Control of Systemic Iron Homeostasis by the 3’ Iron-Responsive Element of Divalent Metal Transporter 1 in Mice

Abstract

Word count abstract: 162 Word count main text: 1198 Number of Figure/Table: 2 Number of references: 24 2 Key points:• Targeted mutagenesis of the 3'IRE of DMT1 in mice reveals its importance for maintenance of systemic iron homeostasis.• The 3'IRE stimulates intestinal DMT1 expression and prevents hypoferremia during early life, but exerts opposite effects in adulthood. AbstractDivalent metal transporter 1 (DMT1) is essential for dietary iron assimilation and erythroid iron acquisition.The 3' untranslated region of the murine DMT1 mRNA contains an iron responsive element (IRE) that is conserved in humans but whose functional role remains unclear. We generated and analyzed mice with targeted disruption of the DMT1 3'IRE. These animals display hypoferremia during the suckling period, associated with a reduction of DMT1 mRNA and protein in the intestine. In contrast, adult mice exhibit hyperferremia, accompanied by enlargement of hepatic and splenic iron stores. Intriguingly, disruption of the DMT1 3'IRE in adult animals augments intestinal DMT1 expression, in part due to increased mRNA translation. Hence, during postnatal growth, the DMT1 3'IRE promotes intestinal DMT1 expression and secures iron sufficiency; in adulthood, it suppresses DMT1 and prevents systemic iron loading. This work demonstrates that the 3'IRE of DMT1 plays a role in the control of DMT1 expression and systemic iron homeostasis, and reveals an age--dependent switch in its activity.

Inhibition of HIF2 Prevents the Development of Neurodegenerative Disorder Induced by Deficiency of IRP2

“…Under conditions of iron de ciency, the IRE in the target mRNA can be recognized and bound by IRPs, but the consequence of IRP binding depends on the position of the IRE on the mRNA of the target genes. If the IRE is in the 5'-untranslated region (UTR) of the target mRNA, the binding of IRPs may inhibit the translation of the genes, including L-and H-ferritin and FPN1; if the IRE is in the 3'-UTR, the binding of IRPs may stabilize the mRNA, such as that of transferrin receptor 1 (TfR1) (Casey et al, 1988;Müllner et al, 1989) and divalent metal transporter 1 (DMT1) (Tybl et al, 2020). When cellular iron is su cient, IRP1 binds to a [4Fe-4S] cluster, therefore, gains aconitase activity and loses the ability to bind IRE, whereas IRP2 is removed by iron and oxygen-mediated proteasome degradation (Salahudeen et al, 2009;Vashisht et al, 2009) to avoid the excessive iron uptake and to promptly stores excess intracellular iron and/or export excess iron.…”