IRP1 regulates erythropoiesis and systemic iron homeostasis by controlling HIF2α mRNA translation

Abstract

Key Points• IRP1 controls HIF2a mRNA translation in vivo and thereby acts as an upstream regulator of Epo expression. • IRP1 deficiency leads to age-dependent erythropoietic abnormalities and misregulation of body iron metabolism via the HIF2a/Epo pathway.Hypoxia inducible factor 2a (HIF2a) transcriptionally activates several genes in response to hypoxia. Under normoxic conditions, it undergoes oxygen-dependent degradation by the prolyl hydroxylase (PHD)/von Hippel-Lindau (VHL) system. The presence of an iron-responsive element (IRE) within the 59 untranslated region of HIF2a mRNA suggests a further iron-and oxygen-dependent mechanism for translational regulation of its expression via iron regulatory proteins 1 and 2 (IRP1 and IRP2, respectively). We show here that the disruption of mouse IRP1, but not IRP2, leads to profound HIF2a-dependent abnormalities in erythropoiesis and systemic iron metabolism. Thus, 4-to 6-week-old IRP1 2/2 mice exhibit splenomegaly and extramedullary hematopoiesis, which is corrected in older animals. These erythropoietic abnormalities are caused by translational de-repression of HIF2a mRNA and subsequent accumulation of HIF2a, which induces expression of erythropoietin (Epo). Increased levels of circulating Epo lead to reticulocytosis, polycythemia, and suppression of hepatic hepcidin mRNA. This in turn promotes hyperferremia and iron depletion in splenic macrophages due to unrestricted expression of ferroportin. Our data demonstrate that IRP1 is the principal regulator of HIF2a mRNA translation in vivo and provide evidence that translational control of HIF2a expression dominates over PHD/VHL-mediated regulation of HIF2a stability in juvenile IRP1 2/2 mice. (Blood. 2013;122(9):1658-1668

Cardioprotective and nonprotective regimens of chronic hypoxia diversely affect the myocardial antioxidant systems

“…Another iron-dependent antioxidant ACO1 displayed elevated mRNA levels under both protective regimens in our study. ACO1, also known as iron-regulatory protein 1 (IRP1), has been demonstrated to serve as a key upstream regulator of HIF2a (50). Accordingly, the Hif2a transcript was also increased in both protective regimens.…”

-thalassemias: paradigmatic diseases for scientific discoveries and development of innovative therapies

“…In fact, Irp1 −/− mice exhibit features of Hif2a overexpression and hyperproduction of Epo, while Irp1 constitutive transgenic mice show defects in erythroid differentiation that can be attributed to decreased Hif2a expression. [113][114][115] These observations indicate that Irp1 acts as an iron and oxygen sensor, linking iron metabolism with erythropoiesis via EPO. In iron deficiency, Irp1 suppresses HIF2a and Epo expression to reduced iron availability, consistently with iron-restricted erythropoiesis.…”

“…123 In addition, Fpn, divalent metal transporter 1 (Dmt1) and apical ferric reductase duodenal cytochrome B (DcytB) in the dudodenum are regulated by hypoxia and intracellular iron concentration. 112,115,161,162 It has been shown that expression of the Dmt1, DcytB and Fpn are increased in the duodenum of Hbb th3/+ mice as a consequence of hypoxia and Hif2a stabilization and activity. 112,162 In fact, Hbb th3/+ mice showed improvement in tissue-iron levels and anemia following genetic ablation of intestinal Hif2a.…”

The Crossroads of Iron with Hypoxia and Cellular Metabolism. Implications in the Pathobiology of Pulmonary Hypertension

“…However, mice in which IRP-1 alone was knocked out did not have an immediate apparent phenotype, suggesting that IRP-1 and IRP-2 have redundant physiologic functions (i.e., IRP-2 rescues the deficiency of IRP-1) (50). However, detailed inspection found that mice with targeted deletion of IRP-1 developed polycythemia (51,52) and spontaneous PH (53). This response was found to be due to translational derepression of HIF2a, with a subsequent increase in erythropoietin and endothelin-1 (a potent pulmonary vascular bed constrictor involved in the development of PH [54]).…”