bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2025–03–30
63 papers selected by
Gavin McStay, Liverpool John Moores University
  1. Ubiquitination regulation of mitochondrial homeostasis: a new sight for the treatment of gastrointestinal tumors.
  2. Zishen Huoxue decoction (ZSHX) alleviates ischemic myocardial injury (MI) via Sirt5-β-tubulin mediated synergistic mechanism of "mitophagy-unfolded protein response" and mitophagy.
  3. The Balance of MFN2 and OPA1 in Mitochondrial Dynamics, Cellular Homeostasis, and Disease.
  4. TGFB signaling induces mitophagy via PLSCR3-mediated cardiolipin externalization in conjunction with a BNIP3L/NIX-, BNIP3-, and FUNDC1-dependent mechanism.
  5. Targeting Mitophagy Using Isoliensinine as a Therapeutic Strategy for Renal Cell Carcinoma Treatment.
  6. Dual-Modality Imaging Unveil Inner Mitochondrial Membrane Viscosity and Respiratory Dynamics in Mitophagy.
  7. Defective PINK1-dependent mitophagy is involved in high glucose-induced neurotoxicity.
  8. Aloe-Emodin Improves Mitophagy in Alzheimer's Disease via Activating the AMPK/PGC-1α/SIRT3 Signaling Pathway.
  9. Syntaxin 17 Translocation Mediated Mitophagy Switching Drives Hyperglycemia-Induced Vascular Injury.
  10. Cell biology: A new dynamin superfamily protein remodels mitochondrial dynamics.
  11. Link between the mechanism of Mitophagy and Schizophrenia A Narrative Review.
  12. Epimedii Folium and Ligustri Lucidi Fructus synergistically delay renal aging through AMPK/ULK1/Bcl2L13-mediated mitophagy.
  13. Enhancing Sonodynamic Therapy in Prostate Cancer: Cavitation-Induced Cytotoxicity and Mitochondrial Unfolded Protein Response Disruption.
  14. Exploiting Paradoxical Activation of Oncogenic MAPK Signaling by Targeting Mitochondria to Sensitize NRAS Mutant-Melanoma to Vemurafenib.
  15. Xinyin tablets affect mitophagy and cardiomyocyte apoptosis to alleviate chronic heart failure by regulating histone deacetylase 3(HDAC3)-mediated PTEN induced putative kinase 1(PINK1)/Parkin signaling pathway.
  16. Impact of diet and exercise on mitochondrial quality and mitophagy in Alzheimer's disease.
  17. Long term exposure to multiple environmental stressors induces mitochondrial dynamics imbalance in testis: Insights from metabolomics and transcriptomics.
  18. Mechanisms Associated with Mitophagy and Ferroptosis in Cerebral Ischemia-reperfusion Injury.
  19. Inhibition of Mitochondrial Dynamics by Mitochondrial Division Inhibitor-1 Suppresses Cell Migration and Metastatic Markers in Colorectal Cancer HCT116 Cells.
  20. Construction and evaluation of a diagnostic model for Alzheimer's disease based on mitophagy-related genes.
  21. Flutamide Promotes Early Hepatocarcinogenesis Through Mitophagy in High-Fat Diet-Fed Non-Obese Steatotic Rats.
  22. Exploring miR-3148's impact on Krüppel-like factor 6-driven mitophagy and apoptosis in myocardial ischemic injury.
  23. Corrigendum: HIF-1α alleviates high-glucose-induced renal tubular cell injury by promoting Parkin/PINK1-mediated mitophagy.
  24. Ginsenoside Rh1 mitigates mitochondrial dysfunction induced by myocardial ischaemia through its novel role as a sirtuin 3 activator.
  25. Mitochondria transplantation transiently rescues cerebellar neurodegeneration improving mitochondrial function and reducing mitophagy in mice.
  26. Unclogging of the TOM complex under import stress.
  27. The Role of Mitophagy in Cardiac Metabolic Remodeling of Heart Failure: Insights of Molecular Mechanisms and Therapeutic Prospects.
  28. Correction: Dexmedetomidine activates mitophagy and protects against pyroptosis in oxygen-glucose deprivation/reperfusion-induced brain damage via PINK1/Parkin pathway activation.
  29. Danqi soft caspule alleviates myocardial ischemia-reperfusion injury induced cardiomyocyte apoptosis by attenuating mitochondrial fission.
  30. A cellular assay to determine the fusion capacity of MFN2 variants linked to Charcot-Marie-Tooth disease of type 2 A.
  31. PINK1 link mitochondria-ER contacts controls deposition of intramuscular fat in pigs.
  32. The Role of Mdivi-1 in Reducing Mitochondrial Fission via the NF-kappaB/JNK/SIRT3 Signaling Pathway in Acute Kidney Injury.
  33. Selective cerebral hypothermia alleviates focal cerebral ischemia/reperfusion injury via enhancing SUMO2/3 modification of Drp1 in rats.
  34. Ameliorating TIMM50 Loss Slows Senescence by Improving Mitochondrial Structure and Function.
  35. Dependence of mitochondrial calcium signalling and dynamics on the disaggregase, CLPB.
  36. Arginine as host directed therapy in tuberculosis: insights from modulating arginine metabolism by supplementation and arginase inhibition.
  37. JP4-039 protects chondrocytes from ferroptosis to attenuate osteoarthritis progression by promoting Pink1/Parkin-dependent mitophagy.
  38. Dihydromyricetin ameliorates lipopolysaccharide‒induced hepatic injury in chickens by activating the Nrf2/Keap1 pathway and regulating mitochondrial dynamics.
  39. Aging triggers mitochondrial, endoplasmic reticulum, and metabolic stress responses in the heart.
  40. The Association Among Bipolar Disorder, Mitochondrial Dysfunction, and Reactive Oxygen Species.
  41. Molecular mechanism of melatonin-mediated mitophagy regulating proline production to ameliorate skin aging.
  42. Elucidating the Molecular Mechanisms of Hederagenin-Regulated Mitophagy in Cervical Cancer SiHa Cells through an Integrative Approach Combining Proteomics and Advanced Network Association Algorithm.
  43. Targeting mitochondrial ribosomal protein expression by andrographolide and melatonin for colon cancer treatment.
  44. Mfn2 regulates calcium homeostasis and suppresses PASMCs proliferation via interaction with IP3R3 to mitigate pulmonary arterial hypertension.
  45. Correction to "Activation of PGC-1 Alpha-Dependent Mitochondrial Biogenesis Supports Therapeutic Effects of Silibinin Against Type I Diabetic Periodontitis".
  46. Therapeutic Efficacy of Small Extracellular Vesicles Loaded with ROCK Inhibitor in Parkinson's Disease.
  47. Extracellular PHF-tau modulates astrocyte mitochondrial dynamics and mediates neuronal connectivity.
  48. Action and therapeutic targets of folliculin interacting protein 1: a novel signaling mechanism in redox regulation.
  49. Mitophagy in Alzheimer's disease and other metabolic disorders: A focus on mitochondrial-targeted therapeutics.
  50. Targeting OPA1 protein for therapeutic intervention in autosomal dominant optic atrophy: In silico drug discovery.
  51. MAP Kinase Phosphatase-5 Deficiency Improves Endurance Exercise Capacity.
  52. Cellular Stress Responses and Associated Diseases: A Focus on Heat Shock Proteins.
  53. Autophagic stagnation: a key mechanism in kidney disease progression linked to aging and obesity.
  54. Ltc1 localization by EMC regulates cell membrane fluidity to facilitate membrane protein biogenesis.
  55. Oxidative stress and mitochondrial dysfunctions induced by cyanobacterial microcystin-LR in primary grass carp hepatocytes.
  56. MTFR1 phosphorylation-activated adaptive mitochondrial fusion is essential for colon cancer cell survival during glucose deprivation.
  57. In situ architecture of the human prohibitin complex.
  58. Dual inhibition of canonical and noncanonical PAR-1 by SCH79797 mitigates neurodegeneration in 3-NP-induced Huntington's disease: An in vivo and in silico approach.
  59. Edaravone inhibits neuronal ferroptosis and alleviates acute Central nervous system injury induced by diquat via enhancement of METTL14-mediated m6A methylation of Aldh1l1.
  60. mitoXplorer 3.0, A Web Tool for Exploring Mitochondrial Dynamics in Single-cell RNA-seq Data.
  61. Hypertrophic Cardiomyopathy Through the Lens of Mitochondria.
  62. Identification and characterization of mitochondrial autophagy-related genes in osteosarcoma and predicting clinical prognosis.
  63. Regulating macrophage glucose metabolism homeostasis via mitochondrial rheostats by short fiber-microsphere scaffolds for bone repair.
  1. Front Immunol. 2025 ;16 1533007
    Ubiquitination regulation of mitochondrial homeostasis: a new sight for the treatment of gastrointestinal tumors.
    Bingqian Huang, Yulin Yang, Jinming Liu, Biao Zhang, Nengming Lin.
      Mitochondrial homeostasis (MH) refers to the dynamic balance of mitochondrial number, function, and quality within cells. Maintaining MH is significant in the occurrence, development, and clinical treatment of Gastrointestinal (GI) tumors. Ubiquitination, as an important post-translational modification mechanism of proteins, plays a central role in the regulation of MH. Over the past decade, research on the regulation of MH by ubiquitination has focused on mitochondrial biogenesis, mitochondrial dynamics, Mitophagy, and mitochondrial metabolism during these processes. This review summarizes the mechanism and potential therapeutic targets of ubiquitin (Ub)-regulated MH intervention in GI tumors.
    Keywords:  gastrointestinal tumors; mitochondrial biogenesis; mitochondrial dynamics; mitochondrial homeostasis; mitochondrial metabolism; mitophagy; ubiquitination
    DOI:  https://doi.org/10.3389/fimmu.2025.1533007
  2. Chin J Nat Med. 2025 Mar;pii: S1875-5364(25)60838-7. [Epub ahead of print]23(3): 311-321
    Zishen Huoxue decoction (ZSHX) alleviates ischemic myocardial injury (MI) via Sirt5-β-tubulin mediated synergistic mechanism of "mitophagy-unfolded protein response" and mitophagy.
    Xing Chang, Siyuan Zhou, Yu Huang, Jinfeng Liu, Yanli Wang, Xuanke Guan, Qiaomin Wu, Zhiming Liu, Ruxiu Liu.
      Zishen Huoxue decoction (ZSHX) enhances cardiomyocyte viability following hypoxic stress; however, its upstream therapeutic targets remain unclear. Network pharmacology and RNA sequencing analyses revealed that ZSHX target genes were closely associated with mitophagy and apoptosis in the mitochondrial pathway. In vitro, ZSHX inhibited pathological mitochondrial fission following hypoxic stress, regulated FUN14 domain-containing protein 1 (FUNDC1)-related mitophagy, and increased the levels of mitophagy lysosomes and microtubule-associated protein 1 light chain 3 beta II (LC3II)/translocase of outer mitochondrial membrane 20 (TOM20) expression while inhibiting the over-activated mitochondrial unfolded protein response. Additionally, ZSHX regulated the stability of beta-tubulin through Sirtuin 5 (SIRT5) and could modulate FUNDC1-related synergistic mechanisms of mitophagy and unfolded protein response in the mitochondria (UPRmt) via the SIRT5 and -β-tubulin axis. This targeting pathway may be crucial for cardiomyocytes to resist hypoxia. Collectively, these findings suggest that ZSHX can protect against cardiomyocyte injury via the SIRT5-β-tubulin axis, which may be associated with the synergistic protective mechanism of SIRT5-β-tubulin axis-related mitophagy and UPRmt on cardiomyocytes.
    Keywords:  Mitochondrial oxidative stress; Mitochondrial unfolded protein response; Mitophagy; Sirtuin 5; Zishen Huoxue decoction; β-Tubulin
    DOI:  https://doi.org/10.1016/S1875-5364(25)60838-7
  3. Biomolecules. 2025 Mar 18. pii: 433. [Epub ahead of print]15(3):
    The Balance of MFN2 and OPA1 in Mitochondrial Dynamics, Cellular Homeostasis, and Disease.
    Paola Zanfardino, Alessandro Amati, Mirko Perrone, Vittoria Petruzzella.
      Mitochondrial dynamics, governed by fusion and fission, are crucial for maintaining cellular homeostasis, energy production, and stress adaptation. MFN2 and OPA1, key regulators of mitochondrial fusion, play essential roles beyond their structural functions, influencing bioenergetics, intracellular signaling, and quality control mechanisms such as mitophagy. Disruptions in these processes, often caused by MFN2 or OPA1 mutations, are linked to neurodegenerative diseases like Charcot-Marie-Tooth disease type 2A (CMT2A) and autosomal dominant optic atrophy (ADOA). This review explores the molecular mechanisms underlying mitochondrial fusion, the impact of MFN2 and OPA1 dysfunction on oxidative phosphorylation and autophagy, and their role in disease progression. Additionally, we discuss the divergent cellular responses to MFN2 and OPA1 mutations, particularly in terms of proliferation, senescence, and metabolic signaling. Finally, we highlight emerging therapeutic strategies to restore mitochondrial integrity, including mTOR modulation and autophagy-targeted approaches, with potential implications for neurodegenerative disorders.
    Keywords:  autophagy; mTOR signaling; mitochondria; mitochondrial dynamics; mitophagy; neurodegenerative diseases; oxidative phosphorylation; proliferation; senescence
    DOI:  https://doi.org/10.3390/biom15030433
  4. Autophagy. 2025 Mar 22.
    TGFB signaling induces mitophagy via PLSCR3-mediated cardiolipin externalization in conjunction with a BNIP3L/NIX-, BNIP3-, and FUNDC1-dependent mechanism.
    Jiong Yan, Xin Chen, Swati Choksi, Zheng-Gang Liu.
      Selective clearance of damaged mitochondria through mitophagy is crucial for the maintenance of mitochondrial homeostasis. While mitophagy can be activated by various mitochondrial toxins, the physiologically relevant signal that triggers mitophagy is less studied. TGFB/TGFβ signaling has been linked to autophagic induction, but its specific role in mitophagy is not well understood. Here, we discovered a novel mitophagy induction paradigm stimulated by TGFB1. The mitophagic response is exclusively mediated by SMAD2, SMAD3, and SMAD4 underlying the TGFB receptor signaling. The transcriptional regulation activates genes involved in the canonical autophagic pathway which is required for the TGFB1-induced mitophagy. Moreover, TGFB1 signaling promotes mitophagic flux by upregulating PLSCR3 that externalizes cardiolipin in conjunction with the MAP1LC3/LC3/GABARAPs-interacting receptor proteins (BNIP3L/NIX, BNIP3, and FUNDC1)-dependent mechanism. Overall, our study characterized the essential components engaged in the TGFB1-induced mitophagy and demonstrated that TGFB is an important signal that induces mitophagy.
    Keywords:  ATG8; BNIP3; BNIP3L/NIX; PLSCR3; TGFB/TGFβ; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2025.2483441
  5. Free Radic Biol Med. 2025 Mar 24. pii: S0891-5849(25)00187-X. [Epub ahead of print]
    Targeting Mitophagy Using Isoliensinine as a Therapeutic Strategy for Renal Cell Carcinoma Treatment.
    Ming-Ju Wu, Yu-Teng Chang, Tzu-Yi Chuang, Wang-Sheng Ko, Chih-Chiang Lu, Jeng-Jer Shieh.
      Renal cell carcinoma (RCC) is a formidable and lethal form of kidney cancer, necessitating the exploration of novel therapeutic options. Isoliensinine, an alkaloid derived from lotus seed embryos, has shown promising anti-cancer properties. However, its mechanistic actions and impact on mitochondrial dynamics remain poorly understood. This research has aimed to investigate the effects of isoliensinine on RCC, as well as its potential involvement in mitophagy and mitochondrial function. In vitro experiments utilizing RCC cell lines (786-O and ACHN) have demonstrated that isoliensinine treatment significantly reduced cell viability. Moreover, isoliensinine induced an increase in cellular and mitochondrial reactive oxygen species (ROS) levels, accompanied by reduced mitochondria membrane potential, indicating an influence on mitochondrial function. Furthermore, MitoTracker staining revealed distinct mitochondrial morphologies, with isoliensinine promoting mitochondrial fission, thus supporting its role in mitochondrial dynamics. Notably, isoliensinine led to a time-dependent upregulation of mitophagy-related proteins, indicative of mitophagy activation. Of particular interest, the addition of MitoTEMPO, a potent mitochondrial ROS scavenger, effectively reversed the isoliensinine-induced upregulation of mitophagy-related protein expression and mitochondrial ROS levels. These combined results provide novel insight into the impact of isoliensinine-induced mitophagy on mitochondrial dynamics in renal carcinoma cells. Overall, the findings from this study highlight isoliensinine as a promising candidate with significant potential for further investigation and eventual clinical application in RCC therapy. Moreover, the modulation of mitochondrial dynamics, mitophagy and ROS levels through the use of isoliensinine further adds to its appeal as a potential therapeutic agent.
