Erythroid precursors require efficient iron uptake from transferrin so that hemoglobin can be produced. This is achieved primarily through recycling of iron through erythrophagocytosis (macrophages - iron homeostasis) and to a lesser extent through dietary iron acquisition. The cellular uptake of iron occurs through receptor-mediated endocytosis of Tf through TfR1 (Figure 1). Iron is then exported from the endosomal vesicle by DMT1 and is thought to enter the putative labile iron pool.
Although erythroid iron uptake is mostly well described, some aspects of this pathway have remained obscure for many years. For example, iron bound to Tf exists in the ferric form, but DMT1 transports ferrous iron, suggesting that a ferrireductase must exist within the endosomal vesicle. The recently reported six-transmembrane epithelial antigen of the prostate-3, Steap3, was identified as the endosomal ferrireductase responsible for reduction of iron in the endosomes of erythroid precursors, and hence for efficient iron utilization. Steap3 is expressed at high levels on erythroid cells and is localized to Tf–TfR1- containing endosomes. However, Steap3 is not required for efficient iron acquisition in other cell types.
It is interesting to consider why erythroid cells reduce Fe(III) only once it is internalized, as opposed to the reduction of Fe(III) that is proposed to occur on the enterocyte cell surface. This could be due to the fact that the intestinal milieu does not contain the high-affinity iron-binding protein Tf, which is found in the serum. In fact, protonation of the iron-binding site of Tf and reduction of Fe(III) to Fe(II) are both needed for iron transport across the endosomal membrane.
The Sec15l1 gene product is part of the mammalian exocyst complex and, in addition to cycling of Tf-containing endosomes, it is hypothesized to dock endosomal vesicles to the mitochondrion, enabling direct delivery of iron to this organelle.
Precise regulation of iron transport in mitochondria is essential for haem biosynthesis, haemoglobin production and Fe–S cluster protein assembly during red cell development. (Mitochondrial iron metabolism)
Fig 1 Erythroid iron uptake A: Erythroid precursors take up iron through the transferrin cycle. Erythroid cells probably have no iron-export mechanism; essentially all iron in these cells is incorporated into haemoglobin. B: Erythrocytes Transferrin-bound iron binds to the transferrin receptor-1 on erythroid cells. The Tf-TfR1 complex is internalized, and a decrease in endosomal pH (H+) releases iron from Tf. In reticulocytes, the iron can be reduced by six-transmembrane epithelial antigen of the prostate-3 Steap3 and exported from the endosome by DMT1. The Sec15l1 protein is predicted to assist Tf cycling and possibly vesicle docking for direct delivery of iron to the mitochondrion. C: Model of mitoferrin (Mfrn) function in importing iron into the mitochondrial matrix for haem synthesis and haemoglobin production in developing erythroblasts. (Mitochondrial iron metabolism)
