Cell and animal research (not human) · in vitro
Tsvetkov P et al., Science, 2022
Landmark T01 #1, main finding (CELL AND MOUSE WORK ONLY; NOT HUMAN PROOF). In cultured human cancer cell lines, death caused by excess copper (delivered by copper ionophores such as elesclomol, or by over-expressing the copper importer SLC31A1) did not behave like apoptosis, ferroptosis or necroptosis: blockers of those pathways did not prevent it and it continued in BAX/BAK-knockout cells (Fig 1; Fig 6G). It depended on mitochondrial respiration - cells relying on respiration were described as 'nearly 1,000-fold more sensitive' than glycolytic cells, and electron-transport-chain inhibitors and 1% oxygen reduced the killing (Fig 2). Genome-wide CRISPR screens found that losing FDX1 or protein-lipoylation genes (LIAS, LIPT1, DLD, DLAT, PDHA1, PDHB) protected cells (Fig 3). Proposed mechanism: copper binds lipoylated TCA-cycle proteins (DLAT, DLST), DLAT clumps (oligomerises), iron-sulfur cluster proteins are lost and proteotoxic stress follows (Figs 5-6). The authors named this 'cuproptosis'. Liver from Atp7b-knockout mice (a Wilson-disease copper-overload model) showed the same protein changes (Fig 6K). No human was treated in this study.
Source: Copper induces cell death by targeting lipoylated TCA cycle proteins. Tsvetkov P, Coy S, Petrova B, Dreishpoon M, Verma A, Abdusamad M, Rossen J, Joesch-Cohen L, Humeidi R, Spangler RD, Eaton JK, Frenkel E, Kocak M, Corsello SM, Lutsenko S, Kanarek N, Santagata S, Golub TR. Science. 2022;375(6586):1254-1261. doi:10.1126/science.abf0529. PMID 35298263; PMC9273333 (NIH author manuscript). Published 2022-03-17. Erratum: Science 2022;376(6591):eabq4855.
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