Copper-mediated oxidative stress pathway

The copper-mediated oxidative stress pathway is a complex biochemical mechanism rather than a single molecular target. It involves the accumulation of intracellular copper ions which catalyze the production of highly reactive oxygen species (ROS), such as hydroxyl radicals, through Fenton-like and Haber-Weiss reactions (Gaetke & Chow, 2003). These ROS subsequently attack and damage essential cellular macromolecules, including DNA, proteins, and lipids, leading to impaired cellular function and death. A specific form of regulated cell death within this pathway, known as cuproptosis, occurs when copper binds directly to lipoylated components of the tricarboxylic acid (TCA) cycle, causing proteotoxic stress and mitochondrial dysfunction (Tsvetkov et al., 2022). In clinical practice, this pathway is targeted in two opposite ways: copper chelators like penicillamine are used to treat copper-overload disorders such as Wilson disease by preventing oxidative injury, while copper ionophores like elesclomol are investigated as anti-cancer agents that exploit the pathway to selectively kill malignant cells (Kirsipuu et al., 2020; NIH, 2023).

Other names

Cuproptosis pathwayCopper-induced reactive oxygen species productionCopper-mediated macromolecular damageCopper-induced oxidative stress

Copper ionophores increase intracellular copper levels to induce cuproptosis via lipoylated protein aggregation and ROS generation, while copper chelators sequester excess copper to prevent oxidative damage to macromolecules (Tsvetkov et al., 2022; Gaetke & Chow, 2003).