bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2025–03–16
58 papers selected by
Gavin McStay, Liverpool John Moores University
  1. Shape Matters: The Utility and Analysis of Altered Yeast Mitochondrial Morphology in Health, Disease, and Biotechnology.
  2. 5-Methoxytryptophan Attenuates Oxidative Stress-Induced Downregulation of PINK1 and Mitigates Mitochondrial Damage and Apoptosis in Cardiac Myocytes.
  3. The Role of G-Protein-Coupled Receptor Kinase 4 in Modulating Mitophagy and Oxidative Stress in Cerebral Ischemia-Reperfusion Injury.
  4. The Essential Role of Mitochondrial Dynamics in Viral Infections.
  5. Acetaldehyde dehydrogenase 2 attenuates lipopolysaccharide -induced endothelial barrier damage by inhibiting mitochondrial fission in sepsis-associated encephalopathy.
  6. Natural products alleviate atrial fibrillation by modulating mitochondrial quality control.
  7. HUWE1-mediated ubiquitination and degradation of oxidative damage repair gene ATM maintains mitochondrial quality control system in lens epithelial cells.
  8. SLC5A3 depletion promotes apoptosis by inducing mitochondrial dysfunction and mitophagy in gemcitabine-resistant pancreatic cancer cells.
  9. Targeting ALG3/FOXD1/BNIP3 Axis Prevents Mitophagy and Gemcitabine Resistance of Nasopharyngeal Carcinoma.
  10. Enhanced mitochondrial biogenesis facilitates the development of cutaneous squamous cell carcinoma.
  11. Rhein alleviates diabetic cardiomyopathy by inhibiting mitochondrial dynamics disorder, apoptosis and hypertrophy in cardiomyocytes.
  12. Hypoxia-Induced Mitochondrial Dysfunction and Mitophagy in the small yellow croaker (Larimichthys polyactis).
  13. The Intersection of Mitophagy and Autism Spectrum Disorder: A Systematic Review.
  14. The mitophagy receptor BNIP3L/Nix coordinates nuclear calcium signaling to modulate the muscle phenotype.
  15. Inhibition of METTL3 promotes mesangial cell mitophagy and attenuates glomerular damage by alleviating FOSL1 m6A modifications via IGF2BP2-dependent mechanisms.
  16. Role of Mitochondrial Dynamics in Skin Homeostasis: An Update.
  17. Faecalibacterium prausnitzii Suppresses Mitophagy to Alleviate Muscle Atrophy in Chronic Renal Failure With Protein-Energy Wasting.
  18. Melatonin attenuates inflammatory bone loss by alleviating mitophagy and lactate production.
  19. Harnessing exercise to combat chronic diseases: the role of Drp1-Mediated mitochondrial fission.
  20. PINCH-1 promotes tumor growth and metastasis by enhancing DRP1-mediated mitochondrial fission in head and neck squamous cell carcinoma.
  21. Fam163a knockdown and mitochondrial stress in the arcuate nucleus of hypothalamus reduce AgRP neuron activity and differentially regulate mitochondrial dynamics in mice.
  22. Met-Exo attenuates pyroptosis in miniature pig liver IRI by improving mitochondrial quality control.
  23. Macrophage-derived mitochondria-rich extracellular vesicles aggravate bone loss in periodontitis by disrupting the mitochondrial dynamics of BMSCs.
  24. Putrescine promotes maturation of oocytes from reproductively old mice via mitochondrial autophagy.
  25. Menin maintains lysosomal and mitochondrial homeostasis through epigenetic mechanisms in lung cancer.
  26. Role of Pink1 in Regulating Osteoclast Differentiation during Periodontitis.
  27. Poria cocos-Derived Exosome-like Nanovesicles Alleviate Metabolic Dysfunction-Associated Fatty Liver Disease by Promoting Mitophagy and Inhibiting NLRP3 Inflammasome Activation.
  28. Astaxanthin Alleviates Oxidative Stress in Mouse Preantral Follicles and Enhances Follicular Development Through the AMPK Signaling Pathway.
  29. A new member of the dynamin superfamily modulates mitochondrial membrane branching in Trypanosoma brucei.
  30. Autophagy in skeletal muscle dysfunction of chronic obstructive pulmonary disease: implications, mechanisms, and perspectives.
  31. Mitochondria are positioned at dendritic branch induction sites, a process requiring rhotekin2 and syndapin I.
  32. The E3 ubiquitin ligase RNF126 facilitates quality control of unimported mitochondrial membrane proteins.
  33. A positive feedback loop between SMAD3 and PINK1 in regulation of mitophagy.
  34. Quality control of mitochondrial nucleoids.
  35. Mitochondria-associated non-coding RNAs and their impact on drug resistance.
  36. Molecular Mechanism of Aerobic Exercise Ameliorating Myocardial Mitochondrial Injury in Mice with Heart Failure.
  37. Cocaine Differentially Affects Mitochondrial Function Depending on Exposure Time.
  38. Mitochondrial Dysfunction in Cardiovascular Diseases.
  39. Spermine alleviates myocardial cell aging by inhibiting mitochondrial oxidative stress damage.
  40. Novel Parkin agonists from Poria cocos against dyslipidemia.
  41. Topoisomerase inhibitor amonafide enhances defense responses to promote longevity in C. elegans.
  42. Changes in Mitochondrial Transcriptional Rhythms and Depression-like Behavior in the Hippocampus of IL-33-Overexpressing Mice.
  43. Mitochondrial autophagy-related lncRNAs as prognostic biomarkers and therapeutic targets in gastric adenocarcinoma.
  44. Combined Loss of Obsc and Obsl1 in Murine Hearts Results in Diastolic Dysfunction, Altered Metabolism, and Deregulated Mitophagy.
  45. Mitochondrial dynamics and metabolism in macrophages for cardiovascular disease: A review.
  46. Parkin characteristics and blood biomarkers of Parkinson's disease in WPBLC study.
  47. Enhanced mitochondrial function and delivery from adipose-derived stem cell spheres via the EZH2-H3K27me3-PPARγ pathway for advanced therapy.
  48. Exploring the interplay between mitochondrial dysfunction, early life adversity and bipolar disorder.
  49. Orientin alleviates chondrocyte senescence and osteoarthritis by inhibiting PI3K/AKT pathway.
  50. The depletion of TFAM and p-β-catenin(S552) in mitochondria in response to BoAHV-1 productive infection leads to decreased mitochondrial biogenesis.
  51. Intestinal 8 gingerol attenuates TBI-induced neuroinflammation by inhibiting microglia NLRP3 inflammasome activation in a PINK1/Parkin-dependent manner.
  52. Global research trends and hotspots in mitochondria and asthma: A bibliometric and visualized analysis.
  53. Structure of human PINK1 at a mitochondrial TOM-VDAC array.
  54. Molecular mechanism of Mfn2 alleviating endoplasmic reticulum stress and inhibiting apoptosis of sheep follicular granulosa cells.
  55. SLC25A35 enhances fatty acid oxidation and mitochondrial biogenesis to promote the carcinogenesis and progression of hepatocellular carcinoma by upregulating PGC-1α.
  56. Mitochondria as therapeutic targets for Natural Products in the treatment of Cardiovascular Diseases.
  57. Salmonella exploits LRRK2-dependent plasma membrane dynamics to invade host cells.
  58. The transcription factor XBP1 regulates mitochondrial remodel and autophagy in spontaneous abortion.
  1. Int J Mol Sci. 2025 Feb 27. pii: 2152. [Epub ahead of print]26(5):
    Shape Matters: The Utility and Analysis of Altered Yeast Mitochondrial Morphology in Health, Disease, and Biotechnology.
    Therese Kichuk, José L Avalos.
      Mitochondria are involved in a wide array of critical cellular processes from energy production to cell death. The morphology (size and shape) of mitochondrial compartments is highly responsive to both intracellular and extracellular conditions, making these organelles highly dynamic. Nutrient levels and stressors both inside and outside the cell inform the balance of mitochondrial fission and fusion and the recycling of mitochondrial components known as mitophagy. The study of mitochondrial morphology and its implications in human disease and microbial engineering have gained significant attention over the past decade. The yeast Saccharomyces cerevisiae offers a valuable model system for studying mitochondria due to its ability to survive without respiring, its genetic tractability, and the high degree of mitochondrial similarity across eukaryotic species. Here, we review how the interplay between mitochondrial fission, fusion, biogenesis, and mitophagy regulates the dynamic nature of mitochondrial networks in both yeast and mammalian systems with an emphasis on yeast as a model organism. Additionally, we examine the crucial role of inter-organelle interactions, particularly between mitochondria and the endoplasmic reticulum, in regulating mitochondrial dynamics. The dysregulation of any of these processes gives rise to abnormal mitochondrial morphologies, which serve as the distinguishing features of numerous diseases, including Parkinson's disease, Alzheimer's disease, and cancer. Notably, yeast models have contributed to revealing the underlying mechanisms driving these human disease states. In addition to furthering our understanding of pathologic processes, aberrant yeast mitochondrial morphologies are of increasing interest to the seemingly distant field of metabolic engineering, following the discovery that compartmentalization of certain biosynthetic pathways within mitochondria can significantly improve chemical production. In this review, we examine the utility of yeast as a model organism to study mitochondrial morphology in both healthy and pathologic states, explore the nascent field of mitochondrial morphology engineering, and discuss the methods available for the quantification and classification of these key mitochondrial morphologies.
    Keywords:  analysis; biofuel; cancer; contact sites; engineering; fission; fusion; imaging; mitochondria; morphology; neurodegenerative; pathology
    DOI:  https://doi.org/10.3390/ijms26052152
  2. Free Radic Biol Med. 2025 Mar 10. pii: S0891-5849(25)00160-1. [Epub ahead of print]
    5-Methoxytryptophan Attenuates Oxidative Stress-Induced Downregulation of PINK1 and Mitigates Mitochondrial Damage and Apoptosis in Cardiac Myocytes.
    Chii-Ming Lee, Tung-Chun Chien, Juo-Shan Wang, Yu-Wei Chen, Chin-Yu Chen, Chen-Chin Kuo, Liang-Ting Chiang, Kenneth K Wu, Wan-Tseng Hsu.
      Mitochondrial dysfunction is a hallmark in the pathogenesis of various cardiovascular diseases. 5-Methoxytryptophan (5-MTP), an intrinsic amino acid metabolite, exerts cardioprotective effects potentially through the preservation of mitochondrial integrity. This study investigates the mechanisms and contexts in which 5-MTP positively impacts mitochondrial function using cultured human ventricular cardiomyocytes (HCMs) and HL-1 cardiac cells subjected to oxidative stress (OS). We first demonstrated that 5-MTP up-regulates the expression of PINK1, a key regulator of mitochondrial homeostasis. PINK1 knockdown attenuated the beneficial effects of 5-MTP on cardiomyocyte apoptosis. Furthermore, in cells exposed to OS, 5-MTP pretreatment led to a notable decrease in mitochondrial superoxide generation. Fluorescence imaging and network analysis showed that 5-MTP preserved mitochondrial membrane potential and enhanced mitochondrial network integrity. The reduction in the phosphorylation of dynamin-related protein 1, which is involved in mitochondrial fission, uncovered the role of 5-MTP in maintaining mitochondrial dynamics. Notably, 5-MTP attenuated OS-induced mitophagy, as evidenced by reduced mitophagy detection dye fluorescence and lower mitochondrial Parkin levels, suggesting that mechanisms beyond the PINK1/Parkin pathway are involved. Restoration of AKT phosphorylation and reduced mitochondrial Bax localization further revealed an additional pathway contributing to mitochondrial protection. Moreover, 5-MTP attenuated pro-apoptotic Bax levels and enhanced PINK1 expression in a rat model of ischemic cardiomyopathy, corroborating its cardioprotective role. Collectively, these findings demonstrate that 5-MTP mitigates mitochondrial dysfunction by integrating the roles of PINK1, AKT, and Bax, offering potential as a therapeutic agent to enhance cellular resilience in OS-driven mitochondrial damage.
    Keywords:  5-Methoxytryptophan; AKT; Bax; PINK1; apoptosis; mitochondria; oxidative stress
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.03.010
  3. Neuromolecular Med. 2025 Mar 07. 27(1): 21
    The Role of G-Protein-Coupled Receptor Kinase 4 in Modulating Mitophagy and Oxidative Stress in Cerebral Ischemia-Reperfusion Injury.
    Jian Wang, Diheng Gu, Ke Jin, Hualong Shen, Yaohua Qian.
      Cerebral ischemia-reperfusion injury (CIRI) causes significant neuronal damage through oxidative stress, inflammation, and mitochondrial dysfunction. The G-protein-coupled receptor kinase 4 (GRK4) has been implicated in regulating stress responses in various tissues, but its role in ischemic brain injury remains unclear. In this study, we investigated the role of GRK4 in oxidative stress, inflammation, and mitophagy during CIRI using both in vivo and in vitro models. For the in vivo experiments, we employed the bilateral common carotid artery occlusion (BCCAO) model to induce ischemia-reperfusion injury. Our finding demonstrated that ischemic reperfusion significantly upregulated GRK4 expression in the brain, correlating with elevated levels of inflammatory cytokines and oxidative stress markers. In cultured cerebellar neurons subjected to oxygen-glucose deprivation (OGD), over-expression of GRK4 decreased cell viability, while GRK4 inhibition enhanced neuronal survival, suggesting that GRK4 exacerbates neuronal damage in ischemic conditions. Furthermore, GRK4 overexpression impaired mitophagy, as indicated by altered expression of key mitophagy-related proteins (Beclin-1, PINK1, and p62), which led to mitochondrial dysfunction and increased oxidative stress. In contrast, GRK4 inhibition promoted more efficient mitophagy and improved mitochondrial quality control. These results highlight the detrimental role of GRK4 in ischemic brain injury and suggest that targeting GRK4 could offer a novel therapeutic strategy to mitigate neuronal damage by balancing oxidative stress, inflammation, and mitochondrial dynamics. Further studies are needed to elucidate the precise molecular mechanisms underlying GRK4-mediated neuroinflammation and mitochondrial dysfunction in ischemic stroke.
    Keywords:  Cerebral ischemia–reperfusion injury; G-protein-coupled receptor kinase 4; Ischemic stroke; Mitophagy; Neuroinflammation; Neuronal survival; Oxidative stress
    DOI:  https://doi.org/10.1007/s12017-025-08843-3
  4. Int J Mol Sci. 2025 Feb 24. pii: 1955. [Epub ahead of print]26(5):
    The Essential Role of Mitochondrial Dynamics in Viral Infections.
    Xujie Duan, Rui Liu, Wenjing Lan, Shuying Liu.
      Mitochondria are dynamic organelles that play crucial roles in energy production, metabolic balance, calcium homeostasis, apoptosis, and innate immunity, and are key determinants of cell fate. They are also targets for viral invasion of the body. Many viral proteins target mitochondria, controlling mitochondrial morphology, metabolism, and immune response, thereby achieving immune evasion, promoting their proliferation, and accelerating the infection process. Mitochondrial quality control is key to maintaining normal physiological functions and mitochondrial homeostasis. Dysregulation of mitochondrial dynamics is closely related to the development of many diseases. New roles of mitochondrial dynamics in viral infection are constantly being discovered. Viruses change mitochondrial dynamics by targeting mitochondria to achieve a persistent state of infection. Currently, understanding of mitochondrial dynamics during viral infection is limited. Research on the impact of viral proteins on mitochondrial dynamics provides a foundation for investigating the pathogenesis of viral infections, the disease process, and identifying potential therapeutic targets. This review focuses on the connection between viral infection and mitochondrial dynamics and priority areas for research on virus-mediated mitochondrial immunity, provides insight into the regulation of mitochondrial dynamics by viruses targeting mitochondria, and explores potential means of mitochondrial-mediated control and treatment of viral diseases.
    Keywords:  apoptosis; innate immunity; mitochondria; mitochondrial dynamics; viral infection
    DOI:  https://doi.org/10.3390/ijms26051955
  5. Eur J Pharmacol. 2025 Mar 05. pii: S0014-2999(25)00222-5. [Epub ahead of print]997 177468
    Acetaldehyde dehydrogenase 2 attenuates lipopolysaccharide -induced endothelial barrier damage by inhibiting mitochondrial fission in sepsis-associated encephalopathy.
