Regulation of Iron Metabolism in Mammalian Cells

Abstract

Iron is an essential nutrient for all mammalian cells, and numerous proteins are dedicated to the uptake and distribution of iron within cells. As discussed in previous chapters, there are proteins that facilitate iron uptake, including transferrin receptors 1 and 2 (TfR1 and TfR2) [1] and DMT1 [2], proteins dedicated to iron storage, including ferritin H and L chains [3, 4], and an iron exporter, ferroportin [5, 6]. Most cellular proteins are synthesized in the cytosol and those that require an iron cofactor generally acquire their iron from the cytosolic iron pool. The nature of the cytosolic iron pool remains uncharacterized, as the iron is not associated with a specific known iron carrier molecule. The iron in this accessible iron pool may be bound with low affinity to abundant negatively charged molecules, including citrate and ATP. Because the cytosol of cells is a reducing environment, most cellular iron is likely in the ferrous (Fe2+) rather than in the ferric (Fe3+) state. Iron that enters the endosome in the transferrin cycle is initially in the ferric state, but an endosomal reductase, Steap3 [7], reduces it to ferrous iron, the form that is transported into cytosol by DMT1. When iron is taken up by ferritin, it is oxidized by ferroxidase activity of the ferritin H chain [3, 4], which facilitates precipitation and storage of iron in the ferritin heteropolymer.