Science (New York, N.Y.) · 2022
Copper induces cell death by targeting lipoylated TCA cycle proteins.
СтатьяПоддержка NIH: внешняя программаНазвание и аннотация: Перевод пока не подготовлен
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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
Аннотация
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.