Copper induces cell death by targeting lipoylated TCA cycle proteins

Abstract

Copper is an essential cofactor for all organisms, and yet it becomes toxic if concentrations exceed a threshold maintained by evolutionarily conserved homeostatic mechanisms. How excess copper induces cell death, however, is unknown. Here, we show in human cells that copper-dependent, regulated cell death is distinct from known death mechanisms and is dependent on mitochondrial respiration. We show that copper-dependent death occurs by means of direct binding of copper to lipoylated components of the tricarboxylic acid (TCA) cycle. This results in lipoylated protein aggregation and subsequent iron-sulfur cluster protein loss, which leads to proteotoxic stress and ultimately cell death. These findings may explain the need for ancient copper homeostatic mechanisms.

Comprehensive Analysis of Cuproptosis-Related Genes in Immune Infiltration and Prognosis in Melanoma

“…As indicated previously, 12 genes (FDX1, LIAS, LIPT1, DLD, DLAT, PDHA1, PDHB, MTF1, GLS, CDKN2A, SLC31A1, and ATP7B) were demonstrated to be associated with cuproptosis (Tsvetkov et al, 2022). In order to confirm the involvement of these cuproptosis-related genes in melanoma, we compared the expression patterns of these 12 cuproptosis-related genes between melanoma and normal tissues downloaded from TCGA and GTEx databases.…”

Cuproptosis: lipoylated TCA cycle proteins-mediated novel cell death pathway

“…In a recent study published in Science , Tsvetkov et al 1 . shed a light on a new form of cell death, copper-dependent cell death (termed cuproptosis).…”

“…Pioneering studies have explored several cell death forms, such as apoptosis, necroptosis, pyroptosis, and ferroptosis, however, the phenomenon that copper overload causes cellular toxicity has been less elucidated. In terms of the exact mechanism by which copper ions cause cell death, several hypotheses have been proposed, including the induction of apoptosis, caspase-independent cell death, the induction of reactive oxygen species (ROS), and inhibition of ubiquitin-proteasome system 1 , etc. However, a well-acknowledged theory has not been clearly defined yet.…”

Pan-cancer analysis reveals the value of FDX1 as a novel biomarker in the prognosis and immunotherapy in human tumors

“…FDX1 expression can promote the death of tumor cells [10] . What's more, the pathway that FDX1 induces tumor cell death has been illuminated in the recent research titled "Copper ionophore-induced cell death" published in the journal Science [17] . Copper death has been proved to be closely related to the progression of many tumors [18][19][20][21] , in which the accumulation of copper in cells results in an overall reduction in proteins involved in mitochondrial respiration, reduced protein lipoylation, and reduced levels of Fe-S cluster proteins.…”