Our goal is to define mitochondrial iron metabolism in eukaryotes at the molecular and biochemical level by studying yeast genes that are involved in mitochondrial iron transport and utilization. YFH1 is the yeast homologue of the mammalian Frataxin gene, which is responsible for Friedreich Ataxia. Defects in YFH1 result in excessive mitochondrial iron accumulation due to a defect in mitochondrial iron export and leads to respiratory deficit due to the generation of toxic oxygen radicals. We propose to determine how YFH1 affects mitochondrial iron export. We plan to test the hypothesis that defects in mitochondrial iron export result from defects in the mitochondrial iron-sulfur cluster synthetic pathway, and that Yfh1p is involved in iron-sulfur cluster syntheses. Genetic experiments are designed to identify proteins that interact with Yfh1p by generating dominant negative alleles of YFH1. Using biochemical assays to measure iron-sulfur cluster synthesis in isolated mitochondria, we plan to examine the affect of YFH1 mutant alleles. We also propose genetic approaches to identify genes that regulate the mitochondrial iron cycle. Different genes are implicated in mitochondrial metal transporter. We propose genetic and biochemical approaches to test the hypothesis that these genes are transition metal transporters which provide iron and other transition metals for mitochondrial processes. The genetic approaches involve identifying the phenotype of cells with deletions in multiple transporter genes. The biochemical approaches include studying metal transport in isolated mitochondria and in liposomes reconstituted with specific transporters. In mammals defective heme biosynthesis results in mitochondrial iron accumulation in reticulocytes but not in other cell types. We discovered that in yeast, defective heme synthesis inhibits high affinity iron transport, which prevents mitochondrial iron accumulation. We propose to determine the mechanism by which the absence of heme affects iron transport.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK052380-08
Application #
6844600
Study Section
Hematology Subcommittee 2 (HEM)
Program Officer
Wright, Daniel G
Project Start
1998-02-01
Project End
2008-01-31
Budget Start
2005-02-01
Budget End
2006-01-31
Support Year
8
Fiscal Year
2005
Total Cost
$351,325
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
Ward, Diane M; Chen, Opal S; Li, Liangtao et al. (2018) Altered sterol metabolism in budding yeast affects mitochondrial iron-sulfur (Fe-S) cluster synthesis. J Biol Chem 293:10782-10795
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
Chung, Jacky; Wittig, Johannes G; Ghamari, Alireza et al. (2017) Erythropoietin signaling regulates heme biosynthesis. Elife 6:
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
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Yien, Yvette Y; Robledo, Raymond F; Schultz, Iman J et al. (2014) TMEM14C is required for erythroid mitochondrial heme metabolism. J Clin Invest 124:4294-304
Chen, Caiyong; Garcia-Santos, Daniel; Ishikawa, Yuichi et al. (2013) Snx3 regulates recycling of the transferrin receptor and iron assimilation. Cell Metab 17:343-52
Shah, Dhvanit I; Takahashi-Makise, Naoko; Cooney, Jeffrey D et al. (2012) Mitochondrial Atpif1 regulates haem synthesis in developing erythroblasts. Nature 491:608-12
Wang, Yongming; Langer, Nathaniel B; Shaw, George C et al. (2011) Abnormal mitoferrin-1 expression in patients with erythropoietic protoporphyria. Exp Hematol 39:784-94
Reeder, Nancy L; Kaplan, Jerry; Xu, Jun et al. (2011) Zinc pyrithione inhibits yeast growth through copper influx and inactivation of iron-sulfur proteins. Antimicrob Agents Chemother 55:5753-60

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