Copper exerts cytotoxicity through inhibition of iron-sulfur cluster biogenesis on ISCA1/ISCA2/ISCU assembly proteins

作者：Jing Du, Zhaoyang Huang, Yanchun Li, Yanchun Li, Xueying Ren, Chaoting Zhou, Ruolan Liu, Ping Zhang, Guojie Lei, Jianxin Lyu, Jianghui Li, Guoqiang Tan · 发表于：Free Radical Biology and Medicine · 年份：2023 · DOI：10.1016/j.freeradbiomed.2023.05.017 · 被引用次数：54 · 研究领域：Trace Elements in Health、Prion Diseases and Protein Misfolding、Iron Metabolism and Disorders

Copper is an essential mineral nutrient that provides the cofactors for some key enzymes . However, excess copper is paradoxically cytotoxic. Wilson’s disease is an autosomal recessive hereditary disease characterized by pathological copper accumulation in many organs, with high mortality and disability. Nevertheless, many questions about the molecular mechanism in Wilson’s disease remain unknown and there is an imperative need to address these questions to better exploit therapeutic strategy. In this study, we constructed the mouse model of Wilson’s disease, ATP7A −/− immortalized lymphocyte cell line and ATP7B knockdown cells to explore whether copper could impair iron-sulfur cluster biogenesis in eukaryotic mitochondria. Through a series of cellular, molecular, and pharmacological analyses, we demonstrated that copper could suppress the assembly of Fe–S cluster, decrease the activity of the Fe–S enzyme and disorder the mitochondrial function both in vivo and in vitro. Mechanistically, we found that human ISCA1, ISCA2 and ISCU proteins have a strong copper-binding activity, which would hinder the process of iron-sulfur assembly. Of note, we proposed a novel mechanism of action to explain the toxicity of copper by providing evidence that iron-sulfur cluster biogenesis may be a primary target of copper toxicity both in cells and mouse models. In summary, the current work provides an in-depth study on the mechanism of copper intoxication and describes a framework for the furth...