    Shasha Wang, Zhongyi Liu, Rong Li, Liya Wang, Yue Wu, Weiping Zhang, Ying Yu.
      Sepsis-associated encephalopathy (SAE) is a common neurological complication of sepsis, and acetaldehyde dehydrogenase 2 (ALDH2) has been identified as a protective factor for endothelial cells against oxidative stress. In this study, we aimed to investigate the therapeutic potential of ALDH2 and its impact on mitochondrial dynamics using both mouse and brain microvascular endothelial cells (BMECs) injury models induced by lipopolysaccharide (LPS). Our findings demonstrated that ALDH2 attenuated LPS-induced brain endothelial barrier damage, as evidenced by reduced brain water content and Evans blue dye in mice, decreased transepithelial electrical resistance (TEER), and increased fluorescein isothiocyanate-dextran (FITC-Dextran) leakage in bEnd.3 cells. Furthermore, ALDH2 reduced the levels of reactive oxygen species (ROS) and malondialdehyde (MDA), while enhancing the activities of superoxide dismutase (SOD) and catalase (CAT). ALDH2 also decreased 4-HNE content and restored mitochondrial membrane potential and ATP production, promoting a balanced mitochondrial fission and fusion. Notably, our use of the mitochondrial fission inhibitor Mdivi-1 confirmed that ALDH2 alleviated mitochondrial damage by inhibiting dynamin-related protein 1 (Drp1). Consequently, our findings suggest that the effects of ALDH2 on LPS-induced blood-brain barrier (BBB) damage and oxidative stress may alleviate SAE by inhibiting Drp1 to maintain mitochondrial homeostasis.
    Keywords:  ALDH2; Endothelial barrier; LPS; Mdivi-1; Mitochondrial fission and fusion; Oxidative stress
    DOI:  https://doi.org/10.1016/j.ejphar.2025.177468
  6. Phytomedicine. 2025 Feb 21. pii: S0944-7113(25)00195-3. [Epub ahead of print]140 156555
    Natural products alleviate atrial fibrillation by modulating mitochondrial quality control.
    Teng Ge, Rongjun Zou, Miao Zhang, Jinlin Hu, Kunyang He, Guanmou Li, Tong Zhang, Xiaoping Fan.
       BACKGROUND: Atrial fibrillation (AF), one of the most common cardiac arrhythmias, is associated with high mortality rates and significant healthcare burdens. Mitochondrial homeostasis has recently emerged as a critical factor in AF pathogenesis but remains at the experimental stage. Current drug and surgical treatments for AF often involve side effects and require ongoing treatment plan evaluation and adjustment. In contrast, natural products (NPs), which have been utilized in China for over 2,000 years, show remarkable efficacy in treating AF and are receiving growing attention.
    PURPOSE: We aimed to investigate the regulatory effects of NPs on mitochondrial quality control (MQC) and their impact on AF occurrence and progression. By constructing a novel NP-mitochondria-AF axis, we propose a framework to translate experimental findings into clinical practice and identify potential therapeutic strategies for AF.
    METHODS: Databases such as PubMed, Web of Science, and China National Knowledge Infrastructure were searched (up to October 2024) using the following keywords: "atrial fibrillation," "traditional Chinese medicine," "mitochondrial biogenesis," "mitochondrial dynamics," "mitophagy," "apoptosis," "oxidative stress," "inflammation," and "Ca2+ concentration." NP targets were identified using the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform, while disease targets were retrieved from Online Mendelian Inheritance in Man, GeneCards, and Therapeutic Target Database. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis was performed using the Metascape database. Protein-protein interactions were analyzed using the STRING database, and core monomers and hub genes were identified using Cytoscape 3.7.2.
    RESULTS: We found a strong relationship between mitochondrial homeostasis and AF development. KEGG pathway analysis indicated that commonly used NPs regulate mitochondrial homeostasis, affecting AF progression through various hub genes, including protein kinase B-alpha (AKT1), jun proto-oncogene (JUN), and tumor necrosis factor (TNF). Molecular docking analysis revealed that NP core monomers exhibited binding affinities to hub genes below -5 kcal/mol and to transforming growth factor-β (TGF-β) below -7 kcal/mol.
    CONCLUSION: NPs, including traditional Chinese medicine (TCM) compounds, TCM monomers, and traditional Chinese patent medicines, alleviate AF by modulating MQC with minimal side effects and high efficacy. These findings highlight the therapeutic potential of NPs as promising candidates for AF treatment and further underscore the importance of MQC in AF pathogenesis.
    Keywords:  Atrial fibrillation; Mitochondrial homeostasis; Mitochondrial quality control; Natural products; Network pharmacology
    DOI:  https://doi.org/10.1016/j.phymed.2025.156555
  7. Biochim Biophys Acta Mol Basis Dis. 2025 Mar 11. pii: S0925-4439(25)00141-3. [Epub ahead of print] 167796
    HUWE1-mediated ubiquitination and degradation of oxidative damage repair gene ATM maintains mitochondrial quality control system in lens epithelial cells.
    Congyu Wang, Siwen Wang, Guowei Zhang, Haihong Shi, Pengfei Li, Sijie Bao, Lihua Kang, Min Ji, Huaijin Guan.
      Mitochondrial dysfunction, resulting from a diminished oxidative damage repair capacity of mitochondrial DNA (mtDNA) in peripheral lens epithelial cells (LECs), is a key pathogenic mechanism in age-related cortical cataract (ARCC). This study aims to investigate the potential role of the E3 ligase HUWE1 and its ubiquitination substrate, the oxidative damage repair gene ATM, in the pathogenesis of ARCC. Our findings reveal that ATM protein expression is downregulated in human peripheral lens epithelial cells and the turbid cortex, correlating with increased expression of HUWE1. Overexpression of ATM is shown to repair damaged mtDNA, protect mitochondria in LECs from oxidative damage, inhibit mitochondrial fission, enhance mitochondrial biogenesis and mitophagy, and prevent LECs apoptosis. Conversely, overexpression of HUWE1 may negate the protective effects of ATM via the ubiquitination pathway, promote oxidative stress-induced mitochondrial damage, increase the expression of mitochondrial fission proteins Drp1/Fis1, and lead to mitochondrial network fragmentation and LECs apoptosis. In a SD rat lens model ex vitro, the ATM inhibitor AZD0156 exacerbated lens opacity, whereas the mitochondrial fission inhibitor Mdivi-1 restored lens transparency. These results suggest that modulating key molecules involved in oxidative damage repair and mitochondrial fission pathways could enhance mitochondrial quality control, paving the way for the development of targeted molecular therapies for the prevention and treatment of ARCC.
    Keywords:  ATM; Age-related cortical cataract; Mitochondrial quality control; Ubiquitination
    DOI:  https://doi.org/10.1016/j.bbadis.2025.167796
  8. Cell Death Dis. 2025 Mar 07. 16(1): 161
    SLC5A3 depletion promotes apoptosis by inducing mitochondrial dysfunction and mitophagy in gemcitabine-resistant pancreatic cancer cells.
    Minsoo Kim, Woosol Chris Hong, Hyeon Woong Kang, Ju Hyun Kim, Dongyong Lee, Jae-Ho Cheong, Hye-Sol Jung, Wooil Kwon, Jin-Young Jang, Hyo Jung Kim, Joon Seong Park.
      Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with poor prognosis, largely due to the rapid development of chemoresistance in patients. Mitochondrial dynamics play a crucial role in cancer cell survival. Currently, the specific mechanisms underlying gemcitabine resistance in PDAC remain unknown. In this study, we identified the sodium/myo-inositol co-transporter solute carrier family 5 member 3 (SLC5A3) as a key modulator promoting chemoresistance in PDAC. SLC5A3 levels were significantly upregulated in gemcitabine-resistant PDAC cells, enhancing their cell survival by stabilizing the mitochondrial functions and inhibiting apoptosis. Mitochondrial analysis showed that SLC5A3 inhibition disrupted the mitochondrial dynamics, leading to increased reactive oxygen species production, mitochondrial fission, and impaired oxidative phosphorylation. Moreover, SLC5A3 inhibition activated the PTEN-induced kinase 1/Parkin-mediated mitophagy pathway, resulting in the excessive removal of damaged and healthy mitochondria, thereby depleting the mitochondrial reserves and sensitizing the cells to apoptosis. In vivo studies revealed that targeting SLC5A3 enhanced the efficacy of gemcitabine and significantly reduced the tumor growth. Collectively, these results suggest SLC5A3-mediated mitochondrial regulation as a promising therapeutic strategy to overcome gemcitabine resistance in PDAC.
    DOI:  https://doi.org/10.1038/s41419-025-07476-5
  9. Int J Biol Sci. 2025 ;21(5): 1894-1913
    Targeting ALG3/FOXD1/BNIP3 Axis Prevents Mitophagy and Gemcitabine Resistance of Nasopharyngeal Carcinoma.
    Zhanwang Wang, Yi Jin, Dong He, Yuxing Zhu, Mengqing Xiao, Xiaoming Liu, Yaxin Cheng, Ke Cao.
      Understanding the specific role and underlying mechanisms of mitophagy may provide therapeutic benefit to patients with nasopharyngeal carcinoma (NPC). Forkhead box D1 (FOXD1), is overexpressed in NPC. However, its roles in NPC progression and therapy resistance remain largely unknown. NPC tissues displayed increased FOXD1 expression compared to paired non-tumor tissues, which correlated with worse overall survival (OS). Upregulation of FOXD1 promoted NPC cell proliferation, colony formation, migration, invasion, and impaired sensitivity to GEM by enhancing mitophagy levels. Mechanistically, FOXD1 promoted mitophagy in NPC cells by transcriptionally initiating BNIP3 expression. This enhanced mitophagy, in turn, promoted proliferation, invasion, and migration and reduced NPC cell sensitivity to gemcitabine (GEM). Most interestingly, Asn176 N-glycosylation of the FOXD1 protein increased its stability and nuclear localization, thereby transcriptionally activating BNIP3 expression to promote mitophagy of NPC cells. ALG3 directly interacted with FOXD1 and induced this N-glycosylation. Targeting the ALG3/FOXD1/BNIP3 axis offers a promising therapeutic strategy to inhibit the progression of NPC, which highlighting the potential of therapeutics targeting ALG3 and FOXD1 for regulating mitophagy and overcoming GEM resistance.
    Keywords:  ALG3; FOXD1; Gemcitabine; Mitophagy; Nasopharyngeal Carcinoma
    DOI:  https://doi.org/10.7150/ijbs.101585
  10. Cancer Lett. 2025 Mar 10. pii: S0304-3835(25)00187-9. [Epub ahead of print] 217623
    Enhanced mitochondrial biogenesis facilitates the development of cutaneous squamous cell carcinoma.
    Ziyang Wang, Ke He, Meng Liu, Weiqiang Lv, Baochen Cheng, Guanfei Zhang, Xueqiang Wang, Mengqi Zeng, Lianying Jiao, Shujun Han, Yan Zheng, Zhihui Feng.
      Mitochondrial malfunction is traditionally viewed as a major factor in tumor growth and malignancy, while recent studies have introduced conflicting views suggesting the necessity of functional mitochondria for tumor growth. Despite these differing perspectives, the specific role of mitochondria in cutaneous squamous cell carcinoma (cSCC) remains poorly understood. In this study, we observed increased mitochondrial abundance and function during the development of cSCC. We also identified retinoic acid receptor response 1 (RARRES1), which is dramatically decreased in human cSCC samples, as a key regulator of mitochondrial homeostasis. Mechanistically, RARRES1 can translocate into mitochondria and facilitate the degradation of TFAM by binding to LONP1, thereby regulating mitochondrial biogenesis. While RARRES1 suppression unleashed TFAM to promote mitochondrial biogenesis, leading to the progression of cSCC. Targeting RARRES1-LONP1/TFAM axis shows significant potential for inhibiting cSCC development. This study reveals a unique network for regulating mitochondrial homeostasis and emphasizes the crucial role of mitochondria in cSCC development, positioning the RARRES1-LONP1/TFAM axis as promising therapeutic target for future clinical applications.
    Keywords:  Cutaneous squamous cell carcinoma; LONP1; Mitochondria biogenesis; RARRES1; TFAM
    DOI:  https://doi.org/10.1016/j.canlet.2025.217623
  11. Cell Signal. 2025 Mar 11. pii: S0898-6568(25)00147-0. [Epub ahead of print] 111734
    Rhein alleviates diabetic cardiomyopathy by inhibiting mitochondrial dynamics disorder, apoptosis and hypertrophy in cardiomyocytes.
    Hejuan Li, Genwang Wang, Yi Tang, Lei Wang, Zhenzhou Jiang, Jing Liu.
       BACKGROUND: Diabetic cardiomyopathy (DCM) is a significant cardiovascular complication in diabetic patients, and treatment regimens are limited. Rhein, a compound extracted from the herb rhubarb, was investigated in this study for its efficacy on DCM and the potential mechanism.
    METHODS: Streptozotocin-induced DCM mice, high-glucose (HG)-treated neonatal rat cardiomyocytes (NRCMs), and H9c2 cells with ClpP knockdown were used for the study. We performed phenotypic and molecular mechanistic studies using immunoblotting, quantitative polymerase chain reaction, transmission electron microscopy, cardiac echocardiography, and histopathological analysis.
    RESULTS: Rhein improved the cardiac function and myocardial fibrosis, and decreased the cross-sectional area of cardiomyocytes in the DCM mice. It also improved mitochondrial dynamic disorder as evidenced by a decreased ratio of mitochondrial fission-related proteins p-Drp1S616/ Drp1 and increased expression of mitochondrial fusion proteins (Opa1, Mfn1 and Mfn2). Rhein mitigated apoptosis as indicated by decreased apoptosis-related proteins (caspase 9, cleaved-caspase 3 and Bax) and increased anti-apoptosis protein Bcl2 in the heart tissue of DCM mice. Upregulations of cardiac hypertrophy associated genes (ANP, BNP and β-MHC) were significantly inhibited by Rhein treatment. In addition, the level of ClpP, a mitochondrial protease, was increased in DCM, but was normalized by Rhein treatment. However, ClpP knockdown exacerbated cardiomyocyte injury in the presence or absence of HG in H9c2 cells, indicating that a normal level of ClpP is essential for cardiomyocytes to survive.
    CONCLUSIONS: Our results suggest that Rhein protects DCM by ameliorating mitochondrial dynamics disorder, inhibiting cardiomyocyte apoptosis, and myocardial hypertrophy. These protective effects of Rhein may be mediated by preventing ClpP upregulation.
    Keywords:  ClpP; Diabetic cardiomyopathy; Mitochondrial dynamics; Mitochondrial dysfunction; Rhein
    DOI:  https://doi.org/10.1016/j.cellsig.2025.111734
  12. Fish Shellfish Immunol. 2025 Mar 12. pii: S1050-4648(25)00164-0. [Epub ahead of print] 110275
    Hypoxia-Induced Mitochondrial Dysfunction and Mitophagy in the small yellow croaker (Larimichthys polyactis).
    Lu Deng, Jingqian Wang, Yang Liu, Li Wang, Feng Liu, Bao Lou, Junquan Zhu.
