Enhances Starvation Resilience in Caenorhabditis elegans by Modulating Lipid Metabolism and Mitochondrial Dynamics.
  56. Effects of 3-(4-Hydroxy-3-methoxyphenyl)propionic Acid on Regulating Oxidative Stress and Muscle Fiber Composition.
  57. Deciphering novel mitochondrial signatures: multi-omics analysis uncovers cross-disease markers and oligodendrocyte pathways in Alzheimer's disease and glioblastoma.
  58. Reversal of metformin's anti-proliferative effect in fission yeast efr3 and dnm1 (DRP1) mutants with elongated mitochondria.
  59. Utilizing Integrated Bioinformatics Analysis to Explore Potential Alterations in Mitochondrial Function Within Immune Cells Associated with Thoracic Aortic Aneurysms.
  60. MTHFR variant links homocysteine metabolism and endothelial cell dysfunction by targeting mitophagy in human thoracic aortic dissection patient induced pluripotent stem cell (iPSC) models.
  61. Salidroside protects against myocardial infarction via activating MIF-mediated mitochondrial quality control.
  62. Role and Mechanism of Mitochondrial Ribosomal Proteins in Septic Myocardial Injury.
  63. Protective Effects of Galangin Against Cyclophosphamide-Induced Cardiotoxicity via Suppressing NF-κB and Improving Mitochondrial Biogenesis.
  1. Int J Biol Macromol. 2025 Feb 25. pii: S0141-8130(25)02039-2. [Epub ahead of print] 141488
    SIRT5 modulates mitochondria function via mitophagy and antioxidant mechanisms to facilitate oocyte maturation in mice.
    Jing-Jing Yan, Yan-Yu Wang, Zhi-Yu Shi, Yuan-Yuan Ding, Hao-Quan Wen, Meng-Ping Wu, Shao-Chen Sun, Ya-Fei Cai, Yu Zhang.
      Mitochondrial homeostasis, closely associated with mitophagy and antioxidant mechanisms, is essential for proper meiotic spindle assembly and chromosome segregation during oocyte maturation. SIRT5, known to modulate mitochondrial function under various conditions, has been shown to impact oocyte quality when inhibited, however, the precise mechanisms linking SIRT5 to mitochondrial homeostasis during meiotic progression remain unclear. In this study, we demonstrate that SIRT5 localizes predominantly at the periphery of the meiotic spindle and is enriched on chromosomes during oocyte maturation. Inhibition of SIRT5 led to significant meiotic defects, including disrupted spindle organization and chromosome misalignment. These defects were associated with increased histone acetylation, which impaired kinetochore-microtubule attachments. Moreover, SIRT5 inhibition resulted in mitochondrial dysfunction, subsequently elevating ROS levels and triggering oxidative stress, which further exacerbated meiotic abnormalities. Mechanistically, SIRT5 inhibition disrupted the balance of Parkin-dependent mitophagy by inducing ULK phosphorylation. Additionally, it activated the PI3K/Akt signaling pathway, which increased NADPH consumption and reduced GSH levels. Collectively, these findings reveal that SIRT5 plays dual roles in maintaining mitochondrial homeostasis during oocyte maturation: (1) by regulating Parkin-dependent mitophagy to prevent excessive mitochondrial clearance, and (2) by preserving the NADPH/GSH antioxidant system to ensure redox balance. These insights provide potential targets for improving oocyte quality and addressing mitochondrial dysfunction-related reproductive disorders in females.
    Keywords:  Antioxidant; Mitochondria; Mitophagy; Oocyte maturation; Oxidative stress; SIRT5
    DOI:  https://doi.org/10.1016/j.ijbiomac.2025.141488
  2. Autophagy. 2025 Feb 27.
    Mitochondrial dynamics and quality control regulate proteostasis in neuronal ischemia-reperfusion.
    Garrett M Fogo, Sarita Raghunayakula, Katlynn J Emaus, Francisco J Torres Torres, Gary Shangguan, Joseph M Wider, Maik Hüttemann, Thomas H Sanderson.
      Mitochondrial damage and dysfunction are hallmarks of neuronal injury during cerebral ischemia-reperfusion (I/R). Critical mitochondrial functions including energy production and cell signaling are perturbed during I/R, often exacerbating damage and contributing to secondary injury. The integrity of the mitochondrial proteome is essential for efficient function. Mitochondrial proteostasis is mediated by the cooperative forces of mitophagy and intramitochondrial proteolysis. The aim of this study was to elucidate the patterns of mitochondrial protein dynamics and their key regulators during an in vitro model of neuronal I/R injury. Utilizing the MitoTimer reporter, we quantified mitochondrial protein oxidation and turnover during I/R injury, highlighting a key point at 2 h reoxygenation for aged/oxidized protein turnover. This turnover was found to be mediated by both LONP1-dependent proteolysis and PRKN/parkin-dependent mitophagy. Additionally, the proteostatic response of neuronal mitochondria is influenced by both mitochondrial fusion and fission machinery. Our findings highlight the involvement of both mitophagy and intramitochondrial proteolysis in the response to I/R injury.
    Keywords:  Fission; LONP1; PRKN; fusion; mitophagy; neuron
    DOI:  https://doi.org/10.1080/15548627.2025.2472586
  3. Autophagy. 2025 Feb 24. 1-2
    Phosphorylation of BCL2L13 by PRKAA2/AMPKα2 activates mitophagy in pressure-overloaded heart.
    Tomokazu Murakawa, Kinya Otsu.
      In heart failure patients, the accumulation of damaged mitochondria is frequently observed in cardiomyocytes. Damaged mitochondria are degraded through mitophagy, a form of mitochondria-specific autophagy. Previously, we identified BCL2L13 as a mitophagy receptor and demonstrated its ability to induce mitophagy and mitochondrial fission in mammalian cells and the necessity of phosphorylation at Ser272 for its activation. However, the in vivo role of BCL2L13 remains unclear. In this study, we investigated the cardiac function of BCL2L13 using bcl2l13 knockout mice and knock-in mice expressing a non-phosphorylatable BCL2L13S272A mutant. In the hearts of these genetically modified mice, pressure overload leads to suppressed mitochondrial fission and mitophagy, resulting in reduced ATP production. Additionally, we analyzed bcl2l13 and prkn/parkin double-knockout mice but found no additive effects of prkn deletion. Furthermore, we identified PRKAA2/AMPKα2 as the kinase responsible for phosphorylating BCL2L13 at Ser272. These findings highlight the critical role of BCL2L13 and its phosphorylation in activating mitophagy as part of the cardiac stress response and suggest that targeting BCL2L13 phosphorylation could serve as a potential therapeutic strategy for heart failure.Abbreviation: BCL2L13, BCL2 like 13; ATG, autophagy related; MAP1LC3B/LC3B, microtubule-associated protein 1 light chain 3 beta; KO, knockout; TAC, transverse aortic constriction; LVFS, left ventricular fractional shortening; ROS, reactive oxygen species; DKO, double knockout; siRNA, small interfering RNA; PRKAA2/AMPKα2, protein kinase, AMP-activated alpha 2 catalytic subunit; CCCP, carbonyl cyanide 3-chlorophenylhydrazone.
    Keywords:  BCL2L13; heart failure; kinase; mitophagy; pressure overload
    DOI:  https://doi.org/10.1080/15548627.2025.2465408
  4. Anal Chim Acta. 2025 Apr 01. pii: S0003-2670(25)00142-4. [Epub ahead of print]1345 343748
    Visualization of mitochondrial molecular dynamics during mitophagy process by label-free surface-enhanced Raman scattering spectroscopy.
    Hailan Jia, Chi Wang, Yan Fu, Yalin Wang, Xiaoyu Zhang, Yuezhou Tang, Jiahao Ding, Kun He, Jing Wang, Yanting Shen.
       BACKGROUND: Mitophagy is a selective way to eliminate dysfunctional mitochondria and recycle their constituents, which plays an important role in regulating and maintaining intracellular homeostasis. Real-time monitoring mitophagy process is of great importance for cellular physiological and pathological processes related to mitochondria. Howbeit, most of the current methods only focus on single-parameter detection of mitochondrial microenvironmental changes such as pH, viscosity and polarity. The mitochondrial molecular responses under mitophagy are not clear. Therefore, developing a new and simple method for molecular profiling is of great importance for accurately and comprehensively visualizing mitophagy.
    RESULTS: In this work, Au NPs-based mitochondria-targeting nanoprobe was developed and the nanoprobe-based label-free surface enhanced Raman spectroscopy (SERS) method was proposed to track starvation induced mitophagy process at molecular level. The nanoprobe displayed good SERS performance and low cytotoxicity. Based on the developed strategy, the molecular response within mitochondria under mitophagy was validated. Meanwhile, the protein denaturation, conformational change, lipid degradation and DNA fragmentation within mitochondria under mitophagy were revealed for the first time, which provides molecular evidence for mitophagy. The changes in reactive oxygen species level and mitochondrial membrane potential further confirmed the damage of mitochondria. Moreover, the developed label-free SERS strategy was used to detect mitophagy in drug (cisplatin)-induced liver injury (DILI) cell model, and obvious mitophagy in DILI cells was observed.
    SIGNIFICANCE: The molecular biochemical signature dynamic changes within mitochondria during mitophagy process were revealed by SERS for the first time. Moreover, compared with the current research, our study can provide new insights into mitophagy and mitophagy-involved diseases at molecular level. This study will provide new insights into the molecular mechanism of mitophagy and offer a simple and effective method for mitochondrial molecular event monitoring in mitophagy-involved cellular processes.
    Keywords:  Label-free; Mitochondria-targeting; Mitophagy; SERS
    DOI:  https://doi.org/10.1016/j.aca.2025.343748
  5. Int J Biol Sci. 2025 ;21(4): 1767-1783
    The Role of Mitochondrial Quality Control in Liver Diseases: Dawn of a Therapeutic Era.
    Jia Li, Wenqin Liu, Jie Zhang, Chao Sun.
      The liver is a vital metabolic organ that detoxifies substances, produces bile, stores nutrients, and regulates versatile metabolic processes. Maintaining normal liver cell function requires the prompt and delicate modulation of mitochondrial quality control (MQC), which encompasses a spectrum of processes such as mitochondrial fission, fusion, biogenesis, and mitophagy. Recent studies have shown that disruptions to this homeostatic status are closely linked to the advent and progression of a variety of acute and chronic liver diseases, including but not limited to alcohol-associated liver disease and metabolic dysfunction-associated fatty liver disease. However, the explicit mechanisms by which mitochondrial dysfunction impacts inflammatory pathways and cell death in the context of liver diseases remain unclear. In this narrative review, we provide a detailed description of MQC, analyze the mechanisms underpinning mitochondrial dysfunction induced by different detrimental insults, and further elucidate how imbalanced/disrupted MQC promotes the progression and aggravation of liver diseases, ultimately shedding light on the mitochondrion-centric therapeutic strategies for these pathophysiological entities.
    Keywords:  liver diseases; macrophage heterogeneity; mitochondrial dynamics; mitochondrial quality control; mitophagy; mtDNA; reactive oxygen species
    DOI:  https://doi.org/10.7150/ijbs.107777
  6. CNS Neurosci Ther. 2025 Feb;31(2): e70305
    High Concentration Hydrogen Protects Sepsis-Associated Encephalopathy by Enhancing Pink1/Parkin-Mediated Mitophagy and Inhibiting cGAS-STING-IRF3 Pathway.
    Yan Cui, Jianfeng Liu, Yu Song, Chen Chen, Yuehao Shen, Keliang Xie.
       BACKGROUND: Sepsis-associated encephalopathy (SAE) leads to increased mortality. Hydrogen (H2) has been proven to be effective in protecting against SAE. This study aimed to investigate the protective mechanism of a high concentration of H2 (HCH) (67%) against SAE.
    METHODS: A mouse sepsis model was established via cecal ligation and puncture (CLP). 67% H2 was inhaled for 1 h at 1 h and 6 h after the operation. First, mice were randomly divided into 5 groups: Sham, CLP, CLP + CQ (a mitophagy inhibitor), CLP + H2, and CLP + H2 + CQ. Seven-day survival, cognitive function, and hippocampal damage were assessed. Then, mice were randomly divided into four groups: Sham, CLP, CLP + UA (a mitophagy agonist), and CLP + H2. Seven-day survival was recorded, cognitive function was assessed via Y-maze and Morris water maze tests, and hippocampal damage was evaluated via Nissl staining. Phosphorylated tau, inflammatory factors, ATP, and antioxidant enzyme levels and mitochondrial membrane potential (MMP) were detected. Mitochondria were observed via transmission electron microscopy. The protein levels of the PINK1/Parkin pathway and STING-TBK-IRF3 pathway were detected via western blotting.
    RESULTS: HCH inhalation improves 7-day survival and cognitive function in septic mice and reduces brain tissue damage, proinflammatory cytokine levels, and phosphorylated tau levels. These effects were reversed by a mitophagy inhibitor. HCH significantly improves mitochondrial function, enhances PINK1/Parkin-mediated mitophagy, and reduces the activity of the STING-TBK-IRF3 pathway in brain tissue.
    CONCLUSIONS: HCH inhalation effectively improved the survival rate of septic mice, alleviated SAE, and reduced tau phosphorylation. The mechanism may involve HCH enhancing PINK1/Parkin-mediated mitophagy, which inhibits the activity of the cGAS-STING-IRF3 pathway, thereby reducing neuroinflammation.
    Keywords:  PINK1/Parkin; cGAS‐STING‐IRF3; hydrogen; mitophagy; sepsis‐associated encephalopathy; tau phosphorylation
    DOI:  https://doi.org/10.1111/cns.70305
  7. bioRxiv. 2025 Feb 15. pii: 2025.02.13.638142. [Epub ahead of print]
    Genetic and pharmacological correction of impaired mitophagy in retinal ganglion cells rescues glaucomatous neurodegeneration.
    Prabhavathi Maddineni, Bindu Kodati, Balasankara Reddy Kaipa, Karthikeyan Kesavan, J Cameron Millar, Sam Yacoub, Ramesh B Kasetti, Abbot F Clark, Gulab S Zode.
      Progressive loss of retinal ganglion cells (RGCs) and degeneration of optic nerve axons are the pathological hallmarks of glaucoma. Ocular hypertension (OHT) and mitochondrial dysfunction are linked to neurodegeneration and vision loss in glaucoma. However, the exact mechanism of mitochondrial dysfunction leading to glaucomatous neurodegeneration is poorly understood. Using multiple mouse models of OHT and human eyes from normal and glaucoma donors, we show that OHT induces impaired mitophagy in RGCs, resulting in the accumulation of dysfunctional mitochondria and contributing to glaucomatous neurodegeneration. Using mitophagy reporter mice, we show that impaired mitophagy precedes glaucomatous neurodegeneration. Notably, the pharmacological rescue of impaired mitophagy via Torin-2 or genetic upregulation of RGC-specific Parkin expression restores the structural and functional integrity of RGCs and their axons in mouse models of glaucoma and ex-vivo human retinal-explant cultures. Our study indicates that impaired mitophagy contributes to mitochondrial dysfunction and oxidative stress, leading to glaucomatous neurodegeneration. Enhancing mitophagy in RGCs represents a promising therapeutic strategy to prevent glaucomatous neurodegeneration.
    DOI:  https://doi.org/10.1101/2025.02.13.638142
  8. CNS Neurosci Ther. 2025 Feb;31(2): e70293
    Cleaving PINK1 or PGAM5? Involvement of PARL in Methamphetamine-Induced Excessive Mitophagy and Neuronal Necroptosis.
    Di An, Chuling Zhang, Peng Zhou, Yifei Wang, Sining Meng, Yanlong Chen, Weixiao Xu, Jiankang Xuan, Jianping Xiong, Jie Cheng, Rong Gao, Jun Wang, Xufeng Chen.
       BACKGROUND: Methamphetamine (Meth) is a potent psychoactive stimulant that triggers complex neurotoxicity characterized by autophagy-associated neuronal death. However, the potential mechanisms remain poorly understood. This study aimed to decipher the Meth-induced neuronal necroptosis involving mitochondrial defect-initiated excessive mitophagy caused by aberrant presenilin-associated rhomboid-like (PARL) cleavage of PTEN-induced kinase 1 (PINK1) and phosphoglycerate mutase family member 5 (PGAM5).
    METHODS AND RESULTS: With the transcriptome analysis, Meth exposure significantly affected autophagy, mitophagy, and necroptosis pathways; meanwhile, the proteomic analysis revealed a marked decline in the level of PARL, which led to an imbalance in intramembrane proteolysis of PINK1 and PGAM5. In behavioral tests, Meth administration elicited pronounced cognitive decline in mice, accompanied by decreased neuronal numbers, massive autophagosomes, and mitochondrial fragmentation, and these processes can be dramatically reversed by knockin of PARL and knockdown of PGAM5 in the mouse hippocampus, molecularly manifesting as decreased necrosome formation and phosphorylated mixed lineage kinase domain-like (p-MLKL) mitochondrial membrane translocation, and improved autophagic flux.
    CONCLUSION: In summary, these findings collectively underscore the key roles of the PARL-PGAM5 axis in Meth-mediated neuronal necroptosis and that targeting this axis may provide promising therapeutic strategies for mitigating Meth-induced neurotoxicity.
