Cellular iron: Ferroportin is the only way out

Ferroportin is the sole cellular efflux channel for iron and is regulated by the iron regulatory hormone hepcidin, which binds ferroportin and induces its internalization and degradation. New studies of ferroportin knockout mice define a key role for this transporter in physiological iron balance. Ferroportin is the sole cellular efflux channel for iron and is regulated by the iron regulatory hormone hepcidin, which binds ferroportin and induces its internalization and degradation. New studies of ferroportin knockout mice define a key role for this transporter in physiological iron balance. Iron, an essential nutrient, is used in proteins that store and transport oxygen and catalyze redox reactions. In vertebrates, most iron in the body is destined for hemoglobin. When iron absorption from the diet is not sufficient to compensate for iron losses, hemoglobin production decreases, resulting in anemia. Not only is iron deficiency deleterious, but iron excess is also. Uncomplexed iron catalyzes the production of reactive oxygen species which cause cellular injury and cell death. In hereditary hemochromatoses (Pietrangelo, 2004Pietrangelo A. N. Engl. J. Med. 2004; 350: 2383-2397Crossref PubMed Scopus (780) Google Scholar), unrestrained iron absorption from the diet leads to the deposition of excess iron in the liver and other organs, with consequent organ damage and functional failure. In this issue of Cell Metabolism, Andrews and colleagues use genetic means to demonstrate the unique and nonredundant function of the cellular iron exporter ferroportin in maintaining extracellular iron homeostasis (Donovan et al., 2005Donovan A. Lima C.A. Pinkus J.L. Pinkus G.S. Zon L.I. Robine S. Andrews N.C. Cell Metab. 2005; 1 (this issue): 191-200Abstract Full Text Full Text PDF PubMed Scopus (749) Google Scholar). Cellular iron homeostasis (Hentze et al., 2004Hentze M.W. Muckenthaler M.U. Andrews N.C. Cell. 2004; 117: 285-297Abstract Full Text Full Text PDF PubMed Scopus (1305) Google Scholar) assures adequate iron supply for the varying metabolic needs of individual cells, as long as extracellular iron concentrations remain in the normal range. Iron circulates in plasma or extracellular fluid complexed with transferrin. Cells take up iron-transferrin by transferrin receptor-mediated endocytosis and store iron predominantly in cytoplasmic ferritin. Two iron regulatory proteins (IRP1 and IRP2) function as cytoplasmic iron sensors. When cellular iron is low, IRPs stabilize transferrin receptor mRNA, thus increasing the number of transferrin receptors for iron uptake. Iron-deficient IRPs also inhibit the translation of ferritin mRNA, allowing the net release of iron from ferritin. Organismal iron homeostasis has apparently evolved to maintain a stable concentration of iron-transferrin in plasma and extracellular fluid. This requires the coordinated control of three major iron flows into the plasma transferrin compartment: iron absorption from the environment (maternal plasma iron in the fetus and intestinal dietary iron after birth), movement of iron out of storage in the liver, and recycling of the iron content of senescent cells (predominantly red blood cells) by macrophages. To maintain stable extracellular iron concentrations, the inflow of iron into plasma transferrin must balance the outflow, which is dominated by the iron requirements of red cell hemoglobin production in the bone marrow. Additional smaller outflows supply the needs of other cells, and the rest enters into storage in hepatocytes. Influences other than the concentration of iron-transferrin also regulate iron flows. Anemia and hypoxia stimulate iron absorption and recycling, thus providing more iron for compensatory erythropoiesis. Moreover, both iron absorption and recycling are inhibited during infections, presumably to deprive invading pathogens of extracellular iron. Despite the potential for great complexity, the regulatory system that has emerged from recent studies is surprisingly simple and elegant (Figure 1). The single iron regulatory hormone, hepcidin (Nicolas et al., 2001Nicolas G. Bennoun M. Devaux I. Beaumont C. Grandchamp B. Kahn A. Vaulont S. Proc. Natl. Acad. Sci. USA. 2001; 98: 8780-8785Crossref PubMed Scopus (1035) Google Scholar, Nicolas et al., 2002Nicolas G. Bennoun M. Porteu A. Mativet S. Beaumont C. Grandchamp B. Sirito M. Sawadogo M. Kahn A. Vaulont S. Proc. Natl. Acad. Sci. USA. 2002; 99: 4596-4601Crossref PubMed Scopus (731) Google Scholar, Roetto et al., 2003Roetto A. Papanikolaou G. Politou M. Alberti F. Girelli D. Christakis J. Loukopoulos D. Camaschella C. Nat. Genet. 2003; 33: 21-22Crossref PubMed Scopus (728) Google Scholar, Ganz, 2004Ganz T. Curr. Opin. Hematol. 2004; 11: 251-254Crossref PubMed Scopus (141) Google Scholar), controls iron flows out of the cells and into the plasma transferrin compartment by binding to a unique cellular iron exporter, ferroportin, and inducing its endocytosis and degradation (Nemeth et al., 2004Nemeth E. Tuttle M.S. Powelson J. Vaughn M.B. Donovan A. Ward D.M. Ganz T. Kaplan J. Science. 