Skip to main content
Log in

Yeast, a model organism for iron and copper metabolism studies

  • Published:
Biometals Aims and scope Submit manuscript

Abstract

Virtually all organisms on earth depend on transition metals for survival. Iron and copper are particularly important because they participate in vital electron transfer reactions, and are thus cofactors of many metabolic enzymes. Their ability to transfer electrons also render them toxic when present in excess. Disturbances of iron and copper steady-state levels can have profound effects on cellular metabolism, growth and development. It is critical to maintain these metals in a narrow range between utility and toxicity. Organisms ranging from bacteria and plants to mammals have developed sophisticated mechanisms to control metal homeostasis. In this review, we will present an overview of the current understanding of iron and copper metabolism in yeast, and the utility of yeast as a model organism to investigate iron and copper metabolism in mammals and plants.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Aisen P, Enns C et al. 2001 Chemistry and biology of eukaryotic iron metabolism. Intern J Biochem Cell Biol 33(10), 940-959.

    Google Scholar 

  • Ambrosini L, Mercer JFB. 1999 Defective copper-induced trafficking and localization of the Menkes protein in patients with mild and copper-treated classical Menkes disease. Hum Mol Gen 8(8), 1547-1555.

    Google Scholar 

  • Andrews GK. 2000 Regulation of metallothionein gene expression by oxidative stress and metal ions. Biochem Pharmacol 59(1), 95-104.

    Google Scholar 

  • Andrews NC, Fleming MD et al. 1999 Iron transport across biologic membranes. Nutri Rev 57(4), 114-123.

    Google Scholar 

  • Babcock M, deSilva D et al. 1997 Regulation of mitochondrial iron accumulation by Yfh1p, a putative homolog of frataxin. Science 276(5319), 1709-1712.

    Google Scholar 

  • Beers J, Glerum DM et al. 1997 Purification, characterization, and localization of yeast Cox17p, a mitochondrial copper shuttle. J Biol Chem 272(52), 33191-33196.

    Google Scholar 

  • Bertoncini CRA, Meneghini R. 1995 DNA strand breaks produced by oxidative stress in mammalian cells exhibit 3'-phosphoglycolate termini. Nucl Acids Res 23(15), 2995-3002.

    Google Scholar 

  • Blaiseau PL, Lesuisse E et al. 2001 Aft2p, a novel iron-regulated transcription activator that modulates, with Aft1p, intracellular iron use and resistance to oxidative stress in yeast. J Biol Chem 276(36), 34221-34226.

    Google Scholar 

  • Briat JF, Lobreaux S et al. 1999 Regulation of plant ferritin synthesis: how and why. Cell Mol Life Sci 56(1-2), 155-166.

    Google Scholar 

  • Bull PC, Cox DW. 1994 Wilson Disease and Menkes Disease - New Handles on Heavy-Metal Transport. Trends Gen 10(7), 246-252.

    Google Scholar 

  • Casas C, Aldea M et al. 1997 The AFT1 transcriptional factor is differentially required for expression of high-affinity iron uptake genes in Saccharomyces cerevisiae. Yeast 13(7), 621-637.

    Google Scholar 

  • Chen OS, Kaplan J. 2000 CCC1 suppresses mitochondrial damage in the yeast model of Friedreich's ataxia by limiting mitochondrial iron accumulation. J Biol Chem 275(11), 7626-7632.

    Google Scholar 

  • Cohen A, Nelson H et al. 2000 The family of SMF metal ion transporters in yeast cells. J Biol Chem 275(43), 33388-33394.

    Google Scholar 

  • DavisKaplan SR, Askwith CC et al. 1998 Chloride is an allosteric effector of copper assembly for the yeast multicopper oxidase Fet3p: an unexpected role for intracellular chloride channels. Proc Natl Acad Sci USA 95(23), 13641-13645.

    Google Scholar 

  • De Freitas JM, Meneghini R. 2001 Iron and its sensitive balance in the cell. Mutat Res Fund Mol Mech Mutagen 475(1-2 SI), 153-159.

    Google Scholar 

  • DeRisi JL, Iyer VR et al. 1997 Exploring the metabolic and genetic control of gene expression on a genomic scale. Science 278(5338), 680-686.

    Google Scholar 

  • Dix D, Bridgham J et al. 1997 Characterization of the FET4 protein of yeast - Evidence for a direct role in the transport of iron. J Biol Chem 272(18), 11770-11777.

