bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2025–09–21
fifty-five papers selected by
Gavin McStay, Liverpool John Moores University
  1. SREBP1a induced PINK1-Parkin mediated mitophagy facilitates ovarian cancer progression.
  2. [Research progress on the role of viral infection-regulated mitophagy in the regulation of immune response].
  3. STX4 is indispensable for mitochondrial homeostasis in skeletal muscle.
  4. Sonlicromanol Mitigates Sepsis-induced Heart Injury via Mitochondrial and Pyroptosis Modulation.
  5. Naringenin's rescue of broiler spleen from LPS-triggered pyroptosis and inflammation: Decoding the AMPK/PINK1/Parkin-driven mitophagy pathway.
  6. The Role of Abnormal Mitochondrial Fusion and Fission in the Inflammatory Senescence of Dental Pulp Stem Cells.
  7. A new perspective on protecting the blood-retinal barrier against injury in diabetic retinopathy: mitophagy.
  8. Sirt1 attenuates necrotizing enterocolitis via Hif-1α deacetylation-mediated suppression of Bnip3-Dependent mitophagy.
  9. ARIH1 Promotes Preeclampsia by Inducing MFN2-Dependent Hypoxia-Triggered Mitophagy and Endoplasmic Reticulum Stress in Trophoblasts.
  10. Mertk+ Liver Sinusoidal Endothelial Cells Negatively Regulate PINK1 Related Mitophagy and Accelerate MASH.
  11. Betulinic acid attenuates lipopolysaccharide-induced cardiac injury by promoting mitophagy with enhancing PINK1/Parkin and suppressing BNIP3.
  12. Subacute exposure of 2, 2', 4, 4'-tetrabromodiphenyl ether induced liver injury by inhibiting mitochondrial autophagy and increasing NLRP3 inflammasome in mice.
  13. Curcumin improves diabetic vascular aging rats and high glucose-induced cells aging by promoting mitophagy.
  14. Dapagliflozin Alleviates Isoprenaline-Induced Cardiac Hypertrophy by Promoting Mitophagy via AMPKα2 Signaling Pathway.
  15. Intracerebral Administration of Hydrogen Sulfide Impairs Bioenergetics, Redox Status and Mitochondrial Quality Control in Rat Striatum.
  16. Autophagy and Mitophagy in Circulating Immune Cells of Women with Polycystic Ovary Syndrome: A Cardiovascular Perspective.
  17. Mitochondrial dysfunction and its impact on pyroptosis and ferroptosis cross talk in glioma cells.
  18. Astaxanthin alleviates oxidative stress and skeletal muscle damage by promoting mitochondrial biogenesis.
  19. The anti-aging mechanisms of Catalpol by elevating mitophagy.
  20. Cyclophilin D (PPIF) and MPTP in hepatic ischemia-reperfusion injury: insights into mechanisms.
  21. Dehydroepiandrosterone Prevents Collagen Loss by Regulating HIF-1α Expression and Mitophagy in Hypoxic Human Scleral Fibroblasts.
  22. Targeting CB1R Rewires Ca2+-Dependent Mitophagy to Promote Nerve Regeneration.
  23. Reactive Oxygen Species-Mediated Mitochondrial-Targeted Therapeutics in Hepatic Disorders: Current Progress and Future Opportunities.
  24. Mechanistic Insights into Myricetin-Regulated Autophagy via the PI3K/Akt and PINK1/Parkin Pathway in Diabetic Kidney Disease Treatment.
  25. Anisotropic Micro/Nanotopography Regulating Mitochondrial Dynamics in Cardiomyocytes.
  26. Macelignan, a lignan from Myristica fragrans Houtt., rescues mitochondrial homeostasis and prevents cognitive decline in vascular dementia by modulating the mTOR-Mitophagy axis.
  27. Troxerutin improves diabetic cognitive dysfunction by inhibiting mitochondrial fission mediated by transient receptor potential melastatin 7/calcineurin/dynamin-related protein 1ser637.
  28. Intricate role of DRP1 and associated mitochondrial fission signaling in carcinogenesis and cancer progression.
  29. Capsaicin attenuates sepsis‑associated encephalopathy by inhibiting neuroinflammation and apoptosis whilst activating mitophagy through the BNIP3/NIX pathway.
  30. Correction: Advances in mitochondrial dysfunction in radiation tissue injury.
  31. DUSP1 alleviates LPS-induced acute lung injury by inhibiting the SHP2-JNK axis and mitochondrial apoptosis.
  32. Melatonin attenuates high-fat diet- and particulate matter-induced cardiac injury: involvement of mitochondrial quality and miR-221/222 expression.
  33. SLC6A14 Drives Mitochondrial Fusion and Oxidative Phosphorylation to Promote Cancer Stemness and Early-Onset of Breast Cancer.
  34. Dual roles of mTOR in skeletal muscle adaptation: coordinating hypertrophic and mitochondrial biogenesis pathways for exercise-induced chronic disease management.
  35. Hepatocyte FAM210A deficiency disrupts mitochondrial function and triggers juvenile steatosis with compensatory repair in adulthood.
  36. Advancing Mitochondrial Health in Huntington Disease (HD): Small Molecule Therapies and Neurodegeneration.
  37. CircNCX1 contributes to mitochondrial fusion in cardiomyocyte by mediating the expression of mitofusin 2.
  38. miR-6126 modulates GRP78 to suppress the Warburg effect and mitochondrial dynamics in triple-negative breast cancer.
  39. Dihuang Yinzi Regulates cAMP/PKA/CREB-BDNF to Improve Synaptic Plasticity in APP/PS1 Mice: A Study Based on Brain Metabolomics.
  40. Preclinical safety and toxicokinetic evaluation of TJ0113, a first-in-class mitophagy inducer for Parkinson's disease.
  41. Advances in mitochondrial dysfunction in radiation tissue injury.
  42. Temporal Effects of Lipid Oversupply on Energy Metabolism and Mitochondrial Homeostasis in Hepatocytes.
  43. Dietary antioxidants alleviate antibiotic-induced mitochondrial dysfunction through protein kinase AMP-activated alpha (AMPKα) and nuclear factor, erythroid 2 like 2 (NRF2) pathway interaction.
  44. Suppression of Rho-associated kinase 1 (ROCK1) promotes human hematopoietic stem cell expansion by attenuating mitochondrial fission.
  45. DRP1 induces neuroinflammation via transcriptional regulation of NF-ĸB.
  46. 17-Methoxyl-7-hydroxy-benzene-furanchalcone improves mitochondrial biogenesis and oxidative stress following myocardial ischemia/reperfusion injury through the AMPK/SIRT1 pathway based on network pharmacology.
  47. InsP3R signaling mediates mitochondrial stress-induced longevity through actomyosin-dependent mitochondrial dynamics.
  48. How to use an extensive Flammer syndrome phenotyping for a holistic protection against health-to-disease transition - facts and practical recommendations.
  49. Molecular mechanisms by which mitochondrial dysfunction drives neuromuscular junction degeneration in amyotrophic lateral sclerosis.
  50. Metformin nanoparticles mitigate cerebral ischemia reperfusion injury by improving mitochondrial dysfunction and inhibiting NLRP3 activation.
  51. Mechanistic study on the role of multi-pathway autophagy in ovarian aging: literature review.
  52. Macrophage Efferocytosis Controls Tissue Repair via Mitochondrial Dynamics in Diabetic Periodontitis.
  53. Correction: Urolithin A Enhances Tight Junction Protein Expression in Endothelial Cells Cultured In Vitro via Pink1-Parkin-Mediated Mitophagy in Irradiated Astrocytes.
  54. Mitochondrial Diseases: Molecular Pathogenesis and Therapeutic Advances.
  55. Reactive Oxygen Species-Mediated TRPM2 Activation Facilitates Phagocytosis of Macrophages to Reverse Profibrotic Phenotype.
  1. Biochim Biophys Acta Mol Basis Dis. 2025 Sep 15. pii: S0925-4439(25)00391-6. [Epub ahead of print]1872(1): 168043
    SREBP1a induced PINK1-Parkin mediated mitophagy facilitates ovarian cancer progression.
    Sk Eashayan Tanbir, Sib Sankar Roy.
      Sterol regulatory element binding protein 1 (SREBP1) has emerged as a central regulator of lipid metabolism, playing a pivotal role in cancer progression. However, the oncogenic potential of SREBP1a is still underexplored. This study investigates the multifaceted contributions of SREBP1a on tumorigenesis, with a particular focus on ovarian cancer. Elevated expression of the SREBP1a isoform was found to enhance proliferation, migration, and invasion of ovarian cancer cells. Mechanistically, SREBP1a induces mitochondrial fission by upregulating DRP1 expression and promoting its activation through ser616 phosphorylation, resulting in a fragmented mitochondrial network that supports enhanced bioenergetic flexibility. In parallel, SREBP1a drives PINK1-Parkin-mediated mitophagy. This coupling of mitochondrial fission and mitophagy possibly ensures mitochondrial quality control, enhances cellular bioenergetics, and increases ATP production, supporting rapid cell proliferation and migration. Experimental evidences reveal that SREBP1 directly regulates DRP1 and PINK1 transcription, reinforcing its role in regulating mitochondrial dynamics. Furthermore, targeting SREBP1 using Fatostatin, a small-molecule inhibitor, effectively disrupts mitochondrial fission, impairs mitophagy, and attenuates tumor progression. These findings highlight the novel role of SREBP1a as a key regulator of mitochondrial dynamics, establishing it as a promising therapeutic target in ovarian cancer. Future studies should explore combinatorial strategies integrating SREBP1a inhibition with existing therapies to improve treatment outcomes.
    Keywords:  DRP1; Fatostatin; Ovarian cancer; PINK1-Parkin mitophagy; SREBP1a
    DOI:  https://doi.org/10.1016/j.bbadis.2025.168043
  2. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2025 Sep;41(9): 827-831
    [Research progress on the role of viral infection-regulated mitophagy in the regulation of immune response].
    Xiaoying Deng, Chao Fan, Ying Zhang.
      Mitochondria are one of the oldest and most important endomembrane systems in eukaryotic cells and serve as the hubs of multiple cellular processes. Mitophagy (mitochondrial autophagy), a major way to maintain mitochondrial homeostasis, is closely linked to antiviral immune regulation. Depending on whether ubiquitination is required for the involved receptors or adaptors, mitophagy can be classified into ubiquitin-dependent and ubiquitin-independent types. Viruses can directly or indirectly regulate mitophagy and mitochondrial dynamics through various pathways. Through these processes, they can affect innate and adaptive immunity, so as to achieve immune escape, aggravate cell damage or promote the formation of adaptive immunity. This review summarizes the latest research progress on the role of viral infection-regulated mitophagy in the regulation of immune response.
  3. bioRxiv. 2025 Sep 03. pii: 2025.09.02.673840. [Epub ahead of print]
    STX4 is indispensable for mitochondrial homeostasis in skeletal muscle.
    Joseph M Hoolachan, Rekha Balakrishnan, Erika M McCown, Karla E Merz, Chunxue Zhou, Elizabeth Bloom-Saldana, Patrick T Fueger, Angelica Hamilton, Tali Kiperman, Ke Ma, Eunjin Oh, Lei Jiang, Patrick Pirrotte, Orian Shirihai, Debbie C Thurmond.
       Background: Mitochondrial homeostasis is vital for optimal skeletal muscle integrity. Mitochondrial quality control (MQC) mechanisms that are essential for maintaining proper functions of mitochondria include mitochondrial biogenesis, dynamics and mitophagy. Previously, Syntaxin 4 (STX4) traditionally considered a cell surface protein known for glucose uptake in skeletal muscle, was also identified at the outer mitochondrial membrane. STX4 enrichment was sufficient to reverse Type 2 diabetes-associated mitochondrial damage in skeletal muscle by inactivation of mitochondrial fission. However, whether STX4 could modulate skeletal muscle mitochondrial homeostasis through MQC mechanisms involving mitochondrial biogenesis or mitophagy remains to be determined.
    Methods: To determine the requirements of STX4 in mitochondrial structure, function and MQC processes of biogenesis and mitophagy, we implemented our in-house generated inducible skeletal muscle-specific STX4-knockout (skmSTX4-iKO) mice ( Stx4 fl/fl ; Tg(HSA-rtTA/TRE-Cre )/B6) and STX4-depleted immortalized L6.GLUT4myc myotubes via siRNA knockdown (siSTX4).
    Results: We found that non-obese skmSTX4-iKO male mice (>50% reduced STX4 abundance, Soleus and Gastrocnemius ***p<0.001, Tibialis anterior (TA) ****p<0.0001) developed insulin resistance (**p<0.01), together with reduced energy expenditure (AUC *p<0.05), respiratory exchange ratio (AUC **p<0.01), and grip strength (*p<0.05). STX4 ablation in muscle also impaired mitochondrial oxygen consumption rate (****p<0.0001). Mitochondrial morphological damage was heterogenous in STX4 depleted muscle, presenting with small fragmented mitochondria (****p<0.0001) and deceased electron transport chain (ETC) abundance (CI ***p<0.001, CII *p<0.05, CIV **p<0.01) in oxidative soleus muscle, while glycolytic TA fibers display enlarged swollen mitochondria (****p<0.0001) with no change in ETC abundance. Notably, >60% reduction of STX4 in siSTX4 L6.GLUT4myc myotubes (****p<0.0001) also decreased ETC abundance (CI ****p<0.0001, CII ****p<0.0001, CIV *p<0.05) without changes in mitochondrial glucose metabolism, as shown by [U- 13 C] glucose isotope tracing. For MQC, both skmSTX4-iKO male mice (*p<0.05) and siSTX4 L6.GLUT4myc myotubes (*p<0.05) showed decreased mitochondrial DNA levels alongside reduced mRNA expression of mitochondrial biogenesis genes Ppargc1a (PGC1-α, *p<0.05) and Tfam (*p<0.05) in skmSTX4-iKO soleus muscle and PGC1-α (mRNA *p<0.05, protein ***p<0.001), NRF1 (mRNA and protein *p<0.05) and Tfam (mRNA *p<0.05) in siSTX4 L6.GLUT4myc myotubes. Furthermore, live cell imaging using mt-Keima mitophagy biosensor in siSTX4 L6.GLUT4myc cells revealed significantly impaired mitochondrial turnover by mitophagy (*p<0.05) and mitochondria-lysosome colocalization (*p<0.05). STX4 depletion also reduced canonical mitophagy markers, PINK1 and PARKIN in both skmSTX4-iKO muscle (PARKIN *p<0.05, PINK1 **p<0.01) and siSTX4 L6.GLUT4myc myotubes (PARKIN ****p<0.0001, PINK1 *p<0.05).
    Conclusions: Our study demonstrated STX4 as a key mitochondrial regulator required for mitochondrial homeostasis in skeletal muscle.
    DOI:  https://doi.org/10.1101/2025.09.02.673840
  4. J Physiol Investig. 2025 Sep 17.
    Sonlicromanol Mitigates Sepsis-induced Heart Injury via Mitochondrial and Pyroptosis Modulation.
    Xinxin Qi, Liang Zhao, Yan Zou.
