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 symptoms of dysregulated stress erythropoiesis. 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 coordinating iron absorption and other adaptive processes with homeostatic and stress-induced erythropoiesis. Consequently, the specific aims are to determine the: 1) tissue specific roles of IRP1 deficiency in the development of polycythemia;2) mechanisms regulating HIF2? mRNA translation by iron and oxygen. 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.

Public Health Relevance

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 erythropoietin production, iron absorption and erythropoiesis in relation to body iron and oxygen status during the life cycle in health and disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK066600-06A1
Application #
8632381
Study Section
Integrative Nutrition and Metabolic Processes Study Section (INMP)
Program Officer
Bishop, Terry Rogers
Project Start
2004-01-01
Project End
2018-07-31
Budget Start
2013-09-15
Budget End
2014-07-31
Support Year
6
Fiscal Year
2013
Total Cost
$343,359
Indirect Cost
$112,384
Name
University of Wisconsin Madison
Department
Nutrition
Type
Schools of Earth Sciences/Natur
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Johnson, Nathan B; Deck, Kathryn M; Nizzi, Christopher P et al. (2017) A synergistic role of IRP1 and FBXL5 proteins in coordinating iron metabolism during cell proliferation. J Biol Chem 292:15976-15989
Vasta, James D; Andersen, Kristen A; Deck, Kathryn M et al. (2016) Selective Inhibition of Collagen Prolyl 4-Hydroxylase in Human Cells. ACS Chem Biol 11:193-9
Chung, Jacky; Bauer, Daniel E; Ghamari, Alireza et al. (2015) The mTORC1/4E-BP pathway coordinates hemoglobin production with L-leucine availability. Sci Signal 8:ra34
Zhao, Ningning; Nizzi, Christopher P; Anderson, Sheila A et al. (2015) Low intracellular iron increases the stability of matriptase-2. J Biol Chem 290:4432-46
Chung, Jacky; Anderson, Sheila A; Gwynn, Babette et al. (2014) Iron regulatory protein-1 protects against mitoferrin-1-deficient porphyria. J Biol Chem 289:7835-43
Ruiz, Julio C; Walker, Scott D; Anderson, Sheila A et al. (2013) F-box and leucine-rich repeat protein 5 (FBXL5) is required for maintenance of cellular and systemic iron homeostasis. J Biol Chem 288:552-60
Anderson, Sheila A; Nizzi, Christopher P; Chang, Yuan-I et al. (2013) The IRP1-HIF-2? axis coordinates iron and oxygen sensing with erythropoiesis and iron absorption. Cell Metab 17:282-90
Anderson, Cole P; Shen, Macy; Eisenstein, Richard S et al. (2012) Mammalian iron metabolism and its control by iron regulatory proteins. Biochim Biophys Acta 1823:1468-83
Zhang, An-Sheng; Anderson, Sheila A; Wang, Jiaohong et al. (2011) Suppression of hepatic hepcidin expression in response to acute iron deprivation is associated with an increase of matriptase-2 protein. Blood 117:1687-99
Goforth, Jeremy B; Anderson, Sheila A; Nizzi, Christopher P et al. (2010) Multiple determinants within iron-responsive elements dictate iron regulatory protein binding and regulatory hierarchy. RNA 16:154-69

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