      Mitophagy serves as a pivotal mechanism for regulating the quantity and quality of mitochondria within cells, exerting significant influence on various processes such as cell differentiation, oxidative stress, inflammatory responses, and apoptosis. Currently, research on whether and how fish activate mitophagy under hypoxic stress conditions is still insufficient. In this study, to determine the mechanisms whereby marine fish adapt to hypoxic environments from the perspective of mitophagy, we used the small yellow croaker (Larimichthys polyactis) as the research subject and combined in vivo (liver) and in vitro (small yellow croaker fry [SYCF] cell line) hypoxic stress experiments. Fish exposed to hypoxic conditions were found to be characterized by liver tissue damage, and we detected significant elevations in the levels of hydrogen peroxide in liver tissues and reactive oxygen species (ROS) in SYCF cells, along with significant reductions in mitochondrial membrane potential. These findings thus indicate that hypoxic stress leads to tissue damage, excessive ROS production, and mitochondrial damage. In further experiments, we pre-treated SYCF cells with the antioxidant N-acetylcysteine, which was found to effectively reduce ROS levels and prevented the loss of mitochondrial membrane potential, thereby indicating that ROS play a crucial role in hypoxic stress-induced mitochondrial damage. Subsequently, to investigate whether hypoxic stress activates mitophagy to remove damaged mitochondria, we examined changes in the mRNA expression of mitophagy-related genes (bnip3, lc3b, bnip3l, beclin1, fundc1, and ulk1) in the liver and SYCF cells of L. polyactis exposed to hypoxic stress, and detected a significant upregulation of the mRNA expression of these genes. Furthermore, examination of liver ultrastructure and changes in the co-localization of mitochondria and lysosomes in SYCF cells revealed that hypoxic stress induces the formation of autophagosomes and autolysosomes in the liver, with an enhanced co-localization of mitochondria and lysosomes being observed after 6 h of hypoxia, which gradually increased with a prolongation of hypoxic exposure. We have, for the first time, exhibited the formation process of autophagosomes and the subsequent formation of autolysosomes in fish under hypoxic stress. These findings reveal the induction of mitophagy in L. polyactis in response to hypoxic stress, and indicate that these fish may initiate a mitophagic response to remove damaged mitochondria, reduce excessive ROS accumulation, and maintain cellular homeostasis. Our findings will not only lay a biological foundation for the breeding of hypoxia-tolerant strains of L. polyactis but also provide new insights into the mechanisms underlying the adaptation of marine fish to hypoxic environments.
    Keywords:  Hypoxic stress; Larimichthys polyactis; Mitochondrial damage; Mitophagy; Reactive oxygen species
    DOI:  https://doi.org/10.1016/j.fsi.2025.110275
  13. Int J Mol Sci. 2025 Feb 28. pii: 2217. [Epub ahead of print]26(5):
    The Intersection of Mitophagy and Autism Spectrum Disorder: A Systematic Review.
    Eleonora Kovacheva, Maria Gevezova, Nikolay Mehterov, Maria Kazakova, Victoria Sarafian.
      Autism spectrum disorder (ASD) is a group of neurodevelopmental and biobehavioral conditions that arises from complex interactions between environmental factors and physiological development in genetically predisposed individuals. Among the most frequently observed metabolic abnormalities in ASD is mitochondrial dysfunction. Mitochondria respond to cellular stress by altering their dynamics or initiating mitophagy. In neurons, the buildup of dysfunctional mitochondria and reactive oxygen species (ROS) poses a significant risk, as these cells cannot regenerate through division. To safeguard mitochondrial health, cells rely on an efficient "clean-up mechanism" to remove compromised organelles. Mitophagy, a specific form of autophagy, is responsible for regulating the turnover of flawed and non-functional mitochondria. Impairments in this process result in the accumulation of defective mitochondria in neurons, a characteristic of several neurodegenerative disorders associated with behavioral abnormalities. This systematic review offers an in-depth summary of the present knowledge of mitophagy and underscores its pivotal role in the pathogenesis of ASD.
    Keywords:  autism; mitophagy; pathways
    DOI:  https://doi.org/10.3390/ijms26052217
  14. Autophagy. 2025 Mar 10.
    The mitophagy receptor BNIP3L/Nix coordinates nuclear calcium signaling to modulate the muscle phenotype.
    Jared T Field, Donald Chapman, Yan Hai, Saeid Ghavami, Adrian R West, Berkay Ozerklig, Ayesha Saleem, Julia Kline, Asher A Mendelson, Jason Kindrachuk, Barbara Triggs-Raine, Joseph W Gordon.
      Mitochondrial quality control is critical in muscle to ensure contractile and metabolic function. BNIP3L/Nix is a BCL2 member, a mitophagy receptor, and has been implicated in muscle atrophy. Human genome-wide association studies (GWAS) suggest altered BNIP3L expression could predispose to mitochondrial disease. To investigate BNIP3L function, we generated a muscle-specific knockout model. bnip3l knockout mice displayed a ragged-red fiber phenotype, along with accumulation of mitochondria and endo/sarcoplasmic reticulum with altered morphology. Intriguingly, bnip3l knockout mice were more insulin sensitive with a corresponding increase in glycogen-rich muscle fibers. Kinome and gene expression analyses revealed that bnip3l knockout impairs NFAT and MSTN (myostatin) signaling, with alterations in muscle fiber-type and evidence of regeneration. Mechanistic experiments demonstrated that BNIP3L modulates mitophagy, along with reticulophagy leading to altered nuclear calcium signaling. Collectively, these observations identify novel roles for BNIP3L coordinating selective autophagy, oxidative gene expression, and signaling pathways that maintain the muscle phenotype.
    Keywords:  BNIP3L/Nix; calcium signaling; mitophagy; muscle; myostatin
    DOI:  https://doi.org/10.1080/15548627.2025.2476872
  15. Biochem Pharmacol. 2025 Mar 11. pii: S0006-2952(25)00129-7. [Epub ahead of print] 116867
    Inhibition of METTL3 promotes mesangial cell mitophagy and attenuates glomerular damage by alleviating FOSL1 m6A modifications via IGF2BP2-dependent mechanisms.
    Tao Liu, Xing Xing Zhuang, Xiao Li Zhu, Xi Wu, Xiu Juan Qin, Liang Bing Wei, Ya Chen Gao, Jia Rong Gao.
      Epigenetic changes are involved in many physiological and pathological processes. Mitophagy plays a critical role in chronic kidney disease (CKD); however, the role of N6-methyladenosine (m6A) modification in renal mitophagy remains unclear. In this research, we aim to elucidate the role of RNA methylation in modulating mitophagy and its involvement in the pathophysiology of chronic glomerulonephritis (CGN). We found that Methyltransferase-like 3 (METTL3) was significantly upregulated in biopsies from CKD patients, as well as in CGN mice and cultured mouse mesangial cells (MMCs), and was inversely correlated with glomerular filtration rate. Adeno-associated virus serotype 9 (AAV9)-mediated METTL3 silencing from mouse kidneys attenuated adenine-induced glomerular damage, and promoted renal mitophagy. METTL3 knockdown significantly reduced the oxidative stress and inflammation levels and promoted mitophagy in lipopolysaccharide (LPS)-stimulated MMCs, while its overexpression significantly aggravated these responses in vitro. Moreover, FOSL1 (Fos-like antigen 1) was identified as a target of METTL3 and the stability of FOSL1 was increased through binding of IGF2BP2 (Insulin-like Growth Factor 2 mRNA-binding Protein 2) to its m6A-modified regions. The mitophagy regulatory effects of FOSL1 were then explored both in vitro and in vivo. Mechanistically, METTL3 modulated AMPK (AMP-activated Protein Kinase)/mTOR (Mechanistic Target of Rapamycin) signaling via the m6A modification of FOSL1 in an IGF2BP2-dependent manner and exerted a mitophagy inhibitory effect. In summary, this study suggested that METTL3-mediated m6A modification is an important mechanism of mesangial cell (MCs) injury in CGN. Targeting m6A through the writer enzyme METTL3 is a potential approach for the treatment of CGN.
    Keywords:  Chronic glomerulonephritics (CGN); FOSL1 (Fos-like antigen 1); IGF2BP2 (Insulin-like Growth Factor 2 mRNA-binding Protein 2); METTL3 (Methyltransferase-like 3); Mesangial cells (MCs); Mitophagy; N6-methyladenosine (m6A)
    DOI:  https://doi.org/10.1016/j.bcp.2025.116867
  16. Int J Mol Sci. 2025 Feb 20. pii: 1803. [Epub ahead of print]26(5):
    Role of Mitochondrial Dynamics in Skin Homeostasis: An Update.
    Tao Quan, Ran Li, Ting Gao.
      Skin aging is the most prominent phenotype of host aging and is the consequence of a combination of genes and environment. Improving skin aging is essential for maintaining the healthy physiological function of the skin and the mental health of the human body. Mitochondria are vital organelles that play important roles in cellular mechanisms, including energy production and free radical balance. However, mitochondrial metabolism, mitochondrial dynamics, biogenesis, and degradation processes vary greatly in various cells in the skin. It is well known that mitochondrial dysfunction can promote the aging and its associated diseases of the skin, resulting in the damage of skin physiology and the occurrence of skin pathology. In this review, we summarize the important role of mitochondria in various skin cells, review the cellular responses to vital steps in mitochondrial quality regulation, mitochondrial dynamics, mitochondrial biogenesis, and mitochondrial phagocytosis, and describe their importance and specific pathways in skin aging.
    Keywords:  mitochondria; oxidative stress; skin aging; ultraviolet radiation
    DOI:  https://doi.org/10.3390/ijms26051803
  17. APMIS. 2025 Mar;133(3): e70014
    Faecalibacterium prausnitzii Suppresses Mitophagy to Alleviate Muscle Atrophy in Chronic Renal Failure With Protein-Energy Wasting.
    Jingwen Ni, Yuting Yin, Pan Liang, Yuanyuan Zheng, Yuying Li, Lvguang Pang, Xiaoshi Zhong, Jianguang Hu.
      Protein-energy wasting (PEW) facilitates major adverse clinical outcomes in chronic renal failure (CRF), with current therapies not suitable for all patients. Faecalibacterium prausnitzii (F. prausnitzii) can alleviate chronic kidney disease, with unclear effects and mechanisms on CRF with PEW. The CRF rat model was constructed by adenine administration, and PEW was induced by a 4% casein diet. The serum creatinine (SCR), urinary protein (UPR), and blood urea nitrogen (BUN) levels were measured by enzyme-linked immunosorbent assay. Pathology of the gastrocnemius muscle was estimated using hematoxylin and eosin staining. The expression of mitophagy-related markers was detected to assess the mitophagy level. Dexamethasone-induced L6 myotubes established myotube atrophy models. The levels of mitophagy-related markers, muscle RING-finger protein-1 (MuRF1), and atrophy gene 1 (Atrogin1) were detected by quantitative reverse transcription-polymerase chain reaction and western blotting. F. prausnitzii suppressed the SCR, UPR, and BUN expression in serum and gastrocnemius muscle atrophy, which were promoted by CRF with PEW. Dexamethasone-induced expression of MuRF1 and Atrogin1 in L6 myotubes was decreased by F. prausnitzii. Additionally, F. prausnitzii repressed mitophagy in the gastrocnemius muscle and L6 myotubes. In conclusion, F. prausnitzii suppressed renal failure progression and muscle atrophy by inhibiting mitophagy in CRF with PEW.
    Keywords:   Faecalibacterium prausnitzii ; chronic renal failure; protein‐energy failure
    DOI:  https://doi.org/10.1111/apm.70014
  18. Apoptosis. 2025 Mar 10.
    Melatonin attenuates inflammatory bone loss by alleviating mitophagy and lactate production.
    Zexin Lin, Yuan Gu, Yingsong Liu, Zilin Chen, Shuai Fang, Zhuan Wang, Zixian Liu, Qingrong Lin, Yanjun Hu, Nan Jiang, Bin Yu, Guanqiao Liu.
      Mitochondrial homeostasis plays a major role in the progression of chronic inflammatory bone loss which has a complex pathogenesis with unsatisfactory therapeutic efficiency. Recently, melatonin has been shown to recipient mitochondrial function and bone formation. However, the effects and underlying molecular mechanism of melatonin in chronic inflammatory bone loss remain unclear. Here, we reported that melatonin ameliorated lipopolysaccharide (LPS)-induced inflammatory bone loss by improving osteogenesis. We found that melatonin rescued LPS-induced mitochondrial dysfunction and metabolic reprogramming in osteoblasts, resulting in reduced osteogenesis impairment. Mechanistically, melatonin inhibited mitochondrial reactive oxygen species (mtROS) production by suppressing LPS-induced mitophagy, which attenuated the activation of the mtROS/HIF-1α/pyruvate dehydrogenase kinase 1 (PDK1) axis. Moreover, melatonin restored pyruvate dehydrogenase (PDH) activity by inhibiting phosphorylation of PDH through the mtROS/HIF-1α/PDK1 axis and eventually downregulated lactate production. These findings indicate the therapeutic effects of melatonin against chronic inflammatory bone loss and demonstrated a potential treatment strategy against inflammatory osteogenic disorders through regulating mitochondrial dysfunction and metabolic reprogramming.
    Keywords:  Inflammatiory bone loss; Lactate; Melatonin; Mitochondrial reactive oxygen species; Mitophagy
    DOI:  https://doi.org/10.1007/s10495-025-02096-y
  19. Front Cell Dev Biol. 2025 ;13 1481756
    Harnessing exercise to combat chronic diseases: the role of Drp1-Mediated mitochondrial fission.
    Yingxin Sun, Junchen He, Lei Bao, Xiaoming Shi, Jinghong Wang, Qingwen Li.
      Enhanced Drp1 activity mediates excessive mitochondrial fission, contributing to the onset and progression of various chronic diseases, including neurodegenerative, cardiovascular, and metabolic disorders. Studies indicate that exercise mitigates mitochondrial dysfunction by modulating Drp1-related signaling targets, thereby inhibiting Drp1 activity and reducing excessive mitochondrial fission. This, in turn, enhances mitochondrial function and cellular metabolism. This review synthesizes the current understanding of Drp1 structure and activation mechanisms, and analyzes the effects of exercise interventions on Drp1-mediated mitochondrial fission in different disease models to improve common chronic conditions. This research deepens our insight into the specific mechanisms of Drp1-induced excessive mitochondrial fission in chronic disease pathogenesis, offering new theoretical support and practical guidance for exercise as a non-pharmacological intervention strategy.
    Keywords:  Drp1; chronic diseases; mechanism; mitochondrial fission; physical exercise
    DOI:  https://doi.org/10.3389/fcell.2025.1481756
  20. Cancer Biol Ther. 2025 Dec;26(1): 2477365
    PINCH-1 promotes tumor growth and metastasis by enhancing DRP1-mediated mitochondrial fission in head and neck squamous cell carcinoma.
    Ruxian Tian, Hao Song, Jiaxuan Li, Ting Yuan, Jiahui Liu, Yaqi Wang, Yumei Li, Xicheng Song.
       PURPOSE: Abnormal expression of PINCH-1 has been observed in various types of human cancers. However, the clinical importance and mechanism underlying its role in head and neck squamous cell carcinoma (HNSCC) is yet to be fully elucidated.
    METHODS: This study evaluated the expression of PINCH-1 in HNSCC samples through immunohistochemical staining and Western blotting. AMC-HN-8, Cal27, and SCC7 cell lines were utilized for cellular function experiments, both in vivo and in vitro. CCK8, colony-formation assay, flow cytometry, wound-healing assay, and transwell assay were employed to investigate the effects of alterations in target proteins on the growth and metastasis of cancer cells. Mito-Tracker Deep Red FM was used to track mitochondrial morphology.
    RESULTS: PINCH-1 was found to be overexpressed in HNSCC and closely associated with lymph node metastasis and poor pathologic differentiation. Its upregulation promoted proliferation, inhibited apoptosis, and enhanced migration and invasion in HNSCC cells. It also promoted mitochondrial fission. We conducted a mechanism analysis, which showed that PINCH-1 knockdown inhibited mitochondrial fission by reducing the expression of DRP1. Furthermore, inhibition of mitochondrial fission could impede the proliferation and metastasis of HNSCC cells. Re-expression of DRP1 reversed the inhibitory effect of PINCH-1 knockdown on mitochondrial fission, cell proliferation, and metastasis in HNSCC cells.
    CONCLUSIONS: PINCH-1 plays a critical oncogenic role in HNSCC by enhancing DRP1-mediated mitochondrial fission, which may serve as a novel therapeutic target for HNSCC.
    Keywords:  DRP1; HNSCC; PINCH-1; growth; metastasis
    DOI:  https://doi.org/10.1080/15384047.2025.2477365
  21. Acta Physiol (Oxf). 2025 Apr;241(4): e70020
    Fam163a knockdown and mitochondrial stress in the arcuate nucleus of hypothalamus reduce AgRP neuron activity and differentially regulate mitochondrial dynamics in mice.
    Cihan Suleyman Erdogan, Yavuz Yavuz, Huseyin Bugra Ozgun, Volkan Adem Bilgin, Sami Agus, Ugur Faruk Kalkan, Bayram Yilmaz.
