Copper induces cell death by targeting lipoylated TCA cycle proteins

IF 44.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Pub Date : 2022-03-17 DOI:10.1126/science.abf0529

Peter Tsvetkov, Shannon Coy, Boryana Petrova, Margaret Dreishpoon, Ana Verma, Mai Abdusamad, Jordan Rossen, Lena Joesch-Cohen, Ranad Humeidi, Ryan D. Spangler, John K. Eaton, Evgeni Frenkel, Mustafa Kocak, Steven M. Corsello, Svetlana Lutsenko, Naama Kanarek, Sandro Santagata, Todd R. Golub

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引用次数: 1017

Abstract

Copper is an essential cofactor for all organisms, and yet it becomes toxic if concentrations exceed a threshold maintained by evolutionarily conserved homeostatic mechanisms. How excess copper induces cell death, however, is unknown. Here, we show in human cells that copper-dependent, regulated cell death is distinct from known death mechanisms and is dependent on mitochondrial respiration. We show that copper-dependent death occurs by means of direct binding of copper to lipoylated components of the tricarboxylic acid (TCA) cycle. This results in lipoylated protein aggregation and subsequent iron-sulfur cluster protein loss, which leads to proteotoxic stress and ultimately cell death. These findings may explain the need for ancient copper homeostatic mechanisms.

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铜通过靶向脂酰化 TCA 循环蛋白诱导细胞死亡

铜是所有生物体内不可或缺的辅助因子，然而，如果铜的浓度超过了由进化保守的平衡机制维持的阈值，铜就会变成有毒物质。然而，过量的铜如何诱导细胞死亡尚不清楚。在这里，我们在人体细胞中发现，依赖铜的调节性细胞死亡不同于已知的死亡机制，它依赖于线粒体呼吸。我们发现，铜依赖性死亡是通过铜与三羧酸（TCA）循环中的脂酰化成分直接结合而发生的。这导致脂酰化蛋白质聚集和随后的铁硫簇蛋白质丢失，从而导致蛋白质毒性应激，最终导致细胞死亡。这些发现可以解释为什么需要古老的铜平衡机制。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Science 综合性期刊-综合性期刊

CiteScore

61.10

自引率

0.90%

发文量

审稿时长

2.1 months

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