bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2025–06–15
forty-five papers selected by
Gavin McStay, Liverpool John Moores University
  1. Shizhifang alleviates hyperuricemia -induced renal injury by inhibiting Drp1 and maintaining mitochondrial homeostasis in renal tubular epithelial cells.
  2. An environmentally relevant concentration of 6-PPD quinone inhibits two types of mitophagy to cause mitochondrial dysfunction and lifespan reduction in Caenorhabditis elegans.
  3. Mitochondrial Dysfunction: The Silent Catalyst of Kidney Disease Progression.
  4. Drp1-Mediated Mitochondrial Fission Is Essential for Chemical-Induced Neuronal Transdifferentiation from Human Primary Fibroblasts.
  5. Baoshentongluo Formula relieves podocyte injury in diabetic kidney disease through regulating mitophagy via PINK1/Parkin signaling pathway.
  6. Targeting mitophagy in the heart: Exploring the therapeutic potential of MicroRNAs.
  7. Umbelliferone attenuates diabetic sarcopenia by modulating mitochondrial quality and the ubiquitin-proteasome system.
  8. The trade-off between reproduction and resilience.
  9. Beta-asarone alleviated cerebral ischemia/reperfusion injury by targeting PINK1/Parkin-dependent mitophagy.
  10. Engineered exosomal miR140 modulates mitophagy of chondrocytes through targeting CAPN1 to alleviate osteoarthritis.
  11. Expression of Concern: Hippocampal mutant APP and amyloid beta-induced cognitive decline, dendritic spine loss, defective autophagy, mitophagy and mitochondrial abnormalities in a mouse model of Alzheimer's disease.
  12. Roles of Mitochondrial Fusion and Division in Harmine Derivative H-2-168-Induced Neurotoxicity.
  13. Identification of mitophagy-related biomarkers in severe acute pancreatitis: integration of WGCNA, machine learning algorithms and scRNA-seq.
  14. Alleviation of metabolic dysfunction-associated steatotic liver disease by silymarin is associated with maintaining mitochondrial homeostasis via regulation of optic atrophy 1.
  15. Unraveling mitochondrial influence on mammalian pluripotency via enforced mitophagy.
  16. Acetyl zingerone inhibits chondrocyte pyroptosis and alleviates osteoarthritis progression by promoting mitophagy through the PINK1/parkin signaling pathway.
  17. Utilizing Multi-omics analysis to elucidate the role of mitochondrial gene defects in Gastric cancer progression.
  18. Expression of Concern: A partial reduction of Drp1 improves cognitive behavior and enhances mitophagy, autophagy and dendritic spines in a transgenic Tau mouse model of Alzheimer disease.
  19. Propofol-mediated inhibition of ovarian function by mitophagy over-activation via TGF-β1/SMAD2/3 signaling pathway.
  20. The critical role of mitophagy in cell senescence-mediated pulmonary fibrosis and potential therapeutic strategies.
  21. Fine particulate matter exacerbates asthma by activating STC2-mediated mitophagy through METTL3/YTHDF2-dependent m6A methylation.
  22. Mitochondrial fusion controls the development of specialized mitochondrial structure and metabolism in rod photoreceptor cells.
  23. The synthetic cannabinoids ADB-FUBINACA and AMB-FUBINACA enhance in vitro neurodifferentiation of NG108-15 cells, along with PGC-1α dysregulation and mitochondrial dysfunction.
  24. Mitochondrial fumarate inhibits Parkin-mediated mitophagy.
  25. ER-mitochondria tethering and its signaling: A novel therapeutic target in breast cancer.
  26. Protein kinase ROCK1 activates mitochondrial fission linking to oxidative stress and muscle atrophy.
  27. Polyphenols and Exercise in Mitochondrial Biogenesis: Focus on Age-Related CNS Disorders.
  28. IL-33 Has a Protective Effect Against Perinatal Listeriosis by Regulating Mitophagy of CD8+ T Lymphocytes.
  29. Polystyrene microplastics exacerbate mitophagy through mitochondrial dysfunction in the duck lung.
  30. Role of neuroglia cell-derived microvesicles in cobalt chloride-induced mitochondrial autophagy in neurons.
  31. Exploring the Potential Regulatory Mechanisms of Mitophagy in Ischemic Cardiomyopathy.
  32. Yellow Wine Polyphenolic Compounds protect against myocardial ischemia-reperfusion injury in rats by activating Nrf2 nuclear translocation to regulate the balance of mitochondrial fission and fusion.
  33. Bavachin ameliorates cisplatin-induced nephrotoxicity by enhancing mitochondrial β-oxidation and lipid metabolism through MFN2.
  34. Mitochondrial Dysfunction in the Development and Progression of Cardiometabolic Diseases: A Narrative Review.
  35. Natural products for the treatment of age-related macular degeneration: New insights focusing on mitochondrial quality control and cGAS/STING pathway.
  36. Impact of PARL-mediated mitochondrial protease activity on calcium regulation.
  37. Tmx2 Maintains Mitochondrial Function to Support Preimplantation Embryogenesis.
  38. Tea polyphenols attenuate glufosinate-induced breast injury by reducing endoplasmic reticulum stress and autophagy.
  39. Mechanism of myocardial damage induced by doxorubicin via calumenin-regulated mitochondrial dynamics and the calcium-Cx43 pathway.
  40. Integrated multi-omics analysis and experimental investigation of mitochondrial dynamics-related genes: molecular subtypes, immune landscape, and prognostic implications in lung adenocarcinoma.
  41. Intelligent Gene Delivery System Functionalized Metal Implants for Fracture Repair via Remodeling Mitochondrial Homeostasis.
  42. Targeting ferroptosis and mitophagy with neutrophil-inspired nanozyme for Parkinson's disease therapy.
  43. Aging-related dysregulation of energy metabolism and mitochondrial dynamics in microglia.
  44. Pharmacological Inhibition of Mitochondrial Division Attenuates Simulated High-Altitude Exposure-Induced Memory Impairment in Mice: Involvement of Inhibition of Microglia-Mediated Synapse Elimination.
  45. Sustained oxygen-releasing hydrogel implants enhance flap regeneration by promoting mitochondrial biogenesis under mild hypoxia.
  1. J Ethnopharmacol. 2025 Jun 09. pii: S0378-8741(25)00771-8. [Epub ahead of print] 120084
    Shizhifang alleviates hyperuricemia -induced renal injury by inhibiting Drp1 and maintaining mitochondrial homeostasis in renal tubular epithelial cells.
    Zhiyuan Wu, Yi Zhou, Feng Yang, Luobing Wang, Feng Wu, Weiwei Liu, Jiandong Gao.
       ETHNOPHARMACOLOGICAL RELEVANCE: Shizhifang (SZF), a traditional Chinese herbal formula used at Shanghai Shuguang Hospital for over 20 years, has shown clinical efficacy in lowering serum uric acid (SUA) and protecting renal function.
    AIM OF THE STUDY: To explore the mechanism by which SZF protects against hyperuricemia (HUA)-induced renal tubular epithelial cell injury, focusing on mitochondrial dysfunction mediated by Drp1.
    MATERIALS AND METHODS: RNA-seq was performed on HK2 cells to identify affected pathways. HUA rat and mouse models were used to assess renal function, oxidative stress, inflammation, and mitophagy. Key interventions included SZF, a Drp1 inhibitor, and autophagy modulators. In vitro, Drp1 knockdown HK2 cells were used to evaluate ROS, mitochondrial membrane potential (MMP), and proteins involved in mitochondrial dynamics and mitophagy.
    RESULTS: SZF significantly reduced SUA, improved renal function, suppressed ROS and inflammation, and alleviated mitochondrial damage. RNA-seq revealed enrichment of ROS and mitophagy pathways. SZF and Drp1 inhibition restored MMP, reduced fission and mitophagy, and enhanced mitochondrial fusion. Combined SZF and Drp1 siRNA treatment showed superior efficacy.
    CONCLUSIONS: SZF mitigates HUA-induced renal injury by inhibiting Drp1-mediated mitochondrial fission and mitophagy, promoting mitochondrial fusion, and reducing oxidative stress. These findings reveal a novel mitochondrial mechanism for SZF's reno-protective effect.
    Keywords:  Shizhifang; hyperuricemia; mitochondrial dynamics; mitophagy; renal injury
    DOI:  https://doi.org/10.1016/j.jep.2025.120084
  2. Environ Sci Process Impacts. 2025 Jun 09.
    An environmentally relevant concentration of 6-PPD quinone inhibits two types of mitophagy to cause mitochondrial dysfunction and lifespan reduction in Caenorhabditis elegans.
    Xin Hua, Dayong Wang.
      N-(1,3-Dimethylbutyl)-N'-phenyl-p-phenylenediamine quinone (6-PPDQ) is widely distributed in the environment and bioavailable to organisms. Exposure to 6-PPDQ can impair the mitochondrial function. However, the underlying mechanisms for 6-PPDQ-induced mitochondrial dysfunction remain largely unclear. Mitophagy is important for organisms to maintain normal mitochondrial function. In the current study, Caenorhabditis elegans was employed as model to determine the role of mitophagy suppression in 6-PPDQ-induced toxicity. After exposure to 6-PPDQ, it was found that, although mitophagy was increased by 0.1-1 μg L-1 6-PPDQ, 10 μg L-1 6-PPDQ downregulated the expression of genes involved in PINK1/Parkin-dependent mitophagy (pink-1, pdr-1, and sqst-1) and receptor-mediated mitophagy (fndc-1 and dct-1). RNAi of these mitophagy-related genes enhanced the 6-PPDQ toxicity on mitochondrial function and lifespan. Moreover, after 6-PPDQ (10 μg L-1) exposure, 6-PPDQ could be accumulated in the nucleus and affected the expressions of some transcription factor (TF) genes (daf-5, elt-2, atf-7, daf-16, bar-1, and skn-1) thereby inducing the inhibition of these two types of mitophagy. Inhibition in both mitophagy and the mitochondrial unfolded protein response (mt UPR) caused more severe 6-PPDQ toxicity on the mitochondrial function and lifespan. Our results demonstrate the crucial role of mitophagy suppression in mediating the toxicity of 6-PPDQ, which is useful for predicting the environmental exposure risk of 6-PPDQ on organisms.
    DOI:  https://doi.org/10.1039/d5em00224a
  3. Cells. 2025 May 28. pii: 794. [Epub ahead of print]14(11):
    Mitochondrial Dysfunction: The Silent Catalyst of Kidney Disease Progression.
    Nikola Pavlović, Marinela Križanac, Marko Kumrić, Katarina Vukojević, Joško Božić.
      Mitochondrial dysfunction is a pivotal driver in the pathogenesis of acute kidney injury (AKI), chronic kidney disease (CKD), and congenital anomalies of the kidney and urinary tract (CAKUT). The kidneys, second only to the heart in mitochondrial density, rely on oxidative phosphorylation to meet the high ATP demands of solute reabsorption and filtration. Disrupted mitochondrial dynamics, such as excessive fission mediated by Drp1, exacerbate tubular apoptosis and inflammation in AKI models like ischemia-reperfusion injury. In CKD, persistent mitochondrial dysfunction drives oxidative stress, fibrosis, and metabolic reprogramming, with epigenetic mechanisms (DNA methylation, histone modifications, non-coding RNAs) regulating genes critical for mitochondrial homeostasis, such as PMPCB and TFAM. Epigenetic dysregulation also impacts mitochondrial-ER crosstalk, influencing calcium signaling and autophagy in renal pathology. Mitophagy, the selective clearance of damaged mitochondria, plays a dual role in kidney disease. While PINK1/Parkin-mediated mitophagy protects against cisplatin-induced AKI by preventing mitochondrial fragmentation and apoptosis, its dysregulation contributes to fibrosis and CKD progression. For instance, macrophage-specific loss of mitophagy regulators like MFN2 amplifies ROS production and fibrotic responses. Conversely, BNIP3/NIX-dependent mitophagy attenuates contrast-induced AKI by suppressing NLRP3 inflammasome activation. In diabetic nephropathy, impaired mitophagy correlates with declining eGFR and interstitial fibrosis, highlighting its diagnostic and therapeutic potential. Emerging therapeutic strategies target mitochondrial dysfunction through antioxidants (e.g., MitoQ, SS-31), mitophagy inducers (e.g., COPT nanoparticles), and mitochondrial transplantation, which mitigates AKI by restoring bioenergetics and modulating inflammatory pathways. Nanotechnology-enhanced drug delivery systems, such as curcumin-loaded nanoparticles, improve renal targeting and reduce oxidative stress. Epigenetic interventions, including PPAR-α agonists and KLF4 modulators, show promise in reversing metabolic reprogramming and fibrosis. These advances underscore mitochondria as central hubs in renal pathophysiology. Tailored interventions-ranging from Drp1 inhibition to mitochondrial transplantation-hold transformative potential to mitigate kidney injury and improve clinical outcomes. Additionally, dietary interventions and novel regulators such as adenogens are emerging as promising strategies to modulate mitochondrial function and attenuate kidney disease progression. Future research should address the gaps in understanding the role of mitophagy in CAKUT and optimize targeted delivery systems for precision therapies.
