Copper-dependent cell death (Cuproptosis) (Cuproptosis)

Copper-dependent cell death, scientifically termed cuproptosis, is a recently identified form of regulated cell death characterized by the direct binding of copper ions to lipoylated components of the tricarboxylic acid (TCA) cycle. This binding occurs specifically at the dihydrolipoamide S-acetyltransferase (DLAT) subunit of the pyruvate dehydrogenase complex, leading to the aggregation of lipoylated proteins and the subsequent loss of iron-sulfur cluster proteins (Tsvetkov et al., 2022; PubMed: 35298263). These molecular events trigger profound proteotoxic stress that ultimately results in cell death, a pathway distinct from apoptosis, ferroptosis, or necroptosis. Cuproptosis is primarily regulated by the enzyme Ferredoxin 1 (FDX1), which reduces copper to its more toxic form and maintains the lipoylation of TCA cycle enzymes (Li et al., 2022; PubMed: 36545166). In a therapeutic context, this pathway is targeted in cancer research, as many tumor cells exhibit a high dependency on mitochondrial metabolism and are therefore hypersensitive to copper-induced stress. Drugs such as copper ionophores (e.g., Elesclomol) are being investigated for their ability to transport copper into cells and selectively induce cuproptosis in metabolically active cancer cells (Kahlson & Colvin, 2022; PubMed: 35508605).

Other names

CuproptosisCopper-induced cell deathCopper-dependent regulated cell deathCopper-triggered mitochondrial cell death

Copper ionophores (such as Elesclomol) facilitate the transport of copper ions across the plasma membrane, leading to an intracellular accumulation of copper. These copper ions are reduced by Ferredoxin 1 (FDX1) and subsequently bind to the lipoylated proteins of the TCA cycle, most notably Dihydrolipoamide S-acetyltransferase (DLAT). This binding induces the aggregation of these proteins and the inhibition of iron-sulfur cluster protein synthesis, resulting in proteotoxic stress and mitochondrial dysfunction that triggers cell death (Tsvetkov et al., 2022; PubMed: 35298263; Wang et al., 2022; PubMed: 36248107).