Fig. 8

Schematic representation of the regulation of endogenous iron metabolism. Iron acquisition is dependent on endocytosis of diferric transferrin via the transferrin receptor (TFRC). In acidified endosomes, iron is freed from transferrin and exported into the cytoplasm by DMT1. In the cytosol, excess iron is sequestered within heteropolymers of ferritin H and L chains. Cellular iron efflux is mediated by ferroportin (FPN1) and requires iron oxidation on the extracellular side [56]. HRG1 is another protein that is localized in acidified vesicles and it serves to export heme groups stored in these compartments to the cytosol [57]. When iron levels in the cytoplasm are high, lipocalin (LCN2), in coordination with siderophores as co-factors, interacts with iron and forms a ternary complex [58]. Iron homeostasis is regulated by iron responsive proteins, such as IREB2, by binding to iron-responsive elements (IREs). When iron is limited, IREB2 binds to the IREs of some iron metabolism genes that repress ferritin and ferroportin translation, and that stabilize DMT1 and TFRC mRNA. By contrast, when iron is found in the cell, IREB2 degradation is induced and thus, it cannot bind to IREs and induce ferritin or ferroportin expression, whereas DMT1 and TFRC degradation is induced [59]