Generalized Regulation of Protein Synthesis by Iron in Erythroid Cells
In addition to the regulation of the synthesis of individual proteins by iron, erythroid cells also contain a mechanism for a generalized adaptive response to iron deficiency. This response is affected by the heme-regulated inhibitor kinase (HRI) belonging to a class of kinases activated by cellular stress, including nutrient deprivation, viral infection, and endoplasmic reticulum stress (Chen 2007). During iron deficiency as heme concentrations drop, heme dissociates from HRI, causing it to undergo specific autophosphorylation to become a catalytically active kinase targeting the α subunit of eukaryotic translational initiation factor 2 (eIF2α). Activated HRI inhibits translational initiation by phoshorylating eIF2α. Not all protein synthesis is inhibited however, as activated HRI may promote the synthesis of transcription factors that are protective during iron-deficient erythropoiesis (Liu et al. 2008). A priori, it is not obvious how iron deficiency results in the production of smaller, less-hemoglobinized erythrocytes rather than fewer normally sized and hemoglobinized cells. Studies with HRI-deficient mice showed that HRI protects erythroid precursors from apoptosis induced by excessive production of globin chains and contributes to the microcytosis and hypochromia seen in iron deficiency, erythropoietic protoporphyria, and β-thalassemia.
Iron and Hypoxia Sensing
The hypoxia-sensing pathway may also contribute to cellular iron homeostasis. Prolyl and asparaginyl hydroxylases, which inactivate the HIF transcription factors, are not only sensitive to oxygen tension but also to iron concentrations because they use iron as a catalytic cofactor. In support of the potential role of HIF in iron regulation, tissue-specific deletion of HIF2α in mouse enterocytes decreased intestinal iron absorption as well as the expression of DMT1 in enterocytes (Mastrogiannaki et al. 2009). HIF2α bound to the DMT1 promoter and transactivated it. The broader physiologic function of HIF in cellular iron homeostasis still remains to be established and may vary in different tissues depending on oxygen tension and other factors.
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SYSTEMIC IRON HOMEOSTASIS
The Central Role of Hepcidin
Systemic iron homeostasis encompasses the regulatory circuitry that controls the absorption of dietary iron, the concentration of iron in extracellular fluid and blood plasma, and the release of iron from macrophages involved in iron recycling and from iron-storing hepatocytes. It now appears that there is a single systemic regulator of iron, the hepatic peptide hormone hepcidin. The hormone inhibits iron delivery to plasma and extracellular fluid thereby controlling the concentration of iron in plasma. Hepcidin inhibits the transfer of dietary iron from duodenal enterocytes to plasma, the release of recycled iron from macrophages to plasma, and the release of stored iron from hepatocytes (Fig. 2). Fetal hepcidin inhibits the transfer of maternal iron across the placenta to the fetal circulation. At the molecular level, hepcidin acts by binding to its receptor, ferroportin, and causing its endocytosis and proteolysis, which results in decreased iron release from cells to plasma and extracellular fluid. Ferroportin is found at very low concentrations in most cell types but much higher amounts in professional iron-transporting tissues, including the duodenal enterocytes and splenic macrophages. Intermediate concentrations of ferroportin are detectable in hepatocytes.
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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.