“Regulation of iron metabolism: Deciphering the biological functions of the iron responsive element of divalent-metal transporter 1”

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Iron is a co-factor required for numerous metabolic processes but toxic when present in excess, and imbalances of iron metabolism account for some of the most common diseases. Extensive research during the last two decades has uncovered key molecules of iron homeostasis. Among those molecules, the transmembrane proton-coupled iron importer DMT1 (divalent metal transporter 1) was shown to be essential for dietary iron assimilation as well as for iron acquisition by erythroid cells. To prevent both iron insufficiency and excess, the expression of DMT1 must be controlled very tightly. In mammals, cellular iron homeostasis is orchestrated by the iron regulatory proteins (IRP)-1 and -2, which control the fate of iron metabolism mRNAs by binding to cis-regulatory RNA structures named iron-responsive elements (IRE). The DMT1 mRNA bears a single, non-canonical IRE in its 3’ untranslated region, and is thus potentially regulated by the IRPs. However, the lack of adequate animal models has so far hampered a better comprehension of the in vivo functions of the DMT1 IRE. To fill this gap, we have created a mouse line with selective disruption of the 3’IRE of DMT1, which represents the first animal model with targeted mutagenesis of such RNA motifs. Our preliminary work indicates that the IRE of DMT1 is required for normal erythropoiesis and to prevent systemic iron overload in young adult mice maintained under standard laboratory conditions. Based on a detailed exploration of tissular and serological iron metabolism parameters, a study of hematological parameters, and a molecular analysis of iron metabolism genes, we propose to determine the cause of the iron imbalance observed in young adult DMT1-mutant mice. In addition, we will examine the iron phenotype at other stages of life asociated with distinct iron metabolism characteristics, more precisely during perinatal life when mice have high iron needs and rely on maternal milk, and in aged animals with high iron stores and feeding on a normal diet. Furthermore, we will assess whether and how the IRE of DMT1 impacts on the adaptative responses of the iron homeostasis machinery to fluctuations in dietary iron availability and in conditions of stress erythropoiesis. With this work we wish to unveil new facets of an essential iron transporter in the cell, and enhance our understanding of the role of posttranscriptional control mechanisms in metabolic regulations.