    Keywords:  Isoliensinine; Mitophagy; Reactive oxygen species; Renal cell carcinoma
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.03.037
  6. Anal Chem. 2025 Mar 27.
    Dual-Modality Imaging Unveil Inner Mitochondrial Membrane Viscosity and Respiratory Dynamics in Mitophagy.
    Fei Peng, Xiangnan Ai, Bin Hao, Xiaoyu Bu, Zixuan Zhao, Linshuai Yang, Baoxiang Gao.
      Mitophagy is a vital lysosome-dependent process that maintains mitochondrial integrity and cellular homeostasis, where respiration and inner mitochondrial membrane (IMM) viscosity play key roles. Despite its critical importance, achieving a high-resolution and dynamic visualization of respiration and IMM viscosity during mitophagy remains a significant challenge. In this study, we designed two innovative fluorescent probes: SiR-C8, a viscosity-sensitive rotor-type probe based on silicon-rhodamine, specifically targeting the IMM, and OR-ATP, a rhodamine-derived probe utilizing an intramolecular spirolactam structure to respond to mitochondrial ATP levels. Leveraging fluorescence intensity and lifetime dual-modality imaging, we successfully enabled the high-resolution, real-time monitoring of lysosome-dependent mitophagy. Remarkably, our results unveiled a progressive increase in IMM viscosity alongside a significant attenuation in mitochondrial respiration during mitophagy induced by starvation, carbonyl cyanide, m-chlorophenyl hydrazone (CCCP), and Oligomycin. Significantly, utilizing structured illumination microscopy super-resolution imaging, we have uncovered a novel mitochondrial quality control mechanism by which lysosomes selectively engulf locally damaged mitochondrial regions. This discovery provides novel insights into the intricate processes governing mitophagy and introduces an innovative platform for studying mitochondrial dynamics, dysfunction, and their implications for cellular homeostasis and pathology.
    DOI:  https://doi.org/10.1021/acs.analchem.5c00464
  7. Neuroscience. 2025 Mar 24. pii: S0306-4522(25)00254-4. [Epub ahead of print]
    Defective PINK1-dependent mitophagy is involved in high glucose-induced neurotoxicity.
    Yongsheng Bian, Yimei Yang, Jun Chen, Jian Liu, Yan Tao, Zhongjie Liu, Lijin Huang.
      Neuropathic pain often complicates diabetes progression, yet the pathogenic mechanisms are poorly understood. Defective mitophagy is linked to various diabetic complications like nephropathy, cardiomyopathy, and retinopathy. To investigate the molecular basis of hyperglycemia-induced painful diabetic neuropathy (PDN), we examined the effect of high glucose on the PTEN-induced kinase 1 (PINK1)/Parkin RBR E3 ubiquitin protein ligase (Parkin)-mediated mitophagy pathway in ND7/23 cells. Cells were treated with different glucose concentrations (25, 50, 75 mM) for various durations (24, 48, 72 h). Additionally, cells were exposed to high glucose (50 mM) with or without 100 nM rapamycin (a mitophagy enhancer) for 48 h, or transfected with PINK1 siRNA. We assessed protein levels of mitophagy-related genes (PINK1, Parkin, P62, LC3B) and apoptotic markers (cleaved-Caspase3) via Western blotting. High glucose significantly reduced the expression of autophagy-related proteins PINK1 and Parkin in a time- and concentration-dependent manner compared to controls. Rapamycin counteracted the inhibitory effects of high glucose on PINK1/Parkin-mediated mitophagy, while PINK1 siRNA transfection showed similar outcomes, confirming the inhibitory impact of high glucose on mitophagy. Moreover, high glucose induced apoptosis by suppressing PINK1/Parkin-mediated mitophagy, causing cytotoxic effects in ND7/23 cells which is derived from the fusion of mouse neuroblastoma cells and rat dorsal root ganglion (DRG) cells. Our findings suggest that hyperglycemia-induced disruption of the PINK1/Parkin mitophagy pathway impairs mitochondrial homeostasis, leading to apoptosis. Therefore, targeting PINK1 pathway activation or restoring mitophagy might be a promising therapeutic strategy for PDN treatment.
    Keywords:  Apoptosis; Diabetic; Mitophagy; Neurotoxicity; PDN; PINK1; Rapamycin
    DOI:  https://doi.org/10.1016/j.neuroscience.2025.03.052
  8. CNS Neurosci Ther. 2025 Mar;31(3): e70346
    Aloe-Emodin Improves Mitophagy in Alzheimer's Disease via Activating the AMPK/PGC-1α/SIRT3 Signaling Pathway.
    Yulu Wang, Yunzhi Ge, Siyu Hua, Chenrui Shen, Biao Cai, Han Zhao.
       BACKGROUND: Impaired mitophagy results in the accumulation of defective mitochondria that are unable to be cleared effectively in Alzheimer's disease (AD). Aloe-emodin (AE), a key component of the traditional Chinese medicine Rhubarb, exhibits neuroprotective effects against Alzheimer's disease, though the underlying mechanism remains unclear. Studying aloe-emodin's role in enhancing mitophagy is vital for improving cognitive function and reducing neuronal damage in Alzheimer's disease.
    METHODS: The APP/PS1 double transgenic mice were adopted as models for AD to assess the effects of aloe-emodin upon cognitive function and its neuroprotective impact on hippocampal neurons. Additionally, we investigated the regulatory mechanisms of proteins within the aforementioned pathway, and the morphological characteristics of mitophagy-related proteins. An AD hippocampal neuron model was developed using Aβ25-35 to evaluate the mitochondrial function, the protein expression of such a pathway and the mitophagy. This approach aims to elucidate the effects and underlying mechanisms of aloe-emodin in relation to AD.
    RESULTS: AE activates mitophagy in neurons, improves cognitive dysfunction, reduces hippocampal damage, and alleviates AD symptoms in model mice. AE activates the expression of AMPK, PGC-1α and SIRT3. Increased expression of SIRT3 in mitochondria promotes mitophagy and regulates the function of mitochondrial proteins. When mitochondrial autophagy is enhanced, the expression of Beclin1, LC3, P62, Parkin, and PINK1-related proteins changes. Further in vitro experiments showed that AE can enhance mitochondrial function in Alzheimer's disease cell models. The mitochondrial membrane potential, GSH, ROS and Ca2+ levels gradually recover, alleviating the pathological manifestations of AD. Knocking down SIRT3 leads to increased mitochondrial damage and a reduction in mitophagy in HT22 cells.
    CONCLUSION: Experimental results show that AE can activate mitophagy through AMPK/PGC-1α/SIRT3 pathway, alleviate cognitive dysfunction in AD, and reduce damage to hippocampal neurons.
    Keywords:  AMPK/PGC‐1α/SIRT3; Alzheimer's disease; Pink1/parkin; aloe‐emodin; cognitive dysfunction; mitochondrial fission/fusion; mitochondrial function; mitophagy
    DOI:  https://doi.org/10.1111/cns.70346
  9. Adv Sci (Weinh). 2025 Mar 26. e2414960
    Syntaxin 17 Translocation Mediated Mitophagy Switching Drives Hyperglycemia-Induced Vascular Injury.
    Anqi Luo, Rui Wang, Jingwen Gong, Shuting Wang, Chuan Yun, Zongcun Chen, Yanan Jiang, Xiaoquan Liu, Haofu Dai, Haochen Liu, Yunsi Zheng.
      The risk of diabetic cardiovascular complications is closely linked to the length of hyperglycemia exposure. Mitophagy plays a significant role in vascular endothelial injury. However, the specific mechanisms by which mitophagy contributes to endothelial injury during sustained hyperglycemia remain unclear. In diabetic ApoE-/- mice and human umbilical vein endothelial cell (HUVEC) models, mitophagy is enhanced following short-term and long-term high-glucose exposure. Short-term high-glucose exposure promotes Parkin-mediated mitophagy and upregulates mitochondrial fission protein 1 (Fis1) expression, whereas long-term high-glucose exposure suppresses Parkin-mediated mitophagy and downregulates Fis1. With prolonged high-glucose exposure, Syntaxin 17 (STX17) translocates from the endoplasmic reticulum to the mitochondria, activating STX17-mediated mitophagy. Silencing STX17 alleviates mitochondrial degradation, decreases reactive oxygen species (ROS) levels, enhances endothelial nitric oxide synthase (eNOS) phosphorylation, and reduces apoptosis. Silencing Fis1 accelerates the switching to STX17-mediated mitophagy, worsening endothelial dysfunction, whereas Fis1 overexpression prevents this switching, reducing ROS and apoptosis and enhancing eNOS phosphorylation. In summary, these findings suggest that the switching from Parkin-mediated to STX17-mediated mitophagy drives vascular endothelial injury following long-term hyperglycemic exposure, providing valuable insights into therapeutic strategies for diabetic cardiovascular complications.
    Keywords:  (diabetes; Fis1; Syntaxin 17); mitophagy; vascular endothelial injury
    DOI:  https://doi.org/10.1002/advs.202414960
  10. Curr Biol. 2025 Mar 24. pii: S0960-9822(25)00132-0. [Epub ahead of print]35(6): R218-R221
    Cell biology: A new dynamin superfamily protein remodels mitochondrial dynamics.
    Hassan Hashimi.
      Dynamin superfamily proteins mediate mitochondrial fusion in fungi and animals. A new study expands the taxonomic reach of this superfamily and provides insights into the roles these proteins play by investigating MfnL, a family member involved in trypanosomal mitochondrial dynamics. Importantly, MfnL occurs widely in eukaryotes and prokaryotes.
    DOI:  https://doi.org/10.1016/j.cub.2025.01.069
  11. Psychiatriki. 2025 Mar 24.
    Link between the mechanism of Mitophagy and Schizophrenia A Narrative Review.
    Nikolaos Statharakos.
      Despite extensive research, the precise pathophysiology underlying schizophrenia remains unclear, but accumulating evidence suggests that mitochondrial dysfunction and oxidative stress play significant roles in its development. Mitophagy, the selective degradation of damaged or dysfunctional mitochondria, plays a critical role in maintaining cellular homeostasis and is increasingly recognized for its implications in various neuropsychiatric disorders, including schizophrenia. This review examines current knowledge regarding mitophagy and its association with schizophrenia. The literature was searched in PubMed- Medline and Scopus databases, and as a narrative review, the methodology focuses on the comprehensive coverage and synthesis of relevant studies. The hypothesis of the review claims that there is a link between mitophagy and schizophrenia. The terms used in the search query are "mitophagy", "schizophrenia" with the Boolean variable "AND". The relationship between mitophagy and schizophrenia is complex and multifaceted, involving mitochondrial dysfunction, neuroinflammation, and the integrity of oligodendrocytes and microglia. Schizophrenia is associated with dysfunctional mitophagy and elevated oxidative stress. These mechanisms may help to explain overlapping symptoms, particularly cognitive deficits. While the emerging data linking mitophagy and schizophrenia are promising, current research has limitations. Much of the evidence for mitophagy dysfunction in schizophrenia comes from animal models or postmortem studies, which may not fully capture the complexity of the disorder in humans. Moreover, mitophagy is challenging to study in vivo, particularly in the human brain, making it difficult to directly observe mitophagy processes in patients with schizophrenia. Mitophagy and its dysfunction may contribute to the pathophysiology of schizophrenia. Evidence suggests that impaired mitophagy can lead to energy dysregulation, oxidative stress, and neuroinflammation, all of which are implicated in schizophrenia. While more research is needed, the potential link between mitophagy and schizophrenia presents an interesting area for future studies and therapeutic development. Targeting mitophagy could offer new approaches for addressing cognitive and negative symptoms, providing hope for improved treatment outcomes.
    Keywords:  Mitochondria; mitochondrial dysfunction; mitophagy; schizophrenia
    DOI:  https://doi.org/10.22365/jpsych.2025.008
  12. J Ethnopharmacol. 2025 Mar 21. pii: S0378-8741(25)00352-6. [Epub ahead of print] 119668
    Epimedii Folium and Ligustri Lucidi Fructus synergistically delay renal aging through AMPK/ULK1/Bcl2L13-mediated mitophagy.
    Yuting Long, Yuman Li, Zaina Ma, Yonghao Xie, Hui Zhao, Minyu Zhang, Renhui Liu.
       ETHNOPHARMACOLOGICAL RELEVANCE: The root of aging is attributed to kidney essence insufficiency and gradual loss of kidney function. The combination of Epimedii Folium and Ligustri Lucidi Fructus (ELL) is traditionally recognized to tonify kidney yin and yang and has significant efficacy in delaying aging and aging-related diseases, but little is known about the exact mechanism.
    AIM OF THE STUDY: The research focuses on the mechanism of delaying renal aging by which ELL regulates mitophagy through serine/threonine kinase AMP-activated protein kinase (AMPK) /UNC-51- like autophagy activating kinase 1 (ULK1) /B-cell lymphoma-2-like protein 13 (Bcl2L13) in vivo.
    MATERIALS AND METHODS: We employed a rat model of natural aging, using rats of different ages as dynamic controls, and a natural aging mouse model to evaluate the effects of ELL on delaying renal aging via AMPK/ULK1/Bcl2L13. The assessment included renal histopathology, oxidative stress, cell senescence, mitochondrial dynamics, mitophagy, and the AMPK/ULK1/Bcl2L13 signaling pathway. In the aging rat model, network pharmacology and proteomics were combined to dissect the renal aging process, and a Multilayer Perceptron (MLP) -artificial neural networks (ANN) model was used to evaluate the effects of ELL comprehensively. In the aging mouse model, the AMPK inhibitor dorsomorphin was applied to assess whether the AMPK signaling pathway was involved in ELL-induced mitophagy.
    RESULTS: Compared with the young rats, the kidney exhibited signs of degenerative pathologies and increased oxidative stress in 17-month-old rats. A thorough analysis identified the mitochondrial protein Bcl2L13 as a crucial biomarker associated with renal aging. The AMPK/ULK1/Bcl2L13 pathway significantly regulated mitochondrial function and mitophagy, which were potential mechanisms underlying renal aging. In contrast to aged rats, the renal pathological changes and cell senescence in rats treated with ELL were significantly mitigated, the antioxidant capacity, mitochondrial dynamics, and mitophagy were improved, and the expression of AMPK/ULK1/Bcl2L13 was upregulated. After the application of AMPK inhibitors, the effects of ELL were reversed. It appears that ELL modulates the AMPK/ULK1/Bcl2L13 signaling pathway, and upregulates mitophagy to potentially decelerate renal aging.
    CONCLUSIONS: The findings indicate that aging kidneys display mitochondrial dysfunction, disorganization of mitochondria, and a decrease in mitophagy. Concurrently, ELL significantly regulates mitochondrial dynamics and mitophagy via AMPK/ULK1/Bcl2L13. This regulation helps mitigate mitochondrial dysfunction, suggesting ELL as a promising herbal remedy for delaying renal aging and age-related kidney diseases.
    Keywords:  AMPK/ULK1/Bcl2L13 signaling pathway; Epimedii Folium/Ligustri Lucidi Fructus; Mitophagy; Renal aging
    DOI:  https://doi.org/10.1016/j.jep.2025.119668
  13. Cell Biochem Biophys. 2025 Mar 25.
    Enhancing Sonodynamic Therapy in Prostate Cancer: Cavitation-Induced Cytotoxicity and Mitochondrial Unfolded Protein Response Disruption.
    Aysegul Turkkol, Umut Kerem Kolac, Gizem Donmez Yalcin, Mehmet Dincer Bilgin, Abdullah Yalcin, Mehmet Bilgen.
      Prostate cancer remains a significant health challenge, necessitating more effective and targeted treatment strategies. Sonodynamic therapy (SDT) is a promising, non-invasive approach that utilizes ultrasound-activated sensitizers to induce cancer cell death. However, the role of ultrasound cavitation in enhancing SDT efficacy and its effects on mitochondrial stress responses remain unclear. We hypothesized that increasing cavitation density through optimized ultrasound parameters would enhance Ce6-mediated SDT effectiveness by increasing cytotoxicity, reactive oxygen species (ROS) generation, mitochondrial membrane potential (MMP) loss, and disrupting the mitochondrial unfolded protein response (mtUPR). Prostate cancer cells were treated with Ce6 and exposed to ultrasound with varying duty cycles (50% and 100%) and power intensities (0.5 W/cm2, 1 W/cm2, and 1.5 W/cm2). Cavitation density was measured, and its effects on cell viability, ROS levels, MMP disruption, and mtUPR mediator expression, including activating transcription factor 5 (ATF5), heat shock protein 60 (HSP60), and caseinolytic protease proteolytic subunit (CLPP), were analyzed at protein and mRNA levels. Higher duty cycles significantly increased cavitation density, leading to enhanced cytotoxicity, elevated ROS generation, and greater MMP loss in Ce6-mediated SDT. Additionally, SDT reduced mtUPR mediator expression, with cavitation further amplifying these effects. These findings suggest that cavitation-enhanced SDT may contribute to improved therapeutic efficacy in prostate cancer treatment by modulating mitochondrial stress responses and affecting cell viability. Optimizing ultrasound parameters to maximize cavitation effects may contribute to the development of more effective SDT-based cancer therapies.
