AbstractHemoglobinopathies 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. Iron overload is a common complication of hemoglobinopathies treated by erythrocyte transfusions (1 mL of packed erythrocytes contains about 1 mg of iron) and those associated with ineffective erythropoiesis, which stimulates the hyperabsorption of dietary iron. With the increasing use of transfusion therapy, iron overload has become a major cause of morbidity and premature mortality. More recently, the effective treatment of iron overload by iron chelation has dramatically improved survival (Cunningham 2008; Telfer 2009). This work reviews recent advances in our understanding of the molecular basis of iron homeostasis and its disorders. Previous SectionNext SectionIRON BIOLOGY AND HOMEOSTASISIron IntakeIron is the most abundant element on Earth by mass and the fourth most abundant in the Earth’s crust but it readily oxidizes into insoluble compounds with poor bioavailability. In this environment, biological organisms evolved to conserve iron. Quantitative analysis of tissue iron distribution and fluxes in humans illustrates how this is accomplished (Finch 1994). The typical adult human male contains about 4 g of iron of which about 2.5 g is in hemoglobin, 1 g is stored predominantly in hepatocytes and hepatic and splenic macrophages, and most of the rest is distributed in myoglobin, cytochromes, and other ferroproteins. Only about 1–2 mg/d, or <0.05%/d, is lost from the body predominantly through desquamation and minor blood loss. In the steady state, this amount is replaced through intestinal iron absorption. Although the loss of iron may increase slightly with increasing iron stores, these changes do not significantly contribute to homeostasis; intestinal iron absorption is by far the predominant determinant of the iron content of the body. A typical Western diet provides about 15 mg of iron per day and only ∼10% is absorbed. Recovery from blood loss causes an increase in iron absorption up to 20-fold, indicating that the duodenum where iron absorption takes place has a large reserve capacity for iron absorption. Pathological increase of intestinal iron absorption is a common cause of iron overload, accounting for the excess iron in hereditary hemochromatosis and untransfused β-thalassemia. Blood transfusions and parenteral administration of iron compounds bypass the regulatory bottleneck of iron absorption and constitute the other major cause of iron overload. Iron RecyclingUnder normal circumstances, the reutilization of iron recycled from senescent cells accounts for most of the iron flux in humans. With the erythrocyte lifespan of 120 d, 20–25 mg of iron is required to replace the 20–25 mL of erythrocytes that must be produced every day to maintain a steady state. Other cell types also turn over but their much lower iron content contributes relatively little to the iron flux. Macrophages in the liver, spleen, and marrow (formerly called the reticuloendothelial system) phagocytose senescent or damaged erythrocytes, degrade their hemoglobin to release heme, extract iron from heme using heme oxygenase (Poss and Tonegawa 1997), and recycle the iron to the extracellular fluid and plasma. Steady-state iron flux from recycling can increase up to 150 mg/d in conditions with ineffective erythropoiesis in which the number of erythroid precursors is increased and accompanied by the apoptosis of hemoglobinized erythrocyte precursors in the marrow and shortened erythrocyte survival (Beguin et al. 1988). Iron Distribution and StorageFree iron is highly reactive and causes cell and tissue injury through its ability to catalyze the production of reactive oxygen species. In living organisms, iron is complexed with proteins or small organic molecules (citrate, acetate), which mitigate its reactivity. Transferrin is the physiological carrier of iron in plasma. Normally, only 20%–40% of the available binding sites on transferrin molecules are occupied by ferric iron. The iron content of plasma is only 2–3 mg so this compartment must turn over every few hours. Erythrocyte precursors take up iron almost exclusively through transferrin receptors (TfR1) so the iron supply to erythrocyte precursors is completely dependent on plasma transferrin. In contrast, hepatocytes and other nonerythroid cells can also take up iron that is not bound to transferrin (nontransferrin-bound iron or NTBI), a process that becomes important during iron overload when plasma transferrin saturation reaches 100% (Breuer et al. 2000). The predominant cellular storage form of iron is the hollow spherical protein ferritin whose cavity contains iron in ferric form complexed with hydroxide and phosphate anions. Regulation of Plasma Iron Concentrations
Despite varying dietary iron intake and changes in erythropoietic activity owing to occasional or periodic blood loss, iron concentrations in plasma normally remain in the 10–30 µM range. Chronically low concentrations decrease iron supply to erythropoiesis and other processes leading to anemia and dysfunction of other cell types sensitive to iron deprivation. Chronically high iron concentrations lead to intermittent or steady-state saturation of transferrin with iron and the generation of NTBI with consequent deposition of excess iron in the liver, endocrine glands, cardiac myocytes, and other tissues. Excess cellular iron may cause tissue injury by catalyzing the generation of reactive oxygen species, which can cause DNA damage, lipid peroxidation, and oxidation of proteins.
Systemic Iron Homeostasis
Phenomenological description of systemic iron homeostasis was developed starting in the 1930s (Finch 1994). Homeostatic mechanisms regulate dietary iron absorption and iron deposition into or withdrawal from stores depending on the amount of stored iron (“stores regulator”) and the requirements of erythropoiesis (“erythropoietic regulator”). The description of the molecular processes that underlie iron homeostasis has progressed rapidly in the last two decades but is still not complete.
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CELLULAR IRON REGULATION
Cellular Iron
Cells require iron predominantly for incorporation into various ferroproteins, where iron exists in iron–sulfur clusters, in heme or hemelike prosthetic moieties, or in other more loosely associated forms. It now appears that most cell types in the body autonomously regulate their iron uptake solely to meet their individual requirements for iron. These cells do not export appreciable amounts of iron and are presumed to give up their iron only when they undergo cell death and are recycled by macrophages. In contrast, several specialized cell types supply or store iron to meet the needs of the entire organism, and are therefore equipped to export iron into extracellular fluid and plasma. Iron-exporting cells include duodenal enterocytes that absorb dietary iron, macrophages that recycle iron from senescent or dead cells, and macrophages and hepatocytes that store iron and release it to meet systemic demand. During pregnancy, the placental syncytiotrophoblast must transport maternal iron into the fetal circulation to meet the iron requirements of fetal growth and development. The endothelial cells that form the blood–brain barrier must also selectively transport iron as it now appears that the iron concentrations in the brain are not appreciably increased in systemic iron overload disorders. Finally, erythroid precursors need much more iron than any other cell type as each cell synthesizes more than a billion heme molecules, therefore facing greater iron-homeostatic challenges.
Cellular Iron Uptake
Transferrin-mediated iron uptake is the best understood mechanism of cellular iron import. Although the transferrin receptor (TfR1) is expressed in many cell types, erythrocyte precursors contain most of the TfR1 molecules and take up the great majority of iron-transferrin in the organism. Iron-transferrin is endocytosed via the cell membrane TfR1 and internalized into endosomal recycling vesicles. As the vesicle acidifies, the low pH releases the transferrin-bound ferric iron and the iron-free (apo)transferrin-TfR1 complex returns to the cell membrane (Fig. 1). The neutral pH at the membrane causes the apotransferrin to dissociate from TfR1, whereupon apotransferrin diffuses away to be loaded with iron again, repeating the cycle. From the vesicle, iron is delivered to mitochondria where it is incorporated into protoporphyrin IX to form heme, or incorporated into nascent iron–sulfur clusters. Alternatively, iron can be exported from the vesicle into the cytoplasm where it is incorporated into cytoplasmic ferroproteins or stored in cytoplasmic ferritin.
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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
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