The Path of Iron from Plasma Transferrin to Hemoglobin in Developing Red Blood Cells.
Authors: Ponka Prem , Zhang An-Shen , Sheftel Alex , Shirihai Orian S. 
Published: October 2019

Abstract
An exquisite relationship between iron and heme in hemoglobin-synthesizing cells makes blood red. Erythroid cells are the most avid consumers of iron (Fe) in the organism and synthesize heme at a breakneck speed. Additionally, there is virtually no free Fe or heme detectable during hemoglobin (Hb) synthesis. Developing red blood cells (RBC) can take up Fe only from the plasma glycoprotein transferrin (Tf). Delivery of iron to these cells occurs following the binding of Tf to its cognate receptors on the cell membrane. The Tf-receptor complexes are then internalized via endocytosis, and iron is released from Tf by a process involving endosomal acidification. Iron, following its reduction to Fe2+ by Steap3, is then transported across the endosomal membrane by the divalent metal transporter, DMT1. However, the post-endosomal path of Fe in the developing RBC remains elusive or is, at best, controversial. It has been commonly accepted that a low molecular weight intermediate chaperones Fe in transit from endosomes to mitochondria and other sites of utilization; however, this much sought iron-binding intermediate has never been identified. In erythroid cells, more than 90% of iron must enter mitochondria since ferrochelatase, the final enzyme in the heme biosynthetic pathway that inserts Fe2+ into protoporphyrin IX, resides in the inner part of the inner mitochondrial membrane. In fact, in erythroid cells, strong evidence does exist for specific targeting of Fe toward mitochondria. This targeting is demonstrated in Hb-synthesizing cells in which Fe acquired from Tf continues to flow into mitochondria, even when the synthesis of protoporphyrin IX is suppressed. Based on this, we have formulated a hypothesis that in erythroid cells a transient mitochondrion-endosome interaction is involved in iron translocation to its final destination. Recently, we have collected strong experimental evidence supporting this hypothesis: we have shown that Fe, delivered to mitochondria via the Tf pathway, is unavailable to cytoplasmic chelators. Moreover, we have demonstrated that Tf-containing endosomes move and contact mitochondria in erythroid cells, that vesicular movement is required for iron delivery to mitochondria, and that “free” cytoplasmic Fe is not efficiently used for heme biosynthesis. As mentioned above, the substrate for the endosomal transporter DMT1 is Fe2+, the redox form of iron that is also the substrate for ferrochelatase. These facts make the above hypothesis quite attractive, since the “chaperone”-like function of endosomes may be one of the mechanisms that keeps the concentrations of reactive Fe2+ at extremely low levels in oxygen-rich cytosol of erythroblasts, preventing ferrous ion’s participation in a dangerous Fenton reaction. In conclusion, the delivery of iron into Hb occurs extremely efficiently, since mature erythrocytes contain about 45,000-fold more heme iron (20 mM) than non-heme iron (440 nM). These facts, together with experimental data that will be discussed, indicate that the iron transport machinery in erythroid cells is an integral part of the heme biosynthetic pathway.