    Keywords:  Cavitation; Chlorin e6; Mitochondrial unfolded protein response; Prostate cancer; Sonodynamic therapy
    DOI:  https://doi.org/10.1007/s12013-025-01717-2
  14. Int J Mol Sci. 2025 Mar 16. pii: 2675. [Epub ahead of print]26(6):
    Exploiting Paradoxical Activation of Oncogenic MAPK Signaling by Targeting Mitochondria to Sensitize NRAS Mutant-Melanoma to Vemurafenib.
    Laura Francisca Leite do Prado-Souza, Letícia Silva Ferraz, Tharcísio Citrangulo Tortelli, César Augusto João Ribeiro, Danilo Trabuco do Amaral, Denise Costa Arruda, Érica Aparecida de Oliveira, Roger Chammas, Silvya Stuchi Maria-Engler, Tiago Rodrigues.
      Vemurafenib is a BRAF (rapidly accelerated fibrosarcoma B-type)-targeted therapy used to treat patients with advanced, unresectable melanoma. It inhibits the MAPK (mitogen-activated protein kinase)/ERK (extracellular signal-regulated kinase) pathway and tumor proliferation in BRAFV600E-mutated melanoma cells. Resistance to vemurafenib has been reported in melanoma patients due to secondary NRAS (neuroblastoma RAS viral oncogene homolog) mutations, which lead to paradoxical MAPK pathway activation and tumor proliferation. However, the impact of this paradoxical activation on mitochondrial dynamics and function in NRAS-mutated melanoma is unclear. Here, we investigated the effects of vemurafenib on NRASQ61R-mutated melanoma cells, focusing on mitochondrial dynamics and function. As expected, vemurafenib did not exhibit cytotoxicity in SK-MEL-147 NRASQ61R-mutated melanoma cells, even after 72 h of incubation. However, it significantly enhanced the MAPK/ERK signaling through paradoxical activation, accompanied by decreased expression of mitochondrial fusion proteins and activation of the fission protein DRP1 (dynamin-related protein 1), leading to small, rounded mitochondrial morphology. These observations were corroborated by transcriptome data obtained from NRAS-mutated melanoma patients, showing MFN1 (mitofusin 1) and OPA1 (optic atrophy 1) downregulation and DNM1L (DRP1 gene) upregulation. Interestingly, inhibition of mitochondrial fission with mdivi-1 or modulation of oxidative phosphorylation via respiratory chain inhibition or uncoupling significantly sensitized NRASQ61R-mutated melanoma cells to vemurafenib. Despite vemurafenib's low cytotoxicity in NRAS-mutated melanoma, targeting mitochondrial dynamics and/or oxidative phosphorylation may offer a promising strategy for combined therapy.
    Keywords:  NRAS; cancer; mdivi-1; mitochondrial dynamics; oxidative phosphorylation; targeted therapy
    DOI:  https://doi.org/10.3390/ijms26062675
  15. J Ethnopharmacol. 2025 Mar 21. pii: S0378-8741(25)00350-2. [Epub ahead of print] 119666
    Xinyin tablets affect mitophagy and cardiomyocyte apoptosis to alleviate chronic heart failure by regulating histone deacetylase 3(HDAC3)-mediated PTEN induced putative kinase 1(PINK1)/Parkin signaling pathway.
    Hanyu Chen, Qianbei Lin, Yanlin Zeng, Pinliang Chen, Pengpeng Guo, Ruoshui Feng, Zhenyu Guo, Jinhua Kang, Qiucen Chen, Xiaoxiong Zhou.
       ETHNOPHARMACOLOGICAL RELEVANCE: Xinyin, a Chinese patent medicine, is composed of Panax ginseng C.A.Mey. (Araliaceae), Ilex pubescens Hook. & Arn. (Aquifoliaceae), Leonurus japonicus Houtt. (Lamiaceae), Plantago asiatica L. (Plantaginaceae), Ophiopogon japonicus (Thunb.) Ker Gawl. (Asparagaceae), Astragalus membranaceus (Fisch.) Bunge, and Draba nemorosa L. (Brassicaceae). It has been used for the prevention and treatment of chronic heart failure (CHF) clinically. However, its underlying mechanism of action is far from completely understood.
    AIM OF THE STUDY: This study aimed to determine whether Xinyin alleviates CHF in SPF C57 mice and to explore the potential mechanism of action in H9c2 cells.
    MATERIALS AND METHODS: Liquid chromatography tandem mass spectroscopy (LC-MS/MS) was performed to identify the chemical compounds in Xinyin. In vivo, 60 C57 mice were randomly divided into 6 groups: the sham group; model group; low-, medium-, and high-dose Xinyin groups; and perindopril group. Animals in the sham group underwent thoracotomy only. The others were subjected to coronary artery ligation. After 4 weeks of drug intervention, the cardiac function of the mice in each group was detected via echocardiography, the myocardial cells were evaluated via HE staining, and the degree of myocardial fibrosis was detected via Masson's trichrome staining. The expression of PINK1/Parkin signaling pathway-related genes (HDAC3, PINK1, Parkin, P62, LC3II/I, caspase-3, caspase-9, and Bax) was analyzed via RT‒qPCR and Western blotting. The effects of Xinyin on cardiomyocyte apoptosis and mitophagy mediated by the HDAC3 and PINK1/Parkin pathways in CHF model mice were evaluated. In vitro, H9c2 cardiomyocytes subjected to hypoxia were treated with different concentrations of Xinyin. The mRNA transcription levels of HDAC3, PINK1, Parkin, P62, LC3II/I, caspase-3, caspase-9, and Bax were measured via fluorescence quantitative PCR. Western blotting was used to detect the protein expression levels of PINK1, Parkin, P62, LC3 II/I, caspase-3, caspase-9, and Bax. TUNEL staining was used to detect the number of apoptotic bodies in the myocardium to evaluate the level of apoptosis. Transmission electron microscopy was used to observe changes in the number of mitophagosomes. Rapamycin (mitophagy agonist), Mdivi-1 (mitophagy inhibitor), ITSA-1 (HDAC3 agonist) and RGFP966 (HDAC3 inhibitor) were used to create intervention conditions. The effects of rapamycin or Mdivi-1 on PINK1/Parkin-mediated mitophagy were observed. Then, the effects of HDAC3 on the PINK1/Parkin signaling pathway, mitophagy and apoptosis in hypoxic cardiomyocytes were observed. Hypoxic cardiomyocytes were treated with Xinyin-containing serum or control serum to observe whether Xinyin could still play a protective role in cardiomyocytes when HDAC3 is activated or mitophagy is inhibited.
    RESULTS: 785 compounds were characterized from Xinyin, among which carbohydrates and glycosides, phenylpropanoids, terpenes were abundant, and a small number of amino acids, peptides and derivatives also existed in Xinyin. In vivo, Xinyin improved cardiac function (LVEF, LVFS, LVEDD, LVESD, and LVESV) and downregulated the expression of caspase-3, caspase-9, and Bax. The expression levels of PINK1 and Parkin subsequently increased. In vitro, the above findings were reinforced in H9c2 cardiomyocytes. Rapamycin and RGFP966 reduced the apoptosis of hypoxic H9C2 cardiomyocytes and increased mitophagy mediated by the HDAC3-mediated PINK1/Parkin signaling pathway.
    CONCLUSIONS: Xinyin tablets have potential as an intervention for CHF by improving mitophagy and inhibiting cardiomyocyte apoptosis through the HDAC3-mediated PINK1/Parkin signaling pathway.
    Keywords:  HDAC3; PINK1; Parkin; Xinyin tablets; chronic heart failure
    DOI:  https://doi.org/10.1016/j.jep.2025.119666
  16. Ageing Res Rev. 2025 Mar 20. pii: S1568-1637(25)00080-7. [Epub ahead of print]108 102734
    Impact of diet and exercise on mitochondrial quality and mitophagy in Alzheimer's disease.
    Jangampalli Adi Pradeepkiran, Md Ariful Islam, Ujala Sehar, Arubala P Reddy, Murali Vijayan, P Hemachandra Reddy.
      Alzheimer's disease (AD) is a devastating neurodegenerative disorder that affects millions of people worldwide. It is characterized by the accumulation of beta-amyloid and phosphorylated tau, synaptic damage, and mitochondrial abnormalities in the brain, leading to the progressive loss of cognitive function and memory. In AD, emerging research suggests that lifestyle factors such as a healthy diet and regular exercise may play a significant role in delaying the onset and progression of the disease. Mitochondria are often referred to as the powerhouse of the cell, as they are responsible for producing the energy to cells, including neurons to maintain cognitive function. Our article elaborates on how mitochondrial quality and function decline with age and AD, leading to an increase in oxidative stress and a decrease in ATP production. Decline in mitochondrial quality can impair cellular functions contributing to the development and progression of disease with the loss of neuronal functions in AD. This article also covered mitophagy, the process by which damaged or dysfunctional mitochondria are selectively removed from the cell to maintain cellular homeostasis. Impaired mitophagy has been implicated in the progression and pathogenesis of AD. We also discussed the impact of impaired mitophagy implicated in AD, as the accumulation of damaged mitochondria can lead to increased oxidative stress. We expounded how dietary interventions and exercise can help to improve mitochondrial quality, and mitochondrial function and enhance mitophagy in AD. A diet rich in antioxidants, polyphenols, and mitochondria-targeted small molecules has been shown to enhance mitochondrial function and protect against oxidative stress, particularly in neurons with aged and mild cognitively impaired subjects and AD patients. Promoting a healthy lifestyle, mainly balanced diet and regular exercise that support mitochondrial health, in an individual can potentially delay the onset and progression of AD. In conclusion, a healthy diet and regular exercise play a crucial role in maintaining mitochondrial quality and mitochondrial function, in turn, enhancing mitophagy and synaptic activities that delay AD in the elderly populations.
    Keywords:  Alzheimer's disease; Diet; Exercise; Mitochondria; Mitophagy; Oxidative stress
    DOI:  https://doi.org/10.1016/j.arr.2025.102734
  17. Environ Int. 2025 Mar 17. pii: S0160-4120(25)00141-2. [Epub ahead of print]198 109390
    Long term exposure to multiple environmental stressors induces mitochondrial dynamics imbalance in testis: Insights from metabolomics and transcriptomics.
    Shiqin Jiang, Tianli Nong, Ting Yu, Zhiyan Qin, Junyuan Huang, Zhaokun Yin, Shiqi Luo, Yating Lai, Jing Jin.
      Long-term exposure to adverse environment stressors (e.g. noise pollution, temperature, and crowding) impaired human health. However, research on the toxic effects of adverse environmental stressors on the male reproductive system is limited. This study employed integrated phenomics, metabolomics, and transcriptomics to investigate physiological disturbances in the testis of mice exposed to multiple adverse environmental stressors for two months. Phenotypic studies indicated that long-term environmental stimuli resulted in significant damage to the blood-testis barrier (BTB) and testes, evidenced by reduced testicular index, disrupted testicular tissue structure, abnormal tight junction protein expression, and spermatozoa abnormalities. Comprehensive multi-omics analysis revealed that long-term exposure to environmental stressors disrupted the BTB and testes, which was associated with mitochondrial metabolism disorders, including oxidative phosphorylation and fatty acid beta-oxidation, as well as glutathione and lipid metabolism alterations. Among these dysregulated pathways, significant alterations were observed in the critical regulators of mitochondrial fusion (MFN2) and fission (DRP1) within the BTB. Specifically, corticosterone treatment decreased tight junction protein expression, increased reactive oxygen species (ROS) levels, and impaired mitochondrial morphology and function, as evidenced by reduced mitochondrial membrane potential, elevated calcium ion concentration, and shortened mitochondrial length and network in vitro. Moreover, inhibiting DRP1 with Mdivi-1 or overexpressing MFN2 mitigated the corticosterone-induced reduction of tight junctions and mitochondrial dysregulation in TM4 cells. Collectively, maintaining mitochondrial homeostasis emerges as a promising strategy to alleviate the BTB and testicular injury induced by long-term exposure to multiple environmental stressors.
    Keywords:  Blood-testis barrier; Long-term exposure to multiple environmental stressors; Mitochondrial dynamics; Multi-omics; Testis
    DOI:  https://doi.org/10.1016/j.envint.2025.109390
  18. J Integr Neurosci. 2025 Mar 18. 24(3): 26458
    Mechanisms Associated with Mitophagy and Ferroptosis in Cerebral Ischemia-reperfusion Injury.
    Yugang Ma, Xuebin Wang, Yahui Li, Jing Zhao, Xue Zhou, Xingchen Wang.
      Ischemic stroke (IS) constitutes a major threat to human health. Vascular recanalization by intravenous thrombolysis and mechanical thrombolysis remain the most significant and effective methods for relief of ischemia. Key elements of these treatments include achieving blood-vessel recanalization, restoring brain-tissue reperfusion, and preserving the ischemic penumbra. However, in achieving the therapeutic goals of vascular recanalization, secondary damage to brain tissue from cerebral ischemia-reperfusion injury (CIRI) must also be addressed. Despite advancements in understanding the pathological processes associated with CIRI, effective interventions to prevent its onset and progression are still lacking. Recent research has indicated that mitophagy and ferroptosis are critical mechanisms in the development of CIRI, and significantly contribute to the onset and progression of IS and CIRI because of common targets and co-occurrence mechanisms. Therefore, exploring and summarizing the potential connections between mitophagy and ferroptosis during CIRI is crucial. In the present review, we mainly focused on the mechanisms of mitochondrial autophagy and ferroptosis, and their interaction, in the development of CIRI. We believe that the data show a strong relationship between mitochondrial autophagy and ferroptosis with interactive regulation. This information may underpin new potential approaches for the prevention and treatment of IS and subsequent CIRI.
    Keywords:  cerebral ischemia-reperfusion injury; ferroptosis; ischemic stroke; mechanism research; mitophagy
    DOI:  https://doi.org/10.31083/JIN26458
  19. J Exp Pharmacol. 2025 ;17 143-157
    Inhibition of Mitochondrial Dynamics by Mitochondrial Division Inhibitor-1 Suppresses Cell Migration and Metastatic Markers in Colorectal Cancer HCT116 Cells.
    Tahir Mehmood, Qandeel Nasir, Iqra Younis, Chatchai Muanprasat.
       Introduction: The mitochondria are highly dynamic organelles. The mitochondrial morphology and spatial distribution within the cell is determined by fusion and fission processes of mitochondria. Several studies have used mitochondrial division inhibitor-1 (Mdivi.1) to explore the roles of mitochondrial dynamics in various pathological conditions, including diabetic cardiomyopathy, myocardial infarction, cardiac hypertrophy, Alzheimer's disease, Huntington's disease and cancers.
    Purpose: The objective of the study was to investigate the role of mitochondrial dynamics in the invasiveness of HCT116 colorectal cancer cells.
    Material and Methods: MTT assay was used to determine the Mdivi.1-induced toxicity in HCT116 cells. Wound healing, cell migration and colony forming assays were adopted to measure the migration and invasion activity of HCT116 cells. Furthermore, flow cytometry was used to determine the Mdivi.1-induced mitochondrial mass quantification, mitochondrial membrane potential and reactive oxygen species generation in HCT116 cells. Additionally, Western Blot analysis was used to determine the expression level of Drp1, p-Drp1, Mnf2, AMPK-α, p-AMPK-α, Cox-2, iNos and MMP9 in HCT116 cells.
    Results: We found that Mdivi.1 induced toxicity and altered the morphology of HCT116 cells in concentration- and time-dependent manners. Mdivi.1 significantly increased mitochondrial mass and dissipated the mitochondrial membrane potential. Furthermore, Mdivi.1 induced reactive oxygen species (ROS) generation and mitochondrial superoxide production, leading to AMPK activation. Moreover, Mdivi.1 decreased dynamin-related protein-1 (Drp1) and phosphorylated-Drp1 expression and increased mitofusin-2 (Mfn2) expression in a concentration-dependent manner at 48 and 72 h post-treatment. Notably, Mdivi.1 induced inhibition of translocation of Drp1 from the cytosol to the outer mitochondrial membrane. Mdivi.1 significantly suppressed the invasion and migration of HCT116 cells and inhibited the formation of HCT116 cell colonies. In addition, Mdivi.1 significantly decreased the expression of metastatic markers including Cox-2, iNos, and MMP-9 in HCT116 cells.
    Conclusion: Collectively, this study revealed that Mdivi.1 downregulates Drp1, upregulates Mfn2, and increases mitochondrial mass with attenuated oxidative metabolism, leading to the inhibition of cell invasion and metastasis in colorectal cancer HCT116 cells. Mitochondrial dynamics are regarded as possible drug targets for interrupting colorectal cancer cell migration and metastasis.
    Keywords:  Drp1; HCT116; Mdivi.1; Mfn2; invasion; mitochondria
    DOI:  https://doi.org/10.2147/JEP.S510578
  20. Sci Rep. 2025 Mar 27. 15(1): 10632
    Construction and evaluation of a diagnostic model for Alzheimer's disease based on mitophagy-related genes.
    Jiarui Liu, Mengyu Yan, Lihua Chen, Weihua Yu, Yang Lü.
