Mitochondrial copper pool

The mitochondrial copper pool refers to the regulated concentration of copper ions within the mitochondria, which serves as an essential cofactor for cytochrome c oxidase (COX) in the electron transport chain [1]. This pool is maintained by specific transporters and chaperones to prevent the formation of reactive oxygen species while ensuring adequate supply for aerobic respiration [1]. Recent discoveries have highlighted the mitochondrial copper pool as the focal point for cuproptosis, a form of regulated cell death where excess copper binds directly to lipoylated components of the tricarboxylic acid (TCA) cycle, such as dihydrolipoamide S-acetyltransferase (DLAT) [2]. This interaction leads to the aggregation of lipoylated proteins and proteotoxic stress, providing a novel therapeutic vulnerability in cancer cells that rely heavily on mitochondrial metabolism [2, 3]. Pharmacological intervention typically involves copper ionophores to induce cuproptosis or copper chelators to manage overload diseases like Wilson's disease or to limit tumor growth and angiogenesis [4, 5]. [1] Cobine et al. (2021) BBA Mol Cell Res; [2] Tsvetkov et al. (2022) Science; [3] Nagai et al. (2012) Free Radic Biol Med; [4] Brewer (2005) Front Biosci; [5] Lutsenko (2010) Biochem Soc Trans.

Other names

Mitochondrial copperIntramitochondrial copper poolLabile mitochondrial copper poolMitochondrial Cu pool

Copper ionophores (e.g., elesclomol) facilitate the transport of copper into the mitochondrial matrix to induce cuproptosis via lipoylated protein aggregation [2, 3]. Copper chelators (e.g., tetrathiomolybdate) sequester copper ions to prevent toxicity or inhibit copper-dependent enzymes [4, 5].