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J Biol Chem. 2004 Aug 6;279(32):33653-61. Epub 2004 May 25.

A mitochondrial-vacuolar signaling pathway in yeast that affects iron and copper metabolism.

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Division of Immunology and Cell Biology, Department of Pathology, School of Medicine, University of Utah, Salt Lake City, Utah 84132, USA.


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.

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