FIGURE 1.

Mechanisms of intracellular copper transport. After Cu is delivered to CTR1 by transcuprein/albumin/ceruloplasmin, it is translocated to cytosol, where it can be transferred either to mitochondria by copper ligand CuL or incorporated into ATOX1. ATOX1 can translocate into nucleus, by a copper-mediated mechanism, and deliver its copper to ATP7A/B. Left panel: mechanisms of copper transport for most cells (except hepatocytes). ATOX1 delivers Cu to ATP7A which in turn transports it to the TGN or transfers it into vesicles to be excreted out of the cell. During copper deficiency and excess, metallothioneins MT-I and MT-II regulate ATP7A trafficking and control cell viability (Gudekar et al., 2020). Right panel: mechanisms of copper transport for hepatocytes. ATOX1 donates copper to ATP7B which transports it to the trans-Golgi network (TGN) for incorporation into ceruloplasmin. ATP7B is also responsible for the transport of Cu to the cellular periphery to be incorporated into the bile (main incharge of copper excretion). Also, we can observe the routes affected by the diseases of Wilson and Menkes in the green and light blue rectangles, respectively. Modified from the study by Fischer and Goode (1994), Puig and Thiele (2002), Cobine et al. (2006a), Cobine et al. (2006b), and Qin et al. (2008).