Biology

Biophysics

Apoptosis

Programmed cell death

Metabolism

Cell biology

Tricarboxylic acid

Mitochondrion

Homeostasis

Biochemistry

Cell cycle

Cell

Organic chemistry

Enzyme

Chemistry

Citric acid cycle

Cofactor

Copper

Science

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.

Copper induces cell death by targeting lipoylated TCA cycle proteins