bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2025–03–09
67 papers selected by
Gavin McStay, Liverpool John Moores University
  1. Palmitic acid-induced insulin resistance triggers granulosa cell senescence by disruption of the UPRmt/mitophagy/lysosome axis.
  2. Inhibition of Drp1-mediated mitochondrial fission by P110 ameliorates renal injury in diabetic nephropathy.
  3. Costunolide Ameliorates the Methylmalonic Acidemia Via the PINK1/Parkin Pathway.
  4. PPTC7 acts as an essential co-factor of the SCFFBXL4 ubiquitin ligase complex to restrict BNIP3/3L-dependent mitophagy.
  5. Lactiplantibacillus plantarum JM113 alleviates mitochondrial dysfunction induced by deoxynivalenol in the jejunum of broiler chickens.
  6. Mesenchymal stem cell-derived small extracellular vesicles reduced hepatic lipid accumulation in MASLD by suppressing mitochondrial fission.
  7. Mitochondrial proteostasis and cellular health: insights from chaperones and autophagy.
  8. Nicotinamide mononucleotide combined with PJ-34 protects microglial cells from lipopolysaccharide-induced mitochondrial impairment through NMNAT3-PARP1 axis.
  9. Inhibition of the expression of TRIM63 alleviates ventilator-induced diaphragmatic dysfunction by modulating the PPARα/PGC-1α pathway.
  10. Novel reporter of the PINK1-Parkin mitophagy pathway identifies its damage sensor in the import gate.
  11. Impact of celastrol on mitochondrial dynamics and proliferation in glioblastoma.
  12. Prohibitin2 knockdown decreases glioma malignant phenotypes and radio-resistance by inhibiting mitophagy.
  13. Cordycepin Ameliorates Renal Interstitial Fibrosis by Inhibiting Drp1-Mediated Mitochondrial Fission.
  14. Enhanced SIRT3 expression restores mitochondrial quality control mechanism to reverse osteogenic impairment in type 2 diabetes mellitus.
  15. Metformin alleviates auditory cell senescence by mitophagy induction.
  16. Compression force regulates cementoblast mineralization via S1PR1/mitophagy axis.
  17. Mitochondrial accumulation and lysosomal dysfunction result in mitochondrial plaques in Alzheimer's disease.
  18. Exploring the Therapeutic Mechanism of Xinbao Pill in Brain Injury After Cardiopulmonary Resuscitation Based on Network Pharmacology, Metabolomics, and Experimental Verification.
  19. Mitochondria in aging and age-associated diseases.
  20. Protective role of mitophagy on microglia-mediated neuroinflammatory injury through mtDNA-STING signaling in manganese-induced parkinsonism.
  21. Selenium-Loaded Porous Silica Nanospheres Improve Cardiac Repair After Myocardial Infarction by Enhancing Antioxidant Activity and Mitophagy.
  22. Deubiquitinating Enzymes Regulate Skeletal Muscle Mitochondrial Quality Control and Insulin Sensitivity in Patients With Type 2 Diabetes.
  23. Protocatechuic Acid Alleviates Inflammation and Oxidative Stress in Acute Respiratory Distress Syndrome by Promoting Unconventional Prefoldin RPB5 Interactor 1-Mediated Mitophagy.
  24. Important regulatory role of mitophagy in diabetic microvascular complications.
  25. Drp1 knockdown aggravates obesity-induced cardiac dysfunction and remodeling.
  26. Molecular cloning, characterization and expression analysis of PINK1 (Phosphatase and tensin homolog-induced putative kinase 1) and Parkin (parkin RBR E3 ubiquitin protein ligase) in grass carp (Ctenopharyngodon idellus).
  27. Mitochondrial fusion and cristae reorganization facilitate acquisition of cardiomyocyte identity during reprogramming of murine fibroblasts.
  28. Elevated levels of S100A8 and S100A9 exacerbate muscle mitochondrial fragmentation in sepsis-induced muscle atrophy.
  29. Mitochondrial Dysfunction in Alzheimer's Disease.
  30. Regulation on mitophagy in adenomyosis by Guizhi Fuling Wan.
  31. Multi-omics-based phenotyping of AFG3L2-mutant lymphoblasts determines key factors of a pathophysiological interplay between mitochondrial vulnerability and neurodegeneration in spastic ataxia type 5.
  32. Maimendong decoction modulates the PINK1/Parkin signaling pathway alleviates type 2 alveolar epithelial cells senescence and enhances mitochondrial autophagy to offer potential therapeutic effects for idiopathic pulmonary fibrosis.
  33. Methionine is an essential amino acid in doxorubicin-induced cardiotoxicity through modulating mitophagy.
  34. 2,3,5,4'-Tetrahydroxystilbene-2-O-beta-D-glucopyranoside promotes skin flap survival by promoting mitophagy through the PINK1/Parkin pathway.
  35. SALL4/ABCB6 Axis Suppresses Ferroptosis in Colon Cancer by Mediating Mitophagy.
  36. Dodging mitochondrial mislocalization.
  37. Ultrastructural analysis of mitochondrial morphology and in the human rhabdosphincter: Insights into urinary incontinence.
  38. Urolithin A provides cardioprotection and mitochondrial quality enhancement preclinically and improves human cardiovascular health biomarkers.
  39. Heart of the matter: mitochondrial dynamics and genome alterations in cardiac aging.
  40. LncRNA H19 overexpression protects against acute kidney injury after cardiopulmonary bypass via activating Pink1/Parkin-mediated mitophagy.
  41. Autophagy Related 5 Promotes Mitochondrial Fission and Inflammation via HSP90-HIF-1α-Mediated Glycolysis in Kidney Fibrosis.
  42. Comprehensive ubiquitome analysis reveals persistent mitochondrial remodeling disruptions from doxorubicin-induced cardiotoxicity in aged CD-1 male mice.
  43. Cerium Dioxide Nanoparticles-Based Inspector Enhances Mitochondrial Quality Control to Maintain Chondrocyte Homeostasis in Osteoarthritis Therapy.
  44. Mitochondria at the crossroads: Quality control mechanisms in neuronal senescence and neurodegeneration.
  45. Esketamine Regulates Mitophagy through ULK1/FUNDC1 Signaling Pathway to Improve LPS-induced Acute Respiratory Distress Syndrome.
  46. Author Correction: Engineered hypoxia-responsive albumin nanoparticles mediating mitophagy regulation for cancer therapy.
  47. SNX10 functions as a modulator of piecemeal mitophagy and mitochondrial bioenergetics.
  48. Pectin-coated Malvidin-3-O-galactoside attenuates silica-induced pulmonary fibrosis by promoting mitochondrial autophagy and inhibiting cell apoptosis.
  49. Artificial intelligence-enabled automated analysis of transmission electron micrographs to evaluate chemotherapy impact on mitochondrial morphology in triple negative breast cancer.
  50. Nanoengineered cargo with targeted in vivo Foxo3 gene editing modulated mitophagy of chondrocytes to alleviate osteoarthritis.
  51. Functional Specialization of S-Adenosylmethionine Synthases Links Phosphatidylcholine to Mitochondrial Function and Stress Survival.
  52. Melatonin refines ovarian mitochondrial dysfunction in PCOS by regulating the circadian rhythm gene Clock.
  53. Cardioprotective potential of transcription factor PRRX1 silencing against myocardial ischemia/reperfusion injury by regulating excessive mitophagy and ferroptosis through FKBP5-p38 MAPK axis.
  54. Author Correction: Tetrahydroberberrubine retards heart aging in mice by promoting PHB2-mediated mitophagy.
  55. Xin-Fu-Kang oral liquid mitigates chronic heart failure through NR4A1-Dependent regulation of endoplasmic reticulum-mitochondrial crosstalk in Cardiomyocytes.
  56. Effects of the VIVIFRAIL Exercise Protocol on Circulatory and Intracellular Peripheral Mediators Bridging Mitochondrial Dynamics and Inflammation in Robust and Frail Older People.
  57. The compound XueShuanTong promotes podocyte mitochondrial autophagy via the AMPK/mTOR pathway to alleviate diabetic nephropathy injury.
  58. Exercise Rescues Blood-Brain Barrier Structural Impairment and Enhances Mitochondrial Biogenesis in a Hypertensive Mouse Model.
  59. Low-dose acrylamide induces mitochondrial autophagy and energy metabolism dysfunction in SH-SY5Y cells via BV2 microglial activation.
  60. Exercise Ameliorates Dysregulated Mitochondrial Fission, Mitochondrial Respiration, and Neuronal Apoptosis in Parkinson's Disease Mice via the Irisin/AMPK/SIRT1 Pathway.
  61. Berberine-loaded albumin nanoparticles alleviate liver damage in rats by modulating mitochondrial biogenesis and mitochondria-endoplasmic reticulum interactions.
  62. Akt3 links mitochondrial function to the regulation of Aurora B and mitotic fidelity.
  63. Role and mechanism of seaweed polysaccharides in regulating mitochondrial dysfunction: A review.
  64. Tas2r123-associated mitochondrial organization and neuroplasticity underlying the antidepressant effect of resveratrol.
  65. A novel, rapidly progressive ataxia due to a spontaneous Myo5a mutation in mice impairs transport proteins and alters mitochondria.
  66. EPAS1 induction drives myocardial degeneration in desmoplakin-cardiomyopathy.
  67. Cytoplasmic ribosomes on mitochondria alter the local membrane environment for protein import.
  1. Chem Biol Interact. 2025 Feb 27. pii: S0009-2797(25)00080-8. [Epub ahead of print]411 111450
    Palmitic acid-induced insulin resistance triggers granulosa cell senescence by disruption of the UPRmt/mitophagy/lysosome axis.
    Yuan Tian, Pengge Pan, Xiaoqiang Luo, Yaqi Sun, Xintong Yang, Hui Gao, Yanzhou Yang.
      Insulin resistance (IR) is the main pathological feature of polycystic ovary syndrome (PCOS), but the adverse impacts of IR on ovary and granulosa cells (GCs) are unknown. Therefore, the role of palmitic acid (PA) induced IR in GCs, and a mitochondrial proteostasis and mitochondrial homeostasis control system, the mitochondrial unfolded protein response (UPRmt)/mitophagy/lysosome axis were investigated to uncover the side effect and the mechanism of IR on GCs. Our results revealed that IR in GC was successfully constructed by 100 μM PA treatment accompanied with cell senescence. In addition, mitochondrial function was impaired by IR-induced GC senescence accompanied by significantly increased reactive oxygen species (ROS) and decreased mitochondrial membrane potential, and mitochondrial proteostasis was impaired by a dysfunctional UPRmt and increased protein aggregation, leading to more unfolded and misfolded proteins accumulating in mitochondria. Mitochondrial homeostasis was maintained by the mitophagy/lysosome degradation system, although mitophagy was significantly increased, lysosomes were damaged; hence, malfunctional mitochondria were not cleared by the mitophagy/lysosome degradation system, more ROS were produced by malfunctional mitochondria. Therefore, accelerated GC senescence was triggered by excessive ROS, and reversed by the mitophagy inhibitor cyclosporin A (CsA) accompanied with reduced IR. Additionally, the mice were administered with PA, and results revealed that the accelerated ovarian aging was caused by PA, which might be attributed to GC senescence. In conclusion, GC senescence was triggered in PA-induced IR by disruption of the UPRmt/mitophagy/lysosome axis, and IR induced GC senescence was reversed by the CsA.
    Keywords:  Cell senescence; Granulosa cells; Mitophagy; Ovarian aging; Palmitic acid; UPR(mt)
    DOI:  https://doi.org/10.1016/j.cbi.2025.111450
  2. Int Immunopharmacol. 2025 Mar 03. pii: S1567-5769(25)00332-7. [Epub ahead of print]152 114342
    Inhibition of Drp1-mediated mitochondrial fission by P110 ameliorates renal injury in diabetic nephropathy.
    Ruchi Yue, Ziyu Yan, Hongchu Zha, Yao Xia, Hua Huang, Huimin Li, Mao Ding, Md Mahabubul Hasan Abdullah, Bin Hu, Lang Shi, Jiefu Zhu, Zhixia Song.
      Diabetic nephropathy (DN) is a leading cause of end-stage renal disease, characterized by progressive renal injury driven by mitochondrial dysfunction and metabolic reprogramming. Excessive mitochondrial fission, mediated by dynamin-related protein 1 (Drp1), contributes to mitochondrial fragmentation and cellular injury in the diabetic kidney. Here, we investigate the therapeutic potential of P110, a selective inhibitor of Drp1-mediated mitochondrial fission, in experimental models of DN. We demonstrate that P110 effectively reduces mitochondrial fragmentation and restores metabolic balance in renal tubular cells from DN patients. In streptozotocin (STZ)-induced diabetic mice and db/db mice, P110 treatment significantly mitigates renal injury, as evidenced by decreased fibrosis, inflammation, and podocyte injury, despite having no impact on hyperglycemia or body weight loss. Mechanistically, P110 disrupts the interaction between Drp1 and Fis1, thereby inhibiting mitochondrial fission, and activates the AMPK/PGC-1α/TFAM pathway, promoting mitochondrial biogenesis and function. Our findings suggest that targeting mitochondrial fission with P110 offers a novel therapeutic strategy for preventing and treating DN, potentially addressing a critical gap in current diabetic nephropathy management.
    Keywords:  Diabetic nephropathy; Drp1; Fis1; Metabolic reprogramming; Mitochondria
    DOI:  https://doi.org/10.1016/j.intimp.2025.114342
  3. Neurochem Res. 2025 Mar 07. 50(2): 115
    Costunolide Ameliorates the Methylmalonic Acidemia Via the PINK1/Parkin Pathway.
    Xiangpeng Lu, Hong Zheng, Huanghuang Bai, Yanfei Wang, Luyao Li, Bingxiang Ma.
      Methylmalonic acidemia (MMA) is a congenital organic acidemia characterized by mitochondrial dysfunction due to the abnormal accumulation of intermediate metabolites, which subsequently leads to brain damage. Currently, there are no specific pharmacological treatments available for MMA in clinical practice. Costunolide (COS) is a sesquiterpenoid compound derived from Radix Aucklandiae, it exhibits a broad spectrum of bioactivities. However, its effects on MMA have not yet been evaluated. For in-vivo studies, the MMA rat model was established by subcutaneous injection of methylmalonic acid (MA). The spatial learning memory flexibility observed by Morris water maze and brain damage were restored in MMA rats after COS treatment. JC-1 detection and measurements of oxidative stress indicators were performed to demonstrate that the abnormal mitochondrial membrane potential (MMP) and oxidative stress levels were recovered in hippocampus of MMA rats after COS (20 mg/kg) treatment. The abnormal expression of autophagy-related proteins induced by MMA was also rectified following COS treatment. In-vitro research utilized PC12 cells to further investigate the underlying mechanisms of COS in regulating MMA. Our results indicated that COS (20µM) ameliorated the oxidative stress level and mitophagy. Pink1 knockdown reversed the apoptosis rate and MMP which were improved by COS (20µM). Concurrently, the beneficial effects of COS on ATP concentration, ROS level and autophagy related protein expression level were also offset by PINK1 knockdown. In conclusion, our study confirms that COS promotes mitochondrial autophagy and mitigates oxidative stress via the PINK1/Parkin pathway, thereby improving cognitive impairments associated with MMA.
    Keywords:  Costunolide; Methylmalonic acidemia; Mitophagy; Oxidative stress; PINK1/Parkin pathway
    DOI:  https://doi.org/10.1007/s11064-025-04364-4
  4. Cell Death Dis. 2025 Mar 01. 16(1): 145
    PPTC7 acts as an essential co-factor of the SCFFBXL4 ubiquitin ligase complex to restrict BNIP3/3L-dependent mitophagy.
    Xiayun Xu, Yingji Chen, Siqi Fei, Xinyue Jiang, Xiaoting Zhou, Yimeng Xue, Yao Li, Shi-Min Zhao, Yan Huang, Chenji Wang.
      Mitophagy is a selective process that targets the damaged, dysfunctional, or superfluous mitochondria for degradation through autophagy. The SCFFBXL4 E3 ubiquitin ligase complex suppresses basal mitophagy by targeting BNIP3 and BNIP3L, two key mitophagy cargo receptors, for ubiquitin-proteasomal degradation. FBXL4 loss-of-function mutations lead to excessive BNIP3/3L-dependent mitophagy, thereby causing a devastating multi-system disorder called mitochondrial DNA depletion syndrome, type 13 (MTDPS13). PPTC7, a mitochondrial matrix phosphatase, is essential for proper mitochondrial function and biogenesis. Here, we show that a proportion of PPTC7 is located on the outer mitochondrial membrane, where it interacts with FBXL4 and BNIP3/3L. PPTC7 decreases BNIP3/3L protein stability in a protein phosphatase activity-independent manner. Using in vitro cell culture and Pptc7 knockout mouse model, we demonstrate that PPTC7 deficiency activates high levels of basal mitophagy in a BNIP3/3L-dependent manner. Mechanistically, PPTC7 facilitates SCFFBXL4-mediated ubiquitin-proteasomal degradation of BNIP3/3L. Overall, these findings establish PPTC7 as an essential co-factor of the SCFFBXL4 complex and a suppressor of BNIP3/3L-dependent mitophagy.
    DOI:  https://doi.org/10.1038/s41419-025-07463-w
  5. Poult Sci. 2025 Feb 24. pii: S0032-5791(25)00187-7. [Epub ahead of print]104(4): 104948
    Lactiplantibacillus plantarum JM113 alleviates mitochondrial dysfunction induced by deoxynivalenol in the jejunum of broiler chickens.
    Haonan Tong, Saisai Liang, Xinying Lv, Haotian Zhang, Qihang Hou, Zhouzheng Ren, Xiaojun Yang, Lvhui Sun, Xin Yang.
