Iron is a component of nearly all living organisms. It plays an important metabolic role, particularly in electron transfer reactions. Most of the iron in the human body is in the hemoglobin of circulating red cells, which contain approximately 1 mg of iron per 1 mL of packed cells. Smaller amounts of iron are present in myoglobin and in many enzymes. Iron is stored within cells inside ferritin and circulates in plasma bound to transferrin. Most of the iron flow into the plasma is generated by the release of iron recycled from senescent erythrocytes by splenic and hepatic macrophages. Plasma iron is largely destined for hemoglobin synthesis in marrow erythroblasts, with much smaller amounts serving the needs of other tissues. Because little iron is lost from the body under normal circumstances, the iron content of the body is controlled by modulating dietary iron absorption. Iron absorption increases in the presence of iron deficiency and it decreases when there is iron overload. The absorption of inorganic iron involves a ferrireductase and a divalent iron transporter, DMT-1, on the gastrointestinal luminal apical membranes of enterocytes, and ferroportin and hephaestin, located on the basolateral enterocyte membranes, in contact with blood. In contrast to elemental iron, heme iron is absorbed by a distinct pathway, which is still not well understood.
Systemic iron homeostasis is orchestrated by the hepatic peptide hormone hepcidin, which regulates plasma iron concentrations, the absorption of dietary iron, and the release of iron from macrophages involved in iron recycling and storage and from hepatocytes that store iron. The cellular iron exporter ferroportin serves as the receptor for hepcidin and is occluded and then destroyed when the complex is formed. This impairs transport from intestinal mucosal cells, from macrophages and from hepatocytes into the plasma, and lowers iron absorption and release from stores. Hepcidin therefore decreases plasma iron levels by causing iron to be sequestered within cells, predominantly in macrophages or enterocytes, the latter of which are then shed along with their absorbed iron.
Once ferric iron enters the plasma, it is bound by transferrin, which after forming a complex with the transferrin receptor, transports the metal into cells. The transferrin receptor is internalized together with bound transferrin and iron, and the iron is released inside the cell into an acidified vacuole. The transferrin receptor then recycles to the cell surface.
Cellular iron homeostasis is largely achieved through posttranscriptional regulation of key proteins involved in iron transport, storage, and utilization. The synthesis of these proteins is regulated by binding of one of the iron-regulatory proteins (IRPs) to iron-responsive elements (IREs) located within stem loop structures of the corresponding messenger ribonucleic acids (mRNAs). IRP-1 is cytoplasmic aconitase that binds to the IRE when it is not complexed with iron and does not bind when iron is present; IRP-2, a closely related protein, is destabilized by the presence of iron. When IRPs bind to IREs at the 5′ end of the mRNA, they prevent translation; ...