    Keywords:  CAKUT; acute kidney injury; chronic kidney disease; mitochondria; mitophagy; renal pathology
    DOI:  https://doi.org/10.3390/cells14110794
  4. J Mol Neurosci. 2025 Jun 13. 75(2): 75
    Drp1-Mediated Mitochondrial Fission Is Essential for Chemical-Induced Neuronal Transdifferentiation from Human Primary Fibroblasts.
    Jijuan Yang, Chun Li, Chunhua Wang, Xuemei Wang, Jiaqi Liu, Nan Yu, Wenqing Du, Shuhong Chi.
      Neuronal replacement therapy recently holds promise for neurodegenerative disease treatment. Somatic cell-derived neurons are the main cell source for this therapy; however, the induction mechanisms remain to be fully elucidated. Emerging evidence indicates that mitochondrial architecture undergoes substantial remodeling throughout cellular reprogramming processes. To explore the implications of mitochondrial dynamics in chemical-induced neuronal transdifferentiation, human foreskin fibroblasts (HFFs) were directly reprogrammed into functional neurons with our previously developed small molecule compound. The results showed that the mitochondrial morphology of HFFs shifted from tubular and reticular to fragmented shapes at an early stage of induced neurulation. Concurrently, gene and protein expression levels of the mitochondrial fission protein Drp1 was significantly increased in HFFs after induction. Both Drp1-specific siRNA and Drp1-GTPase inhibitor mdivi-1 treatment significantly attenuated the neuronal transdifferentiation of HFFs to neurons respectively, which can be attributed to the modulation of mitochondrial dynamics toward a fusion-dominant state through Drp1 suppression. Collectively, our experimental findings establish Drp1-dependent mitochondrial fission as a critical early requirement in the chemical reprogramming cascade that facilitates HFF transdifferentiation into neuronal lineages. Targeting Drp1 may enhance the efficiency of neuronal transdifferentiation, thereby providing sufficient therapeutically relevant neurons for neurodegenerative disease treatment.
    Keywords:  Dynamin-related protein1; Mdivi-1; Mitochondrial dynamics; Neuron transdifferentiation; Somatic reprogramming
    DOI:  https://doi.org/10.1007/s12031-025-02367-y
  5. Front Endocrinol (Lausanne). 2025 ;16 1606326
    Baoshentongluo Formula relieves podocyte injury in diabetic kidney disease through regulating mitophagy via PINK1/Parkin signaling pathway.
    Yanyu Pang, Lei Tian, Yufei Liu, Yifan Guo, Jingwen Zhao, Yutong Wang, Mengdi Wang, Wenjing Zhao.
       Introduction: Diabetic kidney disease (DKD) progression is strongly associated with podocyte mitochondrial dysfunction. The clinically effective Chinese herbal Baoshentongluo formula (BSTL) has demonstrated significant proteinuria reduction in DKD patients. HPLC-ESI-MS analysis identified characteristic bioactive components in BSTL including astragalosides, rehmanniosides, and tanshinones. However, the molecular mechanisms through which BSTL maintains podocyte homeostasis remain incompletely understood.
    Methods: Mouse podocyte clone-5 (MPC-5) cells and db/db mice were used. Db/db mice were randomized into db/db and db/db + BSTL (16.5 g/kg/d, intragastric administration for 12 weeks). A group of m/m mice served as the control. Renal function, urinary albumin-to-creatinine ratio (UACR), histopathological analysis, apoptotic, and mitophagy-related protein levels were evaluated. MPC-5 cells were exposed to high glucose (HG, 30 mM) and BSTL drug-containing serum (8%) for 24 h grouping as control, HG, HG + BSTL, and HG + siPINK1. Podocyte apoptosis, mitophagy levels, and expression of PTEN-induced putative kinase 1 (PINK1) and E3 ubiquitin ligase (Parkin) were assessed.
    Results: In db/db diabetic mice, oral administration of BSTL significantly lowered urinary albumin-to-creatinine ratio (P<0.05), improved glomerular filtration rate, and ameliorated renal histopathological changes, decreased LC3-II/LC3-I ratio, and downregulated expression of mitophagy-related proteins PINK1, Parkin, ATG5 and Beclin-1. Treatment with 8% BSTL-containing serum significantly attenuated HG-induced podocyte apoptosis (P<0.01) and suppressed excessive mitophagy, as evidenced by reduced TOM20/LC3 co-localization (P<0.01). Notably, BSTL treatment markedly reduced protein levels of both PINK1 and Parkin (P<0.01), key regulators of mitophagy initiation. Genetic silencing of PINK1 in podocytes phenocopied BSTL's protective effects, confirming the pathway specificity.
    Discussion: Our integrated in vitro and in vivo findings establish that BSTL protects against DKD progression by selectively inhibiting PINK1/Parkin-dependent mitophagy in podocytes to inhibit podocyte injury, which provides both mechanistic insights and therapeutic potential for clinical DKD management.
    Keywords:  apoptosis; diabetic kidney disease; mitochondria; podocyte; traditional Chinese medicine
    DOI:  https://doi.org/10.3389/fendo.2025.1606326
  6. Mech Ageing Dev. 2025 Jun 06. pii: S0047-6374(25)00058-2. [Epub ahead of print]226 112082
    Targeting mitophagy in the heart: Exploring the therapeutic potential of MicroRNAs.
    Amin Javadifar, Masoud Tahani, Sorousha Khayat, Shiva Rakhshani Nasab, Sercan Karav, Prashant Kesharwani, Amirhossein Sahebkar.
      Mitophagy, a selective form of autophagy, plays an indispensable role in preserving mitochondrial integrity by eliminating dysfunctional mitochondria, thereby sustaining cellular homeostasis. This process is particularly critical in cardiomyocytes, which rely heavily on high-quality mitochondria to meet their substantial energy demands. Impaired mitophagy has been implicated in the pathogenesis of various cardiovascular diseases, including ischemic heart disease, heart failure, and cardiomyopathy. Emerging evidence highlights the pivotal regulatory role of microRNAs (miRNAs)-small non-coding RNA molecules-in modulating mitophagy by targeting key genes such as PINK1, Parkin, and FUNDC1, which are integral to mitochondrial quality control. This review comprehensively examines the dual capacity of miRNAs to either enhance or suppress mitophagy and evaluates the implications of these regulatory actions for cardiovascular health. For instance, miRNAs such as miR-24-3p and miR-125a-5p modulate mitophagy pathways, influencing cardiac function in distinct ways. Additionally, miRNAs like miR-34a and miR-330-3p may exert broader effects on mitochondrial homeostasis in cardiac tissue. This paper further explores the therapeutic potential of targeting miRNAs to restore mitophagy equilibrium and mitigate mitochondrial dysfunction, offering novel avenues for cardiovascular disease management. By synthesizing recent findings, this review underscores the promise of miRNA-based interventions and identifies critical directions for future research.
    Keywords:  Cardiac health; Cardiovascular diseases; MicroRNAs; Mitochondrial quality control; Mitophagy; Therapeutic targets
    DOI:  https://doi.org/10.1016/j.mad.2025.112082
  7. Phytomedicine. 2025 May 31. pii: S0944-7113(25)00568-9. [Epub ahead of print]144 156930
    Umbelliferone attenuates diabetic sarcopenia by modulating mitochondrial quality and the ubiquitin-proteasome system.
    Dong Yeon Kim, Young-Hee Kang, Min-Kyung Kang.
       BACKGROUND: Sarcopenia, characterized by the progressive loss of skeletal muscle mass, strength, and physical performance, is traditionally associated with aging. However, chronic conditions such as type 2 diabetes mellitus (T2DM) have been recognized as key accelerators of its progression. In this study, we investigated the therapeutic effects of umbelliferone on diabetes-induced muscle atrophy using C2C12 myoblasts and a db/db diabetic mouse model.
    PURPOSE: This study aims to provide scientific evidence supporting the potential of umbelliferone, a naturally occurring compound widely found in food, in alleviating diabetes-induced muscle dysfunction and preventing muscle atrophy. Specifically, we evaluated its effectiveness in mitigating diabetic sarcopenia. This study is the first to elucidate the molecular mechanisms by which umbelliferone improves mitochondrial quality control and suppresses proteolysis under hyperglycemic conditions, providing novel insights into its role in preserving muscle homeostasis in diabetes.
    METHODS: C2C12 myoblasts were cultured in DMEM supplemented with 10 % fetal bovine serum (FBS) under normal conditions. Myogenic differentiation was induced by switching to DMEM containing 2 % horse serum (HS) for six days. After differentiation, the cells were exposed to high-glucose (50 mM) medium with or without 10-20 μM umbelliferone before sample collection. Myotube formation was confirmed via microscopy, and protein expression levels of muscle differentiation markers, mitochondrial biogenesis-related factors, and components of the ubiquitin-proteasome system associated with muscle atrophy were analyzed using Western blotting. Additionally, an in vivo study was conducted using db/db mice, a well-established type 2 diabetic model. Umbelliferone was administered orally at a dose of 10 mg/kg daily for eight weeks. Baseline metabolic and physiological parameters were assessed. Muscle tissues were collected for protein expression analysis and histological staining to evaluate morphological and functional changes in muscle structure.
    RESULTS: Our findings demonstrated that umbelliferone effectively attenuated muscle atrophy and improved muscle function in diabetes. Umbelliferone significantly upregulated key myogenic markers, including MyoD, myogenin, Myh2, and skeletal muscle myosin, thereby promoting myoblast differentiation into myotubes. In diabetic mice, umbelliferone treatment enhanced grip strength and lean mass, highlighting its potential to restore overall muscle function. Furthermore, umbelliferone improved mitochondrial quality control by modulating the expression of proteins involved in mitochondrial biogenesis (SIRT1, p-AMPK, PGC-1α), fusion (MFN1, OPA1), and fission (FIS1, DRP1). Additionally, umbelliferone suppressed hyperglycemia-induced activation of the ubiquitin-proteasome system, which plays a crucial role in muscle protein degradation. Specifically, it inhibited the upregulation of muscle atrophy-associated proteins, including muscle ring-finger protein-1 (MuRF-1), forkhead box class O3a (FoxO3a), and Atrogin-1.
    CONCLUSIONS: Importantly, this is the first study to comprehensively demonstrate the dual action of umbelliferone in enhancing mitochondrial dynamics and inhibiting muscle protein degradation in both cellular and diabetic animal models, Theses findings offer a new mechanism perspective on how dietary phytochemicals may combat diabetic sarcopenia. These findings highlight the therapeutic potential of umbelliferone in alleviating diabetes-related muscle atrophy and suggest its potential as a promising intervention for diabetic muscle complications.
    Keywords:  Diabetic sarcopenia; Mitochondrial dynamics; Muscle atrophy; SIRT1–AMPK–PGC-1α signaling; Ubiquitin-proteasome system; Umbelliferone
    DOI:  https://doi.org/10.1016/j.phymed.2025.156930
  8. Trends Endocrinol Metab. 2025 Jun 10. pii: S1043-2760(25)00102-X. [Epub ahead of print]
    The trade-off between reproduction and resilience.
    Liankui Zhou, Ying Liu.
      The mitochondrial unfolded protein response (UPRmt) is a transcriptional program that alleviates mitochondrial dysfunction by facilitating the recovery of the mitochondrial network. In Caenorhabditis elegans, reproductive maturity leads to suppression of the UPRmt, suggesting a trade-off between maintenance of stress resilience and fertility. Here, we examine emerging evidence suggesting that the reproduction-associated suppression of UPRmt is a representative example of the physiological costs of reproduction. We focus on the germline-to-soma intertissue signaling mechanisms recently identified in C. elegans, which modulate systemic physiological responses during reproduction. These findings not only illuminate the trade-offs between stress resistance and reproductive capacity but also underscore the broader implications of intertissue communication in coordinating resource allocation.
    Keywords:  Caenorhabditis elegans; intertissue signaling networks; mitochondrial unfolded protein response; proteostasis regulation; reproduction-associated trade-offs
    DOI:  https://doi.org/10.1016/j.tem.2025.05.003
  9. Eur J Pharmacol. 2025 Jun 07. pii: S0014-2999(25)00585-0. [Epub ahead of print]1002 177831
    Beta-asarone alleviated cerebral ischemia/reperfusion injury by targeting PINK1/Parkin-dependent mitophagy.
    Yujiao Wang, Daojun Xie, Shijia Ma, Yuhe Wang, Chengcheng Zhang, Zhuyue Chen.