      Mitochondria are primary targets of deoxynivalenol (DON), which play a pivotal role in maintaining intestinal health. It has been suggested that Lactiplantibacillus plantarum JM113 (L. plantarum JM113) exhibits protective effects against the enterotoxicity of DON in broilers. However, the changes in mitochondrial homeostasis during this process remain unclear. A total of 144 one-day-old Arbor Acres broilers were randomly assigned to 3 groups, including the CON group (fed a basal diet and gavaged with 0.5 mL PBS), the DON group (supplemented with 5 mg/kg DON based on the CON group) and the DJ group (fed a basal diet challenged with 5 mg/kg DON and gavaged with 1 × 109 CFU L. plantarum JM113). The results showed that deoxynivalenol damaged mitochondrial morphology in the jejunum, characterized by swelling, vacuolation and cristae disruption, while L. plantarum JM113 reversed these alterations. Furthermore, the DON treatment significantly decreased total antioxidant capacity (T-AOC) in the jejunum compared with the CON group at both 7-day-old and 21-day-old, and T-AOC of the jejunum and jejunal mitochondria in the DJ group were notably increased at 21-day-old (P < 0.05). Compared to the DON group, the DJ group showed significantly upregulated expression of Mfn1, Mfn2, and Opa1 involved in mitochondrial fusion, and significantly downregulated expression of Drp1 and Fis1 mediated mitochondrial fission at 21-day-old (P < 0.05). Dietary DON exposure also induced inhibition of genes linked to mitochondrial biogenesis at 21-day-old, such as NRF1, NRF2, TFAM and PGC-1α, while L. plantarum JM113 reversed this state (P < 0.05). Additionally, oral administration of L. plantarum JM113 significantly inhibited the overactivation of mitophagy related genes and proteins in the jejunum caused by DON (P < 0.05). Moreover, L. plantarum JM113 alleviated jejunal apoptosis in broilers exposed to DON, manifested by a significant decrease in mRNA and protein expression of Bax and CASP3 (P < 0.05). In summary, L. plantarum JM113 alleviated oxidative stress induced by DON, improved mitochondrial homeostasis, and ultimately prevented the occurrence of apoptosis.
    Keywords:  Broiler chicken; Deoxynivalenol; Jejunum; Lactiplantibacillus plantarum; Mitochondrion
    DOI:  https://doi.org/10.1016/j.psj.2025.104948
  6. Stem Cell Res Ther. 2025 Mar 05. 16(1): 116
    Mesenchymal stem cell-derived small extracellular vesicles reduced hepatic lipid accumulation in MASLD by suppressing mitochondrial fission.
    Yifei Chen, Fuji Yang, Yanjin Wang, Yujie Shi, Likang Liu, Wei Luo, Jing Zhou, Yongmin Yan.
       BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic liver disease characterized by lipid accumulation in liver cells. Human umbilical cord mesenchymal stem cell-derived small extracellular vesicles (MSC-sEV) have great potential in repairing and regenerating liver diseases. However, it is still unclear whether MSC-sEV can inhibit hepatocyte lipid accumulation by regulating mitochondrial fission.
    METHODS: We investigated the effects of MSC-sEV on mitochondrial fission and its potential mechanism in lipotoxic hepatocytes and high-fat diet (HFD)-induced MASLD mice.
    RESULTS: We found that MSC-sEV can effectively inhibit the expression of the Dynamin-related protein 1 (DRP1), thereby reducing mitochondrial fission, mitochondrial damage, and lipid deposition in lipotoxic hepatocytes and livers of HFD-induced MASLD in mice. Further mechanistic studies revealed that RING finger protein 31 (RNF31) played a crucial role in mediating the inhibitory effect of MSC-sEV on DRP1 and mitochondrial fission. RNF31 can suppress DRP1 expression and mitochondrial fission, thereby improving mitochondrial dysfunction and reducing hepatocyte lipid deposition. These findings suggest that MSC-sEV may downregulate hepatocyte DRP1-mediated mitochondrial fission by transporting RNF31, ultimately inhibiting hepatocyte lipid accumulation.
    CONCLUSIONS: The insights from this study provide a new perspective on the mechanism of MSC-sEV in reducing lipid accumulation and offer a potential therapeutic target by targeting DRP1 to inhibit hepatocyte steatosis and the progression of MASLD.
    Keywords:  DRP1; MASLD; MSC; Mitochondrial fission; Small extracellular vesicles
    DOI:  https://doi.org/10.1186/s13287-025-04228-2
  7. J Physiol. 2025 Mar 06.
    Mitochondrial proteostasis and cellular health: insights from chaperones and autophagy.
    Yuvraj Anandrao Jagtap, Akash Choudhary, Sumit Kinger, Prashant Kumar, Sudipta Bhattacharyya, Hem Chandra Jha, Rohan Dhiman, Vivek Sharma, Anil K Suresh, Krishna Mohan Poluri, Amit Mishra.
      Mitochondria are a cell's powerhouse and also have a vital part in cellular processes. The emerging role of mitochondria in several crucial processes highlights their cellular and physiological importance. Mitochondrial homeostasis mechanisms, including proteostasis pathways, are vital for mitochondrial health. Failure of these processes has an important role in establishment of numerous complex disease conditions, such as neurodegeneration and imperfect ageing. However, details of mitochondrial impairments and their contribution to the pathology of neurodegeneration are poorly understood. This review systematically discusses the involvement of mitochondrial homeostasis mechanisms and their role in rejuvenating cellular health and fitness. We also focus on various cellular protein quality control mechanisms essential for mitochondrial proteostasis and how their failure leads to mitochondrial functional disturbances observed in disease conditions. We discuss recent findings based on mitostasis-associated chaperones, mitoproteases, and autophagy responses, which can lead to emergence of new possible therapeutic interventions against complex diseases.
    Keywords:  chaperones; mitochondrial dynamics; mitochondrial homeostasis; mitophagy; mitoproteases; neurodegeneration; proteostasis
    DOI:  https://doi.org/10.1113/JP287635
  8. J Transl Med. 2025 Mar 06. 23(1): 279
    Nicotinamide mononucleotide combined with PJ-34 protects microglial cells from lipopolysaccharide-induced mitochondrial impairment through NMNAT3-PARP1 axis.
    Jia Li, Xiao-Yu Cheng, Rui-Xia Ma, Bin Zou, Yue Zhang, Miao-Miao Wu, Yao Yao, Juan Li.
      Lipopolysaccharide (LPS) is known to induce cell injury and mitochondrial dysfunction, which are pivotal in neuroinflammation and related disorders. Recent studies have demonstrated the potential of nicotinamide mononucleotide (NMN) and poly(ADP-ribose) polymerase-1 (PARP1) inhibitors to enhance mitochondrial function. However, the underlying mechanisms have not been fully elucidated. This study investigates the impact of NMN in conjunction with PJ-34, a PARP1 inhibitor, on LPS-induced mitochondrial damage, focusing on nicotinamide mononucleotide adenylyl transferase 3 (NMNAT3) -PARP1 axis. The results showed that LPS treatment led to down-regulation of NMNAT3 (decreased 58.72% at 1 µM), up-regulation of PARP1 (enhanced 22.78% at 1 µM), thereby impairing mitophagy and mitochondrial function. The negative effects can be mitigated through supplementation with NMN and PJ-34. Specifically, compared to the LPS group, the expression of NMNAT3 increased by 63.29% and PARP1 decreased by 27.94% at a concentration of 400 µM NMN. Additionally, when 400 µM NMN was combined with 5 µM PJ-34, PARP1 expression decreased by 21.99%. Mechanistic studies reveal that NMN and PJ-34 counteracted the detrimental effects by promoting the binding of FoxO1 to the PINK1 promoter to activate the PINK1/Parkin mediated mitophagy pathway. Further experimental results demonstrate that the down-regulation of NMNAT3 can activate PARP1 and inhibit the initiation of autophagic processes. Consequently, targeting the NMNAT3-PARP1 signaling pathway holds promise for the development of novel therapeutic strategies to alleviate mitochondrial damage-related disorders.
    Keywords:  C57BL/6J mice; LPS; Mitochondrial function; NMN; NMNAT3; Neuroinflammation; PARP1
    DOI:  https://doi.org/10.1186/s12967-025-06280-1
  9. Mitochondrion. 2025 Mar 04. pii: S1567-7249(25)00022-4. [Epub ahead of print] 102025
    Inhibition of the expression of TRIM63 alleviates ventilator-induced diaphragmatic dysfunction by modulating the PPARα/PGC-1α pathway.
    Jun Liu, Yuhan Chen, Dong Han, Ming Huang.
       BACKGROUND: Ventilator-induced diaphragmatic dysfunction (VIDD) significantly affects the prognosis of critically ill patients and has attracted considerable attention. Tripartite motif-containing protein 63 (TRIM63) plays a pivotal role in muscle protein degradation and muscle mass regulation. Its overexpression is closely associated with VIDD; however, data on the specific effects of TRIM63 on this pathological process remain insufficient.
    OBJECTIVES: The aim of this study is to elucidate the role of TRIM63 in VIDD and to assess the correlation between the TRIM63-peroxisome proliferator activated receptor α (PPARα)/PPAR gamma coactivator (PGC-1α) pathway and mitochondrial function.
    METHODS: Specific pathogen-free grade female Wistar rats were divided into four groups: Sham + NS, Sham + MyoMed-205, MV + NS, and MV + MyoMed-205. The inhibitor group received MyoMed-205 to suppress the expression of TRIM63. After the experiment, diaphragmatic contractility, mitochondrial structure and function, oxidative stress levels, autophagy, apoptosis, and the involvement of the PPARα/PGC-1α pathway were evaluated.
    RESULTS: Our findings indicated that inhibiting TRIM63 prevented mechanical ventilation (MV)-induced diaphragmatic contractile dysfunction and atrophy. Mechanistically, inhibition of the expression of TRIM63 resulted in significant upregulation of the PPARα and PGC-1α expression levels, improved mitochondrial dynamics, enhanced the mitochondrial membrane potential, and reduced mitophagy and apoptosis. Structurally, inhibition of the expression of TRIM63 ameliorated MV-induced mitochondrial fragmentation, fusion, and fission.
    CONCLUSIONS: The upregulated expression of TRIM63 in VIDD exacerbated mitochondrial damage by inhibiting the PPARα/PGC-1α signaling pathway, leading to increased reactive oxygen species, mitophagy, and apoptosis. Inhibition of the expression of TRIM63 enhanced mitochondrial function, decreased mitophagy and apoptosis, and mitigated VIDD. Thus, TRIM63 may serve as a potential target for the prevention and treatment of VIDD.
    Keywords:  Diaphragmatic dysfunction; Mechanical ventilation; Mitochondria; TRIM63
    DOI:  https://doi.org/10.1016/j.mito.2025.102025
  10. bioRxiv. 2025 Feb 20. pii: 2025.02.19.639160. [Epub ahead of print]
    Novel reporter of the PINK1-Parkin mitophagy pathway identifies its damage sensor in the import gate.
    Julia A Thayer, Jennifer D Petersen, Xiaoping Huang, James Hawrot, Daniel M Ramos, Shiori Sekine, Yan Li, Michael E Ward, Derek P Narendra.
      Damaged mitochondria can be cleared from the cell by mitophagy, using a pathway formed by the recessive Parkinson's disease genes PINK1 and Parkin. How mitochondrial damage is sensed by the PINK1-Parkin pathway, however, remains uncertain. Here, using a Parkin substrate-based reporter in genome-wide screens, we identified that diverse forms of mitochondrial damage converge on loss of mitochondrial membrane potential (MMP) to activate PINK1. Consistently, the MMP but not the presequence translocase-associated motor (PAM) import motor provided the essential driving force for endogenous PINK1 import through the inner membrane translocase TIM23. In the absence of TIM23, PINK1 arrested in the translocase of the outer membrane (TOM) during import. The energy-state outside of the mitochondria further modulated the pathway by controlling the rate of new PINK1 synthesis. Our results identify separation of PINK1 from TOM by the MMP, as the key damage-sensing switch in the PINK1-Parkin mitophagy pathway.
    Highlights: MFN2-Halo is a quantitative single-cell reporter of PINK1-Parkin activation.Diverse forms of mitochondrial damage, identified in whole-genome screens, activate the PINK1-Parkin pathway by disrupting the mitochondrial membrane potential (MMP).The primary driving force for endogenous PINK1 import through the TIM23 translocase is the MMP with the PAM import motor playing a supporting role.Loss of TIM23 is sufficient to stabilize PINK1 in the TOM complex and activate Parkin.
    DOI:  https://doi.org/10.1101/2025.02.19.639160
  11. BMC Cancer. 2025 Mar 06. 25(1): 412
    Impact of celastrol on mitochondrial dynamics and proliferation in glioblastoma.
    Lei Liang, Wenying Lv, Gang Cheng, Mou Gao, Junzhao Sun, Ning Liu, Hanbo Zhang, Baorui Guo, Jiayu Liu, Yanteng Li, Shengqiang Xie, Jiangting Wang, Junru Hei, Jianning Zhang.
       BACKGROUND: Targeting mitochondrial dynamics offers promising strategies for treating glioblastoma multiforme. Celastrol has demonstrated therapeutic effects on various cancers, but its impact on mitochondrial dynamics in glioblastoma multiforme remains largely unknown. We studied the effects of Celastrol on mitochondrial dynamics, redox homeostasis, and the proliferation.
    METHODS: Mito-Tracker Green staining was conducted on U251, LN229, and U87-MG cells to evaluate the effects of Celastrol on mitochondrial dynamics. The Western blot analysis quantified the expression levels of mitochondrial dynamin, antioxidant enzymes, and cell cycle-related proteins. JC-1 staining was performed to discern mitochondrial membrane potential. Mitochondrial reactive oxygen species were identified using MitoSOX. The proliferative capacity of cells was assessed using Cell Counting Kit-8 analysis, and colony formation assays. Survival analysis was employed to evaluate the therapeutic efficacy of Celastrol in C57BL/6J mice with glioblastoma.
    RESULTS: Our findings suggest that Celastrol (1 and 1.5 µM) promotes mitochondrial fission by downregulating the expression of mitofusin-1. A decrease in mitochondrial membrane potential at 1 and 1.5 µM indicates that Celastrol impaired mitochondrial function. Concurrently, an increase in mitochondrial reactive oxygen species and impaired upregulation of antioxidant enzymes were noted at 1.5 µM, indicating that Celastrol led to an imbalance in mitochondrial redox homeostasis. At both 1 and 1.5 µM, cell proliferation was inhibited, which may be related to the decreased expression levels of Cyclin-dependent kinase 1 and Cyclin B1. Celastrol extended the survival of GBM-afflicted mice.
    CONCLUSION: Celastrol promotes mitochondrial fission in glioblastoma multiforme cells by reducing mitofusin-1 expression, accompanying mitochondrial dysfunction, lower mitochondrial membrane potential, heightened oxidative stress, and decreased Cyclin-dependent kinase 1 and Cyclin B1 levels. This indicates that Celastrol possesses potential for repurposing as an agent targeting mitochondrial dynamics in glioblastoma multiforme, warranting further investigation.
    Keywords:  CDK1 protein; Celastrol; Drug repurposing; Glioblastoma; Mitochondrial dynamics; Oxidative stress
    DOI:  https://doi.org/10.1186/s12885-025-13733-9
  12. Int J Radiat Biol. 2025 Mar 03. 1-12
    Prohibitin2 knockdown decreases glioma malignant phenotypes and radio-resistance by inhibiting mitophagy.
    Xuefei Xue, Huiling Tan, Xingning Jiang, Jingfan Lu, Ting Sun, Wei Yang.
       PURPOSE: Prohibitin2 (PHB2), located in inner mitochondrial membrane (IMM), is an important receptor to induce mitophagy. PHB2 was identified as a cancer-promoting factor in most cancers. However, the function of PHB2 in glioma cells remains unclear. This study delved into the impact of PHB2 knockdown on the phenotype, radiosensitivity and mitophagy of glioma cells.
    METHODS: PHB2 expression and its clinical relevance in glioma were investigated by western blot, quantitative reverse transcription polymerase chain reaction (qRT-PCR) and TCGA databases. The malignant phenotypes of glioma cells were analyzed in vitro using cell proliferation, cell cycle, wound healing and transwell assay. The radiosensitivity of glioma cells was detected by colony forming assay. The potential mechanism by which PHB2 regulated mitophagy was investigated by coimmunoprecipitation assay.
    RESULTS: The expression of PHB2 was significantly upregulated in glioma cells and closely correlated with the malignant degree of glioma. The knockdown of PHB2 inhibited the proliferation, migration and invasion activities of glioma cells. Furthermore, PHB2 knockdown enhanced the radiosensitivity of normoxic and hypoxic glioma cells and suppressed the ionizing radiation-induced mitophagy in glioma cells. Cyanide 3-chlorophenylhydrazone (CCCP), a mitophagy agonist, could reverse the phenotypes and radiosensitivity changes elicited by PHB2 knockdown. Additionally, PHB2 regulated the expression of PGAM5 and PINK1 by directly binding to PARL.
    CONCLUSIONS: Our findings revealed that PHB2 knockdown decreased glioma malignant phenotypes and radio-resistance by inhibiting mitophagy via PARL-PGAM5-PINK1-Parkin pathway. PHB2 is a promising candidate target for the development of new therapeutic strategy to enhance the efficacy of radiotherapy for glioma.
    Keywords:  PHB2; glioma; hypoxia; mitophagy; radiosensitivity
    DOI:  https://doi.org/10.1080/09553002.2025.2470203
  13. Drug Des Devel Ther. 2025 ;19 1271-1287
    Cordycepin Ameliorates Renal Interstitial Fibrosis by Inhibiting Drp1-Mediated Mitochondrial Fission.
    Yingxue Sun, Shi Jin, Jun Chen, Jian Zhang, Yufei Lu, Qiuyu Gu, Zhixin Yan, Weize Chen, Annan Chen, Yi Fang, Wenye Geng, Xialian Xu, Nana Song.
       Objective: This study aimed to investigate the mechanisms and specific targets of cordycepin in the treatment of renal fibrosis using a unilateral ischemia-reperfusion (UIR) model.
    Methods: A UIR mouse model was established, followed by intraperitoneal injections of cordycepin and Mdivi-1. Masson's trichrome staining and PAS staining were used to identify renal tubulointerstitial fibrosis and assess the degree of renal injury. Fibrosis markers and mitochondrial dynamics-related proteins were evaluated using Western blotting, while differential gene expression and pathway enrichment were analyzed by RNA-seq. Molecular docking, molecular dynamics simulations and surface plasmon resonance were conducted to validate the specific binding sites of cordycepin on the target protein Drp1. Immunofluorescence and in vitro experiments further elucidated the therapeutic mechanism of cordycepin.
