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. 2003 Jan;163(1):35–46. doi: 10.1093/genetics/163.1.35

SOD2 functions downstream of Sch9 to extend longevity in yeast.

Paola Fabrizio 1, Lee-Loung Liou 1, Vanessa N Moy 1, Alberto Diaspro 1, Joan SelverstoneValentine 1, Edith Butler Gralla 1, Valter D Longo 1
PMCID: PMC1462415  PMID: 12586694

Abstract

Signal transduction pathways inactivated during periods of starvation are implicated in the regulation of longevity in organisms ranging from yeast to mammals, but the mechanisms responsible for life-span extension are poorly understood. Chronological life-span extension in S. cerevisiae cyr1 and sch9 mutants is mediated by the stress-resistance proteins Msn2/Msn4 and Rim15. Here we show that mitochondrial superoxide dismutase (Sod2) is required for survival extension in yeast. Deletion of SOD2 abolishes life-span extension in sch9Delta mutants and decreases survival in cyr1:mTn mutants. The overexpression of Sods--mitochondrial Sod2 and cytosolic CuZnSod (Sod1)--delays the age-dependent reversible inactivation of mitochondrial aconitase, a superoxide-sensitive enzyme, and extends survival by 30%. Deletion of the RAS2 gene, which functions upstream of CYR1, also doubles the mean life span by a mechanism that requires Msn2/4 and Sod2. These findings link mutations that extend chronological life span in S. cerevisiae to superoxide dismutases and suggest that the induction of other stress-resistance genes regulated by Msn2/4 and Rim15 is required for maximum longevity extension.

