Copper induces cell death by targeting lipoylated TCA cycle proteins

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.

Automated summary

Copper is an essential cofactor for all organisms, but excessive copper can lead to cell death. We found that copper-dependent cell death mechanism is different from known mechanisms, and it is related to mitochondrial respiration. Copper directly binds to lipoylated components of the tricarboxylic acid cycle, causing protein aggregation and loss of iron-sulfur cluster proteins, ultimately leading to cell death.