Iron uptake and metabolism in the new millennium Louise L. Dunn, Yohan Suryo Rahmanto and Des R. Richardson Iron Metabolism and Chelation Program, Department of Pathology, Blackburn Building D06, University of Sydney, Sydney, NSW 2006, Australia Iron is an essential element for metabolic processes intrinsic to life, and yet the properties that make iron a necessity also make it potentially deleterious. To avoid harm, iron homeostasis is achieved through iron trans- port, storage and regulatory proteins. The functions of some of these molecules are well described, for example transferrin and transferrin receptor-1, whereas the roles of others, such as the transferrin homolog melanotrans- ferrin, remain unclear. The past decade has seen the identification of new molecules involved in iron metab- olism, such as divalent metal transporter-1, ferroportin- 1, hepcidin, hemojuvelin and heme carrier protein-1. Here, we focus on these intriguing new molecules and the insights gained from them into cellular iron uptake and the regulation of iron metabolism. Introduction Iron (Fe) is a crucible for life. It is essential for DNA synthesis, respiration and key metabolic reactions. The levels of iron in the cell must be delicately balanced, as iron loading leads to free radical damage by the Fenton reac- tion. The Fenton reaction occurs when excess iron reacts with oxygen to generate hydroxyl radicals. To achieve appropriate levels of cellular iron and to avoid iron-load- ing, transport, storage and regulatory proteins have evolved [1]. Our understanding of iron metabolism was built around its absorption in the duodenum followed by its delivery to tissues through the plasma iron transport protein trans- ferrin (Tf). Transferrin binds to transferrin receptor-1 (TfR1) on the cell membrane and is internalized by recep- tor-mediated endocytosis [1]. Iron is then used for cellular processes, and excess iron is stored within the protein ferritin [1]. In this model, cellular iron levels are post- transcriptionally controlled by iron regulatory protein (IRP)-1 and IRP-2 [2,3]. When cells are iron-deficient, IRP-1 and IRP-2 bind to iron-responsive elements in the 3 0 - or 5 0 -untranslated regions of mRNA transcripts of molecules such as the TfR1 or ferritin, stabilizing them against degradation or inhibiting translation, respectively [2,3]. This results in increased cellular iron uptake through the TfR1 and decreased intracellular iron storage within ferritin, leading to elevated levels of intracellular iron. This straightforward version of events has been overhauled in the last decade by the discovery of many new proteins that mediate iron transport and its metabolism (Box 1). The proteins ferroportin-1 (FPN1) [4], hepcidin [5– 7], hemojuvelin (HJV) [8,9], transferrin receptor-2 (TfR2) [10] and hemochromatosis gene product (HFE) [11], have led to a large shift in our perception of iron homeostasis. Animal models have been crucial in discovering the roles of these molecules in iron homeostasis and disease (Table 1), whereas paradoxically the high-affinity iron-binding Tf homologs, lactoferrin (Lf) [12] and melanotransferrin (MTf) [13], previously thought to contribute to iron trans- port, might not have as significant a role [13,14] (Box 2). The field of iron metabolism is large and diverse, with many new discoveries each year. Here, we identify key developments in our understanding of iron transport and metabolism. Throughout the article the reader is referred to review articles that cover in more detail the specialized areas that we cannot cover here owing to the complexity of the field. We concentrate our attention on the new mech- anisms that tightly regulate iron absorption, cellular uptake and release, and on the control of iron homeostasis through the hormone hepcidin. These exciting recent developments provide greater insight into the role of this essential element in normal physiology and disease. Cellular iron metabolism The cellular metabolism of iron encompasses its absorption, regulation and utilization for cellular processes. In this section we first examine the dietary absorption of iron in the intestine, followed by its uptake by tissues such as erythroid cells and its utilization within the mitochondrion. Overview of dietary iron uptake In mammals, the majority of iron is present as hemoglobin in erythrocytes. Senescent erythrocytes are phagocytosed by macrophages and a significant portion of the iron is efficiently recycled [15]. However, there is some daily loss of iron that must be compensated for by dietary absorption through duodenal enterocytes [1] (Figure 1a). Iron exists in two main forms, Fe(III) (the ferric form) and Fe(II) (the ferrous form). Before absorption, Fe(III) in the diet must be reduced to Fe(II) at the apical surface of enterocytes, a role that was once attributed to the ferrireductase duode- nal cytochrome-b (Dcytb) [16]. However, ablation of the murine Dcytb homolog Cybrd1 results in no iron-deficient phenotype, suggesting that Dcytb is not essential for dietary iron uptake in the mouse and that another ferrir- eductase remains to be discovered [16]. Once in the ferrous state, Fe(II) is transported into the cell by divalent metal Review TRENDS in Cell Biology Vol.17 No.2 Corresponding author: Richardson, D.R. (d.richardson@pathology.usyd.edu.au). Available online 27 December 2006. www.sciencedirect.com 0962-8924/$ – see front matter ß 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.tcb.2006.12.003