Abstract
Mitochondrial carrier proteins are a large protein family, consisting of 35 members in Saccharomyces cerevisiae. Members of this protein family have been shown to transport varied substrates from cytoplasm to mitochondria or mitochondria to cytoplasm, although many family members do not have assigned substrates. We speculated whether one or more of these transporters will play a role in iron metabolism. Haploid yeast strains each deleted for a single mitochondrial carrier protein were analysed for alterations in iron homoeostasis. The strain deleted for YHM1 was characterized by increased and misregulated surface ferric reductase and high-affinity ferrous transport activities. Siderophore uptake from different sources was also increased, and these effects were dependent on the AFT1 iron sensor regulator. Mutants of YHM1 converted into rho degrees, consistent with secondary mitochondrial DNA damage from mitochondrial iron accumulation. In fact, in the Delta yhm1 mutant, iron was found to accumulate in mitochondria. The accumulated iron showed decreased availability for haem synthesis, measured in isolated mitochondria using endogenously available metals and added porphyrins. The phenotypes of Delta yhm1 mutants indicate a role for this mitochondrial transporter in cellular iron homoeostasis.
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- Askwith C., Kaplan J. Iron and copper transport in yeast and its relevance to human disease. Trends Biochem Sci. 1998 Apr;23(4):135–138. doi: 10.1016/s0968-0004(98)01192-x. [DOI] [PubMed] [Google Scholar]
- Belenkiy R., Haefele A., Eisen M. B., Wohlrab H. The yeast mitochondrial transport proteins: new sequences and consensus residues, lack of direct relation between consensus residues and transmembrane helices, expression patterns of the transport protein genes, and protein-protein interactions with other proteins. Biochim Biophys Acta. 2000 Jul 31;1467(1):207–218. doi: 10.1016/s0005-2736(00)00222-4. [DOI] [PubMed] [Google Scholar]
- Blaiseau P. L., Lesuisse E., Camadro J. M. Aft2p, a novel iron-regulated transcription activator that modulates, with Aft1p, intracellular iron use and resistance to oxidative stress in yeast. J Biol Chem. 2001 Jul 11;276(36):34221–34226. doi: 10.1074/jbc.M104987200. [DOI] [PubMed] [Google Scholar]
- Camadro J. M., Chambon H., Jolles J., Labbe P. Purification and properties of coproporphyrinogen oxidase from the yeast Saccharomyces cerevisiae. Eur J Biochem. 1986 May 2;156(3):579–587. doi: 10.1111/j.1432-1033.1986.tb09617.x. [DOI] [PubMed] [Google Scholar]
- Chen O. S., Kaplan J. CCC1 suppresses mitochondrial damage in the yeast model of Friedreich's ataxia by limiting mitochondrial iron accumulation. J Biol Chem. 2000 Mar 17;275(11):7626–7632. doi: 10.1074/jbc.275.11.7626. [DOI] [PubMed] [Google Scholar]
- Craig E. A., Voisine C., Schilke B. Mitochondrial iron metabolism in the yeast Saccharomyces cerevisiae. Biol Chem. 1999 Oct;380(10):1167–1173. doi: 10.1515/BC.1999.148. [DOI] [PubMed] [Google Scholar]
- Dailey H. A. Terminal steps of haem biosynthesis. Biochem Soc Trans. 2002 Aug;30(4):590–595. doi: 10.1042/bst0300590. [DOI] [PubMed] [Google Scholar]
- Dancis A., Yuan D. S., Haile D., Askwith C., Eide D., Moehle C., Kaplan J., Klausner R. D. Molecular characterization of a copper transport protein in S. cerevisiae: an unexpected role for copper in iron transport. Cell. 1994 Jan 28;76(2):393–402. doi: 10.1016/0092-8674(94)90345-x. [DOI] [PubMed] [Google Scholar]
