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 #
2R01DK030534-29
Application #
7779175
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
2010-04-01
Budget End
2011-03-31
Support Year
29
Fiscal Year
2010
Total Cost
$376,250
Indirect Cost
Name
University of Utah
Department
Pathology
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Li, Liangtao; Kaplan, Jerry; Ward, Diane M (2017) The glucose sensor Snf1 and the transcription factors Msn2 and Msn4 regulate transcription of the vacuolar iron importer gene CCC1 and iron resistance in yeast. J Biol Chem 292:15577-15586
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
Li, Liangtao; Ward, Diane M (2017) Iron toxicity in yeast: transcriptional regulation of the vacuolar iron importer Ccc1. Curr Genet :
MacQueen, B C; Christensen, R D; Ward, D M et al. (2017) The iron status at birth of neonates with risk factors for developing iron deficiency: a pilot study. J Perinatol 37:436-440
Li, Liangtao; Miao, Ren; Jia, Xuan et al. (2014) Expression of the yeast cation diffusion facilitators Mmt1 and Mmt2 affects mitochondrial and cellular iron homeostasis: evidence for mitochondrial iron export. J Biol Chem 289:17132-41
Ben-Othman, Rym; Flannery, Andrew R; Miguel, Danilo C et al. (2014) Leishmania-mediated inhibition of iron export promotes parasite replication in macrophages. PLoS Pathog 10:e1003901
Kaplan, Jerry; Ward, Diane M (2013) The essential nature of iron usage and regulation. Curr Biol 23:R642-6
White, Carine; Yuan, Xiaojing; Schmidt, Paul J et al. (2013) HRG1 is essential for heme transport from the phagolysosome of macrophages during erythrophagocytosis. Cell Metab 17:261-70
Li, Liangtao; Miao, Ren; Bertram, Sophie et al. (2012) A role for iron-sulfur clusters in the regulation of transcription factor Yap5-dependent high iron transcriptional responses in yeast. J Biol Chem 287:35709-21
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

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