Iron and the heart: A paradigm shift from systemic to cardiomyocyte abnormalities

Iron is a key micronutrient for the human body and participates in biological processes, such as oxygen transport, storage, and utilization. Iron homeostasis plays a crucial role in the function of the heart and both iron deficiency and iron overload are harmful to the heart, which is partly mediated by increased oxidative stress. Iron enters the cardiomyocyte through the classic pathway, by binding to the transferrin 1 receptor (TfR1), but also through other routes: T-type calcium channel (TTCC), divalent metal transporter 1 (DMT1), L-type calcium channel (LTCC), Zrt-, Irt-like Proteins (ZIP) 8 and 14. Only one protein, ferroportin (FPN), extrudes iron from cardiomyocytes. Intracellular iron is utilized, stored bound to cytoplasmic ferritin or imported by mitochondria. This cardiomyocyte iron homeostasis is controlled by iron regulatory proteins (IRP). When the cellular iron level is low, expression of IRPs increases and they reduce expression of FPN, inhibiting iron efflux, reduce ferritin expression, inhibiting iron storage and augment expression of TfR1, increasing cellular iron availability. Such cellular iron homeostasis explains why the heart is very susceptible to iron overload: while cardiomyocytes possess redundant iron importing mechanisms, they are equipped with only one iron exporting protein, ferroportin. Furthermore, abnormalities of iron homeostasis have been found in heart failure and coronary artery disease, however, no clear picture is emerging yet in this area. If we better understand iron homeostasis in the cardiomyocyte, we may be able to develop better therapies for a variety of heart diseases to which abnormalities of iron homeostasis may contribute.