    Keywords:  PARL; PGAM5; methamphetamine; mitophagy; necroptosis
    DOI:  https://doi.org/10.1111/cns.70293
  9. Arch Biochem Biophys. 2025 Feb 21. pii: S0003-9861(25)00067-0. [Epub ahead of print]767 110354
    Mitochondrial dynamic modulators attenuate iron overload-mediated cardiac toxicity via decreased mitochondrial fission, mitophagy/autophagy, and apoptosis in iron-overloaded rats.
    Sirinart Kumfu, Jirapas Sripetchwandee, Chanisa Thonusin, Chayodom Maneechote, Busarin Arunsak, Titikorn Chunchai, Aphisek Kongkaew, Siriporn C Chattipakorn, Nipon Chattipakorn.
      One of the leading causes of death for individuals with iron overload is iron overload cardiomyopathy (IOC). Iron overload causes cardiac mitochondrial dysfunction, which ultimately results in heart failure and death. The potential mechanism of iron overload-induced mitochondrial dysfunction involves the disequilibrium between cardiac mitochondrial fission and fusion. Nevertheless, the information regarding cardiac mitochondrial dynamics under iron overload conditions remains limited. The roles of mitochondrial dynamics were identified in IOC. To induce iron overload, male Wistar rats were injected with iron dextran for four weeks. Then, while continuing iron dextran injection, four groups of iron-overloaded rats were given injections of either vehicle, mitochondrial fusion promoter (M1), mitochondrial division inhibitor 1 (Mdivi-1), or iron chelator deferoxamine (DFO) for two weeks. In the non-iron loaded (control) group, rats received vehicles without iron dextran injection. Cardiac function, mitochondrial function, mitochondrial dynamics, mitophagy/autophagy, and apoptosis were assessed at the end of treatment. The increased expression of mitochondrial fission-, mitophagy/autophagy-, and apoptosis-related proteins were correlated with impaired mitochondrial and cardiac functions in iron-overloaded rats. Interestingly, both mitochondrial dynamics modulators reduced cardiac mitochondrial fission, mitophagy/autophagy, and apoptosis, as well as restored cardiac function to be comparable to those treated with iron chelator DFO. Our findings indicated that the imbalance of mitochondrial dynamics is a potential mechanism responsible for cardiomyocyte death induced by IOC, and this could be a novel target for interventions for IOC via either the promotion of mitochondrial fusion or the inhibition of mitochondrial fission.
    Keywords:  Apoptosis; Iron overload cardiomyopathy; Mitochondria; Mitochondrial dynamics; Mitophagy
    DOI:  https://doi.org/10.1016/j.abb.2025.110354
  10. bioRxiv. 2025 Feb 12. pii: 2025.02.11.637688. [Epub ahead of print]
    Disruption of Mitochondrial Dynamics and Stasis Leads to Liver Injury and Tumorigenesis.
    Xiaowen Ma, Xiaoli Wei, Mengwei Niu, Chen Zhang, Zheyun Peng, Wanqing Liu, Junrong Yan, Xiaoyang Su, Shaolei Lu, Wei Cui, Hiromi Sesaki, Wei-Xing Zong, Hong-Min Ni, Wen-Xing Ding.
       Background & Aims: Mitochondrial dysfunction has been implicated in aging and various cancer development. As highly dynamic organelles, mitochondria constantly undergo fission, mediated by dynamin-related protein 1 (DRP1, gene name Dnm1l ), and fusion, regulated by mitofusin 1 (MFN1), MFN2, and optic atrophy 1 (OPA1). However, whether and how dysregulation of mitochondria dynamics would be involved in liver pathogenesis and tumorigenesis is unknown.
    Methods: Dnm1l Flox/Flox ( Dnm1l F/F ), Mfn1 F/F and Mfn2 F/F mice were crossed with albumin-Cre mice to generate liver-specific Dnm1l knockout (L- Dnm1l KO), L- Mfn1 KO, L- Mfn2 KO, L- Mfn1, Mfn2 double KO (DKO), and L- Mfn1, Mfn2, Dnm1l triple KO (TKO) mice. These mice were housed for various periods up to 18 months. Some mice also received hydrodynamic tail vein injections of a Sleeping Beauty transposon-transposase plasmid system with c-MYC and YAP . Blood and liver tissues were harvested for biochemical and histological analysis.
    Results: L- Dnm1l KO mice had elevated serum alanine aminotransferase levels and increased hepatic fibrosis as early as two months of age. By 12 to 18 months, male L- Dnm1l KO mice developed spontaneous liver tumors, primarily hepatocellular adenomas. While female L- Dnm1l KO mice also developed liver tumors, their incidence was much lower. In contrast, neither L- Mfn1 KO nor L- Mfn2 KO mice had notable liver injury or tumorigenesis. However, a small portion of DKO mice developed tumors at 15-18 month-old. Increased DNA damage, senescence and compensatory proliferation were observed in L- Dnm1l KO mice but were less evident in L- Mfn1 KO, L- Mfn2 KO or DKO mice, indicating that mitochondrial fission is more important to maintain hepatocyte homeostasis and prevent liver tumorigenesis. Interestingly, further deletion of Mfn1 and Mfn2 in L- Dnm1l KO mice markedly abolished liver injury, fibrosis, and both spontaneous and oncogene-induced tumorigenesis. RNA sequencing and metabolomics analysis revealed significant activation of the cGAS-STING-interferon pathway and alterations in the tumor microenvironment pathways, alongside increased pyrimidine synthesis and metabolism in the livers of L- Dnm1l KO mice. Notably, the changes in gene expression and pyrimidine metabolism were considerably corrected in the TKO mice.
    Conclusions: Mitochondrial dynamics and stability are essential for maintaining hepatic mitochondrial homeostasis and hepatocyte functions. Loss of hepatic DRP1 promotes liver tumorigenesis by increasing pyrimidine metabolism and activating the cGAS-STING-mediated innate immune response.
    DOI:  https://doi.org/10.1101/2025.02.11.637688
  11. Chin J Nat Med. 2025 Feb;pii: S1875-5364(25)60825-9. [Epub ahead of print]23(2): 214-224
    A quinolinyl analog of resveratrol improves neuronal damage after ischemic stroke by promoting Parkin-mediated mitophagy.
    Qingqi Meng, Yan Mi, Libin Xu, Yeshu Liu, Dong Liang, Yongping Wang, Yan Wang, Yueyang Liu, Guoliang Chen, Yue Hou.
      Ischemic stroke (IS) is a prevalent neurological disorder often resulting in significant disability or mortality. Resveratrol, extracted from Polygonum cuspidatum Sieb. et Zucc. (commonly known as Japanese knotweed), has been recognized for its potent neuroprotective properties. However, the neuroprotective efficacy of its derivative, (E)-4-(3,5-dimethoxystyryl) quinoline (RV02), against ischemic stroke remains inadequately explored. This study aimed to evaluate the protective effects of RV02 on neuronal ischemia-reperfusion injury both in vitro and in vivo. The research utilized an animal model of middle cerebral artery occlusion/reperfusion and SH-SY5Y cells subjected to oxygen-glucose deprivation and reperfusion to simulate ischemic conditions. The findings demonstrate that RV02 attenuates neuronal mitochondrial damage and scavenges reactive oxygen species (ROS) through mitophagy activation. Furthermore, Parkin knockdown was found to abolish RV02's ability to activate mitophagy and neuroprotection in vitro. These results suggest that RV02 shows promise as a neuroprotective agent, with the activation of Parkin-mediated mitophagy potentially serving as the primary mechanism underlying its neuroprotective effects.
    Keywords:  (E)-4-(3,5-dimethoxystyryl) quinoline; Ischemic stroke; Mitophagy; Parkin; Resveratrol
    DOI:  https://doi.org/10.1016/S1875-5364(25)60825-9
  12. Diseases. 2025 Feb 16. pii: 60. [Epub ahead of print]13(2):
    TREM2 Alleviates Neuroinflammation by Maintaining Cellular Metabolic Homeostasis and Mitophagy Activity During Early Inflammation.
    Lingfeng Hu, Jie Liu, Jie Peng, Xiao Li, Zhangqiong Huang, Caixing Zhang, Shengtao Fan.
       AIMS: Inflammation is a pivotal characteristic of neurodegenerative diseases. The triggering receptor expressed on the myeloid cells 2 (TREM2) gene has previously been shown to suppress inflammation by directly inhibiting inflammation-related pathways. Mitochondrial dysfunction has recently emerged as another critical pathological manifestation of neurodegenerative diseases. Although TREM2 is involved in the regulation of cellular energy metabolism and mitochondrial autophagy, its role in the relationship between inflammation and mitochondrial autophagy remains unclear.
    METHODS: In this study, we generated TREM2-overexpressing BV-2 cells and established a neuroinflammatory model with LPS. We compared these cells with wild-type cells in terms of inflammation, metabolism, autophagy, and mitochondria using methods such as RT-qPCR, Western blotting, immunocytochemistry, transmission electron microscopy, and flow cytometry.
    RESULTS: Microglia overexpressing TREM2 exhibited increased resistance to inflammation. Additionally, these cells inhibited the metabolic reprogramming that occurs early in LPS-induced inflammation, reduced ROS release, mitigated mitochondrial damage, maintained a certain level of autophagic activity, and cleared damaged mitochondria. Consequently, they alleviated the inflammation caused by the mitochondrial barrier.
    CONCLUSIONS: ur results suggest that TREM2 can alleviate inflammation by maintaining cellular metabolic homeostasis and mitochondrial autophagy activity.
    Keywords:  TREM2; microglia; mitochondrial; mitophagy; neuroinflammation
    DOI:  https://doi.org/10.3390/diseases13020060
  13. Phytomedicine. 2025 Feb 21. pii: S0944-7113(25)00141-2. [Epub ahead of print]139 156500
    Allicin alleviates traumatic brain injury-induced neuroinflammation by enhancing PKC-δ-mediated mitophagy.
    Yue Cheng, Wei Gu, Xuechao Wu, Wei Tian, Zhenqian Mu, Yangfan Ye, Honglu Chao, Zhongyuan Bao.
       BACKGROUND: Traumatic brain injury (TBI) leads to neuroinflammation, which is a key contributor to the negative prognosis in TBI patients. Recent evidence indicates that allicin can prevent neuronal injury after TBI. However, whether allicin alleviates neuroinflammation by promoting mitophagy is unclear.
    PURPOSE: We investigated the suppressive effects of allicin on neuroinflammation and clarified the role of mitophagy in the underlying mechanism.
    STUDY DESIGN/METHODS: The controlled cortical impact (CCI) was employed to effectively mimic TBI in a living system. Cellular mechanical damage was modeled in vitro using a Bv2 cell stretch model. Neuroinflammation was assessed by evaluating levels of TNF-α, IL-1β, IL-6, ROS, IL-4 and IL-10, along with the expression of NLRP3 and TLR4 proteins. RNA-sequence and KEGG analyses revealed allicin-regulated molecular processes in the Bv2 cell stretch model. Immunofluorescence staining was performed to label both the autophagy marker protein LC3 and the outer mitochondrial membrane (OMM) marker COX IV. Lipid MS and lipidomic analyses were used to determine the CL levels in the OMM and IMM. The characteristic bilayer structure of mitochondria was observed using transmission electron microscopy (TEM). PKC-δ expression and phosphorylated phospholipid scramblase-3 (PLS3) levels were detected via western blotting. Stretched Bv2 cells and primary neurons were cocultured to assess the anti-neuroinflammatory effects of allicin. Neuro-rehabilitation was assessed using behavioral experiments such as the rotarod and morris water maze (MWM) tests.
    RESULTS: Allicin treatment reduced TNF-α, IL-1β, IL-6, ROS levels, and the expression of NLRP3 and TLR4 proteins in mice with CCI, while IL-4 and IL-10 levels remained unchanged. Additionally, allicin reduced tissue lesions and cell death after CCI. The transcriptomic analysis revealed that mitophagy was important in allicin-related molecular pathways. The translocation of CL from IMM to OMM was facilitated by allicin, as demonstrated by flow cytometry and lipidomic analyses. Importantly, allicin increased PKC-δ expression and PLS3 phosphorylation in the CL-related mitophagy process in both the CCI and Bv2 cell stretch models. These findings suggest that allicin reduces mitophagy-related neuroinflammation and further prevents neuronal injury in vitro. Rottlerin, a selective PKC-δ inhibitor, effectively diminished allicin's capacity to reduce neuroinflammation, correlating with worsened motor function and cognitive abilities. Thus, CCI-induced behavioral deficits were also ameliorated by the administration of allicin via a PKC-δ-related mitophagy.
    CONCLUSIONS: This study uncovers a novel mechanism where allicin enhances PKC-δ expression and PLS3 phosphorylation, facilitating CL translocation to the OMM and activating mitophagy, thereby reducing TBI-induced neuroinflammation.
    Keywords:  Allicin; Mitophagy; Neuroinflammation; PKC-δ; PLS3
    DOI:  https://doi.org/10.1016/j.phymed.2025.156500
  14. Curr Med Chem. 2025 Feb 27.
    Cells with Defective Mitophagy Do Not Accumulate Atherogenic LDL-Derived Cholesterol.
    Evgeny E Borisov, Volha I Summerhill, Victoria A Khotina, Anna M Kosyreva, Tatiana I Kovyanova, Vasily N Sukhorukov, Alexander N Orekhov.
      
    Keywords:  Atherosclerosis; chronic inflammation.; cybrid; defective mitophagy; low-density lipoprotein; mitochondrial DNA mutations
    DOI:  https://doi.org/10.2174/0109298673294632250108102414
  15. Int J Biol Sci. 2025 ;21(4): 1530-1544
    DARS2 Promotes Bladder Cancer Progression by Enhancing PINK1-Mediated Mitophagy.
    Dongqing Li, Hang Su, Xiaolin Deng, Yuan Huang, Zihuan Wang, Jinge Zhang, Chen Chen, Zaosong Zheng, Qiong Wang, Shanchao Zhao, Zhe-Sheng Chen, Haiyong Chen, Lina Hou, Wanlong Tan, Fei Li.
      Globally, bladder cancer is the tenth most common cancer. Mitophagy, a critical process regulating mitochondrial quantity and quality, has attracted increasing attention for its pivotal function in cancer. Nonetheless, its roles and underlying mechanisms in bladder cancer are yet to be elucidated. Therefore, in this study, 16 mitophagy-related genes were screened to construct a robust prognostic model with exceptional predictive accuracy for the outcomes of patients with bladder cancer. Of these genes, DARS2 was identified as a key regulator that significantly affected cancer progression. The findings established that DARS2 promoted the G1-to-S phase transition by upregulating CDK4 expression, thereby suppressing cellular senescence and driving cell proliferation. In addition, DARS2 augmented PINK1 expression, leading to increased PINK1-mediated mitophagy. Both in vitro and in vivo experiments confirmed that DARS2 inhibited cellular senescence and facilitated tumor progression by enhancing PINK1-mediated mitophagy. The observations from this study have provided novel insights into the multifaceted roles of DARS2-mediated mitophagy in bladder cancer. Targeting DARS2 and its regulation of mitophagy is a promising therapeutic strategy to improve the outcomes for patients with bladder cancer.
    Keywords:  Bladder cancer; Cellular senescence; DARS2; Mitophagy; PINK1
    DOI:  https://doi.org/10.7150/ijbs.107632
  16. J Bioenerg Biomembr. 2025 Feb 22.
    Dexmedetomidine activates mitophagy and protects against pyroptosis in oxygen-glucose deprivation/reperfusion-induced brain damage via PINK1/Parkin pathway activation.
    Jieru Zhang, Ruxia Li, Luyong Wang, Shuqin Ni.
      Accumulating studies have unraveled that dexmedetomidine (DEX) is neuroprotective against brain damage. However, it remains largely unknown about the mechanism involved in the neuroprotective effect of DEX. Therefore, this study explored whether DEX could affect mitophagy and pyroptosis in hypoxic-ischemic brain damage. We established a hippocampal neuron model of oxygen glucose-deprivation (OGD) and a rat model of cerebral ischemia/reperfusion (I/R) injury, which were then intervened with DEX and the autophagy inhibitor (3-MA). It was found that DEX intervention significantly increased neuron viability and mitophagy. Additionally, DEX intervention reversed increased oxidative stress and pyroptosis caused by OGD. DEX intervention further maintained the activation of the PINK1/Parkin pathway, while 3-MA treatment partly counteracted the protective effect of DEX on OGD-induced hippocampal neurons, suggesting that the inhibition of the PINK1/Parkin pathway reversed the function of DEX to increase cell viability and mitophagy and inhibit oxidative stress, pyroptosis, and apoptosis. Animal experiments also revealed that DEX intervention induced PINK1/Parkin pathway activation, reduced cerebral infarction and mitochondrial damage, promoted mitophagy, and inhibited pyroptosis, which was nullified by 3-MA treatment. Conclusively, DEX protects against pyroptosis and activates mitophagy in OGD/R-induced brain damage by activating the PINK1/Parkin pathway.
    Keywords:  Dexmedetomidine; Mitophagy; Oxidative stress; Oxygen-glucose deprivation; PINK1/Parkin pathway; Pyroptosis; Reperfusion injury
    DOI:  https://doi.org/10.1007/s10863-025-10051-4
  17. Int J Mol Sci. 2025 Feb 12. pii: 1551. [Epub ahead of print]26(4):
    A Novel Prognostic Signature of Mitophagy-Related E3 Ubiquitin Ligases in Breast Cancer.
    Kangjing Bian, Chihyu Yang, Feng Zhang, Lei Huang.
