Cellular iron processing. Ferric iron (Fe3+) bound to Tf is taken up by cells through TfR1. The TfR1-Tf complex is internalized through endocytosis. The endosomal matrix is acidified by an ATPase proton pump, which allows dissociation of Tf and Fe3+ from TfR1. The ferric iron is reduced to Fe2+ by the STEAP family of proteins, and it can now be exported to the cytosol by DMT1. Ferrous iron can be delivered to ferritin for storage by the iron chaperone PCBP1. The larger part of iron will be transported to the mitochondrion for heme and FeS cluster synthesis. How iron is delivered to mitochondria is largely unknown. In erythrocytes, mitochondrial iron import is mediated by MFRN1 complexed with ABCB10. The MFRN1 paralog, MFRN2, is thought to import iron into mitochondria of non-erythroid cells, whether or not complexed with ABCB transporters. Factors involved in mitochondrial export of heme remain to be elucidated, whereas ABCB7 is thought to export a yet undefined component “X” needed for cytosolic FeS cluster assembly. After delivery of iron, TfR1 and Tf are recycled back to the cell surface, a pathway in which SEC15L1 plays an important role. mFerritin, mitochondrial ferritin.