    Results: In vivo experiments showed that intraperitoneal injection of cordycepin significantly reduced renal inflammation and fibrosis, lowered serum creatinine levels, and decreased collagen deposition. Transcriptome analysis revealed that cordycepin treatment downregulated the mitochondrial fission pathway and upregulated the mitochondrial fusion pathway. Western blotting showed reduced levels of fibrosis markers α-SMA and FN, as well as downregulation of Drp1, MFF, and Fis1, and upregulation of OPA1 and Mfn2. In vitro, cordycepin inhibited TGF-β-induced injury in NRK-52E cells, reducing Drp1 expression and IL-6 secretion. Crosstalk experiments confirmed that decreased IL-6 levels were crucial for cordycepin anti-fibrotic effects by suppressing fibroblast activation.
    Conclusion: Cordycepin ameliorates renal fibrosis by targeting Drp1 to inhibit mitochondrial fission in injured renal tubular epithelial cells, reducing IL-6 secretion and inhibiting fibroblast activation.
    Keywords:  Drp1; IL-6; UIR; cordycepin; mitochondrial fission; renal fibrosis
    DOI:  https://doi.org/10.2147/DDDT.S498525
  14. Bone Res. 2025 Mar 03. 13(1): 30
    Enhanced SIRT3 expression restores mitochondrial quality control mechanism to reverse osteogenic impairment in type 2 diabetes mellitus.
    Yansi Xian, Bin Liu, Tao Shen, Lin Yang, Rui Peng, Hongdou Shen, Xueying An, Yutian Wang, Yu Ben, Qing Jiang, Baosheng Guo.
      Osteoporosis represents a prevalent and debilitating comorbidity in patients diagnosed with type 2 diabetes mellitus (T2DM), which is characterized by suppressed osteoblast function and disrupted bone microarchitecture. In this study, we utilized male C57BL/6 J mice to investigate the role of SIRT3 in T2DM. Decreased SIRT3 expression and impaired mitochondrial quality control mechanism are observed in both in vitro and in vivo models of T2DM. Mechanistically, SIRT3 suppression results in hyperacetylation of FOXO3, hindering the activation of the PINK1/PRKN mediated mitophagy pathway and resulting in accumulation of dysfunctional mitochondria. Genetical overexpression or pharmacological activation of SIRT3 restores deacetylation status of FOXO3, thus facilitating mitophagy and ameliorating osteogenic impairment in T2DM. Collectively, our findings highlight the fundamental regulatory function of SIRT3 in mitochondrial quality control, crucial for maintaining bone homeostasis in T2DM. These insights not only enhance our understanding of the molecular mechanisms underlying diabetic osteoporosis but also identify SIRT3 as a promising therapeutic target for diabetic osteoporosis.
    DOI:  https://doi.org/10.1038/s41413-024-00399-5
  15. Neurosci Res. 2025 Feb 27. pii: S0168-0102(25)00049-5. [Epub ahead of print]
    Metformin alleviates auditory cell senescence by mitophagy induction.
    Sung Il Cho, Eu-Ri Jo, Hee Sun Jang.
      Age-related hearing loss is the most common type of hearing loss in older adults. However, its underlying cellular mechanism is still unclear. Impaired mitochondrial function is a hallmark of various age-related pathologies. To maintain mitochondrial function in senescent cells, mitophagy is a crucial process for dysfunctional mitochondria turnover. Metformin has been reported to induce mitophagy. This study aimed to investigate the effect of metformin on preventing senescence in auditory cells. Low-dose H2O2 represented senescence-associated secretory phenotype (SASP) and reduced mitophagy-related molecules in House Ear Institute-Organ of Corti 1 (HEI-OC1) cells and cochlear explants. Metformin significantly decreased the expression of SASP in H2O2-induced senescent cells. Metformin also decreased the expression of senescence-associated p53 and p21, and increased the expression of mitophagy-related PINK1, Parkin, and BNIP3 in H2O2-induced senescent cells and cochlear explants. The co-localization of mitophagy dye and lyso dye decreased in H2O2-induced senescent cells, but metformin pre-treatment significantly increased their colocalization. Metformin significantly decreased the percentage of β-galactosidase-stained senescent cells and increased the expression of OXPHOS complexes in H2O2-induced senescent cells and cochlear explants. Metformin also significantly increased mitochondrial function in senescent cells. These results indicate that metformin prevented premature senescence in auditory cells by counteracting reduced mitophagy. Therefore, maintaining mitochondrial function using metformin might be a potential strategy for the prevention of age-related hearing loss.
    Keywords:  Metformin; Mitochondria; Mitophagy; Senescence
    DOI:  https://doi.org/10.1016/j.neures.2025.02.008
  16. FASEB J. 2025 Mar 15. 39(5): e70446
    Compression force regulates cementoblast mineralization via S1PR1/mitophagy axis.
    Han Wang, Jingwen Cai, Linxin Chen, Sihang Chen, Xinhan Yang, Zhonghan Chen, Linyu Xu.
      Orthodontically induced inflammatory root resorption (OIIRR) poses a significant clinical challenge, as excessive orthodontic force shortens tooth longevity by impairing cementoblast-mediated cementum mineralization and promoting root resorption. Cementoblasts, essential for mineralized cementum formation and resistance to resorption, exhibit altered mechanosensitivity and mechanotransduction under orthodontic force, yet the role of mitophagy in this process remains poorly understood. In this study, we investigated how the S1PR1/mitophagy axis modulates cementoblast mineralization and OIIRR progression. The in vivo orthodontic loading model revealed that heavy compression force triggered OIIRR and impaired cementoblast mineralization along with suppression of mitophagy in cementoblasts by downregulating PINK1 and PARKIN expression. The in vitro experiments further confirmed that heavy compression force increased reactive oxygen species (ROS) levels, disrupted mitochondrial membrane potential (MMP), and inhibited mitophagy in OCCM30 cells, thereby impairing their mineralization capacity. Mechanistically, S1PR1 upregulation activated mitophagy, which in turn restored cementoblast mineralization under heavy compression force. Moreover, pharmacological activation of S1PR1 with SEW2871 alleviated OIIRR in vivo. These findings highlight the pivotal role of the S1PR1/mitophagy axis in maintaining cementoblast function and mineralization under orthodontic force, offering novel insights into the molecular mechanisms underlying OIIRR and suggesting potential therapeutic strategies to prevent OIIRR during orthodontic treatment.
    Keywords:  S1PR1; cementoblast; mitophagy; orthodontic force; root resorption
    DOI:  https://doi.org/10.1096/fj.202403234RR
  17. bioRxiv. 2025 Feb 20. pii: 2025.02.19.639081. [Epub ahead of print]
    Mitochondrial accumulation and lysosomal dysfunction result in mitochondrial plaques in Alzheimer's disease.
    Xiuli Dan, Deborah L Croteau, Wenlong Liu, Xixia Chu, Paul D Robbins, Vilhelm A Bohr.
      Dysfunctional mitophagy is a key component of Alzheimer's disease (AD) pathology, yet direct in vivo evidence and mechanistic insights remain limited. Using a mitophagy reporter in an AD mouse model ( APP / PSEN1 /mt-Keima), we identified mitochondrial plaques (MPs) composed of accumulated mitochondria within or outside lysosomes in AD, but not normal mouse brains. Similar structures were also found in AD human brains, but not in healthy controls. Abnormal mitochondrial accumulation in dystrophic neurites, defective mitophagy, and impaired lysosomal function disrupted proper mitochondrial degradation, resulting in excessive mitochondria accumulation both within and outside autophagic vesicles. The resulting intensive mitochondria-containing neurites coalesce into MPs, which co-develop with amyloid plaques to form mixed plaques. These findings establish MPs as novel pathological entity and a promising therapeutic target in AD.
    DOI:  https://doi.org/10.1101/2025.02.19.639081
  18. CNS Neurosci Ther. 2025 Mar;31(3): e70297
    Exploring the Therapeutic Mechanism of Xinbao Pill in Brain Injury After Cardiopulmonary Resuscitation Based on Network Pharmacology, Metabolomics, and Experimental Verification.
    Dongli Li, Qihui Wu, Zunjiang Li, Baijian Chen, Xing Sun, Qiqi Wu, Zhenzhu Ding, Linling Liu, Jiansong Fang, Ruifeng Zeng, Yong Gu, Banghan Ding.
       BACKGROUND: Post-cardiopulmonary resuscitation brain injury (PBI) is essentially the cerebral ischemia reperfusion (CIR) injury, which is the main cause of death and long-term disability in patients with cardiac arrest. So far, there is no treatment for PBI; thus, it is urgent to develop new drugs or therapies for the prevention and treatment of brain injury after cardiopulmonary resuscitation. Although multiple constituent herbs or active ingredients of Xinbao Pill (XBP) have shown neuroprotective effects, whether XBP could play a therapeutic role on PBI is still unknown. This study aimed to illustrate the neuroprotective effect of XBP on PBI and probe the underlying mechanisms.
    METHOD: We first performed the cell and animal experiments to validate the protective effect of XBP on neurological function. We next identified the potential differential metabolites via metabolomics analysis. We further conducted a comprehensive network pharmacology analysis including overlap gene analysis, protein-protein interaction network, and gene-biological process-module function network to preliminarily investigate the specific mechanism of action (MOA) of XBP against PBI. Finally, PCR, MTT, ELISA assay, as well as Western blotting experiments were made to validate our proposed molecular mechanisms.
    RESULT: The in vitro experiment showed that XBP could increase cell viability and ameliorate cell morphological damage in PC12 cells exposed to oxygen-glucose deprivation and reoxygenation (OGD/RO) conditions. The in vivo experiment demonstrated that XBP improved the Neurologic Deficit Score (NDS), lowered the Neuron-Specific Enolase (NSE) level as well as reversed the typical neuropathological changes in PBI rats, indicating its neuroprotective effect on PBI. Further metabolomics analysis identified 94 differential metabolites after XBP treatment, and multiple metabolites were highly related to CIR. Moreover, network pharmacology results revealed that the therapeutic effect of XBP on PBI may be relevant to mitochondrial quality control (MQC). Mechanistically, XBP could not only promote the expressions of marker proteins including PGC1α, NRF1, TFAM, OPA1, MFN1 as well as MFN2 in mitochondrial biogenesis and mitochondrial fusion but also inhibit those proteins containing DRP1, MFF, FIS1, p62, PINK1, Parkin as well as LC3 in mitochondrial fission and mitophagy. Finally, AMP-activated protein kinase (AMPK) inhibitor was demonstrated to play a crucial role in regulating MQC.
    CONCLUSIONS: Our study first determined that XBP might be an underlying anti-PBI formula, which also deciphered the potential MOAs of XBP against PBI by a network pharmacology approach combined with in vivo and in vitro experimental validation.
    Keywords:  AMPK; Xinbao pill; brain injury after cardiopulmonary resuscitation; mitochondrial quality control
    DOI:  https://doi.org/10.1111/cns.70297
  19. Mitochondrion. 2025 Feb 27. pii: S1567-7249(25)00019-4. [Epub ahead of print]82 102022
    Mitochondria in aging and age-associated diseases.
    Sonu Pahal, Nirjal Mainali, Meenakshisundaram Balasubramaniam, Robert J Shmookler Reis, Srinivas Ayyadevara.
      Mitochondria, essential for cellular energy, are crucial in neurodegenerative disorders (NDDs) and their age-related progression. This review highlights mitochondrial dynamics, mitovesicles, homeostasis, and organelle communication. We examine mitochondrial impacts from aging and NDDs, focusing on protein aggregation and dysfunction. Prospective therapeutic approaches include enhancing mitophagy, improving respiratory chain function, maintaining calcium and lipid balance, using microRNAs, and mitochondrial transfer to protect function. These strategies underscore the crucial role of mitochondrial health in neuronal survival and cognitive functions, offering new therapeutic opportunities.
    DOI:  https://doi.org/10.1016/j.mito.2025.102022
  20. J Neuroinflammation. 2025 Feb 28. 22(1): 55
    Protective role of mitophagy on microglia-mediated neuroinflammatory injury through mtDNA-STING signaling in manganese-induced parkinsonism.
    Yang Lu, Liang Gao, Yuqing Yang, Dihang Shi, Zhipeng Zhang, Xiaobai Wang, Ying Huang, Jie Wu, Jia Meng, Hong Li, Dongying Yan.
      Manganese (Mn), the third most abundant transition metal in the earth's crust, has widespread applications in the emerging field of organometallic catalysis and traditional industries. Excessive Mn exposure causes neurological syndrome resembling Parkinson's disease (PD). The pathogenesis of PD is thought to involve microglia-mediated neuroinflammatory injury, with mitochondrial dysfunction playing a role in aberrant microglial activation. In the early stages of PD, PINK1/Parkin-mediated mitophagy contributes to the microglial inflammatory response via the cGAS/STING signaling pathway. Suppression of PINK1/Parkin-mediated mitophagy due to excessive Mn exposure exacerbates neuronal injury. Moreover, excessive Mn exposure leads to neuroinflammatory damage via the microglial cGAS-STING pathway. However, the precise role of microglial mitophagy in modulating neuroinflammation in Mn-induced parkinsonism and its underlying molecular mechanism remains unclear. Here, we observed that Mn-exposed mice exhibited neurobehavioral abnormalities and detrimental microglial activation, along with increased apoptosis of nerve cells, proinflammatory cytokines, and intracellular ROS. Furthermore, in vivo and in vitro experiments showed that excessive Mn exposure resulted in microglial mitochondrial dysfunction, manifested by increased mitochondrial ROS, decreased mitochondrial mass, and membrane potential. Additionally, with the escalating Mn dose, PINK1/Parkin-mediated mitophagy changed from activation to suppression. This was evidenced by decreased levels of LC3-II, PINK1, p-Parkin/Parkin, and increased levels of p62 protein expression level, as well as the colocalization between ATPB and LC3B due to excessive Mn exposure. Upregulation of mitophagy by urolithin A could mitigate Mn-induced mitochondrial dysfunction, as indicated by decreased mitochondrial ROS, increased mitochondrial mass, and membrane potential, along with improvements in neurobehavioral deficits and attenuated detrimental microglial activation. Using single-nucleus RNA-sequencing (snRNA-seq) analysis in the Mn-exposed mouse model, we identified the microglial cGAS-STING signaling pathway as a potential mechanism underlying Mn-induced neuroinflammation. This pathway is associated with an increase in cytosolic mtDNA levels, which activate STING signaling. These findings point to the induction of microglial mitophagy as a viable strategy to alleviate Mn-induced neuroinflammation through mtDNA-STING signaling.
    Keywords:  Manganese; Microglia; Mitophagy; Neuroinflammation; STING
    DOI:  https://doi.org/10.1186/s12974-025-03396-5
  21. Free Radic Biol Med. 2025 Mar 04. pii: S0891-5849(25)00135-2. [Epub ahead of print]
    Selenium-Loaded Porous Silica Nanospheres Improve Cardiac Repair After Myocardial Infarction by Enhancing Antioxidant Activity and Mitophagy.
    Taixi Li, Xijian Liu, Boshen Yang, Zhixiang Wang, Yizhi Chen, Xian Jin, Chengxing Shen.
      Myocardial infarction (MI) is the leading cause of death globally, often resulting to significant loss of cardiac function. A key factor in the pathological progression of MI is the excessive generation of reactive oxygen species (ROS) by dysfunctional mitochondria. However, no antioxidant therapy has been approved for clinical treatment of MI to date. In this study, selenium-loaded porous silica nanospheres (Se@PSN) are synthesized as a novel therapeutic approach for MI. These nanospheres are capable of neutralizing various ROS, thereby reducing hypoxia-induced myocardial cell damage. Additionally, Se@PSN promote the upregulation of antioxidant proteins, providing sustained intracellular ROS scavenging, which helps reduce infarct size and preserve cardiac function post-MI. The sustained antioxidant effects of Se@PSN are attributed to their ability to safeguard mitochondrial function by modulating oxidative phosphorylation, mitochondrial dynamics, and mitophagy. The activation of mitophagy by Se@PSN is achieved through the upregulation of HIF-1α expression. In conclusion, Se@PSN show significant potential for clinical translation as a novel therapeutic strategy for MI.
    Keywords:  mitophagy; myocardial infarction; porous silica nanospheres; reactive oxygen species; selenium
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.03.004
  22. J Cachexia Sarcopenia Muscle. 2025 Apr;16(2): e13763
    Deubiquitinating Enzymes Regulate Skeletal Muscle Mitochondrial Quality Control and Insulin Sensitivity in Patients With Type 2 Diabetes.
    Wagner S Dantas, Elizabeth C Heintz, Elizabeth R M Zunica, Jacob T Mey, Melissa L Erickson, Kathryn P Belmont, Analisa L Taylor, Gangarao Davuluri, Hisashi Fujioka, Ciarán E Fealy, Charles L Hoppel, Christopher L Axelrod, John P Kirwan.
       BACKGROUND: Activation of mitochondrial fission and quality control occur early in the onset of insulin resistance in human skeletal muscle. We hypothesized that differences in mitochondrial dynamics, structure and bioenergetics in humans would explain the onset and progression of type 2 diabetes (T2D).
    METHODS: Fifty-eight sedentary adults (37 ± 12 years) were enrolled into one of three groups: (1) healthy weight (HW), (2) overweight and obesity (Ow/Ob), or (3) T2D. Body composition, aerobic capacity, and insulin sensitivity were assessed during a 3-day inpatient stay. A fasted skeletal muscle biopsy was obtained to assess mitochondrial functions. C2C12 myoblasts were transfected with FLAG-HA-USP15 and FLAG-HA-USP30 and harvested to assess mitochondrial dynamics and cellular insulin action.
    RESULTS: Insulin sensitivity and aerobic capacity were lower in Ow/Ob (132% and 28%, respectively) and T2D (1024% and 83%, respectively) relative to HW. Patients with T2D presented with elevated skeletal muscle mitochondrial fission (3.2 fold relative to HW and Ow/Ob), decreased fusion, and impairments in quality control. Mitochondrial content was lower in Ow/Ob (26%) and T2D (56%). USP13 (84%), USP15 (96%) and USP30 (53%) expression were increased with decreased Parkin and Ub activation in T2D alone. USP15 (R2 = 0.55, p < 0.0001) and USP30 (R2 = 0.40, p < 0.0001) expression negatively correlated with peripheral insulin sensitivity. USP15 and USP30 overexpression activated DRP1 (3.6 and 3.7 fold, respectively) while inhibiting AKT (96% and 81%, respectively) and AS160 (2.1 and 3.5 fold, respectively) phosphorylation.
