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Regulation of iron acquisition and storage: consequences for iron-linked disorders

Nature Reviews Molecular Cell Biology volume 9, pages 72–81 (2008)Cite this article

Key Points

  • Iron is essential but toxic. Mammals regulate systemic iron through acquisition and storage. Iron is absorbed in the gut and transported into plasma by an apical divalent metal transporter, DMT1, and a basolateral transporter, ferroportin. Only 1–2 mg of iron is absorbed per day in the gut.

  • Most of the iron in the body is found as haem in red blood cells. Old red blood cells are ingested by macrophages and degraded; iron is then recycled back into plasma by ferroportin. Iron in plasma is carried by the protein transferrin, which provides a chelating environment in plasma and a delivery system to cells that express transferrin receptors.

  • Iron in cells can be used for cellular processes or stored in the cytosolic protein ferritin. Levels of iron transporters, carriers and storage proteins are regulated transcriptionally and post-transcriptionally according to iron status.

  • Hepcidin, a peptide hormone secreted by the liver, is the key molecule that regulates systemic iron metabolism by regulating iron entry into plasma. The transcription of hepcidin is tightly regulated by signalling molecules, which sense iron levels, oxygen levels and inflammation. Hepcidin binds to ferroportin, leading to ferroportin degradation and a consequent decrease in cellular iron export.

  • Iron-overload diseases result from inappropriate iron acquisition in response to iron need. Excess iron can damage tissue, cause fibrosis and give rise to organ failure. Iron-deficiency disorders result in anaemia, which in turn give rise to poor oxygenation of tissue. Insight into the regulation of iron metabolism and iron-related diseases has occurred through genetics and the use of model organisms.

Abstract

Mammalian iron homeostasis must be meticulously regulated so that this essential element is available for use, but at the same time prevented from promoting the formation of toxic radicals. Controlling the entry of iron into blood plasma is the main mechanism by which iron stores in the body are physiologically manipulated and regulated. Defects in iron acquisition at the cellular and systemic levels lead to human disorders, which involve either iron overload or iron deficiency. Discoveries of iron transporters and insights into their regulation have provided important information about iron metabolism and genetic iron disorders.

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Figure 1: Systemic iron homeostasis.
Figure 2: Iron transport across the enterocyte.
Figure 3: Ferroportin-mediated iron export.
Figure 4: Endocytosis of the complex of iron, transferrin and the transferrin receptor.
Figure 5: Molecular regulation of hepcidin production.

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Acknowledgements

The authors wish to express their appreciation to members of the Kaplan laboratory for reading the manuscript. The authors thank J. Miller for sharing unpublished data. This work is supported by a National Institutes of Health grant to J.K.

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  1. Department of Pathology, School of Medicine, University of Utah, Salt Lake City, 84132, Utah, USA

    Ivana De Domenico, Diane McVey Ward & Jerry Kaplan

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  1. Ivana De Domenico
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DATABASES

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Glossary

Haem

A prosthetic group (a non-protein component of a conjugated protein) that consists of an iron atom within a large heterocyclic organic ring called a porphyrin. Not all porphyrins contain iron, but a substantial fraction of porphyrin-containing metalloproteins have haem as their prosthetic subunit; these are known as haemoproteins.

Enterocyte

An absorptive cell that lines the intestine.

Apical membrane

The membrane of an epithelial or endothelial cell that faces the lumen of a cavity or tube, or the outside of the organism.

Basolateral membrane

The membrane of an epithelial cell that adjoins underlying tissue.

Plasma

The liquid component of blood that accounts for about half of the total blood volume. Plasma is a solution of nutrients and various proteins.

Anaemia

A pathological condition characterized by abnormally low levels of healthy red blood cells or haemoglobin (the component of red blood cells that delivers oxygen to tissues throughout the body).

Iron overload

A pathological condition in which the body accumulates abnormally high levels of iron. Iron deposits can form in organs and cause life-threatening damage.

Parenchymal tissue

A tissue that is part of the essential structure and/or function of an organ, in contrast to stroma or blood vessels.

NADP

A coenzyme similar to NAD that is present in most living cells. It functions as a reducing agent in different metabolic processes and is thought to supply the electrons for the transmembrane reduction of iron from the ferric state (Fe(III)) to the ferrous state (Fe(II)).

Endosome

A vesicle that is formed by invagination of the plasma membrane.

Erythropoiesis

The formation of erythrocytes (red blood cells).

Glycophosphatidylinositol

A phosphatidylinositol to which a carbohydrate chain is linked through the C-6 hydroxyl of the inositol. It functions as an anchor that localizes proteins to the exoplasmic leaflet of membranes by linking to proteins through an ethanolamine phosphate moiety.

Sex-linked iron-limited anaemia

Anaemia that results from a sex-chromosome-inherited defect of intestinal iron absorption.

Erythron

A term describing all circulating red blood cells, reticulocytes and the tissues where they are produced.

Lysosome

A type of organelle that is characterized by a low internal pH, contains hydrolytic enzymes and is involved in the post-translational maturation of proteins, the degradation of receptors and the extracellular release of active enzymes.

Clathrin-coated pit

The initial site of invagination of a clathrin-coated vesicle, which is a transport vesicle that buds with the aid of a coat protein known as clathrin.

Reticulocyte

The youngest of the red blood cells normally found in the circulation, freshly released from the bone marrow (or other site of erythropoiesis).

Iron–sulphur cluster

Iron ions that are complexed by inorganic sulphur and by the amino acid Cys. Such clusters function as redox elements in electron-transfer reactions.

Hypoxia

A pathological condition in which the body is deprived of adequate oxygen.

Defensin

One of a class of small, 15–25-residue, Cys-rich proteins. They have a broad antimicrobial activity against bacteria, fungi and enveloped viruses.

Bone morphogenetic protein

(BMP). One of a family of secreted proteins that interact with surface receptors. BMPs are cytokines and signalling molecules and are members of the transforming growth factor-β superfamily. They have important effects on development.

Major histocompatibility complex

(MHC). A gene family that is important in the immune system. The encoded proteins are cell-surface proteins that bind to and display fragments of proteins that are endogenous (self) or foreign (non-self) for recognition by the immune system.

Founder effect

A gene mutation that is observed in high frequency in a specific population owing to its presence in a single ancestor or a small number of ancestors.

Dominant-negative mutant

A protein encoded by a mutated gene that adversely affects the function of the wild-type protein within the same cell.

Haploinsufficiency

A state in which the loss of only one of two alleles of a gene detectably disables its function.

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De Domenico, I., McVey Ward, D. & Kaplan, J. Regulation of iron acquisition and storage: consequences for iron-linked disorders. Nat Rev Mol Cell Biol 9, 72–81 (2008). https://doi.org/10.1038/nrm2295

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