       AIM: Mitochondria play key roles in neuronal activity, particularly in modulating agouti-related protein (AgRP) and proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus (ARC), which regulates food intake. FAM163A, a newly identified protein, is suggested to be part of the mitochondrial proteome, though its functions remain largely unknown. This study aimed to investigate the effects of Fam163a knockdown and mitochondrial dysfunction on food intake, AgRP neuron activity, and mitochondrial function in the hypothalamus.
    METHODS: Male C57BL/6 and AgRP-Cre mice received intracranial injections of either Fam163a shRNA, rotenone, or appropriate controls. Behavioral assessments included food intake, locomotor activity, and anxiety-like behaviors. qRT-PCR was used to quantify the expression of the genes related to food intake, mitochondrial biogenesis, dynamics, and oxidative stress. Blood glucose, serum insulin, and leptin levels were measured. Electrophysiological patch-clamp recordings were used to assess the AgRP neuronal activity.
    RESULTS: Fam163a knockdown in the ARC increased the cumulative food intake in short term (first 7 days) without altering the 25-day food intake and significantly increased the Pomc mRNA expression. Fam163a silencing significantly reduced leptin levels. Both Fam163a knockdown and rotenone significantly reduced the firing frequency of AgRP neurons. Neither Fam163a silencing nor rotenone altered locomotor or anxiety-like behaviors. Fam163a knockdown and rotenone differentially altered the expression of mitochondrial biogenesis-, mitophagy-, fusion-, and oxidative stress-related genes.
    CONCLUSION: Hypothalamic FAM163A may play a role in modulating AgRP neuronal activity through regulating mitochondrial biogenesis, dynamics, and redox state. These findings provide insights into the role of FAM163A and mitochondrial stress in the central regulation of metabolism.
    Keywords:  AgRP neurons; FAM163A; hypothalamus; mitochondria; rotenone
    DOI:  https://doi.org/10.1111/apha.70020
  22. Int Immunopharmacol. 2025 Mar 10. pii: S1567-5769(25)00427-8. [Epub ahead of print]152 114437
    Met-Exo attenuates pyroptosis in miniature pig liver IRI by improving mitochondrial quality control.
    Lei Cao, Pujun Li, Tao Liu, Yajun Ma, Xiangyu Lu, Hongbin Wang.
      Metformin(Met) and adipose-derived stem cell exosomes(ADSCs-Exo) both demonstrate therapeutic effects on mitochondrial dysfunction and pyroptosis. There is also a phenomenon of mutual promotion between these two pathological states. The synergistic effect of metformin-loaded exosomes (Met-Exo) via electroporation in a miniature pig liver ischemia-reperfusion injury (IRI) model remains unexplored. This study established a liver IRI model in miniature pigs to compare the effects of ADSCs-Exo and Met-Exo. We found that Met-Exo intervention better activated the Adenosine 5'-monophosphate activated protein kinase (AMPK)/NAD-dependent deacetylase sirtuin-1(SIRT1) axis, improved mitochondrial dynamics, promoted mitochondrial biogenesis, and inhibited the sustained excessive autophagy of mitochondria after liver IRI. It was then demonstrated that by improving mitochondrial dysfunction, ATP production in liver tissue could be ensured, and ROS generation could be suppressed. This also further inhibited the occurrence of pyroptosis and ensured that mitochondria were protected from gasdermin D-N(GSDMD-N) attack. Met-Exo inhibited the occurrence of pyroptosis through the above pathways, reducing the release of inflammatory factors such as IL-1β and IL-18, and alleviating inflammation. This provides a new therapeutic approach for clinical treatment of liver IRI and improving the success rate of liver transplantation.
    Keywords:  ADSCs-Exo; Hepatic ischemia reperfusion injury; Metformin; Mitochondrial quality control; Pyroptosis
    DOI:  https://doi.org/10.1016/j.intimp.2025.114437
  23. J Nanobiotechnology. 2025 Mar 12. 23(1): 208
    Macrophage-derived mitochondria-rich extracellular vesicles aggravate bone loss in periodontitis by disrupting the mitochondrial dynamics of BMSCs.
    Jiayin Yan, Tian Yang, Siyuan Ma, Danfeng Li, Cheng Hu, Jiali Tan.
       BACKGROUND: Periodontitis is the leading cause of tooth loss in adults due to progressive bone destruction, which is closely related to the dysfunction of bone mesenchymal stem cells (BMSCs). Existing evidence suggests that mitochondrial disorders are associated with periodontitis. However, whether mitochondrial dysregulation contributes to the osteogenic impairment of BMSCs and the underlying mechanisms remain unclear. Macrophages have been shown to communicate extensively with BMSCs in periodontitis. Recent studies have reported a novel manner of cellular communication in which mitochondria-rich extracellular vesicles（MEVs） transfer mitochondria from parent cells to recipient cells, playing a role in both physiological and pathological conditions. Therefore, we aimed to investigate the role of MEVs in orchestrating the crosstalk between macrophages and BMSCs in periodontitis to formulate management strategies for bone loss.
    RESULTS: Our results revealed that macrophages underwent significant mitochondrial dysfunction and inflammation in periodontitis and that MEVs derived from these macrophages played a role in alveolar bone destruction. Furthermore, cell imaging showed that inflammatory macrophages packaged numerous damaged mitochondria into MEVs, and the entry of these impaired mitochondria into BMSCs disrupted mitochondrial dynamics and hindered donut-shaped mitochondria formation, leading to osteogenic dysfunction. Proteomic analysis revealed that the proteins enriched in macrophage-derived MEVs were largely related to mitochondria and the formation and transport of vesicles. Additionally, we found that MEVs from macrophages significantly increased lipocalin 2 (LCN2) in BMSCs in periodontitis and that LCN2 perturbed mitochondrial morphological changes in BMSCs by inducing the degradation of OMA1 and accumulation of OPA1, resulting in osteogenesis impairment in BMSCs. Inhibition of LCN2 rescued the osteogenic dysfunction of BMSCs and alveolar bone loss in periodontitis.
    CONCLUSIONS: The transfer of mitochondria to BMSCs via MEVs exacerbates alveolar bone resorption through LCN2/OMA1/OPA1 signaling in periodontitis. Inhibition of LCN2 alleviates inflammatory bone loss, suggesting a promising therapeutic strategy for periodontitis.
    Keywords:  Bone mesenchymal stem cells; Lipocalin 2; Macrophages; Mitochondrial dynamics; Periodontitis
    DOI:  https://doi.org/10.1186/s12951-025-03178-4
  24. Reprod Biomed Online. 2024 Oct 19. pii: S1472-6483(24)00684-9. [Epub ahead of print]50(5): 104495
    Putrescine promotes maturation of oocytes from reproductively old mice via mitochondrial autophagy.
    Siyuan Xie, Yuyi Wang, Chenxi Zhao, Yugui Cui, Chunyan Gu, Wei Wu.
       RESEARCH QUESTION: Does putrescine (PUT) improve oocytes from reproductively old mice by promoting mitochondrial autophagy?
    DESIGN: Germinal vesicle stage cumulus-oocyte complexes (COCs) were obtained from 9-month old female C57BL/6N mice and divided into control, PUT and difluoromethylornithine, inhibitor (DFMO) groups. These germinal vesicle COCs underwent mouse in-vitro maturation (IVM) culture to observe the extrusion of the first polar body in each group. Using JC-1, dichloro-dihydro-fluorescein diacetate fluorescent probes and a confocal microscope, the mitochondrial membrane potential integrity and reactive oxygen species levels were measured in metaphase II stage oocytes. The expression and cellular localization of the p53 protein were examined by immunofluorescence. Reverse transcription quantitative polymerase chain reaction was used to detect the activation of mitochondrial autophagy pathways. The potential mechanisms through which PUT improves oocytes from reproductively old mice were explored by single-cell transcriptomic analysis. Autophagosomes, autolysosomes and mitochondria in different groups were directly observed using transmission electron microscopy.
    RESULTS: The addition of exogenous PUT can promote IVM of oocytes from reproductively old mice. It reduces oxidative stress by promoting the autophagy of damaged mitochondria, decreasing the levels of reactive oxygen species and increasing mitochondrial membrane potential. It affects the expression and subcellular localization of the p53 protein, and increases the expression of transcription factor EB, which may be the potential mechanism behind its promotion of autophagy.
    CONCLUSION: The target and regulatory pathway of PUT in oocytes was clarified. Putrescine is an effective small molecule compound with significant potential for non-invasively improving the fertility of elderly women.
    Keywords:  ageing; in-vitro maturation of oocytes; mitochondria; mitophagy; putrescine
    DOI:  https://doi.org/10.1016/j.rbmo.2024.104495
  25. Cell Death Dis. 2025 Mar 08. 16(1): 163
    Menin maintains lysosomal and mitochondrial homeostasis through epigenetic mechanisms in lung cancer.
    Jun-Bo Yuan, Gui-Xin Gu, Bang-Ming Jin, Qing Han, Bing-Hui Li, Li Zhang, Bin Xu, Xuan Zhu, Guang-Hui Jin.
      Lysosome-mediated autophagy (including mitophagy) is crucial for cell survival and homeostasis. Although the mechanisms of lysosome activation during stress are well recognized, the epigenetic regulation of lysosomal gene expression remains largely unexplored. Menin, encoded by the MEN1 gene, is a chromatin-related protein that is widely involved in gene transcription via histone modifications. Here, we report that menin regulates the transcription of specific lysosomal genes, such as CTSB, CTSE, and TFE3, through MLL-mediated H3K4me3 reprogramming, which is necessary for maintaining lysosomal homeostasis. Menin also directly controls the expression of SQSTM1 and MAP1LC3B to maintain autophagic flux in a manner independent of AMPK/mTORC1 pathways. Furthermore, loss of menin led to mitochondrial dysfunction, elevated levels of reactive oxygen species (ROS), and genome instability. In genetically engineered mouse models, Men1 deficiency resulted in severe lysosomal and mitochondrial dysfunction and an impaired self-clearance ability, which further led to metabolite accumulation. SP2509, a histone demethylase inhibitor, effectively reversed the downregulation of lysosomal and mitochondrial genes caused by loss of Men1. Our study confirms the previously unrecognized biological and mechanistic importance of menin-mediated H3K4me3 in maintaining organelle homeostasis.
    DOI:  https://doi.org/10.1038/s41419-025-07489-0
  26. J Dent Res. 2025 Mar 12. 220345251315723
    Role of Pink1 in Regulating Osteoclast Differentiation during Periodontitis.
    H Gou, T Wang, Y Chen, Y Zhou, J Li, Y Xu.
      Periodontitis has recently been recognized as an inflammatory disease caused by oxidative stress, with mitochondrial dysfunction being a key factor leading to oxidative stress. PTEN-induced kinase 1 (PINK1) is an essential protein for mitochondrial quality control, which protects cells from oxidative stress by inducing mitophagy to degrade damaged mitochondria, but its role in periodontitis has not been elucidated. This study aimed to explore the contribution and underlying mechanisms of Pink1 in regulating the differentiation and function of osteoclasts during periodontitis. Here we observed a significant downregulation of PINK1 expression in periodontitis-affected tissues. Then we constructed a periodontitis model in mice with fluorescently labeled mononuclear/macrophages, and the results showed that as the modeling time extended, the alveolar bone destruction gradually worsened and was accompanied by gradually decreased Pink1 expression in osteoclasts and a significantly increased osteoclast number. In vitro experiments further demonstrated a negative correlation between Pink1 and osteoclast differentiation. In addition, alveolar bone destruction in the Pink1 knockout mice was significantly more advanced than that in the littermate wild type mice after ligature-induced periodontitis and enhanced osteoclastogenesis and bone-resorptive capacity in vitro. RNA-sequencing analysis and in vitro validation revealed that the absence of Pink1 led to a decrease in oxidative phosphorylation levels and an enhancement of calcium-mediated signaling, specifically the calcineurin-NFATc1 pathway, via an intracellular calcium source. Further mechanistic studies found that the deficiency of Pink1 inhibited mitophagy but strengthened mitochondrial-endoplasmic reticulum coupling, which, by promoting the interaction of Mfn2-IP3R-VDAC1 proteins, increased the concentration of mitochondrial calcium ions, thereby triggering more active osteoclast differentiation. The aforementioned process can be reversed by the IP3R channel inhibitor Bcl-XL. These findings unveiled that Pink1 was involved in osteoclast differentiation by regulating mitochondrial calcium transport mediated by mitochondria-associated endoplasmic reticulum membranes, providing a new theoretical basis for the pathogenesis and treatment of periodontitis.
    Keywords:  alveolar bone loss; calcium signaling; mitochondria-associated endoplasmic reticulum membranes; mitophagy; osteoclastogenesis
    DOI:  https://doi.org/10.1177/00220345251315723
  27. Int J Mol Sci. 2025 Mar 03. pii: 2253. [Epub ahead of print]26(5):
    Poria cocos-Derived Exosome-like Nanovesicles Alleviate Metabolic Dysfunction-Associated Fatty Liver Disease by Promoting Mitophagy and Inhibiting NLRP3 Inflammasome Activation.
    Tao Wang, Jun Zhao, Qiu-Yi Li, Hui-Qiong Yang, Min Li, Rong Duan, Mei Zhang, Yan Qi, Jie Yu, Xing-Xin Yang.
      Metabolic dysfunction-associated fatty liver disease (MAFLD) affects approximately one-quarter of the world's adult population, and no effective therapeutic drugs are available. Poria cocos is a fungus used as a herb and food nutrient for centuries as well as for MAFLD treatment. Exosome-like nanovesicles have many pharmacological activities; however, studies on the effects of Poria cocos-derived exosome-like nanovesicles (PCELNs) on MAFLD are lacking. Therefore, our study aimed at identifying the effects and mechanism of action of PCELNs on MAFLD. PCELNs were isolated by ultracentrifugation and their morphology was characterized, such as particle size, zeta potential, protein distributions, as well as lipid and miRNA compositions. Then, the absorption and distribution of PCELNs were observed in vivo and in vitro. Finally, L02 cell steatosis model induced by fat emulsion and MAFLD mouse model induced by high-fat diet (HFD) were used to evaluate the effect and mechanism of PCELNs on MAFLD. PCELNs were membrane structured vesicles, with a particle size of 161.4 ± 1.7 nm, a zeta potential of -3.20 ± 0.37 mV, and contained a range of proteins, lipids, and miRNAs. PCELNs were absorbed by L02 cells and targeted the liver and spleen after intraperitoneal injection. PCELNs inhibited body weight gain and improved the index of heart, liver, spleen, and various fats, as well as decreased lipid accumulation and lipid level. They also protected mitochondrial ultrastructure and regulated oxidative stress and energy metabolism disorder. Furthermore, PCELNs increased PTEN induced kinase 1 (PINK1), E3 ubiquitin ligase (Parkin) and microtubule associated protein light chain-3 (LC3) protein expression in the liver, reduced oxidized mitochondrial DNA (Ox-mtDNA) content in mitochondria and cytoplasm of the liver, reduced nucleotide binding oligomerization domain-like receptor protein 3 (NLRP3), pro-cysteinyl aspartate specific proteinase-1 (caspase-1), cleared-caspase-1, and mature-interleukin-1β (IL-1β) protein expression in the liver, and reduced the levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-1β, and interleukin-18 (IL-18) in serum and liver. In conclusion, we demonstrated that PCELNs may alleviate HFD-induced MAFLD by promoting mitochondrial autophagy and inhibiting NLRP3 inflammasome activation.
    Keywords:  Poria cocos-derived exosome-like nanovesicles; fatty liver; high-fat diet; inflammasome; mitophagy
    DOI:  https://doi.org/10.3390/ijms26052253
  28. Int J Mol Sci. 2025 Mar 02. pii: 2241. [Epub ahead of print]26(5):
    Astaxanthin Alleviates Oxidative Stress in Mouse Preantral Follicles and Enhances Follicular Development Through the AMPK Signaling Pathway.
    Jiaqi He, Yue Zhong, Yaqiu Li, Sitong Liu, Xiaoyan Pan.