    CONCLUSION: Mitochondrial fragmentation bypasses defects in mitophagy to sustain skeletal muscle quality control in patients with T2D.
    Keywords:  bioenergetics; fission; fusion; mitochondria; obesity; quality control; type 2 diabetes
    DOI:  https://doi.org/10.1002/jcsm.13763
  23. Chem Biol Drug Des. 2025 Mar;105(3): e70072
    Protocatechuic Acid Alleviates Inflammation and Oxidative Stress in Acute Respiratory Distress Syndrome by Promoting Unconventional Prefoldin RPB5 Interactor 1-Mediated Mitophagy.
    Xianyong Li, Quankuan Gu, Jiaxi Xu, Bowen Liu, Peiyao Luo, Mingyan Zhao.
      Protocatechuic acid (PCA) is a type of polyphenol with diverse biological activities, including antioxidant and anti-inflammatory properties. This study aimed to explore the function of PCA in acute respiratory distress syndrome (ARDS) and delve into its functional mechanism. Lipopolysaccharides were applied to stimulate human pulmonary microvascular endothelial cells (HPMECs) or C57BL/6 mice to generate ARDS models in vitro and in vivo. PCA treatment (300 μM for cells and 20 or 30 mg/kg for mice) reduced proinflammatory cytokine production and oxidative stress in HPMECs or mouse models, and it reduced cell apoptosis while alleviating alveolar septum thickening. Chromobox 4 (CBX4) was identified as a target protein of PCA, and it was found to activate the transcription of unconventional prefoldin RPB5 interactor 1 (URI1) by recruiting histone acetyltransferase general control nondepressible 5 (GCN5) to its promoter region. CBX4 and URI1 levels were reduced by LPS but restored by PCA. Knockdown of either CBX4 or URI1 negated the ameliorating effects of PCA on LPS-induced inflammation and oxidative stress and diminished the promoting roles of PCA in promoting mitochondrial biogenesis and mitophagy. This study suggests that PCA holds promise in alleviating inflammation and oxidative stress in ARDS by promoting CBX4/URI1-mediated mitophagy.
    Keywords:  CBX4; URI1; acute respiratory distress syndrome; mitophagy; oxidative stress; protocatechuic acid
    DOI:  https://doi.org/10.1111/cbdd.70072
  24. J Transl Med. 2025 Mar 04. 23(1): 269
    Important regulatory role of mitophagy in diabetic microvascular complications.
    Xiangjie Hu, Jiao Lv, Yunyun Zhao, Xiangyan Li, Wenxiu Qi, Xiuge Wang.
      Microvascular complications of diabetes pose a significant threat to global health, mainly including diabetic kidney disease (DKD), diabetic retinopathy (DR), diabetic peripheral neuropathy (DPN), and diabetic cardiomyopathy (DCM), which can ultimately lead to kidney failure, blindness, disability, and heart failure. With the increasing prevalence of diabetes, the search for new therapeutic targets for diabetic microvascular complications is imminent. Mitophagy is a widespread and strictly maintained process of self-renewal and energy metabolism that plays an important role in reducing inflammatory responses, inhibiting reactive oxygen species accumulation, and maintaining cellular energy metabolism. Hyperglycemia results in impaired mitophagy, which leads to mitochondrial dysfunction and ultimately exacerbates disease progression. This article summarizes the relevant molecular mechanisms of mitophagy and reviews the current status of research on regulating mitophagy as a potential treatment for diabetic microvascular complications, attempting to give new angles on the treatment of diabetic microvascular complications.
    Keywords:  Diabetic cardiomyopathy; Diabetic kidney disease; Diabetic peripheral neuropathy; Diabetic retinopathy; Mitophagy
    DOI:  https://doi.org/10.1186/s12967-025-06307-7
  25. Mitochondrion. 2025 Mar 04. pii: S1567-7249(25)00020-0. [Epub ahead of print] 102023
    Drp1 knockdown aggravates obesity-induced cardiac dysfunction and remodeling.
    Dan Wu, Qingxun Hu, Huimin Li, Yun Yin, Pei Wang, Wang Wang.
      Obesity is an independent risk factor for heart failure with preserved ejection fraction (HFpEF). Dynamin related protein 1 (Drp1) is a key regulator of mitochondrial morphology, bioenergetics and quality control. The role of endogenous Drp1 in obesity induced HFpEF remains largely unknown. Here, adult heterozygous Drp1 floxed (Drp1fl/+) mice were bred with αMHC-MerCreMer mice and injected with tamoxifen to induce heterogenous Drp1 knockout (hetCKO) in the heart. Control and hetCKO mice exhibited similar increases in body weight and blood glucose and developed insulin resistance after 18-week high-fat diet (HFD)-fed. HFD had no effect on cardiac contractility but induced diastolic dysfunction, fibrosis, cell death and inflammation in Control and hetCKO mice hearts. Importantly, all these adverse effects were exacerbated in the hearts of hetCKO mice, suggesting aggravated cardiac remodeling and diastolic dysfunction. HFD induced mitochondrial fission was blocked, whereas energy deficiency was exaggerated in hetCKO hearts. These effects were associated with suppressed mitochondrial quality control via mitophagy, and increased apoptosis and oxidative stress. These findings suggest that endogenous Drp1 may play an important role in limiting metabolic stress induced heart dysfunction through regulating mitophagy, oxidative stress, mitochondrial function, apoptosis, and inflammation. Our study provides critical insights into how endogenous Drp1 plays a beneficial role in metabolic stress-induced HFpEF.
    Keywords:  Dynamin related protein 1; Heart failure with preserved ejection fraction; Lipid overload; Mitochondrial dysfunction
    DOI:  https://doi.org/10.1016/j.mito.2025.102023
  26. Dev Comp Immunol. 2025 Mar 03. pii: S0145-305X(25)00038-2. [Epub ahead of print] 105349
    Molecular cloning, characterization and expression analysis of PINK1 (Phosphatase and tensin homolog-induced putative kinase 1) and Parkin (parkin RBR E3 ubiquitin protein ligase) in grass carp (Ctenopharyngodon idellus).
    Chenchen Bian, Mingkui Wei, Xiaolong Luo, Jian Sun, Hong Ji.
      Phosphatase and tensin homolog-induced putative kinase 1 (PINK1) and parkin RBR E3 ubiquitin protein ligase (Parkin) emerged as mediators of mitophagy and regulators of the immune response in mammals. However, their gene characterizations and roles remain poorly understood in fish. Herein, we identified and characterized pink1 and parkin genes and studied their involvement in immune responses to lipopolysaccharide (LPS) in Ctenopharyngodon idellus kidney (CIK) cells. Bioinformatic analysis found that PINK1 and Parkin were relatively conservative during evolution. In CIK cells, LPS significantly increased the mRNA expression of the transcription factor nf-κb and its downstream proinflammatory cytokines, such as tnfα, il-6 and il-1β, along with the activation of PINK1/Parkin-mediated mitophagy (P < 0.05). Furthermore, inhibition of mitophagy aggravated LPS-induced inflammation in CIK cells. Overall, our findings suggest that PINK1/Parkin-mediated mitophagy may play a protective role in LPS-induced inflammation in fish.
    Keywords:  Ctenopharyngodon idellus; Inflammation; Mitophagy; Parkin RBR E3 ubiquitin protein ligase; Phosphatase and tensin homolog-induced putative kinase 1
    DOI:  https://doi.org/10.1016/j.dci.2025.105349
  27. Cell Rep. 2025 Mar 05. pii: S2211-1247(25)00148-2. [Epub ahead of print]44(3): 115377
    Mitochondrial fusion and cristae reorganization facilitate acquisition of cardiomyocyte identity during reprogramming of murine fibroblasts.
    Brian M Spurlock, Yifang Xie, Yiran Song, Shea N Ricketts, James Rock Hua, Haley R Chi, Meenakshi Nishtala, Rustem Salmenov, Jiandong Liu, Li Qian.
      Cardiomyocytes (CMs) rely on mitochondrial energy produced in highly interconnected mitochondrial networks. Direct reprogramming of cardiac fibroblasts (CFs) into induced CMs (iCMs) shows promise for treating cardiac injury, but little work has investigated mitochondrial energetics and morphology during the conversion of CFs to iCMs. We characterized mitochondria during direct cardiac reprogramming of murine neonatal CFs (mnCFs). Reprogramming increased mitochondrial respiration and interconnectivity but not to the levels of native CMs. We therefore investigated whether perturbations to mitochondrial dynamics impacted reprogramming. Mitochondrial fusion (joining) was essential for iCM generation, while various fission (dividing) genes were reprogramming barriers. In particular, the loss of mitochondrial fission regulator 1 like (Mtfr1l) significantly increased the yield of functionally mature iCMs and induced mitochondrial fusion and respiration. These changes were countered by the concomitant loss of fusion effector optical atrophy protein 1 (Opa1). The present study advances our understanding of mitochondrial barriers to and mechanisms of direct cardiac reprogramming.
    Keywords:  CP: Metabolism; CP: Stem cell research; Mtfr1l; cell fate conversion; direct cardiac reprogramming; machine learning; mitochondria; mitochondrial dynamics; mitochondrial energetics; mitochondrial fission; mitochondrial fusion; regenerative medicine
    DOI:  https://doi.org/10.1016/j.celrep.2025.115377
  28. Commun Biol. 2025 Feb 28. 8(1): 338
    Elevated levels of S100A8 and S100A9 exacerbate muscle mitochondrial fragmentation in sepsis-induced muscle atrophy.
    Dongqin Huang, Yang Li, Yuqian Guo, Mengcao Weng, Hui Ye, Yan Zhang, Fei Lin, Kai Zhang, Xiangming Fang.
      Sepsis-induced skeletal muscle atrophy is common in septic patients with the increases risk of mortality and is associated with myocellular mitochondrial dysfunction. Nevertheless, the specific mechanism of sepsis muscle atrophy remains unclear. Here we conducted a clinical retrospective analysis and observed the elevation of skeletal muscle index (ΔSMI) was an independent risk factor for 60-day mortality in septic patients. Moreover, in mouse model of sepsis, the skeletal muscle atrophy was also observed, which was associated with the upregulation of S100a8/a9-mediated mitochondrial dysfunction. Inhibition of S100a8/a9 significantly improved mitochondrial function and alleviated muscle atrophy. Conversely, administration of recombinant S100a8/a9 protein exacerbated mitochondrial energy exhaustion and myocyte atrophy. Mechanistically, S100a8/a9 binding to RAGE induced Drp1 phosphorylation and mitochondrial fragmentation, resulting in muscle atrophy. Additionally, RAGE ablation or administration of Drp1 inhibitor significantly reduced Drp1-mediated mitochondrial fission, improved mitochondrial morphology and function. Our findings indicated the pivotal role of S100a8/a9 in driving the mitochondrial fragmentation in septic muscle atrophy. Targeting S100a8/a9-RAGE-initiated mitochondrial fission might offer a promising therapeutic intervention against septic muscle atrophy.
    DOI:  https://doi.org/10.1038/s42003-025-07654-3
  29. Ageing Res Rev. 2025 Feb 27. pii: S1568-1637(25)00059-5. [Epub ahead of print] 102713
    Mitochondrial Dysfunction in Alzheimer's Disease.
    Maria Clara Bila D'alessandro, Salim Kanaan, Mauro Geller, Domenico Praticò, João Paulo Lima Daher.
      Alzheimer's disease (AD) is a chronic neurodegenerative disease characterized by progressive cognitive decline and distinct neuropathological features. The absence of a definitive cure presents a significant challenge in neurology and neuroscience. Early clinical manifestations, such as memory retrieval deficits and apathy, underscore the need for a deeper understanding of the disease's underlying mechanisms. While amyloid-β plaques and tau neurofibrillary tangles have dominated research efforts, accumulating evidence highlights mitochondrial dysfunction as a central factor in AD pathogenesis. Mitochondria, essential cellular organelles responsible for energy production necessary for neuronal function become impaired in AD, triggering several cellular consequences. Factors such as oxidative stress, disturbances in energy metabolism, failures in the mitochondrial quality control system, and dysregulation of calcium release are associated with mitochondrial dysfunction. These abnormalities are closely linked to the neurodegenerative processes driving AD development and progression. This review explores the intricate relationship between mitochondrial dysfunction and AD pathogenesis, emphasizing its role in disease onset and progression, while also considering its potential as a biomarker and a therapeutic target.
    Keywords:  Mitochondrial dysfunction. Alzheimer’ disease. Pathology. Mitophagy. Neurodegeneration
    DOI:  https://doi.org/10.1016/j.arr.2025.102713
  30. J Ethnopharmacol. 2025 Feb 26. pii: S0378-8741(25)00254-5. [Epub ahead of print]344 119570
    Regulation on mitophagy in adenomyosis by Guizhi Fuling Wan.
    Shidan Liu, Chenjie Li, Xianyun Fu, Minmin Chen, Meiling Wang, Kun Wang, Lin Du.
       ETHNOPHARMACOLOGICAL RELEVANCE: Guizhi Fuling Wan (GZFLW), a canonical herbal formulation originating from Synopsis of the Golden Chamber, has been widely utilized in managing pain-associated disorders. While its therapeutic efficacy in adenomyosis (AM) characterized by severe dysmenorrhea is well-documented, the underlying pharmacological mechanisms remain elusive. Emerging evidence suggests that hypoxic mitochondrial damage in endometrial tissue constitutes a pathological hallmark of AM, wherein mitophagy regulation through the PINK1/Parkin signaling pathway plays a pivotal role in mitochondrial quality control. Although certain phytomedicines have demonstrated mitophagy-modulating properties under hypoxic conditions, the specific regulatory effects of GZFLW on this process in AM pathogenesis warrant systematic investigation.
    AIM OF THE STUDY: To elucidate the mitophagy-modulating mechanism of GZFLW in AM through integrated in vivo and in vitro approaches.
    MATERIALS AND METHODS: An allogeneic pituitary transplantation-induced AM mouse model was established. Pharmacodynamic assessment included hotplate testing and serum cancer antigen 125 (CA125) quantification, while blood urea nitrogen (BUN) and alanine aminotransferase (ALT) levels were monitored for hepatorenal toxicity screening. Histopathological characterization employed hematoxylin-eosin (H&E) staining and transmission electron microscopy (TEM) for ultrastructural analysis. Protein expression of PINK1/Parkin pathway components (PINK1, Parkin, OPTIN, NDP52, P62) were determined by Western blot. Primary endometrial stromal cells (ESCs) isolated from clinical AM specimens underwent functional assessment via transwell migration/invasion assays, complemented by flow cytometric quantification of mitochondrial membrane potential (MMP) and reactive oxygen species (ROS). Molecular docking simulations evaluated ligand-receptor interactions between GZFLW bioactive constituents and PINK1/Parkin proteins. This study protocol was approved by the Medical Ethics Committee of China Three Gorges University (No. 2022CA002).
    RESULTS: Histopathological validation confirmed successful AM model establishment. ELISA revealed significantly elevated CA125 levels in AM mice versus controls (P < 0.05), with notable reductions in GZFLW-treated groups (GET: P < 0.05, GZFLW-L: P < 0.01). No intergroup differences emerged in ALT/BUN levels, indicating absence of hepatorenal toxicity. Post-modeling pain threshold depression (P < 0.05 vs control) was attenuated by GZFLW treatment (P < 0.05). TEM analysis demonstrated mitochondrial pathology in AM endometrium, including structural deformation, reduced mitochondrial quantity, and autophagosome accumulation, all ameliorated by GZFLW-L intervention. Western blot showed upregulated PINK1 (P < 0.01), Parkin, OPTIN, and NDP52 (P < 0.05) in AM group, with subsequent downregulation following GZFLW-L administration (P < 0.05). In vitro, AM ESCs exhibited MMP depolarization (P < 0.05), reversed by GZFLW treatment alongside suppressed migratory/invasive capacity (P < 0.01, P < 0.05), ROS reduction (P < 0.05), and attenuated PINK1/Parkin pathway activation. Molecular docking confirmed strong binding affinities (binding energy < -5.0 kcal/mol) between GZFLW phytoconstituents and PINK1/Parkin targets.
    CONCLUSION: This investigation reveals that GZFLW exerts its therapeutic effects on AM via targeted modulation of the PINK1/Parkin-mediated mitophagy axis, supporting its potential as a mitochondria-targeted therapeutic strategy for AM management.
    Keywords:  Adenomyosis; Guizhi fuling wan; Mitophagy
    DOI:  https://doi.org/10.1016/j.jep.2025.119570
  31. Front Mol Neurosci. 2025 ;18 1548255
    Multi-omics-based phenotyping of AFG3L2-mutant lymphoblasts determines key factors of a pathophysiological interplay between mitochondrial vulnerability and neurodegeneration in spastic ataxia type 5.
    Menekse Oeztuerk, Diran Herebian, Kale Dipali, Andreas Hentschel, Nina Rademacher, Florian Kraft, Rita Horvath, Felix Distelmaier, Sven G Meuth, Tobias Ruck, Ulrike Schara-Schmidt, Andreas Roos.
