bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2025–10–26
fifty papers selected by
Gavin McStay, Liverpool John Moores University
  1. CDCA4/SERTAD1/E2F1 Facilitates Lung Adenocarcinoma Progression by Inhibiting PINK1/Parkin-Mediated Mitophagy.
  2. Coenzyme Q10 mitigates high-fat-induced mitochondrial damage in spotted seabass (Lateolabrax maculatus) hepatocytes by promoting mitophagy.
  3. Metformin alleviates renal tubular injury in diabetic kidney disease by activating mitophagy and inhibiting ferroptosis via HIF-1α/MIOX axis.
  4. Wnt/β-catenin/ATF3 signaling promotes the progression from acute kidney injury to chronic kidney disease by regulating mitophagy in mice.
  5. FUNDC1 deficiency aggravates endothelial senescence and retinal dysfunction.
  6. Ba2+-Induced Vasoconstriction as a Model to Investigate the Dynamin Dependence of Biological Processes Regulating Vascular Tone.
  7. Rapamycin alleviates hypothalamic injury in exertional heat stroke rats by activating mitophagy through the mTOR/Pink1/Parkin pathway.
  8. Peroxisome proliferator-activated receptor gamma (PPARγ) promotes the morula-to-blastocyst transition in Tibetan sheep embryos by enhancing mitophagy through suppression of the AKT/mTOR pathway.
  9. Exploring mitophagy levels in Drosophila Malpighian tubules unveils the pivotal role of mitophagy in kidney function and diabetic kidney disease.
  10. Ligustilide alleviates the mitophagy and anxiety-like behavior produced by nighttime lighting.
  11. In situ characterization of mitochondrial Hsp60-Hsp10 chaperone complex under folding stress.
  12. Mitochondrial homeostasis collapse to cardiac remodeling: From mechanisms to novel targeted therapeutic avenues.
  13. MRPL44 regulates lipid metabolism in metabolic dysfunction-associated steatotic liver disease through BNIP3-mediated mitophagy.
  14. Neuroprotective effects of sinomenine and metformin in diabetic stroke: Role of NLRP3/caspase-1 and mitophagy.
  15. Inhibition of glutamine synthetase enhances hepatocellular carcinoma radiosensitivity through ROS-induced excessive mitophagy.
  16. Mitophagy in the adaptation to pancreatic β cell stress in diabetes.
  17. ETV4 promotes ovarian cancer growth by regulating mitochondrial function through Mfn2 ubiquitination mediated by the E3 ubiquitin ligase MARCH9.
  18. Hyperhomocysteinemia Induced Mitochondrial Dysfunction Disrupting the Eye Development.
  19. SerpinB1a induces hepatopulmonary syndrome by promoting CTSG/AMPK/mTOR pathway-mediated mitophagy.
  20. Ticagrelor as a Dual RAS Modulator and Mitochondrial Stabilizer: A Multifaceted Neurotherapeutic Strategy in Huntington's Disease.
  21. Nitrite and microcystins co-exposure triggers PINK1-mediated mitophagy in spermatogonia.
  22. Exercise-induced alleviation of memory impairment in aged mice with neuroinflammation is linked with modulation of mitochondrial homeostasis in the hippocampus.
  23. Exercise training and Silymarin consumption can ameliorate mitophagy signaling flux in hepatocytes of rats with dexamethasone-induced non-alcoholic fatty liver disease.
  24. Polygalasaponin F alleviates cerebral ischemia-reperfusion injury through inhibiting mitophagy.
  25. Duhuo Jisheng decoction alleviates intervertebral disc degeneration via the acacetin-mediated MAPK1/HMOX1 axis by inhibiting nucleus pulposus cell pyroptosis.
  26. Macrophage PTP1B regulates mitochondrial dynamics via the JAK2/STAT3-OPA1 axis and activates the cGAS/STING signaling pathway.
  27. 3-TYP protects against heart failure with preserved ejection fraction by inhibiting Sirtuin 3.
  28. Mic60/Mitofilin inhibitor, Miclxin, induces rat H9C2 cardiomyoblast death by inhibiting the removal of damaged mitochondria.
  29. PHB1 attenuates triptolide-induced cardiotoxicity by regulating mitochondrial dynamics in cultured newborn mice cardiomyocytes.
  30. Upregulation of BNIP3 alleviates renal tubular cell injury by activating mitophagy in diabetic nephropathy.
  31. Targeting mitochondrial structure and dynamics for therapeutic intervention in cancer.
  32. Pulmonary metabolic imbalances and mitochondrial ultrastructural remodeling in lipopolysaccharide-induced acute respiratory distress syndrome.
  33. [Effects of heat-reinforcing acupuncture on Drp1/Mff pathway activity and mitochondrial quality in rabbits with cold-dampness rheumatoid arthritis].
  34. Paricalcitol-mediated vitamin D receptor activation attenuates neuronal ferroptosis via cAMP-PKA-DRP1 signaling pathway after intracerebral hemorrhage.
  35. Author Correction: Mitochondria-associated condensates maintain mitochondrial homeostasis and promote lifespan.
  36. Mitochondrial proteomics reveals the impact of Estrogen in enhancing energy metabolism of patient-derived fibroblast-like synoviocytes in rheumatoid arthritis.
  37. Roles of the Keap1/Nrf2 pathway and mitophagy in liver diseases.
  38. The multifaceted role of autophagy and mitophagy in cardiovascular health and disease.
  39. [Electroacupuncture improves NLRP3-mediated inflammation and gastric motility in diabetic gastroparesis rats by activating AMPK and regulating mitochondrial homeostasis].
  40. The IQ-compete assay for measuring mitochondrial protein import efficiencies in living yeast cells.
  41. Inhibition of MARK4 Promotes Mitochondrial Biogenesis by Inducing the Phosphorylation of AMPKα to Reduce Myocardial Damage in Rats With Myocardial Infarction.
  42. Soy isoflavone Daidzein resembling the vertebrate steroid structure exhibits neuroprotection via mitochondrial biogenesis in rotenone induced Parkinson's disease in preclinical model.
  43. Hypoxia promotes mitochondrial biogenesis in myocardium of broiler with pulmonary hypertension syndrome through AMPK/PGC-1 alpha pathway.
  44. The mitochondrial disulphide relay substrate FAM136A safeguards IMS proteostasis and cellular fitness.
  45. Maternal Exposure to Combined Cadmium and Polystyrene Nanoplastics Induces Offspring Testicular Dysplasia via Mitochondrial Reactive Oxygen Species Overactivating the Peroxisome Proliferator-Activated Receptor α-Mediated Autophagy Signaling Pathway.
  46. IL-11 exacerbates cisplatin-induced acute kidney injury by facilitating apoptosis in renal tubular epithelial cells via ERK1/2-Drp1/TFEB-mediated defective autophagy.
  47. Gossypol acetic acid affects locomotor activity by inducing mitophagy-related ferroptosis and apoptosis in zebrafish.
  48. FLVCR1 Deficiency Impairs Mitochondrial Homeostasis in Retinal Degeneration: Choline as a Potential Therapy.
  49. Delayed protein translocation protects mitochondria against toxic CAT-tailed proteins.
  50. SIRT1-Mediated Mitochondrial Homeostasis in Cardiac Aging: Molecular Mechanisms and Therapeutic Implications.
  1. IUBMB Life. 2025 Oct;77(10): e70073
    CDCA4/SERTAD1/E2F1 Facilitates Lung Adenocarcinoma Progression by Inhibiting PINK1/Parkin-Mediated Mitophagy.
    Jianlong Tan, Jufen Wang, Weidong Zhang, Cuihua Zhang.
      Cell division cycle-associated protein 4 (CDCA4) has the potential to indicate lung adenocarcinoma (LUAD) development, but its regulatory role in mitophagy remains unclear. This study aimed to elucidate the mitophagy regulation and therapeutic implications of CDCA4 in LUAD. CDCA4 expression was significantly elevated in LUAD clinical specimens versus paracancerous tissues and inversely correlated with mitophagy activity. Lentiviral vectors were employed to manipulate established LUAD cells, followed by treatment with chloroquine (CQ; lysosomal inhibitor) and rapamycin (autophagy inducer) in CDCA4-silenced cells. CDCA4 knockdown elevated total and mitochondrial superoxide levels, disrupted mitochondrial membrane potential, activated the PINK1/Parkin pathway, enhanced LC3-II conversion, and degraded mitochondrial membrane proteins, collectively promoting mitophagy. Silencing CDCA4 suppressed malignant phenotypes (proliferation/migration), effects reversed by CQ but exacerbated by rapamycin. Mechanistically, CDCA4 interacted with SERTAD1 and E2F1 and stabilized these proteins. The promotion of mitophagy by CDCA4 silencing was impaired by the overexpression of SERTAD1 and E2F1. LUAD cells silencing CDCA4 were injected into immunodeficient mice for in vivo verification. CDCA4-silenced xenografts exhibited suppressed tumor growth, increased apoptosis, and elevated mitophagy-related markers. This study identifies the CDCA4/SERTAD1/E2F1 complex as a pivotal mitophagy-inhibitory hub in LUAD, proposing this axis as a novel predictive and therapeutic target.
    Keywords:  CDCA4; PINK1/Parkin; autophagy; lung adenocarcinoma; mitochondria
    DOI:  https://doi.org/10.1002/iub.70073
  2. Int J Biol Macromol. 2025 Oct 20. pii: S0141-8130(25)08993-7. [Epub ahead of print] 148436
    Coenzyme Q10 mitigates high-fat-induced mitochondrial damage in spotted seabass (Lateolabrax maculatus) hepatocytes by promoting mitophagy.
    Xiao-Jiang Mao, Xue-Shan Li, Ling Wang, Kai Song, Chun-Xiao Zhang, Ke-Quan Chen, Kang-le Lu.
      Coenzyme Q10 (COQ10), a natural fat-soluble compound, is known to protect mitochondria, though the exact mechanism remains unclear. Here, we explored the mechanism through which COQ10 enhances mitochondrial function using hepatocytes from spotted seabass (Lateolabrax maculatus). Three experimental groups were established: a normal medium control group, a fatty acid (FA) group containing 100 μM FA, and a group containing100 μM FA plus 5 μM COQ10 (FA + COQ10). After incubation, the results showed that FA treatment significantly increased triglyceride content in the cells, while COQ10 treatment reduced triglycerides content (P < 0.05). Additionally, COQ10 alleviated FA-induced hepatocyte damage, restored mitochondrial membrane potential and increased ATP content (P < 0.05). Further analysis showed that FA downregulated key mitophagy genes (PINK1, PARKIN, and LC3B) while upregulating P62 (P < 0.05). To investigate whether the enhancement of mitochondrial function by COQ10 is dependent on mitophagy activation, we used the mitophagy inhibitor Mdivi-1 and set it to FA + COQ10 + Mdivi-1 group. After mtphagy Dye staining, the number of autophagosomes in the FA + COQ10 + Mdivi-1 group was lower than in the FA + COQ10 group, indicating that the mitophagy activation by COQ10 was inhibited. Overall, these results demonstrated that COQ10 enhances mitochondrial function and alleviates excessive fat deposition in hepatocytes via PINK1-mediated mitophagy. This also indicates that COQ10 can be potentially applied to improve the metabolic disorders of fish in aquaculture.
    Keywords:  COQ10; Fat deposition; Mitochondria; Reactive oxygen species
    DOI:  https://doi.org/10.1016/j.ijbiomac.2025.148436
  3. J Pharm Anal. 2025 Oct;15(10): 101284
    Metformin alleviates renal tubular injury in diabetic kidney disease by activating mitophagy and inhibiting ferroptosis via HIF-1α/MIOX axis.
    Qinrui Wu, Yanyan Zhao, Fengjuan Huang.
      Renal tubular injury has emerged as a critical factor in the progression of diabetic kidney disease (DKD). Given renal tubules' high mitochondrial density and susceptibility to mitochondrial dysregulation and ferroptosis, targeting these pathways could offer therapeutic potential. Metformin (MET), a first-line therapy for type 2 diabetes mellitus (T2DM), exerts reno-protective effects by improving mitochondrial function and attenuating fibrosis; however, its role in regulating ferroptosis in DKD remains unclear. This study aimed to investigate the role of MET in modulating mitophagy and ferroptosis in diabetic kidneys. In diabetic mouse models, MET notably alleviated tubular injury by promoting mitophagy and reducing ferroptosis, as shown by increasing levels of phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1) and Parkin, while decreased levels of malondialdehyde (MDA) and iron content. Mechanistically, MET downregulated the hypoxia-inducible factor-1alpha (HIF-1α)/myo-inositol oxygenase (MIOX) signaling axis in renal tubular epithelial cells (RTECs), thereby restoring mitophagy and inhibiting ferroptosis. These findings demonstrate that MET mitigates diabetic renal injury by promoting mitophagy and countering ferroptosis via suppressing the HIF-1α/MIOX pathway, highlighting its potential as a therapeutic intervention for halting DKD progression.
    Keywords:  Diabetic kidney disease; Ferroptosis; HIF-1α; MIOX; Metformin; Mitophagy
    DOI:  https://doi.org/10.1016/j.jpha.2025.101284
  4. Biochem Pharmacol. 2025 Oct 19. pii: S0006-2952(25)00709-9. [Epub ahead of print]242(Pt 4): 117444
    Wnt/β-catenin/ATF3 signaling promotes the progression from acute kidney injury to chronic kidney disease by regulating mitophagy in mice.
    Gewenhan Chen, Yanni Zhou, Mengjiao Lin, Anting Li, Shijie Lu, Junting Li, Liangxiang Xiao, Xue Hong.