      This study investigates the effects of astaxanthin on oxidative stress, mitochondrial function, and follicular development in mouse preantral follicles, with a focus on the involvement of the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway. Astaxanthin (2.5 nM) significantly enhanced both the antrum formation (from 85.96% in the control group to 94.38% in the astaxanthin group) and maturation rates (from 79.15% to 85.12%) of oocytes (p < 0.05). From day 4 of in vitro culture, astaxanthin notably increased the area of follicle attachment (from 0.06 µm2 to 0.32 µm2) and the secretion of estradiol (from 32.10 ng/L to 49.73 ng/L) (p < 0.05). Additionally, it significantly decreased malondialdehyde content (from 80.54 μM to 62.65 μM) within the follicles while increasing the mRNA expression levels of glutathione and superoxide dismutase 1 (p < 0.05). Astaxanthin also reduced reactive oxygen species levels in oocytes (p < 0.05). Notably, astaxanthin enhanced the expression of p-AMPK and PGC-1α, which are key proteins for the AMPK pathway; NRF1 and TFAM, which are crucial for mitochondrial biogenesis; NRF2 and HO-1, which protect against oxidative stress; CO1, CO2, CO3, ATP6, ATP8, and TOM20, which are essential for electron transport chain activity and ATP synthesis; PINK1, Parkin, and LC3-II, which are involved in mitophagy; Bcl-2, which inhibits cell apoptosis; and StAR and P450scc, which promote estrogen synthesis (p < 0.05). Furthermore, astaxanthin improved mitochondrial membrane potential and decreased the expression of cleaved caspase 3, Bax, and P53, which promotes cell apoptosis (p < 0.05). However, these changes induced by astaxanthin were completely reversed by AMPK inhibitors, indicating the involvement of the AMPK pathway. Conclusively, astaxanthin enhances the in vitro development of follicles, alleviates oxidative stress in preantral follicles, and promotes mitochondrial function during in vitro culture, which may be mediated by the AMPK pathway.
    Keywords:  astaxanthin; in vitro culture; mitochondria; oxidative stress; preantral follicles
    DOI:  https://doi.org/10.3390/ijms26052241
  29. Curr Biol. 2025 Mar 06. pii: S0960-9822(25)00196-4. [Epub ahead of print]
    A new member of the dynamin superfamily modulates mitochondrial membrane branching in Trypanosoma brucei.
    Chloé Alexandra Morel, Corinne Asencio, David Moreira, Corinne Blancard, Bénédicte Salin, Etienne Gontier, Stéphane Duvezin-Caubet, Manuel Rojo, Frédéric Bringaud, Emmanuel Tetaud.
      Unlike most other eukaryotes, where mitochondria continuously fuse and divide, the mitochondrion of trypanosome cells forms a single and continuously interconnected network that divides only during cytokinesis. However, the machinery governing mitochondrial remodeling and interconnection of trypanosome mitochondrion remain largely unknown. We functionally characterize a new member of the dynamin superfamily protein (DSP) from T. brucei (TbMfnL), which shares similarity with a family of homologs present in various eukaryotic and prokaryotic phyla but not in opisthokonts like mammals and budding yeast. The sequence and domain organization of TbMfnL is distinct, and it is phylogenetically very distant from the yeast and mammalian dynamin-related proteins involved in mitochondrial fusion/fission dynamics, such as optic atrophy 1 (Opa1) and mitofusin (Mfn). TbMfnL localizes to the inner mitochondrial membrane facing the matrix and, upon overexpression, induces a strong increase in the interconnection and branching of mitochondrial filaments in a GTPase-dependent manner. TbMfnL is a component of a novel membrane remodeling machinery with an unprecedented matrix-side localization that is able to modulate the degree of inter-mitochondrial connections.
    Keywords:  dynamin-superfamily protein; evolution; membrane remodeling; mitochondrial dynamics; trypanosomes
    DOI:  https://doi.org/10.1016/j.cub.2025.02.033
  30. J Zhejiang Univ Sci B. 2025 Mar 01. pii: 1673-1581(2025)03-0227-13. [Epub ahead of print]26(3): 227-239
    Autophagy in skeletal muscle dysfunction of chronic obstructive pulmonary disease: implications, mechanisms, and perspectives.
    Xiaoyu Han, Peijun Li, Meiling Jiang, Yuanyuan Cao, Yingqi Wang, Linhong Jiang, Xiaodan Liu, Weibing Wu.
      Skeletal muscle dysfunction is a common extrapulmonary comorbidity of chronic obstructive pulmonary disease (COPD) and is associated with decreased quality-of-life and survival in patients. The autophagy lysosome pathway is one of the proteolytic systems that significantly affect skeletal muscle structure and function. Intriguingly, both promoting and inhibiting autophagy have been observed to improve COPD skeletal muscle dysfunction, yet the mechanism is unclear. This paper first reviewed the effects of macroautophagy and mitophagy on the structure and function of skeletal muscle in COPD, and then explored the mechanism of autophagy mediating the dysfunction of skeletal muscle in COPD. The results showed that macroautophagy- and mitophagy-related proteins were significantly increased in COPD skeletal muscle. Promoting macroautophagy in COPD improves myogenesis and replication capacity of muscle satellite cells, while inhibiting macroautophagy in COPD myotubes increases their diameters. Mitophagy helps to maintain mitochondrial homeostasis by removing impaired mitochondria in COPD. Autophagy is a promising target for improving COPD skeletal muscle dysfunction, and further research should be conducted to elucidate the specific mechanisms by which autophagy mediates COPD skeletal muscle dysfunction, with the aim of enhancing our understanding in this field.
    Keywords:  Autophagy; Chronic obstructive pulmonary disease; Mitochondria; Muscle satellite cell; Skeletal muscle dysfunction
    DOI:  https://doi.org/10.1631/jzus.B2300680
  31. Nat Commun. 2025 Mar 10. 16(1): 2353
    Mitochondria are positioned at dendritic branch induction sites, a process requiring rhotekin2 and syndapin I.
    Jessica Tröger, Regina Dahlhaus, Anne Bayrhammer, Dennis Koch, Michael M Kessels, Britta Qualmann.
      Proper neuronal development, function and survival critically rely on mitochondrial functions. Yet, how developing neurons ensure spatiotemporal distribution of mitochondria during expansion of their dendritic arbor remained unclear. We demonstrate the existence of effective mitochondrial positioning and tethering mechanisms during dendritic arborization. We identify rhotekin2 as outer mitochondrial membrane-associated protein that tethers mitochondria to dendritic branch induction sites. Rhotekin2-deficient neurons failed to correctly position mitochondria at these sites and also lacked the reduction in mitochondrial dynamics observed at wild-type nascent dendritic branch sites. Rhotekin2 hereby serves as important anchor for the plasma membrane-binding and membrane curvature-inducing F-BAR protein syndapin I (PACSIN1). Consistently, syndapin I loss-of-function phenocopied the rhotekin2 loss-of-function phenotype in mitochondrial positioning at dendritic branch induction sites. The finding that rhotekin2 deficiency impaired dendritic branch induction and that a syndapin binding-deficient rhotekin2 mutant failed to rescue this phenotype highlighted the physiological importance of rhotekin2 functions for neuronal network formation.
    DOI:  https://doi.org/10.1038/s41467-025-57399-0
  32. J Biol Chem. 2025 Mar 12. pii: S0021-9258(25)00252-2. [Epub ahead of print] 108403
    The E3 ubiquitin ligase RNF126 facilitates quality control of unimported mitochondrial membrane proteins.
    Di Liu, Xin-Yu Huo, Xiaoli Zhang, Zai-Rong Zhang.
      Pathological stress can lead to failure in the translocation of mitochondrial proteins, resulting in accumulation of unimported proteins within the cytosol and upregulation of proteasome for their quality control. Malfunction or delay in protein clearance causes dysregulation of mitochondrial protein homeostasis, cellular toxicity, and diseases. Ubiquilins (UBQLNs) are known to serve as chaperone which associates with unimported mitochondrial membrane protein precursors, and facilitates their proteasomal degradation. However, how UBQLN-engaged proteins are ubiquitinated and efficiently targeted to the proteasome are poorly understood. Here, using mitochondrial membrane protein ATP5G1 as a model substrate, we report that E3 ubiquitin ligase RNF126 interacts with substrate-engaged UBQLN1, thereby promoting ubiquitination and degradation of unimported proteins during mitochondrial stress. We find that UBQLN1's ubiquitin-associated domain (UBA) recruits RNF126 when its middle domain binds to unimported protein substrate. Recombinant RNF126 forms ternary complex with UBQLN1 and pATP5G1 in vitro and catalyzes ubiquitination of UBQLN1-bound ATP5G1. Without RNF126, proteasomal degradation of ATP5G1 was compromised. These results explain how RNF126 and ubiquilins interplay to ensure specific quality control of unimported mitochondrial membrane proteins under pathophysiological conditions.
    Keywords:  ATP synthase F(0) complex subunit C1; RNF126; Ubiquilin; cytosolic quality control; mitochondrial membrane protein degradation
    DOI:  https://doi.org/10.1016/j.jbc.2025.108403
  33. Cell Discov. 2025 Mar 11. 11(1): 22
    A positive feedback loop between SMAD3 and PINK1 in regulation of mitophagy.
    Mingzhu Tang, Dade Rong, Xiangzheng Gao, Guang Lu, Haimei Tang, Peng Wang, Ning-Yi Shao, Dajing Xia, Xin-Hua Feng, Wei-Feng He, Weilin Chen, Jia-Hong Lu, Wei Liu, Han-Ming Shen.
      PTEN-induced kinase-1 (PINK1) is a crucial player in selective clearance of damaged mitochondria via the autophagy-lysosome pathway, a process termed mitophagy. Previous studies on PINK1 mainly focused on its post-translational modifications, while the transcriptional regulation of PINK1 is much less understood. Herein, we reported a novel mechanism in control of PINK1 transcription by SMAD Family Member 3 (SMAD3), an essential component of the transforming growth factor beta (TGFβ)-SMAD signaling pathway. First, we observed that mitochondrial depolarization promotes PINK1 transcription, and SMAD3 is likely to be the nuclear transcription factor mediating PINK1 transcription. Intriguingly, SMAD3 positively transactivates PINK1 transcription independent of the canonical TGFβ signaling components, such as TGFβ-R1, SMAD2 or SMAD4. Second, we found that mitochondrial depolarization activates SMAD3 via PINK1-mediated phosphorylation of SMAD3 at serine 423/425. Therefore, PINK1 and SMAD3 constitute a positive feedforward loop in control of mitophagy. Finally, activation of PINK1 transcription by SMAD3 provides an important pro-survival signal, as depletion of SMAD3 sensitizes cells to cell death caused by mitochondrial stress. In summary, our findings identify a non-canonical function of SMAD3 as a nuclear transcriptional factor in regulation of PINK1 transcription and mitophagy and a positive feedback loop via PINK1-mediated SMAD3 phosphorylation and activation. Understanding this novel regulatory mechanism provides a deeper insight into the pathological function of PINK1 in the pathogenesis of neurodegenerative diseases such as Parkinson's disease.
    DOI:  https://doi.org/10.1038/s41421-025-00774-4
  34. Trends Cell Biol. 2025 Mar 07. pii: S0962-8924(25)00039-X. [Epub ahead of print]
    Quality control of mitochondrial nucleoids.
    Hao Liu, Haixia Zhuang, Du Feng.
      Mitochondrial nucleoids, organized complexes that house and protect mitochondrial DNA (mtDNA), are normally confined within the mitochondrial double-membrane system. Under cellular stress conditions, particularly oxidative and inflammatory stress, these nucleoids can undergo structural alterations that lead to their aberrant release into the cytoplasm. This mislocalization of nucleoid components, especially mtDNA, can trigger inflammatory responses and cell death pathways, highlighting the critical importance of nucleoid quality control mechanisms. The release of mitochondrial nucleoids occurs through specific membrane channels and transport pathways, fundamentally disrupting cellular homeostasis. Cells have evolved multiple clearance mechanisms to manage cytoplasmic nucleoids, including nuclease-mediated degradation, lysosomal elimination, and cellular excretion. This review examines the molecular mechanisms governing nucleoid quality control and explores the delicate balance between mitochondrial biology and cellular immunity. Our analysis provides insights that could inform therapeutic strategies for mtDNA-associated diseases and inflammatory disorders.
    Keywords:  mitochondria; mitophagy; mtDNA; nucleoid-phagy; nucleoids
    DOI:  https://doi.org/10.1016/j.tcb.2025.02.005
  35. Front Pharmacol. 2025 ;16 1472804
    Mitochondria-associated non-coding RNAs and their impact on drug resistance.
    Xingna An, Lina Sun, Huan Zheng, Yinghui Xiao, Weixia Sun, Dehai Yu.
      Drug resistance is a prevalent challenge in clinical disease treatment, often leading to disease relapse and poor prognosis. Therefore, it is crucial to gain a deeper understanding of the molecular mechanisms underlying drug resistance and to develop targeted strategies for its effective prevention and management. Mitochondria, as vital energy-producing organelles within cells, have been recognized as key regulators of drug sensitivity. Processes such as mitochondrial fission, fusion, mitophagy, changes in membrane potential, reactive oxygen species (ROS) accumulation, and oxidative phosphorylation (OXPHOS) are all linked to drug sensitivity. Non-coding RNAs (ncRNAs) enriched in mitochondria (mtncRNA), whether transcribed from mitochondrial DNA (mtDNA) or from the nucleus and transported to mitochondria, can regulate the transcription and translation of mtDNA, thus influencing mitochondrial function, including mitochondrial substance exchange and energy metabolism. This, in turn, directly or indirectly affects cellular sensitivity to drugs. This review summarizes the types of mtncRNAs associated with drug resistance and the molecular mechanisms regulating drug resistance. Our aim is to provide insights and strategies for overcoming drug resistance by modulating mtncRNAs.
    Keywords:  cancer; drug resistance; lncRNA; microRNA; mitochondria
    DOI:  https://doi.org/10.3389/fphar.2025.1472804
  36. Int J Mol Sci. 2025 Feb 27. pii: 2136. [Epub ahead of print]26(5):
    Molecular Mechanism of Aerobic Exercise Ameliorating Myocardial Mitochondrial Injury in Mice with Heart Failure.
    Hao Jia, Yinping Song, Yijie Hua, Kunzhe Li, Sujuan Li, Youhua Wang.
      To explore the molecular mechanism of aerobic exercise to improve heart failure and to provide a theoretical basis and experimental reference for the treatment of heart failure. Nine-week-old male mice were used to establish a left ventricular pressure overload-induced heart failure model by transverse aortic constriction (TAC). The mice were randomly divided into four groups: a sham group (SHAM), heart failure group (HF), heart failure + SKQ1 group (HS) and heart failure + aerobic exercise group (HE). The mice in the HE group were subjected to moderate-intensity aerobic exercise interventions. The mitochondrion-targeting antioxidant (SKQ1) contains the lipophilic cation TPP, which targets scavenging mitochondrial ROS. The HS group was subjected to SKQ1 (100 nmol/kg/d) interventions, which were initiated 1 week after the surgery, and the interventions lasted 8 weeks. Cardiac function was assessed by ultrasound, cardiomyocyte size by H&E and WGA staining, myocardial fibrosis by Masson's staining, and myocardial tissue oxidative stress and apoptosis by DHE and TUNEL fluorescence staining, respectively. Western blotting was used to detect the expression of mitochondrial quality control, inflammation, and apoptosis-related proteins. In the cellular level, an in vitro cellular model was established by isolating primary cardiomyocytes from neonatal mice (2-3 days) and intervening with Ang II (1 μM) to mimic heart failure. Oxidative stress and mitochondrial membrane potential were determined in the cardiomyocytes of each group by DHE and JC-1 staining, respectively. Myocardial fibrosis was increased significantly and cardiac function was reduced significantly in the heart failure mice. Aerobic exercise and SKQ1 intervention improved cardiac function and reduced myocardial hypertrophy and myocardial fibrosis in the heart failure mice significantly. Meanwhile, aerobic exercise and SKQ1 intervention reduced the number of DHE-positive particles (p < 0.01) and inhibited myocardial oxidative stress in the heart failure mice significantly. Aerobic exercise also reduced DRP1, Parkin, and BNIP3 protein expression (p < 0.05, p < 0.01), and increased OPA1 and PINK1 protein expression (p < 0.05, p < 0.01) significantly. Moreover, aerobic exercise and SKQ1 intervention decreased the number of TUNEL-positive particles and the expression of inflammation- and apoptosis-related proteins NLRP3, TXNIP, Caspase-1, IL-1β, BAX, BAK, and p53 significantly (p < 0.05, p < 0.01). In addition, the AMPK agonist AICAR and the mitochondria-targeted ROS scavenger (SKQ1) ameliorated AngII-induced mitochondrial fragmentation and decreased mitochondrial membrane potential in cardiomyocytes significantly. It was shown that inhibition of mitochondrial ROS by aerobic exercise, which in turn inhibits mitochondrial damage, improves mitochondrial quality control, and reduces myocardial inflammatory and apoptosis, may be an important molecular mechanism by which aerobic exercise exerts endogenous antioxidant protective effects to improve cardiac function.
