Iron metabolism: interactions with normal and disordered erythropoiesis

Abstract

Hemoglobinopathies and other disorders of erythroid cells are often associated with abnormal iron homeostasis. We review the molecular physiology of intracellular and systemic iron regulation, and the interactions between erythropoiesis and iron homeostasis. Finally, we discuss iron disorders that affect erythropoiesis as well as erythroid disorders that cause iron dysregulation.

Figure 1.

Iron traffic in erythrocyte precursors synthesizing hemoglobin. Iron is taken up as diferric transferrin by the transferrin receptor (TfR1). Acidification of the endocytic vesicle releases ferric iron from transferrin, and the membrane ferrireductase Steap3 reduces it to ferrous iron, which is then exported to the cytoplasm by DMT1. The complex of iron-free apotransferrin (Tf) and TfR1 is returned to the plasma membrane where the neutral pH causes Tf to dissociate from its receptor. The transferrin cycle is completed when Tf is reloaded with ferric iron by duodenal enterocytes or iron-recycling macrophages. Ferrous iron exported by DMT1 may be delivered to mitochondrial mitoferrin-1 (Mfrn1) by direct contact (the kiss-and-run mechanism, K&R) or through intermediate transport by as-yet uncharacterized cytoplasmic chaperones (Fe²⁺Ch). Mitoferrin-1 imports iron into mitochondria where iron is incorporated into newly synthesized heme. Heme is exported via an unknown exporter (Heme export) and incorporated into globin chains to generate hemoglobin. Under some circumstances, iron is exported as ferrous iron via ferroportin (Fpn) or as heme via feline leukemia virus C receptor (FLVCR1).

Figure 2.

Iron homeostasis. Through membrane ferroportin (Fpn), iron flows into plasma (pale blue arrows) from duodenal enterocytes, iron-storing hepatocytes, and iron-recycling macrophages predominantly in the spleen. Iron-transferrin (Fe-Tf) is mostly delivered to the marrow (pale blue arrow) where iron is incorporated into erythrocyte hemoglobin (red). When the erythrocytes live out their lifespan (normally 120 d in humans), their hemoglobin and heme are degraded in the macrophages, mostly in the spleen, and iron is returned into the plasma iron pool. Hepatocytes secrete hepcidin under the control of stimulatory signals that reflect liver iron stores and plasma iron concentrations (blue), inhibitory signals reflecting erythropoietic activity (red), and inflammatory cytokines (green). Hepcidin causes the degradation of Fpn and thereby inhibits iron delivery to plasma and the erythropoietic bone marrow.

Figure 3.

Regulation of hepcidin by iron and inflammation. Hepcidin synthesis is transcriptionally regulated by iron through the BMP receptor complex and its Smad pathway (shades of blue) and by inflammation predominantly via the IL-6 receptor and its JAK-STAT3 pathway (green). Extracellular iron is sensed by transferrin receptors (TfR1 and TfR2) aided by HFE, which can associate with either TfR but is displaced from TfR1 when TfR1 binds diferric transferrin (HoloTf). When HoloTf concentrations are high, HFE is associated mostly with TfR2 and stabilizes it. HFE-TfR2 then potentiates BMP receptor signaling through an unknown mechanism. Stored hepatic intracellular iron increases the concentrations of BMP6 mRNA and presumably BMP6 protein in the liver thereby stimulating the BMP receptor, its Smad pathway, and hepcidin transcription.