Current understanding of iron homeostasis

Abstract

Iron is an essential trace element, but it is also toxic in excess, and thus mammals have developed elegant mechanisms for keeping both cellular and whole-body iron concentrations within the optimal physiologic range. In the diet, iron is either sequestered within heme or in various nonheme forms. Although the absorption of heme iron is poorly understood, nonheme iron is transported across the apical membrane of the intestinal enterocyte by divalent metal-ion transporter 1 (DMT1) and is exported into the circulation via ferroportin 1 (FPN1). Newly absorbed iron binds to plasma transferrin and is distributed around the body to sites of utilization with the erythroid marrow having particularly high iron requirements. Iron-loaded transferrin binds to transferrin receptor 1 on the surface of most body cells, and after endocytosis of the complex, iron enters the cytoplasm via DMT1 in the endosomal membrane. This iron can be used for metabolic functions, stored within cytosolic ferritin, or exported from the cell via FPN1. Cellular iron concentrations are modulated by the iron regulatory proteins (IRPs) IRP1 and IRP2. At the whole-body level, dietary iron absorption and iron export from the tissues into the plasma are regulated by the liver-derived peptide hepcidin. When tissue iron demands are high, hepcidin concentrations are low and vice versa. Too little or too much iron can have important clinical consequences. Most iron deficiency reflects an inadequate supply of iron in the diet, whereas iron excess is usually associated with hereditary disorders. These disorders include various forms of hemochromatosis, which are characterized by inadequate hepcidin production and, thus, increased dietary iron intake, and iron-loading anemias whereby both increased iron absorption and transfusion therapy contribute to the iron overload. Despite major recent advances, much remains to be learned about iron physiology and pathophysiology.

Keywords: anemia; ferritin; hemochromatosis; hepcidin; iron deficiency; iron overload; iron physiology; transferrin.

© 2017 American Society for Nutrition.

Figures

FIGURE 1

Body iron homeostasis. Iron is present in the diet in both heme and nonheme forms. Although the mechanisms underlying heme absorption are poorly understood, nonheme iron enters the circulation after traversing the enterocyte apical membrane via DMT1 and the basolateral membrane via FPN1. Iron binds to plasma TF and is distributed to tissues throughout the body. Quantitatively, most iron is used by immature red blood cells in the bone marrow for hemoglobin production. Senescent erythrocytes are phagocytosed by macrophages, and the iron is released from catabolized hemoglobin and re-enters the circulation. The liver-derived peptide hepcidin plays a critical role in the regulation of body iron intake and distribution by binding to plasma membrane FPN1 on enterocytes, macrophages, and most body cells and facilitating its internalization and degradation. Hepcidin, in turn, is regulated by body iron demand. Thus, when the body is iron deficient, hepcidin concentrations are low, thereby favoring iron absorption and delivery to the plasma from storage sites; but when the body is iron replete, a higher hepcidin concentration reduces iron absorption and impairs iron release from stores. DCYTB, duodenal cytochrome b; DMT1, divalent metal-ion transporter 1; FPN, ferroportin; HP, hephaestin; TF, transferrin.

FIGURE 2

Cellular iron homeostasis. Cells can take up iron in a variety of forms, but all nucleated cells have the capacity to use TF-bound iron. Diferric TF binds to TFR1 on the plasma membrane, and the complex is internalized in endosomes. Acidification of the endosome, which is accompanied by iron reduction by a member of the STEAP family of proteins, releases iron from TF, which subsequently moves across the endosomal membrane via DMT1 and into the cytoplasm. The precise form of this cytosolic iron pool is unclear, but at least some iron is bound by PCBP proteins that act as iron chaperones. These complexes can deliver iron to newly synthesized iron-containing proteins (although whether they can deliver iron to mitochondria is unclear) and to the iron-storage protein ferritin. Iron in excess of cellular needs may be exported through FPN1 with the iron oxidase CP increasing the efficiency of this process. Some cell types can take up iron in other forms, including NTBI, or iron that is contained within ferritin, heme, or hemoglobin. Cellular iron intake and storage are regulated by the iron-responsive element and IRP system such that low iron concentrations favor the synthesis of more TFR1 and suppress ferritin expression, whereas high cellular iron leads to an increase in ferritin concentrations and a decrease in TFR1. CP, ceruloplasmin; DMT1, divalent metal-ion transporter 1; FPN1, ferroportin 1; IRP, iron regulatory protein; LRP, LDL-receptor–related protein; mRNA, messenger RNA; NTBI, non–transferrin-bound iron; PCBP, poly(rC)-binding protein; STEAP, 6-transmembrane epithelial antigen of the prostate; TF, transferrin; TFR1, transferrin receptor 1; ZIP14, Zrt/Irt-like protein 14.