      Sustained activation of Wnt/β-catenin signaling has been shown to promote the progression from acute kidney injury (AKI) to chronic kidney disease (CKD). However, its underlying mechanisms remain largely unclear. In this study, we addressed this question using a unilateral ischemia/reperfusion injury model in mice and a hypoxia/reoxygenation model in HKC-8 cells. In vitro, Wnt1 overexpression disrupted mitochondrial structure, increased the expression of DRP1 and p62, and decreased the levels of MFN2, LC3B-II, and Parkin, indicating a shift of mitochondrial dynamics toward fission and impaired mitophagy. In vivo, similar changes were observed, and KP6 treatment partially rescued these defects. RNA sequencing revealed that ATF3 may be associated with the activation of canonical Wnt/β-catenin signaling. ATF3 was expressed in various CKD animal models. Exogenous ATF3 impaired mitochondrial dynamics and mitophagy both in vivo and in vitro, while ATF3 silencing preserved mitochondrial function. Finally, patients with kidney disease exhibited markedly elevated ATF3 levels compared with healthy controls. ATF3 expression correlated positively with serum creatinine, blood urea nitrogen, the extent of renal fibrosis, and the percentage of glomerulosclerosis, and correlated negatively with estimated glomerular filtration rate (eGFR). Collectively, these findings indicate that activation of Wnt/β-catenin/ATF3 signaling facilitates the transition from AKI to CKD by modulating mitochondrial dynamics and mitophagy. ATF3 may serve as a promising potential biomarker for AKI to CKD progression.
    Keywords:  ATF3; Acute kidney injury; Chronic kidney disease; Mitophagy; Renal fibrosis; Wnt/β-catenin
    DOI:  https://doi.org/10.1016/j.bcp.2025.117444
  5. Biochim Biophys Acta Mol Basis Dis. 2025 Oct 22. pii: S0925-4439(25)00443-0. [Epub ahead of print] 168093
    FUNDC1 deficiency aggravates endothelial senescence and retinal dysfunction.
    Jingxin Ning, Ze Li, Yuxue Mu, Xia Li, Kaifeng Li, Wenjuan Xing, Haifeng Zhang.
      Natural aging leads to various age-related changes that impair visual function and cause ocular diseases. Endothelial cells, key components of blood vessels, play a crucial role in vascular aging and retinal degeneration. However, the exact mechanisms by which endothelial cell aging promotes retinopathy are not fully understood. Mitochondrial homeostasis is vital for endothelial cell function, with mitophagy being essential for removing damaged mitochondria. FUNDC1, a receptor involved in mitophagy, regulates cellular senescence and inflammation. This study investigates whether retinal function decline is linked to mitochondrial imbalance in retinal vessels endothelial cells due to reduced FUNDC1 expression. In aged mice, FUNDC1 expression and mitophagy were significantly lower in retinal blood vessels. Aging leads to retinal vascular dysfunction characterized by increased vascular permeability assessed by fluorescein fundus angiography. Moreover, electron microscopy images showed mitochondrial swelling in endothelial cells of aging retina, accompanied with tight junction disruption and reduced expression of junctional proteins (VE-cadherin, occludin, and ZO-1). Strikingly, endothelial knockout of FUNDC1 exacerbated the age-related decline in retinal blood vessel function and retinal function. Cell senescence induced by D-galactose exhibited significantly decreased FUNDC1, impaired mitophagy, increased reactive oxygen species (ROS), and markedly increased endothelial permeability assessed by transendothelial electrical resistance assay. Conversely, overexpression of FUNDC1 can reverse the reduction of mitochondrial autophagy, the decrease in intercellular junction protein expression and the increase in endothelial permeability caused by aging. Collectively, these data suggest that FUNDC1 serves as a potential therapeutic target for the prevention and treatment of age-related degeneration of retinal function.
    Keywords:  Endothelial senescence; FUNDC1; Mitophagy; ROS; Retinal vessels
    DOI:  https://doi.org/10.1016/j.bbadis.2025.168093
  6. Pharmacol Res Perspect. 2025 Dec;13(6): e70184
    Ba2+-Induced Vasoconstriction as a Model to Investigate the Dynamin Dependence of Biological Processes Regulating Vascular Tone.
    Mariangela Gentile, Alice Panti, Eugenio Paccagnini, Pietro Lupetti, Sergio Bova, Fabio Fusi.
      Understanding the mechanisms underpinning vascular smooth muscle contraction, which are critical targets for cardiovascular disease treatment, is essential for developing novel therapeutic agents. Recently, the role of mitochondrial fission as a key modulatory event in the vascular contractile process has been questioned. Therefore, the present study, conducted on ex vivo rat aorta rings, aimed to elucidate its role. As mitochondrial dynamics is a Ca2+-dependent process, experiments were performed using preparations incubated in a Ca2+-free medium, depleted of sarcoplasmic reticulum Ca2+ content, and stimulated by Ba2+. Contractile responses evoked by Ba2+, either alone or in the presence of phenylephrine or (S)-(-)-Bay K 8644, occurred without mitochondrial fission. Furthermore, hallmarks of mitochondrial fusion were observed in rings stimulated by Ba2+ alone. The Drp1 inhibitors mdivi-1 and dynasore antagonized Ba2+-induced contraction, whereas the dynasore analogue dyngo-4a and the dynamin stimulator ryngo 1-23 synergized with Ba2+-induced contraction. All tested compounds, except mdivi-1, induced mitochondrial fission, with particularly pronounced effects observed with dynasore. Similar results were obtained in rings stimulated by Ba2+ in the presence of either phenylephrine or (S)-(-)-Bay K 8644. In conclusion, these findings indicate that rat aorta contraction can occur independently of mitochondrial fission. Moreover, Ba2+, used in place of Ca2+ as a vasoconstricting agent, provides a valuable experimental framework for identifying off-target effects of dynamin modulators.
    Keywords:  Ba2+‐induced vascular contraction; dynamin; mdivi‐1; mitochondrial fission
    DOI:  https://doi.org/10.1002/prp2.70184
  7. Sci Rep. 2025 Oct 23. 15(1): 37031
    Rapamycin alleviates hypothalamic injury in exertional heat stroke rats by activating mitophagy through the mTOR/Pink1/Parkin pathway.
    Ruxue Chi, Yan Gu, Ran Meng, Lv Xuan, Zhengzhong Sun, Yuxiang Zhang, Jiaxing Wang.
      Exertional heat stroke (EHS) causes severe central nervous system damage, with mitochondrial dysfunction and oxidative stress playing major roles. Mitophagy, regulated by the Pink1/Parkin pathway, removes damaged mitochondria. Here, we investigated the potential of rapamycin (RAPA) to reduce hypothalamic injury in rats subjected to EHS. Forty healthy male Sprague-Dawley rats were randomly assigned to control, RAPA, EHS, and EHS + RAPA groups (10 rats each). Core temperatures were measured, and survival curves were generated. Hypothalamic tissue underwent hematoxylin-eosin and Nissl staining for histopathological assessment. Hypothalamic mitochondrial membrane potential, reactive oxygen species (ROS), and malonaldehyde (MDA) levels were measured. Western blotting assessed mammalian target of RAPA (mTOR), phosphorylated mTOR, Pink1, Parkin, P62, and microtubule-associated protein 1 Light chain 3 (LC3) expression, and calculated the LC3II/LC3I ratio. Immunofluorescence evaluated Pink1-Parkin and LC3-Tom20 co-localization in hypothalamic tissue. EHS and EHS + RAPA groups showed markedly increased core temperatures. RAPA mitigated pathological injury and apoptosis, reduced ROS and MDA levels, and enhanced mitochondrial membrane potential. It downregulated mTOR and p62 levels, upregulated Pink1 and Parkin, increased LC3II/LC3I ratio, and promoted LC3-Tom20 and Pink1-Parkin interactions in the hypothalamic tissue of rats treated with EHS, thereby alleviating hypothalamic injury and preserving hypothalamic function.
    Keywords:  Heat stroke; Hypothalamus; Mitophagy; Parkin; Pink1; Rapamycin
    DOI:  https://doi.org/10.1038/s41598-025-20313-1
  8. Int J Biol Macromol. 2025 Oct 17. pii: S0141-8130(25)08928-7. [Epub ahead of print] 148371
    Peroxisome proliferator-activated receptor gamma (PPARγ) promotes the morula-to-blastocyst transition in Tibetan sheep embryos by enhancing mitophagy through suppression of the AKT/mTOR pathway.
    Tianhao Li, Yangyang Pan, Tian Zhao, Xuefeng Bai, Donglan Zhong, Yuejiao Liao, Qiyong Zuo, Xin Liu, Sijiu Yu, Yan Cui.
      The morula-to-blastocyst transition (MBT) is a critical stage for successful embryo implantation, yet it represents the main developmental block during in vitro culture. In this study, transcriptomic and proteomic analyses were used to investigate the molecular mechanisms underlying MBT in Tibetan sheep embryos. The results revealed that oxidative stress and mitophagy levels were significantly elevated during MBT, with PPAR-γ identified as a key regulatory factor. Pharmacological inhibition of PPAR-γ expression was performed, and changes in the expression of downstream factors (PPAR-γ, p-PPAR-γ, AKT, p-AKT, mTOR, p-mTOR, PINK1, PARKIN, and LC3), as well as ROS levels and mitochondrial membrane potential, were assessed using RT-qPCR and immunofluorescence. The findings showed that inhibition of PPAR-γ activated the AKT/mTOR signaling pathway, decreased the expression of PINK1, PARKIN, and LC3, and reduced ROS accumulation. These results demonstrated that PPAR-γ negatively regulates the AKT/mTOR pathway while being positively correlated with blastocyst development. In conclusion, PPAR-γ promotes MBT by enhancing mitochondrial quality control and maintaining redox and energy homeostasis.
    Keywords:  Early embryonic development; Mitophagy; Morula-to-blastocyst transition; PPAR-γ/AKT/mTOR; Tibetan sheep
    DOI:  https://doi.org/10.1016/j.ijbiomac.2025.148371
  9. Exp Mol Med. 2025 Oct 23.
    Exploring mitophagy levels in Drosophila Malpighian tubules unveils the pivotal role of mitophagy in kidney function and diabetic kidney disease.
    Kang-Min Lee, Jihun Kim, Hye Lim Jung, Young Yeon Kim, Jihoon Lee, Yeon-Ju Lee, Eunhee Yoo, Hyi-Seung Lee, Jeanho Yun.
      Mitophagy has been implicated in kidney function and related diseases. However, a direct analysis of mitophagy in kidney models, including disease models, remains notably lacking. Here we analyzed mitophagy levels in Drosophila Malpighian tubules, a functional analog of the human kidney, using a transgenic model of the engineered mitophagy reporter mt-Keima. We found that mitophagy is highly active in the major cell types of the Malpighian tubules, including renal stem cells, principal cells and stellate cells. Notably, the suppression of mitophagy by genetic downregulation of mitophagy-related genes, such as ATG5 and ULK1, led to a significant decrease in the secretion function of the Malpighian tubules, suggesting that mitophagy is essential for their proper function. Interestingly, a continuous high-sugar diet, which is used as a model for diabetic kidney disease, caused a reduction in mitophagy levels in principal cells before the development of mitochondrial dysfunction and defective secretion. Importantly, stimulation of mitophagy with the recently developed mitophagy inducer PDE701 rescued both mitochondrial dysfunction and defective phenotypes in a diabetic kidney disease model. Our results highlight the pivotal role of mitophagy in kidney function and suggest that modulating mitophagy could be a potential strategy for treating kidney diseases.
    DOI:  https://doi.org/10.1038/s12276-025-01558-2
  10. Phytomedicine. 2025 Oct 10. pii: S0944-7113(25)01034-7. [Epub ahead of print]148 157396
    Ligustilide alleviates the mitophagy and anxiety-like behavior produced by nighttime lighting.
    Chenyi Gao, Keshu Liu, Cuiping Qi, Yifan Liu, Xufeng Li, Yuehua Ruan.
       BACKGROUND: Artificial light at night (ALAN) is an emerging environmental pollutant that disrupts circadian rhythms and increases the risk of neuropsychiatric disorders. Mitochondrial dysfunction and aberrant mitophagy are implicated in ALAN-induced anxiety-like behaviors, yet the underlying mechanisms remain elusive. Plant-derived compounds represent a promising avenue for neuroprotection.
    PURPOSE: This study aimed to explore the therapeutic potential of Ligustilide (LIG)-a natural dihydrophthalide compound extracted from Ligusticum chuanxiong hort (Rhizoma Chuanxiong) and Angelica sinensis (Oliv)-in alleviating ALAN-induced anxiety-like behavior, focusing on the novel mechanistic link between mitophagy modulation and PI3K-AKT pathway regulation to protect mitochondrial and synaptic integrity.
    METHODS: Male mice were exposed to ALAN to induce anxiety-like behaviors, assessed using the elevated plus maze, novelty-suppressed feeding, marble burying, and open field tests. LIG (10 and 30 mg/kg, i.p.) was administered daily for 14 days. Mitochondrial morphology, synaptic integrity, mitophagy activity, and PI3K-AKT pathway activation in the cerebral cortex were examined by electron microscopy, immunofluorescence, and Western blotting.
    RESULTS: ALAN exposure triggered significant anxiety-like behaviors, synaptic damage, and mitophagy hyperactivation, along with PI3K-AKT pathway overactivation. LIG treatment represents the first demonstration of a plant-derived compound simultaneously mitigating ALAN-induced mitophagy dysregulation and PI3K-AKT overactivation, thereby preserving neuronal ultrastructure and behavioral function.