      Cerebral ischemia-reperfusion injury (CIRI) describes a secondary type of brain damage that happens when blood flow is restored to brain tissue; it ranks among the primary contributors of disability and mortality. The activation of PINK1/Parkin-mediated mitophagy exerts neuroprotective effects during CIRI. Beta-asarone (β-ASA), the principal active component of traditional natural drugs such as Acori tatarinowii rhizoma and Ligusticum chuanxiong Hort, possesses anti-inflammatory, antioxidant, and autophagy-enhancing properties. However, whether β-ASA can ameliorate CIRI by regulating the PINK1/Parkin-dependent mitophagy pathway remains unclear and warrants further investigation. The purpose of this study is to explore the underlying mechanism through which β-ASA influences PINK1/Parkin-mediated mitophagy in the hippocampus following ischemia-reperfusion. In the results section, the present study examined the effects of β-ASA on middle cerebral artery occlusion/reperfusion (MCAO/R)-induced neurological deficits using the Longa test and TTC staining, rats were then treated with β-ASA (20, 40, and 80 mg/kg). The findings demonstrate that β-ASA promotes functional recovery in post-ischemic stroke, as evidenced by improved neurological function, reduced infarct volume, decreased neuronal damage, and lowered neuronal apoptosis. Furthermore, β-ASA significantly enhanced autophagy by increasing Beclin1 expression while reducing P62 and LC3-I/LC3-II expression. Additionally, β-ASA markedly activated PINK1/Parkin-mediated mitophagy. Finally, the introduction of mitophagy inhibitors was employed to clarify the relationship between autophagy and β-ASA, indicating that β-ASA promotes autophagy by activating the PINK1/Parkin signalling pathway. In conclusion, this study elucidates that β-ASA alleviates cerebral infarction, neurological impairment, and neuronal damage by targeting PINK1/Parkin-dependent mitophagy, thereby presenting a potential therapeutic strategy for CIRI.
    Keywords:  Beta-asarone; Cerebral ischemia reperfusion injury (CIRI); Mitophagy; PINK1/Parkin
    DOI:  https://doi.org/10.1016/j.ejphar.2025.177831
  10. Sci China Life Sci. 2025 Jun 10.
    Engineered exosomal miR140 modulates mitophagy of chondrocytes through targeting CAPN1 to alleviate osteoarthritis.
    Yuan Liu, Kai Huang, Sheng-Liang Zhou, Shuai Li, Hai-Bo Si, Yi Zeng, Hui-Qi Xie, Bin Shen.
      Osteoarthritis (OA) is a prevalent degenerative disease involving mitophagy dysfunction of chondrocytes. As OA progresses, miR140 expression in chondrocytes decreases, and its therapeutic potential has shown protective effects. However, the variation in mitophagy across different stages of OA in human chondrocytes, as well as the role of miR140 in modulating mitophagy, have remained insufficiently elucidated. In this study, we observed that mitochondrial morphology deteriorates with OA progression, from mild swelling in the early stage of OA (E-OA) to disrupted cristae in the mid-to-late stage of OA (ML-OA). Mitophagy levels were mildly elevated in E-OA chondrocytes compared with normal controls, whilst ML-OA chondrocytes exhibited significantly reduced and impaired mitophagy. Notably, miR140 was found to down-regulate CAPN1, an intracellular cysteine protease affecting mitochondrial and lysosomal membranes. Targeting the miR140/CAPN1 axis was revealed to improve mitochondrial morphology, decrease reactive oxygen species (ROS) accumulation, and promote mitophagy in chondrocytes. To further overcome the inherent instability and limited bioavailability of miR140 when administered directly, engineered exosomes overexpressing miR140 derived from human urine-derived stem cells (hUSCs-140-Exos) were constructed. In vitro, hUSCs-140-Exos were demonstrated to promote mitophagy and preserve mitochondrial function. Moreover, intra-articular injection of hUSCs-140-Exos in vivo effectively delivered miR140 to OA chondrocytes, resulting in improved gait, restoration of subchondral bone structure, and mitigation of OA progression. Overall, this study provides a novel and promising strategy for OA treatment, demonstrating significant therapeutic potential.
    Keywords:  CAPN1; exosomes; human urine-derived stem cells; miR140; mitophagy; osteoarthritis
    DOI:  https://doi.org/10.1007/s11427-024-2843-7
  11. Hum Mol Genet. 2025 06 11. pii: ddaf097. [Epub ahead of print]
    Expression of Concern: Hippocampal mutant APP and amyloid beta-induced cognitive decline, dendritic spine loss, defective autophagy, mitophagy and mitochondrial abnormalities in a mouse model of Alzheimer's disease.
      
    DOI:  https://doi.org/10.1093/hmg/ddaf097
  12. J Immunol Res. 2025 ;2025 6678026
    Roles of Mitochondrial Fusion and Division in Harmine Derivative H-2-168-Induced Neurotoxicity.
    Yuehong Gong, Meichi Pan, Hang Ren, Dongling Peng, Meiling Zhao, Yicong Zhao, Chunlin Luo, Qin Ma, Hao Wen, Jianhua Wang.
      Background: Harmine (HM) has several pharmacological effects; however, severe neurotoxicity limits its clinical application and development. HM neurotoxicity is associated with abnormal energy metabolism. This study aimed to explore the roles and underlying mechanisms of mitochondrial fusion and division in HM derivative H-2-168-induced neurotoxicity. Methods: PC12 cells were treated with H-2-168, Mdivi-1 (an inhibitor of mitochondrial division), or a combination of both. Cell viability, levels of reactive oxygen species (ROS), adenosine triphosphate (ATP), lactic dehydrogenase (LDH), mitochondrial morphology, and membrane potential were measured. Immunofluorescence (IF) and western blotting were used to determine the expression of apoptosis-, mitochondrial fusion-, and division-related proteins. Additionally, PC12 cells with Drp1 knockdown or Mfn2 overexpression were generated to explore their effects. Results: H-2-168 alone or in combination with Mdivi-1 significantly reduced PC12 cell viability, induced apoptosis, and impaired mitochondrial function. These effects were accompanied by increased levels of ROS and LDH, reduced ATP levels, upregulation of caspase-3, cytochrome c (Cyt-c), Drp1, and Fis1, and downregulation of Mfn2 and OPA1. Additionally, Drp1 knockdown or Mfn2 overexpression further enhanced the H-2-168-induced reduction in cell viability. Conclusions: These data implied that H-2-168 may initiate apoptosis in PC12 cells by influencing the balance between mitochondrial fusion and division, accompanied by changes in energy metabolism, which may induce neurotoxicity.
    Keywords:  Drp1; H-2-168; Mfn2; PC12 cells; mitochondrial fusion and division; neurotoxicity
    DOI:  https://doi.org/10.1155/jimr/6678026
  13. Front Immunol. 2025 ;16 1594085
    Identification of mitophagy-related biomarkers in severe acute pancreatitis: integration of WGCNA, machine learning algorithms and scRNA-seq.
    Xiaozhou Xie, Zheng Wang, Haoyu Zhang, Jiongdi Lu, Feng Cao, Fei Li.
       Background: Mitophagy is a highly conserved cellular process in eukaryotic cells that selectively clears dysfunctional or damaged mitochondria through autophagy mechanisms to maintain mitochondrial homeostasis. However, the role of mitophagy in the pathogenesis of severe acute pancreatitis (SAP) has not been fully investigated. In this study, we aimed to identify crucial mitophagy-related genes in SAP to provide a theoretical basis for in-depth mechanistic investigations.
    Methods: We downloaded the GSE194331 dataset from the Gene Expression Omnibus (GEO), identified differentially expressed genes (DEGs), and used weighted gene co-expression network analysis (WGCNA) and three machine learning algorithms to identify crucial genes. In addition, single sample gene set enrichment analysis (ssGSEA) was conducted to explore the relationship between crucial genes and immune infiltration. The expression of crucial genes at the single-cell level was analyzed using single-cell RNA sequencing (scRNA seq) data from the GSE279876 dataset. Finally, we established the SAP mouse model and conducted preliminary validation of the mechanism of crucial genes in SAP.
    Result: We identified MAPK14 as a crucial mitophagy-related gene in SAP by intersecting the results of DEGs, WGCNA, and three machine learning algorithms. In addition, ssGSEA revealed that MAPK14 was strongly associated with immune cell infiltration. The analysis of scRNA-seq data revealed that MAPK14 was highly expressed in pancreatic macrophages, suggesting that macrophage-derived MAPK14 may potentially regulate inflammation in SAP. Finally, we preliminarily validated using the SAP mouse model that inhibiting the protein encoded by MAPK14 increased the expression of mitophagy marker proteins and significantly alleviated SAP inflammation.
    Conclusion: Inhibition of MAPK14 activation may alleviate SAP by enhancing mitophagy. Our study highlights the potential role of the mitophagy-related gene MAPK14 in SAP pathogenesis, providing important insights for future investigations into mitophagy-mediated immune mechanisms in SAP.
    Keywords:  MAPK14; WGCNA; immune cell infiltration; machine learning; mitophagy; p38α; severe acute pancreatitis; single-cell RNA sequencing
    DOI:  https://doi.org/10.3389/fimmu.2025.1594085
  14. J Pharmacol Exp Ther. 2025 May 19. pii: S0022-3565(25)39824-1. [Epub ahead of print]392(7): 103611
    Alleviation of metabolic dysfunction-associated steatotic liver disease by silymarin is associated with maintaining mitochondrial homeostasis via regulation of optic atrophy 1.
    Ming-Qiang Liu, Yuan Wu, Ye Li, Yan-Bo Wei, Ling-Yue Dong, Wei An.
      Silibinin (silybin) is the major active compound of silymarin used to treat several chronic liver diseases including metabolic dysfunction-associated steatotic liver disease (MASLD). However, the molecular mechanism of hepatic protection offered by silibinin remains still incompletely understood. In this study, we aimed to investigate whether silibinin could ameliorate hepatic steatosis by regulating mitochondrial function in Western diet (WD)-fed MASLD mice and free fatty acid-treated HepG2 cells. WD-fed mice and oleic acid/palmitic acid (OA/PA; 2:1)-treated HepG2 cells were established to evaluate the protection of silibinin against hepatocyte steatosis. Mitochondrial quality was detected using transmission electron microscope, confocal microscope, and cell analyzer for energy metabolism. Silibinin effectively attenuated WD-fed steatotic liver in mice and decreased lipid accumulation in hepatocytes, proved to be associated with stabilization of mitochondrial networked areas and inhibition of mitochondrial swelling. Functionally, silibinin at concentrations of 100 ng/μL was found to enhance mitochondrial respiratory capacity in the OA/PA-treated cells. RNA transcriptome analysis showed that, following silibinin administration, the expressions of numerous mitochondria-associated signaling molecules including AMP-activated protein kinase and mitophagy were upregulated. Among them, optic atrophy (OPA)1 expression increased prominently, which coincided with not only elevated mitochondrial fusion but also declined mitochondrial fragmentation in mouse steatotic livers and OA/PA-treated hepatocytes. In contrast, knockdown OPA1 abolished the protective effect offered by silibinin against lipid accumulation and deteriorated hepatocyte steatosis. Our findings suggest that silibinin attenuating hepatic steatosis is potentially attributed to stabilizing mitochondrial homeostasis via upregulation of OPA1. SIGNIFICANCE STATEMENT: The study results revealed that silibinin maintains mitochondrial homeostasis by upregulating optic atrophy 1 expression in hepatocytes to attenuate lipid accumulation and oxidative stress. Therefore, silibinin is a potential therapeutic candidate for the treatment of metabolic dysfunction-associated steatotic liver disease.
    Keywords:  Metabolic dysfunction–associated steatotic liver disease; Mitochondrial fusion; Mitochondrial respiration; Reactive oxygen species; Silibinin
    DOI:  https://doi.org/10.1016/j.jpet.2025.103611
  15. Cell. 2025 Jun 05. pii: S0092-8674(25)00570-7. [Epub ahead of print]
    Unraveling mitochondrial influence on mammalian pluripotency via enforced mitophagy.
    Daniel A Schmitz, Seiya Oura, Leijie Li, Yi Ding, Rashmi Dahiya, Emily Ballard, Carlos Pinzon-Arteaga, Masahiro Sakurai, Daiji Okamura, Leqian Yu, Peter Ly, Jun Wu.
      Mitochondrial abundance and genome are crucial for cellular function, with disruptions often associated with disease. However, methods to modulate these parameters for direct functional dissection remain limited. Here, we eliminate mitochondria from pluripotent stem cells (PSCs) by enforced mitophagy and show that PSCs survived for several days in culture without mitochondria. We then leverage enforced mitophagy to generate interspecies PSC fusions that harbor either human or non-human hominid (NHH) mitochondrial DNA (mtDNA). Comparative analyses indicate that human and NHH mtDNA are largely interchangeable in supporting pluripotency in these PSC fusions. However, species divergence between nuclear and mtDNA leads to subtle species-specific transcriptional and metabolic variations. By developing a transgenic enforced mitophagy approach, we further show that reducing mitochondrial abundance leads to delayed development in pre-implantation mouse embryos. Our study opens avenues for investigating the roles of mitochondria in development, disease, and interspecies biology.