      Mitochondrial integrity is fundamental to cellular function, upheld by a network of proteases that regulate proteostasis and mitochondrial dynamics. Among these proteases, AFG3L2 is critical due to its roles in maintaining mitochondrial homeostasis, regulating mitochondrial protein quality, and facilitating mitochondrial biogenesis. Mutations in AFG3L2 are implicated in a spectrum of diseases, including spinocerebellar ataxia type 28 (SCA28) and spastic ataxia 5 (SPAX5), as well as other systemic conditions. This study employs a multi-omics approach to investigate the biochemical impact of AFG3L2 mutations in immortalized lymphoblastoid cell lines derived from a patient with biallelic variants leading to spastic ataxia (SPAX5). Our proteomic analysis revealed AFG3L2 impairment, with significant dysregulation of proteins critical for mitochondrial function, cytoskeletal integrity, and cellular metabolism. Specifically, disruptions were observed in mitochondrial dynamics and calcium homeostasis, alongside downregulation of key proteins like COX11, a copper chaperone for complex IV assembly, and NFU1, an iron-sulfur cluster protein linked to spastic paraparesis and infection-related worsening. Lipidomic analysis highlighted substantial alterations in lipid composition, with significant decreases in sphingomyelins, phosphatidylethanolamine, and phosphatidylcholine, reflecting disruptions in lipid metabolism and membrane integrity. Metabolomic profiling did not reveal any significant findings. Our comprehensive investigation into loss of functional AFG3L2 elucidates a pathophysiology extending beyond mitochondrial proteostasis, implicating a wide array of cellular processes. The findings reveal substantial cellular disturbances at multiple levels, contributing to neurodegeneration through disrupted mitochondrial respiratory chain, calcium homeostasis, cytoskeletal integrity, and altered lipid homeostasis. This study underscores the complexity of SPAX5 pathophysiology and the importance of multi-omics approaches in developing effective strategies to address the impact of loss of functional AFG3L2. Our data also highlight the value of immortalized lymphoblastoid cells as a tool for pre-clinical testing and research, offering a detailed biochemical fingerprint that enhances our understanding of SPAX5 and identifies potential areas for further investigation.
    Keywords:  AFG3 like matrix AAA peptidase subunit 2; MCU; SPAX5; liquid biopsy; multi-omics lymphoblasts
    DOI:  https://doi.org/10.3389/fnmol.2025.1548255
  32. J Ethnopharmacol. 2025 Mar 02. pii: S0378-8741(25)00252-1. [Epub ahead of print]345 119568
    Maimendong decoction modulates the PINK1/Parkin signaling pathway alleviates type 2 alveolar epithelial cells senescence and enhances mitochondrial autophagy to offer potential therapeutic effects for idiopathic pulmonary fibrosis.
    Yuhe Zhou, Wen Su, Mengzhen Xu, Aijun Zhang, Shaoli Li, Hong Guo, Kai Gong, Kaihui Lu, Xin Yu, Jiang Zhu, Qingjun Zhu, Chuanguo Liu.
       ETHNOPHARMACOLOGICAL RELEVANCE: Maimendong decoction (MMDD) originates from the ancient Chinese medical text Synopsis of the Golden Chamber and is a well-established remedy for treating lung diseases. It has demonstrated efficacy in the long-term clinical management of idiopathic pulmonary fibrosis (IPF); however, its underlying mechanisms remain unclear.
    AIM OF THE STUDY: This study investigates whether MMDD alleviates IPF by reducing type 2 alveolar epithelial cell (AEC2) senescence and enhancing mitochondrial autophagy. It also explores whether these effects are mediated through the PTEN-induced putative kinase 1 (PINK1)/Parkinson juvenile disease protein 2 (Parkin) pathway.
    MATERIALS AND METHODS: An IPF mouse model was established with bleomycin (BLM). Mice were administered MMDD, pirfenidone (PFD), or saline for 7 or 28 days. Body weight, lung coefficient, and lung appearance were monitored, and lung tissue pathology was assessed. The expression levels of p53, p21, p16, SA-β-gal activity, and senescence-associated secretory phenotype (SASP) markers were measured. Ultrastructural changes in AEC2 mitochondria were analyzed using transmission electron microscopy. Protein levels of autophagy markers sequestosome-1 and light chain 3 were assessed. The protein levels of PINK1, Parkin, and phosphorylated Parkin were further assessed using network pharmacology analysis and molecular docking technology.
    RESULTS: MMDD alleviated BLM-induced IPF by improving body weight, lung appearance, and histopathological features. It reduced AEC2 senescence markers, including p53, p21, p16, SA-β-gal, and SASP, while enhancing mitochondrial autophagy and repairing mitochondrial damage. Network pharmacology and molecular docking identified PINK1 as a major target, and Western blot (WB) analysis confirmed that MMDD regulates the PINK1/Parkin signaling pathway in the treatment of IPF.
    CONCLUSIONS: MMDD regulates the PINK1/Parkin signaling pathway, alleviates AEC2 senescence, and enhances mitochondrial autophagy, providing significant therapeutic potential for IPF treatment.
    Keywords:  Cell senescence; Idiopathic pulmonary fibrosis; Maimendong decoction; Mitochondrial autophagy; Type 2 alveolar epithelial cells
    DOI:  https://doi.org/10.1016/j.jep.2025.119568
  33. Free Radic Biol Med. 2025 Mar 01. pii: S0891-5849(25)00127-3. [Epub ahead of print]232 28-39
    Methionine is an essential amino acid in doxorubicin-induced cardiotoxicity through modulating mitophagy.
    Yijun Xin, Yong Zhang, Zhaoji Yuan, Siying Li.
      Doxorubicin (Dox) is a widely used anticancer drug. However, its time- and dose-dependent side effects, particularly severe cardiotoxicity, limit its clinical use. Understanding the molecular mechanisms underlying Dox-induced cardiotoxicity has become a research focus in recent years. Among these, impaired mitophagy which participated in the process of damaged mitochondria clearance, is considered one of the key mechanisms in Dox-induced cardiomyopathy. Methionine (Met) is an essential amino acid that plays a crucial role in various biological processes. This study aims to investigate the role and mechanism of Met in regulating mitophagy in Dox-induced cardiotoxicity. Met deficiency exacerbated Dox-induced cardiotoxicity, primarily by promoting oxidative stress, affecting mitochondria integrity, disrupting autophagy, and thus leading to cardiomyocyte damage and aggravating heart failure. In addition, Met supplementation alleviated Dox-induced cardiotoxicity, via the general control nonderepessible 2 (GCN2) pathway. This study extends our understanding of the relationship between amino acid metabolism and Dox-induced cardiotoxicity, and indicating the Met-GCN2 axis as a promising therapeutic strategy for Dox-induced cardiotoxicity.
    Keywords:  Cardiotoxicity; Doxorubicin; Methionine; Mitophagy
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.02.044
  34. J Ethnopharmacol. 2025 Mar 03. pii: S0378-8741(25)00271-5. [Epub ahead of print]345 119587
    2,3,5,4'-Tetrahydroxystilbene-2-O-beta-D-glucopyranoside promotes skin flap survival by promoting mitophagy through the PINK1/Parkin pathway.
    Weilong Song, Jialong Yang, Kechen Zhang, Panshen Xu, Hebin Pan, Jiapeng Deng, An Wang, Kaitao Wang, Dingsheng Lin.
       ETHNOPHARMACOLOGICAL RELEVANCE: 2,3,5,4'-Tetrahydroxystilbene-2-O-beta-D-glucopyranoside (THSG), the active compound in Polygonum multiflorum (PM), exhibits potential therapeutic effects, including combating oxidative stress, possessing anti-tumor properties, and protecting against ischemia-reperfusion injury. However, the influence and mechanisms by which THSG affects skin flap survival remain unclear.
    AIM OF STUDY: To investigate the effects and underlying mechanisms of THSG to promote the survival rate of skin flap.
    METHODS: McFarlane skin flap models were created in 24 Sprague-Dawley rats, which were randomly divided into four groups: control group, low-dose THSG group (30 mg/kg/day), medium-dose THSG group (60 mg/kg/day), and high-dose THSG group (120 mg/kg/day). Seven days after postoperative administration, blood perfusion was assessed using laser Doppler, and the survival rate was calculated. Anti-tumor necrosis factor (TNF)-α was analyzed via immunofluorescence. Interleukin (IL)-6 and IL-1β were explored by enzyme-linked immunosorbent assay (ELISA). SOD activity and MDA contents in skin flap tissue were detected to evaluate oxidative stress level, while Western blotting was employed to assess proteins of the PINK1/Parkin signaling axis, apoptosis-related proteins, and vascular endothelial growth factor (VEGF).
    RESULTS: THSG upregulated VEGF expression, improved blood flow, and protected flap tissue by reducing inflammation, mitigating oxidative stress, and inhibiting apoptosis. Increased expression of Parkin and PINK1, along with decreased levels of COX IV, suggested that THSG mediates mitophagy via the PINK1/Parkin signaling pathway.
    CONCLUSIONS: THSG enhances the survival rate of skin flap by promoting PINK1/Parkin-mediated mitophagy.
    Keywords:  Mitophagy; Necrosis; Oxidative stress; Skin flap; THSG
    DOI:  https://doi.org/10.1016/j.jep.2025.119587
  35. J Biochem Mol Toxicol. 2025 Mar;39(3): e70183
    SALL4/ABCB6 Axis Suppresses Ferroptosis in Colon Cancer by Mediating Mitophagy.
    Leilei Yang, Yuehuai Xu, Jiaju Han, Chengfeng Fang, Zaiping Yang, Ruili Zhang, Shenkang Zhou.
      According to reports, the inhibition of ferroptosis is an essential culprit of malignant progression in various tumors, including colon cancer (CC). However, the relevant study on the regulatory mechanism of CC ferroptosis is sparse. This project was designed to identify the key genes modulating CC ferroptosis as well as specific mechanisms. Based on The Cancer Genome Atlas (TCGA)-CC mRNA expression data and immunohistochemistry assay, we analyzed the expression of ABCB6 and SALL4 in CC tissue. The HTFtarget was employed to predict the binding sites. The expression of ABCB6 and SALL4 in CC cells was analyzed by quantitative polymerase chain reaction, and the interaction between ABCB6 and SALL4 was verified by dual-luciferase and chromatin immunoprecipitation experiments. Cell viability was tested by cell counting kit-8 and colony formation assay. The malondialdehyde (MDA), Fe2+ content, and lipid reactive oxygen species (ROS) levels were examined by utilizing the corresponding reagent kits. The protein expression of ABCB6, SALL4, GPX4, GCLC, and SLC3A2 were determined via western blot. High expression of ABCB6 was detected in CC. ABCB6 overexpression suppressed ferroptosis and dramatically declined the levels of MDA, lipid ROS, and Fe2+ in cells. Furthermore, it induced mitochondrial membrane potential dysfunction and substantially suppressed the fluorescence intensity of GFP-LC3, which in turn promoted the expression of GPX4, GCLC, and SLC3A2 proteins and prevented CC cell ferroptosis. The cell rescue experiment verified that SALL4 initiated ABCB6 activation to mediate mitophagy and prevent ferroptosis in CC cells. The findings evidenced that the SALL4/ABCB6 axis suppresses mitophagy to hinder ferroptosis in CC. The mitophagy pathway may be essential for ABCB6 to regulate ferroptosis in CC.
    Keywords:  ABCB6; SALL4; colon cancer; ferroptosis; mitophagy
    DOI:  https://doi.org/10.1002/jbt.70183
  36. Nat Rev Mol Cell Biol. 2025 Mar 06.
    Dodging mitochondrial mislocalization.
    Lisa Heinke.
      
    DOI:  https://doi.org/10.1038/s41580-025-00840-5
  37. Physiol Rep. 2025 Mar;13(5): e70265
    Ultrastructural analysis of mitochondrial morphology and in the human rhabdosphincter: Insights into urinary incontinence.
    Shinro Hata, Mayuka Shinohara, Hiromitsu Mimata, Toshitaka Shin.
      Urinary incontinence increases with age, reducing the elderly quality of life. Understanding its mechanisms and developing treatments are urgent tasks. While healthy striated muscle maintains homeostasis through mitophagy, aging is thought to reduce autophagy activity. This study aimed to detect abnormal mitochondrial accumulation in the rhabdosphincter using transmission electron microscopy (TEM). We collected the rhabdosphincter samples from seven patients undergoing cystectomy and used the rectus abdominis as controls. Both tissues were examined with Hematoxylin and eosin (HE) staining and TEM. ImageJ software was used to measure the mitochondrial area, perimeter, and luminance. HE staining revealed that the rhabdosphincter had fewer muscle fibers and more stromal tissue than the rectus abdominis. TEM images showed more gaps in muscle bundles and signs of mitochondrial damage, vacuolation, and swelling in the rhabdosphincter. Quantitative analysis revealed a larger average mitochondrial area (0.21 μm2 vs. 0.063 μm2, p < 0.01), longer perimeter (1.83 μm vs. 0.94 μm, p < 0.01) and higher luminance (156.6 vs. 90.2, p < 0.01) than those of the rectus abdominis. The rhabdosphincter of elderly individuals showed significant mitochondrial morphological abnormalities, with increased swelling and vacuolation.
    Keywords:  mitochondria; rhabdosphincter; urinary incontinence
    DOI:  https://doi.org/10.14814/phy2.70265
  38. iScience. 2025 Feb 21. 28(2): 111814
    Urolithin A provides cardioprotection and mitochondrial quality enhancement preclinically and improves human cardiovascular health biomarkers.
    Sophia Liu, Julie Faitg, Charlotte Tissot, Dimitris Konstantopoulos, Ross Laws, Guillaume Bourdier, Pénélope A Andreux, Tracey Davey, Hector Gallart-Ayala, Julijana Ivanisevic, Anurag Singh, Chris Rinsch, David J Marcinek, Davide D'Amico.
      Cardiovascular diseases (CVDs) remain the primary cause of global mortality. Nutritional interventions hold promise to reduce CVD risks in an increasingly aging population. However, few nutritional interventions are proven to support heart health and act mostly on blood lipid homeostasis rather than at cardiac cell level. Here, we show that mitochondrial quality dysfunctions are common hallmarks in human cardiomyocytes upon heart aging and in chronic conditions. Preclinically, the post-biotic and mitophagy activator, urolithin A (UA), reduced both systolic and diastolic cardiac dysfunction in models of natural aging and heart failure. At a cellular level, this was associated with a recovery of mitochondrial ultrastructural defects and mitophagy. In humans, UA supplementation for 4 months in healthy older adults significantly reduced plasma ceramides clinically validated to predict CVD risks. These findings extend and translate UA's benefits to heart health, making UA a promising nutritional intervention to support cardiovascular function as we age.
    Keywords:  Biological sciences; Cardiovascular medicine; Health sciences; Internal medicine; Medical specialty; Medicine; Natural sciences; Physiology
    DOI:  https://doi.org/10.1016/j.isci.2025.111814
  39. Mech Ageing Dev. 2025 Feb 27. pii: S0047-6374(25)00020-X. [Epub ahead of print] 112044
    Heart of the matter: mitochondrial dynamics and genome alterations in cardiac aging.
    Claudie Gabillard-Lefort, Théophile Thibault, Guy Lenaers, Rudolf J Wiesner, Jeanne Mialet-Perez, Olivier R Baris.
      Cardiac pathological aging is a serious health issue, with cardiovascular diseases still being a leading cause of deaths worldwide. Therefore, there is an urgent need to identify culprit factors involved in this process. In the last decades, mitochondria, which are crucial for cardiac function, have emerged as major contributors. Mitochondria are organelles involved in a plethora of metabolic pathways and cell processes ranging from ATP production to calcium homeostasis or regulation of apoptotic pathways. This review provides a general overview of the pathomechanisms involving mitochondria during cardiac aging, with a focus on the role of mitochondrial dynamics and mitochondrial DNA (mtDNA). These mechanisms involve imbalanced mitochondrial fusion and fission, loss of mtDNA integrity leading to tissue mosaic of mitochondrial deficiency, as well as mtDNA release in the cytoplasm, promoting inflammation via the NLRP3, cGAS/STING and TLR9 pathways. Potential links between mtDNA, mitochondrial damage and the accumulation of senescent cells in the heart are also discussed. A better understanding of how these factors impact on heart function and accelerate its pathological aging should lead to the development of new therapies to promote healthy aging and restore age-induced cardiac dysfunction.
    Keywords:  Aging; Cardiovascular diseases; Inflammation; Mitochondria; Mitochondrial dynamics; Senescence; mtDNA
    DOI:  https://doi.org/10.1016/j.mad.2025.112044
  40. Chin Med J (Engl). 2025 Mar 06.
    LncRNA H19 overexpression protects against acute kidney injury after cardiopulmonary bypass via activating Pink1/Parkin-mediated mitophagy.
    Mingru Zhang, Min Liu, Tianlong Wang, Yingjie Du, Yimeng Chen, Yafan Bai, Yue Zhang, Dinghao Xue, Bingyang Ji, Guyan Wang.
       BACKGROUND: Cardiopulmonary bypass-associated acute kidney injury (CPB-AKI) is a serious and common complication following cardiopulmonary bypass (CPB), leading to worse outcomes and higher mortality. However, the underlying pathological mechanisms of CPB-AKI remain largely unknown. This study aimed to investigate the role of long non-coding RNA H19 (H19) in regulating CPB-AKI.
    METHODS: We examined the expressions of H19 and mitophagy-related proteins in a CPB-AKI rat model and HK-2 cells following oxygen-glucose deprivation/reperfusion (OGD/R). In vivo, lentiviral-mediated overexpression of H19 was induced in the kidney through tail vein injection. We then evaluated renal functions, kidney pathological damage, levels of inflammatory cytokines (tumor necrosis factor-α, interleukin (IL)-1β, IL-6, and IL-10), neutrophil infiltration, and the activation of PTEN-induced putative kinase 1 (Pink1)/Parkin-mediated mitophagy following CPB-AKI. In vitro, small interfering RNA (siRNA) was used to downregulate H19 expression in HK-2 cells. We also examined cell viability, apoptosis, inflammation, and Pink1/Parkin-mediated mitophagy after OGD/R.
    RESULTS: We demonstrated an increase in H19 expression and activation of Pink1/Parkin-mediated mitophagy in the rat model of CPB-AKI and HK-2 cells following OGD/R. In the rat models of CPB-AKI, lentivirus-mediated overexpression of H19 significantly attenuated renal injury, characterized by better renal function, reduced tissue damage, decreased neutrophil infiltration, and lower inflammatory cytokine release (P <0.05). Notably, overexpression of H19 significantly activated Pink1/Parkin-mediated mitophagy. Furthermore, in vitro, downregulation of H19 by specific siRNA in HK-2 cells significantly decreased cell viability, worsened HK-2 injury after OGD/R, increased inflammatory cytokine release, and decreased Pink1/Parkin-mediated mitophagy activity, promoting cell apoptosis (P <0.05).
    CONCLUSIONS: These findings suggest that H19 overexpression may protect against CPB-AKI by activating Pink1/Parkin-mediated mitophagy and decreasing inflammatory responses and cellular apoptosis. Thus, H19 overexpression might be a promising therapeutic target for treating CPB-AKI.
