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