    CONCLUSION: This study demonstrates that Ligustilide exerts neuroprotective effects against ALAN-induced neuronal injury, likely through modulation of mitophagy and PI3K-AKT signaling. Our findings provide novel insights into the mechanistic basis of ALAN neurotoxicity and suggest a promising therapeutic strategy grounded in traditional medicinal compounds.
    Keywords:  Artificial light at night; Ligustilide; Neuronal damage; PI3-AKT signaling pathway
    DOI:  https://doi.org/10.1016/j.phymed.2025.157396
  11. Sci Adv. 2025 Oct 24. 11(43): eadw6064
    In situ characterization of mitochondrial Hsp60-Hsp10 chaperone complex under folding stress.
    Mingyu Jung, Minjung Kim, Su Jin Ham, Jongkyeong Chung, Soung-Hun Roh.
      Mitochondrial proteostasis is critical for maintaining mitochondrial function, and its disruption induces mitochondrial unfolded protein response, which up-regulates chaperones to alleviate protein-folding stress. However, how these chaperones mitigate protein-folding stress remains unclear. Here, using correlated cryo-electron tomography, we show that folding stress triggers marked mitochondrial morphological changes, including the accumulation of amorphous protein aggregates and increased abundance and spatial clustering of the mitochondrial heat shock protein 60-heat shock protein 10 (mtHsp60-Hsp10) complex. Subtomogram analysis revealed the in situ architecture and conformational heterogeneity of mtHsp60-Hsp10 under stress, which retains its canonical double-ring structure while adopting distinct football, half-football, and bullet-like states. Notably, the mtHsp60-Hsp10 complex encapsulates unstructured substrates through conserved hydrophobic interactions. We further demonstrate that knockdown of the mtHsp60-Hsp10 complex exacerbates folding stress, as evidenced by elevated cellular stress responses and activation of mitophagy. Our study defines the in situ structural properties of the mtHsp60-Hsp10 complex and provides mechanistic insight into how it safeguards mitochondrial proteostasis under folding stress.
    DOI:  https://doi.org/10.1126/sciadv.adw6064
  12. Cell Signal. 2025 Oct 17. pii: S0898-6568(25)00585-6. [Epub ahead of print]136 112170
    Mitochondrial homeostasis collapse to cardiac remodeling: From mechanisms to novel targeted therapeutic avenues.
    Qi-Yun Liu, Fan-Liang Meng, Jia-Min Du, Wen-Jing Li, Si-Yuan Zhou, Ying Li.
      Myocardial remodeling is a common pathological process in various cardiovascular diseases (CVDs) and represents the heart's adaptive response to pressure or volume overload. However, prolonged myocardial remodeling often leads to a progressive decline in cardiac function, ultimately resulting in heart failure (HF). This process is primarily characterized by myocardial hypertrophy and fibrosis, both of which are closely linked to mitochondrial dysfunction. Emerging research uncovers a pivotal orchestrator of this lethal transition: mitochondrial homeostasis. As the powerhouse of cardiomyocytes, dysfunctional mitochondria ignite a catastrophic cascade-energy bankruptcy, oxidative tsunamis, and apoptotic avalanches-propelling pathological hypertrophy and fibrosis. Although extensive research has explored mitochondrial homeostasis in cardiovascular diseases, a comprehensive summary of the specific mechanisms and effects of mitochondrial dysfunction in myocardial remodeling remains lacking. This review focuses on pathological myocardial remodeling associated with mitochondrial abnormalities and examines four critical factors: mitochondrial Ca2+ signaling, metabolism, dynamics, and mitophagy. Bridging molecular mechanisms to next-generation therapeutics, we systematically evaluates their roles in disease progression and discusses potential mitochondrial-targeted therapeutic strategies, offering new insights into research and treatment approaches for related conditions.
    Keywords:  Ca(2+); Dynamics; Metabolism; Mitochondrial homeostasis; Mitophagy; Myocardial remodeling
    DOI:  https://doi.org/10.1016/j.cellsig.2025.112170
  13. Front Nutr. 2025 ;12 1662882
    MRPL44 regulates lipid metabolism in metabolic dysfunction-associated steatotic liver disease through BNIP3-mediated mitophagy.
    Siqi Liu, Lianggui Xiao, Qiuchen Cheng, Qichao Liao, Yuxin Huang, Xiangling Li, Zhiwang Zhang, Yang Xiao, Zupeng Luo, Tingli Pan, Yu Sun, Chang Sun, Jiale Wang, Lin Yu, Turtushikh Damba, Batbold Batsaikhan, Xue Liang, Yunxiao Liang, Khongorzul Batchuluun, Yixing Li, Lei Zhou.
       Objective: Mitophagy is a critical defense mechanism against metabolic dysfunction-associated steatotic liver disease. MRPL44, a mitochondrial ribosomal protein that regulates mitochondrial DNA-encoded gene expression, has not previously been linked to lipid metabolism.
    Methods: This study employed an oleic acid/palmitic acid induced HepG2 cell models and a high-fat diet fed mouse models, combined with lentivirus-mediated MRPL44 overexpression and mitophagy assays, to investigate the regulatory role of MRPL44 in the progression of metabolic dysfunction-associated steatotic liver disease.
    Results: Our findings demonstrated that MRPL44 alleviates lipid metabolic disorders induced by high-fat diet through the mitophagy pathway. Specifically, in oleic acid/palmitic acid-stimulated HepG2 cells, overexpression of MRPL44 reduced intracellular triglyceride accumulation and enhanced fatty acid oxidation. Moreover, liver-specific overexpression of MRPL44 in mice attenuated high-fat diet induced hepatic lipid deposition. Mechanistically, MRPL44 activated the BNIP3-dependent mitophagy pathway, promoted mitochondrial biogenesis, and mitigated mitochondrial damage, ultimately reducing lipid accumulation in hepatocytes.
    Conclusion: This study identifies MRPL44 as a novel regulator of lipid metabolism and a potential therapeutic target for metabolic dysfunction-associated steatotic liver disease.
    Keywords:  MRPL44; fatty acid oxidation; metabolic dysfunction-associated steatotic liver disease; mitochondrial quality; mitophagy
    DOI:  https://doi.org/10.3389/fnut.2025.1662882
  14. Exp Physiol. 2025 Oct 19.
    Neuroprotective effects of sinomenine and metformin in diabetic stroke: Role of NLRP3/caspase-1 and mitophagy.
    Wendi Li, Yiying Fan, Shaik Althaf Hussain.
      Type 2 diabetes mellitus (T2DM) significantly increases the risk and severity of cerebral ischaemia-reperfusion (IR) injury, yet effective neuroprotective treatments for diabetic stroke remain limited. This study explored whether a combination of sinomenine and metformin could offer enhanced neuroprotection in diabetic rats subjected to cerebral IR injury, and investigated the molecular pathways involved. Male rats were rendered diabetic using a high-fat diet and low-dose streptozotocin. After establishing diabetes, rats underwent transient middle cerebral artery occlusion followed by 24 h of reperfusion. Animals received sinomenine, metformin, or their combination for 7 days prior to IR induction. Neurological function was assessed using standardized behavioural tests. Molecular analyses measured markers of pyroptosis (NLRP3, cleaved caspase-1, gasdermin D N-terminal fragment), mitophagy (PTEN-induced kinase 1 (PINK-1), Parkin), inflammation (interleukin (IL)-1β, IL-18) and oxidative stress (malondialdehyde, superoxide dismutase, glutathione peroxidase). To determine the role of mitophagy, a subset of animals was pretreated with the mitophagy inhibitor mitochondrial division inhibitor 1 (Mdv-1). Combination therapy led to significant improvements in neurological performance, accompanied by downregulation of pyroptosis-associated proteins and pro-inflammatory cytokines, as well as enhanced activation of the PINK-1/Parkin mitophagy pathway and improved antioxidant status. The neuroprotective effects of the combined treatment were abolished by Mdv-1, indicating a critical role for mitophagy in mediating these benefits. The combination of sinomenine and metformin confers additive neuroprotection against cerebral IR injury in diabetic rats, primarily through inhibition of NLRP3-mediated pyroptosis and activation of the PINK-1/Parkin mitophagy pathway. These findings highlight a promising therapeutic strategy for diabetic stroke and warrant further preclinical and clinical investigation.
    Keywords:  cerebral ischaemia–reperfusion injury; combination therapy; diabetes mellitus; metformin; neuroprotection; sinomenine
    DOI:  https://doi.org/10.1113/EP093135
  15. Mol Biol Rep. 2025 Oct 23. 53(1): 5
    Inhibition of glutamine synthetase enhances hepatocellular carcinoma radiosensitivity through ROS-induced excessive mitophagy.
    Rao Liu, Guangyu Ju, Yijun Lu, Xiao Liu, Qi Ding, Kaiwei Wang, Hongcang Gu, Junchao Qian.
       BACKGROUND: Glutamine' synthetase (GS) plays a central role in glutamine metabolism and has been implicated in the progression and treatment resistance of hepatocellular carcinoma (HCC). Although previous studies have explored GS in tumor metabolism, its role in modulating mitophagy and radiosensitivity in HCC cells remains unclear.
    METHODS: We analyzed GS expression in HCC using data from the TCGA database, followed by treatment of HepG2, Hep3B and Huh7 cells with the GS inhibitor L-methionine sulfoximine (MSO) and exposure to ionizing radiation. Cellular responses were evaluated through CCK-8 assays, Western blotting, immunofluorescence, flow cytometry, colony formation assays, and mitochondrial membrane potential measurements.
    RESULTS: Correlation analysis revealed a positive association between GS expression and mitophagy-related genes in HCC. MSO treatment enhanced the effects of radiotherapy, leading to increased ROS production, reduced antioxidant capacity, and aggravated mitochondrial damage. Mitophagy activation was confirmed by LC3-II accumulation and upregulation of the PINK1/Parkin pathway. Notably, the radiosensitizing effect of MSO was partially reversed by Mdivi-1, indicating that mitophagy contributes to MSO-mediated radiosensitization.
    CONCLUSION: These findings indicate that inhibition of GS enzyme activity enhances oxidative stress and mitophagy, thereby promoting radiosensitivity in HCC cells. This study provides new insights into the role of GS in overcoming radiotherapy resistance and highlights its potential as a therapeutic target to improve radiotherapeutic outcomes in HCC.
    Keywords:  Glutamine synthetase; Hepatocellular carcinoma; Mitophagy; Radiosensitizing
    DOI:  https://doi.org/10.1007/s11033-025-11172-0
  16. Trends Endocrinol Metab. 2025 Oct 17. pii: S1043-2760(25)00201-2. [Epub ahead of print]
    Mitophagy in the adaptation to pancreatic β cell stress in diabetes.
    Elena Levi-D'Ancona, Ava M Stendahl, Belle A Henry-Kanarek, Rebecca K Davidson, Emily M Walker, Scott A Soleimanpour.
      Mitophagy is a crucial quality control process that preserves metabolic efficiency by selectively targeting damaged mitochondria for removal. Given the high metabolic demand of pancreatic β cells' insulin secretion, disruption of mitophagy contributes to the mitochondrial dysfunction and β cell failure that are a common feature of both type 1 and type 2 diabetes (T1D and T2D). We review the impact of mitophagy on β cell responses to (patho)physiologic stressors that underlie the development of T1D and T2D. We examine how β cells engage mitophagy in the adaptive response to metabolic, inflammatory, and oxidative damage. We also dissect the importance of ubiquitin- and receptor-mediated mitophagy, methodological advances to quantify mitophagy in β cells, and ongoing efforts to pharmacologically target mitophagy to preserve β cell health and improve glycemic control.
    Keywords:  CLEC16A; Parkin; islet; mitochondria; ubiquitin
    DOI:  https://doi.org/10.1016/j.tem.2025.09.009
  17. Cell Biol Toxicol. 2025 Oct 20. 41(1): 141
    ETV4 promotes ovarian cancer growth by regulating mitochondrial function through Mfn2 ubiquitination mediated by the E3 ubiquitin ligase MARCH9.
    Ying Wang, Zhan Wang, Juan Chen, Li Cai, Xia Luo, Nayiyuan Wu.
       BACKGROUND: Mitochondrial dysfunction affects the development of ovarian cancer (OC). ETV4 is involved in mitochondrial fusion. The regulatory pathways of ETV4 in OC cells have not been further investigated. In this study, we aimed to explore the effects of ETV4 on OC development and analyze the downstream regulatory pathways of ETV4.
    METHODS: The expression of ETV4 in OC cell lines (SK-OV-3, HEY, A2780, and OVCAR-3) was verified. After silencing ETV4, indicators related to mitochondrial function, including ATP level, mitochondrial membrane potential, mitochondrial DNA (mtDNA), and mitochondrial ROS (mtROS), were analyzed. The expression of mitochondrial fission/fusion-related markers (Mfn1, Mfn2, OPA1, DRP1, MFF, and FIS1) was detected. In vivo experiments were used to verify the effect of ETV4 on OC development.
    RESULTS: The TCGA-OV data indicated that ETV4 was highly expressed in OC. Silencing ETV4 inhibited the proliferation of OC cells. Mitochondrial membrane potential and ATP levels increased after ETV4 silencing, while mtDNA and mtROS levels decreased. ETV4 silencing promoted Mfn2 protein expression but did not affect Mfn2 mRNA level. Mfn2-associated E3 ubiquitin ligase MARCH9 was targeted and regulated by ETV4. MARCH9 overexpression alleviated the regulation of ETV4 silencing on mitochondrial function in OC cells. Lysosomal inhibitor CQ blocked the degradation of ubiquitinated Mfn2 protein. MARCH9 was found to mediate robust ubiquitination of Mfn2 via the K63-linked ubiquitination.
    CONCLUSIONS: ETV4 was highly expressed in OC and involved in the regulation of mitochondrial function. ETV4 regulated Mfn2 ubiquitination linked by K63 by regulating MARCH9.
