Copper induces cell death by targeting lipoylated TCA cycle proteins

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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Affiliated Institutions

• Brigham and Women's Hospital US
• Center for Systems Biology US
• Dana-Farber Cancer Institute US
• Harvard University US
• Boston Children's Hospital US
• Johns Hopkins University US
• Broad Institute US
• Whitehead Institute for Biomedical Research US
• Massachusetts Institute of Technology US

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