       ABSTRACT: Sepsis-induced myocardial dysfunction (SIMD) is a severe consequence of systemic infection, primarily driven by mitochondrial dysfunction, inflammation, and pyroptosis. Sonlicromanol, a mitochondrial redox-modulating therapeutic agent, has shown promise in preserving mitochondrial function, but its role in sepsis-induced cardiac injury remains unclear. This study evaluates the protective effects of sonlicromanol in a rat model of sepsis-induced cardiac dysfunction, with a focus on mitochondrial dynamics, mitophagy, and inflammasome-pyroptosis pathways. Male Sprague-Dawley rats were subjected to cecal ligation and puncture (CLP) to induce sepsis. Sonlicromanol (50 mg/kg/day) was administered intraperitoneally for 2 weeks before CLP. Rats were divided into five groups: (1) Control, (2) CLP, (3) CLP + sonlicromanol, (4) CLP + Mdivi-1 (mitophagy inhibitor), and (5) CLP + sonlicromanol + Mdivi-1. Cardiac function was evaluated via catheter-based pressure analysis, including left ventricular systolic pressure (LVSP), left ventricular end-diastolic pressure (LVEDP), and left ventricular developed pressure (LVDP). Myocardial injury, histopathology, inflammasome-pyroptosis activation, mitophagy, and mitochondrial dynamics were assessed via enzyme-linked immunosorbent assay, H and E staining, Western blot, and mitochondrial fluorometric assays. CLP-induced septic rats showed reduced LVSP and LVDP, along with elevated LVEDP, cardiotroponin, and B-type natriuretic peptide, and significant myocardial damage. Pyroptosis markers (nucleotide-binding oligomerization domain-like receptor pyrin domain-containing protein 3, cleaved caspase-1, gasdermin-D, interleukin-1 β, and lactate-dehydrogenase) were elevated, while mitophagy markers (PTEN-induced kinase 1 and Parkin) and mitochondrial function (membrane potential and adenosine triphosphate levels) declined. Sonlicromanol significantly improved cardiac function and injury markers, suppressed pyroptosis, restored mitochondrial dynamics (increased mitofusin-2, modulated dynamin-related protein 1), enhanced mitophagy, and improved mitochondrial function. Mdivi-1 co-treatment attenuated these effects, indicating a role for mitochondrial dynamics and mitophagy in sonlicromanol's efficacy. Sonlicromanol ameliorates SIMD by modulating mitochondrial homeostasis and inhibiting pyroptosis. These findings support sonlicromanol as a potential therapy for sepsis-related cardiac injury.
    Keywords:  Cardiac dysfunction; cardioprotection; mitochondrial dynamics; mitophagy; pyroptosis; sepsis; sonlicromanol
    DOI:  https://doi.org/10.4103/ejpi.EJPI-D-25-00033
  5. Poult Sci. 2025 Sep 10. pii: S0032-5791(25)01051-X. [Epub ahead of print]104(11): 105810
    Naringenin's rescue of broiler spleen from LPS-triggered pyroptosis and inflammation: Decoding the AMPK/PINK1/Parkin-driven mitophagy pathway.
    Yu Xia, Yidan Wang, Jiahui Xue, Jiahong Chu, Yanhe Zhang, Fuze She, Huijie Chen, Shu Li.
      Naringenin (Nar) is known to maintain mitochondrial homeostasis, antioxidation and anti-inflammation. Damaged mitochondria can promote excessive Reactive oxygen species (ROS) production, triggering pyroptosis and inflammation process in immune tissues. PTEN induced putative kinase 1 (PINK1)/E3 ubiquitin ligase PARK2 (Parkin)-mediated mitophagy contributes to removing damaged mitochondria. This study aims to investigate detailed mechanism of Nar against Lipopolysaccharide (LPS)-induced injury in broiler spleens and the role of mitophagy in this process. We used LPS as a stimulus and treated with Nar to establish relevant models in vivo and in vitro. Our findings demonstrated Nar increased the expression levels of Phospho-Adenosine 5'-monophosphate (AMP)-activated protein kinase (p-AMPK)/AMPK, PINK1, Parkin and Microtubule-Associated Protein 1A/1B Light Chain 3 (LC3), and reduced the level of Sequestosome 1 (P62), leading to a reduction in levels of factors associated with mitochondrial fission, mtDNA release, pyroptosis, and inflammation. Conversely, Nar treatment enhanced the levels of factors related to mitochondrial fusion, energy metabolism, and anti-inflammatory response. Moreover, an increase was observed in ΔΨm, ATP content, and ATPase activity. Molecular docking analysis and cellular thermal shift assay (CETSA) supported the interaction between Nar and AMPK. In summary, Nar enhanced LPS-induced mitophagy and alleviated mitochondrial homeostasis imbalance and oxidative stress in broiler spleens through its interaction with AMPK, resulting in alleviating pyroptosis and inflammation.
    Keywords:  AMPK; Broiler spleen; Mitophagy; Naringenin; Pyroptosis
    DOI:  https://doi.org/10.1016/j.psj.2025.105810
  6. Int Dent J. 2025 Sep 15. pii: S0020-6539(25)03158-2. [Epub ahead of print]75(6): 103877
    The Role of Abnormal Mitochondrial Fusion and Fission in the Inflammatory Senescence of Dental Pulp Stem Cells.
    Wenyue Tang, Wanping Wang, Xinyu Wan, Chenying Shen, Xinyi Qiu, Yue Zhao, Wen Li, Chao Liu, Shuangshuang Ren, Leiying Miao.
       AIM: The regeneration ability of dental pulp stem cells (DPSCs) is essential for vital pulp preservation therapy, but may be disrupted by inflammatory senescence. Mitochondrial dynamics proteins maintain mitochondrial homeostasis and could alleviate inflammatory senescence, though their impact on DPSCs' functions and clinical prognosis remains unclear.
    MATERIALS AND METHODS: Human inflammatory and normal dental pulp were ethically collected from clinic-extracted wisdom teeth to detect inflammation, senescence, mitochondrial dynamics, and oxidative stress markers. The DPSCs' inflammatory senescence model was induced by Escherichia coli lipopolysaccharide, and mitochondrial fusion and fission proteins were modulated with inhibitors to study their relationship with inflammatory senescence.
    RESULTS: The pulpitis group exhibited inflammatory cell infiltration and overexpressed inflammatory factors, oxidative stress, and senescence markers compared to normal tissue. The same trends were observed in the cell model. Lipopolysaccharide downregulated cell proliferation and differentiation, and upregulated senescence and apoptosis, with decreased OPA1 and increased DRP1. Further reducing fusion exacerbated these phenomena, while reducting fission relieved them.
    CONCLUSIONS: This study highlights the critical role of mitochondrial fusion and fission in DPSCs inflammatory senescence. Enhancing mitochondrial fusion (via OPA1) or suppressing fission (via DRP1) may counteract senescence and restore DPSCs regenerative capacity. These findings provide a potential therapeutic strategy to preserve pulp vitality and improve regenerative outcomes.
    CLINICAL RELEVANCE: Maintaining DPSCs functionality is crucial for successful regenerative endodontic treatments. Since inflammation-induced senescence impairs DPSCs regeneration, targeting mitochondrial dynamics - particularly by promoting fusion or inhibiting fission - could enhance pulp tissue repair and long-term tooth preservation. This evidence suggests mitochondrial modulation could be explored for pulpitis management and dental pulp vitality preservation.
    Keywords:  DPSCs; DRP1; Inflammatory senescence; Mitochondrial dynamics; OPA1
    DOI:  https://doi.org/10.1016/j.identj.2025.103877
  7. Front Endocrinol (Lausanne). 2025 ;16 1617797
    A new perspective on protecting the blood-retinal barrier against injury in diabetic retinopathy: mitophagy.
    Mengtian Li, Liyang Yang, Haoyu Zhai, Liping Qiao, Zhaobo Wang, Xuedong An, Jia Wang.
      The blood-retinal barrier (BRB) comprises the inner blood-retinal barrier (iBRB) and the outer blood-retinal barrier (oBRB). The integrity of the BRB is essential to maintaining stability of the retinal microenvironment. Mitophagy plays a crucial role in maintaining organellar integrity by regulating mitochondrial quality and quantity. High glucose-induced mitophagy dysfunction contributes to diabetic retinopathy (DR) by damaging the BRB. This review presents mitophagy mechanisms under physiological conditions and examines changes across different cell types under DR-related pathological conditions that damage the BRB. It also summarizes drugs and targets that regulate mitophagy to stabilize the BRB and alleviate DR, offering new therapeutic insights.
    Keywords:  blood-retinal barrier; diabetic retinopathy; inflammation; mitochondrial dysfunction; mitophagy; oxidative stress; therapeutic strategy
    DOI:  https://doi.org/10.3389/fendo.2025.1617797
  8. Free Radic Biol Med. 2025 Sep 12. pii: S0891-5849(25)00977-3. [Epub ahead of print]241 150-160
    Sirt1 attenuates necrotizing enterocolitis via Hif-1α deacetylation-mediated suppression of Bnip3-Dependent mitophagy.
    Lin Zhu, Mei Huang, Lu He, Zhihui Rong.
      Necrotizing enterocolitis (NEC), a life-threatening neonatal disease, involves mitochondrial dysfunction whose regulation remains unclear. This study identifies a novel Sir1/Hif-1α regulatory axis in NEC pathogenesis. We demonstrate that Sirt1 downregulation in NEC leads to Hif-1α hyperacetylation, resulting in Bnip3-mediated mitophagy activation and intestinal epithelial injury. Using clinical samples and experimental models, we show that Sirt1 downregulation correlates with mitochondrial dysfunction and intestinal barrier disruption. Pharmacological Sirt1 activation by SRT1720 effectively attenuated NEC progression through Hif-1α deacetylation and subsequent mitophagy inhibition. Importantly, we provide the first evidence that Sirt1 directly regulates Hif-1α acetylation status in intestinal epithelial cells, establishing a new molecular mechanism linking protein acetylation to mitochondrial quality control in NEC. These findings reveal Sirt1 as a master regulator of intestinal homeostasis and highlight Sirt1 activation as a promising therapeutic approach for NEC treatment.
    Keywords:  Acetylation; Hif-1α; Inflammation; Mitophagy; Necrotizing enterocolitis; Sirt1
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.09.020
  9. FASEB J. 2025 Sep 30. 39(18): e71060
    ARIH1 Promotes Preeclampsia by Inducing MFN2-Dependent Hypoxia-Triggered Mitophagy and Endoplasmic Reticulum Stress in Trophoblasts.
    Hongyu Liu, Yali Deng, Mei Peng, Yanting Nie, Jingfei Chen.
      The pathogenesis of preeclampsia (PE) involves endoplasmic reticulum stress (ERS) and the subsequent induction of mitophagy. Ariadne RBR E3 ubiquitin protein ligase 1 (ARIH1) is a key factor regulating mitophagy, but its role in PE has not been reported. In this study, we aimed to analyze the role of ARIH1 in the pathogenesis of PE. The role of ARIH1 in the pathogenesis of PE was investigated in a PE rat model and in an in vitro hypoxia/reoxygenation (H/R) model using HTR8 trophoblast cells. The study revealed that ARIH1 was upregulated while Mitochondrial fusion protein 2 (MFN2) was downregulated in PE rats and H/R-treated HTR8 cells. Inhibition of ARIH1 reversed the suppressed proliferation and invasion capacities of HTR8 cells under H/R conditions, reduced intracellular reactive oxygen species (ROS) and calcium ions (Ca2+), and modulated the protein expression of LC3II/LC3I, p62, glucose-regulatory protein 78 (GRP78), and C/EBP homologous protein (CHOP). Additionally, mitochondrial membrane potential was improved. Interestingly, treatment with Tunicamycin or Thapsigargin could reverse the inhibitory effects of ARIH1 downregulation on trophoblastic cells by activating endoplasmic reticulum stress (ERS) and mitophagy. Notably, the study identified for the first time that ARIH1 mediates the ubiquitination degradation of MFN2. Inhibition of MFN2 abolished the regulatory effects of ARIH1 downegulation on ERS and mitophagy in trophoblast cells, as well as the associated damage in PE rats. Overall, the findings underscore the crucial role of ARIH1 in regulating mitophagy and ERS through MFN2, highlighting its significance in the pathogenesis of PE.
    Keywords:  ARIH1; MFN2; endoplasmic reticulum stress; mitophagy; preeclampsia; trophoblast
    DOI:  https://doi.org/10.1096/fj.202500821R
  10. Immun Inflamm Dis. 2025 Sep;13(9): e70256
    Mertk+ Liver Sinusoidal Endothelial Cells Negatively Regulate PINK1 Related Mitophagy and Accelerate MASH.
    Yu-Xuan Gao, Zhong Weng, Long Tang, Ming-Yi Xu, Sheng-Zheng Luo.
       BACKGROUND: Mer tyrosine kinase (Mertk) regulating mitochondrial function of liver sinusoidal endothelial cells (LSECs) in metabolic dysfunction-associated steatohepatitis (MASH) remains unclear.
    METHODS: Mertk/p-Mertk, PINK1, and ERK/p-ERK expression in steatotic LSECs and livers of MASH mice were studied. Mitochondrial functions were assessed via immunofluorescence, Western blot, and qPCR. C-Kit+-bone marrow cells (BMCs)sh-Mertk were bone marrow transplanted (BMT) to MASH mice to evaluate its effect.
    RESULTS: Ov-Mertk would markedly stimulate ERK, and ERK further suppress downstream PINK1. Higher levels of Mertk/p-Mertk and lower levels of PINK1 were confirmed in steatotic LSECs and MASH mice livers. Steatotic LSECssh-Mertk exhibited intact mitophagy, integral mitochondrial membrane potential, reduced reactive oxygen productions and upregulation of the PINK1 pathway. BMT of C-Kit+-BMCssh-Mertk could equivalently protect mitochondrial functions and ameliorate lipid accumulation in MASH mice.
    CONCLUSION: Mertk negatively regulates PINK1-mediated mitophagy in LSECs through the p-ERK signaling pathway, thereby accelerating MASH progression. Therefore, LSECs deficient of Mertk should be a novel therapy for reversing PINK1-related mitophagy and MASH.
    Keywords:  Mer tyrosine kinase (Mertk); PTEN‐induced putative kinase 1 (PINK1); extracellular regulated protein kinase (ERK); liver sinusoidal endothelial cell (LSEC); metabolic dysfunction‐associated steatohepatitis (MASH); mitophagy
    DOI:  https://doi.org/10.1002/iid3.70256
  11. Eur J Pharmacol. 2025 Sep 16. pii: S0014-2999(25)00923-9. [Epub ahead of print] 178169
    Betulinic acid attenuates lipopolysaccharide-induced cardiac injury by promoting mitophagy with enhancing PINK1/Parkin and suppressing BNIP3.
    Xin-Ru Zhou, Xiang-Fei Meng, Yu-Xiao Zhang, Zi-Yan Zhang, Chun-Yan Jiang, Yu-Peng Han, Jin-Ting Yang, Ling-Bo Qian.
