Copper induces cell death by targeting lipoylated TCA cycle proteins.

Science
Authors
Keywords
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.

Year of Publication
2022
Journal
Science
Volume
375
Issue
6586
Pages
1254-1261
Date Published
2022 03 18
ISSN
1095-9203
DOI
10.1126/science.abf0529
PubMed ID
35298263
PubMed Central ID
PMC9273333
Links
Grant list
U54 CA225088 / CA / NCI NIH HHS / United States
K08 CA230220 / CA / NCI NIH HHS / United States
R35 CA242457 / CA / NCI NIH HHS / United States
R01 CA194005 / CA / NCI NIH HHS / United States
T32 GM007748 / GM / NIGMS NIH HHS / United States