Fig. 1

Copper metabolism. Copper homeostasis is tightly regulated. Cellular copper uptake primarily occurs through transporter-mediated mechanisms. Dietary Cu²⁺ is reduced to Cu⁺ by STEAP metalloreductases before binding to SLC31A1, a plasma membrane transporter that facilitates cellular uptake of copper. Under low SLC31A1 activity, compensatory uptake occurs via SLC31A2 or SLC11A2. ZnT1, traditionally a zinc exporter, functions as a Cu²⁺/Zn²⁺ exchanger, importing copper while exporting zinc. Endocytosis represents an alternative pathway – CD44 mediates the internalization of Cu²⁺ in macrophages. Intracellular copper distribution relies on various chaperones. COX17 delivers copper to mitochondrial cytochrome c oxidase via SCO1/2, linking copper availability to oxidative phosphorylation. CCS activates SOD1 by copper insertion and transfers copper to MEK kinases in oncogenic signaling. ATOX1 transports copper to ATP7A/B transporters in the Golgi for subsequent distribution or efflux. Excess copper is sequestered by metallothioneins and glutathione, regulated by NRF2- or HIF-1α-mediated stress responses. ATP7A/B dynamically relocate to export copper via lysosomal exocytosis or plasma membrane trafficking. These transporters also confer chemoresistance in cancers through copper-dependent mechanisms and drug efflux. Copper metabolism integrates precise transport, compartmentalization, and export mechanisms to balance enzymatic needs with toxicity prevention