美国哈佛大学和麻省理工学院布罗德研究所Todd R. Golub和Peter Tsvetkov团队合作取得进展。他们表明铜通过靶向脂酰化三羧酸 (TCA) 循环蛋白诱导细胞死亡。相关论文发表在2022年3月18日出版的《科学》杂志上。

在人类细胞中，依赖于铜的、受调节的细胞死亡不同于已知的死亡机制，并且依赖于线粒体呼吸。他们表明，铜依赖性死亡是通过铜与TCA循环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并最终导致细胞死亡。这些发现可以解释对铜稳态机制的需求。

据介绍，铜是所有生物体必不可少的辅助因子，但如果浓度超过进化保守的稳态机制维持的阈值，它就会变得有毒。然而，过量的铜如何诱导细胞死亡尚不清楚。

附：英文原文

Title: Copper induces cell death by targeting lipoylated TCA cycle proteins

Author: 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

Issue&Volume: 2022-03-18

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.

DOI: abf0529

Source: https://www.science.org/doi/10.1126/science.abf0529