    Keywords:  cell fusion; great apes; interspecies composite; interspecies hybrid; metabolism; mitochondria; mitophagy; mtDNA; pluripotent stem cells
    DOI:  https://doi.org/10.1016/j.cell.2025.05.020
  16. Int Immunopharmacol. 2025 Jun 09. pii: S1567-5769(25)01045-8. [Epub ahead of print]161 115055
    Acetyl zingerone inhibits chondrocyte pyroptosis and alleviates osteoarthritis progression by promoting mitophagy through the PINK1/parkin signaling pathway.
    Zhuangzhuang Zhang, Tianyue Huang, Xu Chen, Jie Chen, Hang Yuan, Ning Yi, Chunbao Miao, Rongbin Sun, Su Ni.
      Osteoarthritis (OA) is a common chronic degenerative joint disease, characterized by osteophyte formation and cartilage degeneration. A growing number of studies have found that nod-like receptor pyrin domain 3 (NLRP3) inflammasome-mediated chondrocyte pyroptosis plays a crucial role in the development of OA. Acetyl zingerone (AZ) is a small molecule compound, chemically synthesized to retain the key functional properties of curcumin and zingerone, while exhibiting enhanced anti-inflammatory, antioxidant, and anti-aging effects. Previous studies in our group have found an inhibitory effect on ferroptosis in AZ osteoarthritis. However, its specific mechanism of action has not been fully explained. Therefore, we further delved into whether AZ could alleviate OA in mice by affecting mitophagy and pyroptosis. In an in vitro study, we observed that AZ alleviated LPS + ATP-induced pyroptosis in chondrocytes and inhibited the activation of the NLRP3 inflammasome, a key factor in pyroptosis. Moreover, by using the mitophagy activators Resveratrol, the autophagy lysosome inhibitor chloroquine (CQ) and siPINK1 to knock down PINK1, we demonstrated that AZ promoted PINK1/Parkin-mediated mitophagy. AZ enhanced PINK1/Parkin-mediated mitophagy, facilitating the clearance of damaged mitochondria, thereby reducing reactive oxygen species (ROS) production and suppressing NLRP3 inflammasome activation. This cascade mitigated chondrocyte pyroptosis and promoted collagen synthesis. Moreover, AZ demonstrated a comparable pro-regenerative effect on the extracellular matrix to that observed with the standard osteoarthritis treatment, rapamycin. In animal experiments, intra-articular administration of AZ similarly promoted mitophagy and inhibited chondrocyte pyroptosis, alleviating osteoid formation and cartilage damage. Collectively, these findings suggest that AZ may mitigate OA progression by activating mitophagy and attenuating pyroptosis, highlighting its potential as a preventive therapeutic approach for OA.
    Keywords:  Acetyl zingerone; Mitophagy; NLRP3 inflammasome; Osteoarthritis; Pyroptosis
    DOI:  https://doi.org/10.1016/j.intimp.2025.115055
  17. PLoS One. 2025 ;20(6): e0325520
    Utilizing Multi-omics analysis to elucidate the role of mitochondrial gene defects in Gastric cancer progression.
    Jie Chu, Hanying Song, Kemin Fu, Wei Xiao, Jiudong Jiang, Qixin Gan, Bo Deng.
       BACKGROUND: Gastric cancer is a leading cause of cancer-related mortality worldwide, with poor survival outcomes despite advances in diagnostic and therapeutic methods. Mitochondrial autophagy, or mitophagy, is crucial for maintaining cellular homeostasis and has significant implications in tumor biology. DUSP1, a bispecific phosphatase regulating MAP kinase activity, has been associated with various cancers, but its role in GC remains unclear.
    MATERIALS AND METHODS: In order to gain a deeper understanding of gastric cancer cells, this study utilized bulk RNA-seq data from TCGA and GEO, combined with the MSigDB database, to screen for mitophagy-related genes. Univariate Cox regression and LASSO analysis were employed to further identify key mitophagy-related genes. Single-cell RNA sequencing data from the database was analyzed using Seurat software to investigate the mitochondrial autophagy genes in each candidate gastric tissue. To clarify the functional pathways involved, enrichment analysis and differential gene expression analysis were conducted. The characteristics of the immune microenvironment were assessed using the CIBERSORT R package. Additionally, both the ssGSEA algorithm and the CIBERSORT algorithm were utilized to evaluate changes and effects in immunological characteristics during gastric cancer pathogenesis.
    RESULTS: We identified eight prognostic genes-STX10, CDC37, VPS35, RCAN1, TRIM25, DUSP1, SEC23A, and GLT8D1-using LASSO-Cox regression analysis. RCAN1 and DUSP1 are strongly positively correlated, while DUSP1 is strongly negatively correlated with TRIM25, and CDC37 is strongly negatively correlated with SEC23A. By incorporating mitochondrial autophagy scores and clinical characteristics, we established a prognostic model that accurately predicts the 3-year survival status of gastric cancer (GC) patients. Additionally, our single-cell analysis identified DUSP1 as a key mitophagy-related gene. Functional studies demonstrated that DUSP1 knockdown significantly inhibits GC cell proliferation and migration.
    CONCLUSION: In this study, we developed a risk score based on eight mitochondrial autophagy-related genes and analyzed their expression across different cell types using single-cell analysis. DUSP1 stood out as a key player in gastric cancer progression, with higher expression in tumor tissues and a significant role in cell proliferation, apoptosis, and drug resistance. Our research also linked this risk score to tumor microenvironment immune cell infiltration and tumor mutational burden, revealing distinct high and low-risk groups in gastric cancer patients. This risk score holds potential for improving patient survival assessment and guiding personalized treatment, including enhancing immunotherapy efficacy.
    DOI:  https://doi.org/10.1371/journal.pone.0325520
  18. Hum Mol Genet. 2025 06 11. pii: ddaf099. [Epub ahead of print]
    Expression of Concern: A partial reduction of Drp1 improves cognitive behavior and enhances mitophagy, autophagy and dendritic spines in a transgenic Tau mouse model of Alzheimer disease.
      
    DOI:  https://doi.org/10.1093/hmg/ddaf099
  19. Cell Signal. 2025 Jun 04. pii: S0898-6568(25)00331-6. [Epub ahead of print]134 111916
    Propofol-mediated inhibition of ovarian function by mitophagy over-activation via TGF-β1/SMAD2/3 signaling pathway.
    Liqing Miao, Mei Chen, Yujia Zhou, Shuangjia Pan, Xiaosheng Li, Yuexin Wang, Jian'an Zhang, Xueqiong Zhu.
      Propofol is widely used to induce and maintain anesthesia during gynecological surgery and assisted reproduction. However, few studies have investigated the influence of propofol on ovarian function and the related mechanism. In this study, propofol was administered to female mice, and ovarian function was evaluated by measuring serum AMH levels, follicle counts, and expression of related proteins. IOSE-80 and KGN cells were treated with propofol to assess mitochondrial function and mitophagy using fluorescence staining, ROS and mitochondrial membrane potential assays, and Western blotting. Recombinant TGF-β1 was applied both in vivo and in vitro to investigate the involvement of the TGF-β/SMAD2/3 signaling pathway. These results showed that propofol reduced the serum AMH level and the number of follicles in the mice ovaries, downregulated the protein expressions of FSHR and CYP19A1, and facilitated ovarian cell apoptosis both in vivo and in vitro. Treatment with propofol significantly decreased the mitochondrial fluorescence intensity and increased mitophagy fluorescence in IOSE-80 and KGN cells. Additionally, propofol enhanced ROS generation, decreased mitochondrial membrane potential and increased the levels of proteins associated with mitophagy (LC3B, PINK1, PARKIN). Propofol lessened the abundance of TGF-β1, SMAD2/3 and phosphorylated-SMAD2/3. Co-treatment with recombinant TGF-β1 significantly increased cell survival, reduced apoptosis, and upregulated the protein expression levels of FSHR, CYP19A1, PINK1, and PARKIN in IOSE-80 and KGN cells. These results demonstrated that propofol over-activates mitophagy through the TGF-β/SMAD2/3 pathway, and thus affects ovarian function. This finding provides some guidance for women with fertility needs when choosing anesthesia drugs for surgery.
    Keywords:  Mitophagy; Ovary; Propofol; SMAD2/3; TGF-β1
    DOI:  https://doi.org/10.1016/j.cellsig.2025.111916
  20. Mol Biol Rep. 2025 Jun 07. 52(1): 565
    The critical role of mitophagy in cell senescence-mediated pulmonary fibrosis and potential therapeutic strategies.
    Xing-Yi Chen, Dong-Mei Wang, Ya Zhou, Li Liu, Tao Zhu, Zhao Ran, Mei-Hong Lu, Ben-Rong Mu.
      Pulmonary fibrosis is often associated with aging, marked notably by the senescence of lung epithelial cells and the development of interstitial fibrosis. Mitophagy plays a crucial role in aging by degrading damaged mitochondria, thereby maintaining mitochondrial quality and cellular homeostasis. When mitophagy is disrupted or impaired, damaged mitochondria fail to be properly degraded by lysosomes. This results in the persistence of dysfunctional mitochondria, which can further damage cells, induce cell senescence and trigger inflammatory responses. These processes can worsen pulmonary fibrosis. Restoring proper mitophagy could be a promising strategy for managing pulmonary fibrosis and countering stress-induced premature cell senescence, potentially improving or even reversing lung function in aging lungs. This review will explore the complex relationship between cell senescence and pulmonary fibrosis, detailing the senescence characteristics in fibrotic lungs. It will also highlight recent advancements in understanding how mitophagy influences lung senescence and fibrosis and discuss potential therapeutic strategies to address mitophagy dysfunction in treating pulmonary fibrosis.
    DOI:  https://doi.org/10.1007/s11033-025-10665-2
  21. J Hazard Mater. 2025 Jun 06. pii: S0304-3894(25)01770-4. [Epub ahead of print]495 138854
    Fine particulate matter exacerbates asthma by activating STC2-mediated mitophagy through METTL3/YTHDF2-dependent m6A methylation.
    Yao Liu, Guoping Li, Anying Xiong, Jiliu Liu, Ruitong Zeng, Lei Zhang, Junyi Wang, Manling Jiang, Jie Gao, Ying Xiong, Xiang He.
      The impact of fine particulate matter (PM2.5) on respiratory health, especially in the context of asthma exacerbation, is a critical environmental concern. Our study delved into the molecular mechanisms by which PM2.5 intensified asthma in mice, with a particular focus on N6-methyladenosine (m6A) methylation, mitophagy, and the regulatory roles of STC2 and SQSTM1. Utilizing single-cell RNA sequencing (scRNA-seq), we identified significant changes in immune cell distribution and a notable decrease in epithelial cell numbers in asthmatic mice exposed to PM2.5. We further uncovered that PM2.5 exposure significantly increased m6A methylation in STC2 mRNA, leading to up-regulation of STC2 expression and activation of mitophagy. Mechanistic investigations revealed that METTL3, a key methyltransferase, up-regulated STC2 through m6A-dependent mRNA stability and YTHDF2 binding. STC2, in turn, increased SQSTM1 levels by inhibiting proteasomal degradation, thereby enhancing mitochondrial autophagy and asthma severity. Additionally, we collected peripheral blood samples from asthma patients across different seasons and found that serum concentrations of METTL3 and STC2 were significantly higher during winter, a period of high PM2.5 levels, compared to summer when PM2.5 levels are typically lower. Our findings underscore the potential of targeting m6A methylation and mitophagy as therapeutic strategies for asthma exacerbated by environmental pollution.
    Keywords:  Asthma exacerbation; Mitophagy; PM(2.5); STC2; Ubiquitination; m6A methylation
    DOI:  https://doi.org/10.1016/j.jhazmat.2025.138854
  22. bioRxiv. 2025 May 26. pii: 2025.05.21.655403. [Epub ahead of print]
    Mitochondrial fusion controls the development of specialized mitochondrial structure and metabolism in rod photoreceptor cells.
    Michael Landowski, Ryo Hagimori, Purnima Gogoi, Vijesh J Bhute, Sakae Ikeda, Tetsuya Takimoto, Akihiro Ikeda.
