Copper ion (Cu) (Cu)

Copper is an essential trace element that serves as a vital cofactor for numerous enzymes involved in energy production, iron metabolism, and antioxidant defense (PubChem). In the context of the ES-Cu complex, copper is utilized as a cytotoxic agent through the action of elesclomol, a small-molecule copper ionophore. Elesclomol binds extracellular Cu2+ with high affinity, forming a stable 1:2 metal-ligand complex that facilitates the transport of copper across cellular and mitochondrial membranes (Kirshner et al., Mol Cancer Ther, 2008). Once inside the mitochondria, the copper ion is reduced from Cu2+ to Cu+, a process that generates high levels of reactive oxygen species (ROS) and disrupts the electron transport chain. This influx of copper triggers a specific form of regulated cell death known as cuproptosis, which is distinct from apoptosis and ferroptosis (Tsvetkov et al., Science, 2022). Cuproptosis is characterized by the direct binding of copper to lipoylated components of the tricarboxylic acid (TCA) cycle, leading to protein aggregation and subsequent cellular metabolic collapse. This mechanism is particularly effective against cancer cells that exhibit high mitochondrial activity and a reliance on oxidative phosphorylation.

Other names

Cupric ionCuprous ionCopper(II)Copper(I)ES-Cu complexElesclomol-copper complex

Copper ionophores like elesclomol bind extracellular Cu2+ to form a lipophilic complex that enters the mitochondria, where copper is reduced to Cu+, leading to the generation of reactive oxygen species (ROS) and the induction of cuproptosis via the aggregation of lipoylated TCA cycle enzymes (Tsvetkov et al., Science, 2022; Kirshner et al., Mol Cancer Ther, 2008).