Copper induces cell death by targeting lipoylated TCA cycle proteins.
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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. |
Year of Publication | 2022
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Journal | Science
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Volume | 375
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Issue | 6586
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Pages | 1254-1261
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Date Published | 2022 03 18
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ISSN | 1095-9203
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DOI | 10.1126/science.abf0529
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PubMed ID | 35298263
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PubMed Central ID | PMC9273333
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Grant list | U54 CA225088 / CA / NCI NIH HHS / United States
K08 CA230220 / CA / NCI NIH HHS / United States
R35 CA242457 / CA / NCI NIH HHS / United States
R01 CA194005 / CA / NCI NIH HHS / United States
T32 GM007748 / GM / NIGMS NIH HHS / United States
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