      Mitochondria are dynamic organelles that undergo continuous morphological changes, yet exhibit unique, cell-type-specific structures. In rod photoreceptor cells of the retina, these structures include elongated mitochondria in the inner segments and a distinct, large, circular mitochondrion in each presynaptic terminal. The mechanisms underlying the establishment and maintenance of these specialized mitochondrial morphologies, along with their functional significance, are not well understood. Here, we investigate the roles of mitochondrial fusion proteins mitofusin 1 (MFN1) and mitofusin 2 (MFN2) in shaping these structures and maintaining photoreceptor cell health. Rod photoreceptor cell-specific ablation of MFN1 and MFN2 resulted in mitochondrial fragmentation by one month of age, suggesting that mitochondrial fusion is essential for the development of photoreceptor cell-specific mitochondrial structures. Notably, the layer structures of the retina examined by light microscopy appeared unaffected at this age. Following this time period, significant photoreceptor cell degeneration occurred by three months of age. Furthermore, we showed that impaired mitochondrial fusion perturbed the balance of proteins involved in glycolysis, oxidative phosphorylation (OXPHOS), and β-oxidation, highlighting the critical role of mitochondrial fusion in ensuring the proper levels of proteins necessary for optimal energy metabolism. Additionally, we identified upregulation of cellular stress pathways such as endoplasmic reticulum (ER) stress and unfolded protein response (UPR), which arise in response to energy deprivation, and cytoprotective biosynthetic pathways mediated by CCAAT/enhancer-binding protein gamma (C/EBPγ) and mammalian target of rapamycin complex 1 (mTORC1) signaling. In summary, our findings indicate that mitochondrial fusion through MFN1 and MFN2 is vital for the development of unique mitochondrial structures and proper energy production, underscoring the fundamental importance of mitochondrial dynamics in photoreceptor cell function and survival.
    Significance Statements: Rod photoreceptor cells exhibit unique mitochondrial morphologies and high energy requirements. In this report, we examined how these unique mitochondrial structures are established and their biological significance. We identified that mitochondrial fusion is essential for the development of characteristic mitochondrial morphologies in rod photoreceptor cells. Furthermore, we demonstrated that impaired mitochondrial fusion disrupts the equilibrium of proteins associated with OXPHOS, glycolysis, and β-oxidation, ultimately leading to an imbalance in cellular energy homeostasis. Our findings also revealed activation of cellular stress pathways, including ER stress and the UPR, which are likely triggered by energy depletion. Additionally, we identified activation of cytoprotective biosynthetic pathways that are engaged to preserve cellular homeostasis and function.
    DOI:  https://doi.org/10.1101/2025.05.21.655403
  23. Toxicology. 2025 Jun 04. pii: S0300-483X(25)00172-6. [Epub ahead of print]517 154213
    The synthetic cannabinoids ADB-FUBINACA and AMB-FUBINACA enhance in vitro neurodifferentiation of NG108-15 cells, along with PGC-1α dysregulation and mitochondrial dysfunction.
    Rui Filipe Malheiro, João Figueiredo, Helena Carmo, Félix Carvalho, João Pedro Silva.
      There is growing concern regarding the use of Synthetic Cannabinoids (SCs) by young adults (including pregnant and breastfeeding women, and women of childbearing age), due to their potential to cause neurodevelopmental disorders. Here, we first-hand assessed the in vitro impact of two indazole-derived SCs, ADB-FUBINACA and AMB-FUBINACA, on the neurodifferentiation of NG108-15 cells, especially focusing on their modulation of mitochondrial function during such process. Both SCs tested enhanced neurite outgrowth in NG108-15 cells at biologically-relevant concentrations (< 1 μM), a process that was blocked by SR141716A and hemopressin (antagonists of cell membrane and intracelular CB1 receptors, respectively). Moreover, this effect was accompanied by a CB1 receptor-independent reduction in mitochondrial membrane potential. Interestingly, ADB-FUBINACA, but not AMB-FUBINACA, decreased intracellular ATP levels through CB1 activation. Notably, voltage-dependent anion channel (VDAC) expression, an indirect marker of mitochondrial mass, remained unchanged during exposure to both SCs. ADB-FUBINACA increased the expression of the key energy regulator PGC-1α in the cytosol (1pM-1µM), while decreasing it in the mitochondrial fraction (1 nM and 1 µM), without affecting its nuclear translocation, supporting its role in mitochondrial turnover. Other mitogenesis markers, like NFR-1 and TFAM, remain unchanged. Additionaly, the Parkin-PINK1 mitophagy pathway was not activated at the concentrations tested. Our findings demonstrate that ADB-FUBINACA and AMB-FUBINACA enhance neuronal differentiation of NG108-15 cells via CB1 receptor activation, while concomitantly promoting mitochondrial dysfunction. Although further research is required to fully elucidate the mechanisms underlying these observations, our data already suggests that these SCs may impact proper neurodevelopment.
    Keywords:  Endocannabinoid system; Mitochondrial biogenesis; Mitophagy; Neurodevelopment; New psychoactive substances
    DOI:  https://doi.org/10.1016/j.tox.2025.154213
  24. Mol Cell. 2025 Jun 03. pii: S1097-2765(25)00460-5. [Epub ahead of print]
    Mitochondrial fumarate inhibits Parkin-mediated mitophagy.
    Su Jin Ham, Sunhoe Bang, Daihn Woo, Jae-Yoon Jo, Takwon Yoo, Eunju Yoon, Yeonju Kyoung, Daehyun Baek, Jong-Seo Kim, Jongkyeong Chung.
      Here, we explore the potential involvement of fumarate, a metabolite generated from the TCA cycle, as a key regulator of PINK1-Parkin-mediated mitophagy. Fumarate engages in a process called succination, forming S-(2-succino) cysteine with protein cysteine residues. Our research demonstrates that this modification specifically targets the sulfhydryl group of cysteine 323 and 451 residues of human Parkin, leading to the inhibition of its mitochondrial localization and E3 ligase activity, thereby impeding PINK1-Parkin-mediated mitophagy. Notably, our investigation reveals that the succinatable cysteines in human Parkin are not conserved in invertebrates, including Drosophila. To assess the functional impact of Parkin succination, we generate Parkin knockin flies with succinatable cysteines. These flies exhibit robust Parkinson's disease (PD)-related phenotypes when exposed to elevated fumarate levels. Collectively, our findings underscore the significance of fumarate as an endogenous regulator of PINK1-Parkin-mediated mitophagy, offering insights into the intricate interplay between mitochondrial metabolic activities and PD pathology.
    Keywords:  ANT1; PINK1; Parkinson's disease; VDAC1/2; fumarate; parkin; succination
    DOI:  https://doi.org/10.1016/j.molcel.2025.05.021
  25. Mol Ther Oncol. 2025 Jun 18. 33(2): 200995
    ER-mitochondria tethering and its signaling: A novel therapeutic target in breast cancer.
    Chamanthi Paidi, Yerusha Nuthalapati, Anuveda Sree Samudrala, Priyamvada Bhamidipati, Charanteja Mangam, Danny R Welch, Ganji Purnachandra Nagaraju, RamaRao Malla.
      Communication between the endoplasmic reticulum (ER) and mitochondria through mitochondria-associated ER membranes (MAMs) is assisted by tethering proteins and signaling pathways, manifesting the dynamic exchange of lipids, calcium, and signaling molecules. However, dysregulation of tethering and signaling proteins contributes to the progression of breast cancer (BC). Abnormal MAM structures and altered ER-mitochondrial tethering impair mitochondrial functions and thereby drive BC progression. Altered mitochondrial dynamics, often characterized by dysregulated dynamin-related protein 1 (Drp1) and mitofusin-2 (Mfn2) activity, enhances BC cell survival. Similarly, ER stress and the unfolded protein response, both modulated by dysregulated ER-mitochondrial contacts, promote drug resistance. In BC, caveolae-dependent and -independent caveolin-1 signaling alongside Yes-associated protein (YAP) signaling pathway alters organelle dynamics by interacting with Drp1 and Mfn2, underscoring their therapeutic potential. This review explores potential therapeutic strategies targeting ER-mitochondrial communications and their potential for hindering BC progression. These strategies include modulating mitochondrial dynamics and promoting controlled ER stress by disrupting aberrant ER-mitochondrial tethering using chemotherapeutics, clinical inhibitors, and natural compounds, alone or in combination. Ultimately, targeting dysregulated ER-mitochondrial tethering has significant potential to improve patient outcomes in BC.
    Keywords:  ER-mitochondria tethering; MT: Regular Issue; ROS; YAP; breast cancer; caveolin-1
    DOI:  https://doi.org/10.1016/j.omton.2025.200995
  26. Kidney Int. 2025 Jun 10. pii: S0085-2538(25)00431-4. [Epub ahead of print]
    Protein kinase ROCK1 activates mitochondrial fission linking to oxidative stress and muscle atrophy.
    Meijun Si, Jihong Chen, Rizhen Yu, Hongchun Lin, Feng Li, Sungyun Jung, Sandhya S Thomas, Farhard R Danesh, Yanlin Wang, Hui Peng, Zhaoyong Hu.
       INTRODUCTION: Chronic kidney disease (CKD) is associated with protein-energy wasting, characterized by a reduction in muscle mass and strength. Although mitochondrial dysfunction and oxidative stress are implicated in the pathogenesis of muscle wasting, underlying mechanisms remain unclear.
    METHODS: Here, we used transcriptomic analysis, metabolomics analyses, and mouse gene manipulation to investigate the effects of mitochondrial plasticity and oxidative stress on muscle wasting the subtotal nephrectomy mouse models of CKD. The mice with CKD were age- and sex-matched to sham-operated controls.
    RESULTS: Through these approaches, Rho-associated kinase ROCK1 emerged as a key molecule responsible for the observed mitochondrial fission and oxidative stress. Specifically, our results showed that the expression of oxidative stress response genes increased, and that of oxidative phosphorylation genes decreased in the muscles of mice with CKD. This was accompanied by reduced oxygen consumption rates, decreased levels of mitochondrial electron transport chain proteins, and increased cellular oxidative damage. Excessive mitochondrial fission was also observed, and we found that the activation of ROCK1 was responsible for this process. Inducible expression of muscle-specific constitutively active ROCK1 exacerbated mitochondrial fragmentation and muscle wasting in CKD mice. Conversely, ROCK1 depletion (ROCK1-/-) alleviated these phenomena. Mechanistically, ROCK1 activation promoted the recruitment of dynamin-related protein 1 to mitochondria, thereby facilitating mitochondrial fission. Notably, pharmacological inhibition of ROCK1 mitigated muscle wasting by suppressing mitochondrial fission and oxidative stress.
    CONCLUSIONS: Our findings demonstrate that ROCK1 participates in CKD-induced muscle wasting by promoting mitochondrial fission and oxidative stress. Pharmacological suppression of ROCK1 could be a therapeutic strategy for combating muscle wasting in CKD conditions.
    Keywords:  Muscle atrophy; ROS; chronic kidney disease; mitochondrial fission; oxidative stress
    DOI:  https://doi.org/10.1016/j.kint.2025.05.019
  27. Mol Neurobiol. 2025 Jun 13.
    Polyphenols and Exercise in Mitochondrial Biogenesis: Focus on Age-Related CNS Disorders.
    Junbiao Tu.
      Age-related central nervous system (CNS) disorders, including neurodegenerative diseases, represent a growing global health burden. Mitochondrial dysfunction is a recognized hallmark in the pathogenesis of these conditions, emphasizing the critical importance of maintaining neuronal energy homeostasis and cellular integrity. Mitochondrial biogenesis, the dynamic process of generating new, functional mitochondria, is paramount for neuronal health and resilience against age-related decline. This review investigates the therapeutic potential of physical activity and polyphenols in modulating mitochondrial biogenesis and offering neuroprotection within the context of age-related CNS disorders. We explore how regular exercise profoundly impacts the brain by enhancing synaptic plasticity, promoting neurogenesis via neurotrophic factors like BDNF, and stimulating mitochondrial biogenesis through pathways such as PGC-1alpha activation. These adaptations collectively improve cognitive function and bolster neuronal resistance to damage. Concurrently, polyphenols, known for their antioxidant and anti-inflammatory properties, demonstrate significant neuroprotective effects. They are capable of crossing the blood-brain barrier and influencing key neuronal signaling pathways, directly stimulating mitochondrial biogenesis, and mitigating oxidative stress, thereby supporting neuronal survival. By synthesizing current evidence, this review highlights the complementary and potentially synergistic roles of exercise and polyphenols in preserving mitochondrial health and function in the CNS. The combined impact of these interventions offers a promising non-pharmacological strategy to combat age-related neurodegeneration. Future research should focus on optimizing exercise protocols and polyphenol interventions in human trials to maximize their neurotherapeutic benefits for CNS disorders.
    Keywords:  Age-related central nervous system disorders; Exercise; Mitochondrial biogenesis; Polyphenol
    DOI:  https://doi.org/10.1007/s12035-025-05121-y
  28. J Interferon Cytokine Res. 2025 Jun 13.
    IL-33 Has a Protective Effect Against Perinatal Listeriosis by Regulating Mitophagy of CD8+ T Lymphocytes.
    Tingjuan Shi, Yuxi Yang, Yingying Li, Ning Xu, Fei Chen, Tian Xia, Hongliang Wu, Yingyi Luan, Chenghong Yin.