      Betulinic acid (BA), a natural pentacyclic triterpene, has been shown to promote autophagy and attenuate sepsis-induced organ injury, yet its role in mitophagy-mediated cardioprotection remains unclear. Here, we evaluated the effects of oral BA treatment (25 mg/kg, 5 days) on lipopolysaccharide (LPS)-induced cardiac injury in male Sprague-Dawley rats. BA significantly improved cardiac function, reduced myocardial injury markers (cardiac troponin I, creatine kinase-MB), and suppressed inflammatory (tumor necrosis factor-α, interleukin-1β, myeloperoxidase activity) and oxidative responses in LPS-induced sepsis. Moreover, BA improved cardiac mitochondrial function by enhancing respiratory chain complex activity and ATP synthesis while limiting the opening of mitochondrial permeability transition pore and loss of mitochondrial membrane potential in LPS-challenged rats. Western blot and immunofluorescence analyses showed that BA enhanced PTEN-induced putative kinase 1 (PINK1)/Parkin-initiated mitophagy and suppressed BNIP3 (Bcl-2/adenovirus E1B 19 kDa interacting protein 3) expression in LPS-challenged rat hearts. Importantly, these cardioprotective effects of BA were abrogated by the mitophagy inhibitor Mdivi-1. Collectively, these results indicate that BA alleviates cardiac injury in LPS-induced sepsis by upregulating PINK1/Parkin to facilitate mitophagy and suppressing BNIP3 signaling.
    Keywords:  BNIP3; Betulinic acid; Cardiac injury; Mitophagy; PINK1/Parkin; Sepsis
    DOI:  https://doi.org/10.1016/j.ejphar.2025.178169
  12. Food Chem Toxicol. 2025 Sep 11. pii: S0278-6915(25)00506-X. [Epub ahead of print]206 115738
    Subacute exposure of 2, 2', 4, 4'-tetrabromodiphenyl ether induced liver injury by inhibiting mitochondrial autophagy and increasing NLRP3 inflammasome in mice.
    Xiyue Cao, Weijue Liu, Shuhua Xi, Yue Wang.
      2',4,4'-tetrabrominated diphenyl ethers (BDE-47) is one of the most common brominated flame retardants found in environment and has been demonstrated to be associated with a variety of adverse human health effects. It has been proven to generate liver toxicity, but little is known about the potential mechanism following BDE-47 exposure. Here, hepatotoxicity of BDE-47 in mice was investigated by gavage exposure to BDE-47 (12.5-100mg/kg/day) for 4 weeks. The results showed the increasing of ALT and AST in serum and histopathological change of liver in BDE-47 exposure mice. In addition, we observed that the mitochondrial membrane potential (MMP) decreased and ROS increased with the increase of BDE-47 dose. BDE-47 also up-regulated NLRP3 protein levels, and proteins expression of caspase-1, IL-1β, IL-18 and TNF-α inflammatory factors. Furthermore, mitophagy was blocked with Parkin and PINK1 protein expression decrease and P62 increase in liver of BDE-47 exposure mice. However, activation of mitophagy with autophagy activator rapamycin (RAPA) alleviated liver injury induced by BDE-47 in mice via increasing the protein expression of PINK1 and Parkin, and decreasing NLRP3 and inflammatory factors. These results suggest NLRP3 inflammasome activation-mediated mitochondrial and liver damage in BDE-47-exposed mice is due to mitophagy downregulation, and activating mitophagy can alleviate BDE-47-induced inflammatory damage by regulating NLRP3 inflammasome.
    Keywords:  BDE-47; Liver damage; Mitophagy; NLRP3 inflammasome
    DOI:  https://doi.org/10.1016/j.fct.2025.115738
  13. 3 Biotech. 2025 Oct;15(10): 341
    Curcumin improves diabetic vascular aging rats and high glucose-induced cells aging by promoting mitophagy.
    Jinlin Wu, Xi Mei, Yong Li, Fang Liu, Dongfang Liu.
      Vascular aging was reported to be closely related to diabetes. This study investigates the inhibitory effects and mechanism of curcumin on diabetic vascular aging by regulating mitophagy through the PINK1 pathway. The diabetic rat model was established by feeding with a high-fat diet and intraperitoneal injection of streptozotocin (STZ), and treated with high-dose (200 mg/kg), low-dose (50 mg/kg) curcumin, or metformin (200 mg/kg), respectively. The role of mitophagy in high glucose (HG)-induced human aortic smooth muscle cells (HASMCs) aging in vitro were investigated. The results indicated that curcumin ameliorated weight loss and improved elevated blood glucose levels in diabetic rats. Curcumin also improved the vascular pathological changes of the common carotid artery, decreased the vascular interstitial collagen fiber and vascular calcium salt deposition, and improved vascular ultrastructure. Furthermore, curcumin significantly decreased ET-1, VCAM-1, and p16 expressions. In addition, curcumin increased the expression of LC3II/I, Beclin1, and PINK1 proteins, while decreasing p62 expression. High-dose curcumin could improve mitochondrial morphology and increase mitochondrial autophagy. Additionally, curcumin increased HASMCs viability and inhibited HG-induced vascular aging by promoting mitophagy in vitro. WB confirmed that LC3II/I, Beclin1, and PINK1 levels were increased, while p62 and p16 levels were decreased. The improvement effect of curcumin on vascular aging was reversed by the mitophagy inhibitor Mdivi-1 or PINK1 siRNA. In conclusion, curcumin alleviates vascular aging in diabetic rats and HG-induced senescence in HASMCs by enhancing mitochondrial autophagy. These results suggest that curcumin has therapeutic potential in alleviating diabetic vascular aging.
    Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-025-04510-3.
    Keywords:  Curcumin; Diabetes; Mitophagy; PINK1; Vascular aging
    DOI:  https://doi.org/10.1007/s13205-025-04510-3
  14. Rev Port Cardiol. 2025 Sep 17. pii: S0870-2551(25)00290-2. [Epub ahead of print]
    Dapagliflozin Alleviates Isoprenaline-Induced Cardiac Hypertrophy by Promoting Mitophagy via AMPKα2 Signaling Pathway.
    Yue Feng, Zixiong Zhu, Xin Jing, Yibo Zhang, Yubin He, Xuewen Li.
       INTRODUCTION AND OBJECTIVES: The global prevalence of heart failure (HF) has been increasing in recent years, posing a significant threat to human health. Several studies have shown that impaired mitophagy accelerates HF progression. Dapagliflozin (DAPA) has demonstrated cardioprotective effects in HF patients. This study aims to investigate the therapeutic effects of DAPA on cardiomyocyte hypertrophy and its underlying mechanism.
    METHODS: The working concentration of isoprenaline (ISO) was determined through combined quantitative real-time polymerase chain reaction (qPCR) and CCK-8 assays. H9c2 cells were stimulated with ISO to induce a hypertrophy model. Cellular hypertrophy was quantified by qPCR and TRITC-Phalloidin staining. Mitochondrial ultrastructure and functional integrity was assessed by transmission electron microscopy and JC-1 staining. Mitophagy levels were measured using Western blotting and co-localization assays. AMPKα2 expression levels were determined via Western blotting. Following AMPKα2 siRNA transfection, cellular hypertrophy and mitophagy levels were reassessed.
    RESULTS: ISO markedly induced cardiomyocyte hypertrophy, mitochondrial damage and mitophagy inhibition, whereas DAPA effectively attenuated these pathologica changes, with AMPK agonists demonstrating comparable cardioprotective effects. In ISO-treated H9c2 cells, AMPKα2 expression was reduced, while DAPA significantly upregulated its expression. Notably, AMPKα2 inhibition significantly weakened DAPA's protective effect on ISO-induced hypertrophy and mitochondrial injury.
    CONCLUSION: DAPA exerts cardioprotective effects by mitigating ISO-induced cardiac hypertrophy and preserving mitochondrial integrity, mediated through AMPKα2-dependent activation of mitophagy.
    Keywords:  AMPKα2; Dapagliflozina; Hipertrofia cardíaca; Insuficiência cardíaca; Mitofagia
    DOI:  https://doi.org/10.1016/j.repc.2025.05.008
  15. Neurotox Res. 2025 Sep 20. 43(5): 35
    Intracerebral Administration of Hydrogen Sulfide Impairs Bioenergetics, Redox Status and Mitochondrial Quality Control in Rat Striatum.
    Manuela Bianchin Marcuzzo, Josyane de Andrade Silveira, Camila Vieira Pinheiro, Jaqueline Santana da Rosa, Angela B Zemniaçak, Morgana Brondani, Nathalia Simon Kist, Chrístofer Ian Hernandez Hoffmann, Helgi B Schioth, Alexandre U Amaral, Moacir Wajner, Guilhian Leipnitz.
      Elevated hydrogen sulfide (sulfide) levels are observed in tissues, including the brain, of patients with ethylmalonic encephalopathy. Clinical manifestations of this disorder involve severe neurological symptoms and abnormalities such as developmental delay, pyramidal and extrapyramidal signs, cortical atrophy and basal ganglia lesions. To elucidate the pathophysiology of basal ganglia alterations, we investigated the effects of sulfide on bioenergetics, redox status and mitochondrial quality control in the striatum of Wistar rats. After placing the rat in a stereotaxic apparatus, a single intrastriatal administration of sulfide (NaHS; 2 or 4 µmol) or PBS (control) was performed. Thirty minutes after the administration, the rats were euthanized, and the striatum was used for the determination of biochemical parameters. Sulfide administration, at both doses, altered the activities of antioxidant enzymes. At the lowest dose, sulfide showed a strong tendency toward increased activity of citrate synthase. Furthermore, the highest dose of sulfide also reduced respiratory chain complex IV activity and mitochondrial respiration with NADH- and FADH2-linked substrates. Levels of Nrf2, the main factor that regulates the expression of antioxidant defenses, were also reduced by 4 µmol of sulfide. The metabolite further increased the content of MFN1, suggesting mitochondrial fusion. Additionally, sulfide elevated Parkin and TBC1D15 and reduced LC3 levels, indicative of mitophagy dysregulation. The content of markers of mitochondrial mass and fission were not changed. Our study shows that high levels of sulfide in the striatum of rats affect bioenergetics, redox status and mitochondrial quality control. We suggest that these pathomechanisms are involved in the pathophysiology of basal ganglia alterations verified in ethylmalonic encephalopathy.
    Keywords:  Bioenergetics; Ethylmalonic encephalopathy; Hydrogen sulfide; Mitochondrial quality control; Redox status; Striatum
    DOI:  https://doi.org/10.1007/s12640-025-00758-y
  16. Free Radic Biol Med. 2025 Sep 14. pii: S0891-5849(25)00982-7. [Epub ahead of print]
    Autophagy and Mitophagy in Circulating Immune Cells of Women with Polycystic Ovary Syndrome: A Cardiovascular Perspective.
    María Pelechá-Salvador, Cecilia Fabiana Márquez-Arrico, Meylin Fernández-Reyes, Laura Perea-Galera, Jonathan Hermenejildo, Carlos Morillas, Xusa Sanz-Llorens, Alberto Hermo-Argibay, Víctor M Víctor, Sandra López-Domènech, Milagros Rocha.
       INTRODUCTION: Polycystic ovary syndrome (PCOS) is a complex endocrine disorder associated with systemic inflammation, oxidative stress, and increased cardiometabolic risk. While impaired autophagy and mitophagy have been implicated in tissue-specific dysfunction, their role in circulating immune cells and relation to early vascular alterations remain unclear.
    METHODS: In this cross-sectional study, 91 women (48 controls, 43 with PCOS) underwent anthropometric and biochemical assessment. Systemic markers included myeloperoxidase (MPO), glutathione, TNFα, and sP-selectin were determined in serum. Superoxide production (dHE), mitochondrial membrane potential (TMRM), and protein levels of BECLIN1, LC3II/I, P62, NBR1, and PINK1 were assessed in peripheral blood mononuclear cells (PBMCs). Neutrophil-endothelial cell interactions were analysed as subclinical markers of endothelial dysfunction.
    RESULTS: PCOS patients presented hormonal, lipid, and glucose abnormalities, accompanied by redox imbalance, elevated MPO and dHE levels and reduced glutathione, and increased mitochondrial membrane potential. Autophagy and mitophagy pathways were significantly impaired in PBMCs, and the expression of all assessed markers was reduced. These alterations were associated with androgen excess, oxidative stress, and inflammation. Elevated sP-selectin and enhanced neutrophil-endothelial interactions indicated early endothelial dysfunction in PCOS women.
    CONCLUSION: Our findings reveal that women with PCOS display autophagy and mitophagy impairment in immune cells, processes that are linked to oxidative and inflammatory stress and accompanied by endothelial alterations, highlighting a potential mechanistic pathway contributing to their cardiometabolic risk.
    Keywords:  PBMCs; PCOS; autophagy; endothelial dysfunction; inflammation; mitophagy; oxidative stress
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.09.025
  17. J Neuropathol Exp Neurol. 2025 Sep 17. pii: nlaf099. [Epub ahead of print]
    Mitochondrial dysfunction and its impact on pyroptosis and ferroptosis cross talk in glioma cells.
    Yunzhu Guo, Hang Liu, Ziqi Gao, Zhengjun Zhou, Yichuan Zhao, Ming Wang, Shenjie Li, Wei Xiang, Jin Liao, Jie Zhou.
      Glioblastomas (GBM), the most aggressive primary brain tumors, remain challenging to treat due to their rapid proliferation, invasiveness, and resistance to current therapies. Emerging evidence highlights pyroptosis and ferroptosis as critical regulators of tumor progression. This review elucidates the pivotal role of mitochondrial dysfunction in driving these programmed cell death pathways in GBM. Specifically, mitochondrial abnormalities induce overproduction of reactive oxygen species (ROS) and disrupt iron homeostasis, thereby triggering pyroptosis through inflammasome activation and ferroptosis via lipid peroxidation accumulation. Impaired mitochondrial dynamics, such as membrane potential collapse, pro-inflammatory cytokine release, and defective mitophagy, synergistically determine tumor cell fates. We propose novel therapeutic strategies targeting mitochondrial ROS-scavenging systems, iron-sulfur cluster biosynthesis, and mitophagy modulation to overcome resistance to treatment of GBM. These investigations not only advance the understanding of the pathobiology of GBM but also underscore mitochondria as multifaceted therapeutic hubs and offer translational potential for other diseases linked to mitochondrial dysregulation. By integrating cutting-edge research data, this review establishes a foundation for developing precision therapies centered on pyroptosis and ferroptosis modulation, bridging mechanistic discoveries with clinical innovation in neuro-oncology.
    Keywords:  ferroptosis; glioma; mitochondria; pyroptosis
    DOI:  https://doi.org/10.1093/jnen/nlaf099
  18. Front Vet Sci. 2025 ;12 1577408
    Astaxanthin alleviates oxidative stress and skeletal muscle damage by promoting mitochondrial biogenesis.
    Chengmu Li, Yining Yan, Kai Wang, Tao Jiang.
       Introduction: This study aimed to investigate the damaging effects of a high-fat diet (HFD) on mitochondria and skeletal muscle and to evaluate the protective role of astaxanthin (Asta), with a focus on mitochondrial biogenesis, oxidative stress, and inflammation under metabolic stress.
    Methods: HFD-fed mice and palmitate acid (PA)-stimulated C2C12 cells were treated with Asta. Skeletal muscle function, pathology, mitochondrial ultrastructure, inflammatory responses, and oxidative stress levels were assessed using behavioral tests, histology, quantitative reverse transcription-polymerase chain reaction, western blotting, transmission electron microscopy, and biochemical assays.