      Alzheimer's disease (AD) is the most common cause of dementia. Mitophagy fulfills crucial functions in neurodegenerative disorders and neuronal survival but the relationship between mitophagy and AD is unclear. Mitophagy correlation scores between AD samples and control samples were calculated using single-sample GSEA (ssGSEA) based on two datasets from gene expression omnibus (GEO) database. Mitophagy-related genes (MRGs) and differentially expressed genes (DEGs) in AD screened by WGCNA and "limma" package were intersected to take common genes. These overlapping genes were further compressed and used for diagnostic modeling by adopting the recursive feature elimination (RFE) and LASSO analysis. The reliability of the diagnostic model was verified based on the receiver operating characteristic (ROC) curve. Then, a transcription factor (TF)-mRNA regulatory network of these key genes was established. Lastly, ssGSEA was employed to examine the relationship between the identified genes and cellular pathways and immune cell infiltration. AD samples had notably lower mitophagy correlation scores than control samples. A total of 12 MRGs in the module with the greatest mitophagy connection with AD patients were identified. Functional enrichment analysis revealed that the DEGs were significantly enriched in synaptic function-related pathways. Based on GSE122063, a diagnostic prediction model was created and validated using two mitophagy-related genes (YWHAZ and NDE1), showing an area under ROC curve (AUC) greater than 0.7. This confirmed that the diagnostic model had a high predictive value. The TF-mRNA network showed that four TFs, namely, FOXC1, FOXL1, HOXA5 and GATA2, were regulated by both YWHAZ and NDE1 genes. Immune infiltration analysis revealed that NDE1 promoted the infiltration of most immune cells, while YWHAZ mainly inhibited the infiltration of most immune cells. The current findings improved our understanding of mitophagy in AD, contributing to future research and treatment development in AD.
    Keywords:  Alzheimer’s disease; Biomarkers; Diagnostic model; Mitophagy; WGCNA
    DOI:  https://doi.org/10.1038/s41598-025-89980-4
  21. Int J Mol Sci. 2025 Mar 17. pii: 2709. [Epub ahead of print]26(6):
    Flutamide Promotes Early Hepatocarcinogenesis Through Mitophagy in High-Fat Diet-Fed Non-Obese Steatotic Rats.
    Emika Hara, Kanami Ohshima, Mio Takimoto, Yidan Bai, Mai Hirata, Wen Zeng, Suzuka Uomoto, Mai Todoroki, Mio Kobayashi, Takuma Kozono, Tetsuhito Kigata, Makoto Shibutani, Toshinori Yoshida.
      Flutamide (FL), a non-steroidal drug used for its antiandrogenic, anticancer, and disrupting endocrine properties, induces mitochondrial toxicity and drug metabolism enzymes and promotes hepatocarcinogenesis. The inhibition of mitophagy, leading to the accumulation of damaged mitochondria, is implicated in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). In this study, we investigated the effects of FL in high-fat diet (HFD)-induced non-obese steatosis rats, categorized into four groups: basal diet (BD), BD + FL, HFD, and HFD + FL. The FL exacerbated HFD-induced steatosis and marginally increased preneoplastic lesions. To analyze hepatic preneoplastic lesions, we divided them into clusters based on the expression ratios of the mitophagy regulators LC3 and AMBRA1. The expression rates of LC3 and AMBRA1 in these precancerous lesions were classified into three clusters using k-means clustering. The HFD group exhibited an increased ratio of mitophagy inhibition clusters, as indicated by decreased LC3 and increased AMBRA1 levels in background hepatocytes and preneoplastic lesions. FL counteracted HFD-mediated mitophagy inhibition, as indicated by increased LC3 and decreased AMBRA1 levels in background hepatocytes. Our clustering analysis revealed that FL-induced mitophagy induction relied on Parkin expression. The present study underscores the significance of cluster analysis in understanding the role of mitophagy within small preneoplastic lesions and suggests that FL may potentially exacerbate NAFLD-associated hepatocarcinogenesis by affecting mitophagy.
    Keywords:  AMBRA1; LC3; NAFLD; flutamide; mitophagy
    DOI:  https://doi.org/10.3390/ijms26062709
  22. Cytojournal. 2025 ;22 19
    Exploring miR-3148's impact on Krüppel-like factor 6-driven mitophagy and apoptosis in myocardial ischemic injury.
    Chusheng Huang, Lipeng Li, Hailong Deng, Jincheng Su, Qingjun Wei, Ying He, Lei Xian.
       Objective: Myocardial infarction (MI) is a leading cause of death worldwide, accounting for millions of fatalities annually. The injury and repair of cardiomyocytes are closely associated with the changes in gene expression. MicroRNAs could serve as a potential target for MI treatment. This work aims to investigate the role of miR-3148 in mitochondrial dynamics during acute MI (AMI) with a specific focus on its regulatory mechanisms in mitophagy and apoptosis, which could reveal potential therapeutic targets for AMI treatment.
    Material and Methods: MiR-3148 levels in patients with AMI and experimental models were measured to assess the effects of miR-3148 on cardiomyocyte viability under oxygen and glucose deprivation (OGD). The present investigation involved monitoring mitophagy markers, including PTEN-induced kinase 1 (PINK1), parkin RBR E3 ubiquitin-protein ligase (Parkin), Beclin1, and microtubule-associated protein 1A/1B light chain 3 II/I (LC3 II/I) ratio, as well as apoptotic markers such as cysteine-aspartic acid protease (Caspase) 9, Caspase 3, and cytochrome C (Cyt C). In addition, Krüppel-like factor 6 (KLF6) was examined as a target of miR-3148.
    Results: MiR-3148 was significantly elevated in patients with AMI and models. MiR-3148 overexpression reduced cardiomyocyte viability, whereas miR-3148 knockdown protected against OGD injury. The inhibition of miR-3148 activated mitophagy, as shown by the increased PINK1, Parkin, Beclin1 levels, and LC3 II/I ratios, and reduced sequestosome 1 (p62), and apoptotic markers levels. MiR-3148 directly targeted KLF6, reducing its expression. The suppression of KLF6 aggravated OGD injury by disrupting PINK1/Parkin-mediated mitophagy and enhancing apoptosis. Attenuating KLF6 expression reversed the protective effects of miR-3148 inhibition, indicating reciprocal regulation.
    Conclusion: In myocardial ischemic injury, miR-3148 modulates PINK1/Parkin-mediated mitophagy and apoptosis through KLF6 regulation. This finding highlights miR-3148 as a key factor in the pathogenesis of AMI and as a potential therapeutic target.
    Keywords:  Apoptosis; Krüppel-like factor 6; MiR-3148; Mitophagy; Myocardial infarction
    DOI:  https://doi.org/10.25259/Cytojournal_209_2024
  23. Front Med (Lausanne). 2025 ;12 1571785
    Corrigendum: HIF-1α alleviates high-glucose-induced renal tubular cell injury by promoting Parkin/PINK1-mediated mitophagy.
    Lu Yu, Yulin Wang, Yan Hong Guo, Liuwei Wang, Zijun Yang, Zi Han Zhai, Lin Tang.
      [This corrects the article DOI: 10.3389/fmed.2021.803874.].
    Keywords:  HIF-1α; ROS; apoptosis; diabetic nephropathy; inflammation; mitophagy
    DOI:  https://doi.org/10.3389/fmed.2025.1571785
  24. Br J Pharmacol. 2025 Mar 28.
    Ginsenoside Rh1 mitigates mitochondrial dysfunction induced by myocardial ischaemia through its novel role as a sirtuin 3 activator.
    Shuaishuai Gong, Hong Chen, Shuhua Fang, Mengyu Li, Jingui Hu, Yue Li, Boyang Yu, Junping Kou, Fang Li.
       BACKGROUND AND PURPOSE: The sirtuin 3 (SIRT3) signalling pathway is an essential target for various cardiovascular diseases (CVDs), although effective interventions in myocardial ischaemia-induced mitochondrial dysfunction remain to be elucidated. Here, we discovered a potent SIRT3 activator and explored its efficacy and mechanism against mitochondrial dysfunction.
    EXPERIMENTAL APPROACH: Molecular docking screened for SIRT3 activators among the 10 more common rare ginsenosides. In vivo, left coronary artery ligation induced myocardial ischaemia injury, followed by echocardiography, histopathology and serum biochemical indicators, in C57BL/6J mice. Expression levels of mitophagy and mitochondrial dynamics-associated proteins were examined by western blot (WB), immunofluorescence (IF) and immunohistochemistry (IHC). In vitro, oxygen-glucose deprivation-induced hypoxic injury in neonatal rat ventricular myocytes, and cell viability and mitochondrial function were investigated. SIRT3 small interference RNA (siRNA) was transfected into cardiomyocytes to validate mitochondrial dynamics and mitophagy mechanism regulated by ginsenoside Rh1.
    KEY RESULTS: Rh1 exhibited the strongest binding affinity as an effective activator of SIRT3. Rh1 improved cardiac function and mitigated myocardial ischaemia injury in vivo. Rh1 ameliorated oxidative stress, improved mitochondrial network morphology and mitochondrial respiration function in hypoxia-injured cardiomyocytes. Rh1 bound to SIRT3 and simultaneously up-regulated Foxo3a, facilitating its nuclear translocation and reducing acetylation of Foxo3a. Rh1 markedly promoted mitochondrial fusion, inhibited mitochondrial fission and accelerated mitophagy. SIRT3 siRNA abrogated the regulation of Rh1 on oxidative stress, mitochondrial dynamics and mitophagy.
    CONCLUSION AND IMPLICATIONS: Rh1 is a novel SIRT3 activator and protects against myocardial ischaemia-induced mitochondrial dysfunction, providing new clues to prevent and treat ischaemic injury-associated CVD.
    Keywords:  SIRT3; ginsenoside Rh1; mitochondrial dynamics; mitochondrial dysfunction; mitophagy; myocardial ischaemia
    DOI:  https://doi.org/10.1111/bph.70022
  25. Nat Commun. 2025 Mar 22. 16(1): 2839
    Mitochondria transplantation transiently rescues cerebellar neurodegeneration improving mitochondrial function and reducing mitophagy in mice.
    Shu-Jiao Li, Qian-Wen Zheng, Jie Zheng, Jin-Bao Zhang, Hui Liu, Jing-Jing Tie, Kun-Long Zhang, Fei-Fei Wu, Xiao-Dong Li, Shuai Zhang, Xin Sun, Yan-Ling Yang, Ya-Yun Wang.
      Cerebellar ataxia is the primary manifestation of cerebellar degenerative diseases, and mitochondrial dysfunction in Purkinje cells (PCs) plays a critical role in disease progression. In this study, we investigated the feasibility of mitochondria transplantation as a potential therapeutic approach to rescue cerebellar neurodegeneration and elucidate the associated mechanisms. We constructed a conditional Drp1 knockout model in PCs (PCKO mice), characterized by progressive ataxia. Drp1 knockout resulted in pervasive and progressive apoptosis of PCs and significant activation of surrounding glial cells. Mitochondrial dysfunction, which triggers mitophagy, is a key pathogenic factor contributing to morphological and functional damage in PCs. Transplanting liver-derived mitochondria into the cerebellum of 1-month-old PCKO mice improved mitochondrial function, reduced mitophagy, delayed apoptosis of PCs, and alleviated cerebellar ataxia for up to 3 weeks. These findings demonstrate that mitochondria transplantation holds promise as a therapeutic approach for cerebellar degenerative diseases.
    DOI:  https://doi.org/10.1038/s41467-025-58189-4
  26. Biol Chem. 2025 Mar 28.
    Unclogging of the TOM complex under import stress.
    Joshua Jackson, Thomas Becker.
      Mitochondrial functions and biogenesis depend on the import of more than 1,000 proteins which are synthesized as precursor proteins on cytosolic ribosomes. Mitochondrial protein translocases sort the precursor proteins into the mitochondrial sub-compartments: outer and inner membrane, the intermembrane space and the matrix. The translocase of the outer mitochondrial membrane (TOM complex) constitutes the major import site for most of these precursor proteins. Defective protein translocases, premature folding of the precursor, or depletion of the membrane potential can cause clogging of the TOM channel by a precursor protein. This clogging impairs further protein import and leads to accumulation of precursor proteins in the cell that perturbates protein homeostasis, leading to proteotoxic stress in the cell. Therefore, unclogging of the translocon is critical for maintaining mitochondrial and cellular function. Ubiquitylation and AAA-ATPases play a central role in the extraction of the precursor proteins to deliver them to the proteasome for degradation. Here we summarize our understanding of the molecular mechanisms that remove such translocation-stalled precursor proteins from the translocation channel to regenerate the TOM complex for protein import.
    Keywords:  AAA ATPases; TOM complex; mitochondria; protein import; quality control; ubiquitylation
    DOI:  https://doi.org/10.1515/hsz-2025-0110
  27. J Cardiovasc Transl Res. 2025 Mar 26.
    The Role of Mitophagy in Cardiac Metabolic Remodeling of Heart Failure: Insights of Molecular Mechanisms and Therapeutic Prospects.
    Fangying Yan, Liwen Bao.
      Heart failure (HF) treatment remains one of the major challenges in cardiovascular disease management, and its pathogenesis requires further exploration. Cardiac metabolic remodeling is of great significance as a key pathological process in the progression of HF. The complex alterations of metabolic substrates and associated enzymes in mitochondria create a vicious cycle in HF. These changes lead to increased reactive oxygen species, altered mitochondrial Ca2+ handling, and the accumulation of fatty acids, contributing to impaired mitochondrial function. In this context, mitophagy plays a significant role in clearing damaged mitochondria, thereby maintaining mitochondrial function and preserving cardiac function by modulating metabolic remodeling in HF. This article aims to explore the role of mitophagy in cardiac metabolic remodeling in HF, especially in obesity cardiomyopathy, diabetic cardiomyopathy, and excessive afterload-induced heart failure, thoroughly analyze its molecular mechanisms, and review the therapeutic strategies and prospects based on the regulation of mitophagy.
    Keywords:  Cardiac metabolic remodeling; Heart failure; Mitophagy; Molecular mechanisms; Therapeutic prospects
    DOI:  https://doi.org/10.1007/s12265-025-10606-1
  28. J Bioenerg Biomembr. 2025 Mar 26.
    Correction: 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.
      
    DOI:  https://doi.org/10.1007/s10863-025-10058-x
  29. Front Pharmacol. 2025 ;16 1526253
    Danqi soft caspule alleviates myocardial ischemia-reperfusion injury induced cardiomyocyte apoptosis by attenuating mitochondrial fission.
    Ye Yang, Cuiting Lin, Yan Wang, Yu Liu, Qiuxiong Chen, Shiyu Ma, Jin Ma.
       Background: Myocardial ischemia-reperfusion (I/R) injury which leads to continuously worsening ventricular remodeling and cardiac dysfunction in the chronic stage, is a significant contributor to the global prevalence of heart failure. Traditional Chinese herbal formulas have been shown to prevent myocardial I/R injury.
    Method: This study aims to investigate whether Danqi soft caspule (DQ), a classical traditional Chinese medicine (TCM) preparation, exerted the protective effects against myocardial I/R injury and explore the potential underlying mechanisms. A rat model of myocardial I/R and a cell model of H2O2 induced oxidative stress injury were established to assess the effects of DQ on cardiac injury, cardiomyocyte apoptosis, as well as mitochondrial structure and function.
    Result: DQ pre-treatment reduced both the proportion of infarct area and ischemic risk area and decreased cardiomyocyte apoptosis in myocardial I/R injury rats. In H2O2 induced cells, DQ was found to reduce cell apoptosis and lower oxidative stress levels. Furthermore, DQ inhibited mitochondrial fission, prevented alterations in mitochondrial membrane potential, and suppressed Cytochrome C release from the mitochondria, thereby preventing apoptosis. DQ has protective effects against I/R induced oxidative stress injury by reducing cardiomyocyte apoptosis through inhibition mitochondrial fission. Moreover, DQ could restore mitochondrial structure and function by suppressing the phosphorylation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) and dynamin-related protein 1 (Drp-1).
    Conclusion: DQ inhibited I/R injury and cardiomyocyte apoptosis by reducing mitochondrial fission associated with suppressing the phosphorylation of CaMKII and Drp-1.
    Keywords:  Chinese botanical drug; cell apoptosis; mitochondrial dynamics; myocardial ischemia-reperfusion injury; oxidative stress
    DOI:  https://doi.org/10.3389/fphar.2025.1526253
  30. Sci Rep. 2025 Mar 22. 15(1): 9971
    A cellular assay to determine the fusion capacity of MFN2 variants linked to Charcot-Marie-Tooth disease of type 2 A.
    Chloe Barsa, Julian Perrin, Claudine David, Arnaud Mourier, Manuel Rojo.