    Keywords:  ETV4; MARCH9; Mfn2; Mitochondrial function; Ovarian cancer (OC)
    DOI:  https://doi.org/10.1007/s10565-025-10094-8
  18. Neurotox Res. 2025 Oct 20. 43(6): 43
    Hyperhomocysteinemia Induced Mitochondrial Dysfunction Disrupting the Eye Development.
    Manuela Sozo Cecchini, Gilian Fernando Bourckhardt, Madson Silveira de Melo, Evelise Maria Nazari.
      Mitochondrial dynamics, including fusion and fission, are essential for neural cell function and survival during central nervous system development. These processes are vital for eye formation, which requires high energy to support cellular events, such as proliferation, differentiation, and apoptosis. However, different conditions can disrupt the normal development of the eye, such as hyperhomocysteinemia (HHcy), a metabolic disorder characterized by elevated homocysteine (Hcy) levels. This study aimed to evaluate the effects of HHcy on eye development of Gallus domesticus. Fertilized eggs were treated with 20 µmol Hcy at embryonic day 2 (E2), with analyses conducted at E6 and E10 using a combination of survival analysis, transmission electron microscopy, flow cytometry for mitochondrial proteins and autophagy markers, and cell viability assay, providing a comprehensive evaluation of HHcy toxicity. A significant 40% reduction in the survival rate relative to control was observed in HHcy-treated embryos. Although eye diameter remained unchanged, ultrastructural analyses revealed mitochondrial damage, including membrane rupture, loss, and disorganization of the cristae, induced by the exposure at both embryonic ages. Analysis of proteins involved in mitochondrial dynamics showed increased Drp1 (fission) and decreased Mfn1 and Mfn2 (fusion) in HHcy-treated embryos. At E10, these changes were accompanied by an increased number of mitochondrial profiles and reduced mitochondrial area. HHcy also induced a reduction in cell viability, highlighting its cytotoxic effects, particularly on mitochondria. Additionally, increased cytoplasmic vesicles and autophagy were observed in HHcy-treated embryos. These findings indicate that mitochondria are key targets of HHcy, with mitochondrial dynamics and ultrastructural integrity significantly impaired by the exposure. These changes highlight the harmful effects of high Hcy levels on embryonic development and eye formation, providing insights into its pathogenic effects.
    Keywords:  Developmental toxicity; Embryotoxicity; Homocysteine; Mitochondrial damage; Ocular development
    DOI:  https://doi.org/10.1007/s12640-025-00767-x
  19. Cell Biol Toxicol. 2025 Oct 21. 41(1): 142
    SerpinB1a induces hepatopulmonary syndrome by promoting CTSG/AMPK/mTOR pathway-mediated mitophagy.
    Liang Li, Jianzhong Li, Wendeng Li, Yuefeng Ma, Shaomin Li.
      Mitophagy, as an important mechanism for selective removal of damaged mitochondria in cells, plays a crucial role in upholding cellular homeostasis. Mounting evidence suggests that autophagy is associated with lung disease. However, the potential molecular mechanisms affecting mitophagy are still obscure in hepatopulmonary syndrome (HPS) development. In this study, elevated SerpinB1a levels were detected in HPS patients' serum, showing a significant inverse correlation with arterial oxygen saturation. In the CBDL-induced rat HPS model, SerpinB1a knockdown attenuated pulmonary hemorrhage, microvascular dilation, and hepatic fibrosis. In vitro studies demonstrated that treatment of PMVECs with serum from HPS rats induced pathological proliferation, migration, and angiogenesis. Silencing of SerpinB1a effectively suppressed these aberrant cellular processes. Mechanistically, SerpinB1a promoted PMVEC dysfunction by interacting with and upregulating Cathepsin G (CTSG), thus activating the VEGF / AMPK / mTOR pathway and subsequent induction of mitophagy. In conclusion, SerpinB1a knockdown attenuated pulmonary microvascular dilation and HPS progression by inhibiting this CTSG/VEGF/AMPK/mTOR axis. These findings elucidate the mechanistic role of SerpinB1a in HPS progression and suggest its potential as a novel therapeutic target for HPS.
    Keywords:  CTSG/VEGF/AMPK/mTOR signaling pathway; Hepatopulmonary syndrome; Mitophagy; Pulmonary microvascular dilatation; SerpinB1a
    DOI:  https://doi.org/10.1007/s10565-025-10082-y
  20. Neuropharmacology. 2025 Oct 18. pii: S0028-3908(25)00434-4. [Epub ahead of print] 110726
    Ticagrelor as a Dual RAS Modulator and Mitochondrial Stabilizer: A Multifaceted Neurotherapeutic Strategy in Huntington's Disease.
    Ola E Mohamed, Rabab H Sayed, Dalaal M Abdallah, Doaa Abou El-Ezz, Amany El-Brairy, Hanan S El-Abhar.
      The pathobiology of Huntington's disease (HD) is far from complete. Although limited, patients have been reported to exhibit altered platelet function, enhanced ENT1, and changes in renin-angiotensin system (RAS), all of which may impact cognitive function. Ticagrelor has demonstrated neuroprotective effects in stroke and parkinsonism models through mechanisms that extend beyond its therapeutic benefits as a P2Y12 receptor antagonist and ENT1 inhibitor. In this study, we investigated the potential efficiency Ticagrelor post-treatment on motor defects in a 3-nitropropionic acid (3-NP)-induced HD-like model. Symptomatic HD rats were daily treated for a week with Ticagrelor, the MAS receptor (MAS-R) antagonist A-779, or Ticagrelor + A-779. Ticagrelor amended body weight loss, motor function in open field and rotarod tests, and striatal histopathological alterations induced by 3-NP. On the striatal molecular level, Ticagrelor downregulated prorenin receptor mRNA expression but upregulated that of the MAS-R. Additionally, it decreased striatal contents of prorenin/renin and angiotensin II (Ang II), while increasing those of angiotensin-converting enzyme 2 and Ang-(1-7). Ticagrelor also hindered the phosphorylation/activation of the inositol trisphosphate receptor (IP3R), dynamin-related protein-1 (DRP-1), and PTEN-induced putative kinase 1 protein (PINK1) expressions. Additionally, it boosted the voltage-dependent anion channel-1 (VDAC-1) and Mitofusin-2 (Mnf-2) striatal contents. A-779 partially reverted Ticagrelor impact on all amendments except for prorenin receptor and p-IP3R. However, prorenin/renin correlated markedly with IP3R, DRP-1, and PINK1, but inversely with VDAC-1 and Mfn-2. In conclusion, Ticagrelor demonstrates promising neurotherapeutic effects in HD partially via the activation of MAS-R, inhibition of prorenin/renin/prorenin receptor, and improvement of mitochondrial homeostasis.
    Keywords:  A-779; Mitochondrial dynamics; Mitophagy; Prorenin/prorenin receptor/Angiotensin II axis; Renin angiotensin system; VDAC-1
    DOI:  https://doi.org/10.1016/j.neuropharm.2025.110726
  21. Ecotoxicol Environ Saf. 2025 Oct 18. pii: S0147-6513(25)01584-2. [Epub ahead of print]305 119239
    Nitrite and microcystins co-exposure triggers PINK1-mediated mitophagy in spermatogonia.
    Fufang Wang, Yu Fu, Haohao Liu, Xingde Du, Ruiyang Meng, Kangfeng Ge, Xiao Liang, Jun Yang, Xin Wang, Feiyang Guo, Hongxiang Guo, Huizhen Zhang.
      Nitrite and Microcystins (MCs) frequently co-occur in eutrophic water bodies, and both are well-documented to elicit reproductive toxicity via direct impairment of reproduction-associated cells. However, the molecular mechanisms underlying their combined cytotoxic effects remain poorly defined. In this study, the mouse germ cell line (GC-1) was exposed to 1/2 IC₅₀ concentrations of sodium nitrite (NaNO₂) or microcystin-leucine-arginine (MC-LR), individually or in combination, for 24 h in vitro. Co-exposure synergistically diminished cell viability, which was accompanied by mitochondrial swelling, cristae loss, and enhanced autophagosome formation. These changes were associated with elevated levels of mitochondrial reactive oxygen species (mtROS) and impaired mitochondrial membrane potential. Transcriptomic profiling revealed significant enrichment of pathways related to autophagy and cell death. Treatment with the mitochondria-targeted antioxidant mitoquidone mesylate (MitoQ) attenuated the loss of cell viability and mitochondrial damage induced by NaNO₂ and MC-LR, while suppressing the expression of the autophagy-related protein PINK1. Furthermore, siRNA-mediated knockdown of PINK1 could reduce the expression of mitochondrial autophagy markers, including phospho-Parkin, Atg12, and LC3-II. These findings identify PINK1 as a key regulator of mitochondrial autophagy triggered by NaNO₂ and MC-LR co-exposure and suggest that mitochondrial antioxidants such as MitoQ may mitigate the reproductive toxicity of these environmental contaminants.
    Keywords:  Co-exposure; Microcystins; Mitophagy; Nitrite; PINK1
    DOI:  https://doi.org/10.1016/j.ecoenv.2025.119239
  22. J Gerontol A Biol Sci Med Sci. 2025 Oct 24. pii: glaf233. [Epub ahead of print]
    Exercise-induced alleviation of memory impairment in aged mice with neuroinflammation is linked with modulation of mitochondrial homeostasis in the hippocampus.
    Peng-Da Li, Chong Han, Yuan-Yuan Qin, Zhi Jiang, Shan-Yao Pan, Bo Liao, Nan Wang, Xin-Han Cao, Gang Zhao, Jia-Qi Zhou, Zheng-Hong Qin, Yiqing Lu, Yaping Huai, Li Luo.
      Neuroinflammation is a critical aspect of aging and neurodegenerative disorders, increasingly recognized for its significant role in the progression of cognitive impairments. Mitochondrial homeostasis is closely linked to cognitive function in the aging brain. However, it remains unclear whether exercise can safeguard cognitive function by enhancing mitochondrial homeostasis in the aged hippocampus affected by neuroinflammation. In this study, we established mouse models exhibiting memory impairment and neuroinflammation in the aged hippocampus to investigate whether exercise can reverse LPS-induced cognitive dysfunction in aged mice, reduce neuroinflammation, and simultaneously improve mitochondrial homeostasis in the hippocampus. Eighteen-month-old male ICR mice underwent eight weeks of moderate-intensity aerobic exercise. The exercise regimen enhanced memory function in LPS-injected aged mice, which was accompanied by reductions in inflammation, oxidative stress, and apoptosis in the aged hippocampus. Importantly, exercise improved mitochondrial homeostasis in the hippocampus of LPS-injected aged mice. Collectively, our results provide the first evidence that exercise can protect cognitive function in the context of neuroinflammation in the aged hippocampus, suggesting that this effect may be associated with the improvement of mitochondrial homeostasis.
    Keywords:  LPS; aging; exercise; memory; mitochondrial homeostasis; neuroinflammation
    DOI:  https://doi.org/10.1093/gerona/glaf233
  23. Sci Rep. 2025 Oct 21. 15(1): 36637
    Exercise training and Silymarin consumption can ameliorate mitophagy signaling flux in hepatocytes of rats with dexamethasone-induced non-alcoholic fatty liver disease.
    Fatemeh Mokhtari-Andani, Elahe Talebi-Garakani, Khadijeh Nasiri, Abolfazl Akbari.
      This study aimed to investigate the effects of exercise training combined with silymarin supplementation on mitophagy markers in hepatocytes of rats with dexamethasone-induced non-alcoholic fatty liver disease (NAFLD). Forty-two male Wistar rats (6 weeks old) were divided into 7 groups (n = 6 per group): 1- Control (CON), 2- Dexamethasone (DEX), 3- DEX + moderate-intensity training (DEX-MIT), 4- DEX + high intensity training (DEX-HIT), 5- DEX + silymarin (DEX-S), 6- DEX + moderate intensity training + silymarin (DEX-MIT-S), 7- DEX-high intensity training + silymarin (DEX-HIT-S). NAFLD was induced by subcutaneous administration of dexamethasone for 7 days. Exercise groups underwent 8 weeks of treadmill running (5 sessions/week) at matched distances for MIT and HIT protocols. Silymarin was administered via oral gavage at a dose of 300 mg/kg body weight/day. Gene expression levels of mTORC1, AMPKα2, Bcl-2, Parkin, and LC3 were measured using real-time PCR. Protein levels of PINK1, Beclin-1, and P62 were assessed by western blotting. Moderate and high intensity training significantly reduced Bcl-2 and LC3 gene expression and increased P62 protein levels compared to the DEX group (P < 0.05). Silymarin supplementation significantly decreased expression of Parkin, Bcl-2, LC3, and PINK1 compared to the DEX (P < 0.05). Bcl-2 and LC3 gene expressions were lower in DEX-MIT-S and DEX-HIT-S compared to DEX (P < 0.05). PINK1 levels were reduced in the DEX-MIT-S relative to DEX (P < 0.05). LC3 gene expression was higher in DEX-HIT-S compared to DEX-MIT-S (P < 0.05). The findings suggest that both exercise training and silymarin supplementation can attenuate excessive mitophagy signaling in hepatocytes of rats with dexamethasone-induced NAFLD, potentially providing hepatoprotective effects against further damage.
    Keywords:  Autophagy; High intensity interval training; LC3; Milk thistle; NAFLD
    DOI:  https://doi.org/10.1038/s41598-025-20512-w
  24. Metab Brain Dis. 2025 Oct 24. 40(8): 296
    Polygalasaponin F alleviates cerebral ischemia-reperfusion injury through inhibiting mitophagy.