    Google Scholar 

  • Eide DJ. 1998 The molecular biology of metal ion transport in Saccharomyces cerevisiae. Ann Rev Nutri 18, 441-469.

    Google Scholar 

  • Eide DJ, Bridgham JT et al. 1993 The vacuolar H+-Atpase of Saccharomyces-Cerevisiae is required for efficient copper detoxification, Mitochondrial Function, and Iron Metabolism. Mol General Gen 241(3-4), 447-456.

    Google Scholar 

  • Foury F, Talibi D. 2001 Mitochondrial control of iron homeostasis - A genome wide analysis of gene expression in a yeast frataxindeficient strain. J Biol Chem 276(11), 7762-7768.

    Google Scholar 

  • Fox TC, Guerinot ML. 1998 Molecular biology of cation transport in plants. Ann Rev Plant Physiol Plant Mol Biol 49, 669-696.

    Google Scholar 

  • Fridovich I. 1995 Superoxide Radical and Superoxide Dismutases. Ann Rev Biochem 64, 97-112.

    Google Scholar 

  • Fridovich I. 1999 Fundamental aspects of reactive oxygen species, or what's the matter with oxygen? Annals of the New York Academy of Sciences; Oxidative/energy metabolism in neurodegenerative disorders. In Blass JP and McDowell FH (eds) New York, Academy of Sciences; New York: 13-18.

    Google Scholar 

  • Fridovich I. 2001 Reflections of a fortunate biochemist. J Biol Chem 276(31), 28629-28636.

    Google Scholar 

  • Garland SA, Hoff K et al. 1999 Saccharomyces cerevisiae ISU1 and ISU2: Members of a well-conserved gene family for iron-sulfur cluster assembly. J Mol Biol 294(4), 897-907.

    Google Scholar 

  • Glerum DM, Shtanko A et al. 1996 Characterization of Cox17, a Yeast Gene Involved in Copper Metabolism and Assembly of Cytochrome Oxidase. J Biol Chem 271(24), 14504-14509.

    Google Scholar 

  • Glerum DM, Shtanko A et al. 1996 Sco1 and Sco2 Act as High Copy Suppressors of a Mitochondrial Copper Recruitment Defect Saccharomyces Cerevisiae. J Biol Chem 271(34), 20531-20535.

    Google Scholar 

  • Gross C, Kelleher M et al. 2000 Identification of the copper regulon in Saccharomyces cerevisiae by DNA microarrays. J Biol Chem 275(41), 32310-32316.

    Google Scholar 

  • Hassett R, Dix DR et al. 2000 The Fe(II) permease Fet4p functions as a low affinity copper transporter and supports normal copper trafficking in Saccharomyces cerevisiae. Biochem J 351 (PT2), 477-484.

    Google Scholar 

  • Hassett RF, Romeo AM et al. (1998). Regulation of high affinity iron uptake in the yeast Saccharomyces cerevisiae - Role of dioxygen and Fe(II). J Biol Chem 273(13), 7628-7636.

    Google Scholar 

  • Heaton D, Nittis T et al. 2000 Mutational analysis of the mitochondrial copper metallochaperone Cox17. J BiolChem 275(48), 37582-37587.

    Google Scholar 

  • Heaton DN, George GN et al. 2001 The mitochondrial copper metallochaperone Cox17 exists as an oligomeric, polycopper complex. Biochemistry 40(3), 743-751.

    Google Scholar 

  • Heymann P, Ernst JF et al. 2000 Identification and substrate speci-ficity of a ferrichrome-type siderophore transporter (Arn1p) in Saccharomyces cerevisiae. Fems Microbiol Lett 186(2), 221-227.

    Google Scholar 

  • Himelblau E, Amasino RM. 2000 Delivering copper within plant cells. Curr Opin Plant Biol 3(3), 205-210.

    Google Scholar 

  • Hughes TR, Marton MJ et al. 2000 Functional discovery via a compendium of expression profiles. Cell 102(1), 109-126.

    Google Scholar 

  • Jensen LT, Culotta VC. 2000 Role of Saccharomyces cerevisiae ISA1 and ISA2 in iron homeostasis. Mol Cell Biol 20(11), 3918-3927.

    Google Scholar 

  • Jensen LT, Howard WR et al. 1996 Enhanced effectiveness of copper ion buffering by Cup1 metallothionein compared with Crs5 metallothionein in Saccharomyces Cerevisiae. J Biol Chem 271(31), 18514-18519.

