Molecular mechanisms underlying copper homeostasis in Mammalian cells

Copper (Cu) is an essential metal for living organisms that utilize oxygen for respiration and is required as a cofactor of redox-regulating enzymes, such as superoxide dismutase, ceruloplasmin, lysyl oxidase, tyrosinase, and dopamine β-hydroxylase. However, the redox-active property of this metal may have toxic effects on cells due to the generation of harmful reactive oxygen species. Given these circumstances, it is said that cells have a dependable system for Cu homeostasis that efficiently distributes this essential metal to cuproenzymes, thereby preventing damage to proteins, nucleic acids, sugars, and lipids. In particular, influx, efflux, and intracellular distribution with maintenance of the oxidation state of Cu are strictly regulated. Several groups of Cu-regulating factors have been identified in mammalian cells, i.e., Cu transporters, Cu chaperones, Cu-binding proteins/peptides, and others. In this review, the features of the Cu-regulating factors are concisely examined in terms of molecular mechanisms underlying Cu homeostasis in cells.