Trends in Cell Biology
ReviewIron uptake and metabolism in the new millennium
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 reaction. 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-loading, 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 transferrin (Tf). Transferrin binds to transferrin receptor-1 (TfR1) on the cell membrane and is internalized by receptor-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′- or 5′-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, 6, 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 transport, 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 mechanisms 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.
Section snippets
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.
New perceptions of iron homeostasis
A new picture of iron homeostasis has resulted from the identification of hepcidin, the hormone and negative regulator of iron metabolism 5, 6, 7, and the proteins that can be mutated in hemochromatosis, HJV 8, 9, TfR2 [10] and HFE [11], that affect hepcidin expression and thereby indirectly regulate iron metabolism (Box 2; Table 1). Increasing awareness of the intimate relationships between these molecules has overhauled our perception of iron homeostasis and is enhancing our understanding of
Iron: a novel role in apoptosis?
The misregulation of iron metabolism can have disastrous effects for cells. Recent evidence from studies with lipocalin suggests that its iron-binding properties regulate apoptosis. Lipocalins are components of neutrophil granules that participate in the iron-depletion strategy of the innate immune system, which limits bacterial growth [58]. The murine lipocalin 24p3 can induce leukocyte apoptosis and also bind bacterial siderophores [58]. In fact, mice deficient in 24p3 develop bacteremia
Concluding remarks
The tightly regulated metabolism of iron is essential, as disruption or overexpression of iron-related molecules can have significant health consequences. The past decade has seen the identification of many new molecules involved in iron metabolism and homeostasis. The discovery of the hormone of iron metabolism, hepcidin, has been crucial in increasing our understanding. In addition, animal models have given invaluable insights into these molecules and how the body maintains its homeostatic
Acknowledgements
D.R.R. thanks the National Health and Medical Research Council, Australian Research Council and Muscular Dystrophy Association USA for project grant and fellowship support. L.L.D. and Y.S.R. were supported by NHMRC and University of Sydney Postgraduate Scholarships, respectively. We thank David Lovejoy, Robert Sutak, Danuta Kalinowski and Megan Whitnall of the Iron Metabolism and Chelation Program for their comments on the article before submission.
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