    Keywords:  aerobic exercise; apoptosis; heart failure; inflammation; mitochondrial quality control; oxidative stress
    DOI:  https://doi.org/10.3390/ijms26052136
  37. Int J Mol Sci. 2025 Feb 27. pii: 2131. [Epub ahead of print]26(5):
    Cocaine Differentially Affects Mitochondrial Function Depending on Exposure Time.
    Sahar Wattad, Gabriella Bryant, Miriam Shmuel, Hannah L Smith, Rami Yaka, Claire Thornton.
      Cocaine use is a rising global concern, and increased use is accompanied by a significant increase in people entering treatment for the first time. However, there are still no complete therapies, and preclinical tools are necessary to both understand the action of cocaine and mitigate for its effects. Cocaine exposure rapidly impacts cellular and mitochondrial health, leading to oxidative stress. This study evaluated the effects of acute, repeated, and chronic cocaine exposure on C17.2 neural precursor cells. A single exposure to high concentrations of cocaine caused rapid cell death, with lower concentrations increasing markers of oxidative stress and mitochondrial dysfunction within 4 h of exposure. Alterations in cellular bioenergetics and mitochondrial fusion and fission gene expression (OPA1, DRP1) were also observed, which returned to baseline by 24 h after insult. Repeated exposure over 3 days reduced cell proliferation and spare mitochondrial respiratory capacity, suggesting compromised cellular resilience. Interestingly, chronic exposure over 4 weeks led to cellular adaptation and restoring mitochondrial bioenergetics and ATP production while mitigating for oxidative stress. These findings highlight the time-dependent cellular effects of cocaine, with initial toxicity and mitochondrial impairment transitioning to adaptive responses under chronic exposure.
    Keywords:  bioenergetics; cocaine; mitochondria; oxidative stress
    DOI:  https://doi.org/10.3390/ijms26052131
  38. Int J Mol Sci. 2025 Feb 23. pii: 1917. [Epub ahead of print]26(5):
    Mitochondrial Dysfunction in Cardiovascular Diseases.
    Han-Mo Yang.
      Mitochondrial dysfunction is increasingly recognized as a central contributor to the pathogenesis of cardiovascular diseases (CVDs), including heart failure, ischemic heart disease, hypertension, and cardiomyopathy. Mitochondria, known as the powerhouses of the cell, play a vital role in maintaining cardiac energy homeostasis, regulating reactive oxygen species (ROS) production and controlling cell death pathways. Dysregulated mitochondrial function results in impaired adenosine triphosphate (ATP) production, excessive ROS generation, and activation of apoptotic and necrotic pathways, collectively driving the progression of CVDs. This review provides a detailed examination of the molecular mechanisms underlying mitochondrial dysfunction in CVDs, including mutations in mitochondrial DNA (mtDNA), defects in oxidative phosphorylation (OXPHOS), and alterations in mitochondrial dynamics (fusion, fission, and mitophagy). Additionally, the role of mitochondrial dysfunction in specific cardiovascular conditions is explored, highlighting its impact on endothelial dysfunction, myocardial remodeling, and arrhythmias. Emerging therapeutic strategies targeting mitochondrial dysfunction, such as mitochondrial antioxidants, metabolic modulators, and gene therapy, are also discussed. By synthesizing recent advances in mitochondrial biology and cardiovascular research, this review aims to enhance understanding of the role of mitochondria in CVDs and identify potential therapeutic targets to improve cardiovascular outcomes.
    Keywords:  cardiovascular disease; mitochondrial dynamics; mitochondrial dysfunction; oxidative stress
    DOI:  https://doi.org/10.3390/ijms26051917
  39. Eur J Pharmacol. 2025 Mar 08. pii: S0014-2999(25)00231-6. [Epub ahead of print]997 177477
    Spermine alleviates myocardial cell aging by inhibiting mitochondrial oxidative stress damage.
    Jing Yang, Chun-Rui Zhang, Zi-Xuan Li, Yi-He Gao, Li Jiang, Jing Zhang, Peng-Yue Wang, Tong Liu.
       BACKGROUND: Myocardial aging, involving oxidative stress, mitochondrial dysfunction, and cellular senescence, is crucial to DOX - induced heart failure. DOX has dose - dependent cardiotoxicity. Sper a natural polyamine with antioxidant and anti - aging effects, remains unstudied in this context.
    AIM: This study hypothesizes Sper can alleviate DOX - induced heart failure by curbing myocardial aging and oxidative stress. It aims to assess Sper's protective impacts on cardiac function, pathology, oxidative stress, mitochondrial damage, and aging in a rat model, using captopril as a control.
    METHODS: 80 male Sprague Dawley rats were assigned to 8 groups: normal control, 150 mg/kg Sper, DOX, and DOX +10/50/100/150 mg/kg Sper, DOX +30 mg/kg captopril. DOX was given intraperitoneally at 15 mg/kg total dose, while Sper or captopril was administered daily via gavage for six weeks. Cardiac function was evaluated using echocardiography, and histopathological changes, oxidative stress markers, mitochondrial damage, and myocardial aging were assessed via H&E staining, immunofluorescence, Western blot, and electron microscopy.
    RESULTS: Sper boosted cardiac function in DOX - treated rats, upping EF and SV, and lessening cardiac tissue damage. It cut oxidative stress by reducing MDA levels and boosting SOD activity. Sper also eased mitochondrial damage by enhancing mitochondrial membrane potential and cutting mitochondrial fission proteins (Drp1 and Fis1). Plus, Sper held back myocardial aging by trimming β - galactosidase activity and downregulating p - P53 and p21 expression. At 150 mg/kg/day, Sper worked much like 30 mg/kg/day captopril.
    CONCLUSION: Sper effectively eased DOX - induced heart failure by targeting oxidative stress and aging, showing potential as an adjunct therapy for DOX - related cardiotoxicity. Future research should explore Sper's molecular mechanisms and clinical efficacy.
    Keywords:  Captopril; Doxorubicin; Mitochondrial damage; Myocardial aging; Oxidative stress; Spermine
    DOI:  https://doi.org/10.1016/j.ejphar.2025.177477
  40. Fitoterapia. 2025 Mar 05. pii: S0367-326X(25)00094-2. [Epub ahead of print]182 106469
    Novel Parkin agonists from Poria cocos against dyslipidemia.
    Xudong He, Yuxuan Tao, Chengzhu Song, Jinbiao He, Dihong Gong, Weimei Yu, Hui Wang, Jie Yu, Xingxin Yang.
      Parkin, a cytosolic E3 ubiquitin ligase, plays a crucial role in targeting damaged mitochondria. The dysfunction of Parkin has been implicated in various diseases, including dyslipidemia, highlighting the significance of regulating Parkin activity for therapeutic interventions. Poria cocos (PC), a traditional Chinese medicine with a history spanning over two thousand years, has shown promising effects in regulating dyslipidemia. However, the scarcity of Parkin ligands, particularly from PC, remains a significant drawback in the field. This study identified two novel Parkin ligands from PC using a Parkin-based centrifugal ultrafiltration/liquid chromatography/mass spectrometry method. Molecular docking analysis, molecular dynamic simulations, and autoubiquitination assays confirmed their abilities to activate Parkin. Furthermore, their mitophagy promotion and dyslipidemia mitigation capacities were validated in fat emulsion-induced human liver L02 cells and high-fat diet-induced mice. The results revealed that the two ligands, tumulosic acid and polyporenic acid C, from PC activated Parkin and further promoted mitophagy to alleviate dyslipidemia. These findings will contribute to developing new drugs and enhance our understanding of the PC anti-dyslipidemia mechanisms.
    Keywords:  Ligands; Lipids; Mitophagy; Parkin; Poria cocos; Ultrafiltration
    DOI:  https://doi.org/10.1016/j.fitote.2025.106469
  41. Geroscience. 2025 Mar 14.
    Topoisomerase inhibitor amonafide enhances defense responses to promote longevity in C. elegans.
    Iman Man Hu, Ana Serna, Stacia Everts, Lale Güngördü, Bauke V Schomakers, Ellen A A Nollen, Arwen W Gao, Riekelt H Houtkooper, Georges E Janssens.
      Aging is a major risk factor for disease, and developing effective pharmaceutical interventions to improve healthspan and promote longevity has become a high priority for society. One of the molecular pathways related to longevity in various model organisms revolves around lowering AKT1 levels. This prompted our in silico drug screen for small molecules capable of mimicking the transcriptional effects of AKT1 knockdown. We found topoisomerase inhibitors as a top candidate longevity-drug class. Evaluating multiple compounds from this class in C. elegans revealed that the topoisomerase inhibitor amonafide has the greatest benefit on healthspan and lifespan. Intriguingly, the longevity effect of amonafide was not solely dependent on DAF-16/FOXO, the canonical pathway for lifespan extension via AKT1 inhibition. We performed RNA-seq on amonafide-treated worms and revealed a more youthful transcriptional signature, including the activation of diverse molecular and cellular defense pathways. We found the mitochondrial unfolded protein response (UPRmt) regulator afts-1 to be crucial for both improved healthspan and extended lifespan upon amonafide treatment. Moreover, healthspan was partially dependent on the immune response transcription factor zip-2 and the integrated stress response transcription factor atf-4. We further examined the potential of amonafide in age-related disease. Treating a C. elegans model for Parkinson's disease with amonafide improved mobility. In conclusion, we identified amonafide as a novel geroprotector, which activates mitochondrial-, pathogen-, and xenobiotic-associated defense responses that-though more studies are needed-may serve as a candidate for Parkinson's disease therapy.
    Keywords:   Caenorhabditis elegans ; Longevity; Topoisomerase inhibitors
    DOI:  https://doi.org/10.1007/s11357-025-01599-5
  42. Int J Mol Sci. 2025 Feb 22. pii: 1895. [Epub ahead of print]26(5):
    Changes in Mitochondrial Transcriptional Rhythms and Depression-like Behavior in the Hippocampus of IL-33-Overexpressing Mice.
    Yang Li, Weinan Gao, Lin Jiao, Delu Dong, Liankun Sun, Yanan Liu, Luyan Shen.
      Neuroinflammation is involved in the development of depression and may induce depression-like behaviors by affecting metabolism through interactions with circadian rhythms. As the hub of metabolism, mitochondria are regulated by various types of metabolism and release signals that regulate cellular functions. In this study, we performed transcriptomic analysis of the hippocampus of IL-33-overexpressing mice to provide new ideas to explore the pathogenesis of inflammation-mediated depression at the transcriptional level. Male C57BL/6J mice and IL-33-overexpressing mice were subjected to behavioral tests. The hippocampus was extracted during the light or dark period, and differential gene expression analysis was conducted using RNA sequencing. Differential gene enrichment analysis was performed, as well as multilayered analysis of mitochondrial transcriptional rhythms by integrating the regulatory networks and Mito 3.0 database. The results were further verified using RT-qPCR. IL-33-overexpressing mice exhibited depressive behaviors associated with rhythmic disorders and shortened circadian cycles. Differential KEGG (Kyoto Encyclopedia of Genes and Genomes) enrichment analysis showed that the top 20 pathways with the lowest p-values included mood-related, immune-related, and circadian rhythm-related pathways. Differential gene GO (Gene Ontology) enrichment analysis showed that 20 of the top 30 pathways with the lowest p-values were related to metabolism. Transcriptome data from IL-33-overexpressing mice showed that the mitochondrial-encoded subunit of the oxidative respiratory complex showed predominantly increased expression during the light period. Metabolic disorders and disrupted mitochondrial transcriptional rhythm were also observed. Weighted gene correlation network analysis showed that the circadian cycle is associated with depression-like behavior disorders. Network analysis showed that circadian-related genes were enriched in mitochondrial pathways related to metabolism and oxidative phosphorylation. Multilayer analysis of mitochondrial transcriptional rhythms using the mitochondrial database Mito 3.0 revealed that mitochondrial dynamics and surveillance pathways were the most enriched. The depressive behavior in mice caused by long-term IL-33 stimulation may be related to changes in the transcriptional rhythms of metabolism-related genes and the interaction between mitochondria and clock genes. This suggests that mitochondrial transcriptional rhythms are central to the pathogenesis of microinflammation-induced depression, further supporting the potential of mitochondria as a target for the prevention and treatment of depression.
    Keywords:  RNA-seq; circadian rhythms; depression-like behavior; mitochondria; neuroinflammation
    DOI:  https://doi.org/10.3390/ijms26051895
  43. Discov Oncol. 2025 Mar 08. 16(1): 283
    Mitochondrial autophagy-related lncRNAs as prognostic biomarkers and therapeutic targets in gastric adenocarcinoma.
    Rongbo Han, Jinxin Wei, Benxin Zhao, Rongchang Zhao.
      Understanding the tumor microenvironment (TME) and the role of long noncoding RNAs (lncRNAs) in gastric adenocarcinoma (GA) is crucial, as these elements not only influence tumor progression but also provide opportunities for more precise prognostic assessments and tailored therapeutic interventions. This study identified mitochondrial autophagy-related lncRNAs, constructed a robust prognostic risk model, and explored the relationship between immune microenvironment characteristics and therapeutic responses. The model's performance was evaluated using ROC curves, Kaplan-Meier survival analysis, and nomograms. Our results demonstrate that the model outperforms traditional clinical factors, such as age and stage, in predicting patient outcomes. Immune cell analysis revealed distinct correlations with risk scores, and several immune checkpoint genes exhibited differential expression between risk groups. Drug sensitivity analysis suggested that low-risk patients could benefit more from ICIs, Oxaliplatin, Irinotecan, Afatinib, and Dabrafenib, while high-risk patients showed higher sensitivity to IGF1R3801, JQI, WZ4003 and NU7441. The identified lncRNA-based risk model provides a reliable prognostic tool for GA patients and highlights distinct immune microenvironment profiles that may influence treatment responses. These findings contribute to developing personalized therapeutic strategies targeting lncRNAs and the TME in GA.
    Keywords:  Gastric adenocarcinoma; Mitophagy; Prognostic model; lncRNAs
    DOI:  https://doi.org/10.1007/s12672-025-02042-z
  44. Circ Heart Fail. 2025 Mar 11. e011867
    Combined Loss of Obsc and Obsl1 in Murine Hearts Results in Diastolic Dysfunction, Altered Metabolism, and Deregulated Mitophagy.
    Kyohei Fujita, Patrick Desmond, Jordan Blondelle, Matúš Soták, Meenu Rohini Rajan, Madison Clark, Éric Estève, Yunghang Chan, Yusu Gu, Virginia Actis Dato, Valeria Marrocco, Nancy D Dalton, Majid Ghassemian, Aryanne Do, Matthew Klos, Kirk L Peterson, Farah Sheikh, Yoshitake Cho, Emma Börgeson, Stephan Lange.
       BACKGROUND: Muscle proteins of the obscurin protein family play important roles in sarcomere organization and sarcoplasmic reticulum and T-tubule architecture and function. However, their precise molecular functions and redundancies between protein family members as well as their involvement in cardiac diseases remain to be fully understood.
    METHODS: To investigate the functional roles of Obsc (obscurin) and its close homolog Obsl1 (obscurin-like 1) in the heart, we generated and analyzed knockout mice for Obsc, Obsl1, as well as Obsc/Obsl1 double knockouts.
    RESULTS: We show that double-knockout mice are viable but show postnatal deficits in cardiac muscle sarcoplasmic reticulum and mitochondrial architecture and function at the microscopic, biochemical, and cellular levels. Altered sarcoplasmic reticulum structure resulted in perturbed calcium cycling, whereas mitochondrial ultrastructure deficits were linked to decreased levels of Chchd3 (coiled-coil-helix-coiled-coil-helix domain containing 3), a Micos (mitochondrial contact site and cristae organizing system) complex protein. Hearts of double-knockout mice also show altered levels of Atg4 proteins, novel Obsl1 interactors, resulting in abnormal mitophagy, and increased unfolded protein response. At the physiological level, loss of obscurin and Obsl1 resulted in a profound delay of cardiac relaxation, associated with metabolic signs of heart failure.