    DOI:  https://doi.org/10.1097/CM9.0000000000003552
  41. Adv Sci (Weinh). 2025 Mar 06. e2414673
    Autophagy Related 5 Promotes Mitochondrial Fission and Inflammation via HSP90-HIF-1α-Mediated Glycolysis in Kidney Fibrosis.
    Yan Hu, Jinqing Li, Hui Chen, Yingfeng Shi, Xiaoyan Ma, Yi Wang, Xialin Li, Qin Zhong, Yishu Wang, Daofang Jiang, Shougang Zhuang, Na Liu.
      Although significant progress in identifying molecular mediators of fibrosis is made, there is still controversy regarding the role and mechanism of autophagy in kidney fibrosis. Here, this study finds that autophagy related 5 (ATG5) is obviously increased in uric acid (UA), aristolochic acid (AA) and transforming growth factor-β1 (TGF-β1)-induced HK-2 cells, as well as in kidneys from patients with chronic kidney disease (CKD) and mice with hyperuricemic nephropathy (HN), aristolochic acid nephropathy (AAN) and unilateral renal ischemia-reperfusion injury (uIRI). Conditional deletion of ATG5 in HN, AAN and uIRI murine models significantly alleviated aberrant glycolysis, attenuated pathological lesions, and improved kidney function. Mechanistically, ATG5 mediates the binding between heat shock protein 90 (HSP90) and hypoxia-inducible factor 1alpha (HIF-1α), thereby enhancing the stability of HIF-1α and further promoting the overactivation of glycolysis. Subsequently, the aberrant glycolysis facilitated the occurrence of mitochondrial fission and inflammatory response, thus leading to kidney fibrosis. Taken together, the study provides solid evidence supporting that persistent activation of ATG5 in kidney tubules promotes kidney fibrosis. The profibrotic function of ATG5 is related to the regulation on HSP90-HIF-1α-mediated glycolysis, resulting in mitochondrial fission and renal inflammation. Thus, ATG5 may be a novel therapeutic target for kidney fibrosis.
    Keywords:  autophagy related 5; glycolysis; heat shock protein 90; hypoxia‐inducible factor 1alpha; kidney fibrosis
    DOI:  https://doi.org/10.1002/advs.202414673
  42. Arch Toxicol. 2025 Mar 04.
    Comprehensive ubiquitome analysis reveals persistent mitochondrial remodeling disruptions from doxorubicin-induced cardiotoxicity in aged CD-1 male mice.
    Sofia Reis Brandão, Elisa Lazzari, Rui Vitorino, Germana Meroni, Ana Reis-Mendes, Maria João Neuparth, Francisco Amado, Félix Carvalho, Rita Ferreira, Vera Marisa Costa.
      Doxorubicin (DOX)-associated cardiotoxicity is characterized by long-term manifestations, whose mechanisms remain incompletely understood, and is exacerbated by various risk factors, with age being a prominent contributor. The objective of this study was to assess the enduring cardiac molecular impacts of DOX in old CD-1 male mice, focusing on ubiquitinated proteins. At 19 months of age, DOX group received a cumulative dose of 9.0 mg/kg of DOX, while control animals got saline solution. Animals were sacrificed 2 months after the administration. DOX induced heart structural changes and increased proteolytic activity. Additionally, increased protein ubiquitination was observed in DOX group, despite the decreased content of the E3 ubiquitin-protein ligase Atrogin-1. A search of poly-ubiquitinated proteins, enriched by tandem ubiquitin-binding entities (TUBEs), showed increased poly-ubiquitination of proteins associated with sarcomere organization and mitochondrial metabolism processes by DOX. Increased mitochondrial density inferred by higher citrate synthase activity was found in DOX group. Moreover, decreased biogenesis and auto(mito)phagy occurred in DOX animals, proven by decreased peroxisome proliferator-activated receptor γ coactivator 1 α, Beclin1 and microtubule-associated protein light chain 3 content. These findings indicate a reduction in mitochondrial biogenesis and accumulation of dysfunctional mitochondria in the aged heart, along with elevated levels of poly-ubiquitinated proteins after DOX treatment. Thus, the disruption of mitochondrial remodeling and impaired protein ubiquitination emerge as enduring consequences of DOX-induced cardiotoxicity, persisting for even 2 months after DOX exposure. This underscores the long-lasting impact of DOX, with significant effects continuing beyond the period of administration, which advocates for longer clinical surveillance.
    Keywords:  Anticancer therapy; Cardio-oncology; Chronic cardiotoxicity; Mitochondrial dynamics; Old; Ubiquitination
    DOI:  https://doi.org/10.1007/s00204-025-04006-2
  43. Adv Healthc Mater. 2025 Mar 03. e2405069
    Cerium Dioxide Nanoparticles-Based Inspector Enhances Mitochondrial Quality Control to Maintain Chondrocyte Homeostasis in Osteoarthritis Therapy.
    Li Chen, Jianye Yang, Zhengwei Cai, Yanran Huang, Qinyang Zhang, Chengqiang Zhou, Juan Wang, Wei Huang, Wenguo Cui, Ning Hu.
      Imbalanced mitochondrial quality control is strongly linked to the onset and development of osteoarthritis (OA). However, current research primarily focuses on local cartilage repair and phenotype maintenance, lacking a systematic approach to subcellular mitochondrial quality control. To address this, the present study proposes a mitochondrial quality control strategy based on nanozyme hydrogel microspheres ("mitochondrial inspector"), constructed through electrostatic self-assembly, incorporation of dynamic diselenide bonds, and microfluidic technology. The mitochondrial oxidative stress microenvironment is improved by cerium dioxide nanoparticles and combined with metformin to activate autophagy to clear persistently dysfunctional mitochondria, thereby inhibiting OA progression. In vitro results showed that "mitochondrial inspector" not only significantly improved the oxidative stress microenvironment of chondrocytes, but also efficiently scavenged the damaged mitochondria, increased the mitochondrial membrane potential by over 20-fold, and notably improved the mitochondrial function and chondrocyte homeostasis. In a rat OA model, minimally invasive intra-articular injection of the "mitochondrial inspector" effectively regulated mitochondrial quality, alleviated cartilage matrix degradation, reduced osteophyte formation by ≈80%, and reduced the Mankin score for cartilage damage by over 70%. In summary, this study presents a novel nanozyme microsphere-based mitochondrial quality control strategy for the treatment of OA, providing new insights for subcellular therapies for other aging-related diseases.
    Keywords:  chondrocyte homeostasis; hydrogel microspheres; mitochondrial quality control; nanozyme; osteoarthritis
    DOI:  https://doi.org/10.1002/adhm.202405069
  44. Neurobiol Dis. 2025 Mar 04. pii: S0969-9961(25)00078-6. [Epub ahead of print] 106862
    Mitochondria at the crossroads: Quality control mechanisms in neuronal senescence and neurodegeneration.
    Yifei Zheng, Jiahui Yang, Xuanyao Li, Linjie Qi, Zhuo Zheng, Jiming Kong, Guohui Zhang, Ying Guo.
      Mitochondria play a central role in essential cellular processes, including energy metabolism, biosynthesis of metabolic substances, calcium ion storage, and regulation of cell death. Maintaining mitochondrial quality control is critical for preserving mitochondrial health and ensuring cellular function. Given their high energy demands, neurons depend on effective mitochondrial quality control to sustain their health and functionality. Neuronal senescence, characterized by a progressive decline in structural integrity and function, is a hallmark of neurodegenerative diseases. In senescent neurons, abnormal mitochondrial morphology, functional impairments, increased reactive oxygen species production and disrupted quality control mechanisms are frequently observed. Understanding the pathological changes in neuronal structure, exploring the intricate relationship between mitochondrial quality control and neuronal health, and leveraging mitochondrial quality control interventions provide a promising foundation for addressing age-related neurodegenerative diseases. This review highlights key mitochondrial quality control, including biogenesis, dynamics, the ubiquitin-proteasome system, autophagy pathways, mitochondria-derived vesicles, and inter-organelle communication, while discussing their roles in neuronal senescence and potential therapeutic strategies. These insights may pave the way for innovative treatments to mitigate neurodegenerative disorders.
    Keywords:  Mitochondrial quality control; Neurodegenerative diseases; Neuron; Senescence; Therapeutic strategies
    DOI:  https://doi.org/10.1016/j.nbd.2025.106862
  45. Curr Pharm Des. 2025 Feb 28.
    Esketamine Regulates Mitophagy through ULK1/FUNDC1 Signaling Pathway to Improve LPS-induced Acute Respiratory Distress Syndrome.
    Mei Ding, Ping Pei, Weihua Liu, Yingli Cao, Yiqi Weng, Wenli Yu.
       BACKGROUND: As a heterogeneous clinical syndrome, acute respiratory distress syndrome (ARDS) is caused by infection-associated inflammation with limited treatment options. Esketamine possesses antiinflammatory properties, and it is effective in treating lung diseases.
    OBJECTIVE: This study aimed to unveil the efficacy and mechanism of esketamine in ARDS.
    METHODS: Lipopolysaccharide (LPS) is widely used to induce inflammatory response in lung injury. The mice model of ARDS in this study was established through the inhalation of LPS. Hematoxylin-eosin (H&E) staining was used to evaluate the pathological changes in the lung tissues of ARDS mice, and the histological index of lung damage was employed. Bicinchoninic acid (BCA) assay kits were utilized to assess the total proteins in bronchoalveolar lavage fluid (BALF), and a hemocytometer was used to count the number of total cells. The pulmonary vascular permeability was detected using Evans blue staining. Western blot was carried out to detect the expressions of tight junction proteins, and enzyme-linked immunosorbent assay (ELISA) detected the release of inflammatory cytokines in BALF and serum. Dihydroethidium (DHE) staining was used to detect reactive oxygen species (ROS) production, and the levels of myeloperoxidase (MPO) and oxidative stress markers were measured using corresponding assay kits. Apoptosis was assessed through terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) and Western blot. Immunostaining detected the FUN14 domain-containing 1 (FUNDC1) and light chain 3B (LC3B) in lung tissues, and the expressions of autophagy-related proteins were detected using Western blot.
    RESULTS: Our data showed that esketamine treatment alleviated LPS-stimulated lung damage, improved pulmonary vascular permeability, and inhibited inflammatory response, oxidative stress, and apoptosis in ARDS mice. Mechanically, esketamine activated mitophagy through UNC-52-like kinase 1 (ULK1)/FUNDC1 signaling pathway. These findings, for the first time, revealed the therapeutic potential of esketamine in treating ARDS.
    CONCLUSION: Collectively, this study revealed the protective role of esketamine against lung injury, inflammation, oxidative stress, and apoptosis in mice with ARDS and revealed the reaction mechanism related to mitophagy.
    Keywords:  Acute respiratory distress syndrome; ULK1/FUNDC1 signaling pathway; esketamine; mitophagy.
    DOI:  https://doi.org/10.2174/0113816128361112250221065359
  46. Nat Commun. 2025 Feb 28. 16(1): 2066
    Author Correction: Engineered hypoxia-responsive albumin nanoparticles mediating mitophagy regulation for cancer therapy.
    Wenyan Wang, Shun-Yu Yao, Jingjing Luo, Chendi Ding, Qili Huang, Yao Yang, Zhaoqing Shi, Jiachan Lin, Yu-Chen Pan, Xiaowei Zeng, Dong-Sheng Guo, Hongzhong Chen.
      
    DOI:  https://doi.org/10.1038/s41467-025-57018-y
  47. J Cell Biol. 2025 May 05. pii: e202404009. [Epub ahead of print]224(5):
    SNX10 functions as a modulator of piecemeal mitophagy and mitochondrial bioenergetics.
    Laura Trachsel-Moncho, Chiara Veroni, Benan John Mathai, Ana Lapao, Sakshi Singh, Nagham Theres Asp, Sebastian W Schultz, Serhiy Pankiv, Anne Simonsen.
      We here identify the endosomal protein SNX10 as a negative regulator of piecemeal mitophagy of OXPHOS machinery components. In control conditions, SNX10 localizes to early endocytic compartments in a PtdIns3P-dependent manner and modulates endosomal trafficking but also shows dynamic connections with mitochondria. Upon hypoxia-mimicking conditions, SNX10 localizes to late endosomal structures containing selected mitochondrial proteins, including COX-IV and SAMM50, and the autophagy proteins SQSTM1/p62 and LC3B. The turnover of COX-IV was enhanced in SNX10-depleted cells, with a corresponding reduced mitochondrial respiration and citrate synthase activity. Importantly, zebrafish larvae lacking Snx10 show reduced levels of Cox-IV, as well as elevated ROS levels and ROS-mediated cell death in the brain, demonstrating the in vivo relevance of SNX10-mediated modulation of mitochondrial bioenergetics.
    DOI:  https://doi.org/10.1083/jcb.202404009
  48. Phytomedicine. 2025 Feb 24. pii: S0944-7113(25)00206-5. [Epub ahead of print]139 156566
    Pectin-coated Malvidin-3-O-galactoside attenuates silica-induced pulmonary fibrosis by promoting mitochondrial autophagy and inhibiting cell apoptosis.
    Yihan Yang, Chuang Ma, Yining Wang, Jinlong Tian, Bin Li, Jin Zhao.
       BACKGROUND: Blueberries are a rich source of anthocyanins, which have been established to have multiple beneficial properties. However, the structure of anthocyanin monomers is unstable and their bioavailability is low. To date, whereas functional studies on anthocyanins have focused mainly on the effects of their monomers on liver and kidney, few have examined the interventional effects on pulmonary fibrosis.
    PURPOSE: In this study, we combined malvidin-3-O-galactoside (M3G)1 derived from blueberries with pectin (PEC)2 to form an anthocyanin-pectin complex (M3G-PEC),3 the anti-fibrotic effects of which were examined by administering to mice with modeled pulmonary fibrosis induced by silica particles (SP).4 METHODS: To evaluate the therapeutic effects and mechanisms of action of M3G-PEC with respect to the progression of pulmonary fibrosis, we measured autophagy- and apoptosis-related indices in C57BL/6 mice and mouse alveolar macrophage cell line (MH-S).5 RESULTS: The results of in vivo and in vitro studies revealed that M3G-PEC can alleviate the degree of pulmonary fibrosis, enhances the expression of Microtubule-associated protein light chain 3 (LC3),6 PTEN-inducible putative kinase 1 (PINK1),7 Parkin and B-cell lymphoma-2 (BCL-2),8 and causes the down-regulation of Caspase-3, P62, p-mammalian target of rapamyein (p-mTOR),9 phosphorylated protein kinase B (p-Akt)10 and Bax. And then, M3G-PEC contributes to maintaining a steady mitochondrial membrane potential and reduces the release of cytochrome c (Cyt-C)11 in cells.
    CONCLUSION: Collectively, these findings indicate that M3G-PEC can preserve the bioactivity of anthocyanins and effectively enhance their bioavailability. Moreover, by regulating the BECN-1/Akt/mTOR pathway, M3G-PEC can influence the progression of silica-induced pulmonary fibrosis.
    Keywords:  Blueberry; Malvidin-3-o-galactoside; Mitophagy; Pectin; Pulmonary fibrosis
    DOI:  https://doi.org/10.1016/j.phymed.2025.156566
  49. bioRxiv. 2025 Feb 23. pii: 2025.02.19.635300. [Epub ahead of print]
    Artificial intelligence-enabled automated analysis of transmission electron micrographs to evaluate chemotherapy impact on mitochondrial morphology in triple negative breast cancer.
    Argenis Arriojas, Lily M Baek, Mariah J Berner, Alexander Zhurkevich, Antentor Othrell Hinton, Matthew D Meyer, Lacey E Dobrolecki, Michael T Lewis, Kourosh Zarringhalam, Gloria V Echeverria.
      Advancements in transmission electron microscopy (TEM) have enabled in-depth studies of biological specimens, offering new avenues to large-scale imaging experiments with subcellular resolution. Mitochondrial structure is of growing interest in cancer biology due to its crucial role in regulating the multi-faceted functions of mitochondria. We and others have established the crucial role of mitochondria in triple-negative breast cancer (TNBC), an aggressive subtype of breast cancer with limited therapeutic options. Building upon our previous work demonstrating the regulatory role of mitochondrial structure dynamics in metabolic adaptation and survival of chemotherapy-refractory TNBC cells, we sought to extend those findings to a large-scale analysis of transmission electron micrographs. Here we present a UNet artificial intelligence (AI) model for automatic annotation and assessment of mitochondrial morphology and feature quantification. Our model is trained on 11,039 manually annotated mitochondria across 125 micrographs derived from a variety of orthotopic patient-derived xenograft (PDX) mouse model tumors and adherent cell cultures. The model achieves an F1 score of 0.85 on test micrographs at the pixel level. To validate the ability of our model to detect expected mitochondrial structural features, we utilized micrographs from mouse primary skeletal muscle cells genetically modified to lack Dynamin-related protein 1 (Drp1). The algorithm successfully detected a significant increase in mitochondrial elongation, in alignment with the well-established role of Drp1 as a driver of mitochondrial fission. Further, we subjected in vitro and in vivo TNBC models to conventional chemotherapy treatments commonly used for clinical management of TNBC, including doxorubicin, carboplatin, paclitaxel, and docetaxel (DTX). We found substantial within-sample heterogeneity of mitochondrial structure in both in vitro and in vivo TNBC models and observed a consistent reduction in mitochondrial elongation in DTX-treated specimens. We went on to compare mammary tumors and matched lung metastases in a highly metastatic PDX model of TNBC, uncovering significant reduction in mitochondrial length in metastatic lesions. Our large, curated dataset provides high statistical power to detect frequent chemotherapy-induced shifts in mitochondrial shapes and sizes in residual cells left behind after treatment. The successful application of our AI model to capture mitochondrial structure marks a step forward in high-throughput analysis of mitochondrial structures, enhancing our understanding of how morphological changes may relate to chemotherapy efficacy and mechanism of action. Finally, our large, manually curated electron micrograph dataset - now publicly available - serves as a unique gold-standard resource for developing, benchmarking, and applying computational models, while further advancing investigations into mitochondrial morphology and its impact on cancer biology.
    DOI:  https://doi.org/10.1101/2025.02.19.635300
  50. Acta Pharm Sin B. 2025 Jan;15(1): 571-591
    Nanoengineered cargo with targeted in vivo Foxo3 gene editing modulated mitophagy of chondrocytes to alleviate osteoarthritis.
