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Iron Homeostasis- Mechanisms and importance in systems (patho)physiology

The iron uptake protein Tranferrin receptor in the placenta (top left, red). The iron export protein ferroportin in the placenta (top right, green). The iron export protein ferroportin in the gut (bottom left, green). Loss of ferroportin regulation in the heart causes fatal heart failure (bottom right).

our research

Unique biochemical properties underpin the essential functions of iron in oxygen transport and oxidative phosphorylation. Those same properties also underpin its propensity to participate in Fenton-type reactions, producing cell-damaging reactive oxygen species. Thus, tight control of iron levels within tissues is paramount for normal physiological function, particularly in tissues of high oxygen demand/flux.

Tissues acquire their iron from the circulation. The levels of iron in the circulation are determined by the hepcidin/ferropotin axis. Ferroportin is the only known mammalian iron export protein and mediates iron release into the circulation from the gut, spleen and liver, sites of iron absorption, recycling and storage respectively. Ferroportin-mediated iron export at these sites is inhibited by the liver-derived hormone hepcidin. In this manner, the hepcidin/ferroportin axis controls serum iron availability.

Until recently, the consensus has been that iron levels within tissues are a function of serum iron availability. Work in our lab has changed that understanding by uncovering new functions for hepcidin and ferroportin in tissue-driven iron control. Our  work has shown that some cells, including cardiomyocytes, pulmonary arterial smooth muscle cells and fetal hepatocytes utilise ferroportin and hepcidin locally to control intracellular iron levels. Our work has also shown that this tissue-driven iron control is essential for normal physiological function.

Why is THIS RESEARCH important?

The mechanisms of iron homeostasis have evolved in the context of an arms race between host and pathogen for access to iron. One by-product of this evolutionary arms race is that hepcidin is induced by the inflammation that accompanies infection, in order to limit iron availability to blood-borne pathogens. However, inflammation is also a hallmark of modern human diseases, e.g chronic heart failure, chronic kidney disease, chronic obstructive pulmonary disease, rheumatoid arthritis and cancer. Consequently, hepcidin is also often elevated in patients with these conditions, causing them to become iron-deficient.  This is termed "iron deficiency of chronic disease".

Our discoveries on the role of hepcidin and ferroportin in tissue-driven iron control have important implications for patients with iron deficiency of chronic disease. They imply that hepcidin elevation in this setting will have direct effects on iron levels within the tissues that utilise ferroportin and hepcidin for tissue-deriven iron control, e.g the heart, the pulmonary vasculature. They change our thinking of iron deficiency from the simplistic view of "too little iron" to that of "iron mal-distribution". Our work is now focussed on understanding how tissue-driven iron control is perturbed in chronic conditions, and the extent to which this perturbation contributes to underlying disease.

Iron deficiency is increasingly being recognised as an important and prevalent co-morbidity in chronic conditions. Different strategies are being developed to tackle the burden of iron deficiency in this setting, including parenteral iron supplementation (to bypass blocked iron absorption in the gut), and hepcidin antagonists. These strategies are primarily focussed on restoring normal serum iron levels. Our work is building a case for considering the impact of these strategies on local iron levels within the diseased tissue, and on developing new strategies that both correct serum iron levels and restore normal tissue-driven iron control.

Our team

Lakhal-Littleton study reveals critical link between iron deficiency and a serious cardiovascular condition

More information on DPAG News.

Selected publications

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