Mitochondrial cuproenzymes and reactive oxygen species (ROS) generating pathways

Mitochondria serve as the metabolic hub of the cell, housing the electron transport chain (ETC) and various copper-dependent enzymes, or cuproenzymes, such as cytochrome c oxidase (Complex IV) [3]. These cuproenzymes are vital for oxidative phosphorylation, while the ETC is a primary source of reactive oxygen species (ROS) during normal and pathological states [4]. Therapeutic targeting of mitochondrial cuproenzymes and ROS-generating pathways is an emerging strategy in cancer treatment, particularly through the induction of cuproptosis—a copper-dependent form of regulated cell death [1]. Drugs like elesclomol exploit this by shuttling copper into the mitochondria, where it interacts with lipoylated enzymes of the tricarboxylic acid (TCA) cycle, such as dihydrolipoamide S-acetyltransferase (DLAT), leading to proteotoxic stress and cell death [1, 2]. Additionally, modulating these pathways is relevant in treating copper metabolism disorders like Wilson disease and neurodegenerative diseases where mitochondrial redox balance is disrupted [3, 4].

Other names

Mitochondrial copper-dependent enzymesMitochondrial ROS pathwaysCuproptosis-related mitochondrial targetsMitochondrial redox pathways

Induction of mitochondrial oxidative stress and proteotoxic stress through copper-dependent inhibition of metabolic enzymes and disruption of the electron transport chain [1, 2].