      Listeriosis is a foodborne disease caused by Listeria monocytogenes (Lm) that usually leads to serious adverse outcomes in pregnant women. Interleukin (IL)-33/serum stimulation (ST)2 axis has an important impact on infectious diseases, but its role in listeriosis is rarely studied. Here, the immunomodulatory effects of IL-33/ST2 axis during perinatal Lm infection were investigated. In our study, the perinatal Lm infection model was constructed by injecting Lm into the tail vein of C57BL/6J mice. IL-33/ST2 axis was blocked by intraperitoneal injection of anti-IL-33Rα/ST2 antibody. In vitro, mouse cytotoxic T lymphocyte cell line (CTLL)-2 cells were activated by using CD3/CD28 antibodies. Perinatal Lm infection caused massive necrosis of liver tissue. Blocking IL-33/ST2 axis in pregnant mice inhibited the infiltration of CD8+ T lymphocytes into the site of infection and further aggravated liver damage. We also found that IL-33 promotes mitochondrial autophagy in activated CTLL-2 cells in vitro. Mitochondrial autophagy was beneficial to the clearance of damaged mitochondria and reduced the production of reactive oxygen species. IL-33/ST2 axis affects the immune function of CD8+ T lymphocytes by regulating mitophagy, which plays a very important role in the occurrence and development of perinatal Lm infection. Immunomodulation targeting IL-33/ST2 axis may be an effective way to adjuvant treatment of perinatal Lm infection.
    Keywords:  CD8+ T lymphocytes; IL-33; listeriosis; mitophagy; perinatal infection
    DOI:  https://doi.org/10.1089/jir.2025.0069
  29. J Nanobiotechnology. 2025 Jun 11. 23(1): 437
    Polystyrene microplastics exacerbate mitophagy through mitochondrial dysfunction in the duck lung.
    Tiantian Gu, Minghua Kong, Mingcai Duan, Li Chen, Yong Tian, Wenwu Xu, Tao Zeng, Lizhi Lu.
      Microplastics (MPs) are widespread environmental pollutants that can enter the human body through the food chain, potentially leading to lung damage. However, the underlying mechanisms responsible for this damage remain unclear. Ducks, a commonly consumed poultry species in China, are particularly susceptible to MPs exposure due to their farming environment. In this study, Shaoxing ducklings were administered two distinct concentrations of polystyrene microplastics (PS-MPs) (1 mg/L and 100 mg/L) via oral route, alongside a control group, over a period of four weeks to establish an in vivo model for evaluating the effects of microplastic exposure in ducks. Simultaneously, rat type II alveolar epithelial (RLE-6TN) cells were exposed to different concentrations of PS-MPs (0, 10, 100, and 500 µg/mL) for 48 h, thereby constructing an in vitro exposure model. Our results showed that PS-MPs caused pathological damage, inflammatory cell infiltration, and activation of the LPS/TLR4 inflammatory pathway in the lung. Further analysis revealed that PS-MPs disrupted the tricarboxylic acid (TCA) cycle and inhibited oxidative phosphorylation. Mechanistic investigation demonstrated that PS-MPs induced mitochondrial dysfunction and consequent excessive mitophagy. This study investigates the mechanisms by which PS-MPs contribute to mitochondrial dysfunction and mitophagy, potentially exacerbating lung inflammation, offering valuable insights for mitigating the toxic effects of PS-MPs on human and animal health.
    Keywords:  Duck; Mitochondrion; Mitophagy; Polystyrene microplastics; TCA cycle
    DOI:  https://doi.org/10.1186/s12951-025-03503-x
  30. Toxicology. 2025 Jun 07. pii: S0300-483X(25)00173-8. [Epub ahead of print] 154214
    Role of neuroglia cell-derived microvesicles in cobalt chloride-induced mitochondrial autophagy in neurons.
    Husheng Li, Fuli Zheng, Wenya Shao, Guangxia Yu, Hong Hu, Zhenkun Guo, Siying Wu, Ying Tang, Huangyuan Li.
      The extensive use of cobalt resources has significantly increased the risk of cobalt contamination globally, with cobalt chloride posing a serious environmental and health concern. Although previous studies have shown that extracellular vesicles play a key role in intercellular communication, the mechanisms by which extracellular vesicles derived from neuroglia cells affect neuronal cells remain poorly understood. This study aimed to investigate whether microvesicles produced by neuroglia cells could mitigate cobalt chloride-induced neuronal damage and to explore the underlying mechanisms. Our results revealed that cobalt chloride induces cytotoxicity in HT22 and MN9D neuronal cells. A 24-hour cobalt chloride treatment triggered mitochondrial autophagy in both cell types and disrupted their mitochondrial dynamics. Further analysis showed that microvesicles secreted by GL261 neuroglia cells were taken up by both types of neuronal cells. Notably, the uptake of GL261-derived microvesicles by MN9D cells inhibited autophagy and restored mitochondrial membrane potential and reactive oxygen species levels. In conclusion, our findings highlight the critical role of neuroglia cell-derived microvesicles in cobalt chloride-induced neuronal toxicity and offer potential new targets and strategies for the prevention and treatment of cobalt chloride toxicity.
    Keywords:  cellular microvesicles; cobalt chloride; mitochondrial autophagy; neuronal damage
    DOI:  https://doi.org/10.1016/j.tox.2025.154214
  31. Int J Gen Med. 2025 ;18 2881-2899
    Exploring the Potential Regulatory Mechanisms of Mitophagy in Ischemic Cardiomyopathy.
    Zhaobin Li, Jiajie Kong, Shuqiang Xi, Zeyue Jin, Fan Yang, Zhe Zhu, Lei Liu.
       Purpose: Ischemic cardiomyopathy (ICM) was a clinical syndrome. Long - term myocardial blood supply insufficiency, caused by coronary atherosclerotic plaque, led to myocardial nutritional disorders and atrophy. After large - scale myocardial infarction, fibrous tissue hyperplasia impaired cardiac systolic and/or diastolic functions, causing heart failure and arrhythmia. Study shows that dysregulated mitophagy can lead to cardiomyocyte death and cardiomyopathy. However, it is still uncertain how mitophagy related genes (MRGs) may affect the diagnosis of ICM.
    Patients and Methods: Data were obtained from public databases. Subsequently, mitochondria autophagy score-related genes (MSRGs) were obtained through Weighted Gene Co-expression Network Analysis (WGCNA). Then, an intersection was taken between MSRGs and the differentially expressed genes (DEGs) obtained from the differential expression analysis to obtain DE-MSRGs. Then, biomarkers were identified through machine learning algorithms and Receiver Operating Characteristic curve (ROC) analysis. Next, analyses of immune infiltration, molecular regulatory network, and drug prediction were carried out. Finally, Reverse Transcription Quantitative Polymerase Chain Reaction (RT-qPCR) was performed on the biomarkers. It provides a certain theoretical basis for the research on the mechanism of the occurrence and development of ICM.
    Results: In total, 99 DE-MSRGs between ICM and control groups were gained. The four biomarkers (PPDPF, DPEP2, LTBP1, SOCS2) were acquired, and all biomarkers had good diagnostic efficacy for ICM. The content of 3 immune cells between ICM and control groups was significantly different, namely T cells, CD8+ T cells, and neutrophil, and all biomarkers were considerably positively correlated with T cells. The ceRNA network contained 4 mRNAs, 14 miRNAs, and 12 lncRNAs, and TF-mRNA network contained 32 nodes and 38 edges. Finally, 45 drugs targeting the biomarkers were predicted, such as Salmeterol, Histamine, Rotavirus vaccine, etc. Importantly, this all 4 biomarkers were higher in ICM samples in RT-qPCR analysis.
    Conclusion: Our findings provided four mitophagy related biomarkers (PPDPF, DPEP2, LTBP1, and SOCS2) for diagnosis of ICM, providing a scientific reference for further studies of ICM.
    Keywords:  LASSO; ROC; ceRNA; ischemic cardiomyopathy; mitophagy
    DOI:  https://doi.org/10.2147/IJGM.S519388
  32. Front Cardiovasc Med. 2025 ;12 1506388
    Yellow Wine Polyphenolic Compounds protect against myocardial ischemia-reperfusion injury in rats by activating Nrf2 nuclear translocation to regulate the balance of mitochondrial fission and fusion.
    Lili Xu, Jiedong Zhou, Haifei Lou, Haodi Gu, Haixia Xu, Zuoquan Zhong, Hui Lin, Chengjian Jiang.
       Background: Myocardial ischemia-reperfusion injury is a pathological phenomenon that occurs after coronary blood flow restoration and poses a threat to patients' lives. Its mechanisms are closely related to oxidative stress and mitochondrial dysfunction. Yellow Wine Polyphenolic Compounds, a dietary polyphenol with significant antioxidant effects, have been shown to offer protection in various cardiovascular diseases. However, their role in MIRI remains under-researched.
    Methods: In vivo experiments, TTC staining was used to assess myocardial viability, and cardiac ultrasound was employed to measure left ventricular ejection function. Morphological staining and detection of myocardial injury markers were used to evaluate cardiac damage. Transmission electron microscopy was used to observe mitochondrial morphology in myocardial tissue, and ELISA was performed to evaluate the activity of mitochondrial complexes. Adeno-associated virus knockdown was utilized to verify the role of Nrf2. In in vitro experiments, confocal microscopy was used to scan mitochondrial morphology in cardiomyocytes and to observe the intracellular localization of the Nrf2 molecule.
    Results: TTC staining showed that MIRI significantly increased the infarct size in the left ventricle, whereas pre-treatment with YWPC (Yellow Wine Polyphenol Compound) significantly reduced the infarct area. Cardiac ultrasound demonstrated that YWPC intervention preserved left ventricular ejection fraction. Morphological staining and detection of myocardial injury markers revealed that MIRI caused tissue edema, increased myocardial apoptosis and damage, but YWPC pre-treatment alleviated these injuries. Transmission electron microscopy showed that YWPC reversed the excessive mitochondrial fission caused by MIRI. Immunofluorescence indicated that YWPC significantly promoted Nrf2 nuclear translocation and increased the expression of downstream antioxidant molecules.
    Conclusion: YWPC pre-treatment can protect myocardial tissue by reducing the excessive mitochondrial fission induced by MIRI, and Nrf2 mediates these effects.
    Keywords:  Nrf2; Yellow Wine Polyphenolic Compounds; ischemia-reperfusion; mitochondrial dynamics; oxidative stress
    DOI:  https://doi.org/10.3389/fcvm.2025.1506388
  33. Mol Med. 2025 Jun 11. 31(1): 234
    Bavachin ameliorates cisplatin-induced nephrotoxicity by enhancing mitochondrial β-oxidation and lipid metabolism through MFN2.
    Shilu Luo, Ming Yang, Na Jiang, Chenrui Li, Yan Liu, Lin Sun.
       BACKGROUND: Cisplatin-induced nephrotoxicity is a critical adverse reaction that restricts the clinical utilization of cisplatin. Alterations in fatty acid metabolism have been associated with the pathogenesis of cisplatin-induced nephrotoxicity, yet the precise mechanisms remain unclear. Bavachin, a natural flavonoid, exhibits anti-inflammatory, antioxidant, and lipid metabolism-regulating properties, yet its role in mitigating cisplatin-induced nephrotoxicity via mitochondrial β-oxidation remains unexplored. Mitofusin-2 (MFN2), a mitochondrial fusion protein, has emerged as a critical regulator of fatty acid oxidation (FAO) and lipid homeostasis. However, its role in cisplatin-induced nephrotoxicity has not been fully explored.
    METHODS: C57/6L mice were randomly divided into control, DMSO, cisplatin, and cisplatin + Bavachin groups. Blood urea nitrogen (BUN), serum creatinine (SCr), reactive-oxygen-species (ROS), lipid accumulation, and apoptosis were assessed. In vitro, the human proximal tubule epithelial cell line (HK-2) cells were treated with 20 µM cisplatin with or without bavachin. ROS production was detected by the DCFH-DA, lipid deposition was detected by oil red O staining, and MFN2, carnitine palmitoyltransferase 1a (CPT1a) were detected by Western blot (WB).
    RESULTS: Compared with the cisplatin group, bavachin treatment reduced BUN (21.8%) and SCr (78.7%) in the cisplatin group, accompanied by improvements in renal pathological changes, lipid deposition, and apoptosis. In addition, bavachin up-regulated the expression of MFN2 and CPT1a, while decreasing the cisplatin-induced ROS overproduction. Similar results were found in vitro. Notably, the mitochondrial FAO has been increased in HK-2 cells treated with bavachin. Further, MFN2 siRNA partially reversed these protective effects, accompanied by decreased CPT1a expression and exacerbated lipid deposition.
    CONCLUSIONS: This study is the first to confirm MFN2 as a target for renal protection by bavachin. Mechanistically, Bavachin alleviated cisplatin-induced lipid accumulation and apoptosis by upregulating MFN2 expression, which activated CPT1a to promote mitochondrial FAO. These results will provide a new strategy for cisplatin-based cancer therapy and the reduction of its nephrotoxicity.
    Keywords:  Acute kidney injury; Bavachin; Lipid accumulation; MFN2; Mitochondrial dynamics; Oxidative stress; Renal protection
    DOI:  https://doi.org/10.1186/s10020-025-01283-6
  34. J Clin Med. 2025 May 25. pii: 3706. [Epub ahead of print]14(11):
    Mitochondrial Dysfunction in the Development and Progression of Cardiometabolic Diseases: A Narrative Review.
