| Literature DB >> 35298263 |
Peter Tsvetkov1, Shannon Coy2,3,4,5, Boryana Petrova5,6, Margaret Dreishpoon1, Ana Verma2,3,4,5, Mai Abdusamad1, Jordan Rossen1, Lena Joesch-Cohen1, Ranad Humeidi1, Ryan D Spangler1, John K Eaton1, Evgeni Frenkel7, Mustafa Kocak1, Steven M Corsello1,5,8, Svetlana Lutsenko9, Naama Kanarek1,5,6, Sandro Santagata2,3,4,5,10, Todd R Golub1,5,11,12.
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.Entities:
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Year: 2022 PMID： 35298263 PMCID： PMC9273333 DOI： 10.1126/science.abf0529
Source DB: PubMed Journal: Science ISSN： 0036-8075 Impact factor: 63.714