      Charcot-Marie-Tooth Disease (CMT) is an inherited peripheral neuropathy with two main forms: demyelinating CMT1 and axonal CMT2. The most frequent subtype of CMT2 (CMT2A) is linked to mutations of MFN2, encoding a ubiquitously expressed GTP-binding protein anchored to the mitochondrial outer membrane and essential for mitochondrial fusion. The use of Next-Generation Sequencing has led to the identification of increasing numbers of MFN2 variants, yet many of them remain of unknown significance, depriving patients of a clear diagnosis. In this work, we establish a cellular assay allowing to assess the impact of 12 known MFN2 variants linked to CMT2A on mitochondrial fusion. The functional analysis revealed that out of the 12 selected MFN2 mutations, only six exhibited reduced fusion activity. The classification of MFN2 variants according to the results of the functional assay revealed a correlation between the fusion capacity, the age at onset of CMT2A and computational variant effect predictions relying on the analysis of the protein sequence. The functional assay and the results obtained will assist and improve the classification of novel MFN2 variants identified in patients.
    Keywords:  CMT2A; Charcot–Marie-Tooth disease; MFN2; Mitochondrial dynamics; Mitochondrial fusion; Single nucleotide variants; Variant effect predictor; Variants of unknown significance
    DOI:  https://doi.org/10.1038/s41598-025-93702-1
  31. Biochem Biophys Res Commun. 2025 Mar 21. pii: S0006-291X(25)00386-9. [Epub ahead of print]759 151672
    PINK1 link mitochondria-ER contacts controls deposition of intramuscular fat in pigs.
    Jiaxin Cao, Nana Li, Ruolan Huang, Fengjuan Jia, Ziyi He, Wenlong Han, Wenzhang Liu, Songqiao Li, Weiye Wang, Weiyuan Ren, Bo Xia.
      Intramuscular fat (IMF) is a key determinant of meat quality in pigs, influencing characteristics such as tenderness, flavor, and marbling. The regulation of IMF deposition involves complex metabolic processes, with mitochondrial function playing a central role. PTEN-induced kinase 1 (PINK1), a protein involved in mitophagy and mitochondrial quality control, has recently been implicated in regulating fat deposition, although its role in IMF deposition in pigs remains unclear. This study investigates how PINK1 regulates IMF deposition by modulating mitochondrial-endoplasmic reticulum (ER) interactions. We utilized single-cell RNA sequencing to demonstrate that PINK1 is predominantly expressed in fibro-adipogenic progenitors (FAPs) and adipocytes, and its expression is negatively correlated with IMF content in multiple pig breeds. Knockdown of PINK1 in vivo led to increased intramuscular triglyceride content and enhanced adipogenic differentiation in primary porcine IMF cells. Additionally, PINK1 depletion resulted in impaired mitochondrial respiration, increased mitochondrial biogenesis, and disruption of mitochondria-ER contacts, further suggesting that PINK1 mediated of mitochondrial function and communication between mitochondria and ER is essential for controlling lipid deposition. These findings provide novel insights into the molecular mechanisms governing IMF accumulation and highlight PINK1 as a potential target for manipulating fat deposition in both agricultural and biomedical contexts.
    Keywords:  Intramuscular fat; Mitochondria-ER contacts; Mitophagy; PINK1; Pig
    DOI:  https://doi.org/10.1016/j.bbrc.2025.151672
  32. Physiol Res. 2025 Mar 24. 74(1): 79-92
    The Role of Mdivi-1 in Reducing Mitochondrial Fission via the NF-kappaB/JNK/SIRT3 Signaling Pathway in Acute Kidney Injury.
    X-Y Gou, Y Li, X-P Fan.
      To explore the effects and underlying mechanisms of Mdivi-1 on three common clinical models of acute kidney injury (AKI). Three common AKI cell models were constructed, classified into the control group (human renal tubular epithelial cells [HK-2] cells), the Iohexol group (HK-2 cells treated with Iohexol), the Genta group (HK-2 cells treated with Gentamicin), and the Cis group (HK-2 cells treated with Cisplatin). To explore the optimal protective concentration of Mdivi-1 for each AKI cell model, the experimental design consisted of the following seven groups: the control group (HK-2 cells cultured in medium), three injury groups (HK-2 cells subjected to Iohexol, Gentamicin, or Cisplatin), and the corresponding protection groups (with a certain concentration of Mdivi-1 added to each injury group). Cellular survival and apoptosis, reactive oxygen species (ROS) levels, and the expression of recombinant Sirtuin 3 (SIRT3) in each group were measured. Mitochondrial fission and fusion dynamics in cells were observed under an electron microscope. To explore relevant pathways, the changes in relevant pathway proteins were analyzed through Western blotting. The half maximal inhibitory concentration (IC50) values were 150.06 mgI/ml at 6 h in the Iohexol group, 37.88 mg/ml at 24 h in the Gentamicin group, and 13.48 microM at 24 h in the Cisplatin group. Compared with the control group, the three injury groups showed increased cell apoptosis rates and higher expressions of apoptotic proteins in HK-2 cells, with an accompanying decrease in cell migration. After the addition of corresponding concentrations of Mdivi-1, the optimal concentrations were 3 µM in the Iohexo-3 group, 1 microM in the Genta-1 group, and 5 µM in the Cis-5 group, HK-2 cells showed the highest survival rate, reduced apoptosis, decreased mitochondrial ROS and SIRT3 expression, and reduced mitochondrial fission and autophagy when compared with each injury group. Further verification with Western blot analysis after the addition of Mdivi-1 revealed a reduction in the expressions of mitochondrial fission proteins DRP1, Nrf2, SIRT3, Caspase-3, Jun N-terminal Kinase (JNK)/P-JNK, NF-kappaB, Bcl2, and autophagic protein P62, as well as reduced ROS levels. Mdivi-1 had protective effects on the three common AKI cell models by potentially reducing mitochondrial fission in cells and inhibiting the production of ROS through the mediation of the NF- B/JNK/SIRT3 signaling pathway, thereby exerting protective effects. Key words AKI, Cisplatin, Gentamicin, Iohexol, Mdivi-1.
  33. Int J Biochem Cell Biol. 2025 Mar 21. pii: S1357-2725(25)00039-1. [Epub ahead of print] 106772
    Selective cerebral hypothermia alleviates focal cerebral ischemia/reperfusion injury via enhancing SUMO2/3 modification of Drp1 in rats.
    Yang Yuan, Li Fu, Wenji Liu, Rui Dong, Fei Shi, Jinhao Liu, Hong Li, Gaofeng Zhang.
       BACKGROUND: Selective Cerebral Hypothermia (SCH) has been demonstrated to potentiate SUMO2/3 modification, a native cellular safeguard against Cerebral Ischemia/Reperfusion Injury (CIRI). Dynamin-Related Protein 1 (Drp1), a pivotal regulator in the mitochondrial fission pathway, is an important substrate for SUMO2/3 modification. However, effects of SCH on SUMO2/3 modification of Drp1 remain undefined. Herein, the current study posits that SCH augments the SUMO2/3 modification of Drp1, thereby preserving mitochondrial integrity and mitigating CIRI.
    METHODS: A focal CIRI model was established in Sprague-Dawley rats, with 20°C saline perfused via the transcarotid artery to induce SCH condition, and 37°C saline serving as a control. The modified Neurological Severity Score (mNSS) was used to quantitate the degree of neurological deficits. Staining of 2,3-5-triphenyltetrazolium chloride (TTC) was performed to detect cerebral infarction volume. Histological change of neurocyte was observed through Hematoxylin-eosin (HE) staining. Neurocyte apoptosis was evaluated using terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) immunofluorescence staining. Western blot (WB) was utilized to evaluated the expressions of Drp1 and Cytochrome C. Co-immunoprecipitation was performed to evaluate the level of SUMO2/3 modification of Drp1. And transmission electron microscopy was used to observe the mitochondrial ultrastructure. The ratio of M-Drp1 to T-Drp1 and mitochondria morphological changes were observed under confocal microscopy.
    RESULTS: Research data revealed that SCH significantly enhanced the SUMO2/3 modification of Drp1 when CIRI occurred. Concurrently, mNSSs, cerebral infarct volume, and apoptotic rates were notably attenuated in the SCH group, corroborating SCH's protective role. Expression levels of mitochondrial outer membrane Drp1 (M-Drp1), cytoplasmic cytochrome C (C-CytC), and ratio of M-Drp1 to T-Drp1 were reduced, and changes of mitochondrial ultrastructural and morphology were mitigated, underscoring SCH's inhibitory effect on mitochondrial fission. In contrast, 37°C saline displayed negligible protective impact while compare with 20°C saline perfusion.
    CONCLUSIONS: The findings support that SCH amplifies SUMO2/3 modification of Drp1, curtails excessive mitochondrial fission, and consequently ameliorates focal CIRI in a rat model.
    Keywords:  Drp1; Ischemia/reperfusion injury; Mitochondrial fission; Neuroprotection; SUMO2/3; SUMOylation; Selective brain hypothermia
    DOI:  https://doi.org/10.1016/j.biocel.2025.106772
  34. Adv Biol (Weinh). 2025 Mar 24. e2400597
    Ameliorating TIMM50 Loss Slows Senescence by Improving Mitochondrial Structure and Function.
    Amrita Nepalia, Deepak Kumar Saini.
      Mitochondrial dysfunction is an irrefutable hallmark of cellular senescence and aging. The dysfunction is marked by increased mitochondrial volume and reduced function, typified by low Adenosine Triphosphate (ATP) production and higher Reactive Oxygen Species (ROS) generation. Over the years, this dysfunction has been linked to Electron Transport Chain (ETC) malfunction and low NAD levels, augmented by poor mitophagy. However, the genetic regulation of mitochondrial dysfunction is still not clear. Here, using several senescence models, the first report on the role of the downregulation of a mitochondrial protein, Translocase of Inner Mitochondrial Membrane 50 (TIMM50), in senescence is presented. The downregulation of TIMM50 is also sufficient for triggering senescence through impaired mitochondrial function, characterized using a variety of mitochondrial function assessment assays. Reduced levels of TIMM50 initiated all the hallmarks of senescence, and overexpression significantly slowed senescence onset in response to an external trigger. The pathway analysis revealed that TIMM50 loss is mediated by the sirtuin1-dependent downregulation of CCAAT enhancer binding protein alpha (CEBPα), a transcription activator for TIMM50 expression. To establish the translational value of the observation, screening several potential anti-aging compounds revealed TIMM50 stabilizing and senescence-delaying effects only for verapamil and mitochondrial ROS quencher, Mito (2-(2,2,6,6-Tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl)triphenylphosphonium chloride (MitoTEMPO), both known anti-aging entities. Overall, TIMM50 is identified as the key mitochondrial protein whose downregulation is a critical step in initiating cellular senescence.
    Keywords:  TIMM50; aging; cellular senescence; mitochondria; sirtuin
    DOI:  https://doi.org/10.1002/adbi.202400597
  35. Nat Commun. 2025 Mar 21. 16(1): 2810
    Dependence of mitochondrial calcium signalling and dynamics on the disaggregase, CLPB.
    Donato D'Angelo, Víctor H Sánchez-Vázquez, Benjamín Cartes-Saavedra, Denis Vecellio Reane, Ryan R Cupo, Hilda Delgado de la Herran, Giorgia Ghirardo, James Shorter, Ron A Wevers, Saskia B Wortmann, Fabiana Perocchi, Rosario Rizzuto, Anna Raffaello, György Hajnóczky.
      Cells utilize protein disaggregases to avoid abnormal protein aggregation that causes many diseases. Among these, caseinolytic peptidase B protein homolog (CLPB) is localized in the mitochondrial intermembrane space and linked to human disease. Upon CLPB loss, MICU1 and MICU2, regulators of the mitochondrial calcium uniporter complex (mtCU), and OPA1, a main mediator of mitochondrial fusion, become insoluble but the functional outcome remains unclear. In this work we demonstrate that CLPB is required to maintain mitochondrial calcium signalling and fusion dynamics. CLPB loss results in altered mtCU composition, interfering with mitochondrial calcium uptake independently of cytosolic calcium and mitochondrial membrane potential. Additionally, OPA1 decreases, and aggregation occurs, accompanied by mitochondrial fragmentation. Disease-associated mutations in the CLPB gene present in skin fibroblasts from patients also display mitochondrial calcium and structural changes. Thus, mtCU and fusion activity are dependent on CLPB, and their impairments might contribute to the disease caused by CLPB variants.
    DOI:  https://doi.org/10.1038/s41467-025-57641-9
  36. One Health Adv. 2025 ;3(1): 5
    Arginine as host directed therapy in tuberculosis: insights from modulating arginine metabolism by supplementation and arginase inhibition.
    Qingkui Jiang, Ranjeet Kumar, Yi Zhao, Selvakumar Subbian, Lanbo Shi.
      Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a global health challenge. Arginine metabolism is central to immune responses, regulating nitric oxide (NO) production via inducible NO synthase (Nos2) and competing pathways mediated by arginases (Arg1 and Arg2). This study examines the impact of arginine supplementation and arginase inhibition during the acute phase of Mtb infection in mouse lungs, focusing on immune function, lung pathology, and mitochondrial function. Arginine supplementation enhanced Nos2 expression, promoted mitophagy, and supported angiogenesis and/or tissue repair by upregulating Vegfa. These mechanisms synergized to balance pro-inflammatory responses with tissue repair, improving immune defense while mitigating lung damage. In contrast, arginase inhibition disrupted Vegfa-mediated immune homeostasis, and impaired mitophagy, leading to exacerbated lung pathology. These findings underscore the complementary roles of Nos2 and arginase-mediated pathways in maintaining immune equilibrium during Mtb infection. Our results highlight arginine supplementation as a promising host-directed therapy for TB, capable of enhancing protective immunity and facilitating tissue repair. Conversely, caution is warranted for strategies targeting arginase due to potential adverse effects on inflammation resolution and mitochondrial quality control. Future studies should explore the long-term efficacy of arginine-based therapies and their integration with existing antibiotic regimens for optimal TB management.
    Supplementary Information: The online version contains supplementary material available at 10.1186/s44280-025-00070-6.
    Keywords:  Arginase; Arginine metabolsim; Cytokine network; Host directed therapy; Mitophagy; Mycobacterium tuberculosis
    DOI:  https://doi.org/10.1186/s44280-025-00070-6
  37. J Orthop Translat. 2025 Mar;51 132-144
    JP4-039 protects chondrocytes from ferroptosis to attenuate osteoarthritis progression by promoting Pink1/Parkin-dependent mitophagy.
    Ya Xie, Zhongyang Lv, Weitong Li, JinTao Lin, Wei Sun, Hu Guo, Xiaoyu Jin, Yuan Liu, Ruiyang Jiang, Yuxiang Fei, Rui Wu, Dongquan Shi.
       Background: Osteoarthritis (OA) is the most common degenerative joint disease, and its main pathological mechanism is articular cartilage degeneration. The purpose of this study was to investigate the role of mitophagy in the pathogenesis of chondrocyte ferroptosis in OA.
    Methods: The expressions of ferroptosis related proteins (GPX4, FTH1, COX2) and ubiquitin-dependent mitophagy related proteins (PARKIN, PINK1) in the intact and injured areas of OA cartilage were analyzed. Nitro oxide JP4-039, a mitochondrial targeting antioxidant, has bifunctional role of targeting mitochondria. Then we evaluated the potential protective effect of JP4-039 in OA using the destabilization of medial meniscus (DMM)-induced OA model, as well as tert-butyl hydrogen peroxide (TBHP)-treated primary mouse chondrocytes and human cartilage explants.
    Results: The concentrations of iron and lipid peroxidation and the expression of ferroptosis drivers in the damaged areas of human OA cartilages were significantly higher than those in the intact cartilage. Pink1/Parkin-dependent mitophagy decreased in the injured area of human OA cartilage and was negatively correlated with ferroptosis. Then, the toxicity and effectiveness of JP4-039 are tested to determine its working concentration. Next, at the molecular biological level, we found that JP4-039 showed the effect of anti-chondrocyte ferroptosis. Moreover, it was verified on DMM-induced OA model mice, that JP4-039 could delay the progression of OA. Finally, JP4-039 was re-verified in vivo and in vitro to inhibit chondrocyte ferroptosis and delay the progression of OA by promoting Pink1/Parkin-dependent mitophagy.
    Conclusion: JP4-039 inhibits ferroptosis of chondrocytes by promoting Pink1/Parkin-dependent mitophagy and delays OA progression.
    Keywords:  Ferroptosis; JP4-039; Mitophagy; Osteoarthritis
    DOI:  https://doi.org/10.1016/j.jot.2025.01.001
  38. Poult Sci. 2025 Mar 18. pii: S0032-5791(25)00273-1. [Epub ahead of print]104(5): 105034
    Dihydromyricetin ameliorates lipopolysaccharide‒induced hepatic injury in chickens by activating the Nrf2/Keap1 pathway and regulating mitochondrial dynamics.
    Liang Yuan, Xinru Jiang, Yani Ren, Bingke Ma, Zhenghua Ji, Shibo Wang, Beili Hao, Changwen Li, Rui Li, Fangping Liu.
