Iron is an essential element but is toxic in excess. Malregulation of iron transport results in tissue injury, either from iron deprivation or overload. The concentration of free iron within cells is determined by regulated transmembrane iron import and export and by iron storage. We propose to identify and characterize systems that affect the transport of iron across the plasma membrane and into the vesicular apparatus. We will continue our approach of using yeast genetics to identify genes involved in iron metabolism. We have shown that the high affinity iron transport system of yeast involves a multicopper oxidase Fet3 and a transmembrane permease Ftr1. Transcription of this transport system is heme dependent and in the absence of heme transcription is repressed. We will determine how the repressor senses heme. Yeast and plants store iron in the vacuole. We identified the iron transporter Ccc1 that mediates iron export from cytosol to vacuole. We have shown that transcription of CCC1 is increased by iron. We will determine how the transcriptional activator of vacuolar iron import, Yap5, senses iron. Vertebrates store iron in ferritin and ferritin accumulation responds to increased cytosolic iron. We determined that expression of the iron exporter ferroportin or treatment with the permeable iron chelator desferasirox leads to ferritin iron release followed by ferritin degradation by the proteasome. We will determine biochemical changes in ferritin following iron release, how ferritin is marked for degradation and how ferritin is disassembled. The concentration of serum ferritin is a useful marker of iron overload disease, as there is a strong correlation with hepatic iron stores in hereditary hemochromatosis. We have determined the conditions that lead to ferritin secretion. Our data show that ferritin monomers can gain access to the secretory apparatus of cells. We propose to identify the sequences in ferritin that permit secretion. We will also test the hypothesis that secretion of ferritin is a mechanism that protects cells from ferritin induced decrease in free cytosolic iron.

Public Health Relevance

Iron is an essential element but is toxic in excess. Malregulation of iron transport results in tissue injury, either from iron deprivation or overload. We will identify and characterize systems that affect the transport of iron across the plasma membrane and membranes of the vesicular system. We also propose to identify mechanisms that regulate iron storage. Our studies will provide information that may be used to manage and diagnose human diseases to altered iron metabolism.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK030534-31
Application #
8286375
Study Section
Erythrocyte and Leukocyte Biology Study Section (ELB)
Program Officer
Wright, Daniel G
Project Start
1982-01-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
31
Fiscal Year
2012
Total Cost
$324,064
Indirect Cost
$108,739
Name
University of Utah
Department
Pathology
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Kaplan, Jerry; Ward, Diane M (2013) The essential nature of iron usage and regulation. Curr Biol 23:R642-6
Lin, Huilan; Li, Liangtao; Jia, Xuan et al. (2011) Genetic and biochemical analysis of high iron toxicity in yeast: iron toxicity is due to the accumulation of cytosolic iron and occurs under both aerobic and anaerobic conditions. J Biol Chem 286:3851-62
De Domenico, Ivana; Ward, Diane McVey; Kaplan, Jerry (2009) Specific iron chelators determine the route of ferritin degradation. Blood 114:4546-51
Lin, Huilan; Burton, Damali; Li, Liangtao et al. (2009) Gain-of-function mutations identify amino acids within transmembrane domains of the yeast vacuolar transporter Zrc1 that determine metal specificity. Biochem J 422:273-83
De Domenico, Ivana; Ward, Diane McVey; Kaplan, Jerry (2009) Serum ferritin regulates blood vessel formation: a role beyond iron storage. Proc Natl Acad Sci U S A 106:1683-4
Li, Liangtao; Bagley, Dustin; Ward, Diane M et al. (2008) Yap5 is an iron-responsive transcriptional activator that regulates vacuolar iron storage in yeast. Mol Cell Biol 28:1326-37
Lin, Huilan; Kumanovics, Attila; Nelson, Jenifer M et al. (2008) A single amino acid change in the yeast vacuolar metal transporters ZRC1 and COT1 alters their substrate specificity. J Biol Chem 283:33865-73
Kumanovics, Attila; Chen, Opal S; Li, Liangtao et al. (2008) Identification of FRA1 and FRA2 as genes involved in regulating the yeast iron regulon in response to decreased mitochondrial iron-sulfur cluster synthesis. J Biol Chem 283:10276-86
De Domenico, Ivana; Ward, Diane M; Kaplan, Jerry (2007) Hepcidin regulation: ironing out the details. J Clin Invest 117:1755-8
De Domenico, Ivana; Vaughn, Michael B; Li, Liangtao et al. (2006) Ferroportin-mediated mobilization of ferritin iron precedes ferritin degradation by the proteasome. EMBO J 25:5396-404

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