    Siqi Quan, Roujia Guo, Jingjing Bu, Nuo Wang, Yapeng Jia, Jiahui Wang, Ming Bai, Erping Xu, Xiangli Yan, Yucheng Li.
      Neurological recovery after ischemic stroke (IS) remains clinically challenging, primarily due to cerebral ischemia-reperfusion injury (CIRI). Oxidative stress contributes to the pathogenesis of CIRI by causing reactive oxygen species excessive accumulation, which disrupts mitochondrial function. Mitophagy maintains mitochondrial function by eliminating damaged or dysfunctional mitochondria. Nevertheless, mitophagy exerts dual effects, either excessive or insufficient activation exacerbates mitochondrial dysfunction. Polygalasaponin F (PGSF), a natural triterpenoid saponin, has been demonstrated to regulate mitochondrial function. Therefore, in this study, we investigated whether PGSF protects against CIRI through inhibiting the mitophagy in vitro and in vivo. Results showed that PGSF attenuated apoptosis both in vivo and in vitro. Moreover, PGSF preserved mitochondrial membrane potential (MMP), reduced mitochondrial reactive oxygen species (mtROS), and ameliorated mitochondrial morphology to improve mitochondrial function in vitro. Furthermore, we revealed that PGSF ameliorates CIRI via modulation of mitophagy, evidenced by a reduced LC3II/LC3I ratio, decreased colocalization of LC3 with mitochondria, while enhancing the levels of TOM20 and p62. In conclusion, our findings imply that PGSF alleviates CIRI through inhibiting mitophagy and reducing apoptosis, demonstrating its therapeutic potential.
    Keywords:  Cerebral ischemia-reperfusion injury; Ischemic stroke; Mitophagy; Neuroprotection; Polygalasaponin F
    DOI:  https://doi.org/10.1007/s11011-025-01734-3
  25. Phytomedicine. 2025 Oct 15. pii: S0944-7113(25)01043-8. [Epub ahead of print]148 157405
    Duhuo Jisheng decoction alleviates intervertebral disc degeneration via the acacetin-mediated MAPK1/HMOX1 axis by inhibiting nucleus pulposus cell pyroptosis.
    Cheng Yu, Jianjun Li, Junjie Cheng, Runjun Luo, Zhihui Zhou, Jianfeng Zhang, Yang Duan.
       BACKGROUND: Intervertebral disc degeneration (IVDD) is the main pathological basis of low back pain, and its occurrence is closely related to the dysfunction of nucleus pulposus cells (NPCs). Although several studies have investigated the role of oxidative stress, apoptosis, and inflammation in IVDD, the specific molecular mechanisms underlying the regulation of pyroptosis and mitophagy remain unclear. This study aims to explore the effect and molecular mechanism of Duhuo Jisheng Decoction (DHJS) and its active component Acacetin (ACA) against IVDD.
    METHODS: In this study, the therapeutic effects of DHJS on IVDD were first evaluated both in vitro and in vivo using histological staining, Western blotting, ROS detection, and flow cytometry. Ultra-high-performance Liquid Chromatography coupled with Quadrupole-Orbitrap High-Resolution Mass Spectrometer (UHPLC-QE-MS) was employed to identify the active components of DHJS that entered systemic circulation. The role of ACA, a key bioactive compound, in regulating NPCs pyroptosis and mitophagy was further investigated through ROS staining, JC-1 mitochondrial membrane potential assay, flow cytometry, and Western blotting. Potential targets of ACA and mitogen-activated protein kinase 1(MAPK1) were identified using network pharmacology and mass spectrometry analysis. Finally, the therapeutic efficacy of ACA was validated in a rat model of IVDD.
    RESULTS: It was found that DHJS could significantly alleviate the pathological process of IVDD by inhibiting NPCs pyroptosis. Further studies revealed that ACA, the key active component of DHJS, directly bound to MAPK1 and inhibited its expression, thereby relieving the negative regulation of MAPK1 on heme oxygenase 1 (HMOX1). This interaction enhanced NPCs mitophagy and ultimately suppressed pyroptosis. Notably, this is the first study to identify the Acacetin-MAPK1/HMOX1 axis as a regulatory pathway linking mitophagy and pyroptosis in IVDD. In vivo experiments further confirmed that ACA could reverse the collagen fiber disorder, proteoglycan reduction and enhanced expression of mitophagy-related proteins in the intervertebral disc tissue of IVDD rats.
    CONCLUSION: This study reveals a new mechanism by which DHJS regulates the function of NPCs through the Acacetin-MAPK1/HMOX1-mitophagy-pyroptosis axis. These findings not only provide a theoretical basis for traditional Chinese medicine intervention in IVDD but also broaden the understanding of mitophagy-pyroptosis crosstalk as a potential strategy for degenerative disc disease therapy.
    Keywords:  Acacetin; Duhuo Jisheng decoction; Intervertebral disc degeneration; Mitophagy; Pyroptosis
    DOI:  https://doi.org/10.1016/j.phymed.2025.157405
  26. Front Immunol. 2025 ;16 1644289
    Macrophage PTP1B regulates mitochondrial dynamics via the JAK2/STAT3-OPA1 axis and activates the cGAS/STING signaling pathway.
    Xuefeng Lei, Diandian Qian, Wenzheng Zhang, Bin'an Zhao, Yabin Li, Hua Hao, Jing Yuan, Le Zhao, Centao Liu.
      Tendinopathy is characterized by degenerative changes in tendon tissue, with its pathogenesis closely associated with macrophage-mediated chronic inflammation and mitochondrial dysfunction. Bioinformatics analysis of tendinopathic tissues revealed a significant upregulation of protein tyrosine phosphatase 1B (PTP1B) in macrophages, which accompanied with robust immune activation and marked Janus Kinase 2/Signal Transducer and Activator of Transcription 3 (JAK2/STAT3) signaling pathway inhibition. In tendinopathy mouse models, both pro-inflammatory cytokines and PTP1B were found to be highly expressed in tendon tissues. However, conditional deletion of Ptpn1 (encoding PTP1B, Ptpn1-/-) in macrophages significantly alleviated tendon inflammation and fibrosis, indicating a strong association between PTP1B and tendinopathy. Mechanistically, in vivo experiments demonstrated that macrophage PTP1B suppressed STAT3 activation by inhibiting JAK2 phosphorylation, and inhibited the mitochondrial fusion protein Optic Atrophy1 (OPA1), resulting in mitochondrial fragmentation and mitochondrial DNA (mtDNA) release. This process activated the Cyclic GMP-AMP synthase/Stimulator of interferon genes (cGAS/STING) pathway, elevating the levels of inflammation and exacerbating tendon injury. In summary, macrophage PTP1B was shown to regulate mitochondrial dynamics via the JAK2/STAT3-OPA1 axis and trigger inflammation through activation of the cGAS/STING pathway, representing a key mechanism underlying the progression of tendinopathy. Targeting PTP1B or associated pathways may provide novel therapeutic strategies for tendinopathy.
    Keywords:  JAK2/STAT3 signaling pathway; PTP1B; macrophages; mitochondrial dynamics; tendinopathy
    DOI:  https://doi.org/10.3389/fimmu.2025.1644289
  27. J Mol Histol. 2025 Oct 23. 56(6): 357
    3-TYP protects against heart failure with preserved ejection fraction by inhibiting Sirtuin 3.
    Ziwei Zhu, Yuqin Wang, Jianshu Chen, Yongnan Li, Hong Ding, Wenbin Wu, Xiaowei Zhang.
      Heart failure with preserved ejection fraction (HFpEF) is characterized by diastolic dysfunction and is commonly observed in elderly, diabetic, hypertensive, and obese patients. Accumulating evidence suggests a close relationship between sirtuins and myocardial damage in HFpEF. This study aimed to explore whether sirtuin 3 (Sirt3) is involved in HFpEF. Wistar-Kyoto (WKY) rats served as the controls, while spontaneously hypertensive rats (SHRs) were randomly divided into three groups: the SHR group, HFpEF group, and HFpEF + 3-TYP group. Except for rats in the WKY and SHR groups, rats in the other groups were subjected to a high-fat diet (45%) and an intraperitoneal (i.p.) injection of streptozotocin (35 mg/kg) to establish the HFpEF model. Moreover, Sirt3 was inhibited using 3-TYP to further explore the regulatory mechanism of key molecules in this process. Cardiac function was evaluated by echocardiography, histological changes were examined by microscopy, and the morphology of the ER and mitochondria was observed through transmission electron microscopy. Western blotting was used to measure the levels of endoplasmic reticulum stress (ERS) and mitophagy-related proteins. Following high-fat feeding and i.p. injection of streptozotocin, SHRs presented markedly impaired diastolic function, decreased exercise tolerance, increased cardiac hypertrophy and fibrosis, and increased Sirt3 protein expression. Treatment with 3-TYP led to a significant reversal of these changes. When Sirt3 expression increased, endoplasmic reticulum stress and mitochondrial autophagy increased. Sirt3 silencing markedly reduced the excessive ERS and mitophagy levels induced by metabolic stress. 3-TYP can mitigate cardiac hypertrophy and improve function in HFpEF patients by inhibiting Sirt3, thereby protecting against metabolic disorders and excessive endoplasmic reticulum stress. These findings suggest that 3-TYP may be a promising therapeutic candidate for patients with metabolic syndrome-related HFpEF.
    Keywords:  3-TYP; Endoplasmic reticulum stress; Heart failure with preserved ejection fraction; Metabolic syndrome; Mitophagy; Silent information regulator 3
    DOI:  https://doi.org/10.1007/s10735-025-10614-0
  28. Am J Transl Res. 2025 ;17(9): 6743-6754
    Mic60/Mitofilin inhibitor, Miclxin, induces rat H9C2 cardiomyoblast death by inhibiting the removal of damaged mitochondria.
    Muhammad S Khan, Somayyeh Nasiripour, Michele Oyarzabal, Swati Banerjee, Kumar Sharma, Manzoor A Bhat, Jean C Bopassa.
      Mitochondrial dysfunction is a hallmark of various pathologic conditions, including ischemia/reperfusion injury, stroke, myocardial infarction, neurodegeneration and metabolic syndrome. As with all biological organelles, the function of mitochondria is tightly linked to their structure. The inner mitochondrial membrane is a highly regulated membrane with a large surface area that hosts the electron transport chain machinery, generates the membrane potential necessary for ATP generation, and forms the signature cristae folds of mitochondria. The mitochondrial inner membrane protein (Mitofilin/Mic60) is part of a large complex that constitutes the mitochondrial inner membrane organizing system, which is critical in maintaining mitochondrial architecture and function. Recent evidence has shown that Mic60/Mitofilin elimination during reperfusion determines the extent of myocardial infarct size after ischemia/reperfusion. Here, we investigated the effects and mechanisms of action of Miclxin, a novel Mic60/Mitofilin inhibitor using H9c2 cardiomyoblasts. Cultured rat H9c2 cardiomyoblasts were incubated with 0, 5, 10, or 20 μM of Miclxin. Cell viability was determined using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assays, and cell death was determined by flow cytometry using propidium iodide dye. Mitochondrial membrane potential was measured using MitoTracker Red CMXROS assay kits, and mitophagy in mitochondria was detected using Mitophagy Detection Kits. Mitochondrial morphology was assessed using electron microscopy, and proteins were measured by Western blot analyses and immunofluorescence staining. After 24 hours of treatment, Miclxin decreased cell viability in a dose-dependent manner and reduced the number of viable cells measured with MTT assays. This effect was associated with pronounced reduction of Mic60 protein levels measured by Western blots and immunocytochemistry. Miclxin's reduction of cell viability was related to its inhibition of mitochondrial elimination by mitophagy. Our findings suggest that Miclxin decreases levels of Mic60, and thereby reduces cell viability by increasing structural damage and dysfunction in mitochondria via impairment of mitophagy.
    Keywords:  H9C2 rat cardiomyomyoblasts; Mic60/Mitofilin protein; Miclxin; cell viability; mitochondria; mitophagy
    DOI:  https://doi.org/10.62347/UPML8062
  29. J Cardiovasc Pharmacol. 2025 Oct 20.
    PHB1 attenuates triptolide-induced cardiotoxicity by regulating mitochondrial dynamics in cultured newborn mice cardiomyocytes.
    Wanlin Chen, XinGuo Li.
      Triptolide (TP) is widely used clinically for multiple diseases, but its cardiotoxicity significantly limits its clinical applications. The underlying mechanisms of its cardiotoxicity are still unclear. Mitochondria are crucial for cellular survival and function. Here, we found that TP induced mitochondrial dysfunction and apoptosis of cardiomyocytes, which might be the key process underlying TP-induced cardiotoxicity. Moreover, the expression of prohibitin1 (PHB1) was significantly decreased after TP treatment in a time-dependent manner. Overexpression of PHB1 alleviated mitochondrial dysfunction and inhibited apoptosis of cardiomyocytes after TP treatment. Mechanistically, PHB1 might regulate mitochondrial dynamics, which maintain normal mitochondrial function. Based on the above results, PHB1 might be a potential therapeutic target for TP-induced cardiotoxicity.
    Keywords:  PHB1; Triptolide; apoptosis; cardiotoxicity; mitochondrial dynamics
    DOI:  https://doi.org/10.1097/FJC.0000000000001766
  30. Biochem Pharmacol. 2025 Oct 19. pii: S0006-2952(25)00705-1. [Epub ahead of print] 117440
    Upregulation of BNIP3 alleviates renal tubular cell injury by activating mitophagy in diabetic nephropathy.
    Zi-Yun Hu, Qi-Hang Sun, Yu Ma, Yu-Kai Wang, Chao-Yi Chen, Xin-Ran Liu, Xiao-Han Ma, Xue-Qi Liu.
