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 #
5R01DK090257-02
Application #
8151032
Study Section
Integrative Nutrition and Metabolic Processes Study Section (INMP)
Program Officer
Wright, Daniel G
Project Start
2010-09-30
Project End
2015-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
2
Fiscal Year
2011
Total Cost
$370,013
Indirect Cost
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
Burch, Joseph S; Marcero, Jason R; Maschek, John Alan et al. (2018) Glutamine via ?-ketoglutarate dehydrogenase provides succinyl-CoA for heme synthesis during erythropoiesis. Blood 132:987-998
Seguin, Alexandra; Takahashi-Makise, Naoko; Yien, Yvette Y et al. (2017) Reductions in the mitochondrial ABC transporter Abcb10 affect the transcriptional profile of heme biosynthesis genes. J Biol Chem 292:16284-16299
Yaish, Hassan M; Farrell, Colin P; Christensen, Robert D et al. (2017) Two novel mutations in TMPRSS6 associated with iron-refractory iron deficiency anemia in a mother and child. Blood Cells Mol Dis 65:38-40
Barton, James C; Chen, Wen-Pin; Emond, Mary J et al. (2017) GNPAT p.D519G is independently associated with markedly increased iron stores in HFE p.C282Y homozygotes. Blood Cells Mol Dis 63:15-20
Chung, Jacky; Wittig, Johannes G; Ghamari, Alireza et al. (2017) Erythropoietin signaling regulates heme biosynthesis. Elife 6:
Yien, Yvette Y; Ducamp, Sarah; van der Vorm, Lisa N et al. (2017) Mutation in human CLPX elevates levels of ?-aminolevulinate synthase and protoporphyrin IX to promote erythropoietic protoporphyria. Proc Natl Acad Sci U S A 114:E8045-E8052
Farrell, Colin P; Overbey, Jessica R; Naik, Hetanshi et al. (2016) The D519G Polymorphism of Glyceronephosphate O-Acyltransferase Is a Risk Factor for Familial Porphyria Cutanea Tarda. PLoS One 11:e0163322
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
Hanson, W Miachel; Chen, Zhe; Jackson, Laurie K et al. (2016) Reversible Oligonucleotide Chain Blocking Enables Bead Capture and Amplification of T-Cell Receptor ? and ? Chain mRNAs. J Am Chem Soc 138:11073-6
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

Showing the most recent 10 out of 16 publications