- Dyall S. D., Koehler C. M., Delgadillo-Correa M. G., Bradley P. J., Plümper E., Leuenberger D., Turck C. W., Johnson P. J. Presence of a member of the mitochondrial carrier family in hydrogenosomes: conservation of membrane-targeting pathways between hydrogenosomes and mitochondria. Mol Cell Biol. 2000 Apr;20(7):2488–2497. doi: 10.1128/mcb.20.7.2488-2497.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Esser Karlheinz, Tursun Baris, Ingenhoven Martin, Michaelis Georg, Pratje Elke. A novel two-step mechanism for removal of a mitochondrial signal sequence involves the mAAA complex and the putative rhomboid protease Pcp1. J Mol Biol. 2002 Nov 8;323(5):835–843. doi: 10.1016/s0022-2836(02)01000-8. [DOI] [PubMed] [Google Scholar]
- Foury Francoise, Roganti Tiziana. Deletion of the mitochondrial carrier genes MRS3 and MRS4 suppresses mitochondrial iron accumulation in a yeast frataxin-deficient strain. J Biol Chem. 2002 May 2;277(27):24475–24483. doi: 10.1074/jbc.M111789200. [DOI] [PubMed] [Google Scholar]
- Fox T. D., Folley L. S., Mulero J. J., McMullin T. W., Thorsness P. E., Hedin L. O., Costanzo M. C. Analysis and manipulation of yeast mitochondrial genes. Methods Enzymol. 1991;194:149–165. doi: 10.1016/0076-6879(91)94013-3. [DOI] [PubMed] [Google Scholar]
- Garland S. A., Hoff K., Vickery L. E., Culotta V. C. Saccharomyces cerevisiae ISU1 and ISU2: members of a well-conserved gene family for iron-sulfur cluster assembly. J Mol Biol. 1999 Dec 10;294(4):897–907. doi: 10.1006/jmbi.1999.3294. [DOI] [PubMed] [Google Scholar]
- Gordon D. M., Kogan M., Knight S. A., Dancis A., Pain D. Distinct roles for two N-terminal cleaved domains in mitochondrial import of the yeast frataxin homolog, Yfh1p. Hum Mol Genet. 2001 Feb 1;10(3):259–269. doi: 10.1093/hmg/10.3.259. [DOI] [PubMed] [Google Scholar]
- Kao L. R., Megraw T. L., Chae C. B. SHM1: a multicopy suppressor of a temperature-sensitive null mutation in the HMG1-like abf2 gene. Yeast. 1996 Sep 30;12(12):1239–1250. doi: 10.1002/(sici)1097-0061(19960930)12:12<1239::aid-yea17>3.0.co;2-8. [DOI] [PubMed] [Google Scholar]
- Karthikeyan Gopalakrishnan, Lewis L. Kevin, Resnick Michael A. The mitochondrial protein frataxin prevents nuclear damage. Hum Mol Genet. 2002 May 15;11(11):1351–1362. doi: 10.1093/hmg/11.11.1351. [DOI] [PubMed] [Google Scholar]
- Kaut A., Lange H., Diekert K., Kispal G., Lill R. Isa1p is a component of the mitochondrial machinery for maturation of cellular iron-sulfur proteins and requires conserved cysteine residues for function. J Biol Chem. 2000 May 26;275(21):15955–15961. doi: 10.1074/jbc.M909502199. [DOI] [PubMed] [Google Scholar]
- Kennedy M. C., Emptage M. H., Dreyer J. L., Beinert H. The role of iron in the activation-inactivation of aconitase. J Biol Chem. 1983 Sep 25;258(18):11098–11105. [PubMed] [Google Scholar]
- Kim R., Saxena S., Gordon D. M., Pain D., Dancis A. J-domain protein, Jac1p, of yeast mitochondria required for iron homeostasis and activity of Fe-S cluster proteins. J Biol Chem. 2001 Feb 27;276(20):17524–17532. doi: 10.1074/jbc.M010695200. [DOI] [PubMed] [Google Scholar]
