Throughout evolution, all organisms have harnessed the redox properties of copper (Cu) and iron (Fe) as a cofactor or structural determinant of proteins that perform critical functions in biology. At its most sobering stance to Earth’s biome, Cu biochemistry allows photosynthetic organisms to harness solar energy and convert it into the organic energy that sustains the existence of all nonphotosynthetic life forms. The conversion of organic energy, in the form of nutrients that include carbohydrates, amino acids and fatty acids, is subsequently released during cellular respiration, itself a Cu-dependent process, and stored as ATP that is used to drive a myriad of critical biological processes such as enzyme-catalyzed biosynthetic processes, transport of cargo around cells and across membranes, and protein degradation. The life-supporting properties of Cu incur a significant challenge to cells that must not only exquisitely balance intracellular Cu concentrations, but also chaperone this redox-active metal from its point of cellular entry to its ultimate destination so as to avert the potential for inappropriate biochemical interactions or generation of damaging reactive oxidative species (ROS). In this review we chart the travels of Cu from the extracellular milieu of fungal and mammalian cells, its path within the cytosol as inferred by the proteins and ligands that escort and deliver Cu to intracellular organelles and protein targets, and its journey throughout the body of mammals.

Significance Copper is essential for normal growth and development because it serves roles in catalysis, signaling, and structure. Cells acquire copper through the copper transporter 1 (Ctr1) protein, a copper transporter that localizes to the cell membrane and intracellular vesicles. Both copper and the anticancer drug cisplatin are imported by Ctr1 by virtue of an extracellular domain rich in metal-binding amino acids. In this report we demonstrate that a protein structurally related to Ctr1, called Ctr2, plays a role in the generation or stability of a truncated form of Ctr1 lacking a large portion of the extracellular domain. Retention of this domain in mice or cells lacking Ctr2 enhances copper and cisplatin uptake, thereby establishing Ctr2 as a regulator of Ctr1 function.

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The Copper transporter 1, Ctr1, is part of a major pathway for cellular copper (Cu) uptake in the intestinal epithelium, in hepatic and cardiac tissue, and likely in many other mammalian cells and tissues. Here we summarize what is currently known about how extracellular Cu travels across the plasma membrane to enter the cytoplasm for intracellular distribution and for use by proteins and enzymes, the physiological roles of Ctr1 and its regulation. As a critical Cu importer, Ctr1 occupies a strategic position to exert a strong modifying influence on diseases and pathophysiological states caused by imbalances in Cu homeostasis. A more thorough understanding of the mechanisms that regulate Ctr1 abundance, trafficking and function will provide new insights and opportunities for disease therapies.