Copper is an essential co-factor 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 copperdependent, regulated cell death is distinct from known death mechanisms, and is dependent on mitochondrial respiration. We show that copper-dependent death occurs via 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 leading to proteotoxic stress and ultimately cell death. These findings may explain the need for ancient copper homeostatic mechanisms.