Document Detail

A mitochondrial-vacuolar signaling pathway in yeast that affects iron and copper metabolism.
MedLine Citation:
PMID:  15161905     Owner:  NLM     Status:  MEDLINE    
Mitochondria utilize iron, but the transporters that mediate mitochondrial iron uptake and efflux are largely unknown. Cells with a deletion in the vacuolar iron/manganese transporter Ccc1p are sensitive to high iron. Overexpression of MRS3 or MRS4 suppresses the high iron sensitivity of Deltaccc1 cells. MRS3 and MRS4 have recently been suggested to encode mitochondrial iron transporters. We demonstrate that deletion of MRS3 and MRS4 severely affects cellular and mitochondrial metal homeostasis, including a reduction in cytosolic and mitochondrial iron acquisition. We show that vacuolar iron transport is increased in Deltamrs3Deltamrs4 cells, resulting in decreased cytosolic iron and activation of the iron-sensing transcription factor Aft1p. Activation of Aft1p leads to increased expression of the high affinity iron transport system and increased iron uptake. Deletion of CCC1 in Deltamrs3Deltamrs4 cells restores cellular and mitochondrial iron homeostasis to near normal levels. Deltamrs3Deltamrs4 cells also show increased resistance to cobalt but decreased resistance to copper and cadmium. These phenotypes are also corrected by deletion of CCC1 in Deltamrs3Deltamrs4 cells. Decreased copper resistance in Deltamrs3Deltamrs4 cells results from activation of Aft1p by Ccc1p-mediated iron depletion, as deletion of CCC1 or AFT1 in Deltamrs3Deltamrs4 cells restores copper resistance. These results suggest that deletion of mitochondrial proteins can alter vacuolar metal homeostasis. The data also indicate that increased expression of the AFT1-regulated gene(s) can disrupt copper homeostasis.
Liangtao Li; Jerry Kaplan
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.     Date:  2004-05-25
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  279     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2004 Aug 
Date Detail:
Created Date:  2004-08-02     Completed Date:  2004-10-25     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  33653-61     Citation Subset:  IM    
Division of Immunology and Cell Biology, Department of Pathology, School of Medicine, University of Utah, Salt Lake City, Utah 84132, USA.
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MeSH Terms
Biological Transport
Cation Transport Proteins / genetics,  physiology
Cell Membrane / chemistry
Copper / metabolism*,  pharmacology
Drug Resistance, Microbial
Gene Deletion
Gene Expression
Gene Library
Iron / metabolism*,  pharmacology
Mitochondria / metabolism*
Mitochondrial Proteins
Saccharomyces cerevisiae / genetics,  metabolism,  ultrastructure
Saccharomyces cerevisiae Proteins / genetics,  physiology
Signal Transduction*
Vacuoles / metabolism*
Grant Support
Reg. No./Substance:
0/CCC1 protein, S cerevisiae; 0/Cation Transport Proteins; 0/MRS3 protein, S cerevisiae; 0/MRS4 protein, S cerevisiae; 0/Mitochondrial Proteins; 0/Saccharomyces cerevisiae Proteins; 7439-89-6/Iron; 7440-50-8/Copper

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