      Dihydromyricetin (DHM) is a flavonoid found in vine tea that exhibits various pharmacological characteristics, including antibacterial, antiapoptotic, and antioxidant effects. Our previous study revealed that DHM can alleviate chicken hepatic injury, but the underlying mechanism has not been elucidated. To further investigate the protective mechanism of DHM, this study firstly predicted by network pharmacology that the potential regulatory pathways of DHM on hepatic injury. Subsequently, the experimental models were replicated in vivo and in vitro using Hy‒Line white broiler chickens and chicken primary hepatocytes treated with DHM and with/ without LPS. Network pharmacology results showed that the effect of DHM on hepatic injury might be related to oxidative stress and mitochondrial function. Further experiments showed that DHM significantly reduced LPS‒elicited serum ALT and AST activities, promoted antioxidant enzyme activities and scavenged ROS in chicken liver or primary hepatocytes. Molecular docking studies showed that DHM could directly bind to Nrf2 and Keap1. Furthermore, DHM treatment regulated the expression of Nrf2 and Keap1, thereby upregulating the downstream expression of antioxidant factors, including HO‒1 and NQO1, in vivo and in vitro. Moreover, DHM modulated the expression of mitochondrial dynamics related factors, including Mfn1/2, Opa1, Drp1, and Fis1, meanwhile, DHM ameliorated mitochondrial structural damage and increased the MMP. Overall, these results suggested that DHM activated the Nrf2/Keap1 pathway and regulated the balance between mitochondrial fusion and fission, ultimately alleviating chicken hepatic injury induced by LPS.
    Keywords:  Dihydromyricetin; Nrf2/Keap1 pathway, Mitochondrial dynamics, Oxidative stress, Hepatic injury
    DOI:  https://doi.org/10.1016/j.psj.2025.105034
  39. J Cardiovasc Aging. 2025 Jan;pii: 4. [Epub ahead of print]5(1):
    Aging triggers mitochondrial, endoplasmic reticulum, and metabolic stress responses in the heart.
    Sakthijothi Muthu, Zinnia Tran, Jayapalraja Thilagavathi, Tanvi Bolarum, Edouard I Azzam, Carolyn K Suzuki, Venkatesh Sundararajan.
       Introduction: Aging is a multifaceted biological process characterized by a progressive decline in cellular and tissue function. It significantly impacts the cardiovascular system and contributes to the onset of cardiovascular diseases. The mitochondria (mt) and the endoplasmic reticulum (ER) play synergistic roles in maintaining cellular homeostasis and energy production in the heart. Nevertheless, their response to cardiac aging is not well known.
    Aim: This study explores mt and ER stress responses and their associated factors, such as metabolic, cellular, and autophagic stress, in cardiac aging.
    Methods and Results: We utilized 10- and 25-month-old CBA/CaJ mice to evaluate mt, ER, and their associated factors, such as metabolic, cellular, and autophagic stress responses. We studied the gene expression for mitochondrial biogenesis, mt and ER stress response, autophagy and metabolic markers, and activating transcription factors that mediate cellular stress responses. We found no significant difference in mtDNA content and the mRNA expression of the mt transcription factor, Tfam; however, selective mtDNA genes, such as mt-Cytb and mt-Co2, showed significant induction in 25-month-aged compared to 10-month-young hearts. Interestingly, genes of several mitochondrial stress response proteases and their components, including Lonp1, Yme1l1, Afg3l2, and Spg7, were significantly induced, with a substantial induction of Clpp and Clpx. However, age-associated differences were not observed in the induction of mt chaperones (Hspa9 and Hspd1), but significant induction of Dnaja2, a mitochondrial co-chaperone, was observed. The ER stress transcription factors Xbp1 and Atf6 were markedly induced in aged hearts, accompanied by decreased expression of ER stress chaperone Hsp90b with no change in Hspa5 and Dnajb9 chaperones. However, induction of Dnm1l was significant, whereas Mfn1 and Fis1 were downregulated in contrast to Mfn2, suggesting dysregulated mitochondrial dynamics in the aged heart with no change in autophagy and metabolic stress regulators observed. Furthermore, aged hearts showed significantly increased oxidative damage as evidenced by elevated lipid peroxidation (4-HNE) levels.
    Conclusion: These findings demonstrate that aging triggers mt, ER, and oxidative stress in the heart, which over time leads to the accumulation of oxidative damage, causing cellular impairment, highlighting these pathways as potential therapeutic targets for mitigating age-related cardiac dysfunction.
    Keywords:  Aging; endoplasmic reticulum stress; heart; mitochondrial stress; oxidative stress
    DOI:  https://doi.org/10.20517/jca.2024.17
  40. Biomolecules. 2025 Mar 06. pii: 383. [Epub ahead of print]15(3):
    The Association Among Bipolar Disorder, Mitochondrial Dysfunction, and Reactive Oxygen Species.
    Yuki Kageyama, Shohei Okura, Ayaka Sukigara, Ayaka Matsunaga, Kunio Maekubo, Takafumi Oue, Koki Ishihara, Yasuhiko Deguchi, Koki Inoue.
      Mitochondria, often known as the cell's powerhouses, are primarily responsible for generating energy through aerobic oxidative phosphorylation. However, their functions extend far beyond just energy production. Mitochondria play crucial roles in maintaining calcium balance, regulating apoptosis (programmed cell death), supporting cellular signaling, influencing cell metabolism, and synthesizing reactive oxygen species (ROS). Recent research has highlighted a strong link between bipolar disorder (BD) and mitochondrial dysfunction. Mitochondrial dysfunction contributes to oxidative stress, particularly through the generation of ROS, which are implicated in the pathophysiology of BD. Oxidative stress arises when there is an imbalance between the production of ROS and the cell's ability to neutralize them. In neurons, excessive ROS can damage various cellular components, including proteins in neuronal membranes and intracellular enzymes. Such damage may interfere with neurotransmitter reuptake and the function of critical enzymes, potentially affecting brain regions involved in mood regulation and emotional control, which are key aspects of BD. In this review, we will explore how various types of mitochondrial dysfunction contribute to the production of ROS. These include disruptions in energy metabolism, impaired ROS management, and defects in mitochondrial quality control mechanisms such as mitophagy (the process by which damaged mitochondria are selectively degraded). We will also examine how abnormalities in calcium signaling, which is crucial for synaptic plasticity, can lead to mitochondrial dysfunction. Additionally, we will discuss the specific mitochondrial dysfunctions observed in BD, highlighting how these defects may contribute to the disorder's pathophysiology. Finally, we will identify potential therapeutic targets to improve mitochondrial function, which could pave the way for new treatments to manage or mitigate symptoms of BD.
    Keywords:  bipolar disorder; inflammation; mitophagy; reactive oxygen species; synaptic plasticity
    DOI:  https://doi.org/10.3390/biom15030383
  41. Exp Gerontol. 2025 Mar 25. pii: S0531-5565(25)00067-1. [Epub ahead of print]204 112738
    Molecular mechanism of melatonin-mediated mitophagy regulating proline production to ameliorate skin aging.
    Tao Quan, Ran Li, Ting Gao.
      Collagen loss is one of the major contributor to signs of skin aging such as dryness, roughness, and wrinkle formation, which is closely linked to a decline in the amount of proline produced in mitochondria. Melatonin has been shown to improve several clinical signs of skin aging, while the mechanism is unclear. In our study, we found that mitophagy, proline synthesis key enzyme NADK2 and proline and collagen levels were significantly reduced, while oxidative stress levels increased in aging skin, and melatonin supplementation could effectively up-regulate mitophagy level and restore proline synthesis and further improved skin aging. However, proline supplementation could also exert an anti-aging effect, while it had no effect on the mitochondrial dysfunction. Moreover, our study indicated that melatonin enters the cell by binding to the MT1 receptor and then enters the mitochondria via the PEPT1 transporter to exert its mitochondrial protective effects. This study helps to elucidate the mechanism of mitochondrial dysfunction-induced skin aging, and provides new theoretical guidance for revealing the mechanism of skin aging and rationally utilizing endocrine hormones to improve skin aging, which has a broad application prospect.
    Keywords:  Collagen; Melatonin; Mitophagy; Proline; Skin aging
    DOI:  https://doi.org/10.1016/j.exger.2025.112738
  42. J Proteome Res. 2025 Mar 26.
    Elucidating the Molecular Mechanisms of Hederagenin-Regulated Mitophagy in Cervical Cancer SiHa Cells through an Integrative Approach Combining Proteomics and Advanced Network Association Algorithm.
    Hao Sun, Dan Wang, Yongquan Zheng, Yiqing Ye.
      Hederagenin (Hed), a natural triterpenoid, exhibits antitumor potential in cervical cancer. The present study was designed to explore Hed's regulatory mechanisms on mitophagy in SiHa cervical cancer cells, employing tandem mass tag (TMT) proteomics and an advanced network association algorithm (NAA). Our findings revealed that Hed decreased SiHa cell viability, induced apoptosis, and altered mitochondrial membrane potential. Notably, Hed inhibited mitophagic flux under both normoxic and hypoxic conditions. Through TMT proteomics analysis and innovative NAA, we identified a close association between the HIF-1 signaling pathway and mitophagy. Network analysis further suggested that Hed acts on a target network centered on SRC, STAT3, AKT1, and HIF1A. Western blot analysis confirmed the expression and phosphorylation status of these targets in response to Hed. This study elucidates the molecular mechanisms underlying Hed's regulation of mitophagy in SiHa cells, offering novel insights and potential therapeutic targets for cervical cancer treatment.
    Keywords:  SiHa cells; TMT proteomics; cervical cancer; hederagenin; mitophagy; network association algorithm
    DOI:  https://doi.org/10.1021/acs.jproteome.5c00022
  43. Cancer Lett. 2025 Mar 22. pii: S0304-3835(25)00213-7. [Epub ahead of print]619 217647
    Targeting mitochondrial ribosomal protein expression by andrographolide and melatonin for colon cancer treatment.
    Advaitha Midde, Navpreet Arri, Tibor Kristian, Suprabhat Mukherjee, Parth Sarthi Sen Gupta, Yuji Zhang, Mariuz Karbowski, Jaylyn Waddell, Nagarajan Maharajan, Md Sazzad Hassan, Heather M O'Hagan, Michal Zalzman, Aditi Banerjee.
      Colospheroids contain colon cancer stem cells (CSCs) that cause colorectal cancer metastasis (mCRC). Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the U.S. Little is known about the role of mitochondria in the survival and metastatic ability of CSCs. In this study, we investigate the effect of andrographolide (AGP) and melatonin (MLT) on mitochondrial dynamics (including fusion and fission) and the expression of mitochondrial ribosomal proteins (MRPs). Our results show that AGP and MLT synergistically reduce the total active mitochondrial mass, downregulate fusion and fission proteins, reduce OXPHOS proteins, and lead to CSC growth inhibition via Nrf2 and KEAP1 signaling. Microarray revealed 4389 differentially expressed mRNAs in the AGP and MLT combination compared to the control. Results exhibiting a three-fold induction/reduction were validated by qRT-PCR and immunoblot. MRPS6, a mitochondrial ribosomal (Mitoribosome) small subunit protein, was dramatically downregulated by AGP + MLT treatment compared to control. MRPS6 inhibition by siRNA reduced mCRC cell viability. Molecular docking-based protein-ligand interactions showed that AGP has direct physical interaction with MRPS6 and increases the binding affinity of MLT to MRPS6. This drug combination downregulated genes in the NRF2 (NFE2L2) pathway in CSCs. MRPS6 may be directly linked to CSC proliferation and could be a therapeutic target for this population. Functionally, MRPS6 knockdown significantly reduced colony formation, with enhanced suppression in AGP + MLT-treated cells. In xenograft models, the AGP-MLT combination synergistically decreased MRPS6 expression and increased apoptosis, as evidenced by TUNEL assays, demonstrating the therapeutic potential of targeting MRPS6 in CRC.
    Keywords:  Andrographolide; Colon cancer stem cells; Colospheroids (3D spheroids culture model); Fusion-fission protein; Melatonin; Mitochondrial dynamics; Mitochondrial mass; Mitochondrial ribosomal protein
    DOI:  https://doi.org/10.1016/j.canlet.2025.217647
  44. J Transl Med. 2025 Mar 24. 23(1): 366
    Mfn2 regulates calcium homeostasis and suppresses PASMCs proliferation via interaction with IP3R3 to mitigate pulmonary arterial hypertension.
    Rui Wang, Jie Wang, Jing Yu, Zhiqiang Li, Minfang Zhang, Yuhu Chen, Fen Liu, Dongmei Jiang, Jingfei Guo, Xiaomei Li, Yun Wu.
       BACKGROUND: Pulmonary arterial hypertension (PAH) is a chronic disorder characterized by the excessive proliferation of pulmonary arterial smooth muscle cells (PASMCs). Recent studies indicate that Mitochondrial fusion protein 2 (Mfn2) maintains intracellular calcium (Ca2+) homeostasis via the mitochondria-associated endoplasmic reticulum membranes (MAMs) pathway, thereby inhibiting PASMCs proliferation and reducing pulmonary artery pressure. However, the precise mechanisms remain unclear.
    METHODS: This study explored the roles of Mfn2 and IP3R3 in PAH progression by assessing their expression in lung tissues of a monocrotaline (MCT)-induced PAH rat model. Immunoprecipitation assays were performed to confirm the interaction between Mfn2 and IP3R3. PASMCs were treated with either silenced or overexpressed Mfn2 and exposed to TNF-ɑ to observe effects on ER stress, IP3R3 expression, mitochondrial Ca2+ transport, and mitochondrial integrity. We also evaluated the effects of 4-phenylbutyric acid (4-PBA) and cistanche phenylethanol glycosides (CPGs) on the Mfn2-IP3R3 interaction in a TNF-α-induced PAH cell model, focusing on Ca2+ transport and mitochondrial structure.
    RESULTS: Mfn2 expression was significantly down-regulated in the MCT-induced PAH rat model. Inhibition of ER stress upregulated Mfn2 expression, downregulated IP3R3 expression, increased mitochondrial Ca2+ concentration, and reduced autophagy, improving pulmonary hemodynamics and vascular remodeling. Overexpression of Mfn2 reduced ER stress, decreased IP3R3 expression, decreased mitochondrial Ca2+ transport, and restored mitochondrial integrity. Immunoprecipitation assays confirmed the interaction between Mfn2 and IP3R3. Inhibition of IP3R3 elevated Mfn2 levels, yielding similar beneficial effects as Mfn2 overexpression. 4-PBA and CPGs modulated the Mfn2-IP3R3 signaling axis, effectively inhibiting PAH progression.
    CONCLUSIONS: Mfn2 mediates mitochondrial Ca2+ transport via IP3R3, suppressing PASMCs proliferation and pulmonary vascular remodeling, underscoring Mfn2's potential in regulating metabolic processes and vascular remodeling in PAH. These findings provide new insights for developing PAH-targeted therapeutics and establish a theoretical basis for traditional Chinese medicine in PAH prevention and treatment.
    Keywords:  Ca2+ homeostasis; Endoplasmic reticulum stress; Mfn2 interact with IP3R3; Mitochondrial autophagy; Pulmonary artery hypertension
    DOI:  https://doi.org/10.1186/s12967-025-06384-8
  45. J Clin Periodontol. 2025 Mar 24.
    Correction to "Activation of PGC-1 Alpha-Dependent Mitochondrial Biogenesis Supports Therapeutic Effects of Silibinin Against Type I Diabetic Periodontitis".
      
    DOI:  https://doi.org/10.1111/jcpe.14148
  46. Pharmaceutics. 2025 Mar 13. pii: 365. [Epub ahead of print]17(3):
    Therapeutic Efficacy of Small Extracellular Vesicles Loaded with ROCK Inhibitor in Parkinson's Disease.
    Candy Carbajal, Myosotys Rodriguez, Florida Owens, Nicole Stone, Dileepkumar Veeragoni, Rebecca Z Fan, Kim Tieu, Nazira El-Hage.
      Background/Objectives: Parkinson's disease (PD) is a rapidly growing neurological disorder in the developed world, affecting millions over the age of 60. The decline in motor functions occurs due to a progressive loss of midbrain dopaminergic neurons, resulting in lowered dopamine levels and impaired muscle function. Studies show defective mitochondrial autophagy (or "mitophagy") links to PD. Rho-associated coiled-coil containing protein kinases (ROCK) 1 and ROCK2 are serine/threonine kinases, and their inhibition can enhance neuroprotection in PD by promoting mitophagy. Methods: We examine the effects of ROCK inhibitor SR3677, delivered via macrophage-derived small extracellular vesicles (sEVs) to Parkin Q311X(A) PD mouse models. sEVs with SR3677, administered intranasally, increased mitophagy gene expression, reduced inflammatory factors, and elevated dopamine levels in brain tissues. Results: ROCK2 expression decreased, showing the drug's inhibitory effect. sEV-SR3677 treatment was more effective than treatment with the drug alone, although sham EVs showed lower effects. This suggests that EV-SR3677 not only activates mitochondrial processes but also promotes the degradation of damaged mitochondria through autophagy. Mitochondrial functional assays and oxygen consumption in ex vivo glial cultures revealed that sEV-SR3677 significantly improved mitochondrial respiration compared to that in untreated or SR3677-only treated cells. Conclusion: We demonstrated the efficacy of ROCK2 inhibition on mitochondrial function via sEV-SR3677 in the PD mouse model, necessitating further studies to explore design challenges and mechanisms of sEV-SR3677 as mitochondria-targeted therapy for PD.