      Mitophagy plays a critical role in maintaining mitochondrial quality and cellular homeostasis. But the specific contribution of mitophagy-related E3 ubiquitin ligases to prognoses remains largely unexplored. In this study, we identified a novel mitophagy-related E3 ubiquitin ligase prognostic signature using least absolute shrinkage and selector operator (LASSO) and multivariate Cox regression analyses in breast cancer. Based on median risk scores, patients were divided into high-risk and low-risk groups. Functional enrichment analyses were conducted to explore the biological differences between the two groups. Immune infiltration, drug sensitivity, and mitochondrial-related phenotypes were also analyzed to evaluate the clinical implications of the model. A four-gene signature (ARIH1, SIAH2, UBR5, and WWP2) was identified, and Kaplan-Meier analysis demonstrated that the high-risk group had significantly worse overall survival (OS). The high-risk patients exhibited disrupted mitochondrial metabolism and immune dysregulation with upregulated immune checkpoint molecules. Additionally, the high-risk group exhibited higher sensitivity to several drugs targeting the Akt/PI3K/mTORC1 signaling axis. Accompanying mitochondrial metabolic dysregulation, mtDNA stress was elevated, contributing to activation of the senescence-associated secretory phenotype (SASP) in the high-risk group. In conclusion, the identified signature provides a robust tool for risk stratification and offers insights into the interplay between mitophagy, immune modulation, and therapeutic responses for breast cancer.
    Keywords:  E3 ubiquitin ligase; breast cancer; immune; metabolic; mitophagy; prognostic signature
    DOI:  https://doi.org/10.3390/ijms26041551
  18. Mol Med Rep. 2025 May;pii: 111. [Epub ahead of print]31(5):
    Semaglutide enhances PINK1/Parkin‑dependent mitophagy in hypoxia/reoxygenation‑induced cardiomyocyte injury.
    Liqin Li, Lili Jin, Yaping Tian, Jun Wang.
      The present study aimed to explore how semaglutide can help protect the heart from injury caused by hypoxia/reoxygenation (H/R) and to reveal the underlying mechanism. Briefly, AC16 cardiomyocytes were subjected to 8 h of hypoxia followed by 12 h of reoxygenation to simulate H/R. The cells were divided into the following five groups: Normoxia, H/R, H/R + semaglutide, H/R + semaglutide + rapamycin (autophagy inducer), and H/R + semaglutide + 3‑methyladenine (3‑MA; autophagy inhibitor) groups. Cell viability was examined using a Cell Counting Kit‑8 assay, ATP levels were examined using a bioluminescent detection kit, reactive oxygen species (ROS) production was detected using a ROS Assay Kit, and monomeric red fluorescent protein (mRFP)‑green fluorescent protein (GFP)‑LC3 was assessed using tandem mRFP‑GFP fluorescence microscopy, while autophagosomes were observed using transmission electron microscopy. Furthermore, the protein expression levels of autophagy markers (LC3, p62 and Beclin1) and regulators of mitochondrial autophagy [PTEN‑induced putative kinase protein‑1 (PINK1) and Parkin] were examined using western blot analysis. In AC16 cells, exposure to hypoxia followed by reoxygenation led to an increase in oxidative stress. This condition also induced an increase in autophagy activity, as evidenced by an increase in the number of autophagosomes, elevated LC3‑II/LC3‑I ratio, and upregulation of p62, Beclin1, PINK1 and Parkin expression compared with those in cells cultured under normoxia. Notably, treatment with semaglutide or rapamycin effectively reversed the H/R‑induced oxidative stress, enhanced the changes in autophagy activity, autophagosome levels and elevated LC3BII/LC3BI ratio, and increased the expression levels of Beclin1, PINK1, Parkin and p62 expression. Notably, the use of 3‑MA exhibited distinct effects under the same conditions; it exacerbated oxidative stress, decreased autophagy activity and reduced the LC3BII/LC3BI ratio. In conclusion, semaglutide was found to reduce oxidative stress caused by H/R and to increase autophagy via the ROS/PINK1/Parkin/p62 pathway. The present study offers a novel understanding of how semaglutide may protect the heart, and suggests its potential use in the treatment of myocardial ischemia/reperfusion injury.
    Keywords:  PTEN‑induced putative kinase protein‑1/Parkin pathway; autophagy; cardioprotection; hypoxia/reoxygenation; semaglutide
    DOI:  https://doi.org/10.3892/mmr.2025.13476
  19. Dev Neurobiol. 2025 Apr;85(2): e22961
    Cordycepin Ameliorates Kainic Acid-Induced HT22 Cell Neurotoxicity by Activating GPR120-Mediated Mitophagy.
    Yongzhi San, Minghua Wang.
       BACKGROUND: Mitophagy is important for normal neural activity. Epilepsy is intimately linked to neurotoxicity due to mitochondrial dysfunction. Cordycepin (Cor) has been shown to exert neuroprotective effects. This study aims to investigate whether Cor could mitigate neurotoxicity in epilepsy by modulating mitophagy.
    METHODS: In vitro, kainic acid (KA) was utilized to induce cytotoxicity in HT22 cell. Cell viability was assessed using the CCK-8 assay, while cell damage was evaluated through an LDH kit. Flow cytometry was used to assess apoptosis. The expressions of G protein-coupled receptor 120 (GPR120), apoptosis, and mitophagy-related proteins were analyzed by western blot. Inflammatory factors and oxidative stress levels were examined by kits. DCFH-DA staining was applied to observe cellular reactive oxygen species (ROS) levels. The three-dimensional coordinates of GPR120 were retrieved from the PDB database, and molecular docking was performed using AutoDock. Immunofluorescence staining was used to observe mitophagy level.
    RESULTS: Cor significantly attenuated KA-induced HT22 cell viability injury and inflammation, while suppressing ROS and oxidative stress levels. Notably, Cor ameliorated the decrease of mitophagy level observed in HT22 cells treated with KA. GPR120 expression was upregulated following KA treatment and further elevated after adding Cor. Cor could bind to GPR120. Interference with GPR120 reversed the ameliorative effects of Cor on KA-induced mitophagy and cytotoxicity in HT22 cells.
    CONCLUSION: Overall, Cor significantly alleviated KA-induced HT22 cell neurotoxic damage and oxidative stress. This protective effect may be mediated through GPR120-regulated mitophagy.
    Keywords:  Cor; epilepsy; mitophagy; neuronal toxicity; oxidative stress
    DOI:  https://doi.org/10.1002/dneu.22961
  20. Diabetes Metab Syndr Obes. 2025 ;18 541-554
    The Role of Placental MFF-Mediated Mitochondrial Fission in Gestational Diabetes Mellitus.
    Lijie Wei, Chenyun Fang, Yi Jiang, Huiting Zhang, Peng Gao, Xuan Zhou, Shenglan Zhu, Yuanyuan Du, Rui Su, Lili Guo, Mengzhou He, Shaoshuai Wang, Ling Feng, Jun Yu.
       Introduction: Gestational diabetes mellitus (GDM) refers to hyperglycemia first recognized during pregnancy, characterized by decreased insulin sensitivity and impaired glucose metabolism. Dynamic fusion and fission processes within mitochondria play critical roles in maintaining glucose metabolism homeostasis. Given the fundamental role of mitochondrial fission factor (MFF) in mitochondrial fission, the intention of this study was to investigate mitochondrial dynamics in the placentae of GDM patients and explore the role of MFF in the etiopathogenesis and progression of GDM through the modulation of glucose metabolism and insulin resistance.
    Methods: 40 Placental tissues were obtained from pregnant women undergoing cesarean section with GDM (n=20) and those with normoglycemia (n=20). To mimic the intrauterine high glucose environment, immortalized human-derived first-trimester extravillous trophoblast cells HTR8/SVneo were used and treated in a high glucose environment. Immunofluorescence was utilized to analyze MFF expression in placental tissues and mitochondrial length in HTR8/SVneo cells. The expression levels of glucose transporters (GLUTs) and other pivotal proteins involved in mitochondrial dynamics and the insulin signaling pathway, were assessed by Western blotting. Additionally, cellular glucose uptake capacity was determined using a glucose assay kit.
    Results: MFF expression was greater in the GDM group than in the normoglycemic group. In a high-glucose environment, the expression of fusion-related proteins OPA1, MFN1 and MFN2 decreased while the expression of DRP1 and MFF increased, indicating that the mitochondrial dynamics of trophoblast cells shift toward fission. Elevated mitochondrial fission hinders the insulin signaling pathway, resulting in a reduction in glucose uptake by HTR8/SVneo cells and a concurrent decrease in GLUT4 expression.
    Discussion: Our study demonstrates that MFF-mediated mitochondrial fission inhibits insulin sensitivity and upregulates glucose transport in GDM, which is related to offspring exposure to a hyperglycemic intrauterine environment. These results provide a novel therapeutic target for addressing GDM that may mitigate unfavorable pregnancy outcomes.
    Keywords:  MFF; gestational diabetes mellitus; insulin resistance; insulin sensitivity
    DOI:  https://doi.org/10.2147/DMSO.S484002
  21. Fish Shellfish Immunol. 2025 Feb 22. pii: S1050-4648(25)00115-9. [Epub ahead of print]160 110226
    CgVDAC2 participated in haemocyte mitophagy induced by Vibrio splendidus in the Pacific oyster Crassostrea gigas.
    Muchun He, Shurong Li, Jiejie Sun, Xiaoqian Lv, Yinan Li, Linsheng Song.
      VDAC2 (Voltage dependent anion channel 2) is a highly conserved pore-forming protein expressed in the outer membrane of eukaryotic mitochondria. In the present study, CgVDAC2 identified from Crassostrea gigas regulated the mitophagy of haemocytes induced by Vibrio splendidus. CgVDAC2 was distributed in the cytoplasm of three subpopulations of haemocytes. After V. splendidus stimulation, the mRNA and protein expressions of CgVDAC2 were induced in haemocytes. Furthermore, the green signals of CgVDAC2 were colocalized with the red signals of mitochondria and Mtphagy Dye, respectively. And their co-localization values were both increased significantly in haemocytes at 12 h after V. splendidus stimulation, respectively. In siCgVDAC2-treated oysters, the mRNA expressions of mitophagy-related genes (CgLC3, CgPINK1, CgParkin1, CgPHB2, and CgATG16L) and the levels of mitophagy decreased significantly in haemocytes after V. splendidus stimulation. In addition, both the fluorescence intensities of the JC-1 monomer/aggregate ratio (Q4/Q2) and mitochondrial reactive oxygen species (mtROS) increased significantly. Collectively, all the results indicated that CgVDAC2 participated in oyster antibacterial immune response through regulating the haemocyte mitophagy.
    Keywords:  Antibacterial immunity; Crassostrea gigas; Mitophagy; Voltage dependent anion channel 2
    DOI:  https://doi.org/10.1016/j.fsi.2025.110226
  22. Acta Neuropathol Commun. 2025 Feb 24. 13(1): 41
    Hippocampal mitophagy alterations in MAPT-associated frontotemporal dementia with parkinsonism.
    Tyrique Richardson, Xu Hou, Fabienne C Fiesel, Zbigniew K Wszolek, Dennis W Dickson, Wolfdieter Springer.
      The enzyme pair PINK1 and PRKN together orchestrates a cytoprotective mitophagy pathway that selectively tags damaged mitochondria with phospho-serine 65 ubiquitin (pS65-Ub) and directs them for autophagic-lysosomal degradation (mitophagy). We previously demonstrated a significant accumulation of pS65-Ub signals in autopsy brains of sporadic Lewy body disease and Alzheimer's disease cases, which strongly correlated with early tau pathology. In this study, we extended our analysis to a series of pathologically confirmed cases of frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) harboring different pathogenic mutations in MAPT, the gene encoding tau. We assessed the morphology, levels, and distribution of the mitophagy tag pS65-Ub in several affected brain regions and hippocampal subregions of these cases. While tau pathological burden was similarly increased across all FTDP-17 cases, pS65-Ub immunopositive signals were strongly accumulated in P301L cases and only weakly present in N279K cases. In the hippocampus of both mutation groups, the density of pS65-Ub positive cells was overall the greatest in the dentate gyrus followed by the subiculum, CA1, and CA2/3, with the CA4 showing only minimal presence. Notably, positive cells in the subiculum carried greater numbers and particularly vacuolar pS65-Ub structures, while cells in the dentate gyrus mostly contained fewer and rather granular pS65-Ub inclusions. Single cell analyses revealed differential co-localization of pS65-Ub with mitochondria, autophagosomes, and lysosomes in these two regions. Together, our study demonstrates distinct mitophagy alteration in different FTDP-17 MAPT cases and hint at selective organelle failure in the hippocampal subregions that was associated with the P301L mutation.
    Keywords:   MAPT P301L; Frontotemporal dementia with parkinsonism; Hippocampus; Mitochondria; Mitophagy; PINK1; PRKN; Parkin; Phosphorylated ubiquitin; Tau
    DOI:  https://doi.org/10.1186/s40478-025-01955-8
  23. Front Pharmacol. 2025 ;16 1538662
    Recent development of mitochondrial metabolism and dysfunction in osteoarthritis.
    Pengchao Guo, Ahmad Alhaskawi, Safwat Adel Abdo Moqbel, Zhijun Pan.
      Osteoarthritis is a degenerative joint disorder characterized by cartilage degradation, synovial inflammation, and altered subchondral bone structure. Recent insights have identified mitochondrial dysfunction as a pivotal factor in OA pathogenesis, contributing to chondrocyte apoptosis, oxidative stress, and extracellular matrix degradation. Disruptions in mitochondrial dynamics, including impaired biogenesis, mitophagy, and metabolic shifts from oxidative phosphorylation to glycolysis, exacerbate cartilage damage by promoting the production of reactive oxygen species and matrix-degrading enzymes such as ADAMTS and MMPs. This review explores the molecular mechanisms underlying mitochondrial dysfunction in OA, emphasizing its role in cartilage homeostasis and inflammation. Furthermore, it highlights emerging therapeutic strategies targeting mitochondrial pathways, including antioxidants, mitophagy enhancers, and metabolic modulators, as potential interventions to mitigate disease progression, which offer promising avenues for advancing personalized and disease-modifying treatments in OA.
    Keywords:  cartilage degradation; inflammation; mitochondrial dysfunction; mitochondrial metabolism; osteoarthritis
    DOI:  https://doi.org/10.3389/fphar.2025.1538662
  24. Autophagy. 2025 Feb 25.
    Histone lactylation stimulated upregulation of PSMD14 alleviates neuron PANoptosis through deubiquitinating PKM/PKM2 to activate PINK1-mediated mitophagy after traumatic brain injury.
    Lei Xu, Yangfan Ye, Wei Gu, Xiao Xu, Chen Nuo, Liuchao Zhang, Wanzhi Cai, Jingming Hu, Tian Wang, Honglu Chao, Yiming Tu, Jing Ji.
      Alleviating the multiple types of programmed neuronal death caused by mechanical injury has been an impetus for designing neuro-therapeutical approaches after traumatic brain injury (TBI). The aim of this study was to elucidate the potential role of PSMD14 (proteasome 26S subunit, non-ATPase 14) in neuron death and the specific mechanism through which it improves prognosis of TBI patients. Here, we identified differential expression of the PSMD14 protein between the controlled cortical impact (CCI) and sham mouse groups by LC-MS proteomic analysis and found that PSMD14 was significantly upregulated in neurons after brain injury by qPCR and western blot. PSMD14 suppressed stretch-induced neuron PANoptosis and improved motor ability and learning performance after CCI in vivo. Mechanistically, PSMD14 improved PINK1 phosphorylation levels at Thr257 and activated PINK1-mediated mitophagy by deubiquitinating PKM/PKM2 (pyruvate kinase M1/2) to maintain PKM protein stability. PSMD14-induced mitophagy promoted mitochondrial homeostasis to reduced ROS production, and ultimately inhibited the neuron PANoptosis. The upregulation of neuronal PSMD14 after TBI was due to the increase of histone lactation modification level and lactate treatment alleviated neuron PANoptosis via increasing PSMD14 expression. Our findings suggest that PSMD14 could be a potential therapeutic approach for improving the prognosis of TBI patients.
    Keywords:  Cell death; H3K18la; PSMD14; TBI; mitophagy; phosphorylation
    DOI:  https://doi.org/10.1080/15548627.2025.2471633
  25. Cells. 2025 Feb 13. pii: 276. [Epub ahead of print]14(4):
    Mitochondrial Dysfunction in Neurodegenerative Diseases.
    Han-Mo Yang.
      Mitochondrial dysfunction represents a pivotal characteristic of numerous neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. These conditions, distinguished by unique clinical and pathological features, exhibit shared pathways leading to neuronal damage, all of which are closely associated with mitochondrial dysfunction. The high metabolic requirements of neurons make even minor mitochondrial deficiencies highly impactful, driving oxidative stress, energy deficits, and aberrant protein processing. Growing evidence from genetic, biochemical, and cellular investigations associates impaired electron transport chain activity and disrupted quality-control mechanisms, such as mitophagy, with the initial phases of disease progression. Furthermore, the overproduction of reactive oxygen species and persistent neuroinflammation can establish feedforward cycles that exacerbate neuronal deterioration. Recent clinical research has increasingly focused on interventions aimed at enhancing mitochondrial resilience-through antioxidants, small molecules that modulate the balance of mitochondrial fusion and fission, or gene-based therapeutic strategies. Concurrently, initiatives to identify dependable mitochondrial biomarkers seek to detect pathological changes prior to the manifestation of overt symptoms. By integrating the current body of knowledge, this review emphasizes the critical role of preserving mitochondrial homeostasis as a viable therapeutic approach. It also addresses the complexities of translating these findings into clinical practice and underscores the potential of innovative strategies designed to delay or potentially halt neurodegenerative processes.