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Selected References

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  1. Ashrafi K., Sinclair D., Gordon J. I., Guarente L. Passage through stationary phase advances replicative aging in Saccharomyces cerevisiae. Proc Natl Acad Sci U S A. 1999 Aug 3;96(16):9100–9105. doi: 10.1073/pnas.96.16.9100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Boveris A., Chance B. The mitochondrial generation of hydrogen peroxide. General properties and effect of hyperbaric oxygen. Biochem J. 1973 Jul;134(3):707–716. doi: 10.1042/bj1340707. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Boy-Marcotte E., Perrot M., Bussereau F., Boucherie H., Jacquet M. Msn2p and Msn4p control a large number of genes induced at the diauxic transition which are repressed by cyclic AMP in Saccharomyces cerevisiae. J Bacteriol. 1998 Mar;180(5):1044–1052. doi: 10.1128/jb.180.5.1044-1052.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Cherkasova V., Ayyadevara S., Egilmez N., Shmookler Reis R. Diverse Caenorhabditis elegans genes that are upregulated in dauer larvae also show elevated transcript levels in long-lived, aged, or starved adults. J Mol Biol. 2000 Jul 14;300(3):433–448. doi: 10.1006/jmbi.2000.3880. [DOI] [PubMed] [Google Scholar]
  5. Do T. Q., Schultz J. R., Clarke C. F. Enhanced sensitivity of ubiquinone-deficient mutants of Saccharomyces cerevisiae to products of autoxidized polyunsaturated fatty acids. Proc Natl Acad Sci U S A. 1996 Jul 23;93(15):7534–7539. doi: 10.1073/pnas.93.15.7534. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Estruch F., Carlson M. Two homologous zinc finger genes identified by multicopy suppression in a SNF1 protein kinase mutant of Saccharomyces cerevisiae. Mol Cell Biol. 1993 Jul;13(7):3872–3881. doi: 10.1128/mcb.13.7.3872. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Fabrizio P., Pozza F., Pletcher S. D., Gendron C. M., Longo V. D. Regulation of longevity and stress resistance by Sch9 in yeast. Science. 2001 Apr 5;292(5515):288–290. doi: 10.1126/science.1059497. [DOI] [PubMed] [Google Scholar]
  8. Flattery-O'Brien J. A., Grant C. M., Dawes I. W. Stationary-phase regulation of the Saccharomyces cerevisiae SOD2 gene is dependent on additive effects of HAP2/3/4/5- and STRE-binding elements. Mol Microbiol. 1997 Jan;23(2):303–312. doi: 10.1046/j.1365-2958.1997.2121581.x. [DOI] [PubMed] [Google Scholar]
  9. Flint D. H., Tuminello J. F., Emptage M. H. The inactivation of Fe-S cluster containing hydro-lyases by superoxide. J Biol Chem. 1993 Oct 25;268(30):22369–22376. [PubMed] [Google Scholar]
  10. Flint Dennis H., Allen Ronda M. Ironminus signSulfur Proteins with Nonredox Functions. Chem Rev. 1996 Nov 7;96(7):2315–2334. doi: 10.1021/cr950041r. [DOI] [PubMed] [Google Scholar]
  11. Fridovich I. Superoxide radical and superoxide dismutases. Annu Rev Biochem. 1995;64:97–112. doi: 10.1146/annurev.bi.64.070195.000525. [DOI] [PubMed] [Google Scholar]
  12. Gardner P. R., Raineri I., Epstein L. B., White C. W. Superoxide radical and iron modulate aconitase activity in mammalian cells. J Biol Chem. 1995 Jun 2;270(22):13399–13405. doi: 10.1074/jbc.270.22.13399. [DOI] [PubMed] [Google Scholar]
  13. Geller B. L., Winge D. R. Subcellular distribution of superoxide dismutases in rat liver. Methods Enzymol. 1984;105:105–114. doi: 10.1016/s0076-6879(84)05014-x. [DOI] [PubMed] [Google Scholar]
  14. Gietz D., St Jean A., Woods R. A., Schiestl R. H. Improved method for high efficiency transformation of intact yeast cells. Nucleic Acids Res. 1992 Mar 25;20(6):1425–1425. doi: 10.1093/nar/20.6.1425. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Gralla E. B., Valentine J. S. Null mutants of Saccharomyces cerevisiae Cu,Zn superoxide dismutase: characterization and spontaneous mutation rates. J Bacteriol. 1991 Sep;173(18):5918–5920. doi: 10.1128/jb.173.18.5918-5920.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Granot D., Snyder M. Glucose induces cAMP-independent growth-related changes in stationary-phase cells of Saccharomyces cerevisiae. Proc Natl Acad Sci U S A. 1991 Jul 1;88(13):5724–5728. doi: 10.1073/pnas.88.13.5724. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Han D., Williams E., Cadenas E. Mitochondrial respiratory chain-dependent generation of superoxide anion and its release into the intermembrane space. Biochem J. 2001 Jan 15;353(Pt 2):411–416. doi: 10.1042/0264-6021:3530411. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Honda Y., Honda S. The daf-2 gene network for longevity regulates oxidative stress resistance and Mn-superoxide dismutase gene expression in Caenorhabditis elegans. FASEB J. 1999 Aug;13(11):1385–1393. [PubMed] [Google Scholar]
  19. Jazwinski S. M. Longevity, genes, and aging. Science. 1996 Jul 5;273(5271):54–59. doi: 10.1126/science.273.5271.54. [DOI] [PubMed] [Google Scholar]
  20. Johnson T. E. Increased life-span of age-1 mutants in Caenorhabditis elegans and lower Gompertz rate of aging. Science. 1990 Aug 24;249(4971):908–912. doi: 10.1126/science.2392681. [DOI] [PubMed] [Google Scholar]
  21. Kane D. J., Sarafian T. A., Anton R., Hahn H., Gralla E. B., Valentine J. S., Ord T., Bredesen D. E. Bcl-2 inhibition of neural death: decreased generation of reactive oxygen species. Science. 1993 Nov 19;262(5137):1274–1277. doi: 10.1126/science.8235659. [DOI] [PubMed] [Google Scholar]
  22. Kataoka T., Powers S., McGill C., Fasano O., Strathern J., Broach J., Wigler M. Genetic analysis of yeast RAS1 and RAS2 genes. Cell. 1984 Jun;37(2):437–445. doi: 10.1016/0092-8674(84)90374-x. [DOI] [PubMed] [Google Scholar]
  23. Kenyon C., Chang J., Gensch E., Rudner A., Tabtiang R. A C. elegans mutant that lives twice as long as wild type. Nature. 1993 Dec 2;366(6454):461–464. doi: 10.1038/366461a0. [DOI] [PubMed] [Google Scholar]
  24. Kimura K. D., Tissenbaum H. A., Liu Y., Ruvkun G. daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans. Science. 1997 Aug 15;277(5328):942–946. doi: 10.1126/science.277.5328.942. [DOI] [PubMed] [Google Scholar]
  25. Li Y., Huang T. T., Carlson E. J., Melov S., Ursell P. C., Olson J. L., Noble L. J., Yoshimura M. P., Berger C., Chan P. H. Dilated cardiomyopathy and neonatal lethality in mutant mice lacking manganese superoxide dismutase. Nat Genet. 1995 Dec;11(4):376–381. doi: 10.1038/ng1295-376. [DOI] [PubMed] [Google Scholar]
  26. Lin K., Dorman J. B., Rodan A., Kenyon C. daf-16: An HNF-3/forkhead family member that can function to double the life-span of Caenorhabditis elegans. Science. 1997 Nov 14;278(5341):1319–1322. doi: 10.1126/science.278.5341.1319. [DOI] [PubMed] [Google Scholar]
  27. Lin K., Dorman J. B., Rodan A., Kenyon C. daf-16: An HNF-3/forkhead family member that can function to double the life-span of Caenorhabditis elegans. Science. 1997 Nov 14;278(5341):1319–1322. doi: 10.1126/science.278.5341.1319. [DOI] [PubMed] [Google Scholar]
  28. Lin S. J., Defossez P. A., Guarente L. Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. Science. 2000 Sep 22;289(5487):2126–2128. doi: 10.1126/science.289.5487.2126. [DOI] [PubMed] [Google Scholar]
  29. Lithgow G. J., White T. M., Melov S., Johnson T. E. Thermotolerance and extended life-span conferred by single-gene mutations and induced by thermal stress. Proc Natl Acad Sci U S A. 1995 Aug 1;92(16):7540–7544. doi: 10.1073/pnas.92.16.7540. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Liu X. F., Elashvili I., Gralla E. B., Valentine J. S., Lapinskas P., Culotta V. C. Yeast lacking superoxide dismutase. Isolation of genetic suppressors. J Biol Chem. 1992 Sep 15;267(26):18298–18302. [PubMed] [Google Scholar]
  31. Longo V. D., Ellerby L. M., Bredesen D. E., Valentine J. S., Gralla E. B. Human Bcl-2 reverses survival defects in yeast lacking superoxide dismutase and delays death of wild-type yeast. J Cell Biol. 1997 Jun 30;137(7):1581–1588. doi: 10.1083/jcb.137.7.1581. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Longo V. D., Fabrizio P. Regulation of longevity and stress resistance: a molecular strategy conserved from yeast to humans? Cell Mol Life Sci. 2002 Jun;59(6):903–908. doi: 10.1007/s00018-002-8477-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Longo V. D., Gralla E. B., Valentine J. S. Superoxide dismutase activity is essential for stationary phase survival in Saccharomyces cerevisiae. Mitochondrial production of toxic oxygen species in vivo. J Biol Chem. 1996 May 24;271(21):12275–12280. doi: 