Dynamic and cell-specific transport networks for intracellular copper ions

Copper (Cu) homeostasis is essential for the development and function of many organisms. In humans, Cu misbalance causes serious pathologies and has been observed in a growing number of diseases. This Review focuses on mammalian Cu(I) transporters and highlights recent studies on regulation of intracellular Cu fluxes. Cu is used by essential metabolic enzymes for their activity. These enzymes are located in various intracellular compartments and outside cells. When cells differentiate, or their metabolic state is otherwise altered, the need for Cu in different cell compartments change, and Cu has to be redistributed to accommodate these changes. The Cu transporters SLC31A1 (CTR1), SLC31A2 (CTR2), ATP7A and ATP7B regulate Cu content in cellular compartments and maintain Cu homeostasis. Increasing numbers of regulatory proteins have been shown to contribute to multifaceted regulation of these Cu transporters. It is becoming abundantly clear that the Cu transport networks are dynamic and cell specific. The comparison of the Cu transport machinery in the liver and intestine illustrates the distinct composition and dissimilar regulatory response of their Cu transporters to changing Cu levels.