    Results: Asta did not alter body weight or serum lipid levels in HFD-fed mice but markedly alleviated skeletal muscle damage and improved function. In both in vivo and in vitro models, Asta suppressed inflammatory gene expression, enhanced mitochondrial biogenesis-related proteins, reduced lipid accumulation and mitochondrial damage, increased antioxidant enzyme activity, and promoted ATP production. Furthermore, Asta inhibited mitochondrial fission and lipid peroxidation in PA-stimulated C2C12 cells.
    Discussion: Asta mitigates oxidative stress, lipid accumulation, and inflammation in skeletal muscle cells by promoting mitochondrial biogenesis, thereby preserving muscle structure and function. These findings highlight Asta's potential as a therapeutic agent for skeletal muscle protection in metabolic stress conditions.
    Keywords:  astaxanthin; high-fat diet; mitochondrial biogenesis; oxidative stress; skeletal muscle
    DOI:  https://doi.org/10.3389/fvets.2025.1577408
  19. Gene. 2025 Sep 16. pii: S0378-1119(25)00554-2. [Epub ahead of print]969 149765
    The anti-aging mechanisms of Catalpol by elevating mitophagy.
    Songtao Bie, Ze Yao, Ming Lu, Chunshuang Li, Xiang Li, Hui Shang.
      Autophagy is an important mechanism for maintaining cell homeostasis, and its decline in function is widely regarded as a key factor in aging. Catalpol (CAT), an active compound derived from the traditional Chinese herbRehmannia glutinosa, has shown potential to treat various age-related diseases through the regulation of autophagy. However, how CAT exerts anti-aging effects by regulating autophagy remains unclear. Therefore, this study sought to explore the anti-aging potential and molecular mechanisms, particularly the role of CAT in autophagy and mitochondrial function in yeast cells. The PI-CLS measurement method was employed to demonstrate enhanced yeast cells viability upon CAT treatment. RNA-Seq combined with bioinformatics analyses identified HSP82 as a key target of CAT. HSP82 knockout and HSP82 overexpression strains were employed to demonstrate that CAT enhances mitochondrial functions and extends cells lifespan by inducing HSP82-dependent mitophagy. We concluded that CAT plays an anti-aging role by regulating HSP82-dependent mitophagy and mitochondrial functions in yeast cells.
    Keywords:  Anti-aging; Autophagy; Bioinformatics Analysis; HSP82; RNA-Seq; Saccharomyces cerevisiae
    DOI:  https://doi.org/10.1016/j.gene.2025.149765
  20. Front Immunol. 2025 ;16 1575242
    Cyclophilin D (PPIF) and MPTP in hepatic ischemia-reperfusion injury: insights into mechanisms.
    Jingxin Liu, Chengyu Wu, Ziyun Lin, Maomao Ma, Wei Ma, Xuefeng Yu, Kai Wang, Bin Zeng.
      Hepatic ischemia-reperfusion injury (HIRI) is a major complication in liver transplantation, hepatic surgeries, and shock-induced acute liver failure. This injury is characterized by mitochondrial dysfunction, oxidative stress, and calcium overload, with the mitochondrial permeability transition pore (mPTP) playing a pivotal role in mediating hepatocyte death. Cyclophilin D (CypD), a key regulator of mPTP opening, has long been associated with the exacerbation of HIRI. However, recent research has uncovered a protective aspect of CypD, revealing that it can regulate intermittent or "flickering" mPTP openings to control calcium overload, preserve mitochondrial integrity, and mitigate damage during ischemic stress. This review highlights the dual role of CypD in regulating mitochondrial damage through mPTP dynamics and its complex interplay with autophagy, specifically mitophagy, in liver injury. We also explore the emerging pharmacological and genetic approaches targeting PPIF, offering potential avenues for mitigating liver injury in clinical settings. This review integrates recent findings on PPIF's role in mPTP regulation, inflammation, autophagy, and mitophagy, proposing a nuanced view of its therapeutic potential in managing hepatic ischemia-reperfusion injury.
    Keywords:  MPTP; calcium overload; cyclophilin D (CypD); hepatic ischemia-reperfusion injury; inflammatary disease; mechanisms; mitophagy
    DOI:  https://doi.org/10.3389/fimmu.2025.1575242
  21. Am J Pathol. 2025 Sep 12. pii: S0002-9440(25)00342-6. [Epub ahead of print]
    Dehydroepiandrosterone Prevents Collagen Loss by Regulating HIF-1α Expression and Mitophagy in Hypoxic Human Scleral Fibroblasts.
    Qi Zhang, Jing Chen, Haichun Li, Jing Yang, Jieyong Huang, Bingqian Liu, Shida Chen, Ping Lian, Lin Lu, Xiujuan Zhao.
      Myopia progression and its associated complications, which can lead to vision impairment, primarily result from persistent abnormal elongation of the eye's axial length. The previous metabonomic analysis of intraocular fluids suggested intraocular hormones may play a role in high myopia pathogenesis. In this study, significantly reduced concentrations of dehydroepiandrosterone (DHEA) were discovered in the vitreous humor (VH) of high myopia eyes. Additionally, DHEA levels in retina tissues of myopic guinea pigs were significantly decreased, further linking intraocular DHEA depletion to myopia-related tissue changes. Recent research has established scleral hypoxia as a fundamental mechanism underlying myopia development, with scleral fibroblasts serving as key functional cells in this process. Thus, this study investigated the effects of DHEA on human scleral fibroblasts (HSFs) under hypoxic conditions to generate novel insights for myopia prevention and treatment. The findings demonstrated that DHEA downregulates Hypoxia-inducible factor 1α (HIF-1α) expression and reduces collagen loss under hypoxic conditions. Additionally, DHEA reversed the decreased cell proliferation observed in HSFs in vitro. These effects appear to be mediated through changes in mitochondrial dynamics and regulation of BNIP3L-mediated mitophagy induced by DHEA under hypoxia. The results suggest DHEA represents a promising novel therapeutic strategy for preventing myopia development.
    Keywords:  BNIP3L-mediated mitophagy; Collagen type I α1; Dehydroepiandrosterone; Form deprivation myopia; Guinea pigs; Human scleral fibroblasts; Hypoxia-inducible factor 1α; Mitochondrial function; Myopia
    DOI:  https://doi.org/10.1016/j.ajpath.2025.07.018
  22. Theranostics. 2025 ;15(17): 8873-8896
    Targeting CB1R Rewires Ca2+-Dependent Mitophagy to Promote Nerve Regeneration.
    Ningning Wang, Weizhen Li, Tuo Yang, Baolong Li, Chuikai Meng, Xiongyao Zhou, Jialu Sun, Kaiming Yu, Shusen Cui, Rangjuan Cao.
      Background: Ion homeostasis is disrupted following nerve injury, and elevated Ca2+ levels have been reported to induce Schwann cell (SC) death. Notably, clinical interventions such as electrical stimulation enhance Ca2+ influx and facilitate nerve regeneration. These findings highlight the need to clarify the precise role of Ca2+ signaling in nerve regeneration. Methods: We assessed extracellular Ca2+ concentrations in both human and murine peripheral nerve tissues after injury. Transcriptomic profiling identified CB1R as a key Ca2+-related gene and in vitro validation was performed with primary cultured SC and nerve explants. A sciatic nerve crush model was established in SC-specific CB1R knockout mice. Mitophagy, cellular metabolic homeostasis, and axonal regeneration were systematically assessed using proteomics, calcium imaging, and in vivo analyses. Additionally, the CB1R antagonist JD5037 was administered in both sciatic and optic nerve injury models to evaluate its translational potential. Results: Peripheral nerve injury (PNI) leads to elevated extracellular Ca2+ levels at the injury site, where a moderate increase (~1.5-fold) favors SC survival. PNI also induces upregulation of CB1R, genetic ablation of CB1R enhances Ca2+ influx, promotes SC survival, and maintains metabolic homeostasis. Mechanistically, CB1R interference upregulates adenine nucleotide translocase 2 (ANT2) expression, promotes mitochondrial permeability transition pore (mPTP) opening and mitochondrial membrane depolarization, thereby activating PINK1/Parkin-mediated mitophagy. This process improves mitochondrial quality and enhances energy metabolic efficiency, ultimately promoting axonal regeneration and functional recovery. Furthermore, systemic administration of the CB1R antagonist JD5037 similarly enhances regeneration of both peripheral and optic nerves in vivo. Conclusion: Moderate extracellular Ca2+ elevation establishes a pro-regenerative microenvironment after nerve injury. Targeting CB1R facilitates Ca2+ influx, enhances mitophagy via the PINK1/Parkin pathway, and promotes nerve regeneration. These findings identify CB1R as a viable therapeutic target and support the translational potential of JD5037 for nerve injury treatment.
    Keywords:  Ca2+; Schwann cell; cannabinoid receptor 1; mitophagy; nerve regeneration.
    DOI:  https://doi.org/10.7150/thno.119712
  23. Mol Pharm. 2025 Sep 18.
    Reactive Oxygen Species-Mediated Mitochondrial-Targeted Therapeutics in Hepatic Disorders: Current Progress and Future Opportunities.
    Ashish Dhiman, Yagni Shah, Umesh Chaudhary, Kalpna Garkhal.
      Reactive oxygen species (ROS) are key mediators of mitochondrial dysfunction, contributing to the onset and development of hepatic disorders, including nonalcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), and liver fibrosis. Mitochondria, as central regulators of cellular energy and metabolism, are both sources and targets of ROS, making them critical in understanding liver disease pathology. Current approaches include the development of mitochondria-specific antioxidants, therapeutic agents that enhance mitochondrial biogenesis, and nanotechnology-based delivery systems to improve precision targeting. Emerging approaches such as the modulation of mitochondrial dynamics and mitophagy hold significant potential to restore mitochondrial function and cellular homeostasis. The various causes of mitochondrial dysfunction, with a focus on ROS involvement in the pathogenesis of hepatic disorders, are discussed. Here, currently explored therapeutic remedies for mitochondrial dysfunction and their potential in translating them into clinical applications are covered. A discussion of recent advances in mitochondrial-targeted therapeutics for hepatic disorders is also included. The review concludes by identifying promising directions for future research, emphasizing the need for innovative strategies to exploit the interplay between ROS and mitochondrial dysfunction. These advances could pave the way for targeted, effective therapies for managing hepatic disorders.
    Keywords:  hepatic disorders; mitochondria dysfunction; mitochondrial targeting; reactive oxygen species (ROS); treatment
    DOI:  https://doi.org/10.1021/acs.molpharmaceut.5c00145
  24. J Ethnopharmacol. 2025 Sep 14. pii: S0378-8741(25)01305-4. [Epub ahead of print] 120613
    Mechanistic Insights into Myricetin-Regulated Autophagy via the PI3K/Akt and PINK1/Parkin Pathway in Diabetic Kidney Disease Treatment.
    Xin Liu, Pu-Yu Wang, Si-Qi Tang, Mei-Ling Zhang, Xiao-Feng Fan, Shu-Qing Sun, Yue Guo, Jin-Xia Wu, Zhi-Heng Su, Hua Zheng.
       ETHNOPHARMACOLOGICAL RELEVANCE: Rubus suavissimus S.Lee (RS), a traditional ethnomedicine Guangxi, China, has long been used to manage diabetes and its complications. Existing studies have demonstrated the antidiabetic activity of RS and its complications, but the pharmacological material basis and molecular mechanism of its efficacy have not been clarified.
    AIM OF THE STUDY: This study aimed to elucidate the active constituents and specific molecular mechanisms underlying the therapeutic effects of RS in diabetic kidney disease (DKD).
    MATERIALS AND METHODS: Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was employed to identify major active components within RS polyphenol extracts. Core signaling pathways and key active components were screened using network pharmacology analysis and enrichment methods. Subsequently, an in vitro MPC-5 podocyte cell model was established under high-glucose and high-lipid conditions. Data-independent acquisition (DIA) mass spectrometry was used to analyze differentially expressed proteins in the cellular secretome. Mitochondrial ultrastructure was assessed using transmission electron microscopy (TEM). Key protein expression changes were validated by Western blotting.
    RESULTS: Network pharmacology screening identified myricetin (Myr) as the compound exhibiting the highest binding affinity to PIK3R1, suggesting its role as a key active component in the anti-DKD effects of RS polyphenols. In vitro, high-glucose and high-lipid exposed MPC-5 cells exhibited pronounced mitochondrial swelling and cristae disruption. Myr treatment significantly preserved mitochondrial morphology and induced the formation of double-membrane autophagic vesicles encapsulating damaged mitochondria, indicative of activated mitophagy. Proteomic analysis corroborated these findings. This study demonstrates for the first time that Myr, a principal active component of RS polyphenols, exerts its therapeutic potential in DKD by inhibiting PIK3R1. This inhibition promotes XBP1 expression, indirectly activating both the PI3K/Akt and PINK1/Parkin pathways, ultimately enhancing autophagic flux.
    CONCLUSIONS: Myr effectively activated autophagy and mitophagy by targeting the PI3K/Akt and PINK1/Parkin signaling pathways, facilitating the removal of dysfunctional mitochondria and mitigating cellular damage in DKD models. These findings provide a mechanistic foundation for the use of RS-derived polyphenols in chronic kidney disease management and highlight Myr's potential as a natural therapeutic agent for DKD.
    Keywords:  Diabetic Kidney Disease; Myricetin; PI3K/Akt Signaling Pathway; PINK1/Parkin Pathway; autophagy
    DOI:  https://doi.org/10.1016/j.jep.2025.120613
  25. Research (Wash D C). 2025 ;2025 0891
    Anisotropic Micro/Nanotopography Regulating Mitochondrial Dynamics in Cardiomyocytes.
    Yan Liu, Bingcheng Yi, Liangliang Yang, Yanyan Yang, Tianxiang Li, Xiaolu Li, Jae Youl Cho, Dengshen Zhang, Qihui Zhou, Tao Yu.
      Introduction: Topographical cues of biomaterial scaffolds directly guide cell behaviors by determining integrin ligation and subsequent mechanotransducive pathways, but their influence on organelle (e.g., mitochondrion) behaviors remains unclear. Objectives: Considering the high sensitivity of mitochondria in cardiomyocytes to topographical signals, this study focused on investigating the impact of oriented micro/nano-wrinkled surfaces with varying wavelengths (0.5 to 25.0 μm) and amplitudes (0.05 to 4.30 μm) on the mitochondrial functions of rat embryonic myocardial cell line H9c2. Methods and Results: The results uncover a nonlinear response of cardiomyocyte behavior and mitochondrial homeostasis to these surface features. Notably, surfaces with a 3-μm wavelength and 0.7-μm amplitude (W3) promoted substantial cell elongation and orientation, whereas surfaces with a 0.5-μm wavelength and 0.05-μm amplitude (W0.5) triggered pronounced mitochondrial division. Remarkably, W0.5 topography facilitated mitochondrial division via cytoskeletal remodeling, involving vinculin and tubulin, which disrupted mitochondrial energy metabolism, enhanced reactive oxygen species (ROS)-mediated oxidative stress, and perturbed mitochondrial homeostasis by stimulating the adenosine 5'-monophosphate-activated protein kinase (AMPK) pathway. The transcriptomic analysis identifies the pivotal involvement of the p53, FoxO, mTOR, HIF-1, and AMPK signaling pathways in regulating mitochondrial dynamics in myocardial cells induced by W0.5, confirming the essential role of the polyadenylation signal (AATAAA) in modulating transcript splicing processes. Conclusion: Overall, this study offers important insights into the regulatory mechanisms by which aligned micro/nano topographical stimuli impact mitochondrial responses in cardiomyocytes, which hold potential for the development of novel biomaterial-focused approaches for diagnosing and treating cardiovascular diseases.
