Cuproptosis pathway

Cuproptosis is a recently identified form of regulated cell death triggered by the excessive accumulation of intracellular copper, leading to mitochondrial dysfunction and proteotoxic stress [1, 6]. This pathway is mechanistically distinct from other forms of cell death, such as apoptosis and ferroptosis, as it involves the direct binding of copper ions to lipoylated proteins within the mitochondrial tricarboxylic acid (TCA) cycle [8, 10]. Specifically, copper causes the aggregation of lipoylated enzymes like dihydrolipoamide S-acetyltransferase (DLAT) and the loss of iron-sulfur cluster proteins, which results in catastrophic metabolic failure [3, 19]. The process is primarily regulated by ferredoxin 1 (FDX1), which reduces copper to its toxic monovalent state and facilitates the lipoylation of TCA cycle components [2, 5]. Therapeutically, the pathway is targeted in oncology through the use of copper ionophores, such as elesclomol and disulfiram, which increase mitochondrial copper levels to selectively kill metabolically active cancer cells [1, 16]. While promising for treating drug-resistant tumors, the pathway's reliance on mitochondrial respiration means that glycolytic cells may be resistant, and systemic copper toxicity remains a significant therapeutic challenge [9, 15].

Other names

Copper-dependent cell deathCopper-induced cell deathCopper deathMitochondrial copper death pathway

Induction of cell death through copper-mediated aggregation of lipoylated mitochondrial proteins and loss of iron-sulfur cluster proteins, leading to proteotoxic stress.