ArticleActa pharmacologica Sinica2023
COX17 restricts renal fibrosis development by maintaining mitochondrial copper homeostasis and restoring complex IV activity.
Article in Acta pharmacologica Sinica, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 41 citations in OpenAlex.
- Mitochondrial dysfunction-ferroptosis crosstalk drives renal fibrosis in chronic kidney disease.Renal failure · 2026Review
- LSD1-mediated demethylation of the DNA damage response factor ATM promotes senescence and organ aging.The Journal of clinical investigation · 2026Article
- Copper Metabolism-Related Cell Death in Kidney Diseases: Molecular Mechanisms, Disease-Specific Evidence, and Translational Implications.International journal of molecular sciences · 2026Review
- Review
- From copper imbalance to immunometabolic remodeling: cuproptosis-related vulnerability and therapeutic hypotheses in autoimmune diseases.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2026Review
- From copper transport to cuproptosis: emerging therapeutic targets in cardiovascular disease.Molecular and cellular biochemistry · 2026Review
- Cuproptosis: potential new direction in liver-related diseases research and treatment.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2026Review
- Regulated cell death: a multidimensional regulatory network in the pathogenesis of renal fibrosis.Apoptosis : an international journal on programmed cell death · 2026Review
- Single-cell profiling and machine learning identify cuproptosis-related fibroblast subpopulations and fibrogenesis modulator AEBP1 in endometriosis.Apoptosis : an international journal on programmed cell death · 2026Article
- Associations of 24-h urinary excretion of heavy metals and trace elements with estimated glomerular filtration rate and chronic kidney disease.Scientific reports · 2026Article
- Lysophosphatidylcholine acyltransferase 1 promotes head and neck squamous cell carcinoma progression by enhancing COX17-dependent oxidative phosphorylation.Cell death discovery · 2026Article
- Cuproptosis promotes inflammatory osteolysis via GYS1-mediated glycogen metabolism.International journal of oral science · 2026Article
- Role of Copper Homeostasis and Cuproptosis in Cardiovascular Disease: Molecular Insights and Metabolic Perspectives.International journal of biological sciences · 2026Review
- p53-associated regulation of COX17 enhances elesclomol-induced copper-associated cytotoxicity and suppresses gastric cancer growth.Frontiers in immunology · 2026Article
- Copper-instigated modulatory cell mortality mechanisms and progress in kidney diseases.Renal failure · 2025Review
- Mitochondrial dysfunction: the hidden catalyst in chronic kidney disease progression.Renal failure · 2025Review
- Novel Evolutionarily Conserved Oncogene COA4 is Driven by KRAS Mutant and Promotes Cancer Metastasis Through Dual Mitochondrial Metabolism-Dependent and -Independent Mechanisms.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- MSCs-derived HGF alleviates senescence after AKI by modulating mitoSTAT3-controlled copper flux and respiration.Stem cell research & therapy · 2025Article
- Cuproptosis and Cardiovascular Diseases: Mechanisms, Pathophysiology, and Therapeutic Strategies-A Narrative Review.Reviews in cardiovascular medicine · 2025Review
- Evaluating the impact of environmental metal mixtures on chronic kidney disease risk: Insights from the National Health and Nutrition Examination Survey 2011-2016.The Journal of international medical research · 2025Article
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
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Abstract
Renal fibrosis relies on multiple proteins and cofactors in its gradual development. Copper is a cofactor of many enzymes involved in renal microenvironment homeostasis. We previously reported that intracellular copper imbalance occurred during renal fibrosis development and was correlated with fibrosis intensity. In this study, we investigated the molecular mechanisms of how copper affected renal fibrosis development. Unilateral ureteral obstruction (UUO) mice were used for in vivo study; rat renal tubular epithelial cells (NRK-52E) treated with TGF-β1 were adapted as an in vitro fibrotic model. We revealed that the accumulation of copper in mitochondria, rather than cytosol, was responsible for mitochondrial dysfunction, cell apoptosis and renal fibrosis in both in vivo and in vitro fibrotic models. Furthermore, we showed that mitochondrial copper overload directly disrupted the activity of respiratory chain complex IV (cytochrome c oxidase), but not complex I, II and III, which hampered respiratory chain and disrupted mitochondrial functions, eventually leading to fibrosis development. Meanwhile, we showed that COX17, the copper chaperone protein, was significantly upregulated in the mitochondria of fibrotic kidneys and NRK-52E cells. Knockdown of COX17 aggravated mitochondrial copper accumulation, inhibited complex IV activity, augmented mitochondrial dysfunction and led to cell apoptosis and renal fibrosis, whereas overexpression of COX17 could discharge copper from mitochondria and protect mitochondrial function, alleviating renal fibrosis. In conclusion, copper accumulation in mitochondria blocks complex IV activity and induces mitochondrial dysfunction. COX17 plays a pivotal role in maintaining mitochondrial copper homeostasis, restoring complex IV activity, and ameliorating renal fibrosis.
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