Review
Regulation of iron transport and the role of transferrin,☆☆

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Abstract

Background

Iron is utilized by several proteins as cofactor for major biological processes. However, iron may also harm cells by catalyzing the generation of free radicals and promoting oxidative stress. Acquisition, transport, utilization and storage of iron are tightly controlled to meet physiological needs and prevent excessive accumulation of the metal within cells. Plasma transferrin has been known for years as a central player in iron metabolism, assigned to circulate iron in a soluble, non-toxic form and deliver it to the erythron and other tissues. Recent data uncovered an additional role of transferrin as an upstream regulator of hepcidin, a liver-derived peptide hormone that controls systemic iron traffic.

Scope of review

Here, we review basic features of iron metabolism, highlighting the function of transferrin in iron transport and cellular iron uptake. We further discuss the role of hepcidin as an orchestrator of systemic iron homeostasis, and the mechanisms underlying hepcidin regulation in response to various physiological cues. Emphasis is given on the role of transferrin on iron-dependent hepcidin regulation.

Major conclusions

Transferrin exerts a crucial function in the maintenance of systemic iron homeostasis as component of a plasma iron sensing system that modulates hepcidin expression.

General significance

Proper expression of transferrin and hepcidin are essential for health, and disruption of their regulatory circuits is associated with iron-related disorders. This article is part of a Special Issue entitled Transferrins: Molecular mechanisms of iron transport and disorders.

Highlights

► Basic concepts of cellular and systemic iron metabolism. ► The role of transferrin in iron transport and cellular iron uptake. ► Hormonal regulation of systemic iron traffic by hepcidin. ► Mechanisms underlying hepcidin regulation in response to various physiological cues. ► The role of transferrin in iron-dependent regulation of hepcidin.

Introduction

The unique ability of iron to serve both as an electron donor and acceptor renders this metal irreplaceable for various physiological and metabolic pathways. Vital biochemical activities, including oxygen transport, energy production and cellular proliferation depend on iron-containing cofactors, such as heme, or iron sulfur clusters (ISC). However, although beneficial at normal levels, excess iron may become toxic due to its ability to catalyze the generation of free radicals and damage cellular macromolecules [1]. Mammals have evolved complex homeostatic circuits and specialized molecules to ensure safe and balanced iron acquisition, transfer and storage. Proteins involved in iron transport and in regulation of iron metabolism are summarized in Table 1, Table 2, respectively.

Plasma transferrin (Tf) is a powerful chelator, capable of binding iron tightly but reversibly [2], [3]. A molecule of Tf can bind two atoms of ferric iron (Fe3 +) with high affinity (Kd = 10 23 M) [2], which is higher in the extracellular pH of 7.4 and decreases in the acidified endosomes, allowing the dissociation of Fe+ 3. Tf belongs to a family of homologous iron-binding glycoproteins that encompasses lactoferrin (found both intracellular and in secretions, including milk), melanotrasferrin (present on melanoma cells) and ovotransferrin (present in egg white) [4]. They are all monomeric proteins of 76–81 kDa and consist of two structurally similar lobes (termed N- and C-lobes), each containing a single iron-binding site.

Iron chelation by transferrin serves three main purposes: i) it maintains Fe3 + in a soluble form under physiologic conditions, ii) it facilitates regulated iron transport and cellular uptake, and iii) it maintains Fe3 + in a redox-inert state, preventing the generation of toxic free radicals. Tf has an indirect defensive role against systemic infections by depriving the potential pathogens of extracellular iron, which is essential for their growth [5]. Moreover, diferric holo-Tf exerts a key regulatory function in the expression of hepcidin (encoded by the HAMP gene), a small hepatic peptide hormone that controls intestinal iron absorption and hepatic and macrophage iron release [6], [7], [8]. This review focuses on the functions of Tf and the regulation of Tf expression in the context of cellular and systemic iron homeostasis.

Section snippets

Tissue and plasma iron pools

The adult human body contains approximately 3–5 g of iron (about 55 mg and 44 mg per kilogram of body weight for males and females respectively), with more than two thirds (> 2 g) incorporated in the hemoglobin of developing erythroid precursors and mature red blood cells [9], [10], [11]. Most of the remaining body iron is found in a transit pool in reticuloendothelial macrophages (~ 600 mg) or stored in hepatocytes (~ 1000 mg) within ferritin, an iron storage protein. A smaller fraction is present in

Transferrin-mediated mechanisms

Erythroid progenitor cells and other rapidly dividing cell populations acquire their metabolic iron from plasma Tf by receptor-mediated endocytosis, following interaction of iron-loaded Tf with the cell surface transferrin receptor 1 (TfR1). This transmembrane glycoprotein forms a disulfide-bonded homodimer, which can bind one Tf molecule at each of its subunits [42], [43]. Interestingly the iron status of Tf impinges on its affinity for TfR1; thus, diferric Tf binds with 30- and 500-fold

Iron trafficking, utilization and storage

The trafficking of iron inside the cells is perplexing and despite significant recent advances several aspects remain poorly understood. It is believed that following its DMT1-mediated transport across the endosomal membrane to the cytosol, newly acquired iron from the Tf/TfR1 cycle enters the labile iron pool (LIP) [90]. This is a transient pool of redox-active iron, presumably associated with several low molecular-weight chelates, such as citrate, ATP, AMP, pyrophosphate or various peptides.

Regulation of Tf expression

Tf is expressed predominantly in the fetal and adult liver, but lower amounts can be synthesized in other tissues such as the brain and the testis [138]. The expression of the Tf gene is controlled by transcriptional mechanisms. The levels of Tf mRNA increase steadily in liver during fetal development, reaching a plateau shortly after birth, and remain high in adult life [13]. By contrast, Tf expression declines rapidly after birth in other tissues such as the kidney, the spleen, the lung, the

Hepcidin, the iron-regulatory peptide hormone

Tight and accurate regulation of iron absorption in humans is critical to prevent systemic excess or deficiency. This complex task is accomplished by hepcidin, a liver-derived peptide hormone that responds to multiple regulatory cues, including, iron availability, erythropoietic activity, anemia, inflammatory signals and hypoxia (Fig. 2) [15], [146].

Hepcidin exerts its biological action by binding to ferroportin and promoting its phosphorylation, internalization and lysosomal degradation [147].

Perspectives

Not too many years ago, the field of iron metabolism was synonymous to the study of Tf and ferritin. The identification of TfR1 and the Tf/TfR1 cycle, and the characterization of the IRE/IRP system in the 80s of the last century, paved the ground for understanding basic mechanisms of cellular iron acquisition and homeostasis. The molecular cloning of iron transporting molecules (DMT1 and ferroportin) and, moreover, the discovery of hepcidin as the principal orchestrator of body iron homeostasis

Acknowledgements

This work was supported by a grant from the Canadian Institutes for Health Research (MOP-86514). KG is supported by doctoral awards from the J. Latsis and A. Onassis Public Benefit Foundations. KP holds a Chercheur National career award from the Fonds de la Recherche en Santé du Quebéc (FRSQ).

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    This article is part of a Special Issue entitled Transferrins: Molecular mechanisms of iron transport and disorders.

    ☆☆

    This work was supported by a grant from the Canadian Institutes for Health Research (CIHR; MOP-86514).

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