Copper induces cell death by targeting lipoylated TCA cycle proteins

• Published in: Science (American Association for the Advancement of Science) Vol. 375; no. 6586; pp. 1254 - 1261
• Main Authors: Tsvetkov, Peter, Coy, Shannon, Petrova, Boryana, Dreishpoon, Margaret, Verma, Ana, Abdusamad, Mai, Rossen, Jordan, Joesch-Cohen, Lena, Humeidi, Ranad, Spangler, Ryan D., Eaton, John K., Frenkel, Evgeni, Kocak, Mustafa, Corsello, Steven M., Lutsenko, Svetlana, Kanarek, Naama, Santagata, Sandro, Golub, Todd R.
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 18.03.2022
• Subjects: Animals; Apoptosis; Cell death; Cell Respiration; Citric Acid Cycle; Copper; Copper - metabolism; Copper - toxicity; CRISPR; Death; Dihydrolipoyllysine-Residue Acetyltransferase - metabolism; Ferroptosis; Genetic modification; Hepatolenticular Degeneration - metabolism; Homeostasis; Humans; Hydrazines - toxicity; Ionophores - toxicity; Iron-Sulfur Proteins - metabolism; Lipoylation; Metabolic Networks and Pathways; Mice; Mitochondria; Mitochondria - metabolism; Mortality; Necroptosis; Proteins; Regulated Cell Death; Tricarboxylic acid cycle
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.abf0529

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. Cell death is an essential, finely tuned process that is critical for the removal of damaged and superfluous cells. Multiple forms of programmed and nonprogrammed cell death have been identified, including apoptosis, ferroptosis, and necroptosis. Tsvetkov et al . investigated whether abnormal copper ion elevations may sensitize cells toward a previously unidentified death pathway (see the Perspective by Kahlson and Dixon). By performing CRISPR/Cas9 screens, several genes were identified that could protect against copper-induced cell killing. Using genetically modified cells and a mouse model of a copper overload disorder, the researchers report that excess copper promotes the aggregation of lipoylated proteins and links mitochondrial metabolism to copper-dependent death. —PNK Lipoylation determines sensitivity to copper-induced cell death.