Fig. 2
From: Copper homeostasis and cuproptosis in health and disease
Schematic model of cuproptosis. Cu ionophores such as elesclomol bind extracellular Cu and transport it to intracellular compartments. Cu then binds to lipoylated mitochondrial enzymes in the TCA cycle such as DLAT, inducing the aggregation of these proteins. FDX1/LIAS is an upstream regulator of protein lipoylation, facilitating the aggregation of mitochondrial proteins and loss of Fe–S clusters. Together, these aberrant processes lead to proteotoxic stress and ultimately cell death. Cu chelators such as TTM inhibit cuproptosis, while inhibitors of ferroptosis (Fer-1), necroptosis (Nec-1), and oxidative stress (NAC) have no effect on cuproptosis. The solid orange circles in the TCA cycle indicate metabolites that are relevant to the lipoic acid pathway. Created with BioRender. α-KG α-ketoglutarate, DLAT dihydrolipoamide S-acetyltransferase, FDX1 ferredoxin-1, Fe–S iron–sulfur, Fer-1 ferrostatin-1, LIAS lipoic acid synthetase, NAC N-acetyl cysteine, Nec-1 necrostatin-1, TCA tricarboxylic acid, TTM tetrathiomolybdate
