A signaling pathway between mitochondria and vacuole affects iron and copper metabolism.
Liangtao Li, Jerry Kaplan
Pathology, University of Utah, 50 No. Medical Drive, Salt Lake City, UT, 84132, U.S.A
Mitochondria utilize iron, but the transporters that mediate mitochondrial iron uptake and efflux are largely unknown. Two members of the yeast mitochondrial carrier family, MRS3 and MRS4, have recently been identified as mitochondrial iron transporters. 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 ∆ccc1 cells. We demonstrate that deletion of MRS3 and MRS4 severely affects cellular and mitochondrial iron homeostasis by increasing the activity of Ccc1p. The increased activity of Ccc1p leads to a reduction in cytosolic iron resulting in decreased mitochondrial iron acquisition and increased transcription of the high affinity iron transport system. Deletion of CCC1 in ∆mrs3∆mrs4 cells restores mitochondrial iron levels and recovers cobalt resistance and copper/cadmium sensitivity phenotypes.The increased copper sensitivity results from the activation of Aft1p, as deletion of AFT1 also decreases copper sensitivity. These results suggest that deletion of mitochondrial carrier genes affects the activity of vacuolar transporter Ccc1p, indicating a new communication pathway between two organelles. The data also indicate that increased expression of Aft1p-regulated gene(s) can disrupt copper homeostasis.
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