- Kispal G., Csere P., Prohl C., Lill R. The mitochondrial proteins Atm1p and Nfs1p are essential for biogenesis of cytosolic Fe/S proteins. EMBO J. 1999 Jul 15;18(14):3981–3989. doi: 10.1093/emboj/18.14.3981. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Knight S. A., Sepuri N. B., Pain D., Dancis A. Mt-Hsp70 homolog, Ssc2p, required for maturation of yeast frataxin and mitochondrial iron homeostasis. J Biol Chem. 1998 Jul 17;273(29):18389–18393. doi: 10.1074/jbc.273.29.18389. [DOI] [PubMed] [Google Scholar]
- Kohlhaw G. B. Isopropylmalate dehydratase from yeast. Methods Enzymol. 1988;166:423–429. doi: 10.1016/s0076-6879(88)66055-1. [DOI] [PubMed] [Google Scholar]
- Kunji Edmund R. S., Harding Marilyn. Projection structure of the atractyloside-inhibited mitochondrial ADP/ATP carrier of Saccharomyces cerevisiae. J Biol Chem. 2003 Jul 31;278(39):36985–36988. doi: 10.1074/jbc.C300304200. [DOI] [PubMed] [Google Scholar]
- Lesuisse E., Blaiseau P. L., Dancis A., Camadro J. M. Siderophore uptake and use by the yeast Saccharomyces cerevisiae. Microbiology. 2001 Feb;147(Pt 2):289–298. doi: 10.1099/00221287-147-2-289. [DOI] [PubMed] [Google Scholar]
- Lesuisse Emmanuel, Knight Simon A. B., Camadro Jean-Michel, Dancis Andrew. Siderophore uptake by Candida albicans: effect of serum treatment and comparison with Saccharomyces cerevisiae. Yeast. 2002 Mar 15;19(4):329–340. doi: 10.1002/yea.840. [DOI] [PubMed] [Google Scholar]
- Lesuisse Emmanuel, Santos Renata, Matzanke Berthold F., Knight Simon A. B., Camadro Jean-Michel, Dancis Andrew. Iron use for haeme synthesis is under control of the yeast frataxin homologue (Yfh1). Hum Mol Genet. 2003 Apr 15;12(8):879–889. doi: 10.1093/hmg/ddg096. [DOI] [PubMed] [Google Scholar]
- Li J., Kogan M., Knight S. A., Pain D., Dancis A. Yeast mitochondrial protein, Nfs1p, coordinately regulates iron-sulfur cluster proteins, cellular iron uptake, and iron distribution. J Biol Chem. 1999 Nov 12;274(46):33025–33034. doi: 10.1074/jbc.274.46.33025. [DOI] [PubMed] [Google Scholar]
- Li J., Saxena S., Pain D., Dancis A. Adrenodoxin reductase homolog (Arh1p) of yeast mitochondria required for iron homeostasis. J Biol Chem. 2001 Jan 12;276(2):1503–1509. doi: 10.1074/jbc.M007198200. [DOI] [PubMed] [Google Scholar]
- Lill R., Kispal G. Maturation of cellular Fe-S proteins: an essential function of mitochondria. Trends Biochem Sci. 2000 Aug;25(8):352–356. doi: 10.1016/s0968-0004(00)01589-9. [DOI] [PubMed] [Google Scholar]
- Luk Edward, Carroll Mark, Baker Michelle, Culotta Valeria Cizewski. Manganese activation of superoxide dismutase 2 in Saccharomyces cerevisiae requires MTM1, a member of the mitochondrial carrier family. Proc Natl Acad Sci U S A. 2003 Jul 30;100(18):10353–10357. doi: 10.1073/pnas.1632471100. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Munujos P., Coll-Cantí J., González-Sastre F., Gella F. J. Assay of succinate dehydrogenase activity by a colorimetric-continuous method using iodonitrotetrazolium chloride as electron acceptor. Anal Biochem. 1993 Aug 1;212(2):506–509. doi: 10.1006/abio.1993.1360. [DOI] [PubMed] [Google Scholar]
- Murakami H., Pain D., Blobel G. 70-kD heat shock-related protein is one of at least two distinct cytosolic factors stimulating protein import into mitochondria. J Cell Biol. 1988 Dec;107(6 Pt 1):2051–2057. doi: 10.1083/jcb.107.6.2051. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mühlenhoff Ulrich, Stadler Jochen A., Richhardt Nadine, Seubert Andreas, Eickhorst Thomas, Schweyen Rudolf J., Lill Roland, Wiesenberger Gerlinde. A specific role of the yeast mitochondrial carriers MRS3/4p in mitochondrial iron acquisition under iron-limiting conditions. J Biol Chem. 2003 Aug 5;278(42):40612–40620. doi: 10.1074/jbc.M307847200. [DOI] [PubMed] [Google Scholar]
