Fig. 5

Iron physiological machinery. The availability of iron in the systemic circulation depends on its absorption from the duodenum, release of iron from old red blood cells (RBCs) engulfed by macrophages, and release of iron from its liver stores, stored as ferritin. Ferritin is an iron storage shell formed of 2 type subunits: Heavy (H ferritin) and Light (L ferritin). H ferritin has a ferroxidase enzymatic activity to oxidize ferrous (Fe⁺²) to ferric iron (Fe⁺³) and load it into the shell. In the duodenum, duodenal cytochrome b (Dcytb), on the apical border of enterocytes, reduces Fe⁺³ to Fe⁺² to enter the cell through the divalent metal transporter 1 (DMT1). Fe⁺² then exit enterocytes through ferroportin 1 (FPN1). FPN1 is under the control of hepcidin, the only hormonal regulation of iron. Exported Fe⁺² is oxidized by hephaestin or ceruloplasmin to form Fe⁺³. Within the circulation, Fe⁺³ binds to apotransferrin, forming transferrin. Iron then gets distributed to body systems and each cell forms its share of labile iron pool (LIP). The LIP can be formed from three routes. First, the release of iron from its stores in ferritin by the process of ferritinophagy mediated by nuclear receptor co-activator 4 (NCOA4). Second, imported into the cell as non-transferrin-bound (NTB) iron through DMT1. Third, imported into the cell as transferrin which binds to transferrin receptors-1 (TfR1). The TfR1-transferrin complex enters the cell by clathrin-mediated endocytosis. In the endosome, the six-transmembrane epithelial antigen of prostate 3 (STEAP3) reduces Fe⁺³ to Fe⁺² by its ferroxidase activity. Then, Fe⁺² is released into the cytoplasm through DMT1. Once in the cell, iron can then be utilized, exported through FPN1, or stored in the form of ferritin. Iron-related proteins are under a tight regulation of a molecular machinery in the form of the iron responsive element/iron regulatory protein (IRE/IRP) system. IRP1 and IRP2 bind to IRE in the mRNA of different target genes and control their translation, including TfR1, DMT1, ferritin, and FPN1