Cuproptosis

Cuproptosis is a copper-dependent form of regulated cell death that is mechanistically distinct from apoptosis, ferroptosis, necroptosis and pyroptosis. When intracellular copper rises beyond the buffering capacity of chaperones such as ATOX1 and CCS, copper ions directly bind lipoylated components of the mitochondrial tricarboxylic acid (TCA) cycle, most notably dihydrolipoamide S-acetyltransferase (DLAT), and trigger their aggregation. This is accompanied by loss of iron-sulfur cluster proteins, leading to proteotoxic stress, mitochondrial dysfunction and cell death. The mitochondrial reductase FDX1 is required for protein lipoylation and acts as a key upstream regulator of cuproptosis. Cells with active oxidative phosphorylation and high lipoylated-protein content are particularly sensitive. Cuproptosis has attracted interest as a potential therapeutic vulnerability in copper-handling-altered cancers and is relevant to metabolic and neurodegenerative contexts.