Iron is a required nutrient but can be toxic in high concentrations. Iron deprivation, as manifested by anemia, may be the most common nutrient deficiency in the world. Iron deprivation also leads to severe defects in developing embryos. In humans iron limitation results in low birth weight and developmental defects that may not be reversible. In contrast, iron overload leads to disease. The toxicity of iron is ascribed to its ability to participate in Fenton reactions generating oxygen radicals that damage biological macromolecules. We have determined that iron supplementation or deprivation can affect cellular physiology by changing transcriptional patterns. Alteration of transcriptional patterns results from an effect of iron on transcriptional activators and repressors, independent of the well-studied iron regulatory protein system. Some of these effects are direct but others are indirect, as they require protein synthesis. The mechanism by which iron affects transcription is the focus of this application. The goal of this grant proposal is to determine how iron leads to transcriptional activation and repression and determined the mechanism and consequences of the peptide hormone hepcidin as a transcriptional regulator of genes required for iron acquisition and distribution.

Public Health Relevance

This study provides new information on how iron distribution is regulated and how changes in iron distribution affect metabolism and developmental programs. The results will lead to better treatment of disorders related to either iron deficiency or iron excess.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK090257-04
Application #
8507218
Study Section
Integrative Nutrition and Metabolic Processes Study Section (INMP)
Program Officer
Bishop, Terry Rogers
Project Start
2010-09-30
Project End
2015-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
4
Fiscal Year
2013
Total Cost
$355,869
Indirect Cost
$117,031
Name
University of Utah
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Yuan, Xiaojing; Rietzschel, Nicole; Kwon, Hanna et al. (2016) Regulation of intracellular heme trafficking revealed by subcellular reporters. Proc Natl Acad Sci U S A 113:E5144-52
Kim, Hyung J; Jeong, Mi-Young; Parnell, Timothy J et al. (2016) The Plasma Membrane Protein Nce102 Implicated in Eisosome Formation Rescues a Heme Defect in Mitochondria. J Biol Chem 291:17417-26
Bergonia, Hector A; Franklin, Michael R; Kushner, James P et al. (2015) A method for determining δ-aminolevulinic acid synthase activity in homogenized cells and tissues. Clin Biochem 48:788-95
Farrell, Colin P; Parker, Charles J; Phillips, John D (2015) Exome sequencing for molecular characterization of non-HFE hereditary hemochromatosis. Blood Cells Mol Dis 55:101-3
Polati, Rita; Castagna, Annalisa; Bossi, Alessandra Maria et al. (2012) Murine macrophages response to iron. J Proteomics 76 Spec No.:10-27
De Domenico, Ivana; Ward, Diane McVey; Kaplan, Jerry (2011) Hepcidin and ferroportin: the new players in iron metabolism. Semin Liver Dis 31:272-9
De Domenico, Ivana; Lo, Eric; Yang, Baoli et al. (2011) The role of ubiquitination in hepcidin-independent and hepcidin-dependent degradation of ferroportin. Cell Metab 14:635-46