    Manyu Chen, Yuan Liu, Quanying Liu, Siyan Deng, Yuhan Liu, Jiehao Chen, Yaojia Zhou, Xiaolin Cui, Jie Liang, Xingdong Zhang, Yujiang Fan, Qiguang Wang, Bin Shen.
      Mitochondrial dysfunction in chondrocytes is a key pathogenic factor in osteoarthritis (OA), but directly modulating mitochondria in vivo remains a significant challenge. This study is the first to verify a correlation between mitochondrial dysfunction and the downregulation of the FOXO3 gene in the cartilage of OA patients, highlighting the potential for regulating mitophagy via FOXO3 gene modulation to alleviate OA. Consequently, we developed a chondrocyte-targeting CRISPR/Cas9-based FOXO3 gene-editing tool (FoxO3) and integrated it within a nanoengineered 'truck' (NETT, FoxO3-NETT). This was further encapsulated in injectable hydrogel microspheres (FoxO3-NETT@SMs) to harness the antioxidant properties of sodium alginate and the enhanced lubrication of hybrid exosomes. Collectively, these FoxO3-NETT@SMs successfully activate mitophagy and rebalance mitochondrial function in OA chondrocytes through the Foxo3 gene-modulated PINK1/Parkin pathway. As a result, FoxO3-NETT@SMs stimulate chondrocytes proliferation, migration, and ECM production in vitro, and effectively alleviate OA progression in vivo, demonstrating significant potential for clinical applications.
    Keywords:  CRISPR/Cas9 gene editing; Cartilage regeneration; Injectable hydrogel microspheres; In vivo Foxo3 gene editing; Mitophagy; Nanoengineered cargo; Osteoarthritis; PINK1/Parkin pathway
    DOI:  https://doi.org/10.1016/j.apsb.2024.12.008
  51. bioRxiv. 2025 Feb 22. pii: 2025.02.20.639242. [Epub ahead of print]
    Functional Specialization of S-Adenosylmethionine Synthases Links Phosphatidylcholine to Mitochondrial Function and Stress Survival.
    Athena L Munden, Dominique S Lui, Daniel P Higgins, Matthew J Fanelli, Thien-Kim Ngyuen, Katherine M Edwards, Maria Ericsson, Adwait A Godbole, John A Haley, Caroline Lewis, Jessica B Spinelli, Benjamin Harrison, Daniel Raftery, Danijel Djukovic, Daniel E L Promislow, Dana L Miller, Amy K Walker.
      S-adenosylmethionine (SAM), produced by SAM synthases, is critical for various cellular regulatory pathways and the synthesis of diverse metabolites. Studies have often equated the effects of knocking down one synthase with broader SAM-dependent outcomes such as histone methylation or phosphatidylcholine (PC) production. Humans and many other organisms express multiple SAM synthases. Evidence in Caenorhabditis elegans , which possesses four SAM synthase genes, suggest that the enzymatic source of SAM impacts its function. For instance, loss of sams-1 leads to enhanced heat shock survival and increased lifespan, whereas reducing sams-4 adversely affects heat stress survival. Here, we show that SAMS-1 contributes to a variety of intermediary metabolic pathways, whereas SAMS-4 is more important to generate SAM for methylation reactions. We demonstrate that loss of sams-1 exerts age-dependent effects on nuclear-encoded mitochondrial gene expression, mitochondrial metabolites, and may induce mitophagy. We propose a mechanistic model where reduced SAM from SAMS-1 acts through PC to impact mitochondria, thereby enhancing survival during heat stress.
    DOI:  https://doi.org/10.1101/2025.02.20.639242
  52. Cell Mol Life Sci. 2025 Mar 06. 82(1): 104
    Melatonin refines ovarian mitochondrial dysfunction in PCOS by regulating the circadian rhythm gene Clock.
    Wenxiu Chen, Hongyan Zhang, Bao Guo, Yumei Tao, Junhui Zhang, Jiayi Wang, Guangyi Chen, Mengting Cheng, Qiang Hong, Yunxia Cao, Fenfen Xie.
      Mitochondrial dysfunction is present in the ovaries of patients with polycystic ovary syndrome (PCOS). Melatonin (MT) has shown promise in treating PCOS by improving mitochondrial dysfunction, though the underlying mechanisms remain unclear. In this study, we first assessed the levels of proteins associated with mitochondrial autophagy and dynamics in ovary granulosa cells (GCs) of PCOS patients and in the ovaries of DHEA-induced PCOS mice. We found abnormal expression of these proteins, indicating the presence of mitochondrial dysfunction in PCOS ovaries. Notably, the expression of the circadian gene Clock and melatonin synthetic enzymes were also decreased in the ovaries of PCOS patients. Studies have suggested a potential role of circadian rhythm genes in the pathogenesis and progression of PCOS. We subsequently observed that pretreatment with MT could ameliorate the abnormal levels of mitochondrial-related proteins, reverse the low expression of CLOCK, and reduce pyroptosis in PCOS ovaries. Given the potential interaction between MT and Clock, we focused on whether exogenous MT improves mitochondrial dysfunction in PCOS ovaries by regulating the expression of the circadian gene Clock. Through in vitro culture of the human ovarian granulosa cell line KGN, we further found that when CLOCK levels were inhibited, the beneficial effects of MT on abnormal mitochondrial autophagy, disturbed mitochondrial dynamics, and mitochondrial dysfunction in PCOS ovaries were not significant, and there was no notable improvement in ovary GCs pyroptosis. Our study suggests that MT may improve ovary mitochondrial dysfunction by regulating circadian gene Clock while also reducing GCs pyroptosis in PCOS.
    Keywords:  Clock; Melatonin; Mitochondrial dysfunction; Polycystic ovary syndrome; Pyroptosis
    DOI:  https://doi.org/10.1007/s00018-025-05609-9
  53. Biochim Biophys Acta Mol Basis Dis. 2025 Mar 06. pii: S0925-4439(25)00111-5. [Epub ahead of print]1871(5): 167766
    Cardioprotective potential of transcription factor PRRX1 silencing against myocardial ischemia/reperfusion injury by regulating excessive mitophagy and ferroptosis through FKBP5-p38 MAPK axis.
    Yongpeng Fang, Xudong Niu, Weifang Zhao, Huali Zhang.
      Myocardial ischemia/reperfusion (I/R) injury is a major cause of various adverse cardiovascular outcomes associated with excessive mitophagy and cardiomyocyte ferroptosis. Paired-related homeobox 1 (PRRX1) is a transcriptional factor involved in cardiovascular injury. However, whether and how PRRX1 regulates excessive mitophagy and cardiomyocyte ferroptosis during myocardial I/R injury remains unclear. Oxygen-glucose deprivation and reperfusion (OGD/R)-treated AC16 cardiomyocytes and myocardial I/R-induced rats were used as in vitro and in vivo models. Our results showed that PRRX1 expression was upregulated in AC16 cells after OGD/R treatment. PRRX1 silencing mitigated OGD/R-induced excessive mitophagy by increasing the mitochondrial membrane potential, adenosine triphosphate and p62 levels, and reducing LC3 II/I level in AC16 cells. In addition, PRRX1 knockdown attenuated OGD/R-induced lactate dehydrogenase (LDH) release and cardiomyocyte ferroptosis by decreasing reactive oxygen species, Fe2+ and acyl-CoA synthetase long-chain family member 4 (ACSL4) levels, and increasing glutathione (GSH) and glutathione peroxidase 4 (GPX4) levels. Furthermore, PRRX1 transcriptionally promoted FK506 binding protein 5 (FKBP5), and increased p38 MAPK activation in AC16 cells. FKBP5 overexpression reversed the effects of PRRX1 silencing on excessive mitophagy and cardiomyocyte ferroptosis in OGD/R-treated AC16 cells. These effects were mitigated by a p38 MAPK inhibitor. Finally, PRRX1 downregulation mitigated myocardial I/R injury by reducing heart infarction and creatine kinase-myocardial band (CK-MB) levels in rat models. These findings demonstrate that PRRX1 silencing attenuates OGD/R-induced excessive mitophagy and cardiomyocyte ferroptosis by decreasing FKBP5 expression and inactivating p38 MAPK signaling, indicating the cardioprotective potential of PRRX1 silencing in myocardial I/R injury.
    Keywords:  Ferroptosis; Mitophagy; Myocardial ischemia/reperfusion injury
    DOI:  https://doi.org/10.1016/j.bbadis.2025.167766
  54. Acta Pharmacol Sin. 2025 Mar 03.
    Author Correction: Tetrahydroberberrubine retards heart aging in mice by promoting PHB2-mediated mitophagy.
    Lei Wang, Xue-Qing Tang, Yang Shi, Hui-Min Li, Zi-Yu Meng, Hui Chen, Xiao-Han Li, Yong-Chao Chen, Heng Liu, Yang Hong, Heng-Hui Xu, Ling Liu, Limin Zhao, Wei-Na Han, Xin Liu, Yong Zhang.
      
    DOI:  https://doi.org/10.1038/s41401-025-01503-z
  55. Phytomedicine. 2025 Feb 17. pii: S0944-7113(25)00108-4. [Epub ahead of print]140 156467
    Xin-Fu-Kang oral liquid mitigates chronic heart failure through NR4A1-Dependent regulation of endoplasmic reticulum-mitochondrial crosstalk in Cardiomyocytes.
    Xiaohan Zhang, Xing Chang, Ruoning Chai, Xuesong Zhang, Jiaran Li, Zezhen Guo, Zhiling Qiu, Yuguo Song, Shuqing Shi, Yuanhui Hu, Bai Du.
       BACKGROUND: Chronic heart failure (CHF) is the terminus of a variety of cardiovascular diseases. Xin-Fu-Kang oral liquid (XFK), a natural herbal compound, has been used in CHF treatment for decades. However, further investigation is required to elucidate the fundamental mechanisms.
    STUDY DESIGN AND METHODS: Transverse aortic constriction (TAC) was performed in mouse models. The pharmacological efficacy of XFK was confirmed by assessing cardiac function and the observation of pathological alterations in myocardial tissue. Following this, single-cell sequencing (scRNA-seq) was implemented. With the identification of XFK metabolites in rat serum via UPLC-QE MS, molecular docking was utilized to conduct preliminary validation of putative therapeutic targets. Subsequently, the phenylephrine-induced model of cardiac pressure overload was established for conducting additional verification and rescue experiments by silencing NR4A1 in vitro.
    RESULTS: XFK intervention significantly ameliorated cardiac function in the TAC-induced CHF model. Based on scRNA-seq, cardiomyocytes exhibited the most notable alterations following XFK intervention, with NR4A1 identified as a significantly differentially expressed gene after both TAC induction and XFK intervention. In vitro experiments demonstrated that XFK enhanced mitochondrial function, mitigated oxidative stress, and restored mitophagy in a NR4A1-dependent manner, consequently decreasing apoptosis in PE-induced H9C2. Furthermore, the upstream mechanism was associated with capacity of XFK to mitigate endoplasmic reticulum stress and regulate crosstalk between the two organelles.
    CONCLUSION: XFK counteracts cardiac chronic pressure overload through regulating NR4A1-mediated functional interaction between endoplasmic reticulum and mitochondria in cardiomyocytes, further preserves mitochondria function and prevents apoptosis. This finding indicates a novel pharmacological therapy for CHF.
    Keywords:  Chronic heart failure(1); Endoplasmic reticulum-Mitochondria Crosstalk(5); NR4A1(6); Serum pharmaco-chemistry(4); Single cell sequencing(3); Xin-Fu-Kang Oral Liquid(2)
    DOI:  https://doi.org/10.1016/j.phymed.2025.156467
  56. Aging Cell. 2025 Mar 04. e70029
    Effects of the VIVIFRAIL Exercise Protocol on Circulatory and Intracellular Peripheral Mediators Bridging Mitochondrial Dynamics and Inflammation in Robust and Frail Older People.
    Fiona Limanaqi, Evelyn Ferri, Pasquale Ogno, Franca Rosa Guerini, Gabriela Alexandra Mihali, Tiziano Lucchi, Mario Clerici, Chiara Fenoglio, Laura D'Andrea, Elena Marcello, Mara Biasin, Beatrice Arosio.
      Physical exercise has been associated with healthier aging trajectories, potentially preventing or mitigating age-related declines. This occurs through a complex, yet poorly characterized network of multi-organ interactions involving mitochondrial, inflammatory, and cell death/survival pathways. Here, we comprehensively evaluated the 12-week VIVIFRAIL multicomponent exercise protocol in physically frail (n = 16, mean age 81.4 ± 5.6) and robust (n = 50, mean-age 73.6 ± 4.7) old individuals. Before (T0) and after (T1) the protocol, functional outcomes were assessed alongside a detailed exploratory analysis of mitochondrial, inflammatory, apoptotic, and neuro-muscular mediators concerning their plasmatic/serum concentrations, and/or mRNA expression from peripheral blood mononuclear cells (PBMCs). Besides significant functional improvements across both groups, our findings highlighted unique and overlapping modulations of key biological pathways. Both groups showed refined mitochondrial integrity/turnover (upregulated mt-ND1, downregulated TFAM, and ULK1), anti-inflammatory responses (upregulated IL10, and TGF-B, and downregulated IL6/IL10 mRNA ratio), as well as reduced cellular damage/apoptosis (reduced plasmatic ccf-nDNA, downregulated BAX, and upregulated BCL-2/BAX ratio). Plasmatic ccf-mtDNA was significantly reduced in robust subjects, while plasmatic IL6 and IL6/IL10 ratio were reduced in frail subjects uniquely. Spearman correlations between physical improvements and biological pathway variations also suggested different adaptation mechanisms influenced not only by chronological age but also by frailty status. In conclusion, this study confirms the benefits of physical activity in the older population and provides novel insights into specific biological mediators of the mitochondria-inflammation axis as key players in such effects. Moreover, our findings establish PBMCs as a valuable tool for monitoring the biological trajectories of aging and health-promoting lifestyle interventions.
    Keywords:  apoptosis; ccf‐mtDNA; cytokines; exercise; inflammaging; mitochondria; mitophagy; peripheral blood cells
    DOI:  https://doi.org/10.1111/acel.70029
  57. Mitochondrion. 2025 Mar 03. pii: S1567-7249(25)00021-2. [Epub ahead of print] 102024
    The compound XueShuanTong promotes podocyte mitochondrial autophagy via the AMPK/mTOR pathway to alleviate diabetic nephropathy injury.
    Chuangbiao Zhang, Weiwei Ren, Xiaohua Lu, Lie Feng, Jiaying Li, Beibei Zhu.
      The study aimed to elucidate the molecular mechanisms underlying the protective effects of Compound Xueshuantong (CXst) in the context of diabetic nephropathy (DN), a major cause of kidney failure driven by podocyte injury and metabolic dysfunction. Given the critical role of the AMPK/mTOR signaling pathway in regulating cellular energy balance, autophagy, and mitochondrial health, we focused on its involvement in podocyte function and how it might be influenced by CXst. Through a series of experiments, we found that CXst treatment led to the upregulation of key proteins involved in autophagy, such as LC3 and p62, as well as proteins critical for mitochondrial function, like PGC-1α. These molecular changes helped to counteract the damaging effects of high glucose levels on podocytes, which are central to maintaining the filtration function of the kidneys. Additionally, CXst's ability to modulate the AMPK/mTOR pathway was shown to be a pivotal factor in its protective effects, as inhibition of AMPK significantly reduced these benefits. This comprehensive study provides strong evidence that CXst exerts its protective effects against DN by modulating the AMPK/mTOR pathway, thus preserving podocyte integrity and function. These findings suggest that CXst could be a promising candidate for the development of new therapeutic strategies for the treatment of DN, offering hope for better management of this challenging condition.
    Keywords:  Adenylate activated protein kinase/mammalian target of rapamycin signaling pathway; Compound Xueshuantong; Diabetic nephropathy; Mitochondrial autophagy; Nephrin; Podocin
    DOI:  https://doi.org/10.1016/j.mito.2025.102024
  58. Med Sci Sports Exerc. 2025 Mar 05.
    Exercise Rescues Blood-Brain Barrier Structural Impairment and Enhances Mitochondrial Biogenesis in a Hypertensive Mouse Model.
    Ying-Shuang Chang, Chu-Wan Lee, Han-Chen Lin, Wan-Erh Hu, Chih-Lung Lin, Yi-Ting Wu, Yao-Hsiang Shih.
       ABSTRACT: Purpose. Blood-brain barrier (BBB) dysfunction is implicated in various neurodegenerative diseases, including Alzheimer's disease and frontotemporal dementia. Over the past decades, numerous studies have suggested that exercise can mitigate neurodegenerative processes by improving mitochondrial function. Recently, we demonstrated that exercise could reverse hippocampus-associated memory deficits and reduce BBB leakage in a modified two-kidney, one-clip (2K1C) hypertensive animal model. Based on these findings, we hypothesize that exercise restores BBB integrity in hypertensive animal models. Methods. Hypertension was induced in C57BL/6 mice via 2K1C surgery. Following three weeks of hypertension induction, mice underwent moderate-intensity treadmill exercise for five weeks. Subsequently, brain tissues were collected for immunofluorescence staining and immunoblotting analyses to assess changes in BBB structure and mitochondria-related protein expression. Results. Exercise restored hypertension-induced reductions in blood vessel density within the hippocampus. Additionally, it repaired BBB structural impairments, as evidenced by increased levels of Claudin-5 co-localization with blood vessels, enhanced perivascular astrocyte levels, and improved perivascular AQP-4 protein expression. An immunoblotting analysis revealed that exercise upregulated the PGC-1α/Nrf1/UCP-2 pathway in the 2K1C hypertensive model. However, exercise did not significantly affect Drp-1 expression. Conclusions. Exercise alleviates BBB leakage by restoring structural integrity to the BBB. These improvements may be mediated through the enhancement of mitochondrial biogenesis.
    DOI:  https://doi.org/10.1249/MSS.0000000000003696
  59. Ecotoxicol Environ Saf. 2025 Mar 04. pii: S0147-6513(25)00297-0. [Epub ahead of print]292 117961
    Low-dose acrylamide induces mitochondrial autophagy and energy metabolism dysfunction in SH-SY5Y cells via BV2 microglial activation.
