Copper homeostasis and cuproptosis in health and disease

Abstract

As an essential micronutrient, copper is required for a wide range of physiological processes in virtually all cell types. Because the accumulation of intracellular copper can induce oxidative stress and perturbing cellular function, copper homeostasis is tightly regulated. Recent studies identified a novel copper-dependent form of cell death called cuproptosis, which is distinct from all other known pathways underlying cell death. Cuproptosis occurs via copper binding to lipoylated enzymes in the tricarboxylic acid (TCA) cycle, which leads to subsequent protein aggregation, proteotoxic stress, and ultimately cell death. Here, we summarize our current knowledge regarding copper metabolism, copper-related disease, the characteristics of cuproptosis, and the mechanisms that regulate cuproptosis. In addition, we discuss the implications of cuproptosis in the pathogenesis of various disease conditions, including Wilson's disease, neurodegenerative diseases, and cancer, and we discuss the therapeutic potential of targeting cuproptosis.

Fig. 1

Summary of the pathways that mediate cellular Cu metabolism. Extracellular Cu²⁺ is reduced by the reductase STEAP to Cu⁺, which is transported into the cell by the Cu transporter CTR1, where it is delivered to cytosolic Cu chaperones such as CCS and SOD1 and then delivered to specific subcellular compartments such as the mitochondria, TGN, and nucleus. In the mitochondria, Cu is involved in the respiratory chain and redox pathways via binding to CCO. In the mitochondrial intermembrane space, COX17 binds to and delivers Cu to either SCO1 or COX11, which transfers Cu to the cytochrome oxidase subunit. In the nucleus, Cu can bind to transcription factors and drive gene expression. Finally, in the TGN the Cu⁺-ATPase transporters ATP7A and ATP7B transfer Cu from the cytosol to the TGN lumen, where it activates Cu-dependent enzymes in the secretory pathway. When cytosolic Cu levels are high, ATP7A and ATP7B exit the TGN and facilitate Cu export. Created with BioRender. ATOX1, antioxidant 1 copper chaperone; ATP7A and ATP7B, ATPase copper transporter 7A and 7B, respectively; CCO, cytochrome c oxidase; CCS, copper chaperone for superoxide dismutase; COX17 cytochrome c oxidase copper chaperone 17, COX11 cytochrome c oxidase copper chaperone 11, SCO1 synthesis of cytochrome c oxidase 1, SOD1 superoxide dismutase 1, STEAP the six-transmembrane epithelial antigen of the prostate, SLC31A1 solute carrier family 31 member 1, TGN trans-Golgi network

Fig. 2

Schematic model of cuproptosis. Cu ionophores such as elesclomol bind extracellular Cu and transport it to intracellular compartments. Cu then binds to lipoylated mitochondrial enzymes in the TCA cycle such as DLAT, inducing the aggregation of these proteins. FDX1/LIAS is an upstream regulator of protein lipoylation, facilitating the aggregation of mitochondrial proteins and loss of Fe–S clusters. Together, these aberrant processes lead to proteotoxic stress and ultimately cell death. Cu chelators such as TTM inhibit cuproptosis, while inhibitors of ferroptosis (Fer-1), necroptosis (Nec-1), and oxidative stress (NAC) have no effect on cuproptosis. The solid orange circles in the TCA cycle indicate metabolites that are relevant to the lipoic acid pathway. Created with BioRender. α-KG α-ketoglutarate, DLAT dihydrolipoamide S-acetyltransferase, FDX1 ferredoxin-1, Fe–S iron–sulfur, Fer-1 ferrostatin-1, LIAS lipoic acid synthetase, NAC N-acetyl cysteine, Nec-1 necrostatin-1, TCA tricarboxylic acid, TTM tetrathiomolybdate

Fig. 3

The putative role of cuproptosis in Wilson’s disease. a Patients with Wilson’s disease present with Cu overload in their hepatocytes. Mutations in ATP7B impair Cu loading into secretory vesicles and into cuproproteins such as ceruloplasmin. Cu excretion via the biliary tract is also impaired, resulting in an accumulation of Cu in the liver. The resulting Cu-induced toxicity leads to chronic liver disease and cirrhosis. Cu also accumulates in other tissues, including the brain, cornea, and kidneys, resulting in neurological impairment, Kayser–Fleischer rings, and impaired kidney function, respectively. b Atp7b knockout mice (a model of Wilson’s disease) develop Cu overload, with a loss of lipoylated and Fe–S cluster proteins in the liver, suggesting that this Cu overload has similar cellular effects as those induced by Cu ionophores, suggesting that cuproptosis may play a pathogenic role in Wilson’s disease. Created with BioRender. ATOX1 antioxidant 1 copper chaperone-1, ATP7B ATPase Cu transporter 7B, Fe–S iron–sulfur, Slc3a1 solute carrier family 3 member 1, STEAP six-transmembrane epithelial antigen of prostate

Fig. 4

Two potential therapeutic strategies to target cuproptosis in cancer. a The Cu ionophore elesclomol is believed to induce cuproptosis in cancer cells that either express high levels of lipoylated mitochondrial enzymes or are in a hyperactive respiratory state. b Disulfiram combined with Cu selectively targets cancer cells with high ALDH expression. Created with BioRender. ALDH aldehyde dehydrogenase, DSF disulfiram