Iron is essential for a variety of biological functions at the cellular and systemic level, such as oxygen transport and the catalytic activity of many enzymes;[1
] however, the specific chemical properties of iron as a transition metal also render it potentially toxic for cells and tissues. In the presence of reactive oxygen species (ROS), iron catalyses the generation of highly reactive hydroxyl radicals (Fenton/Haber-Weiss reactions) that damage membrane lipids, proteins and nucleic acids[2
]. Considering that ROS are inevitable by-products of aerobiosis, organisms have to control iron concentrations tightly at the systemic and at the cellular level to satisfy metabolic needs but minimise iron toxicity. A complex network has evolved in mammals, assuring safe and balanced iron trafficking. Efficient absorption mechanisms exist for various forms of nutritional iron in the proximal small intestine (1 mg/day in humans)[3
]. While the reticuloendothelial system is crucial for iron recycling and redistribution, the liver serves as an iron storage organ. Figure schematically depicts important pathways in iron trafficking in a virtual cell. Iron can enter the cell only in the reduced form (ferrous iron, Fe2+
), but is stored or bound to carrier proteins only in the ferric iron state (Fe3+
). Several enzymes have been identified to oxidise/reduce iron, such as the ferrireductase Dcytb and hephaestin in intestinal cells or ceruloplasmin at the basolateral site of most cells.
Figure 1 The role of ferritin in iron homeostasis. A virtual cell is shown, demonstrating the major cellular functions of iron uptake (TfR1 and -2, DMT1), export (ferroportin), storage (ferritin) and utilisation (eg haem synthesis). The LIP represents a chelated (more ...)
Iron circulates in higher organisms bound to transferrin (Tf). It is internalised by cells via the ubiquitous transferrin receptor 1 (TfR1) - the major iron uptake protein. Expression of TfR2 - a second transferrin receptor - is limited to erythroid, hepatocellular and duodenal cells. The TfR-Tf complex is internalised by endocytosis, iron is then released, reduced and eventually transferred to the cytoplasm by the divalent metal transporter 1 (DMT1). An impaired interaction of TfR1 and/or TfR2 with a mutated human haemochromatosis (HFE) protein causes the most common monogenic hereditary disease in humans (hereditary haemochromatosis), which eventually leads to iron overload and tissue damage in several organs[4
]. The central interchangeable form of iron is called the labile iron pool (LIP), which represents a loosely chelated form of iron that can undergo toxic redox reactions[6
]. Cellular iron can be safely stored in ferritin, a multi-subunit protein of heavy- (H) and light- (L) chains, or it can be redistributed within the cells for major utilisation pathways like Fe-S-cluster or haem synthesis.
At the systemic level, iron can be exported from macrophages, duodenal cells, hepatocytes and some cells of the central nervous system via ferroportin to undergo systemic circulation. This export is regulated by the antimicrobial peptide hepcidin, which inhibits iron efflux by interacting with ferroportin, leading to ferroportin internalisation and degradation[7
]. At present, hepcidin that is secreted from liver cells is generally considered as the 'systemic iron sensor' in higher organisms[3