      Diabetic nephropathy (DN) leads to significant renal tubular and interstitial damage, yet effective preventive and therapeutic strategies remain scarce. Abnormal mitophagy may contribute to DN progression, but the underlying regulatory mechanisms are poorly understood. Bcl-2-interacting protein 3 (BNIP3) expression is reduced in renal tubular cells from both renal biopsies of patients with DN and db/db mice, correlating significantly with urinary albumin-to-creatinine ratio (UACR) and various clinicopathological markers in patients with DN. Gain-of-function experiments in vitro and in vivo confirmed its role in DN pathogenesis. Overexpression of BNIP3 mitigated kidney injury molecule-1 (Kim-1) levels and restored mitophagy function in db/db mice and high glucose-treated renal tubular cells. Bioinformatics analysis identified a high probability of transcription factor binding sites within the BNIP3 sequence, with signal transducer and activator of transcription 3 (STAT3) showing the strongest positive correlation. Knockdown of STAT3 in high glucose (HG)-stimulated mouse renal tubular epithelial cells (MTECs) resulted in increased BNIP3 expression. ChIP assays further revealed that high glucose enhanced STAT3 binding to the BNIP3 promoter. In conclusion, this study demonstrates that BNIP3 expression correlates with the clinical progression of DN, and its overexpression mitigates renal tubular injury by restoring mitophagy. Thus, BNIP3 presents a potential biomarker for the prevention and treatment of DN.
    Keywords:  BNIP3; Diabetic nephropathy; Mitophagy; STAT3; Tubulointerstitial injury
    DOI:  https://doi.org/10.1016/j.bcp.2025.117440
  31. PLoS Biol. 2025 Oct;23(10): e3003453
    Targeting mitochondrial structure and dynamics for therapeutic intervention in cancer.
    Wakiko Iwata, Nora Haggerty, Hiromi Sesaki, Miho Iijima.
      Mitochondrial division and fusion are critical regulators of cancer cell metabolism, proliferation, survival, metastasis, and drug resistance. Division promotes tumor development by reprogramming energy metabolism, whereas its inhibition can suppress tumor growth and metastasis. The mechanochemical GTPase DRP1, a key mediator of mitochondrial division, has emerged as a promising therapeutic target. Mitochondrial cristae also contribute to cancer progression by modulating metabolic reprogramming and oncogenic signaling. Targeting these processes may stimulate anti-tumor innate immune responses through the release of mitochondrial DNA into the cytoplasm. A deeper understanding of tumor-specific mitochondrial membrane structures and dynamics could therefore reveal novel intervention strategies and guide precision cancer therapies.
    DOI:  https://doi.org/10.1371/journal.pbio.3003453
  32. Exp Lung Res. 2025 ;51(1): 104-122
    Pulmonary metabolic imbalances and mitochondrial ultrastructural remodeling in lipopolysaccharide-induced acute respiratory distress syndrome.
    Wen Tan, Li Yu, Maomao Liu, Yu Zhang, Shiyun Tan, Nan Liu.
       STUDY AIM: Acute respiratory distress syndrome (ARDS) is a critical disease of high mortality. Recent studies have confirmed that metabolic alterations and mitochondrial dysfunction is in involved in the progression of various pulmonary diseases. Moreover, significantly altered metabolite abundances are important in determining the severity of ARDS. Therefore, this study aims to illuminate the pulmonary metabolic profile, investigate the mitochondrial features of ARDS via the integration of metabolomic and transcriptomic analyses, elucidate the pathogenetic mechanism of ARDS.
    METHODS: Metabolomic data from ARDS patients were downloaded and reanalyzed. Then Mice were randomly allocated into one of three groups as follows: the sham group; the LPS-2 day group (L2); and the LPS-4 day group (L4). All the mice in LPS group were anesthetized and received an intratracheal instillation of LPS. The sham group mice received only sterile saline. Pulmonary metabolic profiles were measured by integrating metabolomic analyses with transcriptomic analyses, and mitochondrial features in the mouse lungs were investigated via integrative -omics, mitochondrial ultrastructural detection and mitochondrial dynamics quantification.
    RESULTS: Inflamed lungs induce global metabolic perturbations that limit fatty acid oxidation, facilitate glucose consumption, accelerate amino acid metabolism and anaplerotic flux in the TCA cycle. In addition, impaired energetics followed by mitochondrial morphology alteration and mitochondrial dynamics imbalance are also validated in lung of ARDS.
    CONCLUSIONS: Global metabolic imbalance and substantial mitochondrial ultrastructural remodeling, characterized by a reduction in cristae density with significant activation of mitochondrial fission processes, have been verified to be pathogenic mechanisms in the lungs of ARDS patients.
    Keywords:  Acute respiratory distress syndrome; integrative omics; metabolic imbalances; metabolomics; mitochondrial dynamics
    DOI:  https://doi.org/10.1080/01902148.2025.2571783
  33. Zhen Ci Yan Jiu. 2025 Oct 25. pii: 1000-0607(2025)10-1124-09. [Epub ahead of print]50(10): 1124-1132
    [Effects of heat-reinforcing acupuncture on Drp1/Mff pathway activity and mitochondrial quality in rabbits with cold-dampness rheumatoid arthritis].
    Wei-Yao Jing, Cong-Hui Xu, Cui Liu, Li-Mei Liu, Bo Yuan, Xing-Hua Zhang, Feng-Fan Zhang, Ping Chen, Xiao-Zheng DU.
       OBJECTIVES: To observe the efficacy of heat-reinforcing acupuncture at "Zusanli" (ST36) in rabbits with cold-dampness rheumatoid arthritis (RA) and its impact on mitochondrial quality and the dynamin-related protein 1 (Drp1)/mitochondrial fission factor (Mff) pathway in knee synovial tissue.
    METHODS: Twenty-four New Zealand white rabbits were randomly divided into a normal group, a model group, a heat-reinforcing acupuncture group, and an inhibitor group, with 6 rabbits in each group. A cold-dampness RA rabbit model was established using complete Freund's adjuvant-ovalbumin mixture combined with an artificial climate chamber. Rabbits of the heat-reinforcing acupuncture group received heat-reinforcing acupuncture at ST36 once daily for 14 d. Rabbits of the inhibitor group was intraperitoneally injected with the mitochondrial division inhibitor Mdivi-1 (2.5 mg/kg) once every 2 d for a total of 7 times. Rabbits of the normal and model groups were handled and restrained in the same manner but received no other interventions. Knee arthritis scores, mechanical pain thresholds, and joint circumference were assessed after modeling and intervention. Hematoxylin-eosin (HE) staining was used to observe pathological changes in knee synovial tissue. Transmission electron microscopy was used to observe the ultrastructure of mitochondria in synovial cells. Luciferase method was used to measure ATP content in knee synovial tissue. Immunofluorescence staining was used to detect mitochondrial reactive oxygen species (mtROS) expression and Drp1/Mff co-localization in synovial tissue, and Western blot was used to measure the relative expression levels of phosphorylated(p)-Drp1 s616/Drp1 and Mff protein.
    RESULTS: Compared with the normal group, the model group showed increased arthritis scores, joint circumference, mtROS expression, p-Drp1 s616/Drp1 and Mff protein expression, and Drp1/Mff co-localization in knee synovial tissue(P<0.01), while mechanical pain thresholds and ATP content in synovial tissue were significantly decreased (P<0.01). Following acupuncture intervention, compared with the model group, the heat-reinforcing acupuncture group and the inhibitor group showed significantly reduced arthritis scores, joint circumference, mtROS expression , p-Drp1 s616/Drp1 and Mff protein expression, and Drp1/Mff co-localization in synovial tissue(P<0.01), while mechanical pain thresholds and ATP content in synovial tissue were significantly increased (P<0.01). In the model group, synovial tissue showed significant synovial cell proliferation, with visible inflammatory cell infiltration and synovial matrix proliferation in the synovium;synovial cells had indistinct mitochondrial cristae, mitochondrial swelling/rupture, and mitochondrial fragmentation into small bodies. These changes in synovial tissue were alleviated in both the heat-reinforcing acupuncture group and the inhibitor group.
    CONCLUSIONS: Heat-reinforcing acupuncture can significantly improve symptoms in RA rabbits with cold-dampness and enhance mitochondrial quality in synovial cells, which may be related to the inhibition of Drp1/Mff pathway activity.
    Keywords:  Dynamin-related protein 1/mitochondrial fission factor pathway; Heat-reinforcing acupuncture; Mitochondrial quality; Rheumatoid arthritis
    DOI:  https://doi.org/10.13702/j.1000-0607.20240689
  34. Neurotherapeutics. 2025 Oct 21. pii: S1878-7479(25)00245-4. [Epub ahead of print] e00767
    Paricalcitol-mediated vitamin D receptor activation attenuates neuronal ferroptosis via cAMP-PKA-DRP1 signaling pathway after intracerebral hemorrhage.
    Mi Tian, Xin Li, Dongqing Qi, Pengju Wei, Peng Jin.
      The Vitamin D Receptor (VDR) is an emerging therapeutic target for neurological injuries, yet its role in neuronal ferroptosis and mitochondrial dynamics following intracerebral hemorrhage (ICH) remains undefined. This study aimed to determine if VDR activation protects neurons by regulating mitochondrial fission via the Cyclic Adenosine Monophosphate - Protein Kinase A - Dynamin-related Protein 1 (cAMP-PKA-DRP1) signaling pathway. We utilized a mouse ICH model and a hemin-induced injury model in primary neurons to evaluate the neuroprotective efficacy of the selective VDR agonist, Paricalcitol (PAL). Our results first establish that VDR is a key neuronal target, as its expression is robustly upregulated in perihematomal neurons both in vivo and in vitro. Systemic PAL administration in mice conferred significant neuroprotection, reducing acute neuronal death, suppressing ferroptosis, and preventing excessive mitochondrial fission, which translated into lasting improvements in long-term cognitive function and synaptic integrity. Mechanistically, we demonstrate that PAL's anti-ferroptotic action is a direct neuroprotective effect, independent of microglial hematoma clearance. The core signaling cascade involves VDR-dependent activation of the cAMP-PKA pathway, leading to an increase in the inhibitory phosphorylation of DRP1 at Ser637. The necessity of this pathway was confirmed as the protective effects of PAL were abrogated by VDR knockdown or cAMP inhibition. Critically, its sufficiency was demonstrated as direct activation of the pathway with an agonist mimicked PAL's anti-ferroptotic effects. Collectively, these findings reveal that VDR activation by paricalcitol ameliorates neuronal injury after ICH by directly inhibiting ferroptosis through the cAMP-PKA-DRP1-mediated preservation of mitochondrial integrity, highlighting a potent therapeutic strategy.
    Keywords:  Ferroptosis; Intracerebral hemorrhage; Mitochondrial fission; Paricalcitol; Vitamin D receptor
    DOI:  https://doi.org/10.1016/j.neurot.2025.e00767
  35. Nat Aging. 2025 Oct 22.
    Author Correction: Mitochondria-associated condensates maintain mitochondrial homeostasis and promote lifespan.
    Yan Bai, Tengfei Ma, Shan Zhao, Shalan Li, Xin Wang, Jingyang Li, Wenhao Sun, Yang Yang, Fenglian Liu, Qian Shan, Zizhen Qin, Nan Liu, Jie Zhang, Fei Tian, Mei Duan, Shunkai Chen, Fan Lai, Qingfeng Chen, Xuna Wu, Chonglin Yang.
      
    DOI:  https://doi.org/10.1038/s43587-025-01015-9
  36. Inflamm Res. 2025 Oct 22. 74(1): 146
    Mitochondrial proteomics reveals the impact of Estrogen in enhancing energy metabolism of patient-derived fibroblast-like synoviocytes in rheumatoid arthritis.
    Swati Malik, Debolina Chakraborty, Prachi Agnihotri, Ashish Sarkar, Lovely Joshi, Mohd Saquib, Vijay Kumar, Sagarika Biswas.
      Mitochondrial dysfunction drives Rheumatoid Arthritis (RA) progression by disturbing energy metabolism and promoting inflammation. Additionally, the female predominance of RA highlights estrogen deficiency as an important contributor to disease development. The effect of estrogen in RA has been investigated; however, its specific effects on the mitochondrial proteome and function have yet to be studied. This study investigated the effects of 17-β estradiol (E2) on the mitochondrial proteome of patient-derived RA fibroblast-like synoviocytes (RA-FLS) using Sequential Window Acquisition of all Theoretical Mass Spectra (SWATH-MS) analysis, followed by an assessment of key mitochondrial functional parameters and in vitro validation. The results identified an upregulated expression of two mitochondrial proteins, Acyl-CoA dehydrogenase very long chain (ACADVL) and ATP synthase subunit O (ATP5O), after E2 treatment in RA-FLS. This was further validated by increased real-time ATP production and reduced glycolytic capacity, along with increased expression of proteins related to fatty acid β-oxidation. In addition, E2 influenced mitochondrial dynamics by modulating the fission-fusion balance, resulting in improved mitochondrial morphology. E2 treatment also reduced the expression of mitophagy markers and increased mitochondrial membrane potential, indicating improved mitochondrial function. It also lowered mitochondria-centered oxidative stress by upregulating mitochondrial antioxidant enzymes. Mitochondrial proteomics analysis thus, demonstrated that E2 has the potential to enhance mitochondrial energy metabolism and alleviate mitochondrial dysfunction in RA. These findings provide a foundation for further exploration of mitochondria-targeted therapeutic approaches in RA management.
