Cuproptosis: Copper-Dependent Cell Death and Mitochondrial Metabolism

Cuproptosis is a recently defined copper-dependent form of regulated cell death that is mechanistically distinct from apoptosis, necroptosis, pyroptosis, and ferroptosis, and is tightly linked to mitochondrial respiration and tricarboxylic acid (TCA) cycle activity. The concept was formally established in 2022 when Tsvetkov and colleagues demonstrated that excess intracellular copper triggers a unique cell death program and revealed a direct connection between copper toxicity and mitochondrial metabolism. Because dysregulated copper homeostasis is implicated in cancer, neurodegeneration, infection, and metabolic disorders, cuproptosis has rapidly emerged as a major research focus in cell death biology and metabolic regulation. Subsequent studies have expanded interest in its molecular basis, metabolic dependency, and therapeutic relevance, highlighting cuproptosis as an important component of copper biology and mitochondrial function research.^{[1][2][3][4][5]}
The central mechanism of cuproptosis involves direct binding of copper to lipoylated proteins within the TCA cycle, particularly components of the pyruvate dehydrogenase complex, leading to aggregation of lipoylated proteins and loss of iron-sulfur (Fe-S) cluster proteins, which subsequently induces proteotoxic stress and cell death. This process depends on oxidative phosphorylation and active mitochondrial metabolism; therefore, cells relying on TCA cycle-driven respiration are highly sensitive to cuproptosis, whereas glycolysis-dependent cells display relative resistance. FDX1 has been identified as a key regulator because it controls protein lipoylation and influences cellular susceptibility to copper-mediated toxicity. Copper ionophores such as elesclomol and disulfiram facilitate intracellular and mitochondrial copper accumulation and can enhance cuproptotic cell death. Current applications of cuproptosis research are concentrated in cancer drug discovery and precision oncology, where induction of copper-dependent cell death is being explored to suppress tumor growth, overcome therapeutic resistance, and complement metabolic-targeted therapies. Cuproptosis-associated gene signatures are also being investigated as prognostic biomarkers across multiple cancer types. Nevertheless, important questions remain regarding tissue-specific physiological functions, interactions with other regulated cell death pathways, systemic regulation of copper homeostasis, and clinical translation. Future studies should focus on defining context-dependent regulatory mechanisms, developing selective copper-modulating therapeutics, and evaluating the relevance of cuproptosis in cancer, cardiovascular disease, neurodegeneration, and immune regulation.^{[1][2][3][4][6][7][8][9][10]}