    Google Scholar 

  • Jungmann J, Reins HA et al. 1993 Mac1, a nuclear regulatory protein related to Cu-dependent transcription factors is involved in Cu/Fe utilization and stress resistance in yeast. Embo J 12(13), 5051-5056.

    Google Scholar 

  • Kaplan J, Ohalloran TV 1996 Iron metabolism in eukaryotes -Mars and Venus at it again. Science 271(5255), 1510-1512.

    Google Scholar 

  • Kaut A, Lange H et al. 2000 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 275(21), 15955-15961.

    Google Scholar 

  • Kim R, Saxena S et al. 2001 J-domain protein, Jac1p, of yeast mitochondria required for iron homeostasis and activity of Fe-S cluster proteins. J Biol Chem 276(20), 17524-17532.

    Google Scholar 

  • Kispal G, Csere P et al. 1997 The ABC transporter Atm1p is required for mitochondrial iron homeostasis. Febs Lett 418(3), 346-350.

    Google Scholar 

  • Kispal G, Csere P et al. 1999 The mitochondrial proteins Atm1p and Nfs1p are essential for biogenesis of cytosolic Fe/S proteins. Embo J 18(14), 3981-3989.

    Google Scholar 

  • Knight SAB, Labbe S et al. 1996 A widespread transposable element masks expression of a yeast copper transport gene. Genes Develop 10(15), 1917-1929.

    Google Scholar 

  • Koppenol WH. 2001 The Haber-Weiss cycle-70 years later. Redox Rep 6(4), 229-34.

    Google Scholar 

  • Labbe S, Zhu ZWet al. 1997 Copper-specific transcriptional repression of yeast genes encoding critical components in the copper transport pathway. J Biol Chem 272(25), 15951-15958.

    Google Scholar 

  • Lange H, Kaut A et al. 2000 A mitochondrial ferredoxin is essential for biogenesis of cellular iron-sulfur proteins. Proc Natl Acad Sci USA 97(3), 1050-1055.

    Google Scholar 

  • Lange H, Kispal G et al. 1999 Mechanism of iron transport to the site of heme synthesis inside yeast mitochondria. J Biol Chem 274(27), 18989-18996.

    Google Scholar 

  • Lange H, Lisowsky T et al. 2001 An essential function of the mitochondrial sulfhydryl oxidase Erv1p/ALR in the maturation of cytosolic Fe/S proteins. Embo Rep 2(8), 715-720.

    Google Scholar 

  • Lesuisse E, Blaiseau PL et al. 2001 Siderophore uptake and use by the yeast Saccharomyces cerevisiae. Microbiol-Uk 147(PT2), 289-298.

    Google Scholar 

  • Li J, Saxena S et al. 2001 Adrenodoxin reductase homolog (Arh1p) of yeast mitochondria required for iron homeostasis. J Biol Chem 276(2), 1503-1509.

    Google Scholar 

  • Li LT, Chen OS et al. 2001 CCC1 is a transporter that mediates vacuolar iron storage in yeast. J Biol Chem 276(31), 29515-29519.

    Google Scholar 

  • Li LT, Kaplan J. 1996 Characterization of yeast methyl sterol oxidase (Erg25) and identification of a human homologue. J Biol Chem 271(28), 16927-16933.

    Google Scholar 

  • Li LT, Kaplan J 1997 Characterization of two homologous yeast genes that encode mitochondrial iron transporters. J Biol Chem 272(45), 28485-28493.

    Google Scholar 

  • Lill R, Kispal G. 2000 Maturation of cellular Fe-S proteins: an essential function of mitochondria. Trends Biochem Sci 25(8), 352-356.

    Google Scholar 

  • Lill R and Kispal G. 2001 Mitochondrial ABC transporters. Res Microbiol 152(3-4), 331-340.

    Google Scholar 

  • Lin SJ, Pufahl RA et al. 1997 A role for the Saccharomyces cerevisiae ATX1 gene in copper trafficking and iron transport. J Biol Chem 272(14), 9215-9220.

    Google Scholar 

  • Liochev SI, Fridovich I. 1994 The role of O-2-center-dot-in the production of Ho-center-dot-in vitro and in vivo. Free Rad Biol Med 16(1), 29-33.

    Google Scholar 

  • Liochev SI, Fridovich I. 1999 Superoxide and iron: partners in crime. Iubmb Life 48(2), 157-161.

    Google Scholar 

  • Lode A, Kuschel M et al. 2000 Mitochondrial copper metabolism in yeast: interaction between Sco1p and Cox2p. FEBS Lett 485(1), 19-24.