    Loukia Pliouta, Stamatios Lampsas, Aikaterini Kountouri, Emmanouil Korakas, John Thymis, Eva Kassi, Evangelos Oikonomou, Ignatios Ikonomidis, Vaia Lambadiari.
      Mitochondria play a central role in energy metabolism and continuously adapt through dynamic processes such as fusion and fission. When the balance between these processes is disrupted, it can lead to mitochondrial dysfunction and increased oxidative stress, contributing to the development and progression of various cardiometabolic diseases (CMDs). Their role is crucial in diabetes mellitus (DM), since their dysfunction drives β-cell apoptosis, immune activation, and chronic inflammation through excessive ROS production, worsening endogenous insulin secretion. Moreover, sympathetic nervous system activation and altered dynamics, contribute to hypertension through oxidative stress, impaired mitophagy, endothelial dysfunction, and cardiomyocyte hypertrophy. Furthermore, the role of mitochondria is catalytic in endothelial dysfunction through excessive reactive oxygen species (ROS) production, disrupting the vascular tone, permeability, and apoptosis, while impairing antioxidant defense and promoting inflammatory processes. Mitochondrial oxidative stress, resulting from an imbalance between ROS/Reactive nitrogen species (RNS) imbalance, promotes atherosclerotic alterations and oxidative modification of oxidizing low-density lipoprotein (LDL). Mitochondrial DNA (mtDNA), situated in close proximity to the inner mitochondrial membrane where ROS are generated, is particularly susceptible to oxidative damage. ROS activate redox-sensitive inflammatory signaling pathways, notably the nuclear factor kappa B (NF-κB) pathway, leading to the transcriptional upregulation of proinflammatory cytokines, chemokines, and adhesion molecules. This proinflammatory milieu promotes endothelial activation and monocyte recruitment, thereby perpetuating local inflammation and enhancing atherogenesis. Additionally, mitochondrial disruptions in heart failure promote further ischemic injury and excessive oxidative stress release and impair ATP production and Ca2⁺ dysregulation, contributing to cell death, fibrosis, and decreased cardiac performance. This narrative review aims to investigate the intricate relationship between mitochondrial dysfunction and CMDs.
    Keywords:  cardiovascular disease; metabolic syndrome; mitochondrial dynamics; mitochondrial dysfunction
    DOI:  https://doi.org/10.3390/jcm14113706
  35. J Pharm Anal. 2025 May;15(5): 101145
    Natural products for the treatment of age-related macular degeneration: New insights focusing on mitochondrial quality control and cGAS/STING pathway.
    Xuelu Xie, Shan Lian, Wenyong Yang, Sheng He, Jingqiu He, Yuke Wang, Yan Zeng, Fang Lu, Jingwen Jiang.
      Age-related macular degeneration (AMD) is a disease that affects the vision of elderly individuals worldwide. Although current therapeutics have shown effectiveness against AMD, some patients may remain unresponsive and continue to experience disease progression. Therefore, in-depth knowledge of the mechanism underlying AMD pathogenesis is urgently required to identify potential drug targets for AMD treatment. Recently, studies have suggested that dysfunction of mitochondria can lead to the aggregation of reactive oxygen species (ROS) and activation of the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) innate immunity pathways, ultimately resulting in sterile inflammation and cell death in various cells, such as cardiomyocytes and macrophages. Therefore, combining strategies targeting mitochondrial dysfunction and inflammatory mediators may hold great potential in facilitating AMD management. Notably, emerging evidence indicates that natural products targeting mitochondrial quality control (MQC) and the cGAS/STING innate immunity pathways exhibit promise in treating AMD. Here, we summarize phytochemicals that could directly or indirectly influence the MQC and the cGAS/STING innate immunity pathways, as well as their interconnected mediators, which have the potential to mitigate oxidative stress and suppress excessive inflammatory responses, thereby hoping to offer new insights into therapeutic interventions for AMD treatment.
    Keywords:  Age-related macular degeneration; Mitochondrial biogenesis; Mitochondrial quality control; Mitophagy; Phytochemicals; cGAS/STING
    DOI:  https://doi.org/10.1016/j.jpha.2024.101145
  36. Biochim Biophys Acta Mol Cell Res. 2025 Jun 06. pii: S0167-4889(25)00103-X. [Epub ahead of print] 119998
    Impact of PARL-mediated mitochondrial protease activity on calcium regulation.
    Donato D'Angelo, Aya Al Saidi, Giorgia Ghirardo, Denis Vecellio Reane, Nicola Gasparini, Rosario Rizzuto, Anna Raffaello.
      The presenilin-associated rhomboid-like protein (PARL) is a mitochondrial inner membrane serine protease that is a key regulator of several cellular processes, including apoptosis, metabolism, inflammation and stress responses. While recent studies suggest that PARL may play a role in mitochondrial calcium homeostasis, the underlying mechanisms remain poorly understood. In this study, we investigated the effects of PARL modulation on mitochondrial and cytosolic calcium dynamics, as well as mitochondrial membrane potential. Our results show that altering PARL protein levels, through both overexpression and silencing, significantly affects mitochondrial calcium uptake, without influencing cytosolic calcium transients or mitochondrial membrane potential. Despite the observed changes in mitochondrial calcium dynamics, PARL does not interact with the mitochondrial calcium uniporter complex (mtCU) regulators MICU1 and MICU2, which are critical for regulating mitochondrial calcium influx. However, we observed alterations in the protein levels of MICU1 and MICU2, either in their monomeric or dimeric forms, suggesting that PARL may influence these mtCU components indirectly. Interestingly, the pore-forming subunit MCU, and the structural subunit EMRE, essential for the assembly of the mtCU, were unaffected by PARL modulation. These findings suggest that the role of PARL in modulating mitochondrial calcium homeostasis may involve indirect mechanisms, potentially involving other regulatory pathways. Overall, our study provides novel insights into the functional role of PARL in mitochondrial calcium regulation, offering potential avenues for further investigation into its broader cellular functions.
    Keywords:  Calcium signaling; Mitochondria; Mitochondrial calcium uniporter; Mitochondrial intermembrane proteolysis; PARL; Rhomboid protease
    DOI:  https://doi.org/10.1016/j.bbamcr.2025.119998
  37. FASEB J. 2025 Jun 15. 39(11): e70723
    Tmx2 Maintains Mitochondrial Function to Support Preimplantation Embryogenesis.
    Shangrong Zhang, Qing Liu, Siyu Wang, Xiaoyu Zhang, Dingmei Qin, Ruisong Bai, Ji Chen, Zijian Ma, Zhipeng Lin, Yuheng Bi, Huan Liu, Aoxue Sun, Zhongzhi Mo, Hongcheng Wang, Xiaoqing Wu, Yong Liu.
      Thioredoxin (TRX)-related transmembrane proteins (TMX), a subgroup of the protein disulfide isomerase (PDI) family, comprise a class of transmembrane proteins with diverse biological functions. Among these, TMX2 (PDIA12) remains one of the least characterized members. Recent studies have identified missense mutations in TMX2 associated with aberrant brain development and cerebellar malformations, highlighting its potential importance in developmental processes. Notably, Tmx2 mutant embryos exhibit developmental arrest at the E3.5 stage, suggesting a critical role in preimplantation embryogenesis. However, the precise molecular and cellular functions of Tmx2 in mammalian embryonic development remain largely unexplored. In this study, we provide novel insights into the essential role of Tmx2 during preimplantation embryonic development in mice. We demonstrate that TMX2 is specifically expressed in mouse embryos, with its subcellular localization closely associated with mitochondria during the two-cell to eight-cell stages. Knockdown of Tmx2 recapitulates the phenotypic defects observed in genetic mutants, revealing a pronounced impairment in blastomere proliferation, as confirmed by EdU incorporation assays. Furthermore, TUNEL assays indicate a significant increase in apoptotic signaling in Tmx2-deficient embryos, accompanied by elevated mRNA levels of the cell cycle inhibitors p21 and p53. Mechanistically, we show that Tmx2 knockdown disrupts mitochondrial function, leading to oxidative stress and impaired mitophagy and autophagy in developing embryos. These findings suggest that Tmx2 plays a pivotal role in maintaining mitochondrial integrity and cellular homeostasis during preimplantation embryogenesis. In summary, our study elucidates the critical role of Tmx2 in preimplantation embryonic development in mice, primarily through its regulation of mitochondrial function. These results advance our understanding of the molecular mechanisms governing preimplantation embryonic development and establish Tmx2 as a key regulator of mitochondrial dynamics and cellular survival during this critical developmental window.
    Keywords:   Tmx2 ; autophagy; embryo development; mice; mitochondrial dysfunction
    DOI:  https://doi.org/10.1096/fj.202500640R
  38. J Hazard Mater. 2025 Jun 04. pii: S0304-3894(25)01739-X. [Epub ahead of print]495 138823
    Tea polyphenols attenuate glufosinate-induced breast injury by reducing endoplasmic reticulum stress and autophagy.
    Fu Li, Zhanhang Wang, Muhua Luo, Jiaxiang Hu, Haifeng Wang, Yonglong He, Danni Li, Yuan Yuan, Jinxing Hou, Yuxuan Song, Lei Zhang, Binyun Cao, Xiaopeng An.
      Owing to the excessive use of glyphosate-based herbicides (GBHs), the amount of drug residues in corn and alfalfa silage exceeds the standard, which may affect the mammary health of dairy animals. The role of glufosinate-ammonium (GLA) in mammary development is not fully understood. Therefore, the aim of this study was to investigate mammary lesions caused by exposure to GLA in vitro and in vivo. Based on the GLA exposure limit defined, a pregnant mouse exposure model was established to explore the damage caused by GLA exposure in the mammary gland, and a protective mechanism mediated by tea polyphenols (TP) was proposed. Our study shows that perinatal GLA exposure induces inflammation and oxidative stress in the mammary gland. The expression of oxidoreductase complex and mitochondrial protein complex was down-regulated in H-GLA group, suggesting that GLA may affect mitochondrial function. The combined transcriptome and proteomics analysis of mammary gland showed that the differentially expressed genes were enriched in biological regulation and ion transport related biological processes. The key differential gene ER protein retention receptor 1 (KDELR1) suggested that GLA may affect the function of endoplasmic reticulum. In vitro experiments have confirmed that it can activate mitophagy and ERS, and then lead to the up-regulation of apoptosis proteins such as Caspase 3, leading to cell apoptosis, thereby causing breast tissue damage. The strong antioxidant properties of TP can alleviate cell damage by restoring cellular oxidative balance, reducing intracellular ROS content and reducing the expression of inflammatory factors. At the same time, TP could restore the expression of autophagy proteins LC3 and P62, and reduce mitophagy. At the same time, TP can reduce the activation of PERK/eIF2α/CHOP pathway induced by GLA exposure and alleviate ERS, thereby reducing cell apoptosis. These findings shed light on the mechanism of GLA-induced mammary gland damage, improved our understanding of the risk of GLA exposure in domestic animals during pregnancy, and suggested that TP may have potential protective effects against GLA poisoning.
    Keywords:  ER stress; Glufosinate-ammonium (GLA); Mitophagy; Pregnancy toxicity; Tea polyphenols (TP)
    DOI:  https://doi.org/10.1016/j.jhazmat.2025.138823
  39. World J Cardiol. 2025 May 26. 17(5): 104839
    Mechanism of myocardial damage induced by doxorubicin via calumenin-regulated mitochondrial dynamics and the calcium-Cx43 pathway.
    He Shi, Song-Ao Yang, Ling-Yu Bai, Jian-Jun Du, Zhe Wu, Zhi-Hui He, Hao Liu, Jia-Yue Cui, Ming Zhao.
       BACKGROUND: The clinical application of doxorubicin (DOX) is limited by its potential to cause cardiac cardiotoxicity.
    AIM: To investigate the correlation between calumenin (CALU) and mitochondrial kinetic-related proteins in rats with DOX cardiomyopathy.
    METHODS: A rat model of DOX-induced cardiomyopathy was used to evaluate the effects of DOX. We observed the effect of DOX on electrical conduction in cardiomyocytes using the electromapping technique. Masson staining was performed to evaluate myocardium fibrosis. Electron microscopy was used to observe the changes in pathological ultrastructure of the myocardium. Western blotting and ELISAs were performed to detect protein levels and intracellular free Ca2+ concentration.
    RESULTS: DOX slowed conduction and increased conduction dispersion in cardiomyocytes. The myocardial pathology in rats treated with DOX exhibited a significant deterioration, as demonstrated by an increase in mitochondrial Ca2+ concentration and a decrease in the expression of CALU, optic atrophy-1, and Bcl-2. Additionally, there was an increase in the expression of connexin 43 (Cx43) and the mitochondrial mitotic proteins dynamin-related protein 1, CHOP, Cytochrome C, and Bax in DOX rats. Decreased expression of CALU in cardiomyocytes triggered an increase in cytoplasmic free calcium concentration, which would normally be taken up by mitochondria, but decreased expression of mitochondrial outer membrane fusion proteins triggered a decrease in mitochondrial Ca2+ uptake, and the increase in cytoplasmic free calcium concentration triggered cell apoptosis.
