Copper induces cell death by targeting lipoylated TCA cycle proteins
| Autor: | Peter Tsvetkov, Shannon Coy, Boryana Petrova, Margaret Dreishpoon, Ana Verma, Mai Abdusamad, Jordan Rossen, Lena Joesch-Cohen, Ranad Humeidi, Ryan D. Spangler, John K. Eaton, Evgeni Frenkel, Mustafa Kocak, Steven M. Corsello, Svetlana Lutsenko, Naama Kanarek, Sandro Santagata, Todd R. Golub |
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| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
Iron-Sulfur Proteins
Multidisciplinary Ionophores Cell Death Lipoylation Cell Respiration Citric Acid Cycle Dihydrolipoyllysine-Residue Acetyltransferase Article Mitochondria Mice Hydrazines Hepatolenticular Degeneration Animals Homeostasis Humans Regulated Cell Death Metabolic Networks and Pathways Copper |
| Zdroj: | Science |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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