    DOI:  https://doi.org/10.34133/research.0891
  26. J Ethnopharmacol. 2025 Sep 12. pii: S0378-8741(25)01295-4. [Epub ahead of print]355(Pt A): 120603
    Macelignan, a lignan from Myristica fragrans Houtt., rescues mitochondrial homeostasis and prevents cognitive decline in vascular dementia by modulating the mTOR-Mitophagy axis.
    Zhengyu Qi, Xinge Chu, Sha Li, Qiaoyun Bai, Ningpo Ding, Guanghai Yan, Hailing Yu, Chunai Cui.
       ETHNOPHARMACOLOGICAL RELEVANCE: Myristica fragrans Houtt. has a long history of use in traditional medicine as a nervine tonic for enhancing cognitive function, relieving anxiety, and managing neurological symptoms associated with aging. Given its established ethnopharmacological profile, we postulated that its principal active lignan, Macelignan, could exert potent neuroprotective effects in the context of neurodegenerative diseases like vascular dementia (VaD).
    AIM OF THE STUDY: This study was designed to investigate the neuroprotective properties of Macelignan in a preclinical model of vascular dementia (VaD) and to elucidate the underlying molecular mechanisms, with a particular focus on its modulation of the mTOR signaling pathway and mitochondrial homeostasis.
    MATERIALS AND METHODS: In this study, in vivo and in vitro models of ischemia-hypoxia were established in Wistar rats by bilateral common carotid artery occlusion (BCCAo) and in HT22 neuronal cells with cobalt chloride (CoCl2) treatment, respectively. The resulting cognitive, pathological, and cell survival damages were comprehensively assessed using a battery of behavioral tests, histological staining (H&E and Nissl), and the CCK-8 assay. To elucidate the underlying mechanisms, we first predicted and validated the direct interaction between the drug and its core target protein using transcriptome sequencing (RNA-seq) combined with molecular docking and dynamics simulations. Subsequently, changes in key signaling pathways, including mTOR, mitochondrial dynamics, autophagy, and apoptosis, were systematically investigated utilizing Seahorse metabolic flux analysis, transmission electron microscopy (TEM), various fluorescent probes (JC-1, MitoSOX, ROS, Ca2+), Western blotting, and immunofluorescence (IF). All data were statistically analyzed using GraphPad Prism 10.1.2.
    RESULTS: In vivo, we demonstrate that Macelignan ameliorates neuronal damage and cognitive deficits in a model of vascular dementia by directly targeting and activating the mTOR signaling pathway. At the cellular level, this mTOR activation orchestrates a multifaceted protective response, which includes restoring mitochondrial function and homeostasis, enhancing antioxidant defenses, suppressing the stress-induced expression of mitophagy-related proteins Beclin-1 and Parkin, and potently inhibiting apoptosis. Critically, these neuroprotective effects of Mace were completely abrogated by the mTORC1-specific inhibitor rapamycin, definitively establishing that its therapeutic efficacy is dependent on mTOR activation.
    CONCLUSIONS: Macelignan targets and activates mTOR to restore mitochondrial homeostasis, thereby ameliorating vascular dementia.
    Keywords:  Apoptosis; Macelignan; Mitochondrial homeostasis; Mitophagy; Vascular dementia; mTOR signaling axis
    DOI:  https://doi.org/10.1016/j.jep.2025.120603
  27. World J Diabetes. 2025 Aug 15. 16(8): 106833
    Troxerutin improves diabetic cognitive dysfunction by inhibiting mitochondrial fission mediated by transient receptor potential melastatin 7/calcineurin/dynamin-related protein 1ser637.
    Jie Li, Ming Gao, Jia-Xin Wang, Hong-Yan Li, Pin Wang, Fang Yuan, Ai-Jing Liu, Song-Yun Zhang.
       BACKGROUND: Diabetic cognitive dysfunction (DCD) is one of the chronic complications of diabetes, but its mechanism is currently unknown. Studies have shown that mitochondrial fission mediated by calcium overload is an important mechanism of DCD. Blocking calcium overload and restoring calcium homeostasis are key steps in treatment. Transient receptor potential melastatin 7 (TRPM7) is a novel player in causing calcium overload. Our previous studies have shown that genetic silencing of TRPM7 in type 1 diabetic rats leads to significant improvements in cognitive function, but the specific mechanism remains unclear. Troxerutin, extracted from the flowers of Sophora japonica, is one of the derivatives of rutin and has been shown to have neuroprotective effects. However, its association with TRPM7 remains unclear.
    AIM: To use animal and cellular models, we investigated whether TRPM7 mediated mitochondrial fission by upregulation of calcineurin (CaN)/dynamin-related protein 1 (Drp1)ser637 in DCD, and whether Troxerutin improved DCD by inhibiting TRPM7-mediated mitochondrial division.
    METHODS: In this study, we used db/db mice and hippocampal neuronal cell lines (HT22) treated with high-concentration glucose as our study subjects. We evaluated cognitive function using Morris water maze, novel object recognition tasks, and Nesting tests. We observed mitochondrial morphology using transmission electron microscopy and measured mitochondrial energy metabolism indicators using a spectrophotometer. We also detected mRNA and protein expression of TRPM7, CaN, p-Drp1ser637, caspase-3, B-cell lymphoma 2 associated X protein, and B-cell lymphoma 2 using quantitative real-time polymerase chain reaction, western blotting, and immunofluorescence.
    RESULTS: In the db/db diabetic mice with cognitive dysfunction, as well as in hippocampal neurons exposed to high-concentration glucose, TRPM7 and CaN expression were upregulated, phosphorylated Drp1ser637 expression was downregulated, and mitochondrial fission was increased. By modulating (inhibiting or overexpressing) TRPM7, it was further validated that TRPM7 activates the CaN/Drp1ser637 pathway, resulting in an increase in mitochondrial fission and neuronal cell apoptosis. Troxerutin downregulated TRPM7/CaN/Drp1ser637, reduced mitochondrial fission, and improved DCD.
    CONCLUSION: TRPM7 promotes mitochondrial fission via the CaN/Drp1ser637 pathway. Troxerutin improves mitochondrial function and reduces neuronal damage by inhibiting this pathway, suggesting TRPM7 as a potential therapeutic target for DCD.
    Keywords:  Diabetic cognitive dysfunction; Dynamin-related protein 1; Mitochondrial fission; Morris water maze; Nesting tests; Novel object recognition tasks; Transient receptor potential melastatin 7; Troxerutin
    DOI:  https://doi.org/10.4239/wjd.v16.i8.106833
  28. Biochim Biophys Acta Rev Cancer. 2025 Sep 16. pii: S0304-419X(25)00195-7. [Epub ahead of print] 189453
    Intricate role of DRP1 and associated mitochondrial fission signaling in carcinogenesis and cancer progression.
    Soumya Ranjan Mishra, Priyadarshini Mishra, Prakash Kumar Senapati, Kewal Kumar Mahapatra, Sujit Kumar Bhutia.
      The process of mitochondrial fission is a major determinant of mitochondrial homeostasis. DRP1 is the chief architect of the mitochondrial fission process, and the DRP1 recruitment to the mitochondrial outer membrane is necessary for the mitochondrial division. DRP1 contributes to cancer progression by promoting cell proliferation, enhancing resistance to therapy, inhibiting mitochondrial-mediated apoptosis, suppressing immune responses, and sustaining cancer stem cell heterogeneity and self-renewal. Moreover, DRP1 drives metabolic reprogramming to support enhanced energy production and biosynthesis required for tumor growth and survival. In addition, DRP1-mediated mitochondrial fission also favours NLRP3 inflammasome activation within the tumor microenvironment, which regulates cancer progression. Interestingly, elevated levels of DRP1 expression have been identified as a significant prognostic marker, correlating with poor survival outcomes across multiple cancer types. Many DRP1 inhibitors have been developed for cancer treatment, but more specific and selective agents are needed to improve efficacy and reduce off-target effects. A comprehensive understanding of DRP1's role in cancer cells is essential for developing DRP1 inhibitors, which hold promise as novel anticancer therapies and may enhance the effectiveness of conventional treatments.
    Keywords:  Cancer; Chemoresistance; DRP1; Metabolic reprograming; Mitochondrial fission; NLRP3 inflammasome
    DOI:  https://doi.org/10.1016/j.bbcan.2025.189453
  29. Mol Med Rep. 2025 Dec;pii: 322. [Epub ahead of print]32(6):
    Capsaicin attenuates sepsis‑associated encephalopathy by inhibiting neuroinflammation and apoptosis whilst activating mitophagy through the BNIP3/NIX pathway.
    Silun Zhang, Nanbo Luo, Hanxi Wu, Junfa Chen, Yonghan Jiang, Lifei Xiao, Hanlin Liang, Qingsheng Xue, Yan Luo, Buwei Yu, Yuqiang Liu, Zhiheng Liu.
      Sepsis‑induced abnormalities in brain function or sepsis‑associated encephalopathy (SAE) can manifest as cognitive dysfunction and other neuropsychiatric symptoms; however, the underlying mechanisms remain unclear. The aim of the present study was to elucidate the possible effects and mechanism of capsaicin, a transient receptor potential vanilloid 1 (TRPV1) agonist, on the pathological features of SAE. A model of SAE in C57BL/6 mice was generated using cecal ligation and puncture (CLP). Capsaicin (1 mg/kg) was injected subcutaneously before surgery. Cognitive function in mice was evaluated using the novel object recognition test (NORT) and Morris water maze (MWM). Immunofluorescence staining, ELISA, western blotting and transmission electron microscopy were performed to detect the degree of microglial activation (ionized calcium‑binding adapter molecule 1), proinflammatory cytokine levels (TNF‑α), autophagy and apoptosis‑related protein expression, and autophagosomes. Autophagic flux was monitored using the LC3‑GFP‑mCherry fluorescent reporter. Compared with that in the sham group mice, the expression levels of TRPV1 were significantly reduced in the hippocampal tissue of mice with sepsis. Mice with sepsis also exhibited cognitive dysfunction. Notably, a single administration of capsaicin reduced the mortality rate, but did not improve cognitive function in mice with sepsis. Furthermore, repeated administration of capsaicin was revealed to enhance the recognition index of novel objects among mice with sepsis, to reduce the latency to locate the platform and to augment the duration of mouse platform quadrant movements, according to the NORT and MWM tasks. Increased microglial activation, release of proinflammatory cytokines and expression levels of apoptosis‑related proteins were all observed in mice with CLP‑induced sepsis, as was brain tissue destruction in the hippocampal regions. By contrast, capsaicin treatment ameliorated CLP‑induced microglial activation, inflammation, neuronal apoptosis (cleaved caspase 3 expression increased) and brain tissue destruction. Furthermore, application of capsaicin increased the expression levels of LC3, reduced the expression of p62 and elevated autophagic flux compared with those in the CLP group. Finally, treatment with capsaicin effectively enhanced the levels of Bcl‑2‑interacting protein 3 (BNIP3) and BNIP3‑like (NIX) expression. These findings suggested that capsaicin may be considered a potential drug for the treatment of SAE, and BNIP3/NIX‑mediated mitophagy may be involved in this process.
    Keywords:  capsaicin; mitophagy; neuroin-flammation; sepsis‑associated encephalopathy
    DOI:  https://doi.org/10.3892/mmr.2025.13686
  30. Front Physiol. 2025 ;16 1690425
    Correction: Advances in mitochondrial dysfunction in radiation tissue injury.
    Jianhuang Rong, Qiujie Yu, Guilin Huang, Yueyue Wang, Nini Zhang.
      [This corrects the article DOI: 10.3389/fphys.2025.1660330.].
    Keywords:  apoptosis; energy metabolism; mitochondrial dysfunction; mitophagy; oxidative stress; radiation injury
    DOI:  https://doi.org/10.3389/fphys.2025.1690425
  31. Am J Transl Res. 2025 ;17(8): 6414-6424
    DUSP1 alleviates LPS-induced acute lung injury by inhibiting the SHP2-JNK axis and mitochondrial apoptosis.
    Sheng Chen, Yunnan Hu, Lingfeng Li, Jiaxin Zhang, Rongda Huang, Mirong Tang.
       BACKGROUND: Lipopolysaccharide (LPS) induces acute lung injury (ALI), a condition characterized by oxidative stress, inflammation, and apoptosis, ultimately leading to respiratory failure. Dual-specificity phosphatase 1 (DUSP1), a key regulator of MAPK signaling, may offer protection against inflammatory damage.
    OBJECTIVE: This study aimed to investigate the protective effects of DUSP1 overexpression against LPS-induced inflammatory injury and to explore the underlying molecular mechanisms using both in vitro and in vivo models.
    METHODS: Cellular and murine ALI models were established using LPS. DUSP1 was overexpressed via plasmid transfection for in vitro experiments and viral vectors for in vivo studies. Cell viability, apoptosis, reactive oxygen species (ROS), and pro-inflammatory cytokine levels (IL-1β, IL-6, TNF-α) were assessed. In mice, lung injury was evaluated through bronchoalveolar lavage fluid (BALF) analysis, lung mechanics, and histopathology. DUSP1-SHP2 interactions were predicted using bioinformatics and validated through co-immunoprecipitation. JNK pathway activation was analyzed by Western blotting, and dual-luciferase reporter assays confirmed the regulatory interaction between DUSP1 and SHP2.
    RESULTS: In vitro, DUSP1 overexpression significantly enhanced cell viability while reducing apoptosis, ROS, malondialdehyde (MDA), and inflammatory cytokines in LPS-stimulated cells. In vivo, DUSP1 overexpression substantially alleviated LPS-induced lung injury, evidenced by decreased BALF protein, reduced lung water content, lower airway resistance, improved pulmonary function, and less tissue damage. Mechanistically, DUSP1 directly interacted with SHP2, inhibiting its phosphorylation, which in turn suppressed the phosphorylation of p53 and JNK. DUSP1 overexpression also downregulated PINK1/Parkin-mediated mitophagy, key pro-apoptotic proteins (Cytochrome C, Caspase-3, Bax), and the NLRP3 inflammasome. Anisomycin treatment reversed these protective effects, confirming the dependence of DUSP1's protective action on JNK pathway inhibition.
    CONCLUSION: DUSP1 overexpression alleviates LPS-induced lung inflammation and injury by targeting the SHP2-JNK axis and restoring mitochondrial homeostasis. These findings position DUSP1 as a promising therapeutic target for inflammatory lung disorders.
    Keywords:  DUSP1; JNK/P53/NLRP3 signaling pathway; SHP-2; mitochondrial autophagy; septic acute lung injury
    DOI:  https://doi.org/10.62347/QAUM4023
  32. Biochem Pharmacol. 2025 Sep 17. pii: S0006-2952(25)00611-2. [Epub ahead of print] 117346
    Melatonin attenuates high-fat diet- and particulate matter-induced cardiac injury: involvement of mitochondrial quality and miR-221/222 expression.
    Ya-Chun Chen, Ming-Hsueh Lee, Szu-Ju Fu, Chiang-Wen Lee, Wen-Chi Shen, Tsai-Chun Lai, Shu-Rung Lin, Shu-Wha Lin, I-Shing Yu, Tzu-Yi Chuang, Jaw-Shiun Tsai, Yuh-Lien Chen.
