Disorders of iron metabolism, whether caused by inborn genetic errors, maladaptive responses to disease or diet are major public health issues in the U.S. and throughout the world. Nutritional iron deficiency is associated with impaired cognitive development and reduced work output resulting in significant negative economic and social consequences. Other than iron metabolism per se, the physiological pathways involved in the adaptive cellular and organismal response to iron deficiency remain poorly defined. In addition to diet, anemia can be caused by disorders in oxygen sensing pathways associated with renal failure, normal aging, genetic mutations in hemoglobin or other proteins, and as a consequence of preterm delivery when the full switch to post-natal mechanisms of controlling erythropoietin production has not occurred. In sum, these pathological states affect millions of people in the U.S. alone. The ability to properly integrate the control of iron and oxygen metabolism is essential for optimal health throughout the life cycle. In vertebrates, iron regulatory protein 1 (IRP1) and IRP2 are central regulators of cellular iron metabolism. IRP dictate the fate of mRNA encoding proteins required for the maintenance of iron homeostasis and for the adaptive changes in response to iron status. The mRNA encoding hypoxia inducible factor 2 (HIF2 ), a transcription factor central to the genome wide responses to oxygen and iron, has been previously shown to be a specific target of IRP1 in cultured cells. We demonstrate that HIF2 mRNA translation is activated in IRP1-/- mice but not in IRP2-/- mice. IRP1-/- mice have profound disturbances in erythropoiesis, including a transient severe polycythemia, and display other symptoms observed in humans with HIF2 gain-of-function or in animal models of altered HIF2 regulation. Transcriptomic analysis of intestinal mucosal cells in IRP1-/- mice revealed up-regulation of multiple HIF2 gene targets suggesting enhanced iron absorption capacity as would be observed in hypoxia when HIF2 is activated. Our results to date also demonstrate that the 5' untranslated region of HIF2 mRNA contains multiple previously unrecognized putative translational regulatory elements that strongly suggest that translational control is a critical additional level at which changes in iron and oxygen level are integrated with the level of expression and action of HIF2 . We propose that the IRP1-HIF2 regulatory axis is required for the integration of iron and oxygen metabolism in mammals. Consequently, the specific aims are to: 1) determine the tissue-specific roles of IRP1-dependent regulation of HIF2 in the adaptive response to altered iron and oxygen status in mice; 2) determine the mechanisms regulating HIF2 mRNA translation by iron and oxygen and their impact on HIF2 action in erythropoietin-secreting human kidney cells. In elucidating the role of the IRP1-HIF2 axis in the adaptive and maladaptive control of central pathways of iron and oxygen metabolism our studies may ultimately have a transformative effect on the development of new therapeutic strategies for treatment of common disorders.
Disorders of iron metabolism and oxygen sensing, whether caused by genetic errors, maladaptive responses to disease or diet are major public health issues affecting Americans. Iron regulatory protein 1 (IRP1) and its regulatory target, hypoxia inducible factor 2? (HIF2?), are critical direct sensors of iron and oxygen (e.g. hypoxia) status and their dysregulation likely contributes to hematologic, neurologic and oncogenic diseases. This proposal focuses on elucidating the role of IRP1-dependent regulation of HIF2? in coordinating the absorption and interorgan distribution of dietary iron with the formation of red blood cells in relation to body iron and oxygen status during the life cycle in health and disease.
