Identification and Characterization of an Erythrocyte Endosomal Ferrireductase Critical for Transferrin Dependent Iron Uptake.

The transferrin cycle is a critical pathway for iron uptake by developing red blood cells. Defects in the cycle typically result in a hypochromic microcytic anemia due to ineffective hemoglobin synthesis. Recently we described a new microcytic mouse mutant, nm1054, with an autosomal recessive defect in transferrin mediated iron uptake. We now have identified the gene responsible for the defect through positional cloning and complementation experiments. The gene, mammalian ferrireductase 1 (Mfre1) encodes a predicted six pass transmembrane protein with homology to oxidoreductases of archaea and bacteria as well as homology to the yeast family of FRE proteins. Mfre1 is expressed highly in hematopoietic tissues and co-localizes with the transferrin cycle endosome of cells. Over-expression of Mfre1 in cultured cells stimulates reduction of iron while reticulocytes deficient in Mfre1 are defective in conversion of ferric iron to a ferrous form. Here we comprehensively describe the role of Mfre1 in iron metabolism and speculate on the role of several other novel homologues in iron homeostasis.