Molecular Mechanisms of Cellular Copper Homeostasis in Mammals

Abstract

Copper (Cu) is a trace element necessary for the growth and development of all living organisms, and is the third most abundant trace metal in the body after iron and zinc. Copper is essential for maintaining the life processes in all living cells, because several copper-dependent enzymes play an important role in key physiological processes like cellular respiration, oxygen radical scavenging, the transport of iron and neurotransmitter synthesis. Maintaining copper homeostasis implies maintaining the constancy of copper levels in the cells and fluids throughout the body, in order to support the enzymes and other factors that underlie normal life processes. Therefore, living organisms have developed complex mechanisms for maintaining their physiological copper level, because an excess copper level can be toxic for the cells. In the cell, copper homeostasis is controlled by a network of copper-binding proteins and transporters. Furthermore, copper uptake is mediated by the membrane transporter CTR1 and CTR2 proteins. In the cytoplasm, it is bound to a unique group of metallochaperones (ATOX1, CCS COX17) and transported to different cell compartments, where it is linked to the recipient proteins. The Cu-transporting ATPases (ATP7A and ATP7B) are responsible for transferring copper into the Golgi apparatus, where the copper is added to the active sites of enzymes, and it is also directed onto the path of excess cellular copper removal to prevent the occurrence of toxicity.