2004; 306: 2090-2093Crossref PubMed Scopus (3281) Google Scholar). Ferroportin (McKie et al., 2000McKie A.T. Marciani P. Rolfs A. Brennan K. Wehr K. Barrow D. Miret S. Bomford A. Peters T.J. Farzaneh F. et al.Mol. Cell. 2000; 5: 299-309Abstract Full Text Full Text PDF PubMed Scopus (1134) Google Scholar, Donovan et al., 2000Donovan A. Brownlie A. Zhou Y. Shepard J. Pratt S.J. Moynihan J. Paw B.H. Drejer A. Barut B. Zapata A. et al.Nature. 2000; 403: 776-781Crossref PubMed Scopus (1277) Google Scholar, Abboud and Haile, 2000Abboud S. Haile D.J. J. Biol. Chem. 2000; 275: 19906-19912Crossref PubMed Scopus (984) Google Scholar), also called Slc40a1, MTP1, or Ireg1, is found in all the tissues where major iron flows are regulated, including duodenal enterocytes, placental trophoblast, macrophages, and hepatocytes. The work of Donovan et al. has significantly advanced our understanding of ferroportin’s function. Their earlier studies in zebrafish indicated that the complete loss of ferroportin expression is embryonic lethal, unless the embryos are rescued by iron injections (Donovan et al., 2000Donovan A. Brownlie A. Zhou Y. Shepard J. Pratt S.J. Moynihan J. Paw B.H. Drejer A. Barut B. Zapata A. et al.Nature. 2000; 403: 776-781Crossref PubMed Scopus (1277) Google Scholar). The surviving zebrafish had severe iron deficiency anemia and were not able to absorb iron from their diet. In the current study, total deficiency of ferroportin in mammals is also embryonic lethal, almost certainly because the developing embryo cannot import iron across the maternal-fetal interface (extraembryonic visceral endoderm, placenta). If this early defect is selectively circumvented by conditionally deleting ferroportin in all tissues except the maternal-fetal interface, the embryo survives to birth but the newborn mouse rapidly develops severe iron deficiency as it begins to depend on intestinal absorption of iron. The mice also display defects in the release of iron from hepatic storage and in the recovery of iron from recycled red cells. As indicated by abundant trapped iron in intestinal enterocytes, macrophages, and hepatocytes, all these cells are unable to export cytoplasmic iron to plasma in the absence of ferroportin. The importance of ferroportin for intestinal iron absorption was specifically addressed by an intestine-specific ablation of ferroportin expression. Like the mice with total postnatal ablation of ferroportin, these mice also developed severe systemic iron deficiency despite iron-loaded enterocytes. Here, however, macrophages and hepatocytes lacked iron, since these cell types still had ferroportin, and exported iron as is appropriate in systemic iron deficiency. Most discussions of diseases of iron overload make the point that physiological excretion of iron is very limited and cannot be increased. However, Donovan et al., 2005Donovan A. Lima C.A. Pinkus J.L. Pinkus G.S. Zon L.I. Robine S. Andrews N.C. Cell Metab. 2005; 1 (this issue): 191-200Abstract Full Text Full Text PDF PubMed Scopus (749) Google Scholar propose that intestinal epithelium can take up significant amounts of iron from plasma by transferrin receptor-mediated endocytosis through the basolateral membrane. If circulating hepcidin concentrations are high, basolateral ferroportin is degraded and the iron trapped. At the end of their 1–2 day life span, the iron-loaded intestinal epithelial cells would be shed into the fecal stream. It is therefore conceivable (but remains to be shown and quantified) that iron excretion in stool could be homeostatically increased during iron overload. This important and definitive study confirms that the iron-exporting tissues and cells have no significant alternative to the ferroportin iron efflux pathway and provides further support for the fundamental role of the hepcidin-ferroportin interaction in systemic iron homeostasis. This interaction is also the key to understanding the pathogenesis of hereditary hemochromatosis. The excessive intestinal iron absorption characteristic of this group of diseases results from inappropriately high ferroportin activity either because of hepcidin deficiency or, less commonly, because of the insensitivity of mutated ferroportin to hepcidin. At the other end of the spectrum of iron disorders, anemia of inflammation develops when the cytokine-induced hepcidin internalizes and degrades ferroportin on iron-exporting cells, most notably macrophages. Recycled iron is trapped, decreasing the plasma concentration of iron and limiting hemoglobin production in developing erythrocytes in the bone marrow. What next? Although we have learned much about the role of hepcidin and ferroportin in organismal iron homeostasis, we know very little about how and where extracellular iron is sensed and how it regulates hepcidin production and release. With the exception of the hepcidin gene itself, the various mutations that cause hepcidin deficiency involve proteins of unknown function. The mother lode of iron regulation is far from exhausted, and rich iron biology still remains to be explored.