    Keywords:  Energy metabolism; Estrogen; Mitochondria; Mitochondrial proteomics; Rheumatoid arthritis; Synovial fibroblast
    DOI:  https://doi.org/10.1007/s00011-025-02120-6
  37. J Zhejiang Univ Sci B. 2025 Aug 28. pii: 1673-1581(2025)10-0972-23. [Epub ahead of print]26(10): 972-994
    Roles of the Keap1/Nrf2 pathway and mitophagy in liver diseases.
    Qihui Zhou, Panpan Cen, Zhi Chen, Jie Jin.
      Nuclear factor erythroid 2-related factor 2 (Nrf2) is an intracellular transcription factor that helps protect against oxidative stress in different types of cells under pathological conditions. Mitochondria are vital organelles that function in diverse metabolic processes in the body, including redox reactions, lipid metabolism, and cell death. Mitophagy, a specific form of autophagy for damaged mitochondria, plays a critical role in the pathophysiology of liver diseases. In this review, we explain in detail the roles of the Nrf2 signaling pathway and mitophagy, and the relationship between them, in various hepatic diseases (nonalcoholic fatty liver disease, viral hepatitis, alcoholic liver disease, drug-induced liver injury, autoimmune hepatitis, hepatic ischemia‒reperfusion injury, and liver cancer). We also offer some potential insights and treatments relevant to clinical applications.
    Keywords:  Liver disease; Mitophagy; Nrf2 signaling pathway
    DOI:  https://doi.org/10.1631/jzus.B2400053
  38. Autophagy Rep. 2025 ;4(1): 2572511
    The multifaceted role of autophagy and mitophagy in cardiovascular health and disease.
    Mireia Nàger, Mauro Calvoli, Kenneth B Larsen, Asa B Birgisdottir.
      The cardiovascular system, consisting of the heart and blood vessels, ensures delivery of oxygen and nutrient-rich blood throughout the whole body. The major cell types include cardiomyocytes, endothelial cells, and vascular smooth muscle cells. Dramatic consequences, sometimes with a deadly outcome, may arise when the activity of cardiovascular cells is compromised. The cardiomyocytes are terminally differentiated cells and thus do not normally regenerate. To sustain the high energy demand of the beating heart, the cardiomyocytes contain a high amount of energy producing mitochondria. Adaptation to metabolic demands is an integral part of cellular homeostasis and involves autophagy. Autophagy is an evolutionary conserved intracellular degradation pathway of cellular constituents. Mitophagy refers to selective degradation of damaged, and thus potentially harmful, mitochondria through autophagy. Both autophagy and mitophagy are widely implicated in physiological and pathological processes within cardiovascular cells. In this review, we highlight studies applying genetic modifications in mouse models to reveal the impact of autophagy and mitophagy on cardiovascular health and disease.
    Keywords:  Aging; atherosclerosis; development; genetic mouse models; heart failure; myocardial infarction
    DOI:  https://doi.org/10.1080/27694127.2025.2572511
  39. Zhen Ci Yan Jiu. 2025 Oct 25. pii: 1000-0607(2025)10-1133-10. [Epub ahead of print]50(10): 1133-1142
    [Electroacupuncture improves NLRP3-mediated inflammation and gastric motility in diabetic gastroparesis rats by activating AMPK and regulating mitochondrial homeostasis].
    Hao Huang, Yan Peng, Le Xiao, Jing Wang, Zi-Wei Xie, Yu-Hong Xin, Xing Wei.
       OBJECTIVES: To observe whether the effect of electroacupuncture(EA) on the improvement of NOD-like receptor protein 3 (NLRP3)-mediated inflammation and gastric motility in diabetic gastroparesis (DGP) rats is exerted through the activation of AMP-activated protein kinase(AMPK) and the protection of mitochondrial homeostasis, so as to explore the mechanism of EA in the prevention and treatment of DGP.
    METHODS: Forty SD rats were randomly divided into the control group and modeling group, and the ones in modeling group were injected with 2% streptozotocin and fed with high-glucose and high-fat diet irregularly. The 20 successfully modeled rats were randomized into the model group and EA group with 10 rats each. Rats in the EA group received EA at "Zusanli" (ST36), "Liangmen" (ST21) and "Sanyinjiao" (SP6) with sparse and dense waves of 20 Hz/100 Hz for 15 min, while rats in the control and model group received bundled controls. Blood glucose, general symptoms, gastric emptying rate and small intestinal propulsion rate were observed in each group. Hematoxylin-eosin(HE) staining was used to observe the pathological changes of gastric antrum tissues. Western blot was used to detect the protein expression of AMPK, phosphorylated AMPK (p-AMPK), and NLRP3 in gastric antrum tissue, and transmission electron microscopy was used to observe the mitochondrial ultrastructure in gastric antrum cells. Dihydroethidium (DHE) fluorescent probe was used to detect the level of reactive oxygen species (ROS), the JC-1 method was used to detect changes in mitochondrial membrane potential, while a biochemical assay kit was employed to measure adenosine triphosphate (ATP) levels in gastric antrum tissue.
    RESULTS: After modeling, compared with the control group, the blood glucose levels and general symptom scores of rats in the modeling group were significantly increased (P<0.01) while gastric emptying rate and intestinal propulsion rate were significantly decreased(P<0.01). After intervention, compared with the control group, blood glucose and symptom scores remained elevated, gastric emptying rate and intestinal propulsion rate were significantly decreased (P<0.01) in the model group, while gastric antrum tissues showed obvious inflammatory damage. Meanwhile, the model group exhibited decreased AMPK and p-AMPK protein expression levels and increased NLRP3 protein expression level(P<0.01), mitochondrial structure was severely damaged, with an increase in the intracellular ROS content (P<0.01), and a decrease in the mitochondrial membrane potential level and ATP content (P<0.01). Compared with the model group, rats in the EA group had lower blood glucose levels and general symptom scores (P<0.05) and higher gastrointestinal propulsion (P<0.01), and EA had improved gastric histopathology. The expression of AMPK and p-AMPK proteins were increased while NLRP3 protein was decreased in gastric antrum tissue (P<0.01). The ultrastructure of mitochondria was improved, and ROS content was decreased (P<0.01), the mitochondrial membrane potential level and ATP content were elevated (P<0.01).
    CONCLUSIONS: EA may improve DGP by activating AMPK to improve damaged mitochondrial structure and function and promote the restoration of mitochondrial homeostasis, thereby inhibiting NLRP3 inflammasome and its mediated inflammation in gastric antrum tissues.
    Keywords:  AMP-activated protein kinase; Diabetic gastroparesis; Electroacupuncture; Mitochondria; Nod-like receptor protein 3
    DOI:  https://doi.org/10.13702/j.1000-0607.20240614
  40. FEBS Lett. 2025 Oct 25.
    The IQ-compete assay for measuring mitochondrial protein import efficiencies in living yeast cells.
    Yasmin Hoffman, Annika Egeler, Saskia Rödl, Johannes M Herrmann.
      Most mitochondrial proteins are synthesized in the cytosol and imported into the organelle. Here, we describe a novel Import and de-Quenching Competition (IQ-compete) assay which monitors the import efficiency of model proteins by fluorescence in living cells. For this method, the sequence of the tobacco etch virus (TEV) protease is fused to a mitochondrial precursor and coexpressed with a cytosolic reporter which becomes fluorescent upon TEV cleavage. Thus, inefficient import of the fusion protein leads to a fluorescent signal. With the IQ-compete assay, the import efficiency of proteins can be reliably analyzed in fluorescence readers, by flow cytometry, by microscopy, and by western blotting. We are convinced that the IQ-compete assay will be a powerful strategy for many different applications. Impact statement This article describes a novel method to monitor the mitochondrial import efficiency for a given protein in living yeast cells. With this IQ-compete assay, protein import efficiencies can be quantified by fluorescent microscopy, flow cytometry, fluorescence spectrometry or western blotting.
    Keywords:  fluorescence quenching; genetically encoded sensors; mitochondria; presequences; protein targeting
    DOI:  https://doi.org/10.1002/1873-3468.70206
  41. Cardiol Res Pract. 2025 ;2025 5677597
    Inhibition of MARK4 Promotes Mitochondrial Biogenesis by Inducing the Phosphorylation of AMPKα to Reduce Myocardial Damage in Rats With Myocardial Infarction.
    Yi Wu, Sai Wang, Jingqi Zhang, Weiyi Wang, Zhi Zeng, Lu Fu, Bin Li.
       Purpose: Mitochondrial biogenesis is an important factor affecting the development of acute myocardial infarction. MAP/MARK4, a member of the MAP serine/threonine kinase (MARK) family, is involved in a variety of physiological processes. The aim of this study was to investigate the role of microtubule affinity-regulating kinase 4 (MARK4) in regulating mitochondrial biogenesis in rats with myocardial infarction.
    Methods: One week after the left anterior descending, coronary artery was ligated to establish a myocardial infarction model, and MARK4 expression was knocked down in mice. In the fifth week, changes in cardiac function and structure, the myocardial BNP and ATP content, mitochondrial ultrastructure, and the mitochondrial membrane potential and reactive oxygen species levels were observed and detected, and the levels of AMPKα and mitochondrial biogenesis- and apoptosis-related proteins were detected using western blot analysis.
    Results: We found that downregulating the expression of MARK4 in rats with myocardial infarction improved cardiac function, alleviated cardiac pathological injury and restored damaged mitochondrial membrane potential, effectively inhibited myocardial apoptosis and restored the myocardial energy supply, and promoted mitochondrial biosynthesis by increasing AMPKα phosphorylation. However, the addition of an AMPKα inhibitor after MARK4 knockdown did not affect mitochondrial biosynthesis in cardiomyocytes, indicating that the inhibition of MARK4 expression may be a promising therapeutic target for myocardial infarction.
    Conclusion: Inhibition of MARK4 expression in rats with myocardial infarction plays a cardioprotective role and promotes mitochondrial biogenesis by promoting AMPKα phosphorylation.
    Keywords:  AMP-activated protein kinase α; apoptosis; microtubule affinity–regulating kinase 4; mitochondrial biosynthesis; myocardial infarction
    DOI:  https://doi.org/10.1155/crp/5677597
  42. Steroids. 2025 Oct 18. pii: S0039-128X(25)00144-8. [Epub ahead of print] 109703
    Soy isoflavone Daidzein resembling the vertebrate steroid structure exhibits neuroprotection via mitochondrial biogenesis in rotenone induced Parkinson's disease in preclinical model.
    Vaibhavi Peshattiwar, Suraj Muke, Aakruti Kaikini, Sneha Bagle, Vikas Dighe, Sadhana Sathaye.
      Parkinson's disease (PD) ranks as the second most prevalent neurodegenerative disorder but is still devoid of neuroprotective treatment. Although approaches with disease modifying ability along with symptomatic relief has become an utmost necessity, the multifactorial nature of PD presents challenges for efficacy evaluation of potential test compound. This study attempts to address these issues by employing a rotenone induced PD model involving intranigral rotenone injection for evaluation of the neuroprotective efficacy of Daidzein (DZ) a soy isoflavone and a phytoestrogen. In this study, male Sprague Dawley rats after bilateral intranigral rotenone (12 μg) injection, were treated with DZ at a dose of 5, 10 and 20 mg/kg for 30 days. The neurobehavioral evaluation comprised of Rota-rod, Open field and Barnes maze test. The biochemical analysis constituting oxidative stress (Reduced glutathione, superoxide dismutase, catalase and lipid peroxidation), inflammation (TNF-α), mitochondrial alteration (complex I activity and biogenesis) was conducted on mid-brain tissue after 30 days of treatment. The Substantia nigra and striatum were subjected to immunohistochemical analysis (IHC) for TH positive neurons and Glial Fibrillary Acidic Protein. The analysis revealed significant improvement by daidzein in motor co-ordination and attenuation in cognitive deficits due to rotenone. The biochemical assessment exhibited significant decrement in oxidative stress as well as inflammation. DZ treatment also prevented complex I inhibition and promoted mitochondrial biogenesis eventually contributing to the neuroprotection apparent in IHC. Thus, the results strongly corroborate the neuroprotective potential of DZ against rotenone induced model of PD.
    Keywords:  Complex I; Daidzein; Mitochondrial biogenesis; Neuroprotection; Phytoestrogen; Rotenone; Steroid structure
    DOI:  https://doi.org/10.1016/j.steroids.2025.109703
  43. Res Vet Sci. 2025 Oct 16. pii: S0034-5288(25)00415-1. [Epub ahead of print]197 105941
    Hypoxia promotes mitochondrial biogenesis in myocardium of broiler with pulmonary hypertension syndrome through AMPK/PGC-1 alpha pathway.
    M L Jiang, Y Y Yang, M Y Li, X Y Jiang, L M Hu, Y Li, H Zhang, J Z Liao, Z X Tang, J Q Pan.
      Hypoxia is a leading cause of myocardial damage and pulmonary hypertension syndrome (PHS) in broiler. Congenital or acquired myocardial dysfunction is associated with abnormal expression of peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) and its target gene. Here, we investigate the relationship between PGC-1α expression and mitochondrial biogenesis in cardiomyocytes of PHS broiler. For in vivo study, PHS was induced by intravenously injection of CM-32 cellulose through wing vien. For in vitro study, a hypoxia chamber was used, and cardiomyocytes from broiler were cultured with or without hypoxia treatment. The result showed that PGC-1α expression in myocardia of PHS broiler was significantly increased compared with birds in control group. Transmission electron microscopy revealed an increased quantity of mitochondria and ultrastructural abnormalities in myocardial of PHS broiler. Histopathological examinations indicated that the myocardial tissues of PHS broilers showed varying degrees of degenerative remodel compared with controls. In vitro studies showed that hypoxia induced an increase in ROS production, promoted PGC-1α expression, stimulated mitochondrial biosynthesis, and increased ATP content in cardiomyocytes. Further studies suggest that hypoxia-induced PGC-1α expression is regulated through the AMPK signaling pathway. In conclusion, our data suggest that hypoxia stimulates PGC-1α expression and mitochondrial biosynthesis in cardiomyocytes. This process may provide a potential adaptive mechanism for cardiomyocytes to increase ATP production to attenuate hypoxic damage to the heart in the pathological process of PHS.