    Keywords:  mitochondrial dynamics; mitochondrial dysfunction; neurodegenerative disease; oxidative stress
    DOI:  https://doi.org/10.3390/cells14040276
  26. Biomolecules. 2025 Feb 19. pii: 304. [Epub ahead of print]15(2):
    The Curse of the Red Pearl: A Fibroblast-Specific Pearl-Necklace Mitochondrial Phenotype Caused by Phototoxicity.
    Irene M G M Hemel, Kèvin Knoops, Carmen López-Iglesias, Mike Gerards.
      The dynamic nature of mitochondria makes live cell imaging an important tool in mitochondrial research. Although imaging using fluorescent probes is the golden standard in studying mitochondrial morphology, these probes might introduce aspecific features. In this study, live cell fluorescent imaging was applied to investigate a pearl-necklace-shaped mitochondrial phenotype that arises when mitochondrial fission is restricted. In this fibroblast-specific pearl-necklace phenotype, constricted and expanded mitochondrial regions alternate. Imaging studies revealed that the formation time of this pearl-necklace phenotype differs between laser scanning confocal, widefield and spinning disk confocal microscopy. We found that the phenotype formation correlates with the excitation of the fluorescent probe and is the result of phototoxicity. Interestingly, the phenotype only arises in cells stained with red mitochondrial dyes. Serial section electron tomography of the pearl-necklace mitochondria revealed that the mitochondrial membranes remained intact, while the cristae structure was altered. Furthermore, filaments and ER were present at the constricted sites. This study illustrates the importance of considering experimental conditions for live cell imaging to prevent imaging artifacts that can have a major impact on the obtained results.
    Keywords:  electron microscopy; microscopy; mitochondria; mitochondrial dynamics; phototoxicity
    DOI:  https://doi.org/10.3390/biom15020304
  27. Naunyn Schmiedebergs Arch Pharmacol. 2025 Feb 25.
    Rosmarinic acid promotes mitochondrial fission and induces ferroptosis in triple-negative breast cancer cells.
    Chufei Xie, Liujia Chan, Yuheng Pang, Yuefeng Shang, Wenjing Wang, Lichun Zhao.
      Breast cancer is the most common malignant tumor in women. Among its subtypes, triple-negative breast cancer (TNBC) is more aggressive and poses a serious threat to women's health. Rosmarinic acid (RA) is a natural polyphenolic compound known for its diverse pharmacological activities, with its antioxidant and anticancer properties being particularly notable. This study investigated the effects of RA on TNBC cell lines and explored its potential mechanisms. CCK-8 and colony formation assays were used to evaluate the potential inhibitory effects of RA on TNBC cells and to measure intracellular reactive oxygen species (ROS) levels. Flow cytometry was employed to analyze the cell cycle and apoptosis. RNA-seq analysis was performed to investigate the potential mechanisms of RA on MDA-MB-231 cells. RA inhibited the proliferation of TNBC cells in a concentration-dependent manner and reduced intracellular ROS levels. RA induced cell cycle arrest at the G1/G0 phase and promoted apoptosis by decreasing mitochondrial membrane potential. RNA-seq differential expression analysis, identified 1,929 differentially expressed genes, including 601 upregulated genes and 1,328 downregulated genes. Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA) showed that these differentially expressed genes were significantly enriched in pathways associated with ferroptosis, ABC transporters, and fatty acid metabolism. Additionally, RA significantly upregulated the expression of dynamin-related protein 1 (DRP1) in MDA-MB-231 cells, promoting mitochondrial fission, disrupting mitochondrial dynamics, and leading to dysfunction. Furthermore, RA increased the expression of intracellular ferroportin and heme oxygenase 1 (HMOX-1), resulting in elevated intracellular iron levels. The study suggests that RA inhibits the proliferation of TNBC cells through multiple mechanisms and may have potential therapeutic effects in the treatment of TNBC.
    Keywords:  Ferroptosis; Mitochondrion; RNA-seq; Rosmarinic acid; Triple-negative breast cancer
    DOI:  https://doi.org/10.1007/s00210-025-03927-0
  28. Sci Rep. 2025 Feb 25. 15(1): 6794
    Discovery of a new mitophagy-related gene signature for predicting the outlook and immunotherapy in triple-negative breast cancer.
    Gang Liu, Guozheng Yu, Dongzhi Yin, Jianying Ma.
      Mitophagy is an essential cellular process that is conserved and crucial for maintaining cellular balance by selectively eliminating malfunctioning mitochondria. However, there is still limited knowledge regarding the influence of mitophagy-related genes (MRGs) on the prognosis and response to treatment of triple-negative breast cancer (TNBC). In here, the TCGA and GEO databases were used to acquire the transcriptomic and clinical information of patients with TNBC, correspondingly. Using LASSO and multivariable Cox regression analyses, a risk signature related to mitophagy was established based on the prognostic MRGs. The prognostic signature associated with mitophagy consisted of five genes (BSG, JMJD6, DNAJA3, DISC1, and SQSTM1) and independently predicted the prognosis of patients with TNBC, regardless of clinical factors (p < 0.05). Patients classified within the high-risk group demonstrated significantly lower overall survival rates when contrasted with those in the low-risk group. The model exhibited excellent performance in predicting survival and risk stratification, as evidenced by the receiver operating characteristic and C-index. The findings stayed unchanged following external validation. Moreover, we observed a notable variation in the tumor immune microenvironment among the different risk categories. Patients with a low risk of TNBC demonstrated a more favorable response to immunotherapy compared to patients with a high risk. In conclusion, our study uncovered the possible impacts of MRGs on the tumor microenvironment, clinical and pathological characteristics, and outlook of TNBC. The CRG-related signature was strongly linked to the immune response against TNBC and has the potential to serve as a valuable tool in predicting the prognosis and immunotherapy response of patients.
    Keywords:  Immunotherapy; Mitophagy; Prognosis; Triple-negative breast cancer; Tumor microenvironment
    DOI:  https://doi.org/10.1038/s41598-025-91613-9
  29. Front Aging Neurosci. 2025 ;17 1522073
    Optineurin overexpression ameliorates neurodegeneration through regulating neuroinflammation and mitochondrial quality in a murine model of amyotrophic lateral sclerosis.
    Shumin Zhao, Ranran Chen, Yi An, Yali Zhang, Cheng Ma, Ying Gao, Yanchao Lu, Fei Yang, Xue Bai, Jingjing Zhang.
       Introduction: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the loss of motor neurons (MNs). Genetic mutations in Optineurin (OPTN) and Superoxide Dismutase 1 (SOD1) have been identified as causal factors for ALS. OPTN immunopositive inclusions have been confirmed in the cases of ALS with SOD1 mutations. However, the role of the OPTN gene in ALS caused by SOD1 mutations is ambiguous.
    Methods: The murine Optn lentivirus and empty vector lentivirus were injected into SOD1 G93A mice after discovering variations in Optn expression over time. The phenotype onset date, life span, locomotor activity, and pathological changes in the spinal cord were determined and recorded subsequently. In addition, the influences on cellular apoptosis, mitochondrial dynamics, mitophagy, and neuroinflammation were further investigated.
    Results: Optn expression was increased in the spinal cord of SOD1 G93A mice at the pre-symptomatic phase, but decreased after disease onset. Optn overexpression led to a 9.7% delay in the onset of disease and improved motor performance in SOD1 G93A mice. Optn overexpression also ameliorated the MNs loss by 46.8%. Moreover, all these ameliorating effects induced by Optn overexpression might be due to the inhibition of cellular apoptosis, improvement of mitochondrial quality, regulation of mitochondrial dynamics, promotion of mitophagy, and anti-inflammatory properties.
    Conclusion: Our data demonstrate that Optn overexpression protects MNs, inhibites cellular apoptosis, improves mitochondrial quality and regulates neuroinflamation in SOD1 G93A mice at the pre-symptomatic stage.
    Keywords:  amyotrophic lateral sclerosis; apoptosis; mitochondrial quality; neuroinflammation; optineurin
    DOI:  https://doi.org/10.3389/fnagi.2025.1522073
  30. Biochim Biophys Acta Mol Basis Dis. 2025 Feb 22. pii: S0925-4439(25)00084-5. [Epub ahead of print]1871(4): 167739
    Conditional deletion of Pink1 in mesenchymal stem cells suppresses osteogenesis through downregulation of Apoh transcription.
    Wei Zhang, Xiaowen Jiang, Wei Zhang, Weiduo Hou, Mo Chen, Erman Chen, Weixu Li.
       BACKGROUND: Previous research indicates a strong association between PINK1 and osteogenic differentiation of mesenchymal stem cells (MSCs) through the maintenance of mitochondrial homeostasis. Nevertheless, additional inquiry is needed to fully elucidate PINK1's involvement in transcriptional regulation.
    METHODS: To comprehensively investigate Pink1's influence on the osteogenic differentiation of mesenchymal stem cells (MSCs), we utilized Prx1-Cre mice for targeted Pink1 deletion, producing Pink1f/f; Prx1-Cre (Pink1-KO) and Pink1f/f (Control) mice. Additionally, transcriptome sequencing analysis, RT-qPCR, Western blot, and ChIP assays were conducted.
    RESULTS: The Pink1-KO group showed significant reductions in both trabecular and cortical bone mass relative to controls. Additionally, Pink1 deletion decreased the expression of osteogenic differentiation and adipogenic markers. While previous research highlighted the adverse impact of reduced Pink1 on mitophagy and mitochondrial integrity, our study further identifies a decline in autophagy with Pink1 downregulation. The nuclear localization of PINK1 hints at its broader roles, though detailed insights into its nuclear functions are pending. Consequently, we undertook transcriptome sequencing analysis, which suggested Pink1 might influence MSC osteogenic differentiation through cholesterol metabolism-related pathways. Further validations via RT-qPCR, Western blot, and ChIP assays demonstrated PINK1's interaction with the Apoh promoter, enhancing its transcription. Notably, the knockdown of Apoh impairs osteogenic differentiation in BMSCs, whereas the upregulation of Apoh mitigates the adverse effects of Pink1 deficiency on osteogenesis.
    CONCLUSIONS: Our data suggest Pink1 deficiency compromises osteoblastic differentiation in MSCs, partially through disrupted Apoh transcription regulation.
    Keywords:  Apoh; Osteogenic differentiation; Pink1; Transcription
    DOI:  https://doi.org/10.1016/j.bbadis.2025.167739
  31. MedComm (2020). 2025 Mar;6(3): e70118
    SIRT1 Alleviates Mitochondrial Fission and Necroptosis in Cerebral Ischemia/Reperfusion Injury via SIRT1-RIP1 Signaling Pathway.
    Xuan Wei, Hanjing Guo, Guangshan Huang, Haoyue Luo, Lipeng Gong, Pan Meng, Jiyong Liu, Wenli Zhang, Zhigang Mei.
      Programmed cell death, including necroptosis, plays a critical role in the pathogenesis of cerebral ischemia/reperfusion injury (CIRI). Silent information regulator 1 (SIRT1) has been identified as a potential therapeutic target for CIRI, yet its precise role in regulating necroptosis remains controversial. Furthermore, the potential interaction between SIRT1 and receptor-interacting protein kinase 1 (RIP1) in this context is not fully understood. Sanpian Decoction (SPD), a classical traditional herbal formula, was previously shown to enhance SIRT1 expression in our studies. Our findings demonstrated that, both in vivo and in vitro, CIRI was associated with a decrease in SIRT1 levels and phosphorylated dynamin-related protein 1 (p-DRP1) at Ser637, alongside an increase in RIP1 and other necroptosis-related proteins. Co-immunoprecipitation and immunofluorescence analyses revealed a weakened interaction between SIRT1 and RIP1. Furthermore, abnormal mitochondrial fission and dysfunction were mediated through the phosphoglycerate mutase 5-DRP1 pathway. Notably, SPD treatment improved neurological outcomes and reversed these pathological changes by enhancing the SIRT1-RIP1 interaction. In conclusion, this study suggests that SIRT1 is a promising therapeutic target for CIRI, capable of inhibiting necroptosis and mitigating mitochondrial fission via the SIRT1-RIP1 pathway. SPD exhibits therapeutic potential by activating SIRT1, thereby attenuating necroptosis and mitochondrial fission during CIRI.
    Keywords:  DRP1; RIP1; SIRT1; cerebral ischemia/reperfusion injury; mitochondrial fission; necroptosis
    DOI:  https://doi.org/10.1002/mco2.70118
  32. Redox Biol. 2025 Feb 22. pii: S2213-2317(25)00076-X. [Epub ahead of print]81 103563
    PDE4D inhibition ameliorates cardiac hypertrophy and heart failure by activating mitophagy.
    Jing Fu, Congping Su, Yin Ge, Zhou Ao, Li Xia, Yingxiang Chen, Yizheng Yang, Shiwei Chen, Rui Xu, Xiaoyan Yang, Kai Huang, Qin Fu.
      Cyclic adenosine monophosphate (cAMP) plays a major role in normal and pathologic signaling in the heart. Phosphodiesterase 4 (PDE4) is a major PDE degrading cAMP in the heart. There are inconsistencies concerning the roles of the PDE4 isoforms 4B and 4D in regulation of cardiac function. Cardiac PDE4B overexpression is beneficial in remodeling and heart failure (HF), however, the effect of PDE4D and PDE4 inhibitor in HF remains unclear. We generated global and conditional cardiac-specific heterozygous PDE4D knockout mice and adeno-associated virus serotype 9-PDE4D overexpression to determine the role of PDE4D in cardiac hypertrophy and HF. PDE4D upregulation was observed in failing hearts from human and isoproterenol injection and TAC mice. In vitro, isoproterenol stimulation increased PDE4D expression via PKA but had no effect on PDE4B expression in cardiomyocytes. PDE4D overexpression per se induced oxidative stress, mitochondrial damage and cardiomyocyte hypertrophy by decreasing PINK1/Parkin-mediated mitophagy through inhibiting cAMP-PKA-CREB-Sirtuin1 (SIRT1) signaling pathway, while PDE4B overexpression did not affect CREB-SIRT1 pathway and mitophagy but exhibited a protective effect on isoproterenol-induced oxidative stress and hypertrophy in cardiomyocytes. PDE4D silencing or inhibition with PDE4 inhibitor roflumilast ameliorated isoproterenol-induced mitochondrial injury and cardiomyocyte hypertrophy. In vivo, ISO injection or TAC inhibited cardiac mitophagy and caused cardiac hypertrophy and HF, which were ameliorated by roflumilast or cardiac-specific PDE4D haploinsufficiency. Conversely, cardiac PDE4D overexpression suppressed cardiac mitophagy and abolished the protective effects of global PDE4D haploinsufficiency on TAC-induced cardiac hypertrophy and HF. In conclusion, these studies elucidate a novel mechanism by which sustained adrenergic stimulation contributes to cardiac hypertrophy and HF by increasing PDE4D via cAMP-PKA signaling, which in turn reduces cAMP-PKA activity, resulting in cardiomyocyte hypertrophy and mitochondrial injury via inhibition of CREB-SIRT1 signaling-mediated mitophagy. PDE4D inhibition may represent a novel therapeutic strategy for HF.
    Keywords:  CREB; Heart failure; Hypertrophy; Mitophagy; PDE4D; PKA; Phosphodiesterase 4; SIRT1; cAMP
    DOI:  https://doi.org/10.1016/j.redox.2025.103563
  33. Int Urol Nephrol. 2025 Feb 28.
    Global research trends on the associations between chronic kidney disease and mitochondria: insights from the bibliometric analysis.
    Xinfang Tang, Anna Zhang, Xiaojuan Feng, Wenjuan Wang, Fanghong Chen, Yijie Tao, Chuyan Wu, Feng Jiang.
       BACKGROUND: Chronic kidney disease (CKD) is a global health burden characterized by a progressive and irreversible loss of kidney function. Mitochondrial dysfunction has emerged as a pivotal factor in CKD pathogenesis, contributing to renal cell injury, inflammation, and fibrosis through mechanisms such as oxidative stress and impaired bioenergetics. This study aimed to provide a comprehensive bibliometric analysis of global research trends on the associations between CKD and mitochondria over the past two decades.
    METHODS: A bibliometric analysis was conducted using the Web of Science Core Collection database, focusing on publications from 2004 to 2024. Data were analyzed using Citespace and VOSviewer to visualize publication trends, key contributors, keyword co-occurrences, and collaboration networks.
    RESULTS: A total of 2,870 publications were identified, with a significant increase in annual output observed after 2010. The United States, China, and Japan were the leading contributors, fostering strong international collaborations. Institutional analysis highlighted the prominent roles of the US Department of Veterans Affairs and the University of California System. Key authors, such as Jose Pedraza-Chaverri and HM Kang, and influential studies addressing mitochondrial quality control and metabolic reprogramming were identified. Keyword analysis revealed major research themes, including oxidative stress, ischemia-reperfusion injury, and fatty acid oxidation, with recent trends emphasizing mitochondrial dynamics and autophagy.
