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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.<\/jats:p>","DOI":"10.1126\/science.abf0529","type":"journal-article","created":{"date-parts":[[2022,3,17]],"date-time":"2022-03-17T13:59:18Z","timestamp":1647525558000},"page":"1254-1261","source":"Crossref","is-referenced-by-count":4635,"title":["Copper induces cell death by targeting lipoylated TCA cycle proteins"],"prefix":"10.1126","volume":"375","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7577-2342","authenticated-orcid":true,"given":"Peter","family":"Tsvetkov","sequence":"first","affiliation":[{"name":"Broad Institute of Harvard and MIT, Cambridge, MA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0033-9031","authenticated-orcid":true,"given":"Shannon","family":"Coy","sequence":"additional","affiliation":[{"name":"Laboratory of Systems Pharmacology, Department of Systems Biology, Boston, MA, USA."},{"name":"Ludwig Center at Harvard, Harvard 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