    Google Scholar 

  • Lodi R, Taylor DJ et al. 2001 Mitochondrial dysfunction in friedreich's ataxia. Biol Signals Recept 10(3-4), 263-270.

    Google Scholar 

  • Lutz T, Westermann B et al. 2001 The mitochondrial proteins Ssq1 and Jac1 are required for the assembly of iron sulfur clusters in mitochondria. J Mol Biol 307(3), 815-825.

    Google Scholar 

  • Lyons TJ, Gralla EB et al. 1999 Biological chemistry of copperzinc superoxide dismutase and its link to amyotrophic lateral sclerosis. Met Ions Biol Syst 36, 125-177.

    Google Scholar 

  • McLoughlin DM, Standen CL et al. 2001 The neuronal adaptor protein X11 alpha interacts with the copper chaperone for SOD1 and regulates SOD1 activity. J Biol Chem 276(12), 9303-9307.

    Google Scholar 

  • Mello AC, Meneghini R. 1991 Iron is the intracellular metal involved in the production of DNA damage by oxygen radicals. Mutat Res 251(1), 109-113.

    Google Scholar 

  • Meneghini R. 1997 Iron homeostasis, oxidative stress, and DNA damage. Free Rad Biol Med 23(5), 783-792.

    Google Scholar 

  • Muhlenhoff U, Lill R. 2000 Biogenesis of iron-sulfur proteins in eukaryotes: a novel task of mitochondria that is inherited from bacteria. Biochim Biophys ActaBioenerg 1459(2-3), 370-382.

    Google Scholar 

  • Nunez MT, Tapia V et al. 2001 Iron-induced oxidative damage in colon carcinoma (Caco-2) cells. Free Rad Res 34(1), 57-68,U17,U18.

    Google Scholar 

  • O'Halloran TV, Culotta VC. 2000 Metallochaperones, an intracellular shuttle service for metal ions. J Biol Chem 275(33), 25057-25060.

    Google Scholar 

  • Ooi CE, Rabinovich E et al. 1996 Copper-dependent degradation of the Saccharomyces cerevisiae plasma membrane copper transporter Ctr1p in the apparent absence of endocytosis. Embo J 15(14), 3515-3523.

    Google Scholar 

  • Palau F. 2001 Friedreich's ataxia and frataxin: molecular genetics, evolution and pathogenesis (Review). Interl J Mol Med 7(6), 581-589.

    Google Scholar 

  • Pelzer W, Muhlenhoff U et al. 2000 Mitochondrial Isa2p plays a crucial role in the maturation of cellular iron-sulfur proteins. FEBS Lett 476(3), 134-139.

    Google Scholar 

  • Pena MMO, Koch KA et al. 1998 Dynamic regulation of copper uptake and detoxification genes in Saccharomyces cerevisiae. Mol Cell Biol 18(5), 2514-2523.

    Google Scholar 

  • Pena MMO, Lee J et al. 1999 A delicate balance: homeostatic control of copper uptake and distribution. J Nutrit 129(7), 1251-1260.

    Google Scholar 

  • Pena MMO, Puig S et al. 2000 Characterization of the Saccharomyces cerevisiae high affinity copper transporter Ctr3. J Biol Chem 275(43), 33244-33251.

    Google Scholar 

  • Pinner E, Gruenheid S et al. 1997 Functional complementation of the yeast divalent cation transporter family SMF by NRAMP2, a member of the mammalian natural resistanceassociated macrophage protein family. J Biol Chem 272(46), 28933-28938.

    Google Scholar 

  • Punter FA, Adams DL et al. 2000 Characterization and localization of human COX17, a gene involved in mitochondrial copper transport. Hum Gen 107(1), 69-74.

    Google Scholar 

  • Radisky DC, Babcock MC et al. 1999 The yeast frataxin homologue mediates mitochondrial iron efflux - Evidence for a mitochondrial, iron cycle. J Biol Chem 274(8), 4497-4499.

    Google Scholar 

  • Rae TD, Schmidt PJ et al. 1999 Undetectable intracellular free copper: the requirement of a copper chaperone for superoxide dismutase. Science 284(5415), 805-808.

    Google Scholar 

  • Ristow M, Pfister MF et al. 2000 Frataxin activates mitochondrial energy conversion and oxidative phosphorylation. Proc Natl Acad Sci USA 97(22), 12239-12243.