    CONCLUSION: Increased cytoplasmic free calcium ion concentration induces calcium overload in ventricular myocytes, leading to decreased Cx43 protein, slowed conduction in myocytes, and increased conduction dispersion, resulting in arrhythmias.
    Keywords:  Apoptosis; Ca2+ concentration; Calumenin; Cardiotoxicity; Doxorubicin; Mitochondrial dynamics
    DOI:  https://doi.org/10.4330/wjc.v17.i5.104839
  40. Front Immunol. 2025 ;16 1585505
    Integrated multi-omics analysis and experimental investigation of mitochondrial dynamics-related genes: molecular subtypes, immune landscape, and prognostic implications in lung adenocarcinoma.
    Sixuan Wu, Junfan Pan, Lijun Zeng, Qihong Pan, Yao Yu, Jincan Lin, Jing Zhang, Yiling Jiang.
       Background: Lung adenocarcinoma (LUAD) is a common and aggressive subtype of lung cancer associated with poor clinical outcomes. The role of mitochondrial dynamics (MD)-related genes in tumor progression and immune regulation remains poorly understood.
    Methods: Data from public databases were integrated, and subtypes were classified based on 23 MD-related genes. A five-gene prognostic model was constructed. Associations between the model and immune infiltration, tumor mutational burden (TMB), tumor stemness, and drug sensitivity were analyzed. The function of the key gene MTCH2 was validated through in vitro experiments.
    Results: Two distinct MD molecular subtypes were identified, exhibiting significant differences in prognosis and immune characteristics. A corresponding risk score model was established. Patients in the low-risk group showed better prognosis and enhanced immune activity, whereas the high-risk group displayed higher TMB and stemness scores. Drug sensitivity analysis revealed distinct responses to chemotherapeutic agents such as cisplatin and docetaxel between risk groups. Functional assays demonstrated that MTCH2 knockout significantly inhibited LUAD cell proliferation, migration, and invasion, and induced G0/G1 phase arrest, suggesting that MTCH2 may act as a potential adverse prognostic marker.
    Conclusion: MD-related genes exhibit strong prognostic and immune subtyping value. The proposed risk model holds clinical potential, and MTCH2 may serve as a promising target for precision therapy in LUAD.
    Keywords:  LUAD; MTCH2; mitochondrial dynamics; prognostic model; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2025.1585505
  41. Adv Healthc Mater. 2025 Jun 12. e2501411
    Intelligent Gene Delivery System Functionalized Metal Implants for Fracture Repair via Remodeling Mitochondrial Homeostasis.
    Gang Zheng, Feng Hu, Mengqian Wu, Yin Zhao, Fengning Li, Jia Fu, Zhongliang Wang, Bo Yuan, Han Lin, Xiang Guo, Jianlin Shi.
      Delayed union and nonunion of fractures are primarily attributed to the impaired osteogenic activities of bone marrow mesenchymal stem cells (BMSCs). Gene therapy targeting BMSCs is emerging as a promising strategy to promote fracture healing. However, the oxidative stress and mitochondrial dysfunction in BMSCs considerably weaken the efficacy of gene therapy. In this study, an intelligent gene delivery system is engineered for targeted gene delivery to BMSCs, utilizing diselenide-bridged mesoporous organosilica nanoparticles (SeMONs) modified with a BMSC-affinity peptide (E7). Compared to conventional mesoporous organosilica nanoparticles, SeMONs exhibit not only superior gene delivery properties but also unique reactive oxygen species (ROS)-responsive degradation and scavenging capabilities. Given that siRNA-Foxf1 (siFoxf1) is known to promote osteogenesis, this gene delivery system carrying siFoxf1 (E7-SeMONs@siFoxf1) is anchored onto metal implants, to create a novel coating designed to promote fracture repair. In vitro, E7-SeMONs@siFoxf1 synergistically promoted BMSCs osteogenesis by restoring mitochondrial homeostasis and upregulating osteogenic gene expression. In vivo, metal implants coated with E7-SeMONs@siFoxf1 significantly accelerated rat femoral fracture healing. Transcriptome sequencing further revealed that E7-SeMONs@siFoxf1 promotes osteogenesis primarily by activating the PI3K/Akt/GSK3β/β-catenin pathway. This study introduces an innovative strategy that combines gene therapy with mitochondrial homeostasis regulation for fracture treatment, demonstrating promising clinical prospect.
    Keywords:  diselenide‐bridged mesoporous organosilica nanoparticles; fracture; gene therapy; mitochondria; osteogenesis
    DOI:  https://doi.org/10.1002/adhm.202501411
  42. J Control Release. 2025 Jun 10. pii: S0168-3659(25)00570-X. [Epub ahead of print] 113950
    Targeting ferroptosis and mitophagy with neutrophil-inspired nanozyme for Parkinson's disease therapy.
    Yu Tian, Feng Wang, Jing Ma, Wei Huang, Xiaodan Zhang, Chengzhong Du, Penghui Wei, Wen Huang, Yang Zhu, Yuanxiang Lin.
      Parkinson's disease (PD) is characterized by neurodegeneration, oxidative stress, and α-synuclein aggregation. While L-DOPA provides symptomatic relief through dopamine replenishment, it lacks neuroprotective effects and fails to address oxidative stress, iron dysregulation, and protein aggregation underlying PD pathogenesis. The development of antioxidant enzymes shows promise, yet challenges persist in blood-brain barrier (BBB) penetration and effective neuroinflammation mitigation. Our preliminary investigations revealed that the coordination between Icariside II (ICS II) and Fe3+ facilitates the formation of self-assembled metal-polyphenol nanozymes (Fe-Ic) with enhanced antioxidant capabilities and iron chelation functionality. Building on this discovery, we engineered neutrophil membrane-coated nanozymes (R-NM@Fe-Ic) with DSPE-PEG-RVG29 modification through a rational design strategy targeting both iron dysregulation and ferroptosis in PD, enabling targeted delivery to neuroinflammatory regions. R-NM@Fe-Ic demonstrated dual enzyme-like activities, reducing α-synuclein aggregation, suppressing lipid peroxidation, and increasing glutathione peroxidase 4 expression, thereby preventing neuronal ferroptosis more effectively than L-DOPA. Additionally, it promoted mitophagy, inhibiting toxic protein aggregation and reducing neuroinflammation. In vivo studies confirmed efficient BBB penetration with targeted accumulation in PD-affected brain regions. Behavioral analyses showed significant improvements in motor function, spontaneous movement, and cognitive performance, outperforming L-DOPA in both symptom management and neuroprotection. This study establishes a novel platform for biomimetic nanozymes and provides insights into their therapeutic potential by simultaneously targeting ferroptosis and enhancing mitophagy pathways in neuroinflammatory disorders.
    Keywords:  Ferroptosis; Nanozyme; Neuroinflammation; Neutrophil membrane; Parkinson's disease
    DOI:  https://doi.org/10.1016/j.jconrel.2025.113950
  43. J Clin Biochem Nutr. 2025 May;76(3): 239-244
    Aging-related dysregulation of energy metabolism and mitochondrial dynamics in microglia.
    Yoki Nakamura, Manaya Nakano, Kazue Hisaoka-Nakashima, Norimitsu Morioka.
      Microglia, the primary immune cells of the central nervous system, play a pivotal role in maintaining brain homeostasis. Recent studies have highlighted the involvement of microglial dysfunction in the pathogenesis of various age-related neurodegenerative diseases, such as Alzheimer's disease. Moreover, the metabolic state of microglia has emerged as a key factor in these diseases. Interestingly, aging and neurodegenerative diseases are associated with impaired mitochondrial function and a metabolic shift from oxidative phosphorylation to glycolysis in microglia. This metabolic shift may contribute to sustained microglial activation and neuroinflammation. Furthermore, the leakage of mitochondrial DNA into the cytoplasm, because of mitochondrial dysfunction, has been implicated in triggering inflammatory responses and disrupting brain function. This review summarizes recent advances in understanding the role of microglial metabolic shifts, particularly glycolysis, and mitochondrial dysfunction. It also explores the potential of targeting microglial metabolism, for instance by modulating mitophagy or intervening in specific metabolic pathways, as a novel therapeutic approach for changes in brain function and neurodegenerative diseases associated with aging.
    Keywords:  Alzheimer’s disease; aging; glycolysis; microglia; mitochondria
    DOI:  https://doi.org/10.3164/jcbn.24-202
  44. CNS Neurosci Ther. 2025 Jun;31(6): e70473
    Pharmacological Inhibition of Mitochondrial Division Attenuates Simulated High-Altitude Exposure-Induced Memory Impairment in Mice: Involvement of Inhibition of Microglia-Mediated Synapse Elimination.
    Panpan Chang, Mengqing Xu, Jiawei Zhu, Jiangpei Bian, Yapeng Lu, Qianqian Luo, Dan Wang, Li Zhu.
       AIM: To examine the protective effect of mitochondrial division inhibitor-1 (Mdivi-1) against high-altitude-induced memory impairment in mice.
    METHODS: C57BL/6J male mice were administered Mdivi-1 before exposure to a simulated high-altitude hypoxia environment. The novel object recognition test and Morris water maze were used to test cognitive function. Golgi staining was used to visualize dendritic spines. PCR, Western blot, and immunofluorescence were performed to detect microglial activation and synaptic phagocytosis.
    RESULTS: Mice exposed to short-term or long-term simulated high-altitude conditions experienced memory deficits. However, these deficits were significantly mitigated by pre-treatment with Mdivi-1. Simulated high-altitude exposure caused a reduction in synapses (dendritic spines) and the activation of microglia. Following Mdivi-1 injection, synapse density was significantly increased, and microglial activation was attenuated. Under hypoxic conditions, primary cultured microglia exhibited significantly enhanced phagocytic activity towards TRITC-Dextran or synaptosomes, which was abolished by Mdivi-1. Additionally, Mdivi-1 inhibited the HIF-1 signaling pathway and restricted the hypoxia-induced glycolytic activity in microglia. Specific inhibition of glycolysis effectively weakened the phagocytic capacity of microglia under hypoxia.
    CONCLUSION: Mdivi-1 dramatically mitigated memory impairment in mice induced by simulated high-altitude exposure. Mdivi-1 reduced microglial glycolysis in hypoxic conditions, thereby limiting microglial activation and preventing excessive synaptic phagocytosis. Consequently, it effectively protected memory.
    Keywords:  Mdivi‐1; high‐altitude exposure; memory impairment; microglia; phagocytosis of synapses
    DOI:  https://doi.org/10.1111/cns.70473
  45. Bioact Mater. 2025 Sep;51 559-574
    Sustained oxygen-releasing hydrogel implants enhance flap regeneration by promoting mitochondrial biogenesis under mild hypoxia.
    Sungmi Jeon, Seol-Ha Jeong, Mi Hyun Lee, Jeong Wook Seo, Da-Seul Kim, Nicole Joy Bassous, Javier Alejandro Lozano Soto, Cholong Choi, Montserrat Legorreta Gonzalez, Elaine Belén Nolasco Díaz, Hyunho Kim, Su Ryon Shin, Ji-Ung Park.
      In regenerative medicine, effective management of tissue ischemia in surgical skin flaps is crucial, yet challenging, particularly because inadequate blood flow often leads to necrosis at the distal flap tips. This study aimed to examine the therapeutic potential of catalase-coated oxygen-generating microparticles embedded in gelatin methacryloyl (cOMP-GelMA) hydrogel to establish an optimized environment conducive to tissue regeneration. Using a large 3 × 9 cm2 rat random-pattern skin flap model, flap survival and regeneration were evaluated across four groups: control, pure GelMA hydrogel, and cOMP-GelMA hydrogel with two concentrations of cOMPs (0.2 % and 0.5 % w/v). These findings revealed that cOMP-GelMA comprising 0.2 % OMP significantly enhanced angiogenesis, arteriogenesis, mitochondrial biogenesis, and antioxidant capacity compared to 0.5 % cOMP-GelMA. Furthermore, the alleviation of the inflammatory response was more pronounced at lower cOMP concentrations than at higher concentrations. These results demonstrate that mild hypoxia, facilitated by moderate oxygen delivery, is beneficial for tissue repair and regeneration through peroxisome proliferator-activated receptor gamma coactivator 1-alpha- and hypoxia-inducible factor 1-alpha-dependent signaling pathways. This study highlights the innovative aspect of using a large-scale model to explore the therapeutic benefits of mild hypoxia and suggests that controlled oxygen delivery by cOMPs can improve the long-term functional recovery of ischemic tissues.
    Keywords:  Composite hydrogels; Hypoxic; Oxygen-generating microparticle; Surgical skin flaps; Tissue engineering
    DOI:  https://doi.org/10.1016/j.bioactmat.2025.04.010
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