      Previous studies have shown that exposure to hyperlipidemia or particulate matter (PM) individually affects the progression of cardiovascular disease (CVD), but the combined effects of these factors remain understudied. This study investigated whether combined treatment with a high-fat diet (HFD)/palmitate (PA) and PM exacerbates cardiomyocyte injury and proposed using the antioxidant melatonin. Furthermore, we explored the role of mitochondria and miR-221/222 in melatonin-mediated reduction of HFD- and PM-exacerbated cardiomyocyte injury. H9c2 cells were treated with or without 50 μM PA, 10 μg/mL PM, and 100 μM melatonin for 24 h. In the in vivo experiments, 8-12-week-old wild-type (WT) mice, miR-221/222 knockout (miR-221/222-/-) mice, and miR-221/222 overexpression (miR-221/222o/e) mice were treated with HFD for 4 weeks. PM was injected intratracheally at the end of the second and third weeks, and melatonin 20 mg/kg was administered orally daily starting at the end of the second week. Combined PA/HFD and PM induced mitochondrial ROS accumulation, subsequent mitochondrial fission, and excessive mitophagy in cardiomyocytes and cardiac tissues. This cascade increases cardiomyocyte apoptosis and fibrosis, leading to cardiac dysfunction. Melatonin treatment reduced mitochondrial ROS accumulation and improved HFD- and PM-induced cardiac dysfunction. Further exploration of the molecular mechanism highlighted that miR-221/222 upregulation is a downstream effect of melatonin, revealing a novel regulatory pathway for HFD- and PM-induced cardiac injury. This study showed that simultaneous exposure to HFD/PA and PM exacerbated cardiomyocyte apoptosis and fibrosis. These effects could be ameliorated by melatonin-mediated ROS scavenging, maintenance of mitochondrial function, and cardioprotection associated with miR-221/222.
    Keywords:  High-fat diet; Melatonin; Mitochondria; Particulate matter; ROS; miR-221/222
    DOI:  https://doi.org/10.1016/j.bcp.2025.117346
  33. Adv Sci (Weinh). 2025 Sep 17. e10811
    SLC6A14 Drives Mitochondrial Fusion and Oxidative Phosphorylation to Promote Cancer Stemness and Early-Onset of Breast Cancer.
    Dai-Wei Hu, Chih-Hao Huang, Yu-Hao He, Ya-Ling Wei, Shu-Wei Hu, Fang-Ju Cheng, Thanh Kieu Huynh, Bo-Rong Chen, Bo-Wei Wang, Li-Chi Kuan, Der-Yen Lee, Ming-Hsin Yeh, Ya-Jen Chang, Liang-Chih Liu, Mien-Chie Hung, Wei-Chien Huang.
      Early-onset breast cancer (EOBC), diagnosed before the age of 45, is associated with poor therapeutic outcomes and limited survival, yet the underlying mechanisms remain poorly defined. Identifying environmental risk factors and actionable therapeutic targets is an urgent clinical need. Notably, the largest survival gap between younger and older patients occurs in luminal breast cancer, implicating potential endocrine disruption. Here, an association is identified between elevated levels of di(2-ethylhexyl)phthalate (DEHP) in hair, a widely used endocrine-disrupting plasticizer, and earlier age at diagnosis of breast cancer. Mechanistically, DEHP exposure promotes tumor initiation by enhancing cancer stemness through mitochondrial fusion and glutamine-driven oxidative phosphorylation. DEHP upregulates the glutamine transporter SLC6A14 to enhance glutamine uptake, while suppressing mitochondrial fission factor (MFF), which exacerbates mitochondrial fusion. High SLC6A14 expression correlates with cancer stemness signatures and earlier onset in patient cohorts. Inhibition of SLC6A14 reduces stemness, impairs tumor growth, and sensitizes tumors to chemotherapy. Collectively, the findings uncover a novel environmental-metabolic axis linking plasticizer exposure to EOBC and establish SLC6A14 as a promising metabolic vulnerability. These results provide a strong preclinical rationale for targeting SLC6A14 in young breast cancer patients and offer new insights into mitigating the oncogenic impact of environmental pollutants.
    Keywords:  SLC6A14; cancer stemness; early‐onset breast cancer; mitochondria dynamics; plasticizer
    DOI:  https://doi.org/10.1002/advs.202510811
  34. Front Med (Lausanne). 2025 ;12 1635219
    Dual roles of mTOR in skeletal muscle adaptation: coordinating hypertrophic and mitochondrial biogenesis pathways for exercise-induced chronic disease management.
    Yong-Cai Zhao.
      
    Keywords:  exercise; hypertrophy; mammalian target of rapamycin (mTOR); mitochondrial biogenesis; skeletal muscle
    DOI:  https://doi.org/10.3389/fmed.2025.1635219
  35. bioRxiv. 2025 Sep 04. pii: 2025.09.02.673111. [Epub ahead of print]
    Hepatocyte FAM210A deficiency disrupts mitochondrial function and triggers juvenile steatosis with compensatory repair in adulthood.
    Yubo Wang, Leah Chu, Yumei Zhou, Zihao Jin, Kyoungrae Kim, Katie Heiden, Miguel A Gutierrez-Monreal, Junxiao Ren, Yufen Li, Zhiyong Cheng, Kari B Basso, Karyn A Esser, Terence E Ryan, Feng Yue.
      Mitochondrial dynamics are central to maintaining liver metabolic homeostasis, yet the mechanisms that safeguarding mitochondrial integrity during development and metabolic dysfunction remain poorly defined. Here, we identify Family with sequence similarity 210 member A (FAM210A) as a hepatocyte-enriched mitochondrial regulator essential for postnatal liver maturation. Hepatocyte-specific deletion of Fam210a ( Fam210a HKO ) in mice caused early growth restriction, reduced body and liver mass, and pronounced hepatic steatosis with glycogen depletion. These defects were accompanied by lower postprandial glucose levels in the fasted-refeeding state, impaired oxidative phosphorylation, reduced mtDNA content, and abnormal cristae architecture. Transcriptomic and proteomic profiling revealed broad suppression of fatty acid, sterol, and bile acid metabolism, with concomitant glutathione stress responses. Mechanistically, FAM210A deficiency disrupted the YME1L-OPA1 axis, driving excessive OPA1 cleavage and cristae destabilization. Strikingly, these juvenile defects were transient and resolved by adulthood, underpinned by enhanced hepatocyte proliferation and mitochondrial biogenesis, consistent with a compensatory stress-adaptive response via the activation of ISR signaling. Together, these findings uncover FAM210A as a developmental safeguard of mitochondrial remodeling in hepatocytes and indicate compensatory programs with therapeutic relevance for chronic liver disease.
    DOI:  https://doi.org/10.1101/2025.09.02.673111
  36. Curr Aging Sci. 2025 Sep 11.
    Advancing Mitochondrial Health in Huntington Disease (HD): Small Molecule Therapies and Neurodegeneration.
    Vasanth S, Rakhi Mishra, Subhashree Sahoo, Sadia Parveen, Zuber Khan, Mumtaz, Ruqaiya, Rahul Pal.
      Huntington's disease (HD) is a severe neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin gene, leading to the production of a mutant huntingtin protein. This mutation results in progressive motor, cognitive, and psychiatric impairments, alongside significant neuronal loss. Mitochondrial dysfunction plays a pivotal role in the pathophysiology of HD, contributing to disease progression and neuronal death. This article aims to evaluate small molecule-based therapeutic strategies designed to enhance mitochondrial function as a potential approach to alleviate symptoms and slow the progression of HD and related neurodegenerative disorders. A comprehensive review of recent literature is conducted to identify small molecules targeting mitochondrial dysfunction from Google Scholar, Pub- Med/Medline/PMC, ScienceDirect, Elsevier, Google Patents, and Clinicaltrials.gov.in, among others. The analysis focuses on their mechanisms of action, including reducing oxidative stress, enhancing mitochondrial biogenesis, and improving mitochondrial dynamics and function. The review identifies several promising small molecules capable of targeting mitochondrial dysfunction. These agents demonstrate potential in preclinical studies to alleviate HD symptoms and modify disease progression by addressing key aspects of mitochondrial health. Small molecule therapies targeting mitochondrial dysfunction offer considerable promise for treating HD. However, further research is required to optimize these therapies for clinical use and to evaluate their long-term impact on disease progression to fully establish their therapeutic efficacy.
    Keywords:  Huntington’s disease; gene therapy; mitochondrial dysfunction.; mutant huntingtin; neurodegeneration
    DOI:  https://doi.org/10.2174/0118746098387655250818072130
  37. Int J Biol Macromol. 2025 Sep 17. pii: S0141-8130(25)08295-9. [Epub ahead of print] 147738
    CircNCX1 contributes to mitochondrial fusion in cardiomyocyte by mediating the expression of mitofusin 2.
    Heng Zhang, Jiaxin Li, Yu Wang, Qi Li, Lin Song, Mengyang Li.
      Mature mammalian cardiomyocytes highly utilize fatty acid-dependent aerobic respiration to produce energy effectively. However, even embryonic and neonatal cardiomyocytes prefer anaerobic glycolysis. The underlying molecular mechanism of this transformation during cardiomyocyte maturation hasn't been fully understood. Circular RNA-circNCX1 (also named circSLC8A1) is enriched in cardiomyocytes and previously demonstrated to inhibit cardiomyocyte proliferation. Here, our study further indicates that circNCX1 is also essential for mitochondria maturation in cardiomyocytes. It was observed that circNCX1 facilitates mitochondrial fusion and closure of the mitochondrial permeability transition pore, leading to an increase in mitochondrial function and metabolic remodeling in cardiomyocytes. Mechanistically, circNCX1 functions in a mitofusin 2 (MFN2)-dependent manner. It up-regulates MFN2 by inhibiting the expression of miR-16-5p. At the animal level, cardiomyocyte-specific silencing of circNCX1 can simultaneously cause mitochondrial dynamics dysfunction and activate cardiomyocyte proliferation, resulting in non-pathological cardiac enlargement with preserved heart function. In summary, our study revealed the regulatory mechanism of circNCX1 on cardiomyocyte maturation and its therapeutic potential in heart disease treatment.
    Keywords:  Cardiomyocyte maturation; Circular RNA; MFN2; Metabolic remodeling; Mitochondria; circNCX1; miR-16
    DOI:  https://doi.org/10.1016/j.ijbiomac.2025.147738
  38. Int J Med Sci. 2025 ;22(14): 3598-3616
    miR-6126 modulates GRP78 to suppress the Warburg effect and mitochondrial dynamics in triple-negative breast cancer.
    Wei-Jan Wang, Jian-Sheng Liu, Nguyen Hoang Anh Kha, Wan-Jou Shen, Chih-Jung Chen, Shuan-Chu Chen, Pin-Chen Liao, Chih-Yang Huang, Wei-Wen Kuo.
      Cancer cells often exhibit a metabolic shift towards aerobic glycolysis, known as the Warburg effect, leading to excessive energy production that facilitates tumorigenesis, including in breast cancer. Recently, non-coding RNAs, including microRNAs (miRNAs), have been identified as playing crucial roles in various human cancers. However, their roles in regulating metabolic reprogramming in breast cancer remain largely unexplored. Here, we identified the novel miRNA miR-6126, which is highly expressed in TNBC cells by using a miRNA microarray analysis. Overexpression of miR-6126 reduced the growth of TNBC cells and induced apoptosis by targeting GRP78 in vitro and in vivo. In addition, a luciferase reporter assay confirmed that GRP78 is a direct target of miR-6126. Elevated glucose metabolism, indicated by increased levels of LDHA and glucose transporter-1, was observed in TNBC following GRP78 overexpression. Treatment with miR-6126 mimics or GRP78 siRNA not only reduced LDHA and GLUT1 expression but also decreased glucose uptake and lactate release in TNBC cells. Moreover, miR-6126 impaired mitochondrial function by inducing mitochondrial fission through the downregulation of phospho-Drp1 (Ser616) and FIS1. Furthermore, we demonstrated that the expression of miR-6126 is negatively correlated with GRP78 in human tumor tissues. Our findings revealed that miR-6126 is implicated in tumorigenesis via the Warburg effect by targeting GRP78 and restoring mitochondrial function in TNBC.
    Keywords:  GRP78; Warburg effect; miR-6126; mitochondria dynamics; triple-negative breast cancer
    DOI:  https://doi.org/10.7150/ijms.107240
  39. Chin J Integr Med. 2025 Sep 20.
    Dihuang Yinzi Regulates cAMP/PKA/CREB-BDNF to Improve Synaptic Plasticity in APP/PS1 Mice: A Study Based on Brain Metabolomics.
    Huan-Ning Jiang, Bo Zhang, Jian Zhang, Yan-Yan Zhou.
       OBJECTIVE: To explore the mechanism of Dihuang Yinzi (DHYZ) in the treatment of Alzheimer's disease (AD) by integrating metabolomics and experimental verification.
    METHODS: Forty-eight male APP/PS1 mice were divided into model, high- (DHYZ-H), medium- (DHYZ-M), and low-dose DHYZ (DHYZ-L) groups (12 mice per group) according to a random number table. Mice in DHYZ groups were gavaged with DHYZ 6.34, 12.68, and 25.35 g/(kg·d), respectively. Twelve C57BL/6 mice were gavaged with distilled water as the blank group. Metabolomics was used to analyze differential metabolites in the brains of mice. Morris water maze test was used to detect the memory abilities of mice. The hematoxylin-eosin staining and transmission electron microscopy were used to observe the general morphology and ultrastructure of neurons. The enzyme-linked immunosorbent assay was used to detect the levels of superoxide dismutase (SOD), reactive oxygen species (ROS), and amyloid β -protein 1-42 (A β1-42). The real-time quantitative polymerase chain reaction was used to detect the mRNA expressions of density-regulated protein 1 (DRP1), fission 1 (FIS1), mitofusin-1 (MFN1), and optic atrophy protein 1 (OPA1). Western blot was used to detect the protein expressions of cyclic adenosine monophosphate (cAMP), protein kinase A (PKA), cAMP response binding protein (CREB), brain-derived neurotrophic factor (BDNF), synapsin 1 (SYN1), synaptophysin (SYP), and postsynaptic density protein 95 (PSD95).
    RESULTS: A total of 82 differential metabolites were identified in the brains of APP/PS1 mice, among which 7 differential metabolites could be regulated by DHYZ. After DHYZ intervention, the memory abilities of mice significantly increased (P<0.05 or P<0.01), the number of synapses and neurons in the hippocampus increased, and the mitochondrial morphology and structure were relatively intact. The DHYZ groups exhibited a significant reduction in hippocampal ROS and A β1-42 levels, along with a significant elevation in SOD level (P<0.05 or P<0.01). The mRNA expressions of DRP1 and FIS1 were reduced, while the mRNA expressions of MFN1 and OPA1 were increased after DHYZ treatment (P<0.05 or P<0.01). The cAMP/PKA/CREB-BDNF pathway was activated, and the expressions of SYN1, SYP and PSD95 proteins were significantly increased in the DHYZ-H group (P<0.05 or P<0.01).
