Figure 1.

Cellular iron transport and regulation under physiological conditions. Iron transport: Plasma diferric Tf binds with TfR1 expressed on the membrane of cells. The Tf–TfR1 complex is internalized by receptor-mediated endocytosis (1). Within the highly acidified endosome, iron is released from Tf after the reduction of ferric iron takes place with the help of ferrireductase STEAP3 (2). Iron crosses the endosomal membrane into the cytoplasm via DMT1 (3). Iron chaperones exist in the cytoplasm to move iron within the cell (4). Intracellular iron can either be sequestered with ferritin (5) or transported directly to the sites of need (6). Upon mobilization, iron can efficiently detach from ferritin and be exported by FPN (7). Iron regulation: Hepcidin blocks cellular iron egress by binding with FPN and leads to its degradation. Intracellular iron level can be regulated by the IRP-IRE system. When cellular iron concentration is low, IRPs would bind to the 5′ UTR of ferritin mRNA and the 3′ UTR of TfR1 mRNA, which blocks the translation of the former and protects the latter from degradation. Abbreviations: Tf, transferrin; TfR1, transferrin receptor 1; STEAP3, six-transmembrane epithelial antigen of the prostate 3; DMT1, divalent metal transporter 1; FPN, ferroportin; IRP, iron regulatory protein; IRE, iron-responsive element.