    CONCLUSIONS: Taken together, our data suggest that Obsc and Obsl1 play crucial roles in cardiac sarcoplasmic reticulum structure, calcium cycling, mitochondrial function, turnover, and metabolism.
    Keywords:  autophagy; heart failure; mice; mitophagy; muscle proteins
    DOI:  https://doi.org/10.1161/CIRCHEARTFAILURE.124.011867
  45. Phytomedicine. 2025 Mar 07. pii: S0944-7113(25)00260-0. [Epub ahead of print]140 156620
    Mitochondrial dynamics and metabolism in macrophages for cardiovascular disease: A review.
    Yi-Lang Zhong, Chen-Qin Xu, Ji Li, Zhi-Qiang Liang, Miao-Miao Wang, Chao Ma, Cheng-Lin Jia, Yong-Bing Cao, Jian Chen.
       BACKGROUND: Mitochondria regulate macrophage function, affecting cardiovascular diseases like atherosclerosis and heart failure. Their dynamics interact with macrophage cell death mechanisms, including apoptosis and necroptosis.
    PURPOSE: This review explores how mitochondrial dynamics and metabolism influence macrophage inflammation and cell death in CVDs, highlighting therapeutic targets for enhancing macrophage resilience and reducing CVD pathology, while examining molecular pathways and pharmacological agents involved.
    STUDY DESIGN: This is a narrative review that integrates findings from various studies on mitochondrial dynamics and metabolism in macrophages, their interactions with the endoplasmic reticulum (ER) and Golgi apparatus, and their implications for CVDs. The review also considers the potential therapeutic effects of pharmacological agents on these pathways.
    METHODS: The review utilizes a comprehensive literature search to identify relevant studies on mitochondrial dynamics and metabolism in macrophages, their role in CVDs, and the effects of pharmacological agents on these pathways. The selected studies are analyzed and synthesized to provide insights into the complex relationships between mitochondria, the ER, and Golgi apparatus, and their implications for macrophage function and fate.
    RESULTS: The review reveals that mitochondrial metabolism intertwines with cellular architecture and function, particularly through its intricate interactions with the ER and Golgi apparatus. Mitochondrial-associated membranes (MAMs) facilitate Ca2+ transfer from the ER to mitochondria, maintaining mitochondrial homeostasis during ER stress. The Golgi apparatus transports proteins crucial for inflammatory signaling, contributing to immune responses. Inflammation-induced metabolic reprogramming in macrophages, characterized by a shift from oxidative phosphorylation to glycolysis, underscores the multifaceted role of mitochondrial metabolism in regulating immune cell polarization and inflammatory outcomes. Notably, mitochondrial dysfunction, marked by heightened reactive oxygen species generation, fuels inflammatory cascades and promotes cell death, exacerbating CVD pathology. However, pharmacological agents such as Metformin, Nitazoxanide, and Galanin emerge as potential therapeutic modulators of these pathways, offering avenues for mitigating CVD progression.
    CONCLUSION: This review highlights mitochondrial dynamics and metabolism in macrophage inflammation and cell death in CVDs, suggesting therapeutic targets to improve macrophage resilience and reduce pathology, with new pharmacological agents offering treatment opportunities.
    Keywords:  Cardiovascular diseases; Durgs; Macrophages; Mitochondria
    DOI:  https://doi.org/10.1016/j.phymed.2025.156620
  46. Front Aging Neurosci. 2025 ;17 1511272
    Parkin characteristics and blood biomarkers of Parkinson's disease in WPBLC study.
    Haijun He, Xi Xiong, Yi Zheng, Jialong Hou, Tao Jiang, Weiwei Quan, Jiani Huang, Jiaxue Xu, Keke Chen, Jingjing Qian, Jinlai Cai, Yao Lu, Mengjia Lian, Chenglong Xie, Ji Luo.
       Background: The exact mechanisms of PD are unclear, but Parkin-mediated mitophagy dysfunction is believed to play a key role. We investigated whether blood levels of Parkin and other biomarkers are linked to the risk of developing PD.
    Methods: Baseline blood measures of Parkin and other biomarkers, including Homocysteine, carcinoembryonic antigen, Urea, total proteins, total cholesterol, creatine kinase, and albumin, were collected from 197 clinically diagnosed Parkinson's disease participants and 107 age-matched healthy controls in Wenzhou Parkinson's Biomarkers and Living Characteristics study. We conducted bioinformatics analysis using three datasets from the GEO database: GSE90514 (Cohort 1: PD = 4, HC = 4), GSE7621 (Cohort 2: PD = 16, HC = 9), and GSE205450 (Cohort 3: PD = 69, HC = 81).
    Results: Using a bioinformatic approach, we identified dysregulated biological processes in PD patients with PRKN mutations. Compared to controls, significant abnormalities were observed in blood levels of Parkin, Hcy, total proteins, urea, albumin, and CEA in PD patients. A model incorporating Parkin, Hcy, total proteins, and urea effectively distinguished PD from healthy controls, achieving a higher accuracy (AUC 0.841) than other biomarker combinations. Gene set enrichment analysis suggested that pathways such as PINK1-Parkin-mediated mitophagy, urea cycle, cysteine degradation, and riboflavin metabolism may be involved in PRKN mutation. Additionally, the link between Parkin and PD was partially mediated by CEA and albumin, not by Hcy, total proteins, or urea.
    Conclusion: Our findings indicate that blood Parkin levels may be a minimally invasive biomarker for PD diagnosis. The model, which included Parkin, Hcy, total proteins, and urea, effectively distinguished PD from HC with greater accuracy.
    Keywords:  Parkin; Parkinson’s diseaseas; bioinformatics; blood biomarkers; mitophagy
    DOI:  https://doi.org/10.3389/fnagi.2025.1511272
  47. Stem Cell Res Ther. 2025 Mar 11. 16(1): 129
    Enhanced mitochondrial function and delivery from adipose-derived stem cell spheres via the EZH2-H3K27me3-PPARγ pathway for advanced therapy.
    Ming-Min Chang, Dinh Toi Chu, Sheng-Che Lin, Jung-Shun Lee, Thuy Duong Vu, Hue Thi Vu, Thamil Selvee Ramasamy, Shau-Ping Lin, Chia-Ching Wu.
       BACKGROUND: Microenvironmental alterations induce significant genetic and epigenetic changes in stem cells. Mitochondria, essential for regenerative capabilities, provide the necessary energy for stem cell function. However, the specific roles of histone modifications and mitochondrial dynamics in human adipose-derived stem cells (ASCs) during morphological transformations remain poorly understood. In this study, we aim to elucidate the mechanisms by which ASC sphere formation enhances mitochondrial function, delivery, and rescue efficiency.
    METHODS: ASCs were cultured on chitosan nano-deposited surfaces to form 3D spheres. Mitochondrial activity and ATP production were assessed using MitoTracker staining, Seahorse XF analysis, and ATP luminescence assays. Single-cell RNA sequencing, followed by Ingenuity Pathway Analysis (IPA), was conducted to uncover key regulatory pathways, which were validated through molecular techniques. Pathway involvement was confirmed using epigenetic inhibitors or PPARγ-modulating drugs. Mitochondrial structural integrity and delivery efficiency were evaluated after isolation.
    RESULTS: Chitosan-induced ASC spheres exhibited unique compact mitochondrial morphology, characterized by condensed cristae, enhanced mitochondrial activity, and increased ATP production through oxidative phosphorylation. High expressions of mitochondrial complex I genes and elevated levels of mitochondrial complex proteins were observed without an increase in reactive oxygen species (ROS). Epigenetic modification of H3K27me3 and PPARγ involvement were discovered and confirmed by inhibiting H3K27me3 with the specific EZH2 inhibitor GSK126 and by adding the PPARγ agonist Rosiglitazone (RSG). Isolated mitochondria from ASC spheres showed improved structural stability and delivery efficiency, suppressed the of inflammatory cytokines in LPS- and TNFα-induced inflamed cells, and rescued cells from damage, thereby enhancing function and promoting recovery.
    CONCLUSION: Enhancing mitochondrial ATP production via the EZH2-H3K27me3-PPARγ pathway offers an alternative strategy to conventional cell-based therapies. High-functional mitochondria and delivery efficiency show significant potential for regenerative medicine applications.
    Keywords:  3D spheroid culture; Adipose-derived stem cells; Chitosan nano-deposition; EZH2-H3K27me3-PPARγ pathway; Enhanced mitochondrial function; Mitochondrial therapy
    DOI:  https://doi.org/10.1186/s13287-025-04164-1
  48. Int J Psychiatry Clin Pract. 2025 Mar 14. 1-7
    Exploring the interplay between mitochondrial dysfunction, early life adversity and bipolar disorder.
    Cheng Ying Wu, Cheng-Chen Chang, Ta-Tsung Lin, Chin-San Liu, Po See Chen.
       OBJECTIVE: Mitochondria are essential for energy production and reactive oxygen species (ROS) generation, with changes in ROS levels or energy demands affecting mitochondrial DNA (mtDNA) copy numbers, indicating mitochondrial function. Early life adversity (ELA) affects mitochondrial dynamics, influencing long-term health. Both ELA and mitochondrial abnormalities have been independently associated with bipolar disorder (BD). This study aims to explore the complex interplay between mitochondrial dysfunction, ELA, and BD.
    METHODS: The study included 60 participants diagnosed with BD and 66 healthy controls (HCs). Data were collected using the Childhood Trauma Questionnaire (CTQ), and leukocyte mtDNA copy number (MCN) was determined from blood samples.
    RESULTS: The results indicated the CTQ sum scores were significantly higher in the BD group, reflecting greater exposure to ELA. In HCs, a marginally significant nonlinear relationship between the square of the CTQ sum score and MCN was found. Further analysis demonstrated a significant interaction between ELA and BD on MCN (p = 0.023), highlighting a critical connection between ELA and mitochondrial dysfunction in BD and reinforcing its biological underpinnings.
    CONCLUSIONS: Future treatments for BD might target mitochondrial dysfunctions related to chronic stress, with potential pharmaceuticals designed to address these issues and mitigate the negative effects of chronic stress.
    Keywords:  Bipolar disorder; childhood trauma; early life adversity; mitochondrial DNA copy number
    DOI:  https://doi.org/10.1080/13651501.2025.2476505
  49. Bone Joint Res. 2025 Mar 14. 14(3): 245-258
    Orientin alleviates chondrocyte senescence and osteoarthritis by inhibiting PI3K/AKT pathway.
    Haitao Chen, Siyi Liu, Junwei Xing, Yinxian Wen, Liaobin Chen.
       Aims: Osteoarthritis (OA) is a common degenerative disease that leads to pain, disability, and reduced quality of life. Orientin exhibits considerable anti-inflammatory and antioxidative properties, but its role in chondrocyte senescence and OA progress has not yet been fully characterized. The aim of this study was to evaluate the protective effects of orientin on OA.
    Methods: The role of orientin in extracellular matrix (ECM) degradation, mitochondrial homeostasis, and chondrocyte senescence was investigated in vitro. Meanwhile, we used molecular docking, small molecular inhibitors, and RNA interference to screen and validate candidate proteins regulated by orientin. In an anterior cruciate ligament transection (ACLT) rat model, radiograph, micro-CT, and various histological examinations were applied to evaluate the therapeutic effects of orientin on OA.
    Results: We found that orientin inhibited ECM degradation and senescence-associated secretory phenotype (SASP) factor expression in interleukin (IL)-1β-treated chondrocytes. Additionally, orientin reduced the level of reactive oxygen species (ROS) and improved mitochondrial homeostasis. Furthermore, orientin suppressed IL-1β-induced activation of the nuclear factor kappa B (NF-κB) signalling pathway. We also found that orientin bound to phosphoinositide 3-kinase (PI3K) and inhibited NF-κB cascades via the PI3K/AKT pathway. In vivo, we demonstrated that orientin improved cartilage wear and reduced synovial inflammation and osteophyte in an ACLT rat model.
    Conclusion: Orientin improves mitochondrial homeostasis, inhibits chondrocyte senescence, and alleviates OA progress via the PI3K/AKT/NF-κB axis, which suggests that orientin is a potential effective therapeutic agent for OA.
    DOI:  https://doi.org/10.1302/2046-3758.143.BJR-2023-0383.R2
  50. Vet Microbiol. 2025 Mar 05. pii: S0378-1135(25)00089-6. [Epub ahead of print]304 110454
    The depletion of TFAM and p-β-catenin(S552) in mitochondria in response to BoAHV-1 productive infection leads to decreased mitochondrial biogenesis.
    Jiayu Lin, Xiaotian Fu, Xuan Li, Xiuyan Ding, Shitao Li, Filomena Fiorito, Liqian Zhu.
      Varicellovirus bovinealpha (BoAHV) types 1(BoAHV-1) is one of the most significant viruses affecting cattle, causing substantial economic losses in the global cattle industry. Virus productive infection in cell cultures leads to mitochondrial dysfunction, resulting in the overproduction of reactive oxygen species (ROS), which act as inflammatory mediators and exert cytotoxic effects. But the underlying mechanisms remain poorly understood. Mitochondrial transcription factor A (TFAM) is a critical transcriptional activator of the mitochondrial DNA and plays a vital role in mitochondrial biogenesis. In this study, we report that virus acute infection in calves (at 4 days post-infection) increases TFAM protein expression and its accumulation in the peri-nuclear region in a subset of trigeminal ganglia (TG) neurons. Similarly, virus productive infection at later stages in MDBK cells also leads to increased TFAM protein expression and its accumulation in the nucleus. Using TFAM-specific siRNAs, we revealed that TFAM plays a significant role in BoAHV-1 productive infection. Consistent with decreased mitochondrial biogenesis, TFAM protein accumulation in mitochondria was significantly reduced following viral infection, which is corroborated by the reduced accumulation of TOM70 and Tim44 proteins in mitochondria. These proteins are key components of the mitochondrial membrane transport system that facilitates the translocation of TFAM into mitochondria. Interestingly, we found that a subset of β-catenin resides in mitochondria, and viral infection decreases the accumulation of transcriptionally active β-catenin, p-β-catenin(S552), in mitochondria. This may contribute to decreased mitochondrial biogenesis, as the β-catenin-specific inhibitor iCRT14 reduces the protein expression of Cytb, a key regulator of mitochondrial biosynthesis. Collectively, we suggest that the depletion of both TFAM and p-β-catenin(S552) in mitochondria may contribute to the mitochondrial dysfunction induced by BoAHV-1 productive infection.
    Keywords:  BoAHV-1; Mitochondria dysfunction; TFAM
    DOI:  https://doi.org/10.1016/j.vetmic.2025.110454
  51. Phytomedicine. 2025 Feb 26. pii: S0944-7113(25)00220-X. [Epub ahead of print]140 156580
    Intestinal 8 gingerol attenuates TBI-induced neuroinflammation by inhibiting microglia NLRP3 inflammasome activation in a PINK1/Parkin-dependent manner.
    Xuheng Tang, Lin Huang, Weiquan Ma, Mingxin Huang, Zhenhua Zeng, Yiqin Yu, Na Qin, Fei Zhou, Fen Li, Shenhai Gong, Hong Yang.
       BACKGROUND: traumatic brain injury (TBI) is irreversible brain damage, leading to inflammation and cognitive dysfunction. Microglia involved in the inflammatory response after TBI. The gut microbiota, known as the body's "second brain," regulates neurogenesis and immune responses, but its precise role in regulating TBI remains unclear.
    PURPOSE: to investigate the effect of gut microbiota and metabolites disorder on TBI injury.
    STUDY DESIGN: 16SrRNA and metabolomics compared gut microbiota and metabolites in sham group and TBI group, then proved that the differential metabolite 8-gingerol (8G) alleviated the microglia neuroinflammatory response after TBI.