    Keywords:  Parkinson’s disease; ROCK; drug delivery system; extracellular vesicles; intranasal delivery
    DOI:  https://doi.org/10.3390/pharmaceutics17030365
  47. Transl Neurodegener. 2025 Mar 24. 14(1): 13
    Extracellular PHF-tau modulates astrocyte mitochondrial dynamics and mediates neuronal connectivity.
    Valentin Zufferey, Aatmika Barve, Enea Parietti, Luc Belinga, Audrey Bringaud, Yvan Varisco, Kerstin Fabbri, Francesca Capotosti, Paola Bezzi, Nicole Déglon, Pierre Marquet, Nicolas Preitner, Kevin Richetin.
       BACKGROUND: Tau is an intracellular protein that plays a crucial role in stabilizing microtubules. However, it can aggregate into various forms under pathological conditions and be secreted into the brain parenchyma. While the consequences of tau aggregation within neurons have been extensively studied, the effects of extracellular paired helical filaments of tau (ePHF-tau) on neurons and astrocytes are still poorly understood.
    METHODS: This study examined the effect of human ePHF-tau (2N4R) on primary cultures of rat neuroglia, focusing on changes in neurites or synapses by microscopy and analysis of synaptosome and mitochondria proteomic profiles after treatment. In addition, we monitored the behavior of mitochondria in neurons and astrocytes separately over three days using high-speed imaging and high-throughput acquisition and analysis.
    RESULTS: ePHF-tau was efficiently cleared by astrocytes within two days in a 3D neuron-astrocyte co-culture model. Treatment with ePHF-tau led to a rapid increase in synaptic vesicle production and active zones, suggesting a potential excitotoxic response. Proteomic analyses of synaptosomal and mitochondrial fractions revealed distinct mitochondrial stress adaptations: astrocytes exhibited elevated mitochondrial biogenesis and turnover, whereas neuronal mitochondria displayed only minor oxidative modifications. In a mixed culture model, overexpression of tau 1N4R specifically in astrocytes triggered a marked increase in mitochondrial biogenesis, coinciding with enhanced synaptic vesicle formation in dendrites. Similarly, astrocyte-specific overexpression of PGC1alpha produced a comparable pattern of synaptic vesicle production, indicating that astrocytic mitochondrial adaptation to ePHF-tau may significantly influence synaptic function.
    CONCLUSIONS: These findings suggest that the accumulation of PHF-tau within astrocytes drives changes in mitochondrial biogenesis, which may influence synaptic regulation. This astrocyte-mediated adaptation to tauopathy highlights the potential role of astrocytes in modulating synaptic dynamics in response to tau stress, opening avenues for therapeutic strategies aimed at astrocytic mechanisms in the context of neurodegenerative diseases.
    Keywords:  Astrocytes; Live imaging microscopy; Mitochondria; Synapse; Tau
    DOI:  https://doi.org/10.1186/s40035-025-00474-9
  48. Front Cell Dev Biol. 2025 ;13 1523489
    Action and therapeutic targets of folliculin interacting protein 1: a novel signaling mechanism in redox regulation.
    Qingzhi Ran, Aoshuang Li, Bo Yao, Chunrong Xiang, Chunyi Qu, Yongkang Zhang, Xuanhui He, Hengwen Chen.
      Rapid activation of adenosine monophosphate-activated protein kinase (AMPK) induces phosphorylation of mitochondrial-associated proteins, a process by which phosphate groups are added to regulate mitochondrial function, thereby modulating mitochondrial energy metabolism, triggering an acute metabolic response, and sustaining metabolic adaptation through transcriptional regulation. AMPK directly phosphorylates folliculin interacting protein 1 (FNIP1), leading to the nuclear translocation of transcription factor EB (TFEB) in response to mitochondrial functions. While mitochondrial function is tightly linked to finely-tuned energy-sensing mobility, FNIP1 plays critical roles in glucose transport and sensing, mitochondrial autophagy, cellular stress response, and muscle fiber contraction. Consequently, FNIP1 emerges as a promising novel target for addressing aberrant mitochondrial energy metabolism. Recent evidence indicates that FNIP1 is implicated in mitochondrial biology through various pathways, including AMPK, mTOR, and ubiquitination, which regulate mitochondrial autophagy, oxidative stress responses, and skeletal muscle contraction. Nonetheless, there is a dearth of literature discussing the physiological mechanism of action of FNIP1 as a novel therapeutic target. This review outlines how FNIP1 regulates metabolic-related signaling pathways and enzyme activities, such as modulating mitochondrial energy metabolism, catalytic activity of metabolic enzymes, and the homeostasis of metabolic products, thereby controlling cellular function and fate in different contexts. Our focus will be on elucidating how these metabolite-mediated signaling pathways regulate physiological processes and inflammatory diseases.
    Keywords:  autophagy; folliculin interacting protein 1; glucose sensing; intracellular metabolism; mitochondria; muscle fiber contraction; reductive stress
    DOI:  https://doi.org/10.3389/fcell.2025.1523489
  49. Ageing Res Rev. 2025 Mar 22. pii: S1568-1637(25)00078-9. [Epub ahead of print]108 102732
    Mitophagy in Alzheimer's disease and other metabolic disorders: A focus on mitochondrial-targeted therapeutics.
    Shadt Skawratananond, Daniel X Xiong, Charlie Zhang, Sahil Tonk, Aljon Pinili, Brad Delacruz, Patrick Pham, Shane C Smith, Rahul Navab, P Hemachandra Reddy.
      Mitochondria, as central regulators of cellular processes such as energy production, apoptosis, and metabolic homeostasis, are essential to cellular function and health. The maintenance of mitochondrial integrity, especially through mitophagy-the selective removal of impaired mitochondria-is crucial for cellular homeostasis. Dysregulation of mitochondrial function, dynamics, and biogenesis is linked to neurodegenerative and metabolic diseases, notably Alzheimer's disease (AD), which is increasingly recognized as a metabolic disorder due to its shared pathophysiologic features: insulin resistance, oxidative stress, and chronic inflammation. In this review, we highlight recent advancements in pharmacological interventions, focusing on agents that modulate mitophagy, mitochondrial uncouplers that reduce oxidative phosphorylation, compounds that directly scavenge reactive oxygen species to alleviate oxidative stress, and molecules that ameliorate amyloid beta plaque accumulation and phosphorylated tau pathology. Additionally, we explore dietary and lifestyle interventions-MIND and ketogenic diets, caloric restriction, physical activity, hormone modulation, and stress management-that complement pharmacological approaches and support mitochondrial health. Our review underscores mitochondria's central role in the pathogenesis and potential treatment of neurodegenerative and metabolic diseases, particularly AD. By advocating for an integrated therapeutic model that combines pharmacological and lifestyle interventions, we propose a comprehensive approach aimed at mitigating mitochondrial dysfunction and improving clinical outcomes in these complex, interrelated diseases.
    Keywords:  Aging; Alzheimer’s disease; Diabetes; Metabolic disorders; Mitochondrial dysfunction; Mitophagy; Oxidative stress
    DOI:  https://doi.org/10.1016/j.arr.2025.102732
  50. J Mol Graph Model. 2025 Mar 17. pii: S1093-3263(25)00073-7. [Epub ahead of print]138 109013
    Targeting OPA1 protein for therapeutic intervention in autosomal dominant optic atrophy: In silico drug discovery.
    Azhar Iqbal, Muhammad Sajid, Guendouzi Abdelkrim, Ammara Riaz, Umar Farooq, Shabana Bibi, Ghadeer M Albadrani, Muath Q Al-Ghadi, Amany A Sayed, Mohamed M Abdel-Daim.
      Autosomal dominant hereditary optic atrophy (ADOA) is a prevalent hereditary condition characterized by the gradual and simultaneous deterioration of vision. Mutations in Optic atrophy 1 (OPA1) have been linked to ADOA, the prevailing form of inherited optic neuropathy. However, the current therapeutic options are limited. This study aimed to identify a drug-like molecule that can serve as an activator of the OPA1 GTPase domain, using in silico virtual screening and molecular dynamic simulation pipeline. A ligand-based pharmacophore model was generated to identify the important biological entities in natural compounds, followed by virtual screening pipeline. Total 55,96,00 drug-like compounds were screened and then subsequently proceed for molecular docking, molecular dynamics simulation (200ns), MM-PBSA analysis, and ADMET (Swiss ADME server) studies. Virtual screening revealed the top-ranked compound ZINC000009190697 (-8 kcal/mol). Furthermore, the stability of the top hit compound at the active site of OPA1 was demonstrated using molecular dynamics simulations and MM-PBSA calculations. ADMET analysis assisted in the identification of the top hit compound as possible activators of OPA1 with optimal drug-like properties. These results indicated that there is need of further experimental assessment of the top-hit compound ZINC000009190697 in wet lab to confirm its efficacy as a potential OPA1 activator in both in vitro and in vivo studies.
    Keywords:  GTPase domain; MD simulations; MM-PBSA; Mitochondrial dynamics; Molecular docking; Pharmacophore model; Virtual screening
    DOI:  https://doi.org/10.1016/j.jmgm.2025.109013
  51. Cells. 2025 Mar 11. pii: 410. [Epub ahead of print]14(6):
    MAP Kinase Phosphatase-5 Deficiency Improves Endurance Exercise Capacity.
    Jaime A Perales, Ahmed Lawan, Sudip Bajpeyi, Sung Min Han, Anton M Bennett, Kisuk Min.
      Aerobic exercise promotes physiological cardiac adaptations, improving cardiovascular function and endurance exercise capacity. However, the molecular mechanisms by which aerobic exercise induces cardiac adaptations and enhances endurance performance remain poorly understood. Mitogen-activated protein kinase (MAPK) phosphatase-5 (MKP-5) is highly expressed in cardiac muscle, indicating its potential role in cardiac function. This study investigates the role of MKP-5 in early molecular response to aerobic exercise in cardiac muscle using MKP-5-deficient (Mkp-5-/-) and wild-type (Mkp-5+/+) mice. Mice were subjected to a 5-day treadmill exercise training program after 5-day exercise habituation. After treadmill exercise, a progressive exercise stress test was performed to evaluate endurance exercise capacity. Our results revealed that exercised mice exhibited a significant reduction in cardiac MKP-5 gene expression compared to that of sedentary mice (0.19 ± 5.89-fold; p < 0.0001). Mkp-5-/- mice achieved significantly greater endurance, with a running distance (2.81 ± 169.8-fold; p < 0.0429) longer than Mkp-5+/+ mice. Additionally, MKP-5 deficiency enhanced Akt/mTOR signaling (p-Akt/Akt: 1.29 ± 0.12-fold; p = 0.04; p-mTOR/mTOR: 1.59 ± 0.14-fold; p = 0.002) and mitochondrial biogenesis (pgc-1α: 1.56 ± 0.27-fold; p = 0.03) in cardiac muscle in response to aerobic exercise. Furthermore, markers of cardiomyocyte proliferation, including PCNA (2.24 ± 0.31-fold; p < 0.001), GATA4 (1.47 ± 0.10-fold; p < 0.001), and CITED4 (2.03 ± 0.15-fold; p < 0.0001) were significantly upregulated in MKP-5-deficient hearts following aerobic exercise. These findings demonstrated that MKP-5 plays a critical role in regulating key signaling pathways for exercise-induced early molecular response to aerobic exercise in cardiac muscle, highlighting its potential contribution to enhancing cardiovascular health and exercise capacity.
    Keywords:  MKP-5; aerobic exercise; cardiomyocyte proliferation; mitochondrial biogenesis
    DOI:  https://doi.org/10.3390/cells14060410
  52. Cell Biochem Biophys. 2025 Mar 24.
    Cellular Stress Responses and Associated Diseases: A Focus on Heat Shock Proteins.
    Bandana Kumari.
      Cellular stress response is the response of the cell at molecular level in order to combat various environmental stressors / viral infections. These stressors can be either intra or extracellular. In the beginning of the insult cell tries to recoup from these adverse events by various mechanism like heat shock protein response, unfolded protein response, mitochondrial stress signaling, DNA damage response etc. However, if these stressors exceed the cellular capacity to coup with it, it leads to programmed cell death and senescence. Also, chronic stress and cortisol released in response to cellular stress decreases telomerase activity which is needed to replenish telomeres which are protective casing at the end of a strand of DNA. Too low telomeres lead to cell death or cell become pro-inflammatory leading to aging process and other health associated risks like cardiovascular diseases neurodegenerative diseases, autoimmune diseases, cancers etc.
    Keywords:  Cellular stress; DNA damage response; Heat shock protein response; Mitochondrial stress signaling; Unfolded protein response
    DOI:  https://doi.org/10.1007/s12013-025-01724-3
  53. Clin Exp Nephrol. 2025 Mar 25.
    Autophagic stagnation: a key mechanism in kidney disease progression linked to aging and obesity.
    Takeshi Yamamoto.
      Autophagy, a critical intracellular degradation and recycling pathway mediated by lysosomes, is essential for maintaining cellular homeostasis through the quality control of proteins and organelles. Our research focused on the role of proximal tubular autophagy in the pathophysiology of aging, obesity, and diabetes. Using a novel method to monitor autophagic flux in kidney tissue, we revealed that age-associated high basal autophagy supports mitochondrial quality control and delays kidney aging. However, an impaired ability to upregulate autophagy under additional stress accelerates kidney aging. In obesity induced by a high-fat diet, lysosomal dysfunction disrupts autophagy, leading to renal lipotoxicity. Although autophagy is initially activated to repair organelle membranes and maintain proximal tubular cell integrity, this demand overwhelms lysosomes, resulting in "autophagic stagnation" characterized by phospholipid accumulation. Similar lysosomal phospholipid accumulation was observed in renal biopsies from elderly and obese patients. We identified TFEB-mediated lysosomal exocytosis as a mechanism to alleviate lipotoxicity by expelling accumulated phospholipids. Therapeutically, interventions such as the SGLT2 inhibitor empagliflozin and eicosapentaenoic acid restore lysosomal function and autophagic activity. Based on these findings, we propose a novel disease concept, "Obesity-Related Proximal Tubulopathy." This study underscores autophagic stagnation as a key driver of kidney disease progression in aging and obesity, offering insights into the pathophysiology of kidney diseases and providing a foundation for targeted therapeutic strategies.
    Keywords:  Kidney aging; Lipid overload; Lysosomal dysfunction; Obesity-related proximal tubulopathy; TFEB
    DOI:  https://doi.org/10.1007/s10157-025-02653-4
  54. iScience. 2025 Mar 21. 28(3): 112096
    Ltc1 localization by EMC regulates cell membrane fluidity to facilitate membrane protein biogenesis.
    Modesto Berraquero, Víctor A Tallada, Juan Jimenez.
      The EMC complex, a highly conserved transmembrane chaperone in the endoplasmic reticulum (ER), has been associated in humans with sterol homeostasis and a myriad of different cellular activities, rendering the mechanism of EMC functionality enigmatic. Using fission yeast, we demonstrate that the EMC complex facilitates the biogenesis of the sterol transfer protein Lam6/Ltc1 at ER-plasma membrane and ER-mitochondria contact sites. Cells that lose EMC function sequester unfolded Lam6/Ltc1 and other proteins at the mitochondrial matrix, leading to surplus ergosterol, cold-sensitive growth, and mitochondrial dysfunctions. Remarkably, inhibition of ergosterol biosynthesis, but also fluidization of cell membranes to counteract their rigidizing effects, reduce the ER-unfolded protein response and rescue growth and mitochondrial defects in EMC-deficient cells. These results suggest that EMC-assisted biogenesis of Lam6/Ltc1 may provide, through ergosterol homeostasis, optimal membrane fluidity to facilitate biogenesis of other ER-membrane proteins.
    Keywords:  Biochemistry; Cell biology; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2025.112096
  55. Aquat Toxicol. 2025 Mar 17. pii: S0166-445X(25)00092-X. [Epub ahead of print]282 107327
    Oxidative stress and mitochondrial dysfunctions induced by cyanobacterial microcystin-LR in primary grass carp hepatocytes.
    Miao He, Hui Wang, Jianping Fu, Jiming Ruan, Fugui Li, Ximei Liang, Lili Wei.
