The interplay between iron and oxygen homeostasis with a particular focus on the heart

Iron is subject to tight homeostatic control in mammals. At the systemic level, iron homeostasis is controlled by the liver-derived hormone hepcidin acting on its target ferroportin in the gut, spleen, and liver, which form the sites of iron uptake, recycling, and storage, respectively. At the cellular level, iron homeostasis is dependent on the iron regulatory proteins IRP1/IRP2. Unique chemical properties of iron underpin its importance in biochemical reactions involving oxygen. As such, it is not surprising that there are reciprocal regulatory links between iron and oxygen homeostasis, operating both at the systemic and cellular levels. Hypoxia activates the IRP pathway, and in addition suppresses liver hepcidin through endocrine factors that have yet to be fully elucidated. This review summarizes current knowledge on the interplay between oxygen and iron homeostasis and describes recent insights gained into this interaction in the context of the heart. These include the recognition that the hepcidin/ferroportin axis plays a vital role in the regulation of intracellular iron homeostasis as well as regulating systemic iron availability. As is the case for other aspects of iron homeostasis, hypoxia significantly modulates the function of the hepcidin/ferroportin pathway in the heart. Key areas still to understand are the interactions between cardiac iron and diseases of the heart where hypoxia is a recognized component.