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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.

SUBMITTER: Tsvetkov P

PROVIDER: S-EPMC9273333 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Copper induces cell death by targeting lipoylated TCA cycle proteins.

Tsvetkov Peter P Coy Shannon S Petrova Boryana B Dreishpoon Margaret M Verma Ana A Abdusamad Mai M Rossen Jordan J Joesch-Cohen Lena L Humeidi Ranad R Spangler Ryan D RD Eaton John K JK Frenkel Evgeni E Kocak Mustafa M Corsello Steven M SM Lutsenko Svetlana S Kanarek Naama N Santagata Sandro S Golub Todd R TR

Science (New York, N.Y.) 20220317 6586

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 ...[more]

PMID: 35298263

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