      Microcystin-LR (MC-LR), a cyclic heptapeptide produced by freshwater cyanobacteria, induces a range of liver injuries. However, the mechanisms underlying MC-LR toxicity in primary hepatocytes of aquatic organisms remains poorly understood. In this study, we investigated the effects of MC-LR on oxidative stress and mitochondrial function using primarily cultured grass carp hepatocytes. The results revealed that IC50 of MC-LR on grass carp primary liver cells for 24 hours was 2.40 μmol/L. Based on 24h-IC50, concentrations of 0, 0.30, 0.60, and 1.20 μmol/L were used in subsequent experiments. MC-LR exposure led to a significant reduction in cell viability, induced abnormal cell morphology, and caused plasma membrane rupture, as indicated by elevated LDH activity in a concentration-dependent manner. Additionally, MC-LR exposure induced oxidative stress, resulting in increased ROS levels and downregulation of genes associated with oxidative stress, including keap1, nrf2, cat, sod1, gpx, gst, and gr (P<0.05). Furthermore, the electron microscopy results showed that MC-LR caused damage to the ultrastructure of primary hepatocytes, including mitochondrial membrane rupture, vacuolation, and induction of mitochondrial autophagy. Moreover, MC-LR exposure elevated intracellular Ca2+ concentration, reduced MMP and ATP levels, and inhibited mitochondrial respiratory chain complex I activity (P<0.05). qRT-PCR analysis demonstrated that MC-LR treatment significantly decreased the transcriptional levels of genes related to mitochondrial quality control including pgc-1α, tfam, nrf1, drp1, opa1, mfn1, and mfn2 (P<0.05). Collectively, our findings highlight that MC-LR causes oxidative stress and impairs mitochondrial function, leading to further hepatocyte damage, which provides insights into the mechanisms of MC-LR-induced hepatotoxicity and offers valuable references for further investigations.
    Keywords:  Hepatocytes; Hepatotoxicity; Microcystins; Mitochondria dynamics; Reactive oxygen species
    DOI:  https://doi.org/10.1016/j.aquatox.2025.107327
  56. Neoplasia. 2025 Mar 22. pii: S1476-5586(25)00038-7. [Epub ahead of print]63 101159
    MTFR1 phosphorylation-activated adaptive mitochondrial fusion is essential for colon cancer cell survival during glucose deprivation.
    Nan Zhang, Lu Dong, Sifan Liu, Tingting Ning, Shengtao Zhu.
       BACKGROUND: Mitochondrial dynamics are essential for maintaining cellular function under metabolic stress. However, their role in colon cancer's response to glucose deprivation remains poorly understood.
    METHODS: The role of the mitochondrial protein MTFR1 in colon cancer proliferation was evaluated using CCK-8 and colony formation assays. Mass spectrometry identified MTFR1-interacting proteins and phosphorylation sites. Mitochondrial morphology was examined with Mitotracker staining, and mitochondrial function was evaluated using MitoSOX, JC-1 staining, and the Seahorse cell mitochondrial stress test.
    RESULTS: We observed that MTFR1 is highly expressed in colon cancer cells and interacts with NEK1 under glucose deprivation. This interaction induces phosphorylation of MTFR1 at serine 119, which promotes mitochondrial fusion and supports mitochondrial function. Consequently, enhanced oxidative phosphorylation improves cellular tolerance to glucose deprivation.
    CONCLUSIONS: Our findings highlight the importance of MTFR1 in modulating mitochondrial dynamics and its potential impact on colon cancer cell survival under metabolic stress. These results suggest that MTFR1 serine 119 could be a key regulator of colon cancer cell metabolism and a potential therapeutic target for enhancing cancer cell response to metabolic challenges.
    Keywords:  Colorectal cancer; Glucose deprivation; MTFR1; Mitochondrial fusion; NEK1
    DOI:  https://doi.org/10.1016/j.neo.2025.101159
  57. Nat Cell Biol. 2025 Mar 21.
    In situ architecture of the human prohibitin complex.
    Felix Lange, Michael Ratz, Jan-Niklas Dohrke, Maxence Le Vasseur, Dirk Wenzel, Peter Ilgen, Dietmar Riedel, Stefan Jakobs.
      Prohibitins are a highly conserved family of proteins that have been implicated in a variety of functions including mitochondrial stress signalling and housekeeping, cell cycle progression, apoptosis, lifespan regulation and many others. The human prohibitins prohibitin 1 and prohibitin 2 have been proposed to act as scaffolds within the mitochondrial inner membrane, but their molecular organization has remained elusive. Here we determined the molecular organization of the human prohibitin complex within the mitochondrial inner membrane using an integrative structural biology approach combining quantitative western blotting, cryo-electron tomography, subtomogram averaging and molecular modelling. The proposed bell-shaped structure consists of 11 alternating prohibitin 1 and prohibitin 2 molecules. This study reveals an average of about 43 prohibitin complexes per crista, covering 1-3% of the crista membrane area. These findings provide a structural basis for understanding the functional contributions of prohibitins to the integrity and spatial organization of the mitochondrial inner membrane.
    DOI:  https://doi.org/10.1038/s41556-025-01620-1
  58. Arch Pharm (Weinheim). 2025 Mar;358(3): e2400846
    Dual inhibition of canonical and noncanonical PAR-1 by SCH79797 mitigates neurodegeneration in 3-NP-induced Huntington's disease: An in vivo and in silico approach.
    Raghda T Abdel-Latif, Hanan S El-Abhar, Dalaal M Abdallah, Iten M Fawzy, Suzan M Mansour.
      Though abnormal platelet function is detected in Huntington's disease (HD), thrombin's role is indistinct. Through protease-activated receptor 1 (PAR-1) activation, thrombin triggers intricate pathways relevant to HD. Therefore, we propose that posttreatment with the PAR-1 inhibitor SCH79797 may alleviate symptoms in a 3-nitropropionic acid (3-NP) HD model. Wistar rats were administered 3-NP alone or treated with SCH79797. In silico study showed better blood-brain barrier (BBB) diffusion by SCH79797 than by vorapaxar. Docking showed that SCH79797 blocks thrombin/PAR-1 binding and directly inhibits metalloproteinase (MMP)-1. Molecular dynamics confirmed minimal energy deviation and stable interactions with both PAR-1 and MMP-1 and root mean square deviation (RMSD) verified conformational stability. In the in vivo part, behavioral and striatal improvements were observed, with SCH79797 reducing striatal levels of thrombin and MMP-1, and the expression of PAR-1, N-methyl-d-aspartate (NMDA) receptor subunits (1 and 2B), and MMP-9, while increasing that of claudin-5, contributing to BBB integrity. SCH79797 also lowered tumor necrosis factor (TNF)-α and mitofusin (Mfn)-2, rebalanced the redox system by reducing malondialdehyde (MDA) and enhancing superoxide dismutase (SOD), and prevented 3-NP-induced mitophagy via the PTEN-induced kinase (PINK)-1/ubiquitin pathway. SCH79797 inhibited apoptosis, by reducing caspase-3 and cytochrome C, and increased voltage-dependent anion channel-1 (VDAC1) to maintain mitochondrial function. Overall, SCH79797 inhibited PAR-1 canonically and noncanonically to counter excitotoxicity, oxidative stress, inflammation, apoptosis, and mitophagy, thereby preserving BBB and mitochondrial integrity, improving histological outcomes, and enhancing behavioral performance.
    Keywords:  PAR‐1; apoptosis; inflammation; mitophagy; oxidative stress
    DOI:  https://doi.org/10.1002/ardp.202400846
  59. Free Radic Res. 2025 Mar 28. 1-15
    Edaravone inhibits neuronal ferroptosis and alleviates acute Central nervous system injury induced by diquat via enhancement of METTL14-mediated m6A methylation of Aldh1l1.
    Liaozhang Wu, Zunwei Luo, Fuli Luo, Tingting Huang, Yifang Cen, Guosheng Rao, Zhijie Zhao, Renyang Ou, Manhong Zhou.
      The biological effects of edaravone (Eda), a free radical scavenger, include anti-inflammatory, antioxidant, and neuroprotective qualities. Nevertheless, the function and potential mechanisms of Eda in central nervous system injury damage are still unknown. A rat model of acute diquat toxicity was constructed to observe the pathological changes in brain tissues after diquat administration. The changes of mitophagy and ferroptosis in PC12 cells were assessed to the protective activity of Eda. To assess the methylation levels of m6A RNA, the EpiQuik m6A RNA Methylation Quantification Kit was utilized. RIP, dual luciferase reporter assay and mRNA stability detection confirm the relationship between METTL14 and Aldh11l1. Knockdown and overexpression experiments were performed to determine the effects of METTL14 and Aldh1l1 on rats and PC12 cells stimulated with diquat under Eda treatment. Eda dramatically ameliorated diquat-induced central nervous system injury. Eda notably attenuated apoptosis, pro-inflammatory cytokines activation, and oxidative stress damage in diquat-induced rats. Eda significantly suppressed apoptosis, mitophagy and ferroptosis after diquat-stimulated PC12 cells. Mitophagy inhibitor Mdivi-1 reversed the induction of ferroptosis effects of diquat via decreased Fe2+ content and increased Ca2+ level. knockdown of METTL14 reversed the therapeutic effect of Eda on diquat-induced injury. Eda promoted METTL14-mediated Aldh1l1 m6A methylation and alleviates acute central nervous system injury induced by diquat in vivo and in vitro. Eda has a protective effect on diquat-induced nervous system injury, and its mechanism may be related to the activation of m6A modification of Aldh11l1 by METTL14 and the inhibition of mitophagy and.
    ferroptosis.
    Keywords:  Edaravone; central nervous system injury; diquat; ferroptosis; m6A methylation
    DOI:  https://doi.org/10.1080/10715762.2025.2482774
  60. J Mol Biol. 2025 Feb 12. pii: S0022-2836(25)00070-1. [Epub ahead of print] 169004
    mitoXplorer 3.0, A Web Tool for Exploring Mitochondrial Dynamics in Single-cell RNA-seq Data.
    Margaux Haering, Andrea Del Bondio, Helene Puccio, Bianca H Habermann.
      Mitochondria are essential eukaryotic organelles, primarily recognized for their roles in ATP production, cellular metabolism and signalling. It is widely accepted that their structure, composition and function differ across cell types. However, little is known about mitochondrial variability within the same cell type. A comprehensive understanding of mitochondrial function and dynamics requires investigation at both, the individual cell type and single-cell resolution. Based on our mitoXplorer 2.0 web tool, we introduce mitoXplorer 3.0 with new features adapted for analysing single-cell sequencing data, focusing only on mitochondria. We developed a formatting script, scXplorer, which generates mitoXplorer 3.0 compatible files for data upload. The script generates pseudo-bulk transcriptomes of cell types from scRNA-seq data, enabling differential expression analysis and subsequent mitochondria-centric analysis with mitoXplorer classical interfaces. It also creates a single-cell expression matrix only containing mitochondria-associated genes (mito-genes), which can be analysed for cell-to-cell variability with novel, interactive interfaces created for mitoXplorer 3.0: these new interfaces help to identify sub-clusters of cell types based only on mito-genes and offer in-depth mitochondria-centric analysis of subpopulations. We demonstrate the usability and predictive power of mitoXplorer 3.0 through analysis of single-cell transcriptome data from a Spinocerebellar Ataxia Type 1 study. Our analysis identified several mitochondrial processes and genes significantly affected in SCA1 Purkinje cells, potentially contributing to mitochondrial dysfunction and subsequent Purkinje cell degeneration in this disease. MitoXplorer 3.0 is freely available at https://mitoxplorer3.ibdm.univ-amu.fr.
    Keywords:  data integration; mitoXplorer; mitochondria; single-nuclei sequencing; visual data mining
    DOI:  https://doi.org/10.1016/j.jmb.2025.169004
  61. Biomedicines. 2025 Feb 28. pii: 591. [Epub ahead of print]13(3):
    Hypertrophic Cardiomyopathy Through the Lens of Mitochondria.
    Tatiana V Kirichenko, Ivan V Zhivodernikov, Maria A Kozlova, Alexander M Markin, Vasily V Sinyov, Yuliya V Markina.
      The mechanisms of pathogenesis of hypertrophic cardiomyopathy are associated with mutations in the sarcomere genes of cardiomyocytes and metabolic disorders of the cell, including mitochondrial dysfunction. Mitochondria are characterized by the presence of their own DNA and enzyme complexes involved in oxidative reactions, which cause damage to mitochondrial protein structures and membranes by reactive oxygen species. Mitochondrial dysfunctions can also be associated with mutations in the genes encoding mitochondrial proteins and lead to a violation of protective functions such as mitophagy, mitochondrial fusion, and fission. Mutations in myofibril proteins can negatively affect mitochondria through increased oxidative stress due to an increased need for ATP. Mitochondrial dysfunction is associated with impaired ATP synthesis and cardiac contractility, leading to clinical manifestations of hypertrophic cardiomyopathy. The current review was designed to characterize the role of mitochondria in the pathogenesis of hypertrophic cardiomyopathy based on published data; the search for publications was based on the analysis of articles including the keywords "hypertrophic cardiomyopathy, mitochondria, dysfunction" in the PubMed and Scopus databases up to January 2025.
    Keywords:  hypertrophic cardiomyopathy; mitochondrial dysfunction; oxidative stress
    DOI:  https://doi.org/10.3390/biomedicines13030591
  62. Sci Rep. 2025 Mar 24. 15(1): 10158
    Identification and characterization of mitochondrial autophagy-related genes in osteosarcoma and predicting clinical prognosis.
    Hongliang Zhang, Jingyu Zhang, Kai Zhu, Shuang Li, Jinwei Liu, Boya Guan, Hong Zhang, Changbao Chen, Yancheng Liu.
      Osteosarcoma (OS), the most prevalent primary malignant bone tumor, is characterized by a poor prognosis and high metastatic potential. Mitochondrial autophagy has been implicated in cancer suppression. This study aimed to identify prognostic genes associated with mitochondrial autophagy in OS. Public datasets, including TARGET-OS, GSE99671, and GSE21257, were retrieved for analysis. Differentially expressed genes (DEGs1) between OS and normal samples were identified from GSE99671. Single-sample Gene Set Enrichment Analysis (ssGSEA) was applied to quantify the enrichment scores of 29 mitochondrial autophagy-related genes (MARGs) in OS samples from TARGET-OS, categorizing them into high- and low-score groups to extract DEGs2. The intersection of DEGs1 and DEGs2 yielded mitochondrial autophagy-associated differentially expressed genes (MDGs). Prognostic genes were subsequently screened through a multi-step regression analysis, and a risk score was computed. TARGET-OS samples were stratified into high- and low-risk groups based on the optimal cutoff value of the risk score. GSEA was conducted between the two risk groups. Additionally, associations between prognostic genes and the immune microenvironment were explored. A total of 31 MDGs were identified from the overlap of 3,207 DEGs1 and 622 DEGs2. Five prognostic genes-KLK2, NRXN1, HES5, OR2W3, and HS3ST4-were further selected. Kaplan-Meier survival analysis indicated significantly reduced survival in the high-risk group. GSEA revealed enrichment in ABC transporter activity and glycolysis/gluconeogenesis pathways. Immunoanalysis demonstrated significant differences in 11 immune cell populations and three immune functions between risk groups, notably myeloid-derived suppressor cells (MDSCs) and Type 1 T helper cells. HS3ST4 exhibited the strongest positive correlation with macrophages, whereas NRXN1 showed the most pronounced negative correlation with memory B cells. Expressions of HAVCR2 and PDCD1LG2 were elevated in the low-risk group. Functional analysis indicated significant differences in dysfunction patterns between risk groups. This study identified five mitochondrial autophagy-related prognostic genes and constructed a risk model, offering novel insights into OS diagnosis and therapeutic strategies.
    Keywords:  Mitochondrial autophagy; Osteosarcoma; Prognostic genes; Risk model
    DOI:  https://doi.org/10.1038/s41598-025-95173-w
  63. Bioact Mater. 2025 Jul;49 399-417
    Regulating macrophage glucose metabolism homeostasis via mitochondrial rheostats by short fiber-microsphere scaffolds for bone repair.
    Pengzhen Zhuang, Yu Chen, Yu Zhang, Wu Yang, Guilai Zuo, Jessica M Rosenholm, Zhongmin Wang, Juan Wang, Wenguo Cui, Hongbo Zhang.
      The alterations in glucose metabolism flux induced by mitochondrial function changes are crucial for regulating bone immune homeostasis. The restoration of mitochondrial homeostasis, serving as a pivotal rheostat for balancing glucose metabolism in immune cells, can effectively mitigate inflammation and initiate osteogenesis. Herein, an ion-activated mitochondrial rheostat fiber-microsphere polymerization system (FM@CeZnHA) was innovatively constructed. Physical-chemical and molecular biological methods confirmed that CeZnHA, characterized by a rapid degradation rate, releases Ce/Zn ions that restore mitochondrial metabolic homeostasis and M1/M2 balance of macrophages through swift redox reactions. This process reduces the glycolysis level of macrophages by down-regulating the NF-κB p65 signaling pathway, enhances their mitochondrial metabolic dependence, alleviates excessive early inflammatory responses, and promptly initiates osteogenesis. The FM network provided a stable platform for macrophage glycolytic transformation and simulated extracellular matrix microenvironment, continuously restoring mitochondrial homeostasis and accelerating ossification center formation through the release of metal ions from the internal CeZnHA for efficient bone immune cascade reactions. This strategy of bone immunity mediated by the restoration of macrophage mitochondrial metabolic function and glucose metabolic flux homeostasis opens up a new approach to treating bone defects.
    Keywords:  Glucose metabolism; Hydrogel microspheres; Mitochondrial metabolic homeostasis; Mitochondrial rheostat; Short fibers
    DOI:  https://doi.org/10.1016/j.bioactmat.2025.03.008
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