- Mühlenhoff Ulrich, Stadler Jochen A., Richhardt Nadine, Seubert Andreas, Eickhorst Thomas, Schweyen Rudolf J., Lill Roland, Wiesenberger Gerlinde. A specific role of the yeast mitochondrial carriers MRS3/4p in mitochondrial iron acquisition under iron-limiting conditions. J Biol Chem. 2003 Aug 5;278(42):40612–40620. doi: 10.1074/jbc.M307847200. [DOI] [PubMed] [Google Scholar]
- Palmieri L., De Marco V., Iacobazzi V., Palmieri F., Runswick M. J., Walker J. E. Identification of the yeast ARG-11 gene as a mitochondrial ornithine carrier involved in arginine biosynthesis. FEBS Lett. 1997 Jun 30;410(2-3):447–451. doi: 10.1016/s0014-5793(97)00630-3. [DOI] [PubMed] [Google Scholar]
- Palmieri L., Rottensteiner H., Girzalsky W., Scarcia P., Palmieri F., Erdmann R. Identification and functional reconstitution of the yeast peroxisomal adenine nucleotide transporter. EMBO J. 2001 Sep 17;20(18):5049–5059. doi: 10.1093/emboj/20.18.5049. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Palmieri L., Runswick M. J., Fiermonte G., Walker J. E., Palmieri F. Yeast mitochondrial carriers: bacterial expression, biochemical identification and metabolic significance. J Bioenerg Biomembr. 2000 Feb;32(1):67–77. doi: 10.1023/a:1005564429242. [DOI] [PubMed] [Google Scholar]
- Prohl C., Pelzer W., Diekert K., Kmita H., Bedekovics T., Kispal G., Lill R. The yeast mitochondrial carrier Leu5p and its human homologue Graves' disease protein are required for accumulation of coenzyme A in the matrix. Mol Cell Biol. 2001 Feb;21(4):1089–1097. doi: 10.1128/MCB.21.4.1089-1097.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rutherford J. C., Jaron S., Ray E., Brown P. O., Winge D. R. A second iron-regulatory system in yeast independent of Aft1p. Proc Natl Acad Sci U S A. 2001 Dec 4;98(25):14322–14327. doi: 10.1073/pnas.261381198. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sullivan T. D., Kaneko Y. The maize brittle 1 gene encodes amyloplast membrane polypeptides. Planta. 1995;196(3):477–484. doi: 10.1007/BF00203647. [DOI] [PubMed] [Google Scholar]
- Winzeler E. A., Shoemaker D. D., Astromoff A., Liang H., Anderson K., Andre B., Bangham R., Benito R., Boeke J. D., Bussey H. Functional characterization of the S. cerevisiae genome by gene deletion and parallel analysis. Science. 1999 Aug 6;285(5429):901–906. doi: 10.1126/science.285.5429.901. [DOI] [PubMed] [Google Scholar]
- Yamaguchi-Iwai Y., Dancis A., Klausner R. D. AFT1: a mediator of iron regulated transcriptional control in Saccharomyces cerevisiae. EMBO J. 1995 Mar 15;14(6):1231–1239. doi: 10.1002/j.1460-2075.1995.tb07106.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Yun C. W., Ferea T., Rashford J., Ardon O., Brown P. O., Botstein D., Kaplan J., Philpott C. C. Desferrioxamine-mediated iron uptake in Saccharomyces cerevisiae. Evidence for two pathways of iron uptake. J Biol Chem. 2000 Apr 7;275(14):10709–10715. doi: 10.1074/jbc.275.14.10709. [DOI] [PubMed] [Google Scholar]
- Yun C. W., Tiedeman J. S., Moore R. E., Philpott C. C. Siderophore-iron uptake in saccharomyces cerevisiae. Identification of ferrichrome and fusarinine transporters. J Biol Chem. 2000 May 26;275(21):16354–16359. doi: 10.1074/jbc.M001456200. [DOI] [PubMed] [Google Scholar]