    Google Scholar 

  • Schilke B, Forster J et al. 1996 The cold sensitivity of a mutant of Saccharomyces cerevisiae lacking a mitochondrial heat shock protein 70 Is Suppressed by Loss of Mitochondrial DNA. J Cell Biol 134(3), 603-613.

    Google Scholar 

  • Srinivasan C, Posewitz MC et al. 1998 Characterization of the copper chaperone Cox17 of Saccharomyces cerevisiae. Biochemistry 37(20), 7572-7577.

    Google Scholar 

  • Stearman R, Yuan DS et al. 1996 A permease-oxidase complex involved in high-affinity iron uptake in yeast. Science 271(5255), 1552-1557.

    Google Scholar 

  • Strain J, Culotta VC. 1996 Copper ions anti the regulation of Saccharomyces Cerevisiae metallothionein genes under aerobic and anaerobic conditions. Mol Gen Gen 251(2), 139-145.

    Google Scholar 

  • Strain J, Lorenz CR et al. 1998 Suppressors of superoxide dismutase (SOD1) deficiency in Saccharomyces cerevisiae - Identification of proteins predicted to mediate iron-sulfur cluster assembly. J Biol Chem 273(47), 31138-31144.

    Google Scholar 

  • Szczypka MS, Zhu ZW et al. 1997 Saccharomyces cerevisiae mutants altered in vacuole function are defective in copper detoxification and iron-responsive gene transcription. Yeast 13(15), 1423-1435.

    Google Scholar 

  • Urbanowski JL, Piper RC. 1999 The iron transporter fth1p forms a complex with the Fet5 iron oxidase and resides on the vacuolar membrane. J Biol Chem 274(53), 38061-38070.

    Google Scholar 

  • Valentine JS, Gralla EB. 1997 Delivering copper inside yeast and human cells. Science 278(5339), 817-818.

    Google Scholar 

  • Valentine JS, Wertz DL et al. 1998 The dark side of dioxygen biochemistry. Curr Opin Chem Biol 2(2), 253-262.

    Google Scholar 

  • Voisine C, Cheng YC et al. 2001 Jac1, a mitochondrial J-type chaperone, is involved in the biogenesis of Fe/S clusters in Saccharomyces cerevisiae. Proc Natl Acad Sci USA 98(4), 1483-1488.

    Google Scholar 

  • Vulpe CD, Packman S. 1995 Cellular copper transport. Ann Rev Nutrit 15, 293-322.

    Google Scholar 

  • Waggoner DJ, Bartnikas TB et al. 1999 The role of copper in neurodegenerative disease. Neurobiol Dis 6(4), 221-230.

    Google Scholar 

  • Yamaguchi Y, Heiny Me et al. 1996 Biochemical characterization and intracellular localization of theMenkes disease protein. Proc Natl Acad Sci USA 93(24), 14030-14035.

    Google Scholar 

  • Yamaguchi-Iwai Y, Serpe M et al. 1997 Homeostatic regulation of copper uptake in yeast via direct binding of MAC1 protein to upstream regulatory sequences of FRE1 and CTR1. J Biol Chem 272(28), 17711-17718.

    Google Scholar 

  • Yamaguchi-Iwai Y, Stearman R et al. 1996 Iron-regulated DNA binding by the Aft1 protein controls the iron regulon in yeast. Embo J 15(13), 3377-3384.

    Google Scholar 

  • Yamaguchiiwai Y, Dancis A et al. 1995 Aft1 - a mediator of iron regulated transcriptional control in Saccharomyces cerevisiae. Embo J 14(6), 1231-1239.

    Google Scholar 

  • Yu W, Farrell RA et al. 1996 Identification of Slf1 as a new copper homeostasis gene involved in copper sulfide mineralization in Saccharomyces Cerevisiae. Mol Cell Biol 16(5), 2464-2472.

    Google Scholar 

  • Yuan DS, Stearman R et al. 1995 The Menkes Wilson disease gene homologue in yeast provides copper to a ceruloplasmin-Like oxidase required for iron uptake. Proc Natl Acad Sci USA 92(7), 2632-2636.

    Google Scholar 

  • Zhu ZW, Labbe S et al. 1998 Copper differentially regulates the activity and degradation of yeastMac1 transcription factor. J Biol Chem 273(3), 1277-1280.

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

De Freitas, J., Wintz, H., Hyoun Kim, J. et al. Yeast, a model organism for iron and copper metabolism studies. Biometals 16, 185–197 (2003). https://doi.org/10.1023/A:1020771000746

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1020771000746

Navigation