    CONCLUSIONS: This analysis underscored the growing recognition of mitochondrial dysfunction in CKD pathogenesis and highlighted the interdisciplinary nature of this field. The findings revealed key research trends, influential contributors, and emerging topics, providing a foundation for future studies and the development of targeted mitochondrial therapies. These insights hold promise for advancing the understanding and treatment of CKD through precision medicine approaches. Specifically, therapeutic strategies aimed at enhancing mitochondrial biogenesis, promoting mitophagy, and restoring metabolic balance may offer novel avenues for delaying CKD progression and mitigating renal dysfunction. Integrating these mitochondrial-targeted interventions into current clinical practice could improve patient outcomes and guide the development of more effective treatment protocols.
    Keywords:  Bibliometric analysis; Chronic kidney disease; Mitochondria; Mitochondrial dysfunction; Oxidative stress; Research trends
    DOI:  https://doi.org/10.1007/s11255-025-04437-x
  34. Biomedicines. 2025 Jan 31. pii: 327. [Epub ahead of print]13(2):
    Mitochondrial Dysfunction in Neurodegenerative Diseases: Mechanisms and Corresponding Therapeutic Strategies.
    Kai Meng, Haocheng Jia, Xiaoqing Hou, Ziming Zhu, Yuguang Lu, Yingying Feng, Jingwen Feng, Yong Xia, Rubin Tan, Fen Cui, Jinxiang Yuan.
      Neurodegenerative disease (ND) refers to the progressive loss and morphological abnormalities of neurons in the central nervous system (CNS) or peripheral nervous system (PNS). Examples of neurodegenerative diseases include Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Recent studies have shown that mitochondria play a broad role in cell signaling, immune response, and metabolic regulation. For example, mitochondrial dysfunction is closely associated with the onset and progression of a variety of diseases, including ND, cardiovascular diseases, diabetes, and cancer. The dysfunction of energy metabolism, imbalance of mitochondrial dynamics, or abnormal mitophagy can lead to the imbalance of mitochondrial homeostasis, which can induce pathological reactions such as oxidative stress, apoptosis, and inflammation, damage the nervous system, and participate in the occurrence and development of degenerative nervous system diseases such as AD, PD, and ALS. In this paper, the latest research progress of this subject is detailed. The mechanisms of oxidative stress, mitochondrial homeostasis, and mitophagy-mediated ND are reviewed from the perspectives of β-amyloid (Aβ) accumulation, dopamine neuron damage, and superoxide dismutase 1 (SOD1) mutation. Based on the mechanism research, new ideas and methods for the treatment and prevention of ND are proposed.
    Keywords:  mitochondrial dynamics; mitochondrial energy metabolism; mitochondrial homeostasis imbalance; mitophagy; neurodegenerative diseases
    DOI:  https://doi.org/10.3390/biomedicines13020327
  35. Eur J Med Chem. 2025 Feb 22. pii: S0223-5234(25)00204-1. [Epub ahead of print]289 117439
    Arctigenin derivative TZOA restores mitochondrial homeostasis to combat rhabdovirus infections.
    Huan Wang, Zixuan Wang, Xu Zhang, Lipeng Shan, Lei Liu, Yang Hu, Jiong Chen.
      Rhabdoviruses are diverse pathogens known for their broad host range and significant economic and health impacts. Infectious hematopoietic necrosis virus (IHNV), a member of the Novirhabdovirus genus, poses a major threat to aquaculture, particularly affecting rainbow trout. In this study, we further optimize the antiviral properties of arctigenin derivatives based on our previous structure-activity relationship (SAR) research, leading to the synthesis of TZOA. TZOA was synthesized with a 45 % yield and demonstrated no cytotoxicity up to 25 μM in EPC cells. Treatment with TZOA markedly inhibited IHNV replication dose-dependently, achieving over 90 % suppression of viral N, G, and M genes at 25 μM. Notably, TZOA effectively reduced viral titers compared to controls, demonstrating its potent antiviral activity in vitro. Mechanistically, TZOA preserved mitochondrial integrity, mitigated virus-induced mitochondrial fragmentation, and maintained membrane potential in infected cells. Furthermore, TZOA facilitated mitochondrial fusion and mitophagy, clearing damaged mitochondria, which restored MAVS-mediated interferon expression, thus enhancing the host's innate antiviral response. In vivo studies in juvenile rainbow trout revealed a significant 44 % increase in survival rates with TZOA treatment, accompanied by reduced IHNV-induced mortality and viral gene expression in spleen and kidney tissues. Importantly, TZOA also inhibited IHNV horizontal transmission, highlighting its potential application in controlling viral spread. These findings emphasize TZOA as a promising therapeutic candidate, not only for IHNV but also for broader rhabdovirus infections, offering valuable insights for antiviral drug development in aquaculture and beyond.
    Keywords:  Antiviral compounds; Aquaculture; Mitochondrial dynamics; Rhabdovirus
    DOI:  https://doi.org/10.1016/j.ejmech.2025.117439
  36. Phytomedicine. 2025 Feb 16. pii: S0944-7113(25)00144-8. [Epub ahead of print]139 156503
    Shenfuyixin Granules enhance mitochondrial autophagy after myocardial infarction by regulating protein deacetylation via the SIRT3/FOXO1 signaling axis.
    Lanxin Li, Shanshan Nie, Bin Wang, Qifei Zhao, Jingjing Wei, Wenjie Han, Ruipeng Wu, Yanze Liu, Jiale Yun, Yongxia Wang, Mingjun Zhu, Xinlu Wang.
       BACKGROUND: Heart failure (HF) represents the terminal stage of various cardiovascular diseases, with current treatment options remaining limited. Shenfuyixin Granules (SFYX) have been integrated into clinical practice, demonstrating significant therapeutic efficacy. However, the underlying mechanisms of action are still not fully understood.
    PURPOSE: This study aims to investigate whether SFYX promotes mitochondrial autophagy and enhances cardiac function in HF following myocardial infarction via the SIRT3/FOXO1 signaling axis.
    METHODS: The rat model of HF was established by ligation of the left anterior descending artery, while in vitro experiments were conducted using H9C2 cells. The blood-entry components of SFYX were identified using ultra-high-performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS). Network analysis, integrating proteomics and transcriptomics, was conducted to determine the active components of SFYX and elucidate the key regulatory mechanisms involved in its treatment of HF. After a 4-week intervention with SFYX, cardiac function was assessed via echocardiography. Myocardial infarct size was measured using triphenyl tetrazolium chloride (TTC) staining, while H&E and Masson staining were employed to evaluate myocardial tissue fibrosis and hypertrophy. Mitochondrial function was assessed using transmission electron microscopy and JC-1 dye. Cell apoptosis was detected via TUNEL assay. Additionally, molecular docking was performed to assess the binding affinity between key components of SFYX and autophagy-related proteins. Mechanistically, the expression levels of SIRT3, FOXO1, P62, and BNIP3 were determined using quantitative PCR and Western blotting.
    RESULTS: UPLC-MS/MS analysis revealed 21 blood-entry components in SFYX. Integrated analyses of network pharmacology, proteomics, and transcriptomics indicated that SFYX may ameliorate HF by stimulating mitochondrial autophagy through activation of the SIRT3/FOXO1 pathway. Compared with the model group, SFYX significantly attenuated myocardial hypertrophy, apoptosis, and fibrosis while enhancing autophagy, which may be partially attributed to the recovery of mitochondrial function. We propose that SFYX enhances mitochondrial function by reducing membrane potential and reactive oxygen species (ROS) production. Further results demonstrated that SFYX treatment upregulated SIRT3 and FOXO1 levels while inhibiting FOXO1 acetylation. Furthermore, the levels of mitophagy-associated proteins (ATG5, ATG7, BNIP3, and LC3B-II), which are downstream mediators of FOXO1, were enhanced by SFYX. Activation of SIRT3 or overexpression of FOXO1 enhanced the cardioprotective efficacy of SFYX, whereas inhibition of SIRT3 or silencing of FOXO1 partially reversed SFYX-induced favorable activities. Molecular docking analysis revealed that Glyceryl linolenate, a blood-entry component of SFYX, exhibited a strong binding affinity for SIRT3.
    CONCLUSION: This study demonstrates that SFYX exerts cardioprotective effects against HF through the deacetylation-regulated activation of SIRT3/FOXO1 signaling-mediated mitophagy and apoptosis. These findings indicate that SFYX represents a promising therapeutic candidate for the treatment of HF.
    Keywords:  Cardiomyocyte Apoptosis; Deacetylation; Heart Failure; Mitophagy; SIRT3/FOXO1
    DOI:  https://doi.org/10.1016/j.phymed.2025.156503
  37. Mol Biol Rep. 2025 Feb 28. 52(1): 270
    Pharmacological approaches to enhance mitochondrial biogenesis: focus on PGC-1Α, AMPK, and SIRT1 in cellular health.
    Ahmet Alperen Palabiyik, Esra Palabiyik.
       BACKGROUND: Mitochondrial biogenesis is essential for cellular energy balance and metabolic stability. Its dysregulation is linked to various metabolic and neurodegenerative diseases, making it a significant therapeutic target. Pharmacological approaches aimed at enhancing mitochondrial function have gained attention for their potential to restore cellular metabolism.
    OBJECTIVES: This review examines recent advancements in pharmacological strategies targeting mitochondrial biogenesis, focusing on the roles of PGC-1α, AMPK, and SIRT1, alongside novel therapeutic agents and drug delivery systems.
    METHODS: A systematic review of studies published between 2018 and 2023 was conducted using databases such as PubMed, Web of Science, and Elsevier. Keywords related to mitochondrial biogenesis and pharmacological modulation were used to identify relevant literature.
    RESULTS: Various pharmacological agents, including resveratrol, curcumin, and metformin, activate mitochondrial biogenesis through different pathways. SIRT1 activators and AMPK agonists have shown promise in improving mitochondrial function. Advances in mitochondria-targeted drug delivery systems enhance therapeutic efficacy, yet challenges remain in clinical translation due to the complexity of mitochondrial regulation.
    CONCLUSION: Pharmacological modulation of mitochondrial biogenesis holds therapeutic potential for metabolic and neurodegenerative diseases. While preclinical studies are promising, further research is needed to optimize drug efficacy, delivery methods, and personalized treatment strategies.
    Keywords:  AMPK; Mitochondrial biogenesis; Mitochondrial dysfunction; PGC-1α; SIRT1
    DOI:  https://doi.org/10.1007/s11033-025-10368-8
  38. Theranostics. 2025 ;15(6): 2624-2648
    Calnexin promotes glioblastoma progression by inducing protective mitophagy through the MEK/ERK/BNIP3 pathway.
    Xuchen Liu, Jiangli Zhao, Qingyuan Sun, Zhiwei Xue, Ziyi Tang, Wenyu Liu, Junzhi Liu, Baojian Miao, Nan Su, Yanya He, Yuehua Zhu, Bin Huang, Ning Yang, Chao Li, Jiwei Wang, Xinyu Wang.
      Rationale: Glioblastoma multiforme (GBM), one of the most malignant tumors of the central nervous system, has a poor prognosis, mainly because of its high recurrence caused by the rapid development of drug resistance to postoperative chemotherapy. Although macroautophagy/autophagy is believed to be a fundamental factor in tumor survival during chemotherapy, there is still a lack of autophagy biomarkers for predicting patient prognosis and chemotherapeutic efficacy in clinical practice. Methods: We combined transcriptomic and single-cell sequencing data to identify differentially expressed autophagy-related genes in gliomas. Overexpression of calnexin (CANX), a key gene related to protein folding, and its secretion in the endoplasmic reticulum (ER) was identified, suggesting poor prognosis in GBM patients. The autophagy flow related to CANX was detected by transmission electron microscopy (TEM), Western blotting, and immunofluorescence. Flow cytometry, cell proliferation, activity assays, and the GBM intracranial xenograft mouse model were employed to validate CANX's role in GBM progression. Results: CANX knockdown inhibited proliferation and autophagosome formation in GBM cells. On the other hand, CANX overexpression increased mitogen-activated protein kinase (MAPK) activity, leading to the accumulation of BNIP3 (CL2/adenovirus E1B 19 kDa interacting protein 3, a critical factor regulating mitophagy) and protective mitophagy. Notably, when combined with temozolomide (TMZ), CANX knockdown extended the lifespan of GBM-bearing mice. Additionally, our studies revealed that the classic calcium inhibitor nimodipine (ND) decreased CANX expression and thus enhanced the sensitivity to TMZ. Conclusions: Our findings indicate that CANX functions as an oncogene in GBM. We also characterize the CANX/MEK/ERK/BNIP3 mitophagy pathway, provide new insights into the molecular mechanism of GBM drug resistance, and identify a therapeutic target.
    Keywords:  calnexin; glioblastoma; mitophagy; nimodipine; temozolomide
    DOI:  https://doi.org/10.7150/thno.105591
  39. Food Funct. 2025 Feb 24.
    Dietary phytosterol supplementation mitigates renal fibrosis via activating mitophagy and modulating the gut microbiota.
    Fan Yang, Yingjie Gao, Siyi Xie, Wenjing Yang, Qiyan Wang, Wenqian Ye, Lu Sun, Jiangtao Zhou, XiuE Feng.
      Chronic kidney disease (CKD) poses a significant global health challenge, primarily driven by renal fibrosis, with limited treatment options. Addressing this condition necessitates either targeted medical treatments or dietary interventions. Phytosterols (PS) are cholesterol-like bioactive compounds in various plant-based foods with antioxidant and anti-inflammatory effects. A CKD mouse model was established using folic acid (FA) and treated with dietary supplements of two PS, stigmasterol (Stig) and β-sitosterol (β-Sito). The effects and mechanisms of PS were investigated through biochemical indices, pathology, transcriptomics, and 16S rDNA sequencing. The results indicated that high-dose PS are more effective than low-dose PS and Losartan potassium (LP) in reducing renal fibrosis, restoring function, and modulating oxidative stress and inflammation, with no significant differences between high-dose Stig and β-Sito treatments. Gene Ontology (GO) enrichment analysis revealed that PS were significantly enriched in pathways related to the mitochondrial outer membrane, ubiquitin-protein ligase binding, and other cellular components and molecular processes. PS reduced the expression of TGF-β/Smad and cGAS/Sting1/TBK1 and activated PINK1/Parkin pathway proteins, thereby mitigating renal fibrosis in mice. CKD is often associated with imbalanced gut microbiota and compromised intestinal barriers. Our observations indicated that PS restored the intestinal barrier, altered the composition of the gut microbiota, and improved renal function in CKD mice. The present findings indicate that both Stig and β-Sito activate mitophagy via the PINK1/Parkin pathway and modulate the gut microbiota, thereby alleviating renal fibrosis. The findings provide solid and significant implications for developing effective application of PS supplementation in the management of CKD, presenting novel concepts and approaches for research and clinical treatment.
    DOI:  https://doi.org/10.1039/d4fo06043a
  40. Free Radic Biol Med. 2025 Feb 20. pii: S0891-5849(25)00095-4. [Epub ahead of print]
    TIMP2-Mediated Mitochondrial Fragmentation and Glycolytic Reprogramming Drive Renal Fibrogenesis following Ischemia-Reperfusion Injury.
    Jingjing Pang, Dongxue Xu, Xiaoyu Zhang, Jiacheng Qu, Jun Jiang, Jinmeng Suo, Tianlong Li, Yiming Li, Zhiyong Peng.
      Acute kidney injury (AKI) triggers renal structural and functional abnormalities through inflammatory and fibrotic signaling pathways, ultimately progressing to chronic kidney disease (CKD). The mechanisms underlying AKI-to-CKD transition are complex, with hypoxia, mitochondrial dysfunction, and metabolic reprogramming as critical contributors. Public data analysis demonstrated significant upregulation of tissue inhibitors of metalloproteinases (Timp2) in renal biopsy tissues of CKD patients. In both ischemia/reperfusion (I/R) and unilateral ureteral obstruction (UUO) models, Timp2 upregulation was observed. Tubule-specific Timp2 knockout markedly attenuated renal fibrosis. RNA-sequencing revealed Timp2's association with mitochondrial dynamics and glycolysis in I/R mice. Timp2 deletion improved mitochondrial morphology and suppressed glycolytic enzyme expression. In vitro, TGF-β1-treated Timp2-knockdown HK-2 cells exhibited inhibited Drp1 expression, restored Mfn2 levels, alleviated mitochondrial fragmentation, and elevated mitochondrial membrane potential. Additionally, Pfkfb3 and HIF-1α were downregulated, accompanied by reduced extracellular acidification rate (ECAR), PFK activity, and lactate production. Mechanistically, Timp2 interacts with the extracellular domain of Sdc4 in an autocrine manner, activating the Hedgehog (Hh) signaling pathway. Cyclopamine partially rescued Timp2 overexpression-induced mitochondrial dysfunction, suppressed Pfkfb3-mediated glycolysis, and diminished collagen deposition. This study is the first to demonstrate that Timp2 in TECs exacerbates Hh signaling, promoting mitochondrial fragmentation and metabolic reprogramming to accelerate I/R-induced renal fibrosis.
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.02.020
  41. Cells. 2025 Feb 12. pii: 260. [Epub ahead of print]14(4):
    Eugenol Promotes Apoptosis in Leukemia Cells via Targeting the Mitochondrial Biogenesis PPRC1 Gene.
    Sayer Al-Harbi, Elham M A Alkholiwy, Syed Osman Ali Ahmed, Mahmoud Aljurf, Reem Al-Hejailan, Abdelilah Aboussekhra.