    Keywords:  AMPK; Hypoxia; Mitochondrial biogenesis; Myocardium; PGC-1α; PHS
    DOI:  https://doi.org/10.1016/j.rvsc.2025.105941
  44. Redox Biol. 2025 Oct 08. pii: S2213-2317(25)00397-0. [Epub ahead of print]87 103884
    The mitochondrial disulphide relay substrate FAM136A safeguards IMS proteostasis and cellular fitness.
    Christine Zarges, Hanna Fieler, Robin Alexander Rothemann, Simon Poepsel, Lucas T Jae, Jan Riemer.
      The mitochondrial disulphide relay is the key machinery for import and oxidative protein folding in the mitochondrial intermembrane space. Among IMS proteins with unknown function, we identified FAM136A as a new substrate of the mitochondrial disulphide relay. We demonstrate a transient interaction between FAM136A and MIA40, and that MIA40 introduces four disulphide bonds in two twin-CX3C motifs of FAM136A. Consequently, IMS import of FAM136A requires these cysteines and its steady state levels in intact cells are strongly dependent on MIA40 and AIFM1 levels. Furthermore, we show that FAM136A forms non-covalent homodimers as a mature protein. Acute deletion of FAM136A curtails cellular proliferation capacity and elicits a robust induction of the integrated stress response, coincident with the aggregation and/or depletion of selected IMS proteins including HAX1 and CLPB. Together, this establishes FAM136A as a pivotal component of the IMS proteostasis network, with implications for overall cellular function and health.
    Keywords:  FAM136A; Integrated stress response; MIA40; Oxidative protein folding
    DOI:  https://doi.org/10.1016/j.redox.2025.103884
  45. J Agric Food Chem. 2025 Oct 24.
    Maternal Exposure to Combined Cadmium and Polystyrene Nanoplastics Induces Offspring Testicular Dysplasia via Mitochondrial Reactive Oxygen Species Overactivating the Peroxisome Proliferator-Activated Receptor α-Mediated Autophagy Signaling Pathway.
    Ruiying Zhang, Penghui Nie, Yudeng Wang, Yueying Feng, Yuanyuan Xu, Hengyi Xu, Fen Fu.
      Nanoplastics (NPs) can carry other environmental contaminants, including heavy metals, such as cadmium, which is one of the most prevalent heavy metals found in polluted soil in China; cadmium has high toxicity and coexists with microplastics in oceans and soils. Therefore, further investigation over the combined toxicity of NPs and cadmium is necessary. Herein, transcriptomics was used to assess the effect of maternal perinatal exposure to polystyrene nanoplastics (PS-NPs) and cadmium on offspring. The results revealed that the sex ratio of offspring drastically changed, the hormone levels in male mouse offspring were affected, testicular mitochondrial dysfunction with mitochondrial reactive oxygen species (mtROS) accumulation occurred, and the peroxisome proliferator-activated receptor α (PPARα)-mediated autophagy signaling pathway was overactivated, thereby leading to uncontrolled apoptosis and proliferation inhibition. Briefly, the potential mechanism is that maternal exposure to combined cadmium and PS-NPs caused mtROS accumulation, thereby inducing excessive autophagy by activating the PPARα-mediated autophagy signaling pathway in offspring testes.
    Keywords:  cadmium; mitophagy; polystyrene nanoplastics; reproduction toxicity; transcriptome sequencing
    DOI:  https://doi.org/10.1021/acs.jafc.5c10361
  46. Cell Signal. 2025 Oct 20. pii: S0898-6568(25)00597-2. [Epub ahead of print]136 112182
    IL-11 exacerbates cisplatin-induced acute kidney injury by facilitating apoptosis in renal tubular epithelial cells via ERK1/2-Drp1/TFEB-mediated defective autophagy.
    Danping Tao, Wenting Wu, Zerong Zheng, Hui Zhang, Yue Ji, Yiyi Zhuang, Huizhen Wang, Fenfen Peng, Xiaowen Chen, Haibo Long, Congwei Luo.
      Cisplatin-induced acute kidney injury (Cis-AKI) lacks targeted therapies. Here we identify interleukin-11 (IL-11) as a key driver of tubular injury that couples mitochondrial dynamics to autophagic flux in renal tubular epithelial cells. In a mouse Cis-AKI model, IL-11 knockdown ameliorated tubular damage and significantly improved renal function (serum creatinine, blood urea nitrogen), with concordant restoration of AQP1 and reduction of KIM-1/NGAL, indicating robust protection at the tissue and functional levels. Mechanistically, IL-11 activated ERK1/2, increased Drp1 phosphorylation and mitochondrial fission, and suppressed TFEB activity to impair lysosomal maturation and autophagic flux; ERK inhibition (SCH772984) and TFEB overexpression rescued TFEB activity, lysosomal markers, and autophagic completion, and reduced apoptosis/senscence. Tissue-level readouts (IHC for p-Drp1 and p62; immunoblots for LC3-I/II and p62) and TEM ultrastructure corroborated these pathways in vivo, linking mitochondrial fragmentation and autophagic blockade to IL-11-dependent injury. In HK-2 cells, recombinant human IL-11 (50 ng/mL) reproduced ERK-Drp1/TFEB pathway activation and phenotypes, and loss-of-function of IL-11 attenuated cisplatin-induced apoptosis and senescence. Collectively, these data define an ERK1/2-Drp1/TFEB axis by which IL-11 exacerbates Cis-AKI through mitochondrial dysfunction and autophagic flux disruption, culminating in apoptosis and cellular senescence. Targeting IL-11 or restoring TFEB activity emerges as a mechanism-based strategy to mitigate cisplatin nephrotoxicity.
    Keywords:  AKI; Drp1; ERK1/2; IL-11; TFEB
    DOI:  https://doi.org/10.1016/j.cellsig.2025.112182
  47. Toxicol Sci. 2025 Oct 24. pii: kfaf149. [Epub ahead of print]
    Gossypol acetic acid affects locomotor activity by inducing mitophagy-related ferroptosis and apoptosis in zebrafish.
    Yuxin Wang, Fangzhen Li, Liyan Xu, Hanxue Zhao, Attila Sik, Kechun Liu, Rongchun Wang.
      Gossypol acetic acid (GAA), a medicinal form of Gossypol, is a natural phenolic compound found in cottonseed, which possesses various biological activities, such as anti-fertility, antiviral, anti-inflammatory, antibacterial, and anticancer properties. However, its potential risks to aquatic organisms are poorly investigated. Here, the toxic effects on locomotor activity and the underlying mechanism were assessed in vitro and in vivo, using the zebrafish model and PC12 cells. The results showed that after treatment from 6 hpf (hour post fertilization) to 120 hpf, 0.8 μM GAA significantly reduced the locomotor activity of zebrafish larvae. In addition, 0.6 μM and 0.8 μM GAA disrupted the dopamine neurons and the central nervous system, further inhibiting swimming activity. Furthermore, the muscle sarcomeres and hair cells of zebrafish larvae were affected after GAA exposure. Moreover, after GAA exposure, Fe2+ accumulated in the 0.6 μM and 0.8 μM GAA groups, and reactive oxygen species (ROS) increased, especially in the head region. In addition, apoptosis could be observed in both the head and tail muscle regions. RT-qPCR results showed that GAA dysregulated the mRNA expression of the genes correlated to mitophagy, oxidative stress and ferroptosis pathways. The in vitro study using PC12 cells also showed that GAA could induce mitochondrial membrane potential rise, ROS generation, apoptosis and ferroptosis. These results indicate that GAA affects locomotor activity by disrupting the nervous system and muscle in zebrafish, and its toxicity is closely related to mitochondria dysfunction, oxidative stress, apoptosis and ferroptosis.
    Keywords:  Ferroptosis; Gossypol acetic acid; Neurotoxicity; Zebrafish
    DOI:  https://doi.org/10.1093/toxsci/kfaf149
  48. Clin Exp Ophthalmol. 2025 Oct 22.
    FLVCR1 Deficiency Impairs Mitochondrial Homeostasis in Retinal Degeneration: Choline as a Potential Therapy.
    Yi Wang, Hongjing Li, Yingjie Gao, Qianxiong He, Jinrui Cai, Rong Zou, Xianjun Zhu, Lin Zhang.
       BACKGROUND: The Feline Leukaemia Virus Subgroup C Receptor 1 (FLVCR1) has been recognized as a heme exporter essential for erythropoiesis, and emerging research identifies its novel function as a choline transporter. Mutations in FLVCR1 have been associated with the pathogenesis of retinitis pigmentosa (RP); however, the roles of FLVCR1 in retina remain unexplored. This study aims to elucidate the connection between FLVCR1 and RP and investigate potential therapeutic interventions.
    METHODS: Utilizing CRISPR/Cas9 technology, we established retina-specific Flvcr1 knockout (SKO) and rod-specific Flvcr1 knockout (RKO) mouse models to investigate the in vivo functions of FLVCR1 in the retina. We performed optical coherence tomography (OCT) to assess the retinal thickness, electroretinography (ERG) to test the retinal function and histopathological sections and staining to analyse the pathological changes. Additionally, we administered choline supplementation treatment (CST) to evaluate its potential efficacy in alleviating symptoms of retinal degeneration.
    RESULTS: Genotyping and immunoblotting analyses confirmed the successful establishment of the SKO and RKO mouse models. Retinal degeneration in SKO mice manifested at postnatal day 14, while its onset in RKO mice occurred at P25, including diminished scotopic electroretinogram (ERG) responses, progressive degeneration of photoreceptor cells, infiltration of microglia into the outer nuclear layer (ONL) and disruption of mitochondrial homeostasis. Notably, we found that choline supplementation in RKO mice alleviated the associated phenotypes.
    CONCLUSIONS: We developed two innovative mouse models and revealed that FLVCR1 is critical for maintaining mitochondrial homeostasis and supporting photoreceptor survival. Choline supplementation serves as a therapeutic intervention for RP caused by FLVCR1 mutations.
    Keywords:  FLVCR1; choline; mitochondrial homeostasis; retinal degeneration; retinitis pigmentosa
    DOI:  https://doi.org/10.1111/ceo.70014
  49. Mol Cell. 2025 Oct 20. pii: S1097-2765(25)00815-9. [Epub ahead of print]
    Delayed protein translocation protects mitochondria against toxic CAT-tailed proteins.
    Nils Bertram, Toshiaki Izawa, Felix Thoma, Serena Schwenkert, Stéphane Duvezin-Caubet, Sae-Hun Park, Nikola Wagener, Anne Devin, Christof Osman, Walter Neupert, Dejana Mokranjac.
      Ribosome-associated protein quality control (RQC) protects cells against the toxic effects of faulty polypeptides produced by stalled ribosomes. However, mitochondria are vulnerable to C-terminal alanyl and threonyl (CAT)-tailed proteins that are generated in this process, and faulty nuclear-encoded mitochondrial proteins are handled by the recently discovered mitoRQC. Here, we performed a genome-wide screen in yeast to identify additional proteins involved in mitoRQC. We found that peptidyl-tRNA hydrolase 2 (Pth2), present in the mitochondrial outer membrane, influences aggregation of CAT-tailed proteins without majorly affecting the CAT-tailing process itself. Peptidyl-tRNA hydrolase activity is essential during this process, yet the activity of Pth2 can be substituted by another peptidyl-tRNA hydrolase upon proper localization. Our data suggest that Pth2 acts by modulating protein translocation and that the mitochondrial proteostasis network is relieved through increased access of CAT-tailed proteins to cytosolic chaperones. Other hits obtained in the screen show that, in general, delayed protein translocation protects mitochondria against toxic CAT-tailed proteins.
    Keywords:  RQC; TOM complex; cellular homeostasis; mitoRQC; mitochondria; peptidyl-RNA hydrolase; protein translocation
    DOI:  https://doi.org/10.1016/j.molcel.2025.09.030
  50. Aging Dis. 2025 Oct 22.
    SIRT1-Mediated Mitochondrial Homeostasis in Cardiac Aging: Molecular Mechanisms and Therapeutic Implications.
    Sitong Chen, Hanying Xu, Xiaonan Li, Xiaolei Tang, Lan Yang, Jing Lu, Jun Li.
      Cardiovascular disease (CVD) remains the leading cause of global mortality and disability. As an inevitable risk factor, cardiac aging significantly exacerbates the incidence and progression of age-related cardiovascular pathologies, including coronary artery disease, cardiomyopathies, and heart failure in the elderly population. Mitochondria function as central organelles in cardiac energy metabolism. Dysregulation of functional homeostasis, characterized by impaired quality control mechanisms, such as diminished energy production efficiency and exacerbated oxidative stress, is a primary driver of the cardiac aging process. Accumulating evidence in recent years indicates that sirtuin 1 (SIRT1) plays a crucial role in regulating cardiac aging. A range of therapeutic agents, including natural compounds and synthetic molecules, ameliorate cardiac aging and related pathologies by activating SIRT1 to modulate mitochondrial function. This review systematically summarizes the emerging roles of SIRT1 in cardiac aging, with a focus on the molecular mechanisms through which SIRT1 governs mitochondrial homeostasis. We also highlight recent advances in SIRT1-targeted therapeutic strategies, thereby providing a theoretical basis and translational perspectives for preventing and treating cardiac aging-related diseases.
    DOI:  https://doi.org/10.14336/AD.2025.1128
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