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

Iron metabolism proteins in various systems 3
The iron uptake protein Tranferrin receptor in the placenta (top left, red), amd the iron export protein ferroportin in the placenta (top right, green) and gut (bottom left, green). Disruption of ferroportin regulation in the heart causes fatal heart failure (bottom right).

What we study

We study how iron is regulated locally in various tissues (e.g. the heart, the placenta, the kidney, the vasculature), and how local iron control affects the physiology of these tissues.

Why is it important?

According to the World Health Organization, iron deficiency is the most common nutritional disorder worldwide. It affects intrauterine development, reduces mental and physical functional capacity, and increases co-morbidity when concurrent with cardiovascular diseases. When severe, iron deficiency restricts iron supply to the bone marrow, which manifests as anaemia. Both the WHO and National Institute for Health and Care Excellence (NICE) have guidelines on the management of “Iron deficiency anaemia”, but no specific guidelines on iron deficiency itself. However, it is estimated that anaemia only occurs in ~25% of iron-deficient individuals. This reflects the dominant effect exerted by the bone marrow (which accounts for ¾ of iron demand in the body) over systemic iron homeostasis, meaning that its iron supply is maintained at the expense of iron supply to non-erythroid tissues. The effects on health of restricted iron supply to non-erythroid tissues have remained largely unstudied. By understanding the mechanisms of local iron control in various systems, we can begin to probe the consequences of restricted local iron supply on their function. We can also begin to identify specific cell types or pathways that are affected by iron deficiency, and which could present novel therapeutic opportunities in specific disease settings.

The Heart as a Model System

 Systemic iron availability is controlled by the liver-derived hormone hepcidin (HAMP). It exerts this control through its ability to bind, and internalise ferroportin (FPN), the only known mammalian iron export protein at the sites of iron recycling (splenic reticuloendothelial macrophages), absorption (duodenal enterocytes) and storage (hepatocytes). HAMP expression is increased by high transferrin saturation and inflammation (which accounts for ID anaemia of chronic disease), and decreased by low transferrin saturation, erythroid drive (through an endocrine signal from the bone marrow) and hypoxia (through hypoxia-inducible factors HIFs). Intracellular iron availability is orchestrated by Iron Regulatory Proteins (IRPs) in all cells of the body. Our previous work was the first to that some cells require an additional, non-redundant mechanism of intracellular iron homeostasis, that utilises a local FPN/HAMP axis. In the heart, we have shown that disruption of the cardiomyocyte FPN/HAMP axis causes fatal heart failure as a consequence of cardiomyocyte iron deficiency (in cardiomyocytes deficient in HAMP or expressing HAMP-resistant FPN isoform C326Y) or overload (in cardiomyocytes deficient in FPN) (Lakhal-Littleton et al, PNAS 2015, Lakhal-Littleton et al, eLife 2016). In both settings, fatal heart failure occurred against a background of otherwise intact systemic iron homeostasis (and no anaemia), and was prevented by intravenous iron supplementation and dietary iron restriction respectively. Our studies: a) support the notion that restricted iron supply to non-erythroid tissues is detrimental to their function, and b) highlight the need to understand the mechanisms and importance of local iron control in other systems.

Other physiological systems of interest

We study iron control in the placenta, with specific interest in understanding the role of FPN and of its regulation by hepcidin in controlling iron transfer to the foetus. We also study the role of the HAMP/FPN axis in controlling iron re-absorption. Finally, we are interested in the function and importance of FPN and HAMP in the vascular system.

Our team

Selected publications

Related research themes