      Acute myeloid leukemia (AML) is a highly heterogenous and aggressive myeloid neoplasm. To sustain growth and survival, AML cells, like other neoplasms, require energy. This process is orchestrated by mitochondria and is under the control of several genes, such as PPRC1 (PRC), a member of the PGC-1 family, which is a key player in the transcription control of mitochondrial biogenesis. We have shown here that eugenol inhibits cell growth and promotes apoptosis through the mitochondrial pathway in AML cell lines as well as in cells from AML patients but not in cells from healthy donors. Similar effects were also observed on cytarabine-resistant AML cells. Interestingly, eugenol downregulated PPRC1 at both the protein and mRNA levels and reduced mitochondrial membrane potential in AML cells. We have also shown that PPRC1 expression is higher in cancer cells from blood, breast, and other types of cancer relative to normal cells, and high PPRC1 levels correlate significantly with short overall survival (OS). In addition, PPRC1 gene mutations significantly correlate with short OS and/or disease-free survival in several cancers. PPRC1 mutations also correlated significantly with poor OS (p < 0.0001) when tested in a total of 23,456 cancer patients. These findings suggest an oncogenic role of PPRC1 in various types of cancer and the possible eugenol-targeting of this gene for the treatment of AML patients, especially those exhibiting resistance to cytarabine.
    Keywords:  AML; PPRC1; apoptosis; cancer; eugenol
    DOI:  https://doi.org/10.3390/cells14040260
  42. Adv Sci (Weinh). 2025 Feb 22. e2410151
    3-D Sustained-Release Culture Carrier Alleviates Rat Intervertebral Disc Degeneration by Targeting STING in Transplanted Skeletal Stem Cells.
    Liwen Luo, Shiyu Zhang, Junfeng Gong, Ji Zhang, Peng Xie, Jun Yin, MengJie Zhang, Cong Zhang, Hong Chen, Yao Liu, Bing Ni, Changqing Li, Zhiqiang Tian.
      The hypoxic and high-pressure microenvironment of the intervertebral discs poses a major challenge to the survival and therapeutic efficiency of exogenous stem cells. Therefore, improving the utilization efficiency and therapeutic effect of exogenous stem cells to delay intervertebral disc degeneration (IVDD) is of great importance. Here, hypoxic induction studies are conducted in vivo and in vitro using rat costal cartilage-derived skeletal stem cells (SSCs) and find that hypoxia activates the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)/stimulator of interferon genes (STING) signaling pathway and increased reactive oxygen species (ROS) accumulation, triggering ferroptosis in SSCs through hypoxia-inducible factor-1 alpha-dependent mitophagy. Progressive hypoxia preconditioning reduce STING expression and ROS accumulation, inducing SSCs differentiation into nucleus pulposus-like cells via the Wnt signaling pathway. Considering this, a 3-D sustained-release culture carrier is generated by mixing SSCs with methacrylated hyaluronic acid and polydopamine nanoparticles coated with the STING inhibitor C-176 and evaluated its inhibitory effect on IVDD. This carrier is demonstrated to inhibit the cGAS/STING pathway and prevent ROS accumulation by continuously releasing C-176-coated polydopamine nanoparticles, thereby reducing ferroptosis, promoting differentiation, and ultimately attenuating IVDD, suggesting its potential as a novel treatment strategy.
    Keywords:  cGAS/STING; hypoxia; intervertebral disc degeneration; reactive oxygen species; skeletal stem cells
    DOI:  https://doi.org/10.1002/advs.202410151
  43. Biomedicines. 2025 Jan 27. pii: 311. [Epub ahead of print]13(2):
    An Integrated Approach Utilizing Single-Cell and Bulk RNA-Sequencing for the Identification of a Mitophagy-Associated Genes Signature: Implications for Prognostication and Therapeutic Stratification in Prostate Cancer.
    Yuke Zhang, Li Ding, Zhijin Zhang, Liliang Shen, Yadong Guo, Wentao Zhang, Yang Yu, Zhuoran Gu, Ji Liu, Aimaitiaji Kadier, Jiang Geng, Shiyu Mao, Xudong Yao.
      Introduction: Prostate cancer, notably prostate adenocarcinoma (PARD), has high incidence and mortality rates. Although typically resistant to immunotherapy, recent studies have found immune targets for prostate cancer. Stratifying patients by molecular subtypes may identify those who could benefit from immunotherapy. Methods: We used single-cell and bulk RNA sequencing data from GEO and TCGA databases. We characterized the tumor microenvironment at the single-cell level, analyzing cell interactions and identifying fibroblasts linked to mitophagy. Target genes were narrowed down at the bulk transcriptome level to construct a PARD prognosis prediction nomogram. Unsupervised consensus clustering classified PARD into subtypes, analyzing differences in clinical features, immune infiltration, and immunotherapy. Furthermore, the cellular functions of the genes of interest were verified in vitro. Results: We identified ten cell types and 160 mitophagy-related single-cell differentially expressed genes (MR-scDEGs). Strong interactions were observed between fibroblasts, endothelial cells, CD8+ T cells, and NK cells. Fibroblasts linked to mitophagy were divided into six subtypes. Intersection of DEGs from three bulk datasets with MR-scDEGs identified 26 key genes clustered into two subgroups. COX regression analysis identified seven prognostic key genes, enabling a prognostic nomogram model. High and low-risk groups showed significant differences in clinical features, immune infiltration, immunotherapy, and drug sensitivity. In prostate cancer cell lines, CAV1, PALLD, and ITGB8 are upregulated, while CLDN7 is downregulated. Knockdown of PALLD significantly inhibits the proliferation and colony-forming ability of PC3 and DU145 cells, suggesting the important roles of this gene in prostate cancer progression. Conclusions: This study analyzed mitophagy-related genes in PARD, predicting prognosis and aiding in subtype identification and immunotherapy response analysis. This approach offers new strategies for treating prostate cancer with specific molecular subtypes and helps develop potential biomarkers for personalized medicine strategies.
    Keywords:  biomarker; mitophagy-related genes; prognosis; prostate cancer; single-cell RNA sequencing
    DOI:  https://doi.org/10.3390/biomedicines13020311
  44. EPMA J. 2025 Mar;16(1): 1-15
    Mitochondria in cutaneous health, disease, ageing and rejuvenation-the 3PM-guided mitochondria-centric dermatology.
    Olga Golubnitschaja, Nafiseh Sargheini, Janine Bastert.
      Association of both intrinsic and extrinsic risk factors leading to accelerated skin ageing is reflected in excessive ROS production and ir/reversible mitochondrial injury and burnout, as abundantly demonstrated by accumulating research data. Due to the critical role of mitochondrial stress in the pathophysiology of skin ageing and disorders, maintained (primary care) and restored (secondary care) mitochondrial health, rejuvenation and homoeostasis are considered the most effective holistic approach to advance dermatological treatments based on systemic health-supportive and stimulating measures. Per evidence, an effective skin anti-ageing protection, wound healing and scarring quality - all strongly depend on the sustainable mitochondrial functionality and well-balanced homoeostasis. The latter can be objectively measured and, if necessary, restored in a systemic manner by pre- and rehabilitation algorithms tailored to individualised patient profiles. The entire spectrum of corresponding innovations in the area includes natural and systemic skin rejuvenation, aesthetic and reconstructive medicine, sustainable skin protection and targeted treatments of skin disorders. Contextually, mitochondria-centric dermatology is instrumental for advanced 3PM-guided approach which makes a good use of predictive multi-level diagnostics and targeted protection of skin against both - the health-to-disease transition and progression of relevant disorders. Cost-effective targeted protection and new treatment avenues focused on sustainable mitochondrial health and physiologic homoeostasis are proposed in the article including in-depth analysis of patient cases and exemplified 3PM-guided care with detailed mechanisms and corresponding expert recommendations presented.
    Keywords:  Aesthetic medicine; Ageing; CoQ10; Cost-efficacy; Dermatology; Disease; Health; Health policy; Homoeostasis; Individualised patient profile; Inflammation; Mito-dermatology; Mitochondria; Mitophagy; Onco-dermatology; Paradigm change; Predictive Preventive Personalised Medicine (PPPM / 3PM); Quercetin; Rejuvenation; Resveratrol; Scar quality; Skin; Tailored treatments; Targeted prevention; Vitiligo; Wound healing
    DOI:  https://doi.org/10.1007/s13167-025-00400-z
  45. Stem Cell Res Ther. 2025 Feb 23. 16(1): 87
    Transplantation of gastric epithelial mitochondria into human gastric cancer cells inhibits tumor growth and enhances chemosensitivity by reducing cancer stemness and modulating gastric cancer metabolism.
    Hsin-Yi Tsai, Kuen-Jang Tsai, Deng-Chyang Wu, Yaw-Bin Huang, Ming-Wei Lin.
       BACKGROUND: Gastric cancer is the malignant disease. The problems associated with cancer stemness and chemotherapy resistance in gastric cancer therapy remain unresolved. Glucose-regulated protein 78 (GRP78) is a biomarker of gastric cancer and modulates cancer stemness and chemoresistance. Previous studies have shown that mitochondrial transplantation from healthy cells is a promising method for treating various diseases and that the regulation of mitochondrial metabolism is crucial for modulating the stemness and chemoresistance of cancer cells. The aim of this study was to investigate the therapeutic effect of mitochondrial transplantation from normal gastric epithelial cells into gastric cancer and the associated mechanisms.
    METHODS: The expression of cancer stemness markers, intracellular oxidative stress, or apoptotic-related proteins were evaluated via flow cytometry. Western blotting was used to investigate the molecular mechanism involved in MKN45 or AGS human gastric cancer cells after transplantation with human gastric epithelial mitochondria. The mitochondrial metabolic function of gastric cancer cells was determined via a Seahorse bioanalyzer, and extracellular lactate was evaluated via bioluminescent assay. The viability of 5-fluorouracil (5-FU)-treated gastric cancer cells was detected via a CCK-8 assay. Furthermore, a xenograft tumor animal study was performed to validate the therapeutic effects of human gastric epithelial mitochondrial transplantation in gastric cancer. Immunohistochemistry and Western blotting were then used to assess the expressions related to cancer stemness and mitochondrial metabolism-related proteins in tumor tissues.
    RESULTS: Transplanting human gastric epithelial mitochondria downregulates gastric cancer mitochondrial biogenesis, glycolysis, GRP78-mediated cancer stemness, and increases oxidative stress, cell apoptosis under hypoxic conditions and chemosensitivity in response to 5-FU treatment. Moreover, the transplantation of epithelial mitochondria into gastric tumors inhibited the tumor growth in vivo tumor graft animal models. Therefore, mitochondrial transplantation can be considered for the treatment of gastric cancer.
    Keywords:  Apoptosis; Cancer stemness; Chemoresistance; GRP78; Gastric cancer; Metabolism; Mitochondrial transplantation
    DOI:  https://doi.org/10.1186/s13287-025-04223-7
  46. J Orthop Translat. 2025 Mar;51 68-81
    Fibroblast growth factor receptor 3 mutation promotes HSPB6-mediated cuproptosis in hypochondroplasia by impairing chondrocyte autophagy.
    Jing Chen, Dan He, Chengrun Yuan, Na Li, Baohong Shi, Conway Niu, Jiangfei Yang, Liangkai Zheng, Lin Che, Ren Xu.
       Background: Hypochondroplasia (HCH) is a prevalent form of dwarfism linked to mutations in the fibroblast growth factor receptor 3 (FGFR3) gene, causing missense alterations. We previous report was the first to identify FGFR3(G382D) gain-of-function variants with a positive family history as a novel cause of HCH. However, the precise contribution of FGFR3 to the pathogenesis of HCH remains elusive.
    Methods: We generated an Fgfr3 (V376D) mutation mouse model using CRISPR/Cas9 technology and performed proteomic analyses to investigate the molecular mechanisms and potential therapeutic targets of HCH. Radiography and micro-computed tomography were employed to assess the bone-specific phenotype in Fgfr3 (V376D)mutant mice. Immunofluorescence, western blotting, and flow cytometry were used to systematically investigate the underlying mechanisms and therapeutic targets.
    Results: We observed that Fgfr3 (V376D) mutant mice exhibit a bone-specific phenotype, with symmetrically short limb bones, partially resembling the dwarfism phenotype of patients with HCH. We demonstrated that the mutant-activated FGFR3 promotes heat shock protein B 6 (HSPB6)-mediated cuproptosis by inhibiting chondrocyte autophagy both in vivo and in vitro. Additionally, we revealed that FGFR3 (G382D) mutation leads to enhanced ERK signaling, increased Drp1-mediated mitochondrial fission, and upregulated cuproptosis-related protein ferredoxin 1 (FDX1). Furthermore, genetic and pharmacological inhibition of the HSPB6-ERK-Drp1-FDX1 pathway partially alleviate the phenotypes of FGFR3 mutants.
    Conclusions: Our study provides the first evidence for the pathogenicity of a gain-of-function mutation in FGFR3 (G382D) using mouse and cell models, and it underscores the potential of targeting the HSPB6-ERK-Drp1-FDX1 axis as a novel therapeutic approach for HCH.
    Translational potential of this article: We first demonstrate that impaired autophagy and enhanced cuproptosis are pivotal in the pathogenesis of HCH. This study not only enlarged the therapeutic potential of targeting cuproptosis for treating FGFR3 mutation-related HCH but also provided a novel perspective on the role of the HSPB6-ERK-Drp1-FDX1 signaling pathway in the development of HCH. Consequently, this article provides valuable insights into the mechanisms and treatment strategies for FGFR3 mutation-related chondrodysplasia.
    Keywords:  Autophagy; Cuproptosis; Fibroblast growth factor receptor 3; Heat shock protein B 6; Hypochondroplasia; mitochondrial fission
    DOI:  https://doi.org/10.1016/j.jot.2025.01.011
  47. Life (Basel). 2025 Feb 13. pii: 294. [Epub ahead of print]15(2):
    Resveratrol-Enhanced Human Neural Stem Cell-Derived Exosomes Mitigate MPP+-Induced Neurotoxicity Through Activation of AMPK and Nrf2 Pathways and Inhibition of the NLRP3 Inflammasome in SH-SY5Y Cells.
    Ming-Chang Chiang, Yu-Ping Yang, Christopher J B Nicol, Tairui Chiang, Chiahui Yen.
      Parkinson's disease (PD) is a progressive neurodegenerative disorder primarily characterized by the loss of dopaminergic neurons in the substantia nigra. Mitochondrial dysfunction, oxidative stress, and neuroinflammation are recognized as critical pathological mechanisms driving neurodegeneration in PD. Exosome (Exo)-based therapies, particularly those derived from human neural stem cells (hNSCs), offer promising neuroprotective effects due to their ability to transfer bioactive molecules that modulate cellular processes. Resveratrol (RES), a polyphenolic compound with potent antioxidant and anti-inflammatory properties, has been shown to enhance the therapeutic potential of stem cell (SC)-derived Exos. This study investigated the neuroprotective effects of RES-treated hNSCs-derived Exos (RES-hNSCs-Exos) on SH-SY5Y cells exposed to 1-methyl-4-phenylpyridinium (MPP+), a neurotoxin commonly used to model Parkinsonian neurotoxicity. Treating SH-SY5Y cells with MPP+ led to significant reductions in cell viability, mitochondrial dysfunction, increased oxidative stress, and the activation of inflammatory pathways. Treatment with RES-hNSCs-Exos rescued SH-SY5Y cells from MPP+-induced toxicity by improving cell viability, enhancing ATP production, increasing mitochondrial biogenesis, and reducing reactive oxygen species (ROS) generation. The findings also demonstrated the increased expression of essential genes involved in mitochondrial biogenesis, such as PGC1α, NRF1, and Tfam, indicating improved mitochondrial function in the presence of RES-hNSCs-Exos. Further analysis revealed that these protective effects were mediated by activating the AMP-activated protein kinase (AMPK) and Nrf2 signaling pathways, which promoted mitochondrial health and reduced oxidative stress. Moreover, RES-hNSCs-Exos treatment suppressed neuroinflammation by downregulating NLRP3 inflammasome activation and reducing the secretion of pro-inflammatory cytokines IL-1β and IL-18. In conclusion, the results suggest that RES-hNSCs-Exos exhibit potent neuroprotective effects against MPP+-induced neurotoxicity by enhancing mitochondrial function, reducing oxidative stress, and inhibiting neuroinflammation. These findings highlight the potential of hNSCs-Exos as a novel therapeutic strategy for neurodegenerative diseases like PD, with RES as a valuable enhancer of Exos efficacy.
    Keywords:  AMPK; MPP+; exosomes; neuroprotection; resveratrol
    DOI:  https://doi.org/10.3390/life15020294
  48. Cell Metab. 2025 Feb 20. pii: S1550-4131(25)00017-8. [Epub ahead of print]
    MARIGOLD and MitoCIAO, two searchable compendia to visualize and functionalize protein complexes during mitochondrial remodeling.
    Giovanni Rigoni, Enrique Calvo, Christina Glytsou, Marta Carro-Alvarellos, Masafumi Noguchi, Martina Semenzato, Charlotte Quirin, Federico Caicci, Natascia Meneghetti, Mattia Sturlese, Takaya Ishihara, Stefano Moro, Chiara Rampazzo, Naotada Ishihara, Fabrizio Bezzo, Leonardo Salviati, Jesùs Vazquez, Gabriele Sales, Chiara Romualdi, Jose Antonio Enriquez, Luca Scorrano, Maria Eugenia Soriano.