    Xiaoqi Pan, Tingting Zhang, Yuanyuan Li, Qiaoxing Mou, Sirui Liu, Xiaoyu Yan, Jie Liang, Mengfan Yan, Weiying Liu.
      Acrylamide (ACR), a common environmental and food contaminant, can cause neurotoxicity and increase the risk of neurodegenerative diseases. While the neurotoxicity induced by high-dose ACR exposure in occupational workers is evident, the potential adverse effects of low-dose daily exposure remain a subject of debate. In this present study, we aim to explore whether low-dose ACR induces neurotoxicity based on the interactions between microglia and neurons. Results demonstrated that low-dose ACR did not significantly impair mitochondrial homeostasis in SH-SY5Y cells, but induced microglial polarisation towards the M1 pro-inflammatory phenotype at this concentration. Interestingly, the supernatants from ACR pre-activated BV2 microglia were observed to trigger mitochondrial dysfunction, induce autophagy, and disrupt energy metabolism in SH-SY5Y cells, whose effects were not observed in cells solely treated with ACR. Furthermore, muscone, acting as an inhibitor of inflammatory factors, successfully ameliorated the activation of microglia induced by low-dose ACR and notably downregulated the expression levels of IL-1β, IL-6, and TNF-α. In an additional effect, muscone reversed the expression trends of P62 and LC3 proteins, which were perturbed by the activation of microglia in SH-SY5Y cells. In conclusion, our results proved that low-dose ACR induced mitochondrial autophagy and energy metabolism disturbance in SH-SY5Y cells via BV2 microglial activation, which might be significantly influenced by the release of pro-inflammatory factors. Our study emphasized the crucial role of microglia-neuronal interactions, providing novel insights for understanding low-dose ACR induced neurotoxicity.
    Keywords:  Acrylamide; Energy metabolism; Microglial activation; Mitochondrial autophagy; Neurotoxicity
    DOI:  https://doi.org/10.1016/j.ecoenv.2025.117961
  60. Mol Neurobiol. 2025 Mar 06.
    Exercise Ameliorates Dysregulated Mitochondrial Fission, Mitochondrial Respiration, and Neuronal Apoptosis in Parkinson's Disease Mice via the Irisin/AMPK/SIRT1 Pathway.
    Nan Li, Bin Wang, Yuanxin Wang, Xin Tian, Junjie Lin, Xun Sun, Yu Sun, Xin Zhang, Haocheng Xu, Mingzhi Li, Fanxi Zeng, Renqing Zhao.
      Mitochondrial dysfunction plays a crucial role in the pathogenesis of Parkinson's disease (PD), yet therapeutic strategies targeting mitochondrial function remain limited. Exercise has shown neuroprotective benefits in PD, but the underlying mechanisms are not fully understood. This study aimed to investigate how exercise affects MPTP-induced excessive apoptosis, mitochondrial fission, and mitochondrial function in PD mice, with a focus on the Irisin/AMPK/SIRT1 pathway. Thirty-two male C57BL/6 J mice, aged 7-8 weeks, were randomly assigned to control (n = 8) and experimental groups (n = 24). Mice in the experimental groups were administered intraperitoneal injections of MPTP to induce the PD model. Subsequently, the experimental mice were divided into three groups (8 mice in each group): the sedentary group (PD), the group subjected to 10 weeks of treadmill exercise (PDEX), and the group receiving both treadmill exercise and Irisin antagonist injections (EXRG). Upon completion of the 10-week intervention, behavioral assessments were performed. Following this, the mice were euthanized to collect brain samples and subjected to immunohistochemistry, immunofluorescence, ELISA, citrate synthase assay, and Western blot analyses. MPTP-treated mice exhibited significant motor dysfunction and dopaminergic neuron loss in the nigrostriatal regions, which were alleviated after a 10-week exercise intervention. Exercise significantly reduced MPTP-induced neuronal apoptosis, as evidenced by decreased cellular debris and abnormal nuclear morphology, increased Bcl-2 protein levels, and decreased BAX expression. Furthermore, exercise mitigated abnormal mitochondrial fission in PD mice and improved mitochondrial function-related markers. This was reflected by reduced immunohistochemical signals and protein expression levels of Drp1, Fis1, and MFF, as well as increased citrate synthase activity and elevated expression levels of COX-I and COX-IV. In the substantia nigra of PD mice, the expression levels of Irisin, p-AMPK, and SIRT1 were reduced but were notably elevated after the 10-week exercise intervention. However, chronic treatment with Cyclo RGDyk to block Irisin signaling potentially counteracted the exercise-induced increases in p-AMPK and Sirt1 expression. Moreover, blocking the Irisin signaling pathway reversed the beneficial effects of exercise on mitochondrial fission, mitochondrial function, and neuronal apoptosis. Exercise is an effective approach for alleviating PD pathology by reducing excessive mitochondrial fission, dysregulated mitochondrial respiration and metabolism, and neuronal loss. The neuroprotective effects of exercise are achieved, in part, by regulating the Irisin/AMPK/SIRT1 signaling pathway. This study underscores the potential of targeting Irisin signaling as a therapeutic strategy of exercise to enhance mitochondrial function and promote neuronal survival in PD.
    Keywords:  AMPK; Apoptosis; Exercise; Irisin; Mitochondrial dysfunction; Parkinson’s disease
    DOI:  https://doi.org/10.1007/s12035-025-04801-z
  61. Biochem Biophys Res Commun. 2025 Feb 26. pii: S0006-291X(25)00269-4. [Epub ahead of print]754 151555
    Berberine-loaded albumin nanoparticles alleviate liver damage in rats by modulating mitochondrial biogenesis and mitochondria-endoplasmic reticulum interactions.
    Heba Zaied, Mohamed I Ashmawy, Ahmed E Abdel Karim, Doaa A Ghareeb, Abeer El Wakil.
      The liver performs essential functions critical to overall health. This study evaluated the efficacy of berberine-loaded albumin nanoparticles (BRB-BSA NPs) and cisplatin in mitigating hepatic damage caused by diethylnitrosamine (DEN) and carbon tetrachloride (CCl4) in male albino rats. Molecular modeling was conducted to explore BRB interactions with Sirt1, a NAD+-dependent protein deacetylase involved in key cellular pathways. BRB-BSA NPs showed superior results to cisplatin in reducing liver enzymes, oxidative stress, and proinflammatory markers while enhancing antioxidant activities. Cisplatin, however, was more effective in restoring mitochondrial pathway regulators. Additionally, BRB-BSA NPs improved liver tissue histoarchitecture and ultrastructure, bringing them closer to normal. In conclusion, BRB-BSA NPs demonstrated potent efficacy in alleviating DEN/CCl4-induced liver injury in male rats.
    Keywords:  DEN/CCl(4); Molecular docking; Natural product; Sigma1-receptor
    DOI:  https://doi.org/10.1016/j.bbrc.2025.151555
  62. PLoS One. 2025 ;20(3): e0315751
    Akt3 links mitochondrial function to the regulation of Aurora B and mitotic fidelity.
    Zachary J Hough, Fatemeh Nasehi, Daniel G Corum, Russell A Norris, Ann C Foley, Robin C Muise-Helmericks.
      Akt3 is a key regulator of mitochondrial homeostasis in the endothelium. Akt3 depletion results in mitochondrial dysfunction, decreased mitochondrial biogenesis, and decreased angiogenesis. Here we link mitochondrial homeostasis with mitotic fidelity-depletion of Akt3 results in the missegregation of chromosomes as visualized by multinucleation and micronuclei formation. We have connected Akt3 to Aurora B, a significant player in chromosome segregation. Akt3 localizes to the nucleus, where it associates with and regulates WDR12. During mitosis, WDR12 is localized to the dividing chromosomes, and its depletion results in a similar mitotic phenotype to Akt3 depletion. WDR12 associates with Aurora B, both of which are downregulated under conditions of Akt3 depletion. We used the model oxidant paraquat to induce mitochondrial dysfunction to test whether the Akt3-dependent effect on mitochondrial homeostasis is linked to mitotic function. Paraquat treatment also causes chromosome missegregation by inhibiting the expression of Akt3, WDR12, and Aurora B. The inhibition of ROS rescued both the mitotic fidelity and the expression of Akt3 and Aurora B. Akt3 directly phosphorylates the major nuclear export protein CRM-1, causing an increase in its expression, resulting in the inhibition of PGC-1 nuclear localization, the master regulator of mitochondrial biogenesis. The Akt3/Aurora B pathway is also dependent on CRM-1. CRM-1 overexpression resulted in chromosome missegregation and downregulation of Aurora B similar to that of Akt3 depletion. Akt3 null hearts at midgestation (E14.5), a stage in which proliferation is occurring, have decreased Aurora B expression, increased CRM-1 expression, decreased proliferation, and increased apoptosis. Akt3 null hearts are smaller and have a thinner compact cell layer than age-matched wild-type mice. Akt3 null tissue has dysmorphic nuclear structures, suggesting mitotic catastrophe. Our findings show that mitochondrial dysfunction induced by paraquat or Akt3 depletion results in a CRM-1-dependent disruption of Aurora B and mitotic fidelity.
    DOI:  https://doi.org/10.1371/journal.pone.0315751
  63. J Food Sci. 2025 Mar;90(3): e70100
    Role and mechanism of seaweed polysaccharides in regulating mitochondrial dysfunction: A review.
    Lina Wu, Dandan Huang, Sitong Wang, Jiajing Wang, Qingxu Guo, Xiaoyong Chen.
      Seaweed polysaccharides are naturally occurring macromolecules in seaweeds with a variety of health benefits. Their multiple health benefits are attributed to their regulatory effects on mitochondrial function. However, the relationship between the source of seaweed polysaccharides, polysaccharide properties, and mitochondrial dysfunction has not been comprehensively reviewed. This review summarizes the sources of seaweed polysaccharides, effects of polysaccharide properties (including molecular weight, monosaccharide composition, chemical structure, and functional groups) on regulating mitochondrial function, as well as their main potential regulatory mechanisms (including mitochondrial respiratory chain, mitochondrial membrane structural integrity, mitochondrial DNA, mitochondrial dynamic, mitochondrial autophagy, and mitochondrial Ca2+ homeostasis), with the aim to provide a theoretical reference to promote further research on the development and application of seaweed polysaccharides.
    Keywords:  Seaweed polysaccharides; Structural properties; autophagy; mitochondrial dysfunction; mitochondrial membrane potential
    DOI:  https://doi.org/10.1111/1750-3841.70100
  64. Brain Res Bull. 2025 Mar 01. pii: S0361-9230(25)00083-8. [Epub ahead of print] 111271
    Tas2r123-associated mitochondrial organization and neuroplasticity underlying the antidepressant effect of resveratrol.
    Hailong Ge, Lujia Si, Chen Li, Junjie Huang, Limin Sun, Lan Wu, Yinping Xie, Ling Xiao, Gaohua Wang.
       BACKGROUND: Resveratrol, a natural bitter polyphenol, exhibits significant antidepressant property. Numerous studies have linked its antidepressant effect to neuroplasticity enhancement or mitochondrial regulation. However, the interplay between these two mechanisms remains unclear. This study aims to elucidate the relationship among resveratrol's antidepressant effect, its regulatory impact on neuroplasticity and mitochondrial function, and to investigate the potential role of the type 2 bitter taste receptors (Tas2rs) in these processes.
    METHODS: A chronic unpredictable mild stress (CUMS) model was used to induce depressive-like behaviors, while resveratrol was administered as an intervention. Following CUMS and resveratrol treatment, proteomic analysis combined with bioinformatics predicted significantly altered biological pathways in the hippocampus. The aforementioned predictions were validated using Western blotting (WB), Golgi staining, Nissl staining, and electron microscopy. Additionally, Tas2rs expression and calcium (Ca2+) levels in the hippocampus were quantified using quantitative PCR, WB, and calcium assay kit. Finally, immunofluorescence (IF) colocalization was used to examine the association of Tas2r123 with mitochondrial outer membrane in hippocampus.
    RESULTS: Resveratrol significantly alleviated depressive-like behaviors induced by CUMS. Proteomic analysis revealed that resveratrol's therapeutic effects are associated with neuroplasticity-related and metabolic pathways, particularly with differentially expressed proteins (DEPs) predominantly localized in the mitochondria. Gene Ontology analysis of mitochondrial DEPs further revealed substantial changes in mitochondrial organization. Furthermore, molecular biology experiments validated these proteomics findings. Additionally, resveratrol also reversed the CUMS-induced downregulation of Tas2r123 mRNA and protein expression. Moreover, IF colocalization demonstrated a strong association between Tas2r123 and mitochondria.
    CONCLUSIONS: Our findings suggest that resveratrol may exert antidepressant property by modulating neuroplasticity through the Tas2r123-mitochondrial organization pathway. This study introduces a novel perspective linking Tas2rs to resveratrol's antidepressant mechanisms, potentially pave the way for future antidepressant therapies.
    Keywords:  depression; mitochondria; mitochondrial organization; neuroplasticity; resveratrol; tas2r123
    DOI:  https://doi.org/10.1016/j.brainresbull.2025.111271
  65. FASEB J. 2025 Mar 15. 39(5): e70423
    A novel, rapidly progressive ataxia due to a spontaneous Myo5a mutation in mice impairs transport proteins and alters mitochondria.
    Alexander M Telenson, Ryan R Hsieh, Gabrielle J Cowen, Eoin P Sode, Jason M Kwon, Andy H Vo, Michele Hadhazy, Patrick G Page, Nalini R Rao, Lorenzo Pesce, Alexis R Demonbreun, Megan J Puckelwartz, Jeffrey N Savas, Elizabeth M McNally.
      Spontaneous mouse mutants have helped define genetic contributions to many phenotypes. Here we report a spontaneous Novel Ataxic Phenotype in mice. Ataxia findings were evident at post-natal day 11 in NAP mice and rapidly worsened, resulting in preweaning lethality. Using genome sequencing and genome-wide mapping, we identified a 3' donor splice variant in exon 14 of Myo5a, encoding an actin-based motor protein. The variant in Myo5a (c.1752g>a) excises exon 14 and ablates MYO5A protein expression, which is implicated in intracellular transport and Griscelli syndrome type I in humans. NAP mice displayed expansion of PAX6-positive cells in the external granule layer of the cerebellum, and mass spectrometry analysis of cerebellar extracts uncovered differentially abundant proteins involved in short-range organelle transport, and specifically proteins implicated with early endosomes. Using cerebellar lysates and primary neurons, we provide evidence for an interaction between MYO5A and ANKFY1, a known effector for the endosomal protein, RAB5A. We also found neurons from NAP mice had elongated mitochondria, linking MYO5A to mitochondrial homeostasis. This allele provides new insight into Myo5a function in developmental neuropathology.
    Keywords:  Myo5a; ataxia; cerebellum; mitochondria; motor proteins; spontaneous phenotype; transport; whole genome sequencing
    DOI:  https://doi.org/10.1096/fj.202402274R
  66. iScience. 2025 Mar 21. 28(3): 111895
    EPAS1 induction drives myocardial degeneration in desmoplakin-cardiomyopathy.
    Eirini Kyriakopoulou, Sebastiaan J van Kampen, Martijn Wehrens, Su Ji Han, Hesther de Ruiter, Jantine Monshouwer-Kloots, Emma Marshall, Andreas Brodehl, Petra van der Kraak, Anneline S J M Te Riele, Egidius E H L van Aarnhem, Linda W van Laake, Hoyee Tsui, Cornelis J Boogerd, Eva van Rooij.
      Arrhythmogenic cardiomyopathy (ACM) is frequently attributed to desmosomal mutations, such as those in the desmoplakin (DSP) gene. Patients with DSP-cardiomyopathy are predisposed to myocardial degeneration and arrhythmias. Despite advancements, the underlying molecular mechanisms remain incompletely understood, thus limiting therapeutic options. Here, we employed spatial transcriptomics on an explanted heart from a patient with a pathogenic DSP variant. Our transcriptional analysis revealed endothelial PAS domain-containing protein 1 (EPAS1) as a potential regulator of mitochondrial homeostasis in stressed cardiomyocytes. Elevated EPAS1 levels were associated with mitochondrial dysfunction and hypoxic stress in both human-relevant in vitro ACM models and additional explanted hearts with genetic cardiomyopathy. Collectively, cardiomyocytes bearing pathogenic DSP variants exhibit mitochondrial dysfunction, increased apoptosis, and impaired contractility, which are linked to the increased EPAS1 levels. These findings implicate EPAS1 as a key regulator of myocardial degeneration in DSP-cardiomyopathy, which expand to other forms of ACM.
    Keywords:  Cardiovascular medicine; Cell biology; Transcriptomics
    DOI:  https://doi.org/10.1016/j.isci.2025.111895
  67. J Cell Biol. 2025 Apr 07. pii: e202407110. [Epub ahead of print]224(4):
    Cytoplasmic ribosomes on mitochondria alter the local membrane environment for protein import.
    Ya-Ting Chang, Benjamin A Barad, Juliette Hamid, Hamidreza Rahmani, Brian M Zid, Danielle A Grotjahn.
      Most of the mitochondria proteome is nuclear-encoded, synthesized by cytoplasmic ribosomes, and targeted to the mitochondria posttranslationally. However, a subset of mitochondrial-targeted proteins is imported co-translationally, although the molecular mechanisms governing this process remain unclear. We employ cellular cryo-electron tomography to visualize interactions between cytoplasmic ribosomes and mitochondria in Saccharomyces cerevisiae. We use surface morphometrics tools to identify a subset of ribosomes optimally oriented on mitochondrial membranes for protein import. This allows us to establish the first subtomogram average structure of a cytoplasmic ribosome at the mitochondrial surface in the native cellular context, which showed three distinct connections with the outer mitochondrial membrane surrounding the peptide exit tunnel. Further, this analysis demonstrated that cytoplasmic ribosomes primed for mitochondrial protein import cluster on the outer mitochondrial membrane at sites of local constrictions of the outer and inner mitochondrial membranes. Overall, our study reveals the architecture and the spatial organization of cytoplasmic ribosomes at the mitochondrial surface, providing a native cellular context to define the mechanisms that mediate efficient mitochondrial co-translational protein import.
    DOI:  https://doi.org/10.1083/jcb.202407110
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