    CONCLUSIONS: DHYZ could improve mitochondrial dynamics and synaptic plasticity in APP/PS1 mice, inhibit oxidative stress, and thereby enhancing learning and memory abilities in APP/PS1 mice. Its mechanism might be related to activation of the cAMP/PKA/CREB-BDNF signaling pathway.
    Keywords:  Alzheimer’s disease; Chinese medicine; Dihuang Yinzi; cAMP pathway; metabolomics; mitochondria; synapses
    DOI:  https://doi.org/10.1007/s11655-025-3936-4
  40. Toxicol Appl Pharmacol. 2025 Sep 13. pii: S0041-008X(25)00341-2. [Epub ahead of print]505 117565
    Preclinical safety and toxicokinetic evaluation of TJ0113, a first-in-class mitophagy inducer for Parkinson's disease.
    Yanan Tian, Fengqi Wang, Jikai Shen, Ruiqi Zhang, Qianwen Chen, Le Xu, Dong Liu, Mengyang Fan, Zhen Tian, Xufeng Cen, Xiaoyan Xu, Hongguang Xia.
      Mitochondrial dysfunction is a key driver of neurodegeneration, highlighting mitophagy as a tractable therapeutic axis. Yet the clinical translation of mitophagy-targeting agents requires robust, GLP-compliant nonclinical safety data to support and de-risk human trials in line with international guidelines. TJ0113, a first-in-class small-molecule inducer of mitophagy, has shown disease-modifying activity in preclinical models and is being evaluated in a registered, randomized, double-blind, placebo-controlled Phase II trial in Parkinson's disease (NCT06596005). We conducted a comprehensive safety assessment of TJ0113 in Sprague-Dawley rats and Beagle dogs under GLP. Single-dose studies (up to 1500 mg/kg, oral) and repeat-dose studies (rats: 15, 30, 100 mg/kg/day for 26 weeks; dogs: 6, 20, 60 mg/kg/day for 39 weeks) evaluated systemic toxicity, toxicokinetics (TK), safety pharmacology endpoints (including ECG), and a standard genotoxicity battery (Ames, chromosomal aberration, micronucleus) consistent with ICH S2(R1). No treatment-related mortality or target-organ toxicity occurred. A modest increase in relative kidney organ coefficient in rats was observed but without biochemical or histopathological correlates and was considered non-adverse. Clinical pathology, ECG, and dog urinalysis remained within physiological limits; all genotoxicity tests were negative. TK showed rapid absorption with linear, dose-proportional exposure and no accumulation at the end of dosing. The NOAELs were 100 mg/kg/day in rats (26 weeks) and 60 mg/kg/day in dogs (39 weeks). These data establish a favorable nonclinical safety profile for TJ0113 and provide GLP evidence supporting further clinical development of this selective mitophagy-targeting agent.
    Keywords:  Genotoxicity; Mitochondrial quality control; Mitophagy; Parkinson's disease; TJ0113; Toxicokinetics
    DOI:  https://doi.org/10.1016/j.taap.2025.117565
  41. Front Physiol. 2025 ;16 1660330
    Advances in mitochondrial dysfunction in radiation tissue injury.
    Jianhuang Rong, Qiujie Yu, Guilin Huang, Yueyue Wang, Nini Zhang.
      Radiation-induced tissue injury is a major limitation in cancer radiotherapy, often leading to collateral damage in healthy tissues. While the nucleus has long been considered the principal target of ionizing radiation, emerging evidence underscores the pivotal role of mitochondria in mediating radiation-induced damage. This review provides a comprehensive overview of mitochondrial dysfunction in various irradiated tissues, including the intestine, hematopoietic system, heart, lung, brain, and skin. Key mitochondrial alterations-such as disrupted dynamics, impaired energy metabolism, excessive reactive oxygen species (ROS) production, and activation of apoptotic and senescence pathways-are highlighted as central mechanisms underlying radiation pathology. Additionally, we summarize the involvement of crucial signaling pathways such as AMP-activated protein kinase/peroxisome proliferator-activated receptor gamma coactivator 1-alpha (AMPK/PGC-1α),nuclear factor erythroid 2-related factor 2/antioxidant response element/mitochondrial transcription factor A (Nrf2/ARE/TFAM), and NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome in regulating mitochondrial responses to radiation stress. A deeper understanding of mitochondrial involvement provides novel avenues for radioprotection and therapeutic interventions in oncology.
    Keywords:  apoptosis; energy metabolism; mitochondrial dysfunction; mitophagy; oxidative stress; radiation injury
    DOI:  https://doi.org/10.3389/fphys.2025.1660330
  42. Int J Med Sci. 2025 ;22(14): 3664-3681
    Temporal Effects of Lipid Oversupply on Energy Metabolism and Mitochondrial Homeostasis in Hepatocytes.
    Cheng-Chieh Chuang, Ying-Hao Chen, Fang-Yeh Chu, Ching-Ping Yang, Hsiang-Ling Ho, Fu-Pang Chang, Yu-Li Lo, Chun-Jung Chen, Yih-Hsin Chang.
      Obesity is closely associated with multiple metabolic disorders such as non-alcoholic fatty liver disease (NAFLD). Patients with NAFLD are susceptible to develop irreversible life-threatening diseases, however, the evolution concerning mitochondrial and metabolic alterations during NAFLD development and progression remain elusive. This study focused on uncovering the sequential events of energy metabolism and mitochondrial homeostasis of hepatocytes under the environment of lipid oversupply by in vitro and in vivo strategies. Long-chain fatty acid (FA) synthesis and lipid storage were first induced by providing hepatocytes with sufficient energy source, followed by suppressed glucose metabolic efficiency and decreased mitochondrial mass. Intriguingly, distinctive features of hepatic cancer cells in response to FA oversupply were characterized. Insulin signaling and glucose uptake were rapidly deterred while lipid β-oxidation was significantly boosted. Enhanced mitochondrial biogenesis was identified as compensatory feedback for mitochondrial dysfunction. FA-induced mitophagy, cell morphological transition and higher N-cadherin expression potentiates epithelial-mesenchymal transition (EMT) which confers the cells with higher plasticity and accelerates NAFLD progression to irreversible hepatic diseases. This study provides evidence elucidating the temporal events caused by FA oversupply, moreover, delineates the facilitative role of excess nutrients in shaping the environment for lipid-laden hepatocytes to acquire malignant traits. Given the rapidly increasing global prevalence of metabolic disorders and the heterogeneous manifestations exhibited by NAFLD during disease progression, better understanding of the sequential events caused by FA overload aids in identifying promising targets and developing tailor-made treatment protocol according to individual disease status and conditions.
    Keywords:  energy metabolism; hepatocytes; lipid oversupply; mitochondrial homeostasis; obesity
    DOI:  https://doi.org/10.7150/ijms.104128
  43. Br J Pharmacol. 2025 Sep 16.
    Dietary antioxidants alleviate antibiotic-induced mitochondrial dysfunction through protein kinase AMP-activated alpha (AMPKα) and nuclear factor, erythroid 2 like 2 (NRF2) pathway interaction.
    Jingyan Zhao, Bing Shang, Sha Xu, Danfeng Zheng, Xiaofang Zhang, Jiawen Lv, Yaqiong Dong, Xiaoda Yang.
       BACKGROUND AND PURPOSE: Antibiotics and ibuprofen combinations cause mitochondrial toxicity and hepatotoxicity. This study investigated whether dietary antioxidants could protect against this damage via protein kinase AMP-activated alpha (AMPKα)/nuclear factor erythroid 2-related factor 2 (NRF2) pathways.
    EXPERIMENTAL APPROACH: Human umbilical vein endothelial cells (HUVECs) were treated with antibiotics (kanamycin, azithromycin, ampicillin or ciprofloxacin) plus ibuprofen with or without antioxidants. Azithromycin/ibuprofen induced hepatotoxicity was evaluated in C57BL/6J mice. Mitochondrial parameters including morphology, reactive oxygen species (ROS), mitochondrial membrane potential (ΔΨm) and key proteins (mitofusin 2, AMPKα, glycogen synthase kinase 3 beta [GSK3B], NRF2 and haem oxygenase 1 [HO1]) were analysed.
    KEY RESULTS: Antibiotics/ibuprofen combinations triggered mitochondrial fission, ROS overproduction and mitofusin 2 down-regulation. Four antioxidants, that is, coniferaldehyde, raspberry ketone, gastrodin and eugenol, restored mitochondrial function and morphology. Coniferaldehyde and raspberry ketone effectively prevented in vivo hepatotoxicity and inflammation. Moreover, coniferaldehyde/raspberry ketone activated NRF2/HO1 while restoring AMPKα/GSK3B signalling.
    CONCLUSIONS AND IMPLICATIONS: Coniferaldehyde and raspberry ketone showed potent rescue effects in vitro against all antibiotic models and in vivo against azithromycin/ibuprofen-induced hepatotoxicity through AMPKα-GSK3B/NRF2-HO1 modulation, with favourable safety profiles.
    Keywords:  AMPKα; NRF2 signalling; hepatoprotection; mitochondrial dynamics; natural antioxidants; oxidative stress
    DOI:  https://doi.org/10.1111/bph.70191
  44. Leukemia. 2025 Sep 16.
    Suppression of Rho-associated kinase 1 (ROCK1) promotes human hematopoietic stem cell expansion by attenuating mitochondrial fission.
    Xuepeng Wang, Baskar Ramdas, Ramesh Kumar, Ji Zhang, Reuben Kapur.
      
    DOI:  https://doi.org/10.1038/s41375-025-02770-9
  45. bioRxiv. 2025 Sep 06. pii: 2025.09.02.673863. [Epub ahead of print]
    DRP1 induces neuroinflammation via transcriptional regulation of NF-ĸB.
    Yanhao Lai, Rebecca Z Fan, Harry J Brown, Said S Salehe, Ethan K Tieu, Kim Tieu.
      Neuroinflammation is a major pathogenic mechanism in neurodegenerative diseases. Understanding the regulation of neuroinflammation is critical to therapeutic development. We report here that dynamin related protein 1 (DRP1), well-recognized for its role in mitochondrial fission, is a transcription factor that regulates neuroinflammation. Using multiple inflammatory models, we provide evidence demonstrating that DRP1, when challenged with pro-inflammatory lipopolysaccharides, translocates from the cytosol to the nucleus, then binds to the promoter region of Rela (encoding NF-κB) to activate its gene products and other downstream inflammatory cytokines. Our data also demonstrate the significant role of the proinflammatory lipocalin 2 in the brain. In combination, this study highlights a previously unidentified function of DRP1 in mediating neuroinflammation via the NF-κB-lipocalin 2 axis. Through such mechanisms of DRP1, this study also provides potential therapeutic targets for neurodegenerative diseases and other conditions linked to inflammation.
    DOI:  https://doi.org/10.1101/2025.09.02.673863
  46. Toxicol Appl Pharmacol. 2025 Sep 12. pii: S0041-008X(25)00336-9. [Epub ahead of print]505 117560
    17-Methoxyl-7-hydroxy-benzene-furanchalcone improves mitochondrial biogenesis and oxidative stress following myocardial ischemia/reperfusion injury through the AMPK/SIRT1 pathway based on network pharmacology.
    Yuanheng Huang, Yan Zhou, Qiuhua Qin, Sirui Mo, Zudong Xu, Zhiwei Tang, Yaosheng Wu, Feizhang Qin.
       BACKGROUND: Mitochondrial biogenesis and oxidative stress are pivotal in myocardial ischemia/reperfusion (I/R) injury. 17-Methoxyl-7-hydroxy-benzene-furanchalcone (MHBFC) has been shown to significantly protect mitochondria during myocardial I/R injury. However, the potential mechanisms involved remain unknown. This study aimed to investigate the impact of MHBFC on myocardial I/R injury through network pharmacology, molecular docking, molecular dynamics simulation, and experimental validation.
    METHODS AND RESULTS: A rat I/R model was developed by inducing 1 h of coronary occlusion followed by 3 h of reperfusion. It was found that MHBFC significantly ameliorated cardiac function, reduced infarct size and cardiac enzymes, and increased the copy number of mitochondrial DNA and ATP production. MHBFC exposure also significantly elevated antioxidant enzyme activity and suppressed ROS production. Network pharmacology analysis identified that core targets of MHBFC associated with myocardial I/R injury were significantly enriched in the adenosine 5'-monophosphate activated protein kinase (AMPK)/silent mating type information regulation 2 homolog-1 (SIRT1) signaling pathway. Molecular docking analyses showed the strong binding of MHBFC with AMPK and SIRT1. Molecular dynamics simulation verified the stability of the docked complex. Western blot analysis confirmed that MHBFC activated the AMPK/SIRT1 pathway, and its protective effects were further validated in hypoxia/reoxygenation-. treated H9c2 cardiomyocytes.
    CONCLUSION: The study concludes that MHBFC mitigates myocardial I/R injury by improving mitochondrial biogenesis and oxidative stress through activation of the AMPK/SIRT1 pathway.
    Keywords:  17-methoxyl-7-hydroxy-benzene-furanchalcone; AMPK/SIRT1 pathway; Mitochondrial biogenesis; Mitochondrial oxidative stress; Myocardial ischemia/reperfusion injury; Network pharmacology
    DOI:  https://doi.org/10.1016/j.taap.2025.117560
  47. bioRxiv. 2025 Sep 04. pii: 2025.08.30.673265. [Epub ahead of print]
    InsP3R signaling mediates mitochondrial stress-induced longevity through actomyosin-dependent mitochondrial dynamics.
    Gaomin Feng, Elizabeth M Ruark, Alexandra G Mulligan, Eric K F Donahue, Anthony Hoang, Brianne Jacquet-Cribe, Li Peng, Kristopher Burkewitz.
      Certain forms of mitochondrial impairment confer longevity, while mitochondrial dysfunction arising from aging and disease-associated mutations triggers severe pathogenesis. The adaptive pathways that distinguish benefit from pathology remain unclear. Here we reveal that longevity induced by mitochondrial Complex I/ nuo-6 mutation in C. elegans is dependent on the endoplasmic reticulum (ER) Ca 2+ channel, InsP3R. We find that the InsP3R promotes mitochondrial respiration, but the mitochondrial calcium uniporter is dispensable for both respiration and lifespan extension in Complex I mutants, suggesting InsP3R action is independent of matrix Ca 2+ flux. Transcriptomic profiling and imaging reveal a previously unrecognized role for the InsP3R in regulating mitochondrial scaling, where InsP3R impairment results in maladaptive hyper-expansion of dysfunctional mitochondrial networks. We reveal a conserved InsP3R signaling axis through which calmodulin and actomyosin remodeling machineries, including Arp2/3, formin FHOD-1, and MLCK, constrain mitochondrial expansion and promote longevity. Disruption of actin remodeling or autophagy mimics InsP3R loss. Conversely, driving fragmentation ameliorates mitochondrial expansion and rescues longevity, supporting a model in which InsP3R-dependent actin remodeling sustains mitochondrial turnover. These findings establish an inter-organelle signaling axis by which ER calcium release orchestrates mitochondrial-based longevity through cytoskeletal effectors.
    DOI:  https://doi.org/10.1101/2025.08.30.673265
  48. EPMA J. 2025 Sep;16(3): 535-539
    How to use an extensive Flammer syndrome phenotyping for a holistic protection against health-to-disease transition - facts and practical recommendations.
    Olga Golubnitschaja.