    METHODS: fecal microbiota transplantation explored the role of dysbiosis in TBI. LC/MS detected the content of 8-gingerol in cecum, blood, and brain. HE, Nissl, Tunel staining and mNSS score evaluated brain injury. Western blot and immunofluorescence detected the expression of inflammasome-related proteins and mitophagy-related proteins in brain tissue and BV2 cells. RNA sequencing analyzed the molecular mechanism of 8-gingerol.
    RESULT: rats transplanted with TBI feces had worse brain injury and neurological deficits than those with normal feces. 16SrRNA and metabolomics found that TBI caused dysbiosis and decreased 8-gingerol level, leading to severe neuroinflammation. Mechanistically, 8-gingerol inhibited NLRP3 inflammasome by promoting PINK1-Parkin mediated mitophagy in microglia. Inhibition of Parkin, through either small interfering RNA or the inhibitor 3MA reversed the inhibitory effect of 8-gingerol on NLRP3 by blocking mitophagy. BV2 cells transcriptome showed that 8-gingerol significantly increased the expression of autophagy factor Wipi1, and small interfering RNA of Wipi1 abolished the effect of 8-gingerol on promoting mitophagy and the inhibitory effect on NLRP3.
    CONCLUSION: our findings shed light on the pivotal role of gut microbes in TBI, and identify 8 gingerol as an important anti-inflammatory compound during TBI.
    Keywords:  8 gingerol; Gut microbiota; Microglia; Mitophagy; NLRP3 inflammasome; Traumatic brain injury
    DOI:  https://doi.org/10.1016/j.phymed.2025.156580
  52. J Asthma. 2025 Mar 11. 1-16
    Global research trends and hotspots in mitochondria and asthma: A bibliometric and visualized analysis.
    Leming Huang, Chuyan Wu, Feng Jiang, Xinxin Bu.
       BACKGROUND: Asthma is a complex chronic respiratory disease marked by inflammation, bronchoconstriction, and hyperresponsiveness. Mitochondria, key regulators of energy production, ROS, and apoptosis, are increasingly recognized as crucial in asthma pathophysiology. However, a comprehensive analysis of global research trends in this area is lacking. This study aims to perform a bibliometric and visualized analysis of global research on mitochondria and asthma.
    METHODS: A bibliometric analysis was conducted using Web of Science Core Collection data from 2004 to June 2024. CiteSpace and VOSviewer software were used to examine co-authorship, co-citation, keyword co-occurrence, and thematic clusters.
    RESULTS: A total of 669 publications were identified. The number of studies grew significantly after 2015, with the United States, China, and the UK leading research. Co-citation and keyword analyses revealed mitochondrial dysfunction, oxidative stress, apoptosis, and airway inflammation as major themes. Emerging areas of interest include mitochondrial biogenesis, NLRP3 inflammasome, and innate immunity. Collaboration among institutions like Harvard University and the Council of Scientific & Industrial Research was significant, and journals such as European Respiratory Journal and Nature Medicine were highly influential.
    CONCLUSION: This study provides an overview of research on mitochondria and asthma, highlighting emerging trends such as mitochondrial biogenesis and immune pathways. Future research should focus on these areas and the role of environmental triggers in mitochondrial dysfunction, offering valuable insights for therapeutic strategies targeting mitochondria in asthma.
    Keywords:  Asthma; Bibliometric analysis; Co-citation network; Mitochondria; Mitochondrial dysfunction
    DOI:  https://doi.org/10.1080/02770903.2025.2478524
  53. Science. 2025 Mar 13. eadu6445
    Structure of human PINK1 at a mitochondrial TOM-VDAC array.
    Sylvie Callegari, Nicholas S Kirk, Zhong Yan Gan, Toby Dite, Simon A Cobbold, Andrew Leis, Laura F Dagley, Alisa Glukhova, David Komander.
      Mutations in the ubiquitin kinase PINK1 cause early onset Parkinson's Disease, but how PINK1 is stabilized at depolarized mitochondrial translocase complexes has remained poorly understood. We determined a 3.1-Å resolution cryo-electron microscopy structure of dimeric human PINK1 stabilized at an endogenous array of mitochondrial TOM and VDAC complexes. Symmetric arrangement of two TOM core complexes around a central VDAC2 dimer is facilitated by TOM5 and TOM20, both of which also bind PINK1 kinase C-lobes. PINK1 enters mitochondria through the proximal TOM40 barrel of the TOM core complex, guided by TOM7 and TOM22. Our structure explains how human PINK1 is stabilized at the TOM complex and regulated by oxidation, uncovers a previously unknown TOM-VDAC assembly, and reveals how a physiological substrate traverses TOM40 during translocation.
    DOI:  https://doi.org/10.1126/science.adu6445
  54. Yi Chuan. 2025 Mar;47(3): 342-350
    Molecular mechanism of Mfn2 alleviating endoplasmic reticulum stress and inhibiting apoptosis of sheep follicular granulosa cells.
    Gulimire Abudureyimu, Ying Chen, Shuhong Tang, Hong Dong, Liqin Wang, Yangsheng Wu, Juncheng Huang, Jiapeng Lin.
      Follicle development is a crucial step in mammalian reproductive processes, the specific role of Mfn2 in regulating mitochondrial function and endoplasmic reticulum stress in this process is still unclear, this study aimed to investigate the role of Mfn2 in the follicular development of adult sheep. Large, medium, and small follicles were collected, and granulosa cells (GCs) were isolated from large follicles. The expression levels of Mfn2 in different follicles were detected using qRT-PCR and Western blot, and the localization of Mfn2 in follicles was determined through immunofluorescence. Additionally, the expression levels of the mitochondrial autophagy-related protein Pink1, endoplasmic reticulum stress proteins (Grp78, Perk, Chop), and apoptosis-related proteins (Bcl2 and BAX) were detected. Furthermore, siRNAs were transfected into GCs to knock down Mfn2 expression, and changes in intracellular Ca2+ accumulation and mitochondrial membrane potential were evaluated, along with the expression levels of the aforementioned proteins. The results showed that Mfn2 expression was significantly higher in large follicles compared to small follicles and was primarily localized in GCs. Compared to small follicles, the expression levels of Pink1, Grp78, Perk, Chop, and BAX were significantly lower in large follicles, while Bcl2 expression was significantly increased (P<0.01). After Mfn2 knockdown, intracellular Ca2+ levels and mitochondrial membrane potential were significantly reduced, while the expression levels of Pink1, Grp78, Perk, Chop, and BAX were significantly increased, and Bcl2 expression was significantly decreased (P<0.01). Mfn2 may influence cell apoptosis during sheep follicular development by regulating mitochondrial function and endoplasmic reticulum stress.
    Keywords:  Mfn2; cell apoptosis; endoplasmic reticulum stress; granulosa cells; sheep follicles
    DOI:  https://doi.org/10.16288/j.yczz.24-247
  55. Cell Commun Signal. 2025 Mar 10. 23(1): 130
    SLC25A35 enhances fatty acid oxidation and mitochondrial biogenesis to promote the carcinogenesis and progression of hepatocellular carcinoma by upregulating PGC-1α.
    Heng-Chao Yu, Lu Bai, Liang Jin, Yu-Jia Zhang, Zi-Han Xi, De-Sheng Wang.
      Mitochondria dysfunction has been closely linked to a wide spectrum of human cancers, whereas the molecular basis has yet to be fully understood. SLC25A35 belongs to the SLC25 family of mitochondrial carrier proteins. However, the role of SLC25A35 in mitochondrial metabolism reprogramming, development and progression in human cancers remains unclear. Here, we found that SLC25A35 markedly reprogramed mitochondrial metabolism, characterized by increased oxygen consumption rate and ATP production and decreased ROS level, via enhancing fatty acid oxidation (FAO). Meanwhile, SLC25A35 also enhanced mitochondrial biogenesis characterized by increased mitochondrial mass and DNA content. Mechanistic studies revealed that SLC25A35 facilitated FAO and mitochondrial biogenesis through upregulating peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) via increasing acetyl-CoA-mediated acetylation of PGC-1α. Clinically, SLC25A35 was highly expressed in HCC and correlated with adverse patients' survival. Functionally, SLC25A35 promoted the proliferation and metastasis of HCC cells both in vitro and in vivo, as well as the carcinogenesis in a DEN-induced HCC mice model. Moreover, we found that SLC25A35 upregulation is caused, at least in part, by decreased miR-663a in HCC cells. Together, our results suggest a crucial oncogenic role of SLC25A35 in HCC by reprogramming mitochondrial metabolism and suggest SLC25A35 as a potential therapeutic target for the treatment of HCC.
    Keywords:  Fatty acid oxidation; HCC; Metastasis; Mitochondrial biogenesis; Proliferation; SLC25A35
    DOI:  https://doi.org/10.1186/s12964-025-02109-y
  56. J Ethnopharmacol. 2025 Mar 06. pii: S0378-8741(25)00272-7. [Epub ahead of print] 119588
    Mitochondria as therapeutic targets for Natural Products in the treatment of Cardiovascular Diseases.
    Yanzhe Yang, Felix Boahen Owusu, Han Wu, Xinyue Zhang, Ruiqiao Li, Zhanbiao Liu, Shaozhuo Zhang, Ling Leng, Qilong Wang.
       ETHNOPHARMACOLOGICAL RELEVANCE: Natural products represent a unique medical approach to treating disease and have been used in clinical practice for thousands of years in cardiovascular disease (CVDs). In recent years, natural products have received increasing attention for their high efficiency, safety, and low toxicity, and their targeted regulation of mitochondria offers promising strategies for the treatment of CVDs. However, the potential mechanisms by which natural products target mitochondria for cardiovascular treatment have not been fully elucidated.
    AIM OF THE STUDY: The literature of the past decade is reviewed to emphasize the therapeutic efficacy and potential mechanisms of natural products targeting mitochondria for the treatment of CVDs.
    MATERIALS AND METHODS: In the NCBI PubMed database, relevant literature was searched using 'natural products', 'mitochondria' and 'cardiovascular disease' as search terms, and review papers were excluded. The remaining articles were screened for relevance. Priority was given to articles using rat models, in vivo, ex vivo or in vitro assays. The resulting articles were categorized into natural product categories, including saponins, alkaloids, plant extracts and preparations. This article reviews the research progress on mitochondria as potential therapeutic targets for CVDs and summarizes the application of mitochondria-targeted natural products in the treatment of CVDs.
    RESULTS: Mitochondrial damage attribute to impairment of biogenesis (mitochondrial number and mitochondrial DNA damage), dynamics disruption (mitophagy inhibition and overpromotion, fusion and fission), and optimal dysfunction (ATP generation, ROS production, fatty acid β oxidation, mitochondrial membrane permeability, calcium homeostasis imbalance, membrane potential depolarization). Mitochondrial dysfunction or damage lead to cardiomyocyte dysfunction, ion disorders, cell death, and ultimately CVDs, such as myocardial infarction, heart failure, ischemia reperfusion, and diabetic heart disease. Natural products, which include flavonoids, saponins, phenolic acids, alkaloids, polysaccharides, extracts, and formulations, are seen to have significant clinical efficacy in the treatment of CVDs. Mechanistically, natural products regulate mitophagy, mitochondrial fusion and fission, while improving mitochondrial respiratory function, reducing ROS production, and inhibiting mitochondria-dependent apoptosis in cardiomyocytes, thereby protecting myocardial cells and heart function.
    CONCLUSIONS: In this paper, we reviewed the great potential and mechanism of natural products to regulate mitochondria for the treatment of CVDs, creating more opportunities for understanding their therapeutic targets and derivatization of lead compounds, and providing a scientific basis for advancing CVDs drug research.
    Keywords:  Cardiomyocyte damage; Cardiovascular diseases; Mitochondrial dysfunction; Natural products; Traditional Chinese medicine
    DOI:  https://doi.org/10.1016/j.jep.2025.119588
  57. Nat Commun. 2025 Mar 08. 16(1): 2329
    Salmonella exploits LRRK2-dependent plasma membrane dynamics to invade host cells.
    Hongxian Zhu, Andrew M Sydor, Bing-Ru Yan, Ren Li, Michal T Boniecki, Carina Lyons, Miroslaw Cygler, Aleixo M Muise, Michelle E Maxson, Sergio Grinstein, Brian Raught, John H Brumell.
      Salmonella utilizes type 3 secreted effector proteins to induce plasma membrane (PM) perturbations during invasion of host cells1. The effectors drive mobilization of host membranes to generate cell surface ruffles, followed by invagination and scission of the PM to generate Salmonella-containing vacuoles (SCVs)2. Here, we show that LRRK2 kinase generates membrane reservoirs exploited by Salmonella during invasion. The reservoirs are tubular compartments associated with the PM under basal conditions and are formed through the phosphorylation of RAB10 GTPase by LRRK2. Mobilization of membrane reservoirs to generate invasion ruffles mediates delivery of phosphorylated RAB10 to invasion sites. Subsequently, RAB10 dephosphorylation is required for its inactivation by a bacterial GTPase activating protein and subsequent scission of the PM. RAB10 dephosphorylation is mediated by a TLR4/PIEZO1/TMEM16F-dependent pathway and is inhibited by hyperactive variants of LRRK2. Our findings reveal how Salmonella exploits LRRK2-dependent PM dynamics during invasion and provide new insight into how LRRK2 variants can protect against bacterial infection3,4.
    DOI:  https://doi.org/10.1038/s41467-025-57453-x
  58. Int Immunopharmacol. 2025 Mar 10. pii: S1567-5769(25)00388-1. [Epub ahead of print]152 114398
    The transcription factor XBP1 regulates mitochondrial remodel and autophagy in spontaneous abortion.
    Weihua He, Yating Zhao, Lijun Yin, Qiangxing Du, Wenfen Ren, Liwei Mao, Aixia Liu, Dimin Wang, Jianhua Qian.
       PURPOSE: Spontaneous abortion (SA) remains a clinical challenge in early pregnancy. It has been reported that endoplasmic reticulum stress (ERS) is implicated in pregnancy-related complications. However, the precise mechanistic role of ERS in SA pathogenesis remains elusive. This study aims to explore the therapeutic potential of targeting ERS-related decidual dysfunction in SA.
    METHODS: An ERS model was established in both decidualized stromal cells (DSCs) and pregnant mice through tunicamycin (Tu) administration. Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays were performed to determine the interaction between XBP1s and the transcription factor binding site (TFBS) of tumor necrosis factor receptor-associated factor 6 (TRAF6). Mitochondrial membrane potential (MMP) and mitochondrial function were assessed using JC-1 and TMRM staining following ERS induction in DSCs. The effects of XBP1s inhibitors on mitochondrial metabolism and autophagy were evaluated through RT-qPCR, Western blotting, RNA-Seq, TUNEL assays, ROS and MitoSOX detection, and histological analyses in Tu-treated DSCs and SA patients. STF-083010 (STF) or shXBP1 was utilized to assess the inhibitory effects of X-box binding protein 1 (XBP1s) on DSC function both in vitro and in vivo.
    RESULTS: We observed significant upregulation of XBP1s in decidual tissues from SA patients and Tu-exposed DSCs. Tu exposure significantly increased the proportion of TUNEL-positive cells and upregulated pro-inflammatory cytokines (IL-1β, TNF-α, IL-6, IL-18) in DSCs. XBP1s inhibition via shXBP1 or pharmacological inhibitor STF attenuated Tu-induced apoptosis and inflammatory cytokine expression. Notably, STF or shXBP1 treatment enhanced MMP and upregulated LC3-II expression in Tu-treated DSCs, indicating autophagy activation.Intriguingly, chloroquine (CQ)-mediated autophagy suppression exacerbated apoptosis in STF/Tu-co-treated DSCs, suggesting that XBP1s inhibition confers cytoprotection through autophagy induction. Mechanistically, XBP1s directly bound to the TFBS of TRAF6, a ubiquitin E3 ligase. TRAF6 overexpression exacerbated mitochondrial dysfunction and apoptosis while suppressing autophagy via inhibition of mTORC2/Akt pathway in Tu-treated DSCs.
    CONCLUSION: XBP1s inhibition restored mitochondrial homeostasis and promoted autophagy by modulating the TRAF6/mTORC2 axis under ERS conditions, providing novel mechanistic insights into SA pathogenesis and potential therapeutic targets.
    Keywords:  Autophagy; ERS; Mitochondrial function; SA; XBP1
    DOI:  https://doi.org/10.1016/j.intimp.2025.114398
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