Working model for the regulation of iron metabolism in differentiating primary erythroblasts. (A) The model shown in this scheme is essentially based on the “kiss-and-run” hypothesis62 of vectorial iron transport toward mitochondria. It depicts the distribution of iron (cytosolic versus mitochondrial) in differentiating erythroid cells as well as how the expression levels of TfR1, Fer, and ALAS-E are regulated via IRP. Thick and thin black arrows symbolize high and low rates of iron flow, respectively; open white arrows depict heme synthesis; lettering size for hemoglobin, TfR1, Fer, ALAS-E and “Fe” (iron-loaded heme) indicates the expression level of the corresponding protein or compound. (B) Predicted and in part experimentally verified consequences of (1) perturbation of mitochondrial iron uptake/flow by adding inhibitors of heme biosynthesis like succinylacetone (SA; left panel) or (2) of direct cytoplasmic iron overload with low-molecular-weight iron salts (ie, addition of ferric ammonium citrate, FAC; right panel).
