Transworld Research Network 37/661 (2), Fort P.O. Trivandrum-695 023 Kerala, India Biochemical Aspects of Human Nutrition, 2010: 101-126 ISBN: 978-81-7895-478-3 Editors: Luciana Avigliano and Luisa Rossi 7. Iron regulatory proteins Anja Hausmann and Kostas Pantopoulos 1,2 1 Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, Montreal, QC, Canada; 2 Department of Medicine McGill University, Montreal, QC, Canada Abstract. Iron is an essential nutrient but also a potential biohazard. Elaborate homeostatic mechanisms have evolved to regulate dietary iron absorption at levels sufficient to satisfy metabolic needs and prevent the accumulation of metal excess. Internalized dietary iron enters the pool of plasma transferrin for delivery into the erythron and other tissues. Nevertheless, in healthy adults, the daily contribution of dietary iron for erythropoiesis is minimal and the vast majority of circulating transferrin-iron derives from macrophages, that eliminate senescent red blood cells and recycle their iron. Cellular iron uptake is mediated by endocytosis of iron-loaded transferrin upon binding to its transferrin receptor 1 (TfR1). Excess of intracellular iron that is not required for metabolic purposes is stored within ferritin. The expression of TfR1 and ferritin is coordinately and reciprocally controlled by a post-transcriptional mechanism. This involves two cytoplasmic iron regulatory proteins (IRP1 and IRP2), which interact with the iron responsive elements (IREs) of TfR1 and ferritin mRNAs. IRE/IRP interactions that occur in iron-deficient cells, stabilize TfR1 mRNA and inhibit ferritin mRNA translation. In iron-replete cells, IRP1 assembles an aconitase- type [4Fe-4S] 2+ cluster, which precludes IRE-binding. By contrast, IRP2 undergoes iron-dependent proteasomal degradation following ubiquitination. IRPs control the expression of additional mRNAs and respond not only to cellular iron levels but also to other stimuli, such as oxygen, oxidative stress and nitric oxide. The targeted disruption of both IRP1 and IRP2 in mice is associated with early embryonic lethality, underlying the physiological significance of the IRE/IRP regulatory system. While the ablation of IRP1 alone does not manifest any discernible pathology, IRP2(-/-) mice exhibit microcytic anemia and neurological defects. The ongoing development of mouse strains with spatial and temporal disruption of IRPs is providing further insight on their physiological functions. Correspondence/Reprint request: Dr. Kostas Pantopoulos, 3755 Cote-Ste-Catherine Road, Montreal, Quebec H3T 1E2 Canada. E-mail: kostas.pantopoulos@mcgill.ca