Iron Homeostasis- Mechanisms and importance in systems (patho)physiology
What we study
We study the mechanisms and physiological importance of local iron regulation.
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.
Physiological systems of interest
1. THE HEART- The heart is a site of high energetic demand. As a functional component of heme and iron-sulfur clusters, iron is required for the delivery, sensing and utilisation of oxygen. At the same time, excess labile iron participates in Fenton type reactions leading to the generation of reactive oxygen species ROS. Our work has shown that cardiac cells regulate intracellular iron levels in a cell-autonomous fashion using the hepcidin/ferroportin axis. Disruption of this axis specifically within the heart leads to fatal heart failure in the absence of anaemia (Lakhal-Littleton et al, PNAS 2015, and Lakhal-Littleton et al, eLife 2016). These findings provide a mechanistic underpinning for the detrimental effects of non-anaemic iron deficiency and the beneficial effects of intravenous iron treatment in chronic heart failure.
2. THE VASCULATURE- Iron availability affects the normal pulmonary vascular responses to changes in oxygen tension. Until recently, the underlying mechanisms were unknown. Our work has shown that iron deficiency specfifically with the smooth muscle layer of the blood vessels is sufficient to raise pulmonary arterial pressure and cause pulmonary arterial hypertension. This effect is mediated by increased expression of the vasoconstrictor endothelin-1 (Lakhal-Littleton et al, PNAS 2019). These findings highlight the therapeutic potential of targetting vascular iron homeostasis.
1. British Heart Foundation- Intermediate Basic Science Research Fellowship
2. Vifor Pharma Research Grant
3. Medical Research Council Research Grant
4. BHF-Centre of Research Excellence Pump Priming Grant
5. La Jolla Pharmaceutical
6. Kidney Research UK