Mammalian copper homeostasis: physiological roles and molecular mechanisms

In the past decade, evidence for the numerous roles of copper (Cu) in mammalian physiology has grown exponentially. The discoveries of Cu involvement in cell signaling, autophagy, cell motility, differentiation, and regulated cell death (cuproptosis) have markedly extended the list of already known functions of Cu, such as a cofactor of essential metabolic enzymes, a protein structural component, and a regulator of protein trafficking. Novel and unexpected functions of Cu transporting proteins and enzymes have been identified, and new disorders of Cu homeostasis have been described. Significant progress has been made in the mechanistic studies of two classic disorders of Cu metabolism, Menkes disease and Wilson's disease, which paved the way for novel approaches to their treatment. The discovery of cuproptosis and the role of Cu in cell metastatic growth have markedly increased interest in targeting Cu homeostatic pathways to treat cancer. In this review, we summarize the established concepts in the field of mammalian Cu physiology and discuss how new discoveries of the past decade expand and modify these concepts. The roles of Cu in brain metabolism and in cell functional speciation and a recently discovered regulated cell death have attracted significant attention and are highlighted in this review.