      Due to their phenotype-associated attitude predominantly oriented towards high performance, Flammer syndrome (FS) phenotype carriers are blessed to a successful career in corresponding professional branches. This advantage is however associated with significant health risks. FSP carriers are extremely stress-sensitive. Corresponding pathways are epigenetically regulated, and modifiable risk factors are associated with the phenotype-specific psycho-somatic patterns such as a drive for meticulousness, perfectionism and exercised rigour applying strictness, discipline, or thoroughness to their own behaviour and actions. The FS phenotype is typically characterised by chronication of the transient sympathoexcitation and its dominance over parasympathetic relaxation. Chronification of the parasympathetic-sympathetic imbalance in form of sympathetic overdrive leads to chronic ischemic events in peripheral vessels and progressing tissue damage associated with the cyclic ischemia-reperfusion. Ischemic damage can be roughly estimated by levels of the vasoconstrictor endotelin-1 (ET-1) measured in blood. However, other risk factors on the one hand and compensatory mechanisms on the other hand are decisive for the damage extent at individual level. For example, chronically increased ET-1 and even mild hyperhomocysteinaemia synergistically may cause a progressing disease of small vessels, systemic inflammation and chronification of mitochondrial stress potentially resulting in chronic fatigue and mitochondrial burnout with a spectrum of associated pathologies in affected individuals. That is why predictive diagnostics utilising comprehensive individualised patient profiles are crucial for the cost-effective targeted prevention and creation of personalised treatment algorithms. Due to the high level of algorithms' complexity, an application of AI is essential. FS is usually established early in life during pubertal maturation of otherwise healthy individuals. Therefore, FS phenotyping is instrumental for 3PM-guided cost-effective primary healthcare. To meet the needs of this patient cohort, an application of the digital health monitoring including records of mitochondrial homeostasis is strongly recommended to protect the FS phenotype carriers against health-to-disease transition. To this end, patient friendly non-invasive approach is already established utilising tear fluid multi-omics, mitochondria as vital biosensors and AI-based multi-professional data interpretation; the approach is offered to the FS phenotype carriers.
    Keywords:   Sympathetic overdrive; AI; Endothelin-1; Flammer syndrome phenotype (FSP); Health policy; Health risk assessment; Health-to-disease transition; Holistic approach; Homocysteine; Individualised protection; Ischemia-reperfusion; Mitochondrial stress and burnout; Mitophagy; Paradigm shift; Parasympathetic-sympathetic imbalance; Phenotyping; Population screening; Predictive preventive personalised medicine (PPPM / 3PM); Primary care; Small vessel disease; Suboptimal health; Sympathoexcitation; Systemic effects; Tear fluid
    DOI:  https://doi.org/10.1007/s13167-025-00423-6
  49. Neurobiol Dis. 2025 Sep 15. pii: S0969-9961(25)00320-1. [Epub ahead of print] 107103
    Molecular mechanisms by which mitochondrial dysfunction drives neuromuscular junction degeneration in amyotrophic lateral sclerosis.
    Xie Yipeng, Wang Guiqian, Zhu Qiaochu, He Tengjie, Zhao Yan, Huang Hai, Zhou Jing.
       BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder marked by progressive degeneration of motor neurons and early deterioration of neuromuscular junctions (NMJs). Increasing evidence indicates that mitochondrial dysfunction plays a pivotal role in driving NMJ degeneration in ALS.
    OBJECTIVE: This review aims to comprehensively summarize the molecular mechanisms by which mitochondrial defects contribute to NMJ instability, with a particular focus on bioenergetics, calcium homeostasis, oxidative stress, and impaired mitochondrial biogenesis.
    CONCLUSION: Mitochondrial dysfunction is a core driver of NMJ degeneration in ALS. Targeting mitochondrial biogenesis and metabolism-particularly through the PGC-1α pathway-represents a promising strategy to preserve NMJ integrity and slow disease progression.
    Keywords:  Amyotrophic lateral sclerosis; Calcium homeostasis; Mitochondria; Mitochondrial biogenesis; Neuromuscular junction; PGC-1α; ROS
    DOI:  https://doi.org/10.1016/j.nbd.2025.107103
  50. Biomater Adv. 2025 Sep 11. pii: S2772-9508(25)00334-6. [Epub ahead of print]179 214507
    Metformin nanoparticles mitigate cerebral ischemia reperfusion injury by improving mitochondrial dysfunction and inhibiting NLRP3 activation.
    Lin Deng, Ting Cai, Jiayu Li, Yinfei Song, Sheng Guo, Tao Tao.
       BACKGROUND: Cerebral ischemia reperfusion injury (CIRI) is a serious condition that lacks highly effective treatment methods. After CIRI, microglia in the cortex of mice show high expression of CD44, which offers a potential target for the development of targeted drug-delivery systems to treat ischemic brain injury.
    OBJECTIVE: This study aimed to design a targeted drug-delivery system for ischemic brain injury, and explore the underlying molecular mechanisms on CIRI.
    METHODOLOGY: Hyaluronic acid-PEG-DSPE@metformin (HA@MET) nanoparticles were designed to specifically target the CD44 receptor on microglia. HA@MET was used to intervene in a CIRI mouse model, and then the infarct size and neurological scores were measured. Moreover, experiments on the expression of autophagy-related proteins (Beclin-1, Atg5, Sirt3), the production of reactive oxygen species (ROS), the activation of the NLRP3 inflammasome and the release of associated inflammatory factors (Caspase-1, IL-6, IL-1β) were performed.
    RESULTS: In the CIRI mouse model, HA@MET treatment led to a significant reduction in infarct size and an improvement in neurological scores, indicating a strong therapeutic effect on ischemic brain injury. Mechanistically, HA@MET inhibited the expression of key autophagy proteins Beclin-1 and Atg5, while increasing the expression of Sirt3 protein. This action alleviated excessive mitochondrial autophagy and promoted the clearance of damaged mitochondria. After entering microglia, HA@MET released metformin, which decreased ROS production and inhibited the activation of the NLRP3 inflammasome, resulting in reduced concentrations of inflammatory factors (Caspase-1, IL-6, IL-1β) and alleviating the inflammatory responses associated with CIRI.
    CONCLUSIONS: This study provides new perspectives and potential therapeutic targets for the treatment of ischemic brain injury. HA@MET, as a targeted drug-delivery system, shows promise in treating CIRI through multiple mechanisms, including regulating mitochondrial autophagy and inhibiting inflammation.
    Keywords:  Cerebral ischemia reperfusion injury; Hyaluronic acid; Metformin nanoparticles; Microglia; Mitochondrial autophagy; NLRP3 inflammasome; Reactive oxygen species
    DOI:  https://doi.org/10.1016/j.bioadv.2025.214507
  51. Apoptosis. 2025 Sep 16.
    Mechanistic study on the role of multi-pathway autophagy in ovarian aging: literature review.
    Xinyu Zhu, Huihui Li, Tingting Xue, Shu Wang, Ruixiang Zhu, Jiali Luo, Ruotong Ju, Puhua Zhang, Xiangrong Cui, Xuan Jing.
      Ovarian aging is one of the common diseases in the female reproductive system. It is characterized by complex etiologies, involving multiple factors such as genetics, environment, metabolism, and cellular stress. In recent years, autophagy, a crucial cellular self-degradation and repair mechanism, has received substantial attention for its role in maintaining and deteriorating ovarian function. This review systematically summarizes the molecular mechanisms of autophagy and its regulation, as well as the latest research progress of macroautophagy, chaperone-mediated autophagy (CMA) and mitophagy in ovarian aging. Studies have shown that dysregulation of autophagic pathways is closely associated with decreased oocyte quality and reduced ovarian reserve function. Additionally, signaling pathways such as PI3K, AMPK, and mTOR participate in the process of ovarian aging by regulating autophagic activity. Although numerous studies have revealed the critical role of autophagy in ovarian aging, many issues remain to be resolved, such as the crosstalk mechanisms between different autophagic pathways and the precise spatiotemporal dynamics of the autophagic regulatory network. A deep understanding of the regulatory network of multi-pathway autophagy will provide new insights for developing intervention strategies to delay ovarian aging, holding significant scientific and clinical application value.
    Keywords:  CMA; Macroautophagy; Mitophagy; Multi-pathway autophagy; Ovarian aging
    DOI:  https://doi.org/10.1007/s10495-025-02181-2
  52. J Periodontal Res. 2025 Sep 15.
    Macrophage Efferocytosis Controls Tissue Repair via Mitochondrial Dynamics in Diabetic Periodontitis.
    Hongrui Liu, Yujun Jiang, Changyun Sun, Jie Guo, Minqi Li.
       AIMS: Diabetes induces disorders in macrophage immunometabolism, leading to increased destruction of periodontal tissue. Identifying key factors to restore metabolic alterations and promote resolution of inflammation remains an unmet objective.
    METHODS: In the present study, the effect of macrophage efferocytosis on inflammatory regression and tissue repair was assessed using a diabetic periodontitis (DPD) model. The mitochondrial function of macrophages cultured under different conditions was assessed in vitro, and macrophage efferocytosis function and polarization phenotypes were examined. Osteogenic differentiation and migration capacity were examined using periodontal ligament stem cells (PDLSCs) co-cultured with macrophages to assess the effect on tissue repair.
    RESULTS: We demonstrated that the high-glucose inflammatory microenvironment exacerbated the pro-inflammatory metabolic profile of macrophages and disrupted mitochondrial dynamics. Rats with DPD exhibited heightened periodontal tissue damage during the ligation period, characterized by increased neutrophil infiltration and apoptotic cells. Following ligature removal, the transition to the repair phase was inhibited. Impaired efferocytosis in macrophages led to reduced expression of anti-inflammatory cytokines. Inhibiting excessive mitochondrial division mitigated macrophage damage, ultimately improving the osteogenic differentiation and migration of PDLSCs.
    CONCLUSIONS: This research suggested the critical role of mitochondria in the resolution of inflammation in diabetic periodontitis through regulating macrophage efferocytosis and interaction with PDLSCs.
    Keywords:  immunomodulation; macrophage efferocytosis; macrophage polarization; mitochondrial dynamics; periodontium regeneration
    DOI:  https://doi.org/10.1111/jre.70030
  53. J Mol Neurosci. 2025 Sep 18. 75(4): 118
    Correction: Urolithin A Enhances Tight Junction Protein Expression in Endothelial Cells Cultured In Vitro via Pink1-Parkin-Mediated Mitophagy in Irradiated Astrocytes.
    Gengxin Lu, Junyu Wu, Zhihui Zheng, Zhezhi Deng, Xue Xu, Xintian Li, Xiaoqiu Liang, Weiwei Qi, Shifeng Zhang, Yuemin Qiu, Minping Li, Junjie Guo, Haiwei Huang.
      
    DOI:  https://doi.org/10.1007/s12031-025-02346-3
  54. MedComm (2020). 2025 Sep;6(9): e70385
    Mitochondrial Diseases: Molecular Pathogenesis and Therapeutic Advances.
    Jialun Mei, Peng Ding, Chuan Gao, Jian Zhou, Zhiwei Li, Changqing Zhang, Junjie Gao.
      Mitochondrial diseases are a heterogeneous group of inherited disorders caused by pathogenic variants in mitochondrial DNA (mtDNA) or nuclear genes encoding mitochondrial proteins, culminating in defective oxidative phosphorylation and multisystem involvement. Key pathogenic mechanisms include heteroplasmy driven threshold effects, excess reactive oxygen species, disrupted mitochondrial dynamics and mitophagy, abnormal calcium signaling, and compromised mtDNA repair, which together cause tissue-specific energy failure in high demand organs. Recent advances have expanded the therapeutic landscape. Precision mitochondrial genome editing-using mitochondrial zinc finger nucleases, mitochondrial transcription activator-like effector nucleases, DddA-derived cytosine base editor, and other base editing tools-enables targeted correction or rebalancing of mutant genomes, while highlighting challenges of delivery and off-target effects. In parallel, metabolic modulators (e.g., coenzyme Q10, idebenone, EPI-743) aim to restore bioenergetics, and mitochondrial replacement technologies and transplantation are being explored. Despite these promising strategies, major challenges remain, including off-target effects, precise delivery, and ethical considerations. Addressing these issues through multidisciplinary research and clinical translation holds promise for transforming mitochondrial disease management and improving patient outcomes. By bridging the understanding of mitochondrial dysfunction with advanced therapeutic interventions, this review aims to shed light on effective solutions for managing these complex disorders.
    Keywords:  base editing; gene therapy; genetic medicine; mitochondrial DNA (mtDNA); mitochondrial diseases; mitochondrial gene editing; therapeutic strategies
    DOI:  https://doi.org/10.1002/mco2.70385
  55. Liver Int. 2025 Oct;45(10): e70341
    Reactive Oxygen Species-Mediated TRPM2 Activation Facilitates Phagocytosis of Macrophages to Reverse Profibrotic Phenotype.
    Shaoying Zhang, Fanfan Liang, Dan Wan, Chongyu Zhang, Yinggang Zhang, Xurui Zhang, Na Huang, Keping Feng, Xiao Liang, Ni Guo, Chen Zhang, Zhe Zhou, Yuehua Li, Jing Geng, Pengfei Liu, Guangyao Kong, Shemin Lu, Zongfang Li.
       BACKGROUND AND AIMS: Macrophages play plastic roles during fibrogenesis and fibrosis regression. Phagocytosis is considered a trigger for shifting macrophages from a profibrotic phenotype to a restorative phenotype. However, the underlying mechanism by which macrophages enhance phagocytosis remains unclear. Our present study investigated the role of reactive oxygen species (ROS)-modulated TRPM2 activation in this process.
    METHODS: The changes of TRPM2 expression, ROS intensity, and macrophage phagocytosis were assessed in fibrogenesis and fibrosis regression models. RNA sequencing was utilised to reveal pathway enrichment caused by TRPM2, and the role of TRPM2 in enhancing phagocytosis was verified. The coordinate regulation of ROS-TRPM2 in different functions of macrophages was demonstrated by modulating ROS intensity and TRPM2 expression. Mitochondrial dynamics changes induced by ROS-stimulated TRPM2 activation were evaluated by analysing the expression of dynamics-related molecules and mitochondrial imaging, and intervention in mitochondrial dynamics confirmed their impact on macrophage phagocytosis.
    RESULTS: Low-intensity ROS stimulation up-regulated the expression of TRPM2 and coordinately enhanced macrophage phagocytosis and the expression of matrix degradation-related proteins (MMPs), a process akin to fibrosis regression. However, high-intensity ROS inclined macrophages to produce more profibrotic cytokines, associating with oxidative stress caused by liver injury. ROS-mediated TRPM2 activation mobilised Ca2+ and promoted mitochondrial fission; either inhibiting mitochondrial fission or chelating Ca2+ counteracted phagocytosis, as well as decreasing MMPs.
    CONCLUSIONS: ROS-TRPM2 coordinately regulate macrophage functions. During the liver fibrosis regression period, ROS-induced activation of TRPM2 helps enhance macrophage phagocytosis and switches them to a restorative phenotype. Modulating this process may provide means for developing effective therapeutic strategies.
    Keywords:  TRPM2 (transient receptor potential melastatin 2); fibrosis regression; macrophage; mitochondrial fission; phagocytosis; phenotypic transformation
    DOI:  https://doi.org/10.1111/liv.70341
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