      Mitochondrial proteins assemble dynamically in high molecular weight complexes essential for their functions. We generated and validated two searchable compendia of these mitochondrial complexes. Following identification by mass spectrometry of proteins in complexes separated using blue-native gel electrophoresis from unperturbed, cristae-remodeled, and outer membrane-permeabilized mitochondria, we created MARIGOLD, a mitochondrial apoptotic remodeling complexome database of 627 proteins. MARIGOLD elucidates how dynamically proteins distribute in complexes upon mitochondrial membrane remodeling. From MARIGOLD, we developed MitoCIAO, a mitochondrial complexes interactome tool that, by statistical correlation, calculates the likelihood of protein cooccurrence in complexes. MitoCIAO correctly predicted biologically validated interactions among components of the mitochondrial cristae organization system (MICOS) and optic atrophy 1 (OPA1) complexes. We used MitoCIAO to functionalize two ATPase family AAA domain-containing 3A (ATAD3A) complexes: one with OPA1 that regulates mitochondrial ultrastructure and the second containing ribosomal proteins that is essential for mitoribosome stability. These compendia reveal the dynamic nature of mitochondrial complexes and enable their functionalization.
    Keywords:  ATAD3A; OPA1; cristae remodeling; interactome; mitochondria; mitochondrial complexes; mitoribosome stability
    DOI:  https://doi.org/10.1016/j.cmet.2025.01.017
  49. Am J Pathol. 2025 Feb 24. pii: S0002-9440(25)00069-0. [Epub ahead of print]
    The involvement of mitochondrial dysfunction during the development of adenomyosis.
    Nari Kay, Chun-Yen Huang, Ya-Chun Yu, Chih-Chen Chen, Chi-Chang Chang, S Joseph Huang.
      The etiology of adenomyosis remains unclear. The association between epithelial-mesenchymal transition (EMT) and mitochondrial dysfunction has been proposed to be involved in fibrotic diseases. Adenomyosis is defined as the existence of endometrial glands and stroma in the myometrium with EMT and ultimate fibrosis. Thus, we aimed to investigate the involvement of mitochondrial dysfunction in fibrotic adenomyosis. Mitochondrial integrity was examined in mouse and human adenomyotic tissues. Control and tamoxifen-treated mice were treated with 3-nitropropionic acid (3-NPA, a mitochondrial dysfunction inducer) and NG-nitro-L-arginine methyl ester (L-NAME, a mitochondrial dysfunction inhibitor), respectively, at postnatal day (PND) 21 followed by an evaluation of adenomyosis, EMT and fibrosis as well as the expression of mitophagy, oxidative stress, transforming growth factor beta-1 (TGF-β1). The gene profiles of adenomyotic uteri were examined at PND42. Adenomyotic mice exhibited increased development of EMT and fibrosis. Adenomyotic tissues showed consistent mitochondrial destruction with increased fission, mitophagosomes, and lysosomes. Besides, mitophagy, oxidative stress, and TGF-β1 levels were consistently increased. The mitochondrial dysfunction, the development of mitophagy and fibrosis, and TGF-β1 expression were induced by 3-NPA in control uteri. In contrast, L-NAME attenuated mitochondrial dysfunction, mitophagy, fibrosis, and TGF-β1 in adenomyotic uteri. Gene profiling demonstrated increased expression of mitochondrial dysfunction-related genes in adenomyotic uteri. We showed that mitochondrial dysfunction-induced TGF-β1 dysregulation and fibrosis were associated with the development of adenomyosis.
    Keywords:  Adenomyosis; Fibrosis; Mitochondrial destruction; Mitochondrial dysfunction; Oxidative stress
    DOI:  https://doi.org/10.1016/j.ajpath.2025.01.014
  50. J Cell Mol Med. 2025 Feb;29(4): e70422
    The Noncanonical Wnt5a-Ca2+ Pathway Mediates Mitochondrial Dysfunction in the Progression of Diabetic Nephropathy via the Mitochondrial Calcium Uniporter.
    Yang Fei, Qunzi Zhang, Junjie Jia, Li He, Sijie Gu, Dongsheng Cheng, Wenjun Lin, Haifan Xing, Niansong Wang, Ying Fan.
      Abnormal Wnt5a expression, mitochondrial abnormalities and calcium overload have been detected in many metabolic diseases. However, the association of Wnt5a-Ca2+ and mitochondrial dysfunction in diabetic nephropathy (DN) progression remains unknown. We used streptozotocin-induced DBA2/J male mice as a DN model. The mice were treated with losartan (10 mg/kg/d*12 w) or losartan (10 mg/kg/d*12 w) + levamlodipine (5 mg/kg/d*12 w). High glucose (HG) (40 mmol/L)-induced HK-2 cells were used for in vitro experiments. Wnt5a and mitochondrial calcium uniporter (MCU) expression, mitochondrial dynamics, morphological changes and Ca2+ concentration were detected in different groups. Levamlodipine, a kind of calcium channel blocker, in combination with losartan ameliorated tubular injury and reversed mitochondrial fragmentation and dynamic dysfunction more efficiently than losartan alone in diabetic mice. Wnt5a induced Ca2+ uptake and aggravated mitochondrial fusion-fission disorder in HG-stimulated HK-2 cells. In addition, increased MCU formation was found in the mitochondria of tubular cells under HG stimulation and was upregulated by the activation of the Wnt5a-Ca2+ pathway. Our study showed that the Wnt5a-Ca2+ signalling pathway was involved in Ca2+ overload-induced mitochondrial dysfunction possibly through MCU in tubular injury and DN progression. A calcium channel blocker in combination with a renin-angiotensin system inhibitor (RASi) could be a promising therapeutic strategy in DN patients.
    Keywords:  MCU; Wnt5a; calcium; diabetic nephropathy; levamlodipine; tubular injury
    DOI:  https://doi.org/10.1111/jcmm.70422
  51. Antioxidants (Basel). 2025 Jan 22. pii: 125. [Epub ahead of print]14(2):
    Lysosome-Mitochondrial Crosstalk in Cellular Stress and Disease.
    Szilvia Kiraly, Jack Stanley, Emily R Eden.
      The perception of lysosomes and mitochondria as entirely separate and independent entities that degrade material and produce ATP, respectively, has been challenged in recent years as not only more complex roles for both organelles, but also an unanticipated level of interdependence are being uncovered. Coupled lysosome and mitochondrial function and dysfunction involve complex crosstalk between the two organelles which goes beyond mitochondrial quality control and lysosome-mediated clearance of damaged mitochondria through mitophagy. Our understanding of crosstalk between these two essential metabolic organelles has been transformed by major advances in the field of membrane contact sites biology. We now know that membrane contact sites between lysosomes and mitochondria play central roles in inter-organelle communication. This importance of mitochondria-lysosome contacts (MLCs) in cellular homeostasis, evinced by the growing number of diseases that have been associated with their dysregulation, is starting to be appreciated. How MLCs are regulated and how their coordination with other pathways of lysosome-mitochondria crosstalk is achieved are the subjects of ongoing scrutiny, but this review explores the current understanding of the complex crosstalk governing the function of the two organelles and its impact on cellular stress and disease.
    Keywords:  crosstalk; lysosomes; membrane contact sites; mitochondria
    DOI:  https://doi.org/10.3390/antiox14020125
  52. Ecotoxicol Environ Saf. 2025 Feb 21. pii: S0147-6513(25)00274-X. [Epub ahead of print]292 117938
    Taurine ameliorates deoxynivalenol-induced intestinal injury in piglets: Restoration of mitochondrial function linked to the PGC1α-NRF1/2 axis.
    Xu Ji, Hongyan Ding, Fen Zhou, Feng Zhang, Dong Wu.
      Deoxynivalenol (DON) is a prevalent foodborne contaminant present in crops, posing significant risks to food safety and public health worldwide. Mitochondria, as the primary target of DON, play a crucial role in DON-mediated gastrointestinal toxicity. Taurine, a multifunctional nutrient, has been reported to exert antioxidant and anti-inflammatory effects by modulating mitochondrial function. However, whether taurine could alleviate intestinal injury by restoring mitochondrial function under DON exposure remains unclear. To address this knowledge gap, this study systematically investigated the potential protective effects of taurine on DON-induced intestinal damage in a piglet model. Twenty-four piglets were randomly assigned to four groups for 24 days: BD group (basal diet), DON group (3 mg/kg DON-contaminated diet), DON+LT group (DON diet with 0.3 % taurine), and DON+HT group (DON diet with 0.6 % taurine). Serum samples were collected for biochemical analysis, while jejunal tissues were examined for histology, barrier function, oxidative stress, inflammation, apoptosis, mitochondrial function, as well as related gene and protein expression. The results revealed that taurine effectively restored jejunal morphology disrupted by DON, as evidenced by increases in villus height/width and the villus height to crypt depth ratio. It preserved intestinal barrier integrity, reflected by reductions in diamine oxidase and D-lactate levels, alongside increased expression of genes and proteins related to intestinal mucus and mechanical barrier function. Furthermore, taurine mitigated intestinal oxidative stress by reducing reactive oxygen species, 8-hydroxydeoxyguanosine, and malondialdehyde levels, while enhancing antioxidant defenses. It also alleviated inflammation by suppressing pro-inflammatory cytokines and attenuated intestinal epithelial apoptosis through mitochondrial caspase-dependent and apoptosis-inducing factor-mediated pathways. Intriguingly, taurine improved the damaged mitochondrial structure and functionality within the intestinal epithelium irritated by DON. This improvement included enhanced respiratory chain complex activity, increased ATP levels, and mtDNA copy number. Additionally, taurine regulated gene expression related to mitochondrial respiration, fusion, fission, and autophagy. Simultaneously, taurine reversed the DON-induced inhibition of the peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1α)-nuclear respiratory factor 1/2 (NRF1/2) axis, a critical pathway regulating mitochondrial biogenesis, respiratory function, and oxidative stress responses. Correlation analysis revealed significant associations between the PGC1α-NRF1/2 axis and mitochondrial function, as well as correlations with intestinal health parameters, including barrier function, redox status, inflammation, and apoptosis. In summary, this study provides the first evidence that dietary taurine supplementation effectively alleviates intestinal injury in DON-challenged piglets through mitochondrial restoration, which is strongly associated with the reactivation of the PGC1α-NRF1/2 axis. Our findings highlight the potential of mitochondrial-targeted therapies to mitigate gastrointestinal toxicity caused by the foodborne contaminant DON in both humans and animals.
    Keywords:  Deoxynivalenol; Intestinal injury; Mitochondria function; PGC1α-NRF1/2 axis; Piglet model; Taurine
    DOI:  https://doi.org/10.1016/j.ecoenv.2025.117938
  53. J Biochem Mol Toxicol. 2025 Mar;39(3): e70194
    Mitochondrial Quality Control and Melatonin: A Strategy Against Myocardial Injury.
    Nima Ghavamikia, Faranak Mehrnoosh, Farshad Zare, Payam Ali-Khiavi, Ali Sinehsepehr, Yasaman Ghodsi Boushehri, Milad Vahedinezhad, Elham Abdollahi, Ahmed Hjazi, Siamak Aminnezhad, Hossein Saffarfar, Sina Hamzehzadeh, Mehrdad Nourizadeh, Sepideh KarkonShayan.
      Melatonin exhibits various biological functions, including regulation of circadian and endocrine rhythms, anti-inflammatory, and antioxidant effects. Aging and damaged mitochondria are major sources of oxidative stress (OS), and mitochondrial quality control (MQC) is crucial for maintaining normal mitochondrial function. Myocardial ischemia-reperfusion injury is a major complication that can arise during reperfusion therapy for coronary heart disease. However, effective intervention strategies are currently lacking. Mitochondrial dysfunction and OS are considered central mechanisms of myocardial reperfusion injury, with mitochondrial-targeted interventions being a potential treatment direction. Recent studies have shown that melatonin improves mitochondrial structure and function through multiple pathways. This review discusses the mechanisms by which melatonin ameliorates myocardial ischemia-reperfusion injury, focusing on MQC, and explores its potential applications in the prevention and treatment of myocardial ischemia-reperfusion injury.
    Keywords:  melatonin; melatonin receptors; mitochondrial quality control; myocardial ischemia‐reperfusion injury
    DOI:  https://doi.org/10.1002/jbt.70194
  54. Int J Mol Sci. 2025 Feb 19. pii: 1771. [Epub ahead of print]26(4):
    Bioactivity and Neuroprotective Effects of Extra Virgin Olive Oil in a Mouse Model of Cerebral Ischemia: An In Vitro and In Vivo Study.
    Salvatore Scacco, Silvia Acquaviva, Fábio França Vieira E Silva, John H Zhang, Lorenzo Lo Muzio, Gaetano Corso, Vito Carlo Alberto Caponio, Pierluigi Reveglia, Lucia Lecce, Maria Eleonora Bizzoca, Prativa Sherchan, Stefania Cantore, Andrea Ballini.
      Cerebral ischemia is a pathological condition characterized by complete blood and oxygen supply deprivation to neuronal tissue. The ischemic brain compensates for the rapid decline in ATP levels by increasing the anaerobic glycolysis rate, which leads to lactate accumulation and subsequent acidosis. Astrocytes play a critical role in regulating cerebral energy metabolism. Mitochondria are significant targets in hypoxia-ischemia injury, and disruptions in mitochondrial homeostasis and cellular energetics worsen outcomes, especially in the elderly. Elevated levels of n-3 polyunsaturated fatty acids (PUFAs) protect the adult and neonatal brain from ischemic damage by suppressing inflammation, countering oxidative stress, supporting neurovascular unit reconstruction, and promoting oligodendrogenesis. This study examines extra virgin olive oil (EVOO) treatment on TNC WT and TNC M23 cells, focusing on oxygen consumption and reactive oxygen species (ROS) production. This study investigates the effects of different durations of middle cerebral artery occlusion (MCAo) and EVOO administration on cerebral infarct volume, neurological scores, mitochondrial function, and cell viability. Cerebral infarct volume increased with longer ischemia times, while EVOO treatment (0.5 mg/kg/day) significantly reduced infarction across all MCAo durations. The oxygen consumption assays demonstrate EVOO's dose-dependent stimulation of mitochondrial respiration in astrocytes, particularly at lower concentrations. Furthermore, EVOO-treated cells reduce ROS production during hypoxia, improve cell viability under ischemic stress, and enhance ATP production in ischemic conditions, underscoring EVOO's neuroprotective potential.
    Keywords:  cerebral ischemia; mitochondria homeostasis; polyunsaturated fatty acids
    DOI:  https://doi.org/10.3390/ijms26041771
  55. Toxins (Basel). 2025 Feb 06. pii: 72. [Epub ahead of print]17(2):
    Pore-Forming Protein LIN-24 Enhances Starvation Resilience in Caenorhabditis elegans by Modulating Lipid Metabolism and Mitochondrial Dynamics.
    Xinqiang Lan, Mengqi Yang, Jiali Wang, Chunping Huang, Andong Wu, Leilei Cui, Yingqi Guo, Lin Zeng, Xiaolong Guo, Yun Zhang, Yang Xiang, Qiquan Wang.
      The ability to survive starvation is a critical evolutionary adaptation, yet the molecular mechanisms underlying this capability remain incompletely understood. Pore-forming proteins (PFPs) are typically associated with immune defense, where they disturb the membranes of target cells. However, the role of PFPs in non-immune functions, particularly in metabolic and structural adaptations to starvation, is less explored. Here, we investigate the aerolysin-like PFP LIN-24 in Caenorhabditis elegans and uncover its novel function in enhancing starvation resistance. We found that LIN-24 expression is upregulated during starvation, leading to increased expression of the lipase-encoding gene lipl-3. This upregulation accelerates the mobilization and degradation of lipid stores, thereby sustaining energy levels. Additionally, LIN-24 overexpression significantly preserves muscle integrity, as evidenced by the maintenance of muscle structure compared to wild-type worms. Furthermore, we demonstrate that LIN-24 induces the formation of donut-shaped mitochondria, a structural change likely aimed at reducing ATP production to conserve energy during prolonged nutrient deprivation. This mitochondrial remodeling depends on genes involved in mitochondrial dynamics, including mff-1, mff-2, drp-1, and clk-1. Collectively, these findings expand our understanding of PFPs, demonstrating their multifaceted role in stress resistance beyond immune defense. LIN-24's involvement in regulating metabolism, preserving muscle structure, and remodeling mitochondria highlights its crucial role in the adaptive response to starvation, offering novel insights into the evolution of stress resistance mechanisms and potential therapeutic targets for conditions related to muscle preservation and metabolic regulation.
    Keywords:  LIN-24; donut-shaped mitochondria; fatty acid degradation; pore-forming protein; skeletal muscle; starvation
    DOI:  https://doi.org/10.3390/toxins17020072
  56. Nutrients. 2025 Feb 13. pii: 668. [Epub ahead of print]17(4):
    Effects of 3-(4-Hydroxy-3-methoxyphenyl)propionic Acid on Regulating Oxidative Stress and Muscle Fiber Composition.
    Yishan Tong, Sihui Ma, Riyo Awa, Takashi Tagawa, Yasuhiro Seki, Tiehan Cao, Haruki Kobori, Katsuhiko Suzuki.
