bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2025–04–20
76 papers selected by
Gavin McStay, Liverpool John Moores University
  1. ROS-DRP1-mediated excessive mitochondrial fission and autophagic flux inhibition contribute to heat stress-induced apoptosis in goat Sertoli cells.
  2. Mitochondrial quality control in hematopoietic stem cells: mechanisms, implications, and therapeutic opportunities.
  3. Drp1 mitochondrial fission in astrocyte modulates behavior and neuroinflammation during morphine addiction.
  4. SPI1 activates mitochondrial unfolded response signaling to inhibit chondrocyte senescence and relieves osteoarthritis.
  5. OGA promotes human dental pulp stem cell senescence and inhibits mitophagy by inhibition of O-GlcNAcylation of KLF2.
  6. The mitochondrial unfolded protein response: acting near and far.
  7. High glucose induces senescence in synovial mesenchymal stem cells through mitochondrial dysfunction.
  8. Consecutive skeletal muscle PGC-1α overexpression: A double-edged sword for mitochondrial health in the aging brain.
  9. Gel@CAT-L hydrogel mediates mitochondrial unfolded protein response to regulate reactive oxygen species and mitochondrial homeostasis in osteoarthritis.
  10. Region-specific mitophagy in nucleus pulposus, annulus fibrosus, and cartilage endplate of intervertebral disc degeneration: mechanisms and therapeutic strategies.
  11. Mitophagy in Brain Injuries: Mechanisms, Roles, and Therapeutic Potential.
  12. Chondrocyte Mitochondrial Quality Control: A Novel Insight into Osteoarthritis and Cartilage Regeneration.
  13. Schisandrin B regulates mitochondrial dynamics via AKT1 activation and mitochondrial targeting to ameliorate renal ischemia-reperfusion injury.
  14. Dimethyl fumarate modulates M1/M2 macrophage polarization to ameliorate periodontal destruction by increasing TUFM-mediated mitophagy.
  15. Sulforaphane Restores Mitochondrial β-Oxidation and Reduces Renal Lipid Accumulation in a Model of Releasing Unilateral Ureteral Obstruction.
  16. Tangeretin protects against Aβ1-42-induced toxicity and exploring mitochondria-lysosome interactions in HT22 cells.
  17. 14,15-EET Maintains Mitochondrial Homeostasis to Inhibit Neuronal Pyroptosis After Ischemic Stroke.
  18. BNIP3-mediated mitophagy aggravates placental injury in preeclampsia via NLRP1 inflammasome.
  19. Mitochondrial dysfunction is driven by imbalanced fission and fusion of mitochondria in myofibrillar myopathy type 5.
  20. The effects of different exercise training protocols on mitochondrial dynamics in skeletal and cardiac muscles of Wistar rats.
  21. Shen-fu Injection Modulates HIF- 1α/BNIP3-Mediated Mitophagy to Alleviate Myocardial Ischemia-Reperfusion Injury.
  22. Research dynamics and drug treatment of renal fibrosis from a mitochondrial perspective: a historical text data analysis based on bibliometrics.
  23. N6-Methyladenosine Modification in the Metabolic Dysfunction-Associated Steatotic Liver Disease.
  24. Polysaccharides from Ganoderma lucidum attenuate cognitive impairment in 5xFAD mice by inhibiting oxidative stress and modulating mitochondrial dynamics via the Nrf2/antioxidative axis activation.
  25. Mitochondrial Imbalance in Down Syndrome: A Driver of Accelerated Brain Aging?
  26. Effects of mitochondrial O-GlcNAcylation in pericytes after mechanical injury.
  27. Icarisid Ⅱ modulates mitochondrial dynamics for anti-HBV activity.
  28. Effect of regular exercise on ocular inflammation and mitochondrial biogenesis in experimental Alzheimer's disease model.
  29. High urea promotes mitochondrial fission and functional impairments in astrocytes inducing anxiety-like behavior in chronic kidney disease mice.
  30. Active control of mitochondrial network morphology by metabolism-driven redox state.
  31. Disturbances in mitochondrial quality control and mitochondria-lysosome contact underlie the cerebral cortex and heart damage of mucopolysaccharidosis type II mice.
  32. Integrated analysis of transcriptional and metabolic responses to mitochondrial stress.
  33. Ganoderma atrum polysaccharide inhibits ROS/NLRP3/pyroptosis axis by fixing mitochondrial dynamics disorder in PD-1 inhibitors-induced carditis of Lewis lung carcinoma mice.
  34. A novel mechanism of FBXW7 in combating intervertebral disc degeneration: Mitigating ferroptosis in nucleus pulposus cells through the regulation of mitophagy.
  35. Small molecule DDQ involvement of ERK-mediated signaling pathway with enhanced mitophagy in HT22 cells transfected with mTau.
  36. Stigmasterol alleviates endplate chondrocyte degeneration through inducing mitophagy by enhancing PINK1 mRNA acetylation via the ESR1/NAT10 axis.
  37. Mitochondrial function regulates cell growth kinetics to actively maintain mitochondrial homeostasis.
  38. Interleukin-13-mediated alterations in esophageal epithelial mitochondria contribute to tissue remodeling in eosinophilic esophagitis.
  39. Cadmium disrupted homeostasis of proximal renal tubular cells via targeting ATF4-CHOP complex into the nucleus.
  40. STAR/STARD1: a mitochondrial intermembrane space cholesterol shuttle degraded through mitophagy.
  41. The mechanism of dexmedetomidine regulation of the HIF-1α/FUNDC1 axis in myocardial ischemia/reperfusion injury.
  42. Mitochondrial Dynamics: Deciphering the Role of HDL-C in Regulating Mitochondrial Function and Fatty Acid Oxidation in Human Skeletal Muscle.
  43. BAM8-22 targets spinal MrgC receptors to modulate UPRmt activity in the mechanism of bone cancer pain.
  44. A review on fumonisin B1-induced mitochondrial dysfunction and its impact on mitophagy and DNA methylation.
  45. Berberine improves cardiac insufficiency through AMPK/PGC-1α signaling-mediated mitochondrial homeostasis and apoptosis in HFpEF mice.
  46. Mipep deficiency in adipocytes impairs mitochondrial protein maturation and leads to systemic inflammation and metabolic dysfunctions.
  47. Lipids: emerging actors in mitochondrial protein import.
  48. The mitochondrial LONP1 protease: molecular targets and role in pathophysiology.
  49. An Msp1-Protease Chimera Captures Transient AAA+ Interactions and Unveils Ost4 Mislocalization Errors.
  50. Tissue-resident Klebsiella quasipneumoniae contributes to progression of idiopathic pulmonary fibrosis by triggering macrophages mitophagy in mice.
  51. Mechanism of allosteric activation in human mitochondrial ClpP protease.
  52. Thymoquinone-loaded solid lipid nanoparticles mitigate 3-Nitropropionic acid-induced mitochondrial dysfunction and oxidative damage via regulating PGC-1α/Nrf2 pathway.
  53. Perinuclear mitochondrial clustering for mesenchymal-to-epithelial transition in pluripotency induction.
  54. Mitochondrial and cardiovascular responses to aerobic exercise training in supine and upright positions in healthy young adults: a randomized parallel arm trial.
  55. Oxidative stress-mediated tetrabromobisphenol A disrupts mitochondrial function in HepG2 cells and activates ferroptosis signalling to induce apoptosis.
  56. HIIT versus MICT in MASLD: mechanisms mediated by gut-liver axis crosstalk, mitochondrial dynamics remodeling, and adipokine signaling attenuation.
  57. Roles of Oxidative Stress and Autophagy in Alcohol-Mediated Brain Damage.
  58. Identification of a Novel Mitochondrial-Related Gene Signature for BMSCs in Osteoporosis Combining Single-Cell and Bulk Transcriptome Data.
  59. 2,3,5,4'-Tetrahydroxystilbene-2-O-β-D-glucoside (TSG) from Polygonum multiflorum Thunb.: A Systematic Review on Anti-Aging.
  60. In vivo composition of the mitochondrial nucleoid in mice.
  61. Chlorogenic Acid Improves High-Fat Diet-Induced Skeletal Muscle Metabolic Disorders by Regulating Mitochondrial Function and Lactate Metabolism.
  62. Genetically encoded tool for manipulation of ΔΨm identifies its role as the driver of ISR induced by ATP synthase dysfunction.
  63. HSCA2 G87D point mutation enhances Arabidopsis proline tolerance via boosting mitochondrial Fe-S cluster assembly.
  64. Ameliorating effect of the aldose reductase inhibitor 1-Acetyl-5-phenyl-1 H-pyrrol-3-ylacetate on galactose-induced cataract.
  65. The role of Bcl‑2 in controlling the transition between autophagy and apoptosis (Review).
  66. Mitochondria at the Crossroads: Linking the Mediterranean Diet to Metabolic Health and Non-Pharmacological Approaches to NAFLD.
  67. Loss of popdc3 Impairs Mitochondrial Function and Causes Skeletal Muscle Atrophy and Reduced Swimming Ability in Zebrafish.
  68. Promoting mitocytosis via gene-engineered aligned fibers for fascia regeneration.
  69. The role of PKM2-mediated metabolic reprogramming in the osteogenic differentiation of BMSCs under diabetic periodontitis conditions.
  70. Transcriptome analysis of atad3-null zebrafish embryos elucidates possible disease mechanisms.
  71. Coupling of ribosome biogenesis and translation initiation in human mitochondria.
  72. Calcium acts as a critical determinant of mitochondria-nuclear networking driven retrograde signaling.
  73. Melatonin and Exercise Restore Myogenesis and Mitochondrial Dynamics Deficits Associated With Sarcopenia in iMS-Bmal1-/- Mice.
  74. Mitochondrial Quality Control Systems in Septic AKI: Molecular Mechanisms and Therapeutic Implications.
  75. Effects of Maternal Blood β-Hydroxybutyrate on Brown Adipose Tissue Functions and Thermogenic and Metabolic Health in Neonatal Calves.
  76. Novel pH-responsive lipid nanoparticles deliver UA-mediated mitophagy and ferroptosis for osteoarthritis treatment.
  1. J Anim Sci Biotechnol. 2025 Apr 16. 16(1): 58
    ROS-DRP1-mediated excessive mitochondrial fission and autophagic flux inhibition contribute to heat stress-induced apoptosis in goat Sertoli cells.
    Fei Wen, Jiajing Gao, Guoyu Zhang, Songmao Guo, Xing Zhang, Shuaiqi Han, Xianzou Feng, Xiaoxu Chen, Jianhong Hu.
       BACKGROUND: Heat stress (HS) poses a significant threat to male goat reproduction. Sertoli cells (SCs) provide both structural and nutritional support necessary for germ cells. HS induces physiological and biochemical changes in SCs. Nevertheless, the molecular mechanisms involved are still not fully understood. Melatonin is a classic antioxidant that can alleviate HS-induced male reproductive damage. However, the underlying molecular mechanisms by which melatonin mitigates damage to goat testicular SCs remain unclear and require further investigation.
    RESULTS: In this study, an in vivo heat stress model was established in goats. The results showed that HS exposure led to testicular injury, abnormal spermatogenesis and apoptosis of SCs. To elucidate the mechanism of HS-induced SC apoptosis, primary SCs were isolated and cultured from goat testes, then exposed to HS. HS exposure increased the production of reactive oxygen species (ROS), decreased adenosine triphosphate (ATP) synthesis, and reduced mitochondrial membrane potential in SCs. Additionally, HS increased the expression of mitochondrial fission proteins 1 (FIS1) and dynamin-related protein 1 (DRP1) while decreasing the expression of mitochondrial fusion proteins Mitofusin 1 (MFN1), Mitofusin 2 (MFN2), and optic atrophy 1 (OPA1). This resulted in excessive mitochondrial fission and mitochondria-dependent apoptosis. Mdivi-1 (DRP1 inhibitor) reduces mitochondria-dependent apoptosis by inhibiting excessive mitochondrial fission. Mitochondrial fission is closely related to mitophagy. HS activated upstream mitophagy but inhibited autophagic flux, disrupting mitophagy and exacerbating mitochondria-dependent apoptosis. Finally, the classical antioxidant melatonin was shown to reduce mitochondria-dependent apoptosis in SCs exposed to HS by decreasing ROS levels, restoring mitochondrial homeostasis, and normalizing mitophagy.
    CONCLUSIONS: In summary, these findings indicated that the mechanism of HS-induced mitochondria-dependent apoptosis in SCs is mediated by hyperactivation of the ROS-DRP1-mitochondrial fission axis and inhibition of mitochondrial autophagy. Melatonin inhibited HS-induced mitochondria-dependent apoptosis in SCs by restoring mitochondrial homeostasis. This study enhances the understanding of the mechanisms through which heat stress triggers apoptosis and provides a vision for the development of drugs against HS by targeting mitochondria in goats.
    Keywords:  Apoptosis; Goat Sertoli cells; Heat stress; Melatonin; Mitochondria; Mitophagy
    DOI:  https://doi.org/10.1186/s40104-025-01180-2
  2. Stem Cell Res Ther. 2025 Apr 15. 16(1): 180
    Mitochondrial quality control in hematopoietic stem cells: mechanisms, implications, and therapeutic opportunities.
    Yun Liao, Stacia Octaviani, Zhen Tian, Samuel R Wang, Chunlan Huang, Jian Huang.
      Mitochondrial quality control (MQC) is a critical mechanism for maintaining mitochondrial function and cellular metabolic homeostasis, playing an essential role in the self-renewal, differentiation, and long-term stability of hematopoietic stem cells (HSCs). Recent research highlights the central importance of MQC in HSC biology, particularly the roles of mitophagy, mitochondrial biogenesis, fission, fusion and mitochondrial transfer in regulating HSC function. Mitophagy ensures the removal of damaged mitochondria, maintaining low levels of reactive oxygen species (ROS) in HSCs, thereby preventing premature aging and functional decline. Concurrently, mitochondrial biogenesis adjusts key metabolic regulators such as mitochondrial transcription factor A (TFAM) and peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) to meet environmental demands, ensuring the metabolic needs of HSCs are met. Additionally, mitochondrial transfer, as an essential form of intercellular material exchange, facilitates the transfer of functional mitochondria from bone marrow stromal cells to HSCs, contributing to damage repair and metabolic support. Although existing studies have revealed the significance of MQC in maintaining HSC function, the precise molecular mechanisms and interactions among different regulatory pathways remain to be fully elucidated. Furthermore, the potential role of MQC dysfunction in hematopoietic disorders, including its involvement in disease progression and therapeutic resistance, is not yet fully understood. This review discusses the molecular mechanisms of MQC in HSCs, its functions under physiological and pathological conditions, and its potential therapeutic applications. By summarizing the current progress in this field, we aim to provide insights for further research and the development of innovative treatment strategies.
    Keywords:  Hematopoietic stem cell; Mitochondrial biogenesis; Mitochondrial dynamics; Mitochondrial metabolism; Mitochondrial quality control; Mitochondrial transfer; Mitophagy
    DOI:  https://doi.org/10.1186/s13287-025-04304-7
  3. J Neuroinflammation. 2025 Apr 17. 22(1): 108
    Drp1 mitochondrial fission in astrocyte modulates behavior and neuroinflammation during morphine addiction.
    Xiaotong Gu, Wenjing Chen, Zixin Li, Xinran Wang, Qianying Su, Feifan Zhou.
       BACKGROUND: Mitochondrial dynamics in neurons accompanied by neuroinflammation has been proved as pivotal events during repeated morphine exposure, however, the relationship between mitochondrial dynamics and neuroinflammation still remains unknown.
    METHODS: This study was designed to investigate the potential role of astrocyte Drp1 in neuroinflammation during morphine addiction. Nucleus accumbens (NAc) tissues were collected for immunofluorescence, transmission electron microscopy (TEM) and quantitative real-time polymerase chain reaction (qRT-PCR) to detect the expression of pro-inflammatory cytokines and mitochondrial fission proteins. Morphine-induced conditioned place preference (CPP) and open field test (OFT) were used to determine the effects of Mdivi-1, a selective inhibitor of mitochondrial fission protein Drp1 in the rewarding properties of morphine. Astrocyte-specific knockdown experiments by an adeno-associated virus (AAV) vector containing shRNADrp1-EGFP infusion were performed to determine the effects of astrocyte Drp1 in NAc of mice with morphine treatment.
    RESULTS: In this study, we found that repeated morphine exposure induced mitochondrial fragmentation in neurons, astrocytes, and microglia in NAc, correlating with increased inflammatory markers and addictive behaviors. The application of Mdivi-1 effectively mitigated mitochondrial fragmentation and astrocyte-mediated neuroinflammation within the NAc, thereby alleviating morphine-induced addictive behaviors. Crucially, the astrocyte-specific knockdown of Drp1 in NAc significantly curtailed drug-seeking behavior and substantially reduced neuroinflammation.
    CONCLUSIONS: Collectively, our findings suggest that alterations in mitochondrial dynamics, particularly within astrocytes, play an important role in regulating neuroinflammation associated with morphine addiction. This research offers novel insights into potential therapeutic strategies for addressing substance use disorder (SUD) by regulating mitochondrial dynamics within astrocyte.
    Keywords:  Addiction; Astrocyte; Drp1; Mitochondrial dynamics; Morphine; Neuroinflammation
    DOI:  https://doi.org/10.1186/s12974-025-03438-y
  4. Bone Res. 2025 Apr 14. 13(1): 47
    SPI1 activates mitochondrial unfolded response signaling to inhibit chondrocyte senescence and relieves osteoarthritis.
    Xiangyu Zu, Shenghong Chen, Zhengyuan Li, Lin Hao, Wenhan Fu, Hui Zhang, Zongsheng Yin, Yin Wang, Jun Wang.
      Chondrocyte senescence is a critical pathological hallmark of osteoarthritis (OA). Aberrant mechanical stress is considered a pivotal determinant in chondrocyte aging; however, the precise underlying mechanism remains elusive. Our findings demonstrate that SPI1 plays a significant role in counteracting chondrocyte senescence and inhibiting OA progression. SPI1 binds to the PERK promoter, thereby promoting its transcriptional activity. Importantly, PERK, rather than GCN2, facilitates eIF2α phosphorylation, activating the mitochondrial unfolded protein response (UPRmt) and impeding chondrocyte senescence. Deficiency of SPI1 in mechanical overload-induced mice leads to diminished UPRmt activation and accelerated OA progression. Intra-articular injection of adenovirus vectors overexpressing SPI1 and PERK effectively mitigates cartilage degeneration. In summary, our study elucidates the crucial regulatory role of SPI1 in the pathogenesis of chondrocyte senescence by activating UPRmt signaling through PERK, which may present a novel therapeutic target for treating OA. SPI1 alleviates the progression of OA by inhibiting mechanical stress-induced chondrocyte senescence through mitochondrial UPR signaling.
    DOI:  https://doi.org/10.1038/s41413-025-00421-4
  5. BMC Oral Health. 2025 Apr 18. 25(1): 595
    OGA promotes human dental pulp stem cell senescence and inhibits mitophagy by inhibition of O-GlcNAcylation of KLF2.
    Yinhao Ding, Yan Ran.
       BACKGROUND: Dental pulp stem cells (DPSCs) aging impedes its application in tooth regeneration techniques, involving abnormal mitophagy. O-GlcNAcylation is a post-translational modification that regulates various cellular processes. Here, we aimed to investigate the role of O-GlcNAcylation in mitophagy and senescence.
    METHODS: DPSCs were cultured and passaged in vitro, and the 7th (p7) and 15th (p15) generation cells were collected. OGA and KLF2 were knocked down in p15 cells. Cell senescence was evaluated using senescence associated β-galactosidase staining, enzyme-linked immunosorbent assay, and western blotting; mitophagy was evaluated using western blotting. The regulation of OGA on the O-GlcNAcylation of KLF2 was analyzed using immunoprecipitation and western blotting.
    RESULTS: The results showed that p15 cells were more senescent than p7 cells and had poor mitophagy, with the higher expression of OGA. Knockdown of OGA inhibited senescence and promoted mitophagy in DPSCs. Moreover, silencing of KLF2 reversed the effects on senescence and mitophagy mediated by OGA knockdown. Additionally, OGA suppressed the O-GlcNAcylation of KLF2 at S177 site and thus reduced its stability.
    CONCLUSION: Silencing of OGA promotes mitophagy and inhibits DPSC senescence by promoting the O-GlcNAcylation of KLF2, suggesting a novel mechanism underlying DPSC senescence.
    Keywords:  Dental pulp stem cells; KLF2; Mitophagy; O-GlcNAcylation; OGA; Senescence
    DOI:  https://doi.org/10.1186/s12903-025-05927-1
  6. Biol Chem. 2025 Apr 17.
    The mitochondrial unfolded protein response: acting near and far.
    Nikolaos Charmpilas, Qiaochu Li, Thorsten Hoppe.
