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Copper is an essential co-factor for all organisms, and yet it becomes toxic if concentrations exceed a threshold maintained by evolutionarily conserved homeostatic mechanisms. The precise mechanisms through which excess copper induces cell death, are still poorly characterized. Our recent discoveries illuminated that copper ionophores targeted to the mitochondria induce a new form of regulated cell death, distinct from other forms of regulated cell death (i.e apoptosis, ferroptosis and necroptosis) which is metabolism dependent. We term this new mechanism of cell death "cuproptosis." Chemical genomic approaches and thorough biochemical validation studies established that cuproptosis is regulated by mitochondrial ferredoxin 1 (FDX1) and protein lipoylation, a conserved lysine post-translational modification regulating only 4 key mitochondrial enzymes. Here we describe our current understanding of how copper targets both lipoylated and Fe-S cluster proteins, the regulation of this processes by FDX1 and the unique cellular and biochemical characteristics of cuproptosis. PT is sponsored by NIH Research Project Grant, NCI R011R01CA279550-01 and Office of Naval Research (ONR), N00014-23-1-2465.
Tsvetkov et al. (Fri,) studied this question.