      Background/Objectives: Our previous study demonstrated that 3-(4-hydroxy-3-methoxyphenyl)propionic acid (HMPA) administration improved grip strength and reduced blood urea nitrogen levels, but its underlying mechanisms remain unclear. This study aimed to investigate the effects of HMPA on oxidative stress and muscle fiber composition, emphasizing its potential role in modulating redox signaling pathways and influencing muscle development. Methods: Eight-week-old male C57BL/6 mice were orally administered HMPA solution (50 or 500 mg/kg/day) or distilled water (10 mL/kg) for 14 days, and then divided into sedentary and exhaustive exercise groups to evaluate oxidative stress status, myosin heavy chain (MHC) isoform expression, and underlying mechanisms. Results: Both low and high doses of HMPA reduced oxidative stress by decreasing plasma reactive oxygen metabolites. High-dose HMPA reduced plasma nitrite/nitrate levels and enhanced antioxidant capacity post-exercise, accompanied by changes in the mRNA abundance of antioxidant enzymes (e.g., Sod1 and Nqo1) and reductions in the mRNA abundance of nitric oxide synthases (e.g., Nos2 and Nos3) in the soleus. Additionally, high-dose HMPA administration increased the protein expression of MYH4 in the soleus, while low-dose HMPA enhanced the gene expression of Myh4 and Igf1, suggesting that HMPA may promote fast-twitch fiber hypertrophy through the activation of the IGF-1 pathway. Furthermore, low-dose HMPA significantly increased the gene expression of Sirt1 and Nrf1, as well as AMPK phosphorylation post-exercise, suggesting low-dose HMPA may improve mitochondrial biogenesis and exercise adaptation. Conclusions: These findings suggest that HMPA may serve as a dietary supplement to regulate redox balance, enhance antioxidant defenses, and promote the formation of fast-twitch fibers.
    Keywords:  3-(4-hydroxy-3-methoxyphenyl)propionic acid; dihydroferulic acid; gut microbiota-derived metabolite; muscle fiber composition; oxidative stress
    DOI:  https://doi.org/10.3390/nu17040668
  57. Front Aging Neurosci. 2025 ;17 1536142
    Deciphering novel mitochondrial signatures: multi-omics analysis uncovers cross-disease markers and oligodendrocyte pathways in Alzheimer's disease and glioblastoma.
    Xuan Xu, Jiaqi Wang, Tong Chen, Shuaibin Wang, Fei Wang, Junwen He, Xiang-Yu Meng, Yin Shen.
       Introduction: Alzheimer's disease (AD) and glioblastoma (GBM) are severe neurological disorders that pose significant global healthcare challenges. Despite extensive research, the molecular mechanisms, particularly those involving mitochondrial dysfunction, remain poorly understood. A major limitation in current studies is the lack of cell-specific markers that effectively represent mitochondrial dynamics in AD and GBM.
    Methods: In this study, we analyzed single-cell transcriptomic data using 10 machine learning algorithms to identify mitochondria-associated cell-specific markers. We validated these markers through the integration of gene expression and methylation data across diverse cell types. Our dataset comprised single-nucleus RNA sequencing (snRNA-seq) from AD patients, single-cell RNA sequencing (scRNA-seq) from GBM patients, and additional DNA methylation and transcriptomic data from the ROSMAP, ADNI, TCGA, and CGGA cohorts.
    Results: Our analysis identified four significant cross-disease mitochondrial markers: EFHD1, SASH1, FAM110B, and SLC25A18. These markers showed both shared and unique expression profiles in AD and GBM, suggesting a common mitochondrial mechanism contributing to both diseases. Additionally, oligodendrocytes and their interactions with astrocytes were implicated in disease progression, particularly through the APP signaling pathway. Key hub genes, such as HS6ST3 and TUBB2B, were identified across different cellular subpopulations, highlighting a cell-specific co-expression network linked to mitochondrial function.
    Keywords:  Alzheimer’s disease; biomarker; glioblastoma; mitochondria; multi-omics
    DOI:  https://doi.org/10.3389/fnagi.2025.1536142
  58. NPJ Metab Health Dis. 2025 ;3(1): 5
    Reversal of metformin's anti-proliferative effect in fission yeast efr3 and dnm1 (DRP1) mutants with elongated mitochondria.
    Ari Gillespie, Anne-Sophie Mehdorn, Tiffany Q Lim, Tingting Wang, Bridget A Mooney, Ashley J Ovens, Ayla Orang, Jonathan S Oakhill, Michael Z Michael, Janni Petersen.
      Metformin is a well-tolerated drug frequently prescribed for managing type 2 diabetes. Extended metformin use has been linked to a significant decrease in cancer incidence across both diabetic and non-diabetic populations. Here we investigate the anti-proliferative effects of metformin on fission yeast S. pombe. Our findings demonstrate that metformin's inhibitory impact on cell proliferation is effective in the absence of AMP-activated protein kinase (AMPK). Using an unbiased genetic screen we identified the plasma membrane signalling scaffold Efr3, critical for phosphatidylinositol signalling and the generation of PI4Ps, as a key determinant of resistance to the anti-proliferative effect of metformin. Deletion of efr3 resulted in both AMPK-dependent and AMPK-independent resistance to metformin. We show that Efr3 does not influence cell proliferation by controlling Ras1 activity or its cellular localization in yeast. We observe that dnm1 (DRP1) mutants with elongated mitochondria are also resistant to the anti-proliferative effect of metformin and that metformin treatment promotes mitochondrial fusion. Metabolic measurements after prolonged metformin exposure demonstrated a reduction in respiration in both wild type and the efr3 deletion, however, that reduction is less pronounced in the efr3 deletion, which also contained elongated mitochondria. It is likely that mitochondrial fusion enhances yeast fitness in response to metformin exposure. Together we provide a new perspective on the cellular response to metformin.
    Keywords:  Cancer; Cell biology
    DOI:  https://doi.org/10.1038/s44324-024-00048-9
  59. Bioengineering (Basel). 2025 Feb 17. pii: 197. [Epub ahead of print]12(2):
    Utilizing Integrated Bioinformatics Analysis to Explore Potential Alterations in Mitochondrial Function Within Immune Cells Associated with Thoracic Aortic Aneurysms.
    Chang Guan, Si-Xu Chen, Chun-Ling Huang, Yi-Peng Du, Kai-Hao Wang, Pei-Xin Li, Shen-Rong Liu, Zhao-Yu Liu, Zheng Huang.
      Thoracic aortic aneurysm (TAA) is a life-threatening peripheral vascular disease with a complex pathogenesis. Altered mitochondrial function in vascular smooth muscle cells has been implicated in TAA development. However, the link between mitochondrial functional status and immune cell behavior in TAA patients remains largely unexplored. In this study, we analyzed several bulk RNA-seq and snRNA-seq datasets of TAA from the NCBI-GEO and Genome Sequence Archive database, identifying differentially expressed mitochondrial-related genes (DE-MRGs). To assess mitochondrial function, we calculated a mitoscore to represent the overall expression level of MRGs. Our analysis revealed mitochondrial-mediated apoptosis occurring in M1 macrophages, while CD4 + T cells demonstrated the activation of quality control mechanisms, such as mitochondrial fission. Through LASSO regression and SVM-RFE, we identified key MRGs, including MUCB, ARRB2, FRG, and ALPL, which we further validated using TAA mouse models. Additionally, we found that DE-MRGs were closely linked to methionine metabolism. In conclusion, this study highlights mitochondrial dysfunction in immune cells associated with TAA, shedding light on potential mitochondrial roles in TAA pathogenesis.
    Keywords:  immune cells; machine learning; mitochondrial dysfunction; thoracic aortic aneurysm (TAA)
    DOI:  https://doi.org/10.3390/bioengineering12020197
  60. J Adv Res. 2025 Feb 25. pii: S2090-1232(25)00130-4. [Epub ahead of print]
    MTHFR variant links homocysteine metabolism and endothelial cell dysfunction by targeting mitophagy in human thoracic aortic dissection patient induced pluripotent stem cell (iPSC) models.
    You Yu, Lianbo Shao, Meng Zhang, Xingyou Guo, Yihuan Chen, Han Shen, Xiaomei Teng, Jingze Zhu, Miao Yu, Shijun Hu, Zhenya Shen.
       AIMS: Genetics and environmental cues boost the development of human diseases. Methylenetetrahydrofolate reductase (MTHFR) is involved in the metabolism of homocysteine, and a common variant rs1801133 of MTHFR has been reported in human cardiovascular diseases. This study aims to providing a novel strategy for patient stratification with specific genetic and metabolic screening, finally for personalized healthcare for patients with thoracic aortic dissection.
    METHODS AND RESULTS: We corrected the MTHFR variant to generate an isogenic control iPSC line (Isogenic-iPSC) with CRISPR/Cas9 method, and this isogenic-iPSC shared the same other genetic information with our previously established MTHFR-iPSC line, providing a promising approach for analysis the phenotype and mechanism of rs1801133. During the direct differentiation of endothelial cells from both iPSC lines, rs1801133 variant did not affect the endothelial cell fate determination. Without homocysteine, this variant has little effect on endothelial cell function. While administration of homocysteine, the MTHFR-iPSC derived endothelial cells exhibited disrupted mitophagy, increased cell apoptosis and decreased cell viability. Bulk RNA-seq data indicated LAMP3 is a target of homocysteine, activation of LAMP3 might contribute to homocysteine induced the disruption of mitochondrial structure and cell apoptosis. With chemical compounds screening, kaempferol ameliorated the homocysteine-induced cell toxicity by restoring the mitochondrial structure. The direct relationship between homocysteine metabolism and MTHFR rs1801133 variant was investigated, and the molecular target for homocysteine and translational perspective has also been demonstrated.
    CONCLUSIONS: Collectively, this study provided the direct evidence of a specific genetic variant in MTHFR and homocysteine metabolism. Investigating the molecular mechanism of homocysteine activated LAMP3 on endothelial cell dysfunction and mitophagy could provide novel insights for targeted disease prevention and improving individual outcomes.
    TRANSLATIONAL PERSPECTIVE: Thoracic aortic dissection (TAD) is a life-threatening cardiovascular disease with a high mortality, lacking effective medical treatment and early diagnosis. Endothelial cells dysfunction has been considered into the development of TAD. Here, we show that MTHFR variant is responsible for the elevated homocysteine in iPSC-ECs, and disrupted mitochondrial structures by homocysteine significantly impaired endothelial function. Understanding the mechanism and translational medicine of homocysteine-induced endothelial toxicity in human with MTHFR variant could benefit the novel strategy for prevention and vessel protection against metabolism injury. Meanwhile, targeting mitophagy and application of small molecule, such as kaempferol, also provide an insight for endothelial protection.
    Keywords:  Genetic variant; Homocysteine; Mitophagy; Patient stratification; Systemic effects; Thoracic aortic dissection
    DOI:  https://doi.org/10.1016/j.jare.2025.02.032
  61. Chin Med. 2025 Feb 28. 20(1): 27
    Salidroside protects against myocardial infarction via activating MIF-mediated mitochondrial quality control.
    Baiyang You, Jie Zhang, Chuyan Yang, Yaoshan Dun, Dake Qi, Yuqiong Long, Jing Cheng, Yuan Lin, Nanjiang Zhou, Tanghao Zeng, Jie Dong, Suixin Liu.
       BACKGROUND: Salidroside is a potential therapeutic agent for myocardial infarction (MI), exerting therapeutic effects on macrophage migration inhibitory factor (MIF)-regulated mitochondrial quality control. Our aim was to explore the mechanism through which the MIF pathway regulates salidroside-mediated resistance to hypoxia-induced cardiomyocyte apoptosis.
    METHODS: Ligation surgery of the left anterior descending branch of the coronary artery was employed to establish a myocardial infarction mouse model. Salidroside at low and high doses was administered to the mice for 4 weeks after the surgery. Cardiac function was evaluated via echocardiography. Morphological changes, apoptosis, and mitochondrial damage in the myocardium were examined. For the cell experiments, cardiomyocytes were treated with salidroside under oxygen‒glucose deprivation (OGD) conditions and were either treated with recombinant MIF (rMIF) or transfected with Mif-siRNA. Subsequently, mitochondrial quality control and apoptosis were assessed.
    RESULTS: Salidroside enhanced mitochondrial quality control in MI model mice, mitigated apoptosis and improved cardiac dysfunction. Transmission electron microscopy indicated that there were fewer damaged mitochondria in the salidroside-treated mice compared with the control mice. MIF and downstream mitochondrial quality control pathways were activated in the mice treated with salidroside. Consistently, the cell experiments demonstrated that salidroside and rMIF alleviated apoptosis, improved impaired mitochondrial quality control in OGD-induced cells and activated MIF signaling in OGD-induced cells. However, these effects of salidroside were partially blocked by Mif-siRNA transfection.
    CONCLUSION: Salidroside alleviated myocardial apoptosis and ameliorated cardiac dysfunction in MI model mice through the MIF pathway and downstream mitochondrial quality control.
    Keywords:  Cardiomyocyte apoptosis; Macrophage migration inhibitory factor; Mitochondrial quality control; Myocardial infarction; Salidroside
    DOI:  https://doi.org/10.1186/s13020-025-01076-3
  62. J Inflamm Res. 2025 ;18 2677-2698
    Role and Mechanism of Mitochondrial Ribosomal Proteins in Septic Myocardial Injury.
    Liuli Wu, Junchao Huang, Xiongfei Jia, Xiaoqin Mao.
       Objective: To investigate the role of mitochondrial ribosomal proteins (MRPs) in the pathogenesis and progression of septic myocardial injury. Additionally, we aim to propose new technical strategies and experimental foundations for the prevention and treatment of septic myocardial injury.
    Methods: Animal and cell models of septic myocardial injury were established. Aberrantly expressed MRPs were screened using transcriptome sequencing, and their expression was verified by RT-qPCR and Western blot. Subsequently, overexpressed and knockdown cell models of myocardial injury were constructed. The effects on CO I, PGC-1α, ATP content, ROS fluorescence intensity, mitochondrial membrane potential, and GSDMD were assessed, along with changes in caspase-4 and IL-1β expression levels.
    Results: Transcriptome sequencing revealed a reduction in MRPs expression in mice with septic myocardial injury. Both RT-qPCR and Western blot analysis confirmed the decreased expression of MRPs in animal and cell models of septic myocardial injury. Furthermore, overexpression of both MRPS16 and MRPL47 mitigated the decrease in CO I and PGC-1α levels induced by septic myocardial injury. Additionally, overexpression of MRPS16 and MRPL47 alleviated the elevated levels of IL-1β, caspase-4, and GSDMD caused by septic myocardial injury.
    Conclusion: The findings suggest that both MRPS16 and MRPL47 can mitigate mitochondrial injury by attenuating mitochondrial biosynthesis dysfunction, energy metabolism disorders, and Ca2+ disturbances caused by septic myocardial injury. This ultimately reduces cellular damage and alleviates septic myocardial injury.
    Keywords:  MRPL47; MRPS16; mitochondrial function; septic myocardial injury
    DOI:  https://doi.org/10.2147/JIR.S495987
  63. J Biochem Mol Toxicol. 2025 Mar;39(3): e70193
    Protective Effects of Galangin Against Cyclophosphamide-Induced Cardiotoxicity via Suppressing NF-κB and Improving Mitochondrial Biogenesis.
    Manar Ali Elsayed, Doaa A Radwan, Hanem Mohamed Rabah, Hemat El-Sayed El-Horany, Nahla Anas Nasef, Rehab E Abo El Gheit, Marwa N Emam, Rasha Osama Elesawy, Walaa Elseady, Alia Mahmoud.
      Cyclophosphamide (CYP) is an effective chemotherapeutic and immunosuppressive agent; however, its clinical application is limited by a variety of toxic side effects. Mitochondrial dysfunction has been associated with the pathogenesis of chemotherapy-induced cardiotoxicity. This work aimed to evaluate the possible protective effect of galangin (Gal) on CYP-induced cardiotoxicity, pointing to its ability to promote mitochondrial biogenesis. Thirty two male rats were allocated equally into four groups: control; Gal-treated; CYP-treated; and Gal + CYP-treated groups. Markers of cardiac injury, oxidative/antioxidant status, inflammation, apoptosis, and mitochondrial function were assessed in addition to histopathological and electrocardiographic (ECG) evaluation. The current results revealed that Gal treatment significantly attenuated the cardiac injury and retrieved the alterations in cardiac histopathology and ECG changes. Also, it restored redox balance, as evidenced by the alleviation of malondialdehyde (MDA) levels and increased glutathione peroxidase (GPx) activity. Gal activated the sirtuin (SIRT) 1/nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated signaling pathway, as indicated by upregulation of SIRT1, Nrf2, SIRT3, and mitochondrial transcription factor (TFAM), in addition to increased levels of superoxide dismutase 2 (SOD)2 and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), together with increased activity of citrate synthase (CS), pointing to improved mitochondrial function. It ameliorated the inflammation and apoptosis-associated markers supported by biochemical and immunostaining data. Our study provided novel insights elucidating the mitigative potential of against CYP-induced cardiac oxidative damage, inflammation, apoptosis, and mitochondrial dysfunction by upregulating the SIRT1/Nrf2/SIRT3/PGC-1α/TFAM survival pathway.
    Keywords:  SIRT3; cyclophosphamide; cyclophosphamide‐induced cardiotoxicity; galangin; mitochondrial biogenesis
    DOI:  https://doi.org/10.1002/jbt.70193
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