      Mitochondria are central hubs of cellular metabolism and their dysfunction has been implicated in a variety of human pathologies and the onset of aging. To ensure proper mitochondrial function under misfolding stress, a retrograde mitochondrial signaling pathway known as UPRmt is activated. The UPRmt ensures that mitochondrial stress is communicated to the nucleus, where gene expression for several mitochondrial proteases and chaperones is induced, forming a protective mechanism to restore mitochondrial proteostasis and function. Importantly, the UPRmt not only acts within cells, but also exhibits a conserved cell-nonautonomous activation across species, where mitochondrial stress in a defined tissue triggers a systemic response that affects distant organs. Here, we summarize the molecular basis of the UPRmt in the invertebrate model organism Caenorhabditis elegans and in mammals. We also describe recent findings on cell-nonautonomous activation of the UPRmt in worms, flies and mice, and how UPRmt activation in specific tissues affects organismal metabolism and longevity.
    Keywords:  cell-nonautonomous regulation; integrated stress response; mitochondria; mitochondrial unfolded protein response; stress signaling
    DOI:  https://doi.org/10.1515/hsz-2025-0107
  7. BMC Oral Health. 2025 Apr 15. 25(1): 569
    High glucose induces senescence in synovial mesenchymal stem cells through mitochondrial dysfunction.
    Shuyi Tan, Wangxi Wu, Yifan Chen, Hai Gao.
       PURPOSE: To investigate the impact of high glucose on the senescence of synovial mesenchymal stem cells (SMSCs) and to elucidate the role of mitochondrial dysfunction in this process.
    METHODS: ‌SMSCs were treated with medium containing high glucose (25 mmol/L) or low glucose (5.5 mmol/L) concentrations. The effects of high glucose concentrations on the proliferation, senescence, mitochondrial reactive oxygen species (ROS) levels, mitochondrial fission, and mitophagy of SMSCs were investigated. First, the impact of 24-hour high glucose treatment on SMSCs was investigated‌. After this initial 24-hour exposure, the medium was subsequently changed to low glucose, and the cells were cultivated for an additional 24 h; this was then compared with the effects of continuous 48-hour high-glucose exposure and continuous 48-hour low-glucose exposure.
    RESULTS: High glucose concentrations did not promote the proliferation of SMSCs but rather accelerated their senescence by ‌upregulating‌ the mRNA expression of senescence-associated secretory phenotype (SASP) genes and increasing the number of senescence-associated β-galactosidase (SA-β-gal)-positive cells. Additionally, high glucose ‌concentrations elevated‌ ROS levels in mitochondria and ‌facilitated‌ mitochondrial fission; they also ‌inhibited‌ the mitophagy of SMSCs by suppressing the expression of mitophagy-related proteins (PINK1, PARKIN, and LC3B). High glucose-induced suppression of mRNA (Il-6, Cxcl1, Dnm1, Pink1, Prkn, Lc3b) and protein (P21) expression, along with increased SA-β-gal-positive cell numbers and elevated MitoSOX intensity, can be reversed by terminating the high glucose treatment.
    CONCLUSION: High glucose concentrations induce senescence in SMSCs via mitochondrial dysfunction, manifested as ROS accumulation, excessive fission, and mitophagy suppression. Glucose normalization reversed senescence phenotypes, accompanied by restored mitophagy and reduced oxidative stress. Mitochondrial dysfunction may be one of the key mechanisms underlying high glucose-induced senescence in SMSCs.
    Keywords:  High glucose; Mitochondrial dysfunction; OA; SMSCs; Senescence
    DOI:  https://doi.org/10.1186/s12903-025-05938-y
  8. Biochim Biophys Acta Mol Basis Dis. 2025 Apr 12. pii: S0925-4439(25)00196-6. [Epub ahead of print]1871(6): 167851
    Consecutive skeletal muscle PGC-1α overexpression: A double-edged sword for mitochondrial health in the aging brain.
    Lei Zhou, Soroosh Mozaffaritabar, Erika Koltai, Smaragda Giannopoulou, Attila Kolonics, Yaodong Gu, Ricardo A Pinho, Ildiko Miklossy, Istvan Boldogh, Zsolt Radák.
      Mitochondrial dysfunction is a critical contributor to age-related functional declines in skeletal muscle and brain. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) is essential for mitochondrial biogenesis and function during aging. While skeletal muscle-specific overexpression of PGC-1α is known to mimic exercise-induced benefits in young animals, its chronic systemic effects on aging tissues remain unclear. This study aimed to determine the lifelong impact of skeletal muscle-specific PGC-1α overexpression on mitochondrial health, oxidative stress, inflammation, and cognitive function in aged mice. We established three experimental groups: young wild-type mice (3-4 months old), aged wild-type mice (25-27 months old), and aged mice with skeletal muscle-specific PGC-1α overexpression (24-27 months old). In skeletal muscle, aging led to significant reductions in mitochondrial biogenesis markers, including PGC-1α, FNDC5, and mtDNA content. PGC-1α overexpression reversed this decline, elevating the expression of PGC-1α, SIRT1, LONP1, SDHA, CS, TFAM, eNOS, and mtDNA levels, suggesting preserved mitochondrial biogenesis. However, FNDC5 and SIRT3 were paradoxically suppressed, indicating potential compensatory feedback mechanisms. PGC-1α overexpression also enhanced anabolic signaling, as evidenced by increased phosphorylation of mTOR and S6, and reduced FOXO1 expression, favoring a muscle growth-promoting environment. Moreover, aging impaired mitochondrial dynamics by downregulating MFN1, MFN2, OPA1, FIS1, and PINK1. While PGC-1α overexpression did not restore fusion-related proteins, it further reduced fission-related protein and enhanced mitophagy proteins, as evidenced by increased PINK1 phosphorylation. In contrast, in the hippocampus, muscle-specific PGC-1α overexpression exacerbated age-associated mitochondrial biogenesis decline. Expression levels of key mitochondrial markers, including PGC-1α, SIRT1, CS, FNDC5, Cytochrome C, and TFAM, were further reduced compared to aged wild-type controls. mTOR phosphorylation was also significantly suppressed, whereas cognition-related proteins (BDNF, VEGF, eNOS) and performance in behavioral tests remained unchanged. Importantly, skeletal muscle-specific PGC-1α overexpression triggered pronounced oxidative stress and inflammatory responses in both skeletal muscle and the hippocampus. In skeletal muscle, elevated levels of protein carbonyls, IκB-α, NF-κB, TNF-α, SOD2, and NRF2 were observed, accompanied by a reduction in the DNA repair enzyme OGG1. Notably, similar patterns were detected in the hippocampus, including increased expression of protein carbonyls, iNOS, NF-κB, TNF-α, SOD2, GPX1, and NRF2, alongside decreased OGG1 levels. These findings suggest that the overexpression of PGC-1α in skeletal muscle may have contributed to systemic oxidative stress and inflammation. In conclusion, skeletal muscle-specific PGC-1α overexpression preserves mitochondrial biogenesis and enhances anabolic signaling in aging muscle but concurrently induces oxidative stress and inflammatory responses, which may adversely affect mitochondrial health in the brain. These results emphasize the complex role of the skeletal muscle PGC-1α during aging.
    Keywords:  Aging; Hippocampus; Inflammation; Mitochondrial biogenesis; Oxidative stress; PGC-1α; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.bbadis.2025.167851
  9. Biomaterials. 2025 Mar 21. pii: S0142-9612(25)00202-9. [Epub ahead of print]321 123283
    Gel@CAT-L hydrogel mediates mitochondrial unfolded protein response to regulate reactive oxygen species and mitochondrial homeostasis in osteoarthritis.
    Jiajia Lu, Jiao Cai, Zhibin Zhou, Jun Ma, Tianyu Han, Nan Lu, Lei Zhu.
       OBJECTIVE: This study investigates the role of Gelatin-Catalase (Gel@CAT)-L hydrogel in mediating reactive oxygen species (ROS) production and maintaining mitochondrial homeostasis through SIRT3-mediated unfolded protein response (UPRmt), while exploring its involvement in the molecular mechanism of osteoarthritis (OA).
    METHODS: Self-assembled Gel@CAT-L hydrogels were fabricated and characterized using transmission electron microscopy, mechanical testing, external release property evaluation, and oxygen production measurement. Biocompatibility was assessed via live/dead cell staining and CCK8 assays. An OA mouse model was established using destabilization of the medial meniscus (DMM) surgery. X-ray and micro-CT imaging were employed to evaluate the structural integrity of the mouse knee joints, while histological staining was used to assess cartilage degeneration. Immunohistochemistry was performed to analyze the expression of proteins including Col2a1, Aggrecan, MMP13, ADAMTS5, SIRT3, PINK1, and Parkin. Multi-omics analyses-encompassing high-throughput sequencing, proteomics, and metabolomics-were conducted to identify key genes and metabolic pathways targeted by Gel@CAT-L hydrogel intervention in OA. Immunofluorescence techniques were utilized to measure ROS levels, mitochondrial membrane potential, and the expression of SIRT3, PINK1, Parkin, LYSO, LC3B, Col2a1, and MMP13 in primary mouse chondrocytes and mouse knee joints. Flow cytometry was applied to quantify ROS-positive cells. RT-qPCR analysis was conducted to determine mRNA levels of Aggrecan, Col2a1, ADAMTS5, MMP13, SIRT3, mtDNA, HSP60, LONP1, CLPP, and Atf5 in primary mouse chondrocytes, mouse knee joints, and human knee joints. Western blotting was performed to measure protein expression levels of SIRT3, HSP60, LONP1, CLPP, and Atf5 in both primary mouse chondrocytes and mouse knee joints. Additionally, 20 samples each from the control (CON) and OA groups were collected for analysis. Hematoxylin and eosin staining was used to evaluate cartilage degeneration in human knee joints. The Mankin histological scoring system quantified the degree of cartilage degradation, while immunofluorescence analyzed SIRT3 protein expression in human knee joints.
    RESULTS: In vitro experiments demonstrated that self-assembled Gel@CAT-L hydrogels exhibited excellent biodegradability and oxygen-releasing capabilities, providing a stable three-dimensional environment conducive to cell viability and proliferation while reducing ROS levels. Multi-omics analysis identified SIRT3 as a key regulatory gene in mitigating OA and revealed its central role in the UPRmt pathway. Furthermore, Gel@CAT-L was confirmed to regulate mitochondrial homeostasis. Both in vitro experiments and in vivo mouse model studies confirmed that Gel@CAT-L significantly reduced ROS levels and regulated mitochondrial autophagy by activating the SIRT3-mediated UPRmt pathway, thereby improving the pathological state of OA. Clinical trials indicated downregulation of SIRT3 and UPRmt-related proteins in OA patients.
    CONCLUSION: Gel@CAT-L hydrogel activates SIRT3-mediated UPRmt to regulate ROS and mitochondrial homeostasis, providing potential therapeutic benefits for OA.
    Keywords:  Mitochondrial homeostasis; Multi-omics; Osteoarthritis; Primary mouse chondrocytes; Reactive oxygen species; SIRT3; Self-assembled Gel@CAT-L hydrogel; Unfolded protein response
    DOI:  https://doi.org/10.1016/j.biomaterials.2025.123283
  10. Front Pharmacol. 2025 ;16 1579507
    Region-specific mitophagy in nucleus pulposus, annulus fibrosus, and cartilage endplate of intervertebral disc degeneration: mechanisms and therapeutic strategies.
    Chaoqun Feng, Ziang Hu, Min Zhao, Chuan Leng, Guangye Li, Fei Yang, Xiaohong Fan.
      Intervertebral disc degeneration (IVDD) is a prevalent condition contributing to various spinal disorders, posing a significant global health burden. Mitophagy plays a crucial role in maintaining mitochondrial quantity and quality and is closely associated with the onset and progression of IVDD. Well-documented region-specific mitophagy mechanisms in IVDD are guiding the development of therapeutic strategies. In the nucleus pulposus (NP), impaired mitochondria lead to apoptosis, oxidative stress, senescence, extracellular matrix degradation and synthesis, excessive autophagy, inflammation, mitochondrial instability, and pyroptosis, with key regulatory targets including AMPK, PGC-1α, SIRT1, SIRT3, Progerin, p65, Mfn2, FOXO3, NDUFA4L2, SLC39A7, ITGα5/β1, Nrf2, and NLRP3 inflammasome. In the annulus fibrosus (AF), mitochondrial damage induces apoptosis and oxidative stress mediated by PGC-1α, while in the cartilage endplate (CEP), mitochondrial dysfunction similarly triggers apoptosis and oxidative stress. These mechanistic insights highlight therapeutic strategies such as activating Parkin-dependent and Ub-independent mitophagy pathways for NP, enhancing Parkin-dependent mitophagy for AF, and targeting Parkin-mediated mitophagy for CEP. These strategies include the use of natural ingredients, hormonal modulation, gene editing technologies, targeted compounds, and manipulation of related proteins. This review summarizes the mechanisms of mitophagy in different regions of the intervertebral disc and highlights therapeutic approaches using mitophagy modulators to ameliorate IVDD. It discusses the complex mechanisms of mitophagy and underscores its potential as a therapeutic target. The objective is to provide valuable insights and a scientific basis for the development of mitochondrial-targeted drugs for anti-IVDD.
    Keywords:  annulus fibrosus; cartilage endplate; intervertebral disc degeneration; mechanisms; mitophagy; nucleus pulposus; therapeutic strategies
    DOI:  https://doi.org/10.3389/fphar.2025.1579507
  11. Mol Neurobiol. 2025 Apr 16.
    Mitophagy in Brain Injuries: Mechanisms, Roles, and Therapeutic Potential.
    Jiayu Tian, Yanna Mao, Dandan Liu, Tao Li, Yafeng Wang, Changlian Zhu.
      Mitophagy is an intracellular degradation pathway crucial for clearing damaged or dysfunctional mitochondria, thereby maintaining cellular homeostasis and responding to various brain injuries. By promptly removing damaged mitochondria, mitophagy protects cells from further harm and support cellular repair and recovery after injury. In different types of brain injury, mitophagy plays complex and critical roles, from regulating the balance between cell death and survival to influencing neurological recovery. This review aims to deeply explore the role and mechanism of mitophagy in the context of brain injuries and uncover how mitophagy regulates the brain response to injury and its potential therapeutic significance. It emphasizes mitophagy's potential in treating brain injuries, including reducing cell damage, promoting cell recovery, and improving neurological function, thus opening new perspectives and directions for future research and clinical applications.
    Keywords:  Brain injury; Cell death; Mitophagy; Mitophagy regulation; Therapeutic strategy
    DOI:  https://doi.org/10.1007/s12035-025-04936-z
  12. Adv Wound Care (New Rochelle). 2025 Apr 18.
    Chondrocyte Mitochondrial Quality Control: A Novel Insight into Osteoarthritis and Cartilage Regeneration.
    Jinni Wu, Jiawen Xu, Menghan Zhang, Jiahui Zhong, Weijin Gao, Mengjie Wu.
      Significance: Osteoarthritis (OA), one of the most prevalent joint diseases affecting more than 240 million people, strongly influences human health and reduces life quality. This review aims to fill the current research gap regarding the application and potential of mitochondrial quality control (MQC) based therapies in the treatment of OA, thereby providing guidance for future research and clinical practice. Recent Advances: Chondrocytes respond to the inflammatory microenvironment via an array of signaling pathways and thus are critical in cartilage degeneration and OA progression. Mitochondria, as an important metabolic center in chondrocytes, play a vital role in responding to inflammatory stimuli. Multiple MQC mechanisms, including mitochondrial antioxidant defense, mitochondrial protein quality control, mitochondrial DNA repair, mitochondrial dynamics, mitophagy, and mitochondrial biogenesis, sustain mitochondrial homeostasis under pathological conditions. Critical Issues: Despite extensive OA research, effective therapies remain limited. Elucidating MQC mechanisms in disease progression and post-traumatic cartilage repair is crucial. While preclinical studies demonstrate potential, clinical translation requires addressing protocol standardization, patient stratification, and long-term efficacy, as well as safety validation. Future Directions: Future research should focus on developing personalized MQC-based OA therapies guided by biomarker profiling and signaling pathway modulation. However, translational challenges persist, particularly regarding pervasive off-target effects, inadequate OA-specific targeting capacity, interpatient heterogeneity, and reliable evaluation of long-term therapeutic efficacy. Strategic prioritization of OA-specific MQC targets coupled with delivery system optimization may significantly improve both clinical translatability and therapeutic outcomes.
    Keywords:  cartilage regeneration; chondrocyte; mitochondria; mitochondrial quality control; osteoarthritis
    DOI:  https://doi.org/10.1089/wound.2024.0270
  13. Phytomedicine. 2025 Mar 24. pii: S0944-7113(25)00312-5. [Epub ahead of print]141 156672
    Schisandrin B regulates mitochondrial dynamics via AKT1 activation and mitochondrial targeting to ameliorate renal ischemia-reperfusion injury.
    Changhong Xu, HuaBin Wang, Hailong Wang, Jiangwei Man, Yun Deng, Yi Li, Kun Cheng, Jiping Niu, Huiming Gui, Shengjun Fu, Li Yang.
       BACKGROUND: Renal ischemia-reperfusion injury (RIRI) is a significant cause of acute kidney injury(AKI) and delayed graft function(DGF), impacting post-transplant outcomes. Mitochondrial dynamics, in particular fission and fusion, play a pivotal role in the cellular response to RIRI. The modulation of these dynamics represents a potential therapeutic target. Schisandrin B (Sch B), a component derived from traditional Chinese medicine, has shown protective roles in various organ injuries, but its effect on RIRI through mitochondrial dynamics remains unexplored.
    OBJECTIVE: This study explores the previously uninvestigated role of Sch B in modulating mitochondrial dynamics as a potential means of alleviating RIRI. By focusing on mitochondrial fission and fusion, this research provides novel insights into the therapeutic potential of Sch B, distinguishing it from existing approaches.
    METHODS: HK-2 cells were treated with hypoxia/reoxygenation (HR) in order to simulate renal ischemia-reperfusion injury (RIRI) in vitro. In vivo, mice underwent renal ischemia followed by reperfusion, which allowed for the simulation of the injury. Sch B's impact on mitochondrial dynamics, apoptosis, and oxidative stress was assessed through mitochondrial morphology assays, Western blotting for mitochondrial and apoptotic markers, TUNEL staining, and measurement of reactive oxygen species. Key molecular interactions were explored via Western blotting, molecular docking, SPR, and cellular thermal shift assays. In vivo, renal pathological damage was evaluated using HE, PAS, and TUNEL staining, while immunohistochemistry and immunofluorescence were employed to detect the expression levels of mitochondrial dynamics proteins and p-AKT1.
    RESULTS: First, we unveiled that Schisandrin B (Sch B) significantly mitigated oxidative stress and apoptosis in HK-2 cells subjected to hypoxia-reoxygenation conditions. Sch B pretreatment notably enhanced cell viability and mitochondrial function, demonstrating its superior antioxidant capabilities compared to NAC. Second, we discovered that Sch B's protective effects involve regulating mitochondrial dynamics by decreasing fission markers, such as DRP1, while increasing fusion proteins, including OPA1 and MFN2. Furthermore, our studies revealed that Sch B directly binds to AKT1, promoting its phosphorylation and localization to mitochondria, thereby enhancing mitochondrial resilience. Finally, we demonstrated that in vivo administration of Sch B reduced renal damage and apoptosis in mouse models of renal ischemia-reperfusion injury (RIRI), while immunohistochemical analyses unveiled its role in promoting mitochondrial fusion and reducing fission, marking a significant advancement in understanding Sch B's therapeutic potential in RIRI.
    CONCLUSION: Our findings demonstrate for the first time that Sch B directly interacts with AKT1 protein, enhancing its phosphorylation and promoting mitochondrial localization. This innovative mechanism reduces oxidative stress, apoptosis, and mitochondrial fission, highlighting Sch B's unique capability to modulate mitochondrial dynamics in RIRI. These results establish Sch B as a promising therapeutic agent, offering a new dimension in the management of RIRI by targeting mitochondrial health.
    Keywords:  AKT1; Mitochondrial dynamics; Network Pharmacology; Renal ischemia reperfusion injury; Schisandrin B
    DOI:  https://doi.org/10.1016/j.phymed.2025.156672
  14. Int J Oral Sci. 2025 Apr 17. 17(1): 32
    Dimethyl fumarate modulates M1/M2 macrophage polarization to ameliorate periodontal destruction by increasing TUFM-mediated mitophagy.
    Liang Chen, Pengxiao Hu, Xinhua Hong, Bin Li, Yifan Ping, ShuoMin Chen, Tianle Jiang, Haofu Jiang, Yixin Mao, Yang Chen, Zhongchen Song, Zhou Ye, Xiaoyu Sun, Shufan Zhao, Shengbin Huang.
