title: Rim2, a pyrimidine nucleotide exchanger, is needed for iron utilization in mitochondria.
abstract: Mitochondria transport and utilize iron for the synthesis of haem and Fe-S clusters. Although many proteins are known to be involved in these processes, additional proteins are likely to participate. To test this hypothesis, in the present study we used a genetic screen looking for yeast mutants that are synthetically lethal with the mitochondrial iron carriers Mrs3 and Mrs4. Several genes were identified, including an isolate mutated for Yfh1, the yeast frataxin homologue. All such triple mutants were complemented by increased expression of Rim2, another mitochondrial carrier protein. Rim2 overexpression was able to enhance haem and Fe-S cluster synthesis in wild-type or Δmrs3/Δmrs4 backgrounds. Conversely Rim2 depletion impaired haem and Fe-S cluster synthesis in wild-type or Δmrs3/Δmrs4 backgrounds, indicating a unique requirement for this mitochondrial transporter for these processes. Rim2 was previously shown to mediate pyrimidine exchange in and out of vesicles. In the present study we found that isolated mitochondria lacking Rim2 exhibited concordant iron defects and pyrimidine transport defects, although the connection between these two functions is not explained. When organellar membranes were ruptured to bypass iron transport, haem synthesis from added iron and porphyrin was still markedly deficient in Rim2-depleted mitochondrial lysate. The results indicate that Rim2 is a pyrimidine exchanger with an additional unique function in promoting mitochondrial iron utilization.
authors.affiliation: Department of Medicine, Division of Hematology-Oncology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Heeyong
authors.initials: H
authors.lastname: Yoon
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jayashree
authors.initials: J
authors.lastname: Pain
authors.forename: Elise R
authors.initials: ER
authors.lastname: Lyver
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Lesuisse
authors.forename: Debkumar
authors.initials: D
authors.lastname: Pain
authors.forename: Andrew
authors.initials: A
authors.lastname: Dancis
mesh_terms: D027682:Cation Transport Proteins / Q000172:deficiency / Q000378:metabolism; D007501:Iron / Q000378:metabolism*; D007506:Iron-Sulfur Proteins / Q000096:biosynthesis; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000172:deficiency / Q000378:metabolism; D033704:Nucleotide Transport Proteins / Q000502:physiology*; D011743:Pyrimidines / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism / Q000502:physiology*
chemical_list: D027682:Cation Transport Proteins; D007506:Iron-Sulfur Proteins; C066985:MRS3 protein, S cerevisiae; C066986:MRS4 protein, S cerevisiae; D024101:Mitochondrial Proteins; D033704:Nucleotide Transport Proteins; D011743:Pyrimidines; C092511:RIM2 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D007501:Iron