Recent advances in cellular iron metabolism

Abstract

AbstractIron is essential for oxidation–reduction catalysis and bioenergetics, but unless appropriately shielded, iron plays a key role in the formation of toxic oxygen radicals that can attack all biological molecules. Hence, specialized molecules for the acquisition, transport, and storage (ferritin) of iron in a soluble nontoxic form have evolved. The delivery of iron to most cells occurs after 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. Iron is then transported through the endosomal membrane by the Fe2+ transporter Nramp2/DMT1. Importantly, the identical transporter is involved in the absorption of inorganic iron in the duodenum, a process that is facilitated by the ferric reductase, Dcytb, which provides Fe2+ for Nramp2/DMT1. Organisms and cells have limited ability to excrete excess iron and only some specialized cells evolved active mechanisms to export iron. Iron release from these “donor cells” (primarily enterocytes and macrophages that recycle hemoglobin iron) is mediated by ferroportin 1. 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 regulatory proteins to bind to the iron responsive elements present in the untranslated regions of mRNAs for several proteins involved in iron metabolism (e.g., ferritin, transferrin receptor, Nramp2); these associations, or lack of them, in turn control the expression of these proteins. Despite these homeostatic mechanisms, organisms often face the threat of either iron deficiency or iron overload. J. Trace Elem. Exp. Med. 16:201–217, 2003. © 2003 Wiley‐Liss, Inc.