Copper induces cell death by targeting lipoylated TCA cycle proteins
Peter Tsvetkov, Shannon Coy, Boryana Petrova, Margaret B. Dreishpoon, Ana Verma, Mai Abdusamad, Jordan Rossen, Lena M. Joesch-Cohen, Ranad Humeidi, Ryan D. Spangler, John K. Eaton, Evgeni M. Frenkel, Mustafa Kocak, Steven M. Corsello, Svetlana Lutsenko, Naama Kanarek, Sandro Santagata, Todd R. Golub
Science · 2022 · 5,052 citationsOpen access
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.
Cite this paper
Tsvetkov, P., Coy, S., Petrova, B., Dreishpoon, M. B., Verma, A., Abdusamad, M., Rossen, J., Joesch-Cohen, L. M., Humeidi, R., Spangler, R. D., Eaton, J. K., Frenkel, E. M., Kocak, M., Corsello, S. M., Lutsenko, S., Kanarek, N., Santagata, S., & Golub, T. R. (2022). Copper induces cell death by targeting lipoylated TCA cycle proteins. Science, 375(6586), 1254–1261. https://doi.org/10.1126/science.abf0529
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