Chapter 41 - Iron

Abstract

Iron is the fourth most abundant metal in the Earth’s crust and the most abundant transition metal. Iron can easily change valence and form complexes with oxygen, and iron-mediated reactions support the respiration of nearly all aerobic organisms. However, unless appropriately shielded, iron catalyzes the formation of radicals that can damage biological molecules, cells, tissues, and entire organisms. Exposure to excess iron—typically from multiple blood transfusions over many years—can have numerous pathological consequences. In contrast, severe iron deficiency may also have serious health consequences. Because of the inherent danger of iron, specialized molecules for the acquisition, transport, and storage (ferritin) of iron in a soluble nontoxic form have evolved. Delivery of iron to most cells occurs following the binding of transferrin to transferrin receptors on the cell membrane. The transferrin-receptor complexes are then internalized by endocytosis and iron is released from transferrin by a process involving endosomal acidification and reduction. Iron is then transported through the endosomal membrane by the natural resistance-associated macrophage protein (NRAMP2/DMT-1; encoded by SLC11A2, previously NRAMP2) Fe(II) transporter. Importantly, this transporter is involved in the absorption of inorganic iron in the duodenum, a process facilitated by the ferric reductase, cytochrome b reductase 1/duodenal cytochrome b (Dcytb; encoded by DCYTB), which presumably provides Fe(II) for NRAMP2/DMT-1. Organisms and cells possess limited ability to excrete excess iron, and only some specialized cells have active mechanisms to export iron. Iron release from these “donor cells” (primarily enterocytes and macrophages that recycle hemoglobin iron) is mediated by ferroportin. The ferroxidase activity of copper-containing proteins, hephaestin and ceruloplasmin, facilitates the movement of iron across the membranes of enterocytes and macrophages, respectively. Cells are also equipped with a regulatory system that controls iron levels in the labile pool. Levels of iron modulate the capacity of iron-responsive element-binding proteins [IRE-BPs; also known as iron regulatory proteins (IRPs)] to bind to the iron-responsive elements (IREs) present in the untranslated regions of several mRNAs encoding proteins involved in iron metabolism (e.g. ferritin, transferrin receptor, DMT-1); these associations, or lack of them, in turn control the expression of these proteins. In fact, important information about regulation of iron metabolism came from studies of proteins (e.g. HFE, ferroportin, and hepcidin) encoded by genes, mutations in which cause different types of hereditary hemochromatoses. Despite these homeostatic mechanisms, organisms can face the threat of either iron deficiency or iron overload.