      Periodontitis is a common oral disease characterized by progressive alveolar bone resorption and inflammation of the periodontal tissues. Dimethyl fumarate (DMF) has been used in the treatment of various immune-inflammatory diseases due to its excellent anti-inflammatory and antioxidant functions. Here, we investigated for the first time the therapeutic effect of DMF on periodontitis. In vivo studies showed that DMF significantly inhibited periodontal destruction, enhanced mitophagy, and decreased the M1/M2 macrophage ratio. In vitro studies showed that DMF inhibited macrophage polarization toward M1 macrophages and promoted polarization toward M2 macrophages, with improved mitochondrial function, inhibited oxidative stress, and increased mitophagy in RAW 264.7 cells. Furthermore, DMF increased intracellular mitochondrial Tu translation elongation factor (TUFM) levels to maintain mitochondrial homeostasis, promoted mitophagy, and modulated macrophage polarization, whereas TUFM knockdown decreased the protective effect of DMF. Finally, mechanistic studies showed that DMF increased intracellular TUFM levels by protecting TUFM from degradation via the ubiquitin-proteasomal degradation pathway. Our results demonstrate for the first time that DMF protects mitochondrial function and inhibits oxidative stress through TUFM-mediated mitophagy in macrophages, resulting in a shift in the balance of macrophage polarization, thereby attenuating periodontitis. Importantly, this study provides new insights into the prevention of periodontitis.
    DOI:  https://doi.org/10.1038/s41368-025-00360-0
  15. Antioxidants (Basel). 2025 Feb 28. pii: 288. [Epub ahead of print]14(3):
    Sulforaphane Restores Mitochondrial β-Oxidation and Reduces Renal Lipid Accumulation in a Model of Releasing Unilateral Ureteral Obstruction.
    Ana Karina Aranda-Rivera, Isabel Amador-Martínez, Omar Emiliano Aparicio-Trejo, Juan Carlos León-Contreras, Rogelio Hernández-Pando, Emma Saavedra, Fernando E García-Arroyo, José Pedraza-Chaverri, Laura Gabriela Sánchez-Lozada, Edilia Tapia.
      Obstructive nephropathy (ON), characterized by urine flow disruption, can induce chronic kidney disease (CKD). Although the release of the obstruction is performed as the primary intervention, renal pathology often persists and progresses. Accordingly, the murine model of releasing unilateral ureteral obstruction (RUUO) is valuable for investigating the molecular events underlying renal damage after obstruction release. Remarkably, after RUUO, disturbances such as oxidative stress, inflammation, lipid accumulation, and fibrosis continue to increase. Mitochondrial dysfunction contributes to fibrosis in the UUO model, but its role in RUUO remains unclear. Additionally, the impact of using antioxidants to restore mitochondrial function and prevent renal fibrosis in RUUO has not been determined. This study aimed to determine the therapeutic effect of pre-administering the antioxidant sulforaphane (SFN) in the RUUO model. SFN was administered 1 day before RUUO to evaluate mitochondrial biogenesis, fatty acids (FA) metabolism, bioenergetics, dynamics, and mitophagy/autophagy mechanisms in the kidney. Our data demonstrated that SFN enhanced mitochondrial biogenesis and reestablished mitochondrial oxygen consumption and β-oxidation. These effects collectively reduced lipid accumulation and normalized mitochondrial dynamics, mitophagy, and autophagy, thereby mitigating fibrosis after obstruction. Our findings suggest that SFN holds promise as a potential therapeutic agent in ON-induced CKD progression in RUUO and opens new avenues in studying antioxidant molecules to treat this disease.
    Keywords:  fatty acid metabolism; mitochondrial biogenesis; mitochondrial dynamics; obstructive nephropathy (ON); sulforaphane (SFN); β-oxidation
    DOI:  https://doi.org/10.3390/antiox14030288
  16. Biochem Biophys Res Commun. 2025 Apr 06. pii: S0006-291X(25)00483-8. [Epub ahead of print]762 151769
    Tangeretin protects against Aβ1-42-induced toxicity and exploring mitochondria-lysosome interactions in HT22 cells.
    Ying He, Meng-Hui He, Tingting Jin, Siju-Li, Hua-Qiao Wang, Feng He.
      Tangeretin, a flavonoid from Citri Reticulatae Pericarpium, is known for its neuroprotective effects, but the mechanisms are not fully understood. Alzheimer's disease, a leading neurodegenerative disorder, characterized by amyloid-beta (Aβ) accumulation, represents a significant therapeutic challenge. This study investigates the protective effects of tangeretin against Aβ1-42-induced neurotoxicity using HT22 cells and zebrafish larvae as experimental models. Tangeretin mitigated Aβ1-42-induced cytotoxicity, as evidenced by enhanced cell viability and reduced apoptosis. Tangeretin treatment mitigated Aβ1-42-induced cytotoxicity in HT22 cells, as evidenced by enhanced cell viability and reduced apoptosis. Mechanistically, tangeretin ameliorated mitochondrial dysfunction by reducing mitochondrial fragmentation, decreasing donut-shaped mitochondria, restoring mitochondrial membrane potential, and attenuating reactive oxygen species (ROS) production. Moreover, tangeretin modulated mitochondria-lysosome interactions by promoting mitophagy and normalizing the prolonged mitochondria-lysosome contact induced by Aβ1-42. In zebrafish larvae, Aβ1-42 exposure resulted in developmental malformations, including pericardial and yolk sac edema, elevated ROS levels, increased apoptosis, and impaired neurodevelopment. Tangeretin effectively counteracted these deficits, as revealed by live imaging, supporting its neuroprotective role observed in cellular models. Collectively, our study suggests that tangeretin may serve as a promising protective agent against Aβ1-42-induced neurotoxicity.
    Keywords:  Apoptosis; Mitochondria; Mitochondria-lysosome contact; Mitophagy; Tangeretin; Zebrafish larvae
    DOI:  https://doi.org/10.1016/j.bbrc.2025.151769
  17. Stroke. 2025 Apr 16.
    14,15-EET Maintains Mitochondrial Homeostasis to Inhibit Neuronal Pyroptosis After Ischemic Stroke.
    Huixia Geng, Jing Tang, Zhen Li, Yanshuo Zhang, Congwei Ye, Yibo Zhang, Xiaohui Li, Yunxia Li, Yanming Wang, Yi Wang, Xinrui Lv, Lai Wang.
       BACKGROUND: Neuronal pyroptosis is involved in neuronal cell death and neurological damage after cerebral ischemia-reperfusion. 14,15-Epoxyeicosatrienoic acid (14,15-EET) can reduce neuronal loss induced by cerebral ischemia-reperfusion by regulating mitochondrial biological processes. However, it remains unclear how 14,15-EET regulates mitochondrial homeostasis, inhibits neuronal pyroptosis, and promotes neurological functional recovery after cerebral ischemia-reperfusion.
    METHODS: Mice with middle cerebral artery occlusion and reperfusion were used as an animal model to study the cerebral ischemia-reperfusion disease. The neurological function of mice was performed at 1, 3, and 5 days to test the therapeutic effects of 14,15-EET. Transmission electron microscope imaging and Nissl staining were used to analyze neuronal morphological structure, mitophagy, and neuronal pyroptosis. Western blot and transcriptome were used to detect the levels of mitophagy and neuronal pyroptosis signaling pathway-related molecules. HT22 cells were used in in vitro studies to detect the mechanism by which 14,15-EET reduces neuronal pyroptosis after oxygen-glucose deprivation/reoxygenation treatment.
    RESULTS: 14,15-EET treatment reduced cerebral infarct volumes and improved neurological functional recovery in mice after cerebral ischemia-reperfusion. 14,15-EET treatment maintained the morphological structure of neurons in the ischemic penumbra area as well as the dendritic spine density in mice after cerebral ischemia-reperfusion. The upregulation of NLRP1 (NOD-like receptor thermal protein domain associated protein 1), IL (interleukin)-1β, caspase-1, and GSDMD (gasdermin D) induced by cerebral ischemia-reperfusion was inhibited, and the expression of mitophagy proteins Parkin and LC3B was increased by 14,15-EET treatment. Transcriptome profiling found that 14,15-EET exerts a neuroprotection role in promoting neural function recovery by activating the WNT (wingless-type MMTV integration site family) signaling pathway. We found that 14,15-EET upregulated the WNT pathway proteins such as WNT1, WNT3A, β-catenin, and p-GSK-3β (phosphorylation of glycogen synthase kinase 3β) in vivo and in vitro. The WNT signaling pathway inhibitor XAV-939 reduced the expression of mitophagy protein Parkin and upregulated the expression of caspase-1 and GSDMD in HT22 cells with oxygen-glucose deprivation/reoxygenation and 14,15-EET treatment.
    CONCLUSIONS: 14,15-EET regulates mitochondrial homeostasis to inhibit neuronal pyroptosis, thereby promoting the recovery of neurological function in mice after cerebral ischemia-reperfusion. These results provide new ideas for maintaining mitochondrial homeostasis and inhibiting neuronal pyroptosis after cerebral ischemia-reperfusion.
    Keywords:  homeostasis; ischemia; mitophagy; pyroptosis; reperfusion
    DOI:  https://doi.org/10.1161/STROKEAHA.124.049143
  18. Front Immunol. 2025 ;16 1530015
    BNIP3-mediated mitophagy aggravates placental injury in preeclampsia via NLRP1 inflammasome.
    Man Zhao, Zexin Yang, Yan Kang, Zhenya Fang, Changqing Zhang, Chunying Wang, Meijuan Zhou, Junjun Guo, Anna Li, Meihua Zhang.
       Introduction: Preeclampsia (PE) is a hypertensive disorder of pregnancy characterized by pronounced placental oxidative stress and inflammatory damage. However, the contribution of mitophagy to inflammation-induced placental injury in PE remains unclear.
    Methods: Human placenta samples were collected from 15 normal pregnant women and 15 preeclampsia pregnant women. Protein expression was analyzed by western blotting, while immunofluorescence staining was employed to localize inflammatory mediators. Mitochondrial reactive oxygen species were quantified using MitoSOX. The concentrations of pro-inflammatory cytokines were quantified using ELISA, and ultrastructural alterations were evaluated by transmission electron microscopy. To investigate molecular mechanisms in vivo, a PE mouse model was established via daily subcutaneous administration of L-NAME, followed by tail vein delivery of AAV9 carrying shRNA for targeted gene knockdown.
    Results: In this study, we demonstrate that BNIP3-mediated mitophagy and NLRP1 inflammasome activation occur in an L-NAME-induced PE mouse model and human PE placenta. The results also indicate that knockdown of BNIP3 abolishes mitophagy and NLRP1 inflammasome activation in JEG3 cells in H/R condition, suggesting a positive regulatory role for the BNIP3 in controlling mitophagy and NLRP1-dependent inflammation. Furthermore, silencing BNIP3 leads to a significant reduction in mitochondrial damage and mtROS production. Treatment with MitoTEMPO after BNIP3 silencing further decreases the expression of NLRP1, while overexpression of NLRP1 nullifies the impact of BNIP3 knockdown. Additionally, knockdown of BNIP3 alleviates placental injury in the PE mouse model.
    Discussion: These findings reveal a novel mechanism through which BNIP3-mediated mitophagy exacerbates H/R-induced placental injury by inducing mtROS production and activating the NLRP1 inflammasome in PE.
    Keywords:  BNIP3; NLRP1; mitophagy; preeclampsia; trophoblast
    DOI:  https://doi.org/10.3389/fimmu.2025.1530015
  19. Hum Mol Genet. 2025 Apr 17. pii: ddaf051. [Epub ahead of print]
    Mitochondrial dysfunction is driven by imbalanced fission and fusion of mitochondria in myofibrillar myopathy type 5.
    Wenjing Wu, Xiaoqing Lv, Yifei Feng, Mengqi Yang, Guiguan Yang, Dandan Zhao, Chuanzhu Yan, Pengfei Lin.
      Myofibrillar myopathy type 5 (MFM5) is a dominantly inherited myopathy caused by mutations in the FLNC gene. The underlying pathogenic mechanisms of MFM5 remain unclear, and there are currently no effective treatments available. This study hypothesizes that mitochondrial dysfunction plays a key role in the pathogenesis of MFM5, on the basis of the COX-negative fibres observed in MFM5 patients. To test this hypothesis, a zebrafish model was developed to explore the impact of filamin-C on mitochondrial dynamics. These results demonstrated that defects in filamin-C disrupt mitochondrial fission, leading to mitochondrial dysfunction and mitophagy. This hypothesis was further validated through the analysis of skeletal muscle samples from MFM5 patients. These findings suggest that mitochondrial dysfunction caused by imbalanced fission and fusion of mitochondria and mitophagy contributes to MFM5 pathology. Importantly, this study identified potential therapeutic targets for MFM5 treatment, opening avenues for future research aimed at developing targeted interventions.
    Keywords:  filamin-C; mitochondria; mitochondrial dynamics; myofibrillar myopathy
    DOI:  https://doi.org/10.1093/hmg/ddaf051
  20. J Orthop Surg Res. 2025 Apr 19. 20(1): 395
    The effects of different exercise training protocols on mitochondrial dynamics in skeletal and cardiac muscles of Wistar rats.
    Amir Hossein Haghighi, Mohammad Reza Bandali, Roya Askari, Hadi Shahrabadi, Rosario Barone, Roberto Bei, Pasquale Farsetti, Marco Alfonso Perrone.
       BACKGROUND: Mitochondrial fission and fusion both contribute to maintaining mitochondrial function and optimizing bioenergetic capacity.
    OBJECTIVE: The aim of this study was to compare the effect of aerobic and resistance training on mitochondrial fission and fusion markers in skeletal and cardiac muscles of Wistar rats.
    METHOD: 24 male Wistar rats were randomly divided into four groups of moderate-intensity interval training (MIIT), high-intensity interval training (HIIT), resistance training (RT) and control (CON). The MIIT and HIIT groups performed treadmill exercises with an intensity of 60-65% and 80-85% of the maximum speed, respectively, while the RT group performed resistance training with an intensity of 30-60% of the rat's body weight for 8 weeks. The soleus (SOL), extensor digitorum longus (EDL) and left ventricular tissues were used to evaluate markers of mitochondrial fission and fusion PGC-1α (fusion/fission), Opa-1 (fusion), Fis-1 (fission), Drp-1 (fission), Mfn-1 and Mfn-2 (fusion) genes expression.
    RESULTS: In all three tissues, a significant increase in some mitochondrial fusion markers was observed after 8 weeks of training (p = < 0.0001-0.0452). Furthermore, a significant decrease in cardiac mitochondrial fission markers was observed in all three groups (p = < 0.0001-0.0156). This reduction in some markers was evident in the SOL tissue of the HIIT group (p < 0.0001 for Drp-1 and p = 0.0007 for Fis-1) and in the EDL tissue of the RT group (p = 0.0005 for Fis-1 and p = 0.0012 for Drp-1). The mitochondrial fission/fusion markers in the heart (p = 0.0007-0.0449) and SOL (p = 0.0050-0.0258) tissues of the HIIT group had more changes than the RT group, while the mitochondrial fission markers in the EDL tissue of the RT group had a lower level than the HIIT (p = 0.0087 for Drp-1) and MIIT (p = 0.0130 for Fis-1 and p = 0.0010 for Drp-1) groups.
    CONCLUSION: Our study demonstrated that HIIT, through better regulation of mitochondrial fusion and fission than RT, improves mitochondrial dynamics in cardiac and SOL tissues.
    Keywords:  Exercise; Mitochondrial dynamics; Muscles; Myocardium; Rats
    DOI:  https://doi.org/10.1186/s13018-025-05809-w
  21. Cardiovasc Toxicol. 2025 Apr 17.
    Shen-fu Injection Modulates HIF- 1α/BNIP3-Mediated Mitophagy to Alleviate Myocardial Ischemia-Reperfusion Injury.
    Zhian Chen, Tianying Liu, Lihui Xiong, Zhi Liu.
      Coronary reperfusion therapy is the most common surgical treatment for myocardial infarction, but it can further induce myocardial ischemia-reperfusion injury (MIRI). Therefore, MIRI following coronary intervention is a challenging clinical issue. This study aims to investigate the involvement of HIF- 1α/BNIP3-mediated mitophagy in the protective effects of Shen-fu Injection (SFI) on MIRI in rats. Key targets and signaling pathways of myocardial MIRI were analyzed using high-throughput transcriptome data from the GSE240842 dataset in the GEO database.To establish the MIRI rat model, the left anterior descending coronary artery was ligated for 30 min, followed by reperfusion for 120 min. Hypoxia/reoxygenation (H/R) in neonatal rat primary cardiomyocytes was induced by oxygen-glucose deprivation for 4 h, followed by reoxygenation for 2 h. Two hours after reperfusion, assessments included myocardial infarction area, CK-MB, CTnI, HE staining, TUNEL, mitochondrial ultrastructure and autophagosomes, HIF- 1α, BNIP3, LC3B-II, LC3B-I protein expression, immunofluorescence, and qRT-PCR. Cardiac function was also evaluated using M-mode ultrasound 2 h after reperfusion. In cardiomyocytes, CCK- 8, EdU cell proliferation levels, scratch assay, mitochondrial membrane potential, ROS levels, cardiomyocyte apoptosis, protein expression levels, and immunofluorescence were assessed 2 h after reoxygenation. Our results indicate that HIF- 1α and BNIP3 are key targets in MIRI. SFI upregulates HIF- 1α expression, promoting moderate mitophagy. This process clears excessively damaged mitochondria, reduces cardiomyocyte apoptosis, and decreases myocardial injury. Additionally, SFI reduces autophagosome accumulation, lowers ROS production, and stabilizes membrane potential. Consequently, the area of myocardial infarction is reduced, and cardiac function is improved. SFI activates the HIF- 1α/BNIP3 pathway to mediate moderate mitophagy, effectively reducing cardiomyocyte apoptosis and alleviating myocardial ischemia-reperfusion injury, thereby protecting cardiomyocytes.
    Keywords:  BNIP3; HIF- 1α; Mitophagy; Myocardial ischemia–reperfusion injury; Shen-fu injection
    DOI:  https://doi.org/10.1007/s12012-025-09993-3
  22. Naunyn Schmiedebergs Arch Pharmacol. 2025 Apr 14.
    Research dynamics and drug treatment of renal fibrosis from a mitochondrial perspective: a historical text data analysis based on bibliometrics.
    Xu Li, Lan Hu, Qin Hu, Hua Jin.
      Renal fibrosis (RF) represents a significant public health challenge, necessitating the urgent identification of effective and safe therapeutic agents. Mitochondrial-targeted strategies have demonstrated considerable promise in restoring renal function and mitigating fibrosis. This study aims to examine the evolution of research and therapeutic interventions for RF from a mitochondrial perspective through bibliometric analysis. Literature retrieval was primarily conducted using the Web of Science Core Collection. Visual analysis was performed utilizing the Bibliometrix package (R- 4.4.2), CiteSpace 6.3.R1, and VOSviewer 1.6.19. A total of 819 documents were included for analysis. Significant contributions were made by researchers from China and the USA, with Nanjing Medical University leading in publication volume. Zhang Aihua and Huang Songming emerge as key scholars in the field, while the International Journal of Molecular Sciences is the journal with the highest publication output. Key research themes include oxidative stress, expression, injury, activation, mechanisms, and mitochondrial dysfunction. Mitochondrial-targeted approaches for treating RF can be categorized into six main strategies: mitochondrial biogenesis regulators, mitochondrial dynamics modulators, mitophagy inducers, oxidative stress regulators, NLRP3 inhibitors, and other mitochondrial-targeted therapeutic approaches. This study comprehensively examines the current state of RF research from a mitochondrial standpoint, summarizing key drugs and potential mechanisms of mitochondrial regulation. The findings aim to enhance scholarly understanding of the ongoing research trends and provide valuable insights for the development of targeted therapeutic agents.
    Keywords:  Bibliometrics; Mitochondria; Renal fibrosis; Visual analysis
    DOI:  https://doi.org/10.1007/s00210-025-04151-6
  23. Nutrients. 2025 Mar 27. pii: 1158. [Epub ahead of print]17(7):
    N6-Methyladenosine Modification in the Metabolic Dysfunction-Associated Steatotic Liver Disease.
    Satoru Matsuda, Moeka Nakashima, Akari Fukumoto, Naoko Suga.
      Epigenetics of N6-methyladenine (m6A) modification may play a key role during the regulation of various diseases, including metabolic dysfunction-associated steatotic liver disease (MASLD). The m6A modification has been shown to be accomplished via the exploitation of several players such as methyltransferases, demethylases, and/or methylation-binding molecules. Significantly, the m6A methylation can regulate the key eukaryotic transcriptome by affecting the subcellular localization, splicing, export, stability, translation, and decay of those RNAs. An increasing amount of data has designated that the m6A modification of RNAs can also modulate the expression of autophagy-related genes, which could also control the autophagy in hepatocytes. Oxidative stress with reactive oxygen species (ROS) can induce m6A RNA methylation, which might be associated with the regulation of mitochondrial autophagy (mitophagy) and/or the development of MASLD. Therefore, both autophagy and the m6A modification could play important roles in regulating the pathogenesis of MASLD. Comprehending the relationship between m6A and mitophagy may be helpful for the development of future therapeutic strategies against MASLD. This review would advance the understanding of the regulatory mechanisms of m6A RNA modification, focusing on the impact of mitochondrial dysregulation and mitophagy in the liver with MASLD.
    Keywords:  MASLD; N6-methyladenine; RNA binding protein; autophagy; liver dysfunction; mitophagy; non-coding RNA; reactive oxygen species
    DOI:  https://doi.org/10.3390/nu17071158
  24. Metab Brain Dis. 2025 Apr 14. 40(4): 180
    Polysaccharides from Ganoderma lucidum attenuate cognitive impairment in 5xFAD mice by inhibiting oxidative stress and modulating mitochondrial dynamics via the Nrf2/antioxidative axis activation.
    Xiaoqin Liu, Yanbing Li, Jiwei Wang, Tao Meng, Lijuan Song, Lizhi Yang, Jiezhong Yu, Cungen Ma.
      Oxidative stress and mitochondrial dynamics imbalance are key contributors to AD pathogenesis. GLPS, an extract from Ganoderma lucidum spores, exhibits anti-inflammatory, antioxidant, and immunomodulatory properties. However, the roles of GLPS in regulating oxidative stress and mitochondrial dynamics in AD remain poorly understood. Here, the underlying mechanisms of neuroprotective effects on cognitive dysfunction in 5 × FAD mice were explored. C57BL/6 mice served as WT controls, while 5 × FAD mice were divided into an AD group and an AD + GLPS group. The mice in AD + GLPS group were administered daily GLPS (25 mg/kg) by i.p. injection for two months, while WT and AD mice received an equivalent volume of normal saline. The results indicated that GLPS markedly improved cognitive function and decreased p-tau and Aβ levels in 5 × FAD mice. Moreover, GLPS alleviated oxidative stress by increasing SOD levels and decreasing MDA concentrations. It also inhibited excessive mitochondrial fragmentation by decreasing the expression of p-Drp1 and Fis1, while increasing the levels of Mfn1, Mfn2, and OPA1 in 5 × FAD mice. Mechanistically, GLPS activated Nrf2, leading to a marked upregulation of antioxidant enzymes, including HO- 1, NQO1, and SOD2 in 5 × FAD mice. Collectively, these findings suggest that GLPS ameliorates cognitive deficits in 5 × FAD mice by reducing oxidative stress and modulating mitochondrial dynamics through Nrf2-mediated antioxidant enzyme activation.
    Keywords:  AD; GLPS; Mitochondrial dynamics; Nrf2/antioxidative pathway; Oxidative stress
    DOI:  https://doi.org/10.1007/s11011-025-01601-1
  25. Aging Dis. 2025 Apr 08.
    Mitochondrial Imbalance in Down Syndrome: A Driver of Accelerated Brain Aging?
    Xinxin Zuo.
      Down syndrome (DS), caused by trisomy of chromosome 21 (HSA21), is a complex condition associated with neurodevelopmental impairments and accelerated brain aging, often culminating in early-onset Alzheimer's disease (AD). Central to this accelerated aging is mitochondrial imbalance, characterized by disrupted energy metabolism, increased oxidative stress, impaired dynamics, and defective quality control mechanisms like mitophagy. These abnormalities exacerbate neuronal vulnerability, driving cognitive decline and neurodegeneration. This review examines the genetic and biochemical underpinnings of mitochondrial dysfunction in DS, with a focus on the role of HSA21-encoded genes. We also highlight how mitochondrial dysfunction, amplified by oxidative stress and HSA21 gene dosage effects, converges with cellular senescence and neuroinflammation to accelerate Alzheimer-like pathology and brain aging in DS. Finally, we discuss emerging therapeutic strategies targeting mitochondrial pathways, which hold promise for mitigating neurodegenerative phenotypes and improving outcomes in DS.
    DOI:  https://doi.org/10.14336/AD.2025.0189
  26. Brain Res. 2025 Apr 16. pii: S0006-8993(25)00206-9. [Epub ahead of print] 149647
    Effects of mitochondrial O-GlcNAcylation in pericytes after mechanical injury.
    Ji Hyun Park, Dong Bin Back, Shuzhen Guo, Masayoshi Tanaka, Hajime Takase, Michael J Whalen, Ken Arai, Kazuhide Hayakawa, Eng H Lo.
      Damage to vascular cells comprise an important part of traumatic brain injury (TBI) but the underlying pathophysiology remains to be fully elucidated. Here, we investigate the loss of O-Linked β-N-acetylglucosamine(O-GlcNAc) modification (O-GlcNAcylation) and mitochondrial disruption in vascular pericytes as a candidate mechanism. In mouse models in vivo, TBI rapidly induces vascular oxidative stress and down-regulates mitochondrial O-GlcNAcylation. In pericytes but not brain endothelial cultures in vitro, mechanical stretch injury down-regulates mitochondrial O-GlcNAcylation. This is accompanied by disruptions in mitochondrial dynamics, comprising a decrease in mitochondrial fusion and an increase in mitochondrial fission proteins. Pharmacologic rescue of endogenous mitochondrial O-GlcNAcylation with an O-GlcNAcase inhibitor Thiamet-G or addition of exogenous O-GlcNAc-enhanced extracellular mitochondria ameliorates the mitochondrial disruption in pericytes damaged by mechanical injury. Finally, in a pericyte-endothelial co-culture model, mechanical injury increased trans-cellular permeability; adding Thiamet-G or O-GlcNAc-enhanced extracellular mitochondria rescued trans-cellular permeability following mechanical injury. These proof-of-concept findings suggest that mitochondrial O-GlcNAcylation in pericytes may represent a novel therapeutic target for ameliorating oxidative stress and vascular damage after mechanical injury following TBI.
    Keywords:  Mitochondrial dynamics; O-GlcNAcylation; Oxidative stress; Traumatic brain injury; Vascular pericyte
    DOI:  https://doi.org/10.1016/j.brainres.2025.149647
  27. Front Pharmacol. 2025 ;16 1544714
    Icarisid Ⅱ modulates mitochondrial dynamics for anti-HBV activity.
    Zhengyun Liu, Haiyan Yang, Juan Wen, Dongyan Xiao, Wan Yu, Guo Luo, Qihai Gong, Huan Wang.
       Introduction: To investigate the potential anti-hepatitis B virus (HBV) activity of Icariside Ⅱ (ICS Ⅱ), and elucidate its underlying mitochondrial dynamics mechanisms.
    Methods: The study employed in vivo and in vitro assays to evaluate anti-HBV effects of ICS Ⅱ. An HBV replicating mouse model was established through hydrodynamic injection of pAAV/HBV1.2, the impact of ICS Ⅱ on HBV replication and liver toxicity was assessed. In vitro cell-based assays used HBV-positive HepG2.2.15 cells. Cytotoxicity was determined with CCK-8 assay, while ELISA and qPCR were employed to measure HBsAg, HBeAg, and HBV DNA levels. The livers of ICS II-treated HBV-infected mice were taken for transcriptome sequencing to screen for different genes, and the results were verified by Western Blot. Mitochondrial morphology and dynamics were visualized using confocal imaging and transmission electron microscopy. Key protein expressions related to mitochondrial fission and fusion were analyzed via WB. Intracellular ROS generation was assessed using fluorescence staining.
    Results: The study found that ICS Ⅱ exhibited significant anti-HBV effects both in vivo and in vitro. The results of RNA-Seq indicated that ICS Ⅱ modulated the mRNA levels of Fisl, a protein associated with mitochondrial dynamics, during the anti-HBV response. It induced mitochondrial fragmentation and enhanced mitochondrial motility in HBV-positive cells. Notably, key proteins associated with mitochondrial fission and fusion demonstrated alterations favoring fission. Furthermore, ICS Ⅱ effectively reduced ROS production in HBV-positive cells.
    Conclusion: ICS Ⅱ exhibits significant anti-HBV potential through its regulation of mitochondrial dynamics and ROS production.
    Keywords:  HepG2.2.15 cell; ROS; hepatitis B virus; icariside II; mitochondrial dynamic; reactive oxygen species
    DOI:  https://doi.org/10.3389/fphar.2025.1544714
  28. Cell Mol Biol (Noisy-le-grand). 2025 Apr 15. 71(3): 117-123
    Effect of regular exercise on ocular inflammation and mitochondrial biogenesis in experimental Alzheimer's disease model.
    Suleyman Okudan, Tuğba Sezer, Emine Tınkır Kayırbatmaz, Muaz Belviranli, Nilsel Okudan.
      This study investigates the effects of regular exercise on inflammation and mitochondrial biogenesis in the eye using a controlled experimental Alzheimer's disease (AD) model. Twenty-four male Wistar rats were divided into four groups: control, Alzheimer, exercise, and Alzheimer with exercise. Molecular markers, including Nuclear Factor Kappa B (NF-κB), Fibronectin Type III Domain-Containing Protein 5 (FNDC5), Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-Alpha (PGC-1α), Sirtuin 1 (SIRT1) were analyzed through real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) Matrix Metalloproteinase 2 (MMP-2), and Interleukin-1 Beta (IL-1β) were analyzed enzyme-linked immunosorbent assay (ELISA)  to evaluate exercise-induced changes in inflammation and mitochondrial function. NF-κB levels were significantly elevated in the Alzheimer group, reflecting neuroinflammation, while exercise partially mitigated these effects. Exercise increased FNDC5, PGC-1α, and SIRT1 levels, suggesting a role in promoting neuroprotection and mitochondrial biogenesis. However, MMP-2 and IL-1β effects were primarily observed at the gene expression level, without substantial changes in protein levels. The use of an Alzheimer-specific model reduced confounding factors, such as age-related pathologies, providing a clearer perspective on Alzheimer-associated ocular changes. These findings highlight the potential of exercise in modulating key molecular pathways involved in AD.
    DOI:  https://doi.org/10.14715/cmb/2025.71.3.14
  29. Metab Brain Dis. 2025 Apr 17. 40(5): 186
    High urea promotes mitochondrial fission and functional impairments in astrocytes inducing anxiety-like behavior in chronic kidney disease mice.
    Xi Zhao, Shengyao Zhang, Mengna Wu, Binyun Zhang, Guoran Wan, Meng Zhang, Jing Li, Zhuo Fei, Guoqi Zhu, Shaoqiu Jiang, Mohan Xiao, Wanjia Liu, Zhelun Zhao, Boyue Huang, Jianhua Ran.
      High urea can induce depression and anxiety. Activation of astrocytes is closely associated with psychiatric disorders. However, the pathological mechanism of whether high urea affects astrocyte structure and function to induce anxiety-like behaviors remain unclear. We established a high-urea chronic kidney disease (CKD) mouse model and found that these mice exhibited elevated levels of anxiety through behavioral experiments. Immunofluorescence and transmission electron microscopy studies of astrocytes revealed a decrease in density and branching of mPFC astrocytes. Additionally, we observed a significant reduction in ATP and BDNF levels in the mPFC and primary astrocytes of CKD mice induced by high urea. Analysis of gene expression differences in astrocytes between WT and high-urea mice indicated alterations in mitochondrial dynamics-related signaling pathways in astrocytes. We established a high-urea primary astrocyte model to assess mitochondrial function and levels of fusion and fission proteins. Treatment of primary astrocytes with high urea led to mitochondrial fragmentation and downregulation of Mfn2 expression. These results suggested that high urea downregulates Mfn2 expression in mPFC astrocytes, induced mitochondrial fusion-fission abnormalities, disrupted astrocyte energy metabolism, and promoted high-urea-related anxiety. Mfn2 may represent a potential therapeutic target for high-urea-related anxiety.
    Keywords:  Anxiety; Astrocytes; Mitochondria; Urea
    DOI:  https://doi.org/10.1007/s11011-025-01612-y
  30. Proc Natl Acad Sci U S A. 2025 Apr 22. 122(16): e2421953122
    Active control of mitochondrial network morphology by metabolism-driven redox state.
    Gaurav Singh, Vineeth Vengayil, Aayushee Khanna, Swagata Adhikary, Sunil Laxman.
      Mitochondria are dynamic organelles that constantly change morphology. What controls mitochondrial morphology however remains unresolved. Using actively respiring yeast cells growing in distinct carbon sources, we find that mitochondrial morphology and activity are unrelated. Cells can exhibit fragmented or networked mitochondrial morphology in different nutrient environments independent of mitochondrial activity. Instead, mitochondrial morphology is controlled by the intracellular redox state, which itself depends on the nature of electron entry into the electron transport chain (ETC)-through complex I/II or directly to coenzyme Q/cytochrome c. In metabolic conditions where direct electron entry is high, reactive oxygen species (ROS) increase, resulting in an oxidized cytosolic environment and rapid mitochondrial fragmentation. Decreasing direct electron entry into the ETC by genetic or chemical means, or reducing the cytosolic environment rapidly restores networked morphologies. Using controlled disruptions of electron flow to alter ROS and redox state, we demonstrate minute-scale, reversible control between networked and fragmented forms in an activity-independent manner. Mechanistically, the fission machinery through Dnm1 responds in minute-scale to redox state changes, preceding the change in mitochondrial form. Thus, the metabolic state of the cell and its consequent cellular redox state actively control mitochondrial form.
    Keywords:  electron transport chain; mitochondrial network; reactive oxygen species; redox state
    DOI:  https://doi.org/10.1073/pnas.2421953122
  31. Metab Brain Dis. 2025 Apr 12. 40(4): 177
    Disturbances in mitochondrial quality control and mitochondria-lysosome contact underlie the cerebral cortex and heart damage of mucopolysaccharidosis type II mice.
    Camila Vieira Pinheiro, Rafael Teixeira Ribeiro, Ana Cristina Roginski, Morgana Brondani, Ângela Beatris Zemniaçak, Chrístofer Ian Hernandez Hoffmann, Adriana Fernanda K Vizuete, Carlos-Alberto Gonçalves, Alexandre Umpierrez Amaral, Moacir Wajner, Guilherme Baldo, Guilhian Leipnitz.
      Mucopolysaccharidosis type II (or Hunter syndrome) is a lysosomal disease caused by mutations in the IDS gene, which encodes the enzyme iduronate 2-sulfatase. MPS II patients present with systemic clinical manifestations and, in the most severe cases, with severe central nervous system abnormalities. Cardiac alterations are also commonly observed. In this study, we evaluated the communication between mitochondria and lysosomes, as well as mitochondrial dynamics and bioenergetics, mitophagy/autophagy, and redox homeostasis in the cerebral cortex and heart of 6-month-old MPS II mice. Our findings showed a reduction in the content of protein TBC1D15 in the cerebral cortex and heart of MPS II mice and an increase in Rab7 in the heart of these animals, suggesting disturbances in the communication between mitochondria and lysosomes. Furthermore, decreased Drp1 levels, indicative of reduced fission, and increased VDAC1 and COX IV, suggesting an increase in mitochondrial mass, were seen in both tissues. Tom20 was also augmented in the cortex. Changes in parkin levels were also verified, indicating disrupted mitophagy. In the field of bioenergetics, we observed reduced activities of citrate synthase and malate dehydrogenase in the cortex, as well as decreased activities of isocitrate dehydrogenase, creatine kinase, and pyruvate kinase, along with diminished mitochondrial respiration in the cardiac tissue of deficient mice. However, a mild increase in lipid peroxidation was seen only in the heart. Our findings suggest that mitochondria-lysosome crosstalk disruption and bioenergetic failure contribute to the pathophysiology of brain and heart alterations in MPS II.
    Keywords:  Cerebral cortex; Heart; MPS II mice; Mitochondria-lysosome communication; Mitochondrial alterations; Mucopolysaccharidosis type II
    DOI:  https://doi.org/10.1007/s11011-025-01605-x
  32. Cell Rep Methods. 2025 Apr 08. pii: S2667-2375(25)00063-3. [Epub ahead of print] 101027
    Integrated analysis of transcriptional and metabolic responses to mitochondrial stress.
    Liam P Kelley, Song-Hua Hu, Sarah A Boswell, Peter K Sorger, Alison E Ringel, Marcia C Haigis.
      Mitochondrial stress arises from a variety of sources, including mutations to mitochondrial DNA, the generation of reactive oxygen species, and an insufficient supply of oxygen or fuel. Mitochondrial stress induces a range of dedicated responses that repair damage and restore mitochondrial health. However, a systematic characterization of transcriptional and metabolic signatures induced by distinct types of mitochondrial stress is lacking. Here, we defined how primary human fibroblasts respond to a panel of mitochondrial inhibitors to trigger adaptive stress responses. Using metabolomic and transcriptomic analyses, we established integrated signatures of mitochondrial stress. We developed a tool, stress quantification using integrated datasets (SQUID), to deconvolute mitochondrial stress signatures from existing datasets. Using SQUID, we profiled mitochondrial stress in The Cancer Genome Atlas (TCGA) PanCancer Atlas, identifying a signature of pyruvate import deficiency in IDH1-mutant glioma. Thus, this study defines a tool to identify specific mitochondrial stress signatures, which may be applied to a range of systems.
    Keywords:  CP: Metabolism; CP: Systems biology; cancer metabolism; integrated multi-omics; integrated stress response; metabolomics; mitochondria; mitochondrial stress response; mitochondrial unfolded protein response; stress signatures
    DOI:  https://doi.org/10.1016/j.crmeth.2025.101027
  33. Int J Biol Macromol. 2025 Apr 15. pii: S0141-8130(25)03715-8. [Epub ahead of print] 143163
    Ganoderma atrum polysaccharide inhibits ROS/NLRP3/pyroptosis axis by fixing mitochondrial dynamics disorder in PD-1 inhibitors-induced carditis of Lewis lung carcinoma mice.
    Xiao-Yu Mu, Sheng-Bin Chen, Song-Yu Yang, Wen-Sheng Wang, Hong-Mei Zhou, Yi-Xuan Wang, Xuan-Ying Chen, Xiao-Ping Peng, Wen-Juan Li.
      Mitochondria were critical for pathogenesis of PD-1 inhibitors-induced carditis, which was demonstrated to be the mechanism for Ganoderma atrum polysaccharide (PSG) against cardiomyopathy. Hence, the present study aimed to determine the role of PSG in controlling mitochondrial homeostasis in PD-1 inhibitors-induced carditis of Lewis lung carcinoma mice. Results showed that PSG significantly alleviated PD-1 inhibitors-induced cardiotoxicity without compromising their anti-tumor effects, as evidenced by inhibiting cardiac histopathological disorders, creatine kinase (CK) release, and tumor growth. PSG administration significantly ameliorated inflammation by reducing pro-inflammatory cytokine IL-1β release and NLRP3 expression. Meanwhile, the reduction of pyroptosis was demonstrated to be implicated in PSG-inhibited carditis evidenced by the decrease in Caspase-1, gasdermin D (GSDMD). Mechanistically, mitochondria were sites of ROS generation and NLRP3 inflammasome activation. Our results showed that PSG suppressed NLRP3- induced pyroptosis, which was associated with inhibition of ROS attack and mitochondrial protection by maintaining mitochondrial membrane potential, reversing a deficiency in mitochondrial fission, suppressing mitochondrial hyper-fusion, suggesting that ROS/NLRP3/pyroptosis axis was a vital process in avoiding mitochondrial dysfunction during PSG-mediated cardioprotection. Additionally, the modification of the redox system was also shown in the context of cardioprotection of PSG, by elevating antioxidant enzyme activities and suppressing lipid oxidation.
    Keywords:  Carditis; Gandoerma atrum polysaccharide; Mitochondrial dynamics; NLRP3 inflammasome; PD-1 inhibitors
    DOI:  https://doi.org/10.1016/j.ijbiomac.2025.143163
  34. Int Immunopharmacol. 2025 Apr 15. pii: S1567-5769(25)00658-7. [Epub ahead of print]155 114668
    A novel mechanism of FBXW7 in combating intervertebral disc degeneration: Mitigating ferroptosis in nucleus pulposus cells through the regulation of mitophagy.
    Xiao Lu, Zhidi Lin, Dachuan Li, Zhaoyang Gong, Tiancong Ma, Jiongdong Wu, Wenbiao Xiao, Chenpei Xu, Yunzhi Guan, Shuo Yang, Yuxuan Zhang, Chi Sun, Xinlei Xia, Feizhou Lu, Jian Song, Jianyuan Jiang, Wei Zhu, Guangyu Xu, Xiaosheng Ma, Fei Zou.
      With the aging of the global population, the prevalence of intervertebral disc degeneration (IVDD) disease is gradually increasing. This disease not only leads to a substantial reduction in the quality of life of patients but also imposes a considerable burden on the health care system. At present, the understanding of its pathogenesis is relatively limited, and in-depth research is urgently needed to identify effective treatment methods. One of the main causes of IVDD is the compression of the spine caused by body weight. The objective of this study was to investigate the potential regulatory mechanism underlying IVDD induced by excessive compression. Moreover, to investigate whether FBXW7 is involved in the regulation of mitophagy and ferroptosis, we used 1 MPa pressure to induce nucleus pulposus cell (NPC) degeneration and then constructed plasmids or small interfering RNAs to overexpress or knock down FBXW7. In addition, in vivo animal experiments were performed to verify the function of FBXW7. We found that FBXW7 expression was decreased in degenerative NP tissues. Compression promoted the initiation of mitophagy, but blocked autophagic flux and ultimately caused ferroptosis in NPCs. However, overexpression of FBXW7 can activate mitophagy, improve autophagic flux, and alleviate ferroptosis. Moreover, FBXW7 can bind to mTOR and promote its ubiquitination and degradation, thus increasing the expression of PINK1 and Parkin. Taken together, the results of both in vitro and in vivo experiments suggested that FBXW7 induced mitophagy, alleviated ferroptosis, and delayed IVDD via the mTOR signaling pathway.
    Keywords:  FBXW7; Ferroptosis; Intervertebral disc degeneration; Mitophagy; Nucleus pulposus; mTOR
    DOI:  https://doi.org/10.1016/j.intimp.2025.114668
  35. Biochim Biophys Acta Mol Basis Dis. 2025 Apr 11. pii: S0925-4439(25)00195-4. [Epub ahead of print]1871(6): 167850
    Small molecule DDQ involvement of ERK-mediated signaling pathway with enhanced mitophagy in HT22 cells transfected with mTau.
    Jangampalli Adi Pradeepkiran, Sudhir Kshirsagar, Rainier Vladlen Alvir, Philip Irwin Motakatla, P Hemachandra Reddy.
      Tau hyperphosphorylation was the initial recognized pathogenic tau protein post-translational modification in Alzheimer's disease. In our present research, treatment of diethyl (3,4-dihydroxy phenethylamine) (quinolin-4-yl) methylphosphonate (DDQ) HT22 cells with mTau transfected HT22 cells decreased the phosphorylation of tau at Ser202, Thr205, p-ERK, and increased LC3B, and TOM20 as detected by Western blots. Moreover, DDQ p-tau and p-ERK inhibition of phosphorylation also contributed to significant mitochondrial protection in the presence of mTau. Taken together, for the first time, we found that DDQ is involved in phosphorylation inhibition to restore the mitophagy, which may relate to the Sirt3 activation of the ERK-CREB mediated pathway.
    Keywords:  Alzheimer's disease; DDQ; Hyperphosphorylation; P-ERK; P-tau
    DOI:  https://doi.org/10.1016/j.bbadis.2025.167850
  36. Open Life Sci. 2025 ;20(1): 20220913
    Stigmasterol alleviates endplate chondrocyte degeneration through inducing mitophagy by enhancing PINK1 mRNA acetylation via the ESR1/NAT10 axis.
    Hao Li, Xiaofeng Chen, Baoci Huang, Junjie He, Junxian Xie, Weijun Guo, Jinjun Liang, Jiajian Ruan, Jincheng Liu, Zhen Xiang, Lixin Zhu.
      Intervertebral disc degeneration (IVDD) is a core factor in spinal degeneration. To date, there is no effective treatment for IVDD. It is urgent to identify the pathogenesis of IVDD to develop effective strategies for IVDD treatment. Alleviating endplate chondrocyte degeneration is a promising strategy for IVDD treatment, while mitophagy prevents degeneration of endplate chondrocytes. Stigmasterol (STM) protects neurons from injuries by triggering mitophagy, yet the effect of STM on the mitophagy of endplate chondrocytes in IVDD has not been reported. In this study, endplate chondrocyte degeneration was induced by interleukin-1β, and the ribonucleic acid (RNA) acetylation level was identified by acetylated RNA immunoprecipitation. Herein, results indicated that STM alleviated endplate chondrocyte degeneration. Besides, STM induced PTEN-induced kinase 1 (PINK1)-mediated mitophagy in degenerated endplate chondrocytes. Moreover, N-acetyltransferase 10 (NAT10) increased PINK1 expression by improving PINK1 mRNA acetylation in endplate chondrocytes. In addition, STM regulated NAT10 expression by estrogen receptor 1 (ESR1) in degenerated endplate chondrocytes. In summary, the present study revealed that STM attenuated endplate chondrocyte degeneration through inducing mitophagy by enhancing PINK1 mRNA acetylation via the ESR1/NAT10 axis. These findings would provide novel strategies for the treatment of IVDD.
    Keywords:  RNA acetylation; endplate chondrocyte degeneration; intervertebral disc degeneration; mitophagy; stigmasterol
    DOI:  https://doi.org/10.1515/biol-2022-0913
  37. bioRxiv. 2025 Apr 01. pii: 2025.03.31.646474. [Epub ahead of print]
    Mitochondrial function regulates cell growth kinetics to actively maintain mitochondrial homeostasis.
    Leeba Ann Chacko, Hidenori Nakaoka, Richard Morris, Wallace Marshall, Vaishnavi Ananthanarayanan.
      Mitochondria are not produced de novo in newly divided daughter cells, but are inherited from the mother cell during mitosis. While mitochondrial homeostasis is crucial for living cells, the feedback responses that maintain mitochondrial volume across generations of dividing cells remain elusive. Here, using a microfluidic yeast 'mother machine', we tracked several generations of fission yeast cells and observed that cell size and mitochondrial volume grew exponentially during the cell cycle. We discovered that while mitochondrial homeostasis relied on the 'sizer' mechanism of cell size maintenance, mitochondrial function was a critical determinant of the timing of cell division: cells born with lower than average amounts of mitochondria grew slower and thus added more mitochondria before they divided. Thus, mitochondrial addition during the cell cycle was tailored to the volume of mitochondria at birth, such that all cells ultimately contained the same mitochondrial volume at cell division. Quantitative modelling and experiments with mitochondrial DNA-deficient rho0 cells additionally revealed that mitochondrial function was essential for driving the exponential growth of cells. Taken together, we demonstrate a central role for mitochondrial activity in dictating cellular growth rates and ensuring mitochondrial volume homeostasis.
    DOI:  https://doi.org/10.1101/2025.03.31.646474
  38. bioRxiv. 2025 Apr 02. pii: 2025.04.02.646853. [Epub ahead of print]
    Interleukin-13-mediated alterations in esophageal epithelial mitochondria contribute to tissue remodeling in eosinophilic esophagitis.
    Jazmyne L Jackson, Reshu Saxena, Mary Grace Murray, Abigail J Staub, Alena Klochkova, Travis H Bordner, Courtney Worrell, Annie D Fuller, John M Crespo, Andres J Klein-Szanto, John Elrod, Tatiana A Karakasheva, Melanie Ruffner, Amanda B Muir, Kelly A Whelan.
       Background: The significance of mitochondria in EoE pathobiology remains elusive.
    Objective: To determine the impact of EoE inflammatory mediators upon mitochondrial biology in esophageal epithelium, the mechanisms mediating these effects, and their functional significance to EoE pathobiology.
    Methods: Mitochondria were evaluated in human biopsies, MC903/Ovalbumin-induced murine EoE, and human esophageal keratinocytes. Esophageal keratinocytes were treated with EoE-relevant cytokines and JAK/STAT inhibitor ruxolitinib. To deplete mitochondria, 3D organoids generated from TFAM loxp/loxp mice were subjected ex vivo to Cre or siRNA against Transcription factor A, mitochondria (TFAM) was transfected into esophageal keratinocytes. Mitochondrial respiration, membrane potential, and superoxide levels were measured.
    Results: We find evidence of increased mitochondria in esophageal epithelium of patients with EoE and mice with EoE-like inflammation. In esophageal keratinocytes, IL-4 and IL-13 increase mitochondrial mass. IL-13 increases mitochondrial biogenesis in a JAK/STAT-dependent manner. In 3D organoids, IL-13 limits squamous cell differentiation (SCD), and this is blunted upon TFAM depletion. IL-13 decreases mitochondrial respiration and superoxide level, although mitochondria remain intact. IL-13-mediated suppression of superoxide was abrogated upon TFAM depletion in esophageal keratinocytes.
    Conclusions: We report that increased mitochondrial mass is a feature of EoE. Among EoE-relevant cytokines, IL-13 is the primary driver of increased mitochondrial mass in esophageal keratinocytes by promoting mitochondrial biogenesis in a JAK/STAT-dependent manner. IL-13-mediated accumulation of mitochondria impairs SCD in esophageal keratinocytes and also suppresses oxidative stress, a factor that is known to induce SCD. These findings identify a novel mechanism through which IL-13 promotes EoE-associated epithelial remodeling.
    Clinical Implication: These findings further lay a foundation for exploration of level of esophageal epithelial mitochondria as a predictive biomarker for response to dupilumab.
    Capsule summary: IL-13 promotes mitochondrial biogenesis in esophageal epithelium, contributing to impaired squamous cell differentiation.
    DOI:  https://doi.org/10.1101/2025.04.02.646853
  39. Poult Sci. 2025 Mar 18. pii: S0032-5791(25)00298-6. [Epub ahead of print]104(5): 105059
    Cadmium disrupted homeostasis of proximal renal tubular cells via targeting ATF4-CHOP complex into the nucleus.
    Muhammad Asmat Ullah Saleem, Ying-Xin Zhao, Farhat Bano, Yi-Xi Tang, Mu-Zi Li, Kanwar Kumar Malhi, Xiao-Wei Li, Xue-Nan Li, Yi Zhao, Jin-Long Li.
      Cadmium, a ubiquitous toxic metal and environmental pollutant, is associated with several renal metabolic disorders and disrupts the homeostasis of kidneys in humans and animals. However, the precise molecular mechanism remains poorly elucidated. The present study investigated the role of the ATF4-CHOP nuclear transcriptional axis and its interactions with cellular pathways in cadmium-induced nephrotoxicity. We acquired 120 one-day-old chickens, randomly divided them into four groups (Con, Cd35, Cd70, Cd140), and were treated with graded cadmium doses for 90 days. The kidney tissues were collected for comprehensive histopathological, biochemical, and molecular analyses using western blotting, qRT-PCR, immunofluorescence, and tunel assay. Subsequently, we revealed that cadmium exposure induced ER stress, significantly upregulated CHOP expression, and activated pro-apoptotic ATF4-CHOP axis. Our findings revealed a complex interplay, where ER stress activated inflammation. Concurrently, mitochondrial disruption elevated ROS production and oxidative stress, which impaired renal homeostasis. Moreover, inhibition of autophagy and mitophagy led to the accumulation of damaged cell organelles, further exacerbating apoptotic signaling. Our results elucidate that an integrated network of cellular stress pathways mediates cadmium-induced renal toxicity, with the ATF4-CHOP axis acting as a crucial pro-apoptotic pathway. This study provides critical insights into the mechanisms of cadmium-induced nephrotoxicity and potential therapeutic interventions to mitigate heavy metal-induced renal homeostasis disruption and renal damage.
    Keywords:  ATF4-CHOP axis; Cadmium; Homeostasis; Kidney; Nephrotoxicity
    DOI:  https://doi.org/10.1016/j.psj.2025.105059
  40. bioRxiv. 2025 Apr 10. pii: 2025.04.03.647084. [Epub ahead of print]
    STAR/STARD1: a mitochondrial intermembrane space cholesterol shuttle degraded through mitophagy.
    Prasanthi P Koganti, Amy H Zhao, Michael C Kern, Auriole C R Fassinou, Vimal Selvaraj.
      The import of cholesterol to the inner mitochondrial membrane by the steroidogenic acute regulatory protein (STAR/STARD1) is essential for de novo steroid hormone biosynthesis and the acidic pathway of bile acid synthesis. This robust system, evolved to start and stop colossal cholesterol movement, ensures pulsatile yet swift mitochondrial steroid metabolism in cells. Nonetheless, the proposed mechanism and components involved in this process has remained a topic of ongoing debate. In this study, we elucidate the mitochondrial import machinery and structural aspects of STAR, revealing its role as an intermembrane space cholesterol shuttle that subsequently undergoes rapid degradation by mitophagy. This newfound mechanism illuminates a fundamental process in cell biology and provides precise interpretations for the full range of human STAR mutation-driven lipoid congenital adrenal hyperplasia in patients.
    DOI:  https://doi.org/10.1101/2025.04.03.647084
  41. Histol Histopathol. 2025 Mar 28. 18914
    The mechanism of dexmedetomidine regulation of the HIF-1α/FUNDC1 axis in myocardial ischemia/reperfusion injury.
    Zhenfei Hu, Yidan Huang.
       OBJECTIVE: Myocardial ischemia/reperfusion injury (MIRI) is a life-threatening event that typically follows reperfusion therapy for myocardial infarction. Regarding the effects of dexmedetomidine (Dex) in MIRI, we explored its specific mechanism.
    METHODS: The MIRI rat model was treated with Dex, Topotecan [a hypoxia-inducible factor-1α (HIF-1α) inhibitor], and lentiviral-overexpressing FUN14 domain-containing protein 1 (Lv-oe-FUNDC1), with rat heart rate analysis. The pathological damage of rat myocardial tissue was evaluated by hematoxylin-eosin (HE) and Masson staining. Positive expression levels of PTEN-induced kinase 1 (PINK1), Parkin, microtubule-associated protein 1 light chain 3 (LC3) II/I, p62 and Beclin1 proteins, HIF-1α and FUNDC1 messenger RNA (mRNA), and HIF-1α and FUNDC1 were assessed by western blot, reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and immunohistochemical staining, respectively. HIF-1α-FUNDC1 binding sites and targeted binding relationships were predicted and verified via databases and dual-luciferase assay. HIF-1α enrichment levels in the FUNDC1 promoter region were evaluated using a ChIP assay.
    RESULTS: MIRI rats exhibited myocardial injury and severe myocardial dysfunction, with elevated left ventricular diastolic pressure and p62 expression, reduced left ventricular systolic pressure, and maximum rate of change in left ventricular pressure and PINK1, Parkin, LC3 II/I ratio and Beclin-1 protein levels, which were reversed by Dex treatment. MIRI rats had increased HIF-1α and FUNDC1 expression levels, which were further boosted after Dex treatment. Dex promoted mitophagy to ameliorate myocardial injury in MIRI rats via the HIF-1α/FUNDC1 axis.
    CONCLUSION: Dex promoted mitophagy by up-regulating HIF-1α to facilitate the transcriptional expression of FUNDC1, thereby ameliorating myocardial injury in MIRI rats.
    DOI:  https://doi.org/10.14670/HH-18-914
  42. Am J Physiol Heart Circ Physiol. 2025 Apr 15.
    Mitochondrial Dynamics: Deciphering the Role of HDL-C in Regulating Mitochondrial Function and Fatty Acid Oxidation in Human Skeletal Muscle.
    Mauricio Castro-Sepulveda, Francesca Amati.
      XXXX.
    Keywords:  Mitochondria; cholesterol; metabolism; physiology; skeletal muscle
    DOI:  https://doi.org/10.1152/ajpheart.00219.2025
  43. Front Pharmacol. 2025 ;16 1575733
    BAM8-22 targets spinal MrgC receptors to modulate UPRmt activity in the mechanism of bone cancer pain.
    Mingming Xie, Dan Li, Haohao Zeng, Yulin Huang, Rui Xu, Zhen Wang, Jiacheng Yu, Yu'e Sun.
       Background: Bone cancer pain (BCP) significantly impacts patients' overall quality of life. Cellular energy metabolism homeostasis is critically dependent on mitochondrial integrity, and emerging evidence suggests that mitochondrial dysfunction in chronic BCP exacerbates pain progression by disrupting nociceptive signaling pathways. Notably, G protein-coupled receptors (GPCRs), a major class of membrane receptors, modulate mitochondrial function through diverse molecular mechanisms. In this study, we investigated the role of Mas-related G protein-coupled receptor C (MrgC) in BCP pathogenesis and its regulatory effects on mitochondrial function.
    Methods: Male C3H/HeN mice were utilized to establish a BCP model. Transmission electron microscopy and flow cytometry were employed to assess changes in mitochondrial ultrastructure, as well as levels of mtROS, ATP, and MMP in mice experiencing BCP. Following intrathecal injection of BAM8-22, we analyzed the effects of activated MrgC on mitochondrial unfolded protein response (UPRmt)-related molecules (ATF5, HSP60, LONP1, CLPP) and pain-related behaviors in BCP mice. The regulatory mechanism of MrgC on UPRmt was further explored in N2a and 293T cells.
    Results: Mice with bone cancer pain showed improved mRNA and protein levels of UPRmt-related molecules, increased MMP and ATP, decreased mitochondrial ROS levels in the spinal cord after receiving an intrathecal injection of BAM8-22. Additionally, the paw withdrawal mechanical threshold in BCP mice increased, while the number of spontaneous foot lifts decreased. In complementary cellular studies, transfection-mediated overexpression of MrgC in N2a cells enhanced UPRmt biomarker expression, whereas RNA interference-mediated MrgC knockdown produced the opposite effect.
    Conclusion: By activating spinal MrgC to mediate UPRmt activity and protect mitochondrial function, BAM8-22 contributes to the molecular development of BCP. This discovery suggests a new therapeutic target for BCP and offers a possible research avenue.
    Keywords:  BAM8-22; Mas-related G protein-coupled receptor C; bone cancer pain; mitochondrial dysfunction; mitochondrial unfolded protein response
    DOI:  https://doi.org/10.3389/fphar.2025.1575733
  44. Food Chem Toxicol. 2025 Apr 14. pii: S0278-6915(25)00226-1. [Epub ahead of print] 115458
    A review on fumonisin B1-induced mitochondrial dysfunction and its impact on mitophagy and DNA methylation.
    Anthia C Govender, Anil A Chuturgoon, Terisha Ghazi.
      Fumonisin B1 (FB1) is a food-borne mycotoxin synthesized by Fusarium verticillioides and has been identified as a group 2B carcinogen. Recent research shows that the mitochondria and DNA in cells are targets of FB1. Mitophagy is a form of autophagy that functions to break down impaired mitochondria to preserve the overall functionality of the cell. DNA methylation is an epigenetic process that involves the enzymatic transfer of methyl groups from S-adenosylmethionine (SAM) to the C-5 region of the DNA cytosine ring by DNA methyltransferases (DNMTs). DNA methylation plays a key role in maintaining DNA integrity and FB1 disrupts DNA methylation via FB1-induced folate deficiency. However, there is limited research available on the impact of FB1 on mitophagy as well as FB1-induced oxidative stress and its influence on DNA methylation regulation. In this review, we aim to combine and summarize the current information on FB1-induced mitochondrial dysfunction, its impact on mitophagy as well as its DNA methylation effects.
    Keywords:  Antioxidant response; DNA methylation; Fumonisin B(1); Mitochondrial dysfunction; Mitophagy; Mycotoxin; Oxidative stress
    DOI:  https://doi.org/10.1016/j.fct.2025.115458
  45. Int Immunopharmacol. 2025 Apr 12. pii: S1567-5769(25)00603-4. [Epub ahead of print]155 114613
    Berberine improves cardiac insufficiency through AMPK/PGC-1α signaling-mediated mitochondrial homeostasis and apoptosis in HFpEF mice.
    Yingchun Hu, Xiaoyu Chen, Qiming Zhao, Guohao Li, Hao Zhang, Zhuang Ma, Hao Yu, Qingchun Zeng, Hanping Zhang, Dingli Xu.
       BACKGROUND: Heart failure (HF) with preserved ejection fraction (HFpEF) accounts for approximately half of cases of HF and is frequently clinically underdiagnosed. Although new therapies continue to emerge, determining optimal treatment strategies persists as a key clinical dilemma. Berberine(BBR), an isoquinoline alkaloid, is known to attenuate HF with reduced ejection fraction.
    PURPOSE: In this study, we explored the cardiovascular benefits of BBR in diastolic dysfunction associated with HFpEF, both in vitro and in vivo.
    METHODS: In vivo, adult male mice were fed with chow or a high-fat diet (60 % calories from lard) with L-NAME (0.5 g/L in drinking water) for 15 weeks. During the last 4 weeks, BBR (100 mg/Kg/d and 200 mg/Kg/d) was administered orally. Rat cardiac myoblast H9C2 cells were pretreated with BBR for 2 h, followed by exposure to palmitic acid (PA, 100 μM) for 24 h.
    RESULTS: Exposure to a high-fat stimulation led to p-AMPK and PGC-1α downregulation, apoptotic cascade activation, elevated mt-ROS production, and disruption of mitochondrial homeostasis both in vivo and in vitro. Notably, BBR intervention elevated the expressions of p-AMPK and PGC-1α, inhibited apoptotic reaction, reduced mt-ROS, ameliorated TFAM/NRF1-mediated mitochondrial biogenesis disorder, alleviated mitochondrial impairment, and improved cardiac function. On the other hand, AMPK knockdown abolished the beneficial impact of BBR. Collectively, our findings underscored the cardioprotective role of BBR in maintaining mitochondrial homeostasis and preventing apoptosis, achieved through the modulation of the AMPK/PGC-1α pathway.
    CONCLUSIONS: In summary, BBR possesses protective activity against cardiac insufficiency in HFpEF by maintaining mitochondrial homeostasis and inhibiting apoptosis.
    Keywords:  Berberine; Heart failure with preserved ejection fraction; Mitochondrial homeostasis; Palmitic acid
    DOI:  https://doi.org/10.1016/j.intimp.2025.114613
  46. Sci Rep. 2025 Apr 14. 15(1): 12839
    Mipep deficiency in adipocytes impairs mitochondrial protein maturation and leads to systemic inflammation and metabolic dysfunctions.
    Yuka Nozaki, Masaki Kobayashi, Tomoyoshi Fukuoh, Mamiko Ishimatsu, Takumi Narita, Kanari Taki, Yuto Hirao, Shota Ayabe, Miku Yokoyama, Yuina Otani, Yuhei Mizunoe, Mami Matsumoto, Nobuhiko Ohno, Tomonori Kaifu, Shogo Okazaki, Ryo Goitsuka, Yoshimi Nakagawa, Hitoshi Shimano, Yoichiro Iwakura, Yoshikazu Higami.
      Most mitochondrial proteins encoded in the nuclear genome are synthesized in the cytoplasm. These proteins subsequently undergo maturation through the cleavage of a signal sequence at the N-terminus by one or two mitochondrial signal peptidases, which is essential for their function within mitochondria. The present study demonstrates that adipocyte-specific knockout of one mitochondrial signal peptidase, mitochondrial intermediate peptidase (MIPEP), resulted in disordered mitochondrial proteostasis of MIPEP substrate proteins and their defective maturation. MIPEP deficiency in white and brown adipocytes suppressed the expression of adipocyte differentiation, lipid metabolism, and mitochondrial biogenesis genes. These alterations led to lipoatrophy in white adipose tissue and the whitening of brown adipose tissue. Additionally, it induced an atypical mitochondrial unfolded protein response and local inflammation in white and brown adipose tissue. Furthermore, it induced fatty liver and splenomegaly and caused systemic impairments in glucose metabolism and inflammation. These findings indicate that maturation defects of certain mitochondrial proteins and subsequent proteostasis disorders in white and brown adipocytes cause chronic and systemic inflammatory and metabolic dysfunctions.
    DOI:  https://doi.org/10.1038/s41598-025-97307-6
  47. Trends Biochem Sci. 2025 Apr 15. pii: S0968-0004(25)00060-X. [Epub ahead of print]
    Lipids: emerging actors in mitochondrial protein import.
    Mayra A Borrero-Landazabal, Vanessa Linke, Agnieszka Chacinska.
      Lipids are emerging as functional players in mitochondrial protein import beyond constituting membranes. Cryo-electron microscopy structures of protein translocases such as translocase of the outer membrane (TOM) and insertases such as translocase of the inner membrane (TIM22) link lipids to protein import by suggesting structural and functional roles for lipids in protein translocation and insertion, and for protein insertases in lipid scrambling.
    Keywords:  membrane complexes; mitochondrial biology; mitochondrial protein import; protein–lipid interactions
    DOI:  https://doi.org/10.1016/j.tibs.2025.03.011
  48. Mol Biol Rep. 2025 Apr 18. 52(1): 401
    The mitochondrial LONP1 protease: molecular targets and role in pathophysiology.
    Pei Tang, Qun Zeng, Yihao Li, Jing Wang, Meihua She.
      Lon peptidase 1 (LONP1), a member of the AAA + family, is essential for maintaining mitochondrial function. Recent studies have revealed that LONP1 serves as a multifunctional enzyme, acting not only as a protease but also as a molecular chaperone, interacting with mitochondrial DNA (mtDNA), and playing roles in mitochondrial dynamics, oxidative stress, cellular respiration, and energy metabolism. LONP1 is evolutionarily highly conserved, and mutations or dysfunctions in LONP1 can lead to diseases. There is growing evidence linking LONP1 to various human diseases, such as tumors, neurodegenerative diseases, and heart diseases. This review discusses the discovery, molecular structure, subcellular localization, tissue distribution, and mitochondrial function of LONP1. Furthermore, it summarizes the associations between LONP1 and tumors, neurodegenerative diseases, and heart diseases, exploring its role in different diseases and potential molecular mechanisms. It also analyzes the regulatory effects of related inhibitors and agonists on LONP1. Considering the pleiotropic effects of LONP1, the study of LONP1 is crucial to understanding the relevant pathophysiological processes and developing strategies to modulate and control these related diseases.
    Keywords:  Heart disease; LONP1; Mitochondria; Neurodegenerative disease; Tumor
    DOI:  https://doi.org/10.1007/s11033-025-10500-8
  49. bioRxiv. 2025 Apr 01. pii: 2025.03.31.646376. [Epub ahead of print]
    An Msp1-Protease Chimera Captures Transient AAA+ Interactions and Unveils Ost4 Mislocalization Errors.
    Deepika Gaur, Brian Acquaviva, Matthew L Wohlever.
      Membrane protein homeostasis (proteostasis) is essential for maintaining the integrity of eukaryotic organelles. Msp1 is a membrane anchored AAA+ (ATPase Associated with cellular Activities) protein that maintains mitochondrial proteostasis by extracting aberrant proteins from the outer mitochondrial membrane. A comprehensive understanding of the physiological roles of Msp1 has been hindered because AAA+ proteins interact with substrates transiently and common strategies to stabilize this interaction lead to undesirable mitochondrial phenotypes. To circumvent these drawbacks, we fused catalytically active Msp1 to the inactivated protease domain of the AAA+ protease Yme1. The resulting chimera sequesters substrates in the catalytically inactive degradation chamber formed by the protease domain. We performed mass spectrometry analysis with the Msp1-protease chimera and identified the signal anchored protein Ost4 as a novel Msp1 substrate. Topology experiments show that Ost4 adopts mixed orientations when mislocalized to mitochondria and that Msp1 extracts mislocalized Ost4 regardless of orientation. Together, this work develops new tools for capturing transient interactions with AAA+ proteins, identifies new Msp1 substrates, and shows a surprising error in targeting of Ost4.
    DOI:  https://doi.org/10.1101/2025.03.31.646376
  50. Cell Death Discov. 2025 Apr 12. 11(1): 168
    Tissue-resident Klebsiella quasipneumoniae contributes to progression of idiopathic pulmonary fibrosis by triggering macrophages mitophagy in mice.
    Chunjie Xu, Peiyi Sun, Qiyue Jiang, Yao Meng, Luyao Dong, Xiukun Wang, Xinxin Hu, Congran Li, Guoqing Li, Ruifang Zheng, Xuefu You, Xinyi Yang.
      Idiopathic pulmonary fibrosis (IPF) is a progressive and chronic interstitial lung disease with unclear underlying pathogenic mechanisms. Dysbiosis of the lung microbiota is believed to be associated with the development of fibrosis; however, the roles of the microbiome in the respiratory functions of hosts with IPF remain poorly understood. To investigate the relationship between the lung microbiome and the pathological processes of idiopathic pulmonary fibrosis under laboratory conditions, C57BL/6 J mice were exposed to bleomycin and observed at 7, 14, 21, and 28 days post-exposure. 16S rDNA analysis revealed that the lung microbial community exhibited dysbiosis in the bleomycin-induced pulmonary fibrosis model, characterized by an abnormally high proportion of Klebsiella quasipneumoniae (K. quasipneumoniae), as confirmed by RNA fluorescence in situ hybridization. Throughout the progression of experimental pulmonary fibrosis, Tax4Fun analysis indicated that the abundance of K. quasipneumoniae differed significantly between model mice and control mice, correlating with the sustained activation of reactive oxygen species (ROS) pathways. Importantly, the dysbiosis of K. quasipneumoniae may serve as a critical factor triggering increased ROS levels, accompanied by macrophage mitophagy, ultimately leading to the overexpression of TGF-β1, a key player in the pathogenesis of pulmonary fibrosis. These findings suggest that lung microbiota dysbiosis exacerbates the progression of bleomycin-induced pulmonary fibrosis related to macrophage mitophagy.
    DOI:  https://doi.org/10.1038/s41420-025-02444-6
  51. Proc Natl Acad Sci U S A. 2025 Apr 22. 122(16): e2419881122
    Mechanism of allosteric activation in human mitochondrial ClpP protease.
    Monica M Goncalves, Adwaith B Uday, Taylor J B Forrester, S Quinn W Currie, Angelina S Kim, Yue Feng, Yulia Jitkova, Algirdas Velyvis, Robert W Harkness, Matthew S Kimber, Aaron D Schimmer, Natalie Zeytuni, Siavash Vahidi.
      Human ClpP protease contributes to mitochondrial protein quality control by degrading misfolded proteins. ClpP is overexpressed in cancers such as acute myeloid leukemia (AML), where its inhibition leads to the accumulation of damaged respiratory chain subunits and cell death. Conversely, hyperactivating ClpP with small-molecule activators, such as the recently discovered ONC201, disrupts mitochondrial protein degradation and impairs respiration in cancer cells. Despite its critical role in human health, the mechanism underlying the structural and functional properties of human ClpP remains elusive. Notably, human ClpP is paradoxically activated by active-site inhibitors. All available structures of human ClpP published to date are in the inactive compact or compressed states, surprisingly even when ClpP is bound to an activator molecule such as ONC201. Here, we present structures of human mitochondrial ClpP in the active extended state, including a pair of structures where ClpP is bound to an active-site inhibitor. We demonstrate that amino acid substitutions in the handle region (A192E and E196R) recreate a conserved salt bridge found in bacterial ClpP, stabilizing the extended active state and significantly enhancing ClpP activity. We elucidate the ClpP activation mechanism, highlighting a hormetic effect where substoichiometric inhibitor binding triggers an allosteric transition that drives ClpP into its active extended state. Our findings link the conformational dynamics of ClpP to its catalytic function and provide high-resolution structures for the rational design of potent and specific ClpP inhibitors, with implications for targeting AML and other disorders with ClpP involvement.
    Keywords:  ClpP protease; HDX–MS; allostery; cryo-EM; intracellular protein degradation
    DOI:  https://doi.org/10.1073/pnas.2419881122
  52. Neurotoxicology. 2025 Apr 12. pii: S0161-813X(25)00040-3. [Epub ahead of print]108 191-205
    Thymoquinone-loaded solid lipid nanoparticles mitigate 3-Nitropropionic acid-induced mitochondrial dysfunction and oxidative damage via regulating PGC-1α/Nrf2 pathway.
    Surekha Ramachandran, Sumathi Thangarajan.
      3-Nitropropionic acid (3-NP) is a mitochondrial toxin which causes bilateral striatal lesions in experimental animals, mimicking Huntington's disease (HD) pathology. The molecular mechanisms underlying 3-NP-induced neuronal death involve mitochondrial dysfunction, transcriptional dysregulation, and impaired antioxidant defense systems. This study investigated the effects of thymoquinone (TQ) encapsulated in solid lipid nanoparticles (NanoTQ), on mitochondrial biogenesis in 3-NP-induced neurotoxicity in the striatum of male Wistar rats. Systemic administration of 3-NP (10 mg/kg) for 14 days inhibited mitochondrial complex enzymes and increased mitochondrial membrane permeability in the striatum. 3-NP exposure significantly altered the translational level of PGC-1α by modifying the expression of p-CREB/TORC1/SIRT1/PPARγ. Additionally, 3-NP exposure significantly reduced striatal levels of BDNF, GDNF, and their downstream effectors. Treatment with NanoTQ (10 and 20 mg/kg) and TQ (80 mg/kg) significantly (P < 0.01) increased mitochondrial complex enzyme activity compared to TQ (40 mg/kg). NanoTQ also significantly (P < 0.01) regulated the expression of regulatory proteins, promoting PGC-1α mediated mitochondrial biogenesis. Furthermore, NanoTQ restored BDNF and GDNF signaling and enhanced the antioxidant defense mechanism by increasing Nrf-2 and HO-1 expression while reducing Keap1 levels in the striatum. In conclusion, NanoTQ effectively mitigated 3-NP-induced neurotoxicity by regulating the mitochondrial biogenesis, neurotrophic factors, and antioxidant defense system, thereby preventing HD-like symptoms in rats.
    Keywords:  Huntington’s disease; Mitochondrial biogenesis; PGC-1α; Solid lipid nanoparticles; Thymoquinone
    DOI:  https://doi.org/10.1016/j.neuro.2025.04.005
  53. Stem Cell Reports. 2025 Apr 12. pii: S2213-6711(25)00078-5. [Epub ahead of print] 102474
    Perinuclear mitochondrial clustering for mesenchymal-to-epithelial transition in pluripotency induction.
    Ge Xiang, Zihuang Liu, Zebin Yuan, Zhongfu Ying, Yingzhe Ding, Dongtong Lin, Haihao Qin, Shanshan Dong, Shihe Zhou, Hao Yuan, Wei Xie, Zhihong Zheng, Yongqiang Chen, Linpeng Li, Qi Long, Liang Yang, Yi Wu, Keshi Chen, Feixiang Bao, Yile Huang, Wei Li, Junwei Wang, Yang Liu, Dajiang Qin, Xingguo Liu.
      Remodeled mitochondria are characteristic of pluripotent stem cells. However, a role for mitochondrial movement and distribution in pluripotency remains unknown. Here, we show that mitochondrial retrograde transport-mediated perinuclear clustering via dynein complex occurs at the early phase of pluripotency induction. Interestingly, this mitochondrial redistribution is regulated by Yamanaka factor OCT4 but not SOX2 or KLF4. This mitochondrial redistribution, which has effect on the efficiency of somatic cell reprogramming, also depends on DRP1-mediated mitochondrial fission. Importantly, perinuclear mitochondrial clustering is required for mesenchymal-to-epithelial transition (MET), an early step in reprogramming, during which β-catenin regulates the MET process. Furthermore, sufficient amount of β-catenin plays a key role in maintaining stabilization of E-CADHERIN. Taken together, these studies show that perinuclear mitochondrial clustering is an essential organellar step for MET process of pluripotency induction, which may shed light on the subcellular relationship between mitochondrial dynamics, pluripotency, and cellular morphology.
    Keywords:  Drp1; Dynein; Oct4; Wnt signaling; mesenchymal-to-epithelial transition
    DOI:  https://doi.org/10.1016/j.stemcr.2025.102474
  54. Transl Exerc Biomed. 2025 May;2(1): 9-20
    Mitochondrial and cardiovascular responses to aerobic exercise training in supine and upright positions in healthy young adults: a randomized parallel arm trial.
    Nicholas Preobrazenski, Stuart P S Mladen, Ejaz Causer, Eveline Menezes, Hashim Islam, Patrick J Drouin, Michael E Tschakovsky, Brendon J Gurd.
       Objectives: Aerobic exercise training can increase skeletal muscle mitochondrial content. Supine exercise training with legs above the heart potentially augments these increases. However, the impact of supine exercise training on mitochondrial biogenesis and cardiovascular adaptations remains unclear.
    Methods: In this single-centred, randomized, parallel arm trial, 19 recreationally active individuals underwent seven sessions of either supine with legs up (SUP; n=9, 6 females) or upright with legs down (UP; n=10, 7 females) aerobic training on a recumbent bike at 71 ± 7 % and 71 ± 2 % of peak work rate (WRpeak), respectively. The study aimed to test the effects of training with decreased muscle oxygenation on indices of muscle mitochondrial remodelling. Secondary outcomes included exercise performance, muscle oxygenation, and cardiovascular responses.
    Results: Secondary outcomes revealed significant interaction effects for time to fatigue (TTF) and WRpeak in the SUP group during supine testing, suggesting enhanced exercise tolerance and performance. No between group interaction effects were observed for upright testing. No clear effects on mitochondrial biogenesis were observed based on expression of mitochondrial protein subunits and transcriptional regulators. Acutely, HRpeak was lower during the SUP Test compared to the UP Test. No central cardiovascular adaptations were observed following training.
    Conclusions: Our exploratory analyses showed that supine aerobic training more effectively improves supine exercise tolerance and performance compared with upright training, despite no differences in measured proteins related to mitochondrial biogenesis. Further research is needed to elucidate the mechanisms underlying these postural-specific training effects.
    Registration: clinicaltrials.gov: NCT04151095.
    Keywords:  PGC-1α; aerobic training; cardiovascular response; exercise performance; supine exercise
    DOI:  https://doi.org/10.1515/teb-2025-0002
  55. J Environ Manage. 2025 Apr 14. pii: S0301-4797(25)01336-2. [Epub ahead of print]382 125360
    Oxidative stress-mediated tetrabromobisphenol A disrupts mitochondrial function in HepG2 cells and activates ferroptosis signalling to induce apoptosis.
    Xiaotian Huang, Zuhong Lin, Denglong Lu, Haipu Li.
      Tetrabromobisphenol A (TBBPA), a brominated flame retardant extensively used in consumer electronics, has been classified as a persistent environmental contaminant. While TBBPA-induced mitochondrial dysfunction is implicated in apoptosis, the precise oxidative stress-mediated mechanisms remain incompletely characterized. In this study, using human liver cancer cells (HepG2) as an in vitro model, we systematically investigated TBBPA's mitochondrial toxicity and associated cell death pathways. In vitro assays demonstrated that 10 μM TBBPA induced approximately 50 % cell death and reduced cell viability. This treatment also markedly elevated intracellular reactive oxygen species (ROS) levels. A comprehensive analysis of mitochondrial function, including assessments of mitochondrial membrane potential (MMP), oxygen consumption rate (OCR), ATP production, respiratory chain complex activities, and mitochondrial autophagy markers (LC3B, PINK1, Parkin), revealed that TBBPA entry into cells resulted in mitochondrial dysfunction. Furthermore, Ferroptosis biomarkers quantification further revealed TBBPA-driven Fe2+ and malondialdehyde (MDA) accumulation, coupled with upregulated expression of ferroptosis-related proteins (GPX4, SLC7A11, COX-2, Beclin-1). These findings provide novel insights into the molecular pathways underlying TBBPA-induced cytotoxicity.
    Keywords:  Autophagy; Mitochondrial; Oxidative stress; Tetrabromobisphenol A(TBBPA)
    DOI:  https://doi.org/10.1016/j.jenvman.2025.125360
  56. Lipids Health Dis. 2025 Apr 16. 24(1): 144
    HIIT versus MICT in MASLD: mechanisms mediated by gut-liver axis crosstalk, mitochondrial dynamics remodeling, and adipokine signaling attenuation.
    Dongkun Deng, Lin Xu, Yufei Liu, Chang Li, Qingfeng Jiang, Jiaming Shi, Shuo Feng, Yunhua Lin.
       OBJECTIVE: Compare the effects of high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) on metabolic dysfunction-associated steatotic liver disease (MASLD), focusing on the mechanisms by which these two exercise modalities influence gut microbiota structure, bile acid metabolism, and intestinal barrier function, as well as their regulatory roles in hepatic lipid synthesis and oxidative dynamics. Explore the synergistic effects of exercise-mediated mitochondrial fusion remodeling and leptin signaling, elucidate the causal relationship between gut-derived factors and hepatic metabolic reprogramming, and reveal the potential multi-scale and cross-organ dominant mechanisms of exercise, providing a theoretical basis for systematically comparing the effects of different exercise modalities.
    METHODS: Thirty-two male rats were randomly divided into NFD (n = 8) and HFD (n = 24) groups and fed normal chow and high-fat chow, respectively. After eight weeks, the HFD group was randomly divided into three groups: (1) MICT-8; (2) HIIT-8; and (3) HFD-8. At the end of the experiment, blood, liver, ileum, and skeletal muscle samples were collected for analysis of the rats' baseline conditions, mitochondrial function, hepatic lipid metabolism, bile acid pathway and gut microbiota, and synthesis of analyses.
    RESULTS: Both modes of exercise ameliorated metabolic dysregulation and attenuated pathological progression, insulin resistance, and liver fat accumulation in rats with MASLD. Furthermore, both interventions counteracted HFD-induced intestinal barrier dysfunction and restored gut-liver axis homeostasis. HIIT and MICT also upregulated bile acid-related gene expression modulated butyrate-producing bacterial taxa, and adjusted the abundance of butyrate-generating bacteria.
    CONCLUSION: Both HIIT and MICT improved lipid metabolism in MASLD rats and the difference between the HIIT and MICT groups was not statistically significant. It is noteworthy that HIIT was more effective in improving mitochondrial function in MASLD than MICT (P < 0.001).
    Keywords:  Gut-liver axis; Lipid metabolism; MASLD; Mitochondrial function; Oxidative stress
    DOI:  https://doi.org/10.1186/s12944-025-02565-y
  57. Antioxidants (Basel). 2025 Feb 28. pii: 302. [Epub ahead of print]14(3):
    Roles of Oxidative Stress and Autophagy in Alcohol-Mediated Brain Damage.
    Leon Ruiter-Lopez, Mohammed A S Khan, Xin Wang, Byoung-Joon Song.
      Excessive alcohol consumption significantly impacts human health, particularly the brain, due to its susceptibility to oxidative stress, which contributes to neurodegenerative conditions. Alcohol metabolism in the brain occurs primarily via catalase, followed by CYP2E1 pathways. Excess alcohol metabolized by CYP2E1 generates reactive oxygen/nitrogen species (ROS/RNS), leading to cell injury via altering many different pathways. Elevated oxidative stress impairs autophagic processes, increasing post-translational modifications and further exacerbating mitochondrial dysfunction and ER stress, leading to cell death. The literature highlights that alcohol-induced oxidative stress disrupts autophagy and mitophagy, contributing to neuronal damage. Key mechanisms include mitochondrial dysfunction, ER stress, epigenetics, and the accumulation of oxidatively modified proteins, which lead to neuroinflammation and impaired cellular quality control. These processes are exacerbated by chronic alcohol exposure, resulting in the suppression of protective pathways like NRF2-mediated antioxidant responses and increased susceptibility to neurodegenerative changes in the brain. Alcohol-mediated neurotoxicity involves complex interactions between alcohol metabolism, oxidative stress, and autophagy regulation, which are influenced by various factors such as drinking patterns, nutritional status, and genetic/environmental factors, highlighting the need for further molecular studies to unravel these mechanisms and develop targeted interventions.
    Keywords:  alcohol metabolism; antioxidants; autophagy; brain; ethanol; mitophagy; neurodegeneration; neurotoxicity; oxidative stress
    DOI:  https://doi.org/10.3390/antiox14030302
  58. Biochem Genet. 2025 Apr 13.
    Identification of a Novel Mitochondrial-Related Gene Signature for BMSCs in Osteoporosis Combining Single-Cell and Bulk Transcriptome Data.
    Jishi Jiang, Dan Li, Di Cui, Yunpeng Wan, Pinghui Zhou, Xilong Cui, Haiyang Yu.
      Osteoporosis (OS) is a prevalent skeletal disorder characterized by reduced bone mass and increased fracture risk, often linked to compromised functions of bone mesenchymal stem cells (BMSCs). Mitochondrial dysfunction and aberrant mitophagy are implicated in OS pathogenesis. This study aimed to identify a novel mitochondrial-related gene signature in BMSCs from OS patients by integrating single-cell and bulk transcriptome data. We analyzed single-cell RNA sequencing data from GSE147287 and bulk transcriptome data from GSE35956 to identify differentially expressed mitochondrial-related genes (MRGs) in BMSCs between healthy individuals and OS patients. Key genes were identified using LASSO logistic regression and random forest algorithms, and their differential expression was validated by RT-qPCR, Western blot, and immunofluorescence. Functional assays, including osteogenic differentiation and β-galactosidase staining, were conducted following siRNA-mediated knockdown of DUT. We identified 28 differentially expressed MRGs, with four key genes (DUT, UQCR10, DNAJC4, and MRPL33) further confirmed. Electron microscopy scanning showed damage to BMSCs mitochondria and decreased osteogenic differentiation ability in OS. Silencing DUT significantly impairs the mitochondrial function and osteogenic differentiation ability of BMSCs, indicating its potential role in OS development. This study identifies a mitochondrial gene signature in BMSCs linked to osteoporosis, with DUT emerging as a key regulator. DUT silencing impairs mitochondrial function and osteogenic differentiation, suggesting it as a potential therapeutic target for OS.
    Keywords:  Bone mesenchymal stem cells; DUT; Mitochondrial; Osteogenic differentiation; Osteoporosis
    DOI:  https://doi.org/10.1007/s10528-025-11099-y
  59. Int J Mol Sci. 2025 Apr 04. pii: 3381. [Epub ahead of print]26(7):
    2,3,5,4'-Tetrahydroxystilbene-2-O-β-D-glucoside (TSG) from Polygonum multiflorum Thunb.: A Systematic Review on Anti-Aging.
    Can Zhu, Jinhong Li, Wenchao Tang, Yaofeng Li, Chang Lin, Danhong Peng, Changfu Yang.
      The global rise in aging populations has made healthy longevity a critical priority in medical research. 2,3,5,4'-Tetrahydroxystilbene-2-O-β-D-glucoside (TSG), the primary bioactive component of Polygonum multiflorum Thunb. (commonly known as Fallopia multiflora Thunb., He shou wu, Fo-ti, or Polygoni multiflori radix), has emerged as a promising agent for combating aging and age-related diseases. This systematic review evaluates the anti-aging properties of TSG and its protective effects against age-related pathologies. The current evidence demonstrates that TSG exhibits comprehensive anti-aging effects, including lifespan extension, neuroprotection (e.g., ameliorating Alzheimer's and Parkinson's diseases), cardiovascular protection (e.g., reducing atherosclerosis and hypertension), delay of gonadal aging, reduction in bone loss (e.g., mitigating osteoporosis), and promotion of hair regrowth. Mechanistically, TSG alleviates oxidative stress, inflammation, and apoptosis while enhancing mitophagy, mitochondrial function telomerase activity, and epigenetic regulation. These multi-target actions align with the holistic principles of traditional Chinese medicine, highlighting TSG's potential as a multifaceted anti-aging agent. However, further research is required to establish standardized quantitative systems for evaluating TSG's efficacy, paving the way for its broader clinical application in promoting healthy aging.
    Keywords:  2,3,5,4′-tetrahydroxystilbene-2-O-β-D-glucoside (TSG); Polygonum multiflorum; age-related diseases; aging; healthy longevity
    DOI:  https://doi.org/10.3390/ijms26073381
  60. Biochim Biophys Acta Mol Cell Res. 2025 Apr 15. pii: S0167-4889(25)00060-6. [Epub ahead of print] 119955
    In vivo composition of the mitochondrial nucleoid in mice.
    Rodolfo García-Villegas, Franka Odenthal, Yvonne Giannoula, Nina A Bonekamp, Inge Kühl, Chan Bae Park, Henrik Spåhr, Elisa Motori, Fredrik Levander, Nils-Göran Larsson.
      Mitochondrial DNA (mtDNA) is compacted into dynamic structures called mitochondrial nucleoids (mt-nucleoids), with the mitochondrial transcription factor A (TFAM) as the core packaging protein. We generated bacterial artificial chromosome (BAC) transgenic mice expressing FLAG-tagged TFAM protein (Tfam-FLAGBAC mice) to investigate the mt-nucleoid composition in vivo. Importantly, we show that the TFAM-FLAG protein is functional and complements the absence of the wild-type TFAM protein in homozygous Tfam knockout mice. We performed immunoprecipitation experiments from different mouse tissues and identified 12 proteins as core mt-nucleoid components by proteomics analysis. Among these, eight proteins correspond to mtDNA replication and transcription factors, while the other four are involved in the mitoribosome assembly. In addition, we used the Tfam-FLAGBAC mice to identify ten proteins that may stabilize TFAM-FLAG upon depletion of the mitochondrial RNA polymerase despite the absence of mtDNA and induction of the LONP1 protease. Finally, we evaluated the changes in mt-nucleoids caused by very high levels of TFAM unraveling nine interactors that could counteract the high TFAM levels to maintain active mtDNA transcription. Altogether, we demonstrate that the Tfam-FLAGBAC mice are a valuable tool for investigating the mt-nucleoid composition in vivo.
    Keywords:  Mitochondrial nucleoid; Mitochondrial translation; TFAM; Transgenic mice; mtDNA expression
    DOI:  https://doi.org/10.1016/j.bbamcr.2025.119955
  61. J Agric Food Chem. 2025 Apr 15.
    Chlorogenic Acid Improves High-Fat Diet-Induced Skeletal Muscle Metabolic Disorders by Regulating Mitochondrial Function and Lactate Metabolism.
    Yu Wang, Juan Sun, Lamei Xue, Yujie Sun, Kuiliang Zhang, Mingcong Fan, Haifeng Qian, Yan Li, Li Wang.
      Mitochondria are pivotal in sustaining skeletal muscle and the systemic metabolic balance. Chlorogenic acid (CA) is a common dietary antioxidant known for its ability to modulate metabolic homeostasis. This study aimed to investigate the impact of CA on high-fat diet (HFD)-induced mitochondrial dysfunction and metabolic disorder in skeletal muscle. C57BL/6J mice fed with a HFD were treated with CA for 12 weeks. The study assessed the overall glycolipid metabolic status, exercise performance, muscle fiber type, and antioxidant capacity of skeletal muscle in HFD-fed mice treated with CA. Results showed that CA reduced fat accumulation, improved exercise capacity, and enhanced mitochondrial performance in HFD-fed mice. Untargeted metabolomics analysis revealed that lactate metabolism and mitochondrial fatty acid oxidation (FAO) responded positively to CA intervention. Molecular mechanisms demonstrated that CA intervention improved mitochondrial biogenesis and function, promoting FAO and oxidative phosphorylation in mitochondria and ultimately reducing fat deposition in skeletal muscle induced by HFD feeding. Mechanistically, CA decreased HFD-induced lactate production and protein lactylation in skeletal muscle, highlighting the importance of the LDHA-lactate axis in mitochondrial function improvement by CA. Therefore, this study provides additional insights supporting the potential of CA as a natural dietary supplement for metabolic syndrome and associated disorders.
    Keywords:  LDHA; chlorogenic acid; lactate; mitochondrial function; skeletal muscle
    DOI:  https://doi.org/10.1021/acs.jafc.5c03967
  62. Cell Chem Biol. 2025 Apr 17. pii: S2451-9456(25)00097-2. [Epub ahead of print]32(4): 620-630.e6
    Genetically encoded tool for manipulation of ΔΨm identifies its role as the driver of ISR induced by ATP synthase dysfunction.
    Mangyu Choe, Alex E Ekvik, Gretchen Stalnaker, Hijai R Shin, Denis V Titov.
      Mitochondrial membrane potential (ΔΨm) is one of the key parameters controlling cellular bioenergetics. Investigation of the role of ΔΨm in live cells is complicated by a lack of tools for its direct manipulation without off-target effects. Here, we adopted the uncoupling protein UCP1 from brown adipocytes as a genetically encoded tool for direct manipulation of ΔΨm. We validated the ability of exogenously expressed UCP1 to induce uncoupled respiration and lower ΔΨm in mammalian cells. UCP1 expression lowered ΔΨm to the same extent as chemical uncouplers but did not inhibit cell proliferation, suggesting that it manipulates ΔΨm without the off-target effects of chemical uncouplers. Using UCP1, we revealed that elevated ΔΨm is the driver of the integrated stress response induced by ATP synthase inhibition in mammalian cells.
    Keywords:  ATP synthase inhibition; GEMMs; ISR; UCP1; genetically encoded tools for manipulation of metabolism; integrated stress response,; mitochondrial membrane potential; ΔΨm
    DOI:  https://doi.org/10.1016/j.chembiol.2025.03.007
  63. Plant Physiol Biochem. 2025 Apr 11. pii: S0981-9428(25)00444-9. [Epub ahead of print]224 109916
    HSCA2 G87D point mutation enhances Arabidopsis proline tolerance via boosting mitochondrial Fe-S cluster assembly.
    Yifan Zhang, Yunhui Liu, Chunni Zhang, Tao Xie, Jibenben Xia, Rong Ma, Jieyao Wang, Huiyu You, Liping Ke, Xuejun Hua.
      As a mitochondrial HSP70 chaperone, HSCA2 orchestrates iron-sulfur (Fe-S) cluster assembly through dynamic interactions with scaffold protein ISU1, facilitating Fe-S cluster transfer to recipient proteins critical for electron transport chain (ETC) function. However, its regulatory roles in plant development and stress adaptation remain elusive. This study investigated the potential stress resistance function and molecular mechanisms of a novel G87D mutation in Arabidopsis HSCA2 (HSCA2m). We found that HSCA2m mutant exhibited increased resistance to high proline levels without altering proline uptake capacity. Under proline treatment, HSCA2m seedlings displayed lower malondialdehyde (MDA) and reactive oxygen species (ROS) levels, and higher superoxide dismutase (SOD) activity, indicating reduced stress damage. Molecular characterization revealed the induction of mitochondrial stress-related marker genes AOX1a and AT12CYS-2 in HSCA2m was suppressed. Strikingly, the G87D substitution enhanced intrinsic ATPase activity without disrupting ISU1 binding, while promoting HSCA2 transcript up-regulation under proline stress. Additionally, HSCA2m demonstrated increased tolerance to higher Fe2+ concentrations. These findings suggested that this mutation might enhance the supply of Fe-S clusters to Fe-S proteins, thereby mitigating proline-induced mitochondrial stress. Transgenic Arabidopsis overexpressing HSCA2m, but not HSCA2, showed enhanced proline resistance, highlighting the potential of HSCA2m as an elite allele for improving plant stress tolerance.
    Keywords:  ATPase activity; Fe-S cluster; HSCA2; Mitochondria; Proline
    DOI:  https://doi.org/10.1016/j.plaphy.2025.109916
  64. Sci Rep. 2025 Apr 14. 15(1): 12759
    Ameliorating effect of the aldose reductase inhibitor 1-Acetyl-5-phenyl-1 H-pyrrol-3-ylacetate on galactose-induced cataract.
    Xi Wang, Zhuoya Li, Ying Xing, Yaru Wang, Shiyao Wang, Liping Wang, Hui Zhang.
      Diabetes mellitus, as a common chronic disease, easily leads to significant changes in the structure of the eye, among which diabetic cataract is particularly common. Although surgery is the main treatment for this complication, it may be accompanied by postoperative complications. Therefore, it is particularly important to develop specific drugs for diabetic cataract, aiming to fundamentally reduce its incidence and reduce the need for surgery. At present, the greatest challenge is to develop therapeutic agents with multiple synergistic effects based on the complex pathogenesis of cataract. 1-Acetyl-5-phenyl-1 H-pyrrol-3-ylacetate (APPA) is designed based on the pathological mechanism as a potential drug to alleviate the occurrence of diabetic cataract. Our observations suggest that APPA is more effective than bendazaclysine in alleviating high galactose-induced oxidative stress (The malondialdehyde content in the APPA group and bendazaclysine group was significantly reduced to 0.45-fold and 0.58-fold compared to the high galactose-induced group, respectively.) and apoptosis (The apoptosis rate in the APPA group and bendazaclysine group was significantly reduced to 0.28-fold and 0.35-fold compared to the high galactose-induced group, respectively.) in lens epithelial cells by increasing antioxidant enzyme activity, and restoring mitochondrial homeostasis. Mechanistic studies have shown that APPA restoration of mitochondrial homeostasis is mediated through the SIRT1-PGC-1α pathway. In the galactose-induced cataract rat model, APPA is effective in alleviating the occurrence of galactose-induced cataract. In conclusion, APPA with multiple synergistic functions may be a potential drug to alleviate the occurrence of diabetic cataract, and it has a wider range of indications than benzydalysine.
    Keywords:  Aldose reductase inhibitor; Apoptosis; Diabetic cataract; Mitochondrial homeostasis; Oxidative stress
    DOI:  https://doi.org/10.1038/s41598-025-98079-9
  65. Mol Med Rep. 2025 Jul;pii: 172. [Epub ahead of print]32(1):
    The role of Bcl‑2 in controlling the transition between autophagy and apoptosis (Review).
    Ahmet Alperen Palabiyik.
      The Bcl‑2 protein family serves a key role in maintaining cellular homeostasis by regulating the balance between autophagy and apoptosis. The present review aimed to summarize interactions of Bcl‑2 with key proteins, including Beclin 1, Bax and Bcl‑2 homologous antagonist/killer, as well as its influence on cellular processes such as mitophagy, nutrient sensing and endoplasmic reticulum stress response. The impact of post‑translational modifications of Bcl‑2, including phosphorylation, ubiquitination and sumoylation, is discussed with respect to their regulatory roles under stress. In pathological states, Bcl‑2 upregulation in cancer suppresses apoptosis and autophagy, thereby facilitating tumor survival and resistance to chemotherapy. Conversely, in neurodegenerative diseases, impaired autophagy and increased apoptosis contribute to neuronal loss. Therapeutic strategies targeting Bcl‑2 (for example inhibitors such as venetoclax, navitoclax, obatoclax and combination therapies involving autophagy modulators) were evaluated for their potential efficacy. There is lack of understanding of tissue‑specific functions of Bcl‑2 and its interactions with non‑coding RNAs. Future research should prioritize these areas and leverage advanced single‑cell technologies to elucidate the real‑time dynamics of Bcl‑2 in cell processes. The present review highlights the key role of Bcl‑2 in cell fate determination and highlights its potential as a therapeutic target, offering insight for the development of innovative treatments for cancer, neurodegenerative disorder and age‑related diseases.
    Keywords:  Bcl‑2; Beclin 1; apoptosis; autophagy; mitophagy
    DOI:  https://doi.org/10.3892/mmr.2025.13537
  66. Nutrients. 2025 Mar 30. pii: 1214. [Epub ahead of print]17(7):
    Mitochondria at the Crossroads: Linking the Mediterranean Diet to Metabolic Health and Non-Pharmacological Approaches to NAFLD.
    Giovanna Mercurio, Antonia Giacco, Nicla Scopigno, Michela Vigliotti, Fernando Goglia, Federica Cioffi, Elena Silvestri.
      Nonalcoholic fatty liver disease (NAFLD) is a growing global health concern that is closely linked to metabolic syndrome, yet no approved pharmacological treatment exists. The Mediterranean diet (MD) emerged as a first-line dietary intervention for NAFLD, offering metabolic and hepatoprotective benefits. Now conceptualized as a complex chemical matrix rich in bioactive compounds, the MD exerts antioxidant and anti-inflammatory effects, improving insulin sensitivity and lipid metabolism. Mitochondria play a central role in NAFLD pathophysiology, influencing energy metabolism, oxidative stress, and lipid homeostasis. Emerging evidence suggests that the MD's bioactive compounds enhance mitochondrial function by modulating oxidative phosphorylation, biogenesis, and mitophagy. However, most research has focused on individual compounds rather than the MD as a whole, leaving gaps in understanding its collective impact as a complex dietary pattern. This narrative review explores how the MD and its bioactive compounds influence mitochondrial health in NAFLD, highlighting key pathways such as mitochondrial substrate control, dynamics, and energy efficiency. A literature search was conducted to identify relevant studies on the MD, mitochondria, and NAFLD. While the search was promising, our understanding remains incomplete, particularly when current knowledge is limited by the lack of mechanistic and comprehensive studies on the MD's holistic impact. Future research integrating cutting-edge experimental approaches is needed to elucidate the intricate diet-mitochondria interactions. A deeper understanding of how the MD influences mitochondrial health in NAFLD is essential for developing precision-targeted nutritional strategies that can effectively prevent and manage the disease.
    Keywords:  MASLD; MUFA; PUFA; fatty liver; fructose; lifestyle; metabolic syndrome; mitochondrial bioenergetics; mitochondrial quality control; polyphenols
    DOI:  https://doi.org/10.3390/nu17071214
  67. J Cachexia Sarcopenia Muscle. 2025 Apr;16(2): e13794
    Loss of popdc3 Impairs Mitochondrial Function and Causes Skeletal Muscle Atrophy and Reduced Swimming Ability in Zebrafish.
    Chen-Chen Sun, Zhang-Lin Chen, Dong Yang, Jiang-Ling Xiao, Xiang-Tao Chen, Xi-Yang Peng, Xiu-Shan Wu, Chang-Fa Tang.
       BACKGROUND: The Popeye domain containing 3 (POPDC3) protein is essential for the maintenance of skeletal muscle homeostasis. POPDC3 is a pathogenic variant gene of limb-girdle muscular dystrophy (LGMD), and its variants lead to LGMDR26. At the animal level, zebrafish larvae with popdc3 mutations develop tail curls and muscle atrophy. However, the mechanism of skeletal muscle atrophy induced by POPDC3 variants/loss remains unclear.
    METHODS: Eight-month-old male WT and popdc3 mKO zebrafish were used for this research. Loli Track (Denwmark) and Loligo Swimming Respirometer were used to observe the zebrafish's swimming ability. The zebrafish skeletal muscle structure and cross-sectional area (CSA) were observed and counted by transmission electron microscopy (TEM), H&E and wheat germ agglutinin (WGA). Enriched genes and signalling pathways were analysed using RNA sequencing, and the effects of popdc3 mKO on zebrafish skeletal muscle mitochondrial respiration, biogenesis and dynamics were examined to investigate possible mechanisms.
    RESULTS: The swimming ability of popdc3 mKO zebrafish was reduced, and as evidenced by the reluctance to move, fewer movement trajectories, the total distance travelled (p < 0.001), the average velocity of movement (p < 0.001), oxygen consumption (MO2) (p < 0.01), maximum oxygen consumption (MO2max) (p < 0.05), critical swimming speed (Ucrit) (p < 0.01) and relative swimming speed (Ucrit-r) (p < 0.01) were significantly decreased and increased of the exhaustive swimming time (p < 0.01). In addition, loss of popdc3 reduced zebrafish skeletal muscle weight (p < 0.001), muscle/body weight (p < 0.01), myofibre size and CSA (p < 0.01), increased protein degradation (ubiquitination and autophagy) (p < 0.05) and decreased protein synthesis (p < 0.05), suggesting that popdc3 deficiency induces zebrafish skeletal muscle atrophy. Further, popdc3 mKO zebrafish mitochondrial function is reduced, as evidenced by impaired mitochondrial respiration, decreased biogenesis and kinetic imbalance (p < 0.05).
    CONCLUSIONS: POPDC3, a Popeye protein, plays an important role in controlling mitochondrial function and skeletal muscle mass and strength. Loss of popdc3 decreases mitochondrial respiration and mitochondrial biogenesis, disrupting kinetic homeostasis, which induces mitochondrial dysfunction and impaired protein turnover (reduced synthesis and increased degradation), leading to zebrafish skeletal muscle atrophy.
    Keywords:  POPDC3; mitochondrial dysfunction; protein homeostasis; skeletal muscle atrophy; skeletal muscle mass
    DOI:  https://doi.org/10.1002/jcsm.13794
  68. J Control Release. 2025 Apr 13. pii: S0168-3659(25)00345-1. [Epub ahead of print] 113725
    Promoting mitocytosis via gene-engineered aligned fibers for fascia regeneration.
    Yiru Xu, Qimanguli Saiding, Xue Zhou, Rui Wang, Juan Wang, Wenguo Cui, Xinliang Chen.
      The abnormal accumulation of damaged mitochondria severely impedes tissue repair, and conventional therapeutic approaches, such as drug treatments, are often ineffective to remove damaged mitochondria. In this study, we developed gene-engineered aligned electrospun fibers by integrating microfluidic chip technology with a micro-sol oriented electrospinning technique. This study is the first to demonstrate the repair of damaged fascia by promoting mitocytosis through upregulating tetraspanin-9 (TSPAN9). The key gene for mitochondrial exocytosis, TSPAN9, was initially encapsulated into liposomes using microfluidic chip technology. Subsequently, core-shell structured aligned electrospun fibers were fabricated via oriented micro-sol electrospinning, where TSPAN9-loaded liposomes were protected by hyaluronic acid (HA) in the core layer, while aligned polylactic acid (PLA) fibers formed the outer shell layer. In vitro studies revealed that the aligned fibers closely mimicked the oriented structure of fascia tissue and significantly enhanced cell migration by providing directional physical cues. By sustained release of gene-loaded liposomes into cells, mitochondrial homeostasis was effectively restored, mitochondrial respiration was recovered, reactive oxygen species levels were reduced, and mitochondrial membrane potential was maintained. In vivo studies confirmed that these gene-engineered fibers effectively suppressed inflammatory responses and promoted fascia regeneration by facilitating the removal of damaged mitochondria through mitocytosis. In conclusion, gene-engineered fibers developed in this study, which enhance mitocytosis, offer a novel and promising therapeutic strategy for fascia tissue repair.
    Keywords:  Electrospun fibers; Fascia regeneration; Inflammation; Mitochondrial quality control; Mitocytosis; Tissue repair
    DOI:  https://doi.org/10.1016/j.jconrel.2025.113725
  69. Stem Cell Res Ther. 2025 Apr 18. 16(1): 186
    The role of PKM2-mediated metabolic reprogramming in the osteogenic differentiation of BMSCs under diabetic periodontitis conditions.
    Yanlin Zhu, Yuhan Yang, Yuyan Lan, Zun Yang, Xiang Gao, Jie Zhou.
       BACKGROUND: Diabetes mellitus (DM) and periodontitis have a bidirectional relationship, with each being a high-risk factor for the other. Prolonged hyperglycemia exacerbates periodontal inflammation and disrupts bone homeostasis. Pyruvate kinase M2 (PKM2), a key enzyme in glycolysis, is involved in metabolic reprogramming, but its role in osteogenesis under high-glucose (HG) inflammatory conditions remains largely unknown. This study aimed to investigate the effects of HG and inflammation on bone marrow mesenchymal stem cells (BMSCs) under indirect co-culture conditions and to explore how PKM2 regulates metabolism and mitochondrial function during osteogenic differentiation in HG inflammatory environments, elucidating its role in diabetic periodontitis (DP).
    METHODS: Expose BMSCs to conditioned medium (CM) collected from RAW264.7 cells stimulated with HG and/or lipopolysaccharide (LPS). BMSCs functionality was assessed using CCK8, EdU, Annexin V-PI apoptosis assay, alkaline phosphatase (ALP), and Alizarin Red S (ARS) staining. Metabolic characteristics were evaluated through Seahorse assays, lactate production, glucose uptake, and ATP measurements. Mitochondrial function was assessed via JC-1, and ROS staining, Mito-Tracker staining, and transmission electron microscopy (TEM). Gene and protein expression were analyzed by quantitative real-time PCR and western blotting. In vivo therapeutic effects of shikonin were validated via micro-CT and histological staining in a diabetic periodontitis mouse model.
    RESULTS: In vitro experiments demonstrated that HG inflammatory conditions impaired the survival of BMSCs, suppressed osteogenic differentiation, and induced metabolic reprogramming. This reprogramming was characterized by enhanced glycolysis, impaired oxidative phosphorylation (OXPHOS), abnormal upregulation of PKM2 expression, and mitochondrial dysfunction accompanied by morphological alterations. Shikonin effectively reversed these adverse effects by inhibiting PKM2 tetramerization, rescuing the loss of osteogenic function in BMSCs. The therapeutic potential of shikonin was confirmed in the diabetic periodontitis mouse model.
    CONCLUSION: PKM2 impairs the osteogenesis of BMSCs by affecting metabolism and mitochondrial function, suggesting it as a potential therapeutic target for diabetic periodontitis.
    Keywords:  Diabetes periodontitis; Metabolic reprogramming; Mitochondrial dynamics; Osteogenic differentiation; PKM2
    DOI:  https://doi.org/10.1186/s13287-025-04301-w
  70. Orphanet J Rare Dis. 2025 Apr 15. 20(1): 181
    Transcriptome analysis of atad3-null zebrafish embryos elucidates possible disease mechanisms.
    Shlomit Ezer, Nathan Ronin, Shira Yanovsky-Dagan, Shahar Rotem-Bamberger, Orli Halstuk, Yair Wexler, Zohar Ben-Moshe, Inbar Plaschkes, Hadar Benyamini, Ann Saada, Adi Inbal, Tamar Harel.
       BACKGROUND: ATAD3A, a nuclear gene encoding the ATAD3A protein, has diverse roles in mitochondrial processes, encompassing mitochondrial dynamics, mitochondrial DNA maintenance, metabolic pathways and inter-organellar interactions. Pathogenic variants in this gene cause neurological diseases in humans with recognizable genotype-phenotype correlations. Yet, gaps in knowledge remain regarding the underlying pathogenesis.
    METHODS: To further investigate the gene function and its implication in health and disease, we utilized CRISPR/Cas9 genome editing to generate a knockout model of the zebrafish ortholog gene, atad3. We characterized the phenotype of the null model, performed mitochondrial and functional tests, and compared the transcriptome of null embryos to their healthy siblings.
    RESULTS: Analysis of atad3-null zebrafish embryos revealed microcephaly, small eyes, pericardial edema and musculature thinning, closely mirroring the human rare disease phenotype. Larvae exhibited delayed hatching and embryonic lethality by 13 days post-fertilization (dpf). Locomotor activity, ATP content, mitochondrial content, and mitochondrial activity were all reduced in the mutant embryos. Transcriptome analysis at 3 dpf via RNA-sequencing indicated decline in most mitochondrial pathways, accompanied by a global upregulation of cytosolic tRNA synthetases, presumably secondary to mitochondrial stress and possibly endoplasmic reticulum (ER)-stress. Differential expression of select genes was corroborated in fibroblasts from an affected individual.
    CONCLUSIONS: The atad3-null zebrafish model emerges as a reliable representation of human ATAD3A-associated disorders, with similarities in differentially expressed pathways and processes. Furthermore, our study underscores mitochondrial dysfunction as the primary underlying pathogenic mechanism in ATAD3A-associated disorders and identifies potential readouts for therapeutic studies.
    Keywords:   ATAD3A ; CRISPR/Cas9; Mitochondria; RNA-seq; Transcriptome; Zebrafish knockout model
    DOI:  https://doi.org/10.1186/s13023-025-03709-0
  71. Nat Commun. 2025 Apr 17. 16(1): 3641
    Coupling of ribosome biogenesis and translation initiation in human mitochondria.
    Marleen Heinrichs, Anna Franziska Finke, Shintaro Aibara, Angelique Krempler, Angela Boshnakovska, Peter Rehling, Hauke S Hillen, Ricarda Richter-Dennerlein.
      Biogenesis of mitoribosomes requires dedicated chaperones, RNA-modifying enzymes, and GTPases, and defects in mitoribosome assembly lead to severe mitochondriopathies in humans. Here, we characterize late-step assembly states of the small mitoribosomal subunit (mtSSU) by combining genetic perturbation and mutagenesis analysis with biochemical and structural approaches. Isolation of native mtSSU biogenesis intermediates via a FLAG-tagged variant of the GTPase MTG3 reveals three distinct assembly states, which show how factors cooperate to mature the 12S rRNA. In addition, we observe four distinct primed initiation mtSSU states with an incompletely matured rRNA, suggesting that biogenesis and translation initiation are not mutually exclusive processes but can occur simultaneously. Together, these results provide insights into mtSSU biogenesis and suggest a functional coupling between ribosome biogenesis and translation initiation in human mitochondria.
    DOI:  https://doi.org/10.1038/s41467-025-58827-x
  72. Cell Calcium. 2025 Apr 08. pii: S0143-4160(25)00026-0. [Epub ahead of print]127 103017
    Calcium acts as a critical determinant of mitochondria-nuclear networking driven retrograde signaling.
    Kriti Ahuja, Rajender K Motiani.
      Mitochondria are robust signaling organelle that regulate a variety of cellular functions. One of the key mechanisms that drive mitochondrial signaling is inter-organelle crosstalk. Mitochondria communicates with other organelles primarily via exchange of calcium (Ca2+), reactive oxygen species (ROS) and lipids across organelle membranes. Mitochondria has its own genome but a majority of mitochondrial proteins are encoded by nuclear genome. Therefore, several mitochondrial functions are controlled by nucleus via anterograde signaling. However, the role of mitochondria in driving expression of genes encoded by nuclear genome has recently gained attention. Recent studies from independent groups have demonstrated a critical role for mitochondrial Ca2+signaling in stimulating nuclear gene expression. These studies report that inhibition of mitochondrial Ca2+uptake through silencing of Mitochondrial Ca2+Uniporter (MCU) leads to Ca2+oscillations in the cytosol. The rise in cytosolic Ca2+ results in activation of Ca2+ sensitive transcription factors such as NFATs and NF-κB. These transcription factors consequently induce expression of their target genes in the nuclear genome. It is important to highlight that these groups used different cell types and elegantly presented a phenomenon that is conserved across various systems. Notably, mitochondrial Ca2+ signaling mediated transcriptional regulation controls diverse cellular functions ranging from B-cell activation, melanogenesis and aging associated inflammation. Future studies on this signaling module would result in better understanding of this axis in human pathophysiology and could lead to development of novel therapeutic strategies.
    Keywords:  Calcium sensitive transcription factors; Mitochondrial calcium signaling; Nuclear transcription; Retrograde signaling
    DOI:  https://doi.org/10.1016/j.ceca.2025.103017
  73. J Pineal Res. 2025 Apr;77(3): e70049
    Melatonin and Exercise Restore Myogenesis and Mitochondrial Dynamics Deficits Associated With Sarcopenia in iMS-Bmal1-/- Mice.
    Yolanda Ramírez-Casas, José Fernández-Martínez, María Martín-Estebané, Paula Aranda-Martínez, Alba López-Rodríguez, Sergio Esquivel-Ruiz, Yang Yang, Germaine Escames, Darío Acuña-Castroviejo.
      Sarcopenia, a condition associated with aging, involves progressive loss of muscle mass, strength, and function, leading to impaired mobility, health, and increased mortality. The underlying mechanisms remain unclear, which limits the development of effective therapeutic interventions. Emerging evidence implicates chronodisruption as a key contributor to sarcopenia, emphasizing the role of Bmal1, a circadian clock gene critical for muscle integrity and mitochondrial function. In a skeletal muscle-specific and inducible Bmal1 knockout model (iMS-Bmal1-/-), we observed hallmark features of sarcopenia, including disrupted rhythms, impaired muscle function, and mitochondrial dysfunction. Exercise and melatonin treatment reversed these deficits independently of Bmal1. Building on these findings, the present study elucidates several mechanisms underlying these changes and the pathways by which melatonin and exercise exert their beneficial effects. Our findings indicate that iMS-Bmal1-/- mice exhibit reduced expression of satellite cell and muscle regulatory factors, indicating impaired muscle regeneration. While mitochondrial respiration remained unchanged, notable alterations in mitochondrial dynamics disrupted mitochondria in skeletal muscle. In addition, these mice showed alterations in muscle energy metabolism, compromised antioxidant defense, and inflammatory response. Remarkably, exercise and/or melatonin successfully mitigated these deficits, restoring muscle health in Bmal1-deficient mice. These findings position exercise and melatonin as promising therapeutic candidates for combating sarcopenia and emphasize the need to elucidate the molecular pathways underlying their protective effects.
    Keywords:  Bmal1; exercise; melatonin; mitochondrial dysfunction; myogenesis; sarcopenia; skeletal muscle
    DOI:  https://doi.org/10.1111/jpi.70049
  74. Int J Med Sci. 2025 ;22(8): 1852-1864
    Mitochondrial Quality Control Systems in Septic AKI: Molecular Mechanisms and Therapeutic Implications.
    Ying Tan, Yue Ouyang, Zisheng Ma, Jianming Huang, Chuhong Tan, Junxiong Qiu, Feng Wu.
      Objectives: Despite significant advancements in medical treatments, the creation of a successful treatment strategy for acute kidney injury (AKI) remains a pressing concern. Given the well-documented clinical benefits of canagliflozin in renal protection, our research focused on exploring the possible therapeutic benefits of canagliflozin in treating AKI, with a focus on its underlying mechanisms of action. Methods: To induce AKI, we utilized lipopolysaccharide (LPS) in the presence of canagliflozin, allowing us to assess the drug's effects on kidney function and structure. Results: Our results indicate that canagliflozin lowered blood urea nitrogen and serum creatinine concentrations while enhancing tubular architecture in rodents with LPS-triggered septic AKI. It additionally diminished inflammation, oxidative damage, and tubular cell apoptosis. In vitro, canagliflozin maintained mitochondrial functionality in LPS-exposed HK-2 cells by stabilizing membrane potential, reducing ROS generation, and normalizing respiratory chain activity. Its benefits were facilitated through the AMPKα1/PGC1α/NRF1 axis, promoting mitochondrial regeneration. Importantly, blocking this pathway or employing AMPKα1-deficient animals negated canagliflozin's protective effects, highlighting the essential role of AMPKα1 in its kidney-protective mechanisms. Conclusion: Our investigation implies that canagliflozin might represent a viable treatment strategy for septic AKI, operating through the stimulation of the AMPKα1/PGC1α/NRF1 axis to preserve kidney performance and structural integrity. These findings warrant further investigation into the clinical potential of canagliflozin in this context.
    Keywords:  AMP.; LPS-mediated kidney damage; SGLT2i; mitochondria
    DOI:  https://doi.org/10.7150/ijms.107012
  75. J Dairy Sci. 2025 Apr 11. pii: S0022-0302(25)00233-4. [Epub ahead of print]
    Effects of Maternal Blood β-Hydroxybutyrate on Brown Adipose Tissue Functions and Thermogenic and Metabolic Health in Neonatal Calves.
    Yang Gai, Guiling Ma, Shuyan Yang, Zhiyong Hu, Yulin Ma, Rui He, Yu Zhang, Shilong Huang, Hossam H Azzaz, Zhaobing Gu, Shengyong Mao, Morteza H Ghaffari, Yanting Chen.
      Maternal metabolic health, particularly during late pregnancy, plays a crucial role in fetal development and postnatal metabolic function. Elevated levels of β-hydroxybutyrate (BHB) in dry cows, commonly observed in late gestation, may affect offspring development, but the effects on brown adipose tissue (BAT) and metabolic health remain unclear. In this study, 60 pregnant Holstein dairy cows were categorized into 2 groups based on serum BHB concentrations measured at 1, 3, 5 and 7 wk after dry-off: Maternal-Low-BHB (n = 30; mean ± SEM, 0.21 ± 0.005 mM) and Maternal-High-BHB (n = 30; mean ± SEM, 0.64 ± 0.02 mM). Blood metabolites, including BHB, nonesterified fatty acids (NEFA) and glucose, were monitored throughout the dry period. Calves born from these cows were evaluated for body growth, body temperature, glucose sensitivity, fecal and cough score during the first month of life, with perirenal BAT and skin samples collected for analysis of thermogenic gene expression. Expression of stress genes, including Cold-Inducible RNA-Binding Protein (CIRBP), Heat Shock Protein 70 (HSP70) and Heat Shock Factor Binding Protein 1 (HSBP1), was analyzed in skin tissue. Expression of thermogenic genes, including Uncoupling Protein 1 (UCP-1), Cyclic AMP Response Element-Binding Protein 4 (CREBP4) and Carnitine Palmitoyltransferase 1B (CPT1B), and protein contents of UCP-1, Activated Receptor Gamma Coactivator 1 Alpha (PGC-1a) were analyzed in BAT. In vitro, stromal vascular fractions (SVFs) were also isolated in calf's BAT, and further induced for brown adipocyte formation with dosed BHB supplementation. Results showed no differences in birth weight, body size and body temperatures of calves born to Maternal High BHB cows compared with calves born to Maternal Low BHB cows. However, the calves from the Maternal High BHB group had higher expressions of stress genes in the skin, and decreased BAT mass and expression of thermogenic genes. Compared with the Maternal Low BHB group, one-month-old calves in the Maternal High BHB group also showed significantly lower BAT mass, decreased expression of thermogenic genes such as UCP-1, CREBP4 and CPT1B, and decreased mitochondrial density, indicating impaired BAT development. In addition, the calves from the Maternal High BHB group showed reduced glucose sensitivity, as evidenced by their inability to maintain stable blood glucose levels during a glucose tolerance test. Protein concentrations of UCP-1 and PGC-1a were significantly lower in the BAT of calves born to Maternal High BHB cows. In vitro, BHB supplementation inhibited brown adipocyte differentiation and thermogenesis, supporting the elevated maternal BHB impairs brown adipogenesis and mitochondrial biogenesis. Overall, this study demonstrates that calves born from elevated maternal BHB levels (∼0.64 mM) within the normal physiological range in dry period significantly had impaired perinatal BAT development, thermogenesis, and glucose metabolism, highlighting the roles of maternal metabolic health in programming metabolic and thermoregulatory capacity in offspring.
    Keywords:  calf; maternal ketone bodies; mitochondrial biogenesis; thermogenesis
    DOI:  https://doi.org/10.3168/jds.2024-26123
  76. Mater Today Bio. 2025 Jun;32 101697
    Novel pH-responsive lipid nanoparticles deliver UA-mediated mitophagy and ferroptosis for osteoarthritis treatment.
    Guoliang Yi, Min Li, Jiayi Zhou, Jinxin Li, Xizheng Song, Siming Li, Jianghua Liu, Haowei Zhang, Zhiwei Chen.
      Synovial inflammation plays a crucial role in osteoarthritis (OA) development, leading to chronic inflammation and cartilage destruction. Although targeting synovitis can alleviate OA, clinical outcomes have been disappointing due to poor drug targeting and joint cavity heterogeneity. This study presents pH-responsive lipid nanoparticles (LNPs@UA), loaded with Urolithin A (UA), as a potential OA treatment. LNPs@UA showed uniform particle size, low zeta potential, and effective mitochondria-targeting and pH-responsive capabilities. In vitro, LNPs@UA reduced reactive oxygen species (ROS), pro-inflammatory factors (IL-1β, IL-6, TNF-α), and promoted M2 macrophage polarization. It improved mitochondrial structure, enhanced autophagy, and inhibited ferroptosis. In vivo, LNPs@UA alleviated OA progression in an ACLT-induced OA mouse model. Transcriptomic analysis revealed inhibition of NF-κB signaling and activation of repair pathways. These results suggest LNPs@UA could offer a promising therapeutic approach for OA.
    Keywords:  Lipid nanoparticles; Osteoarthritis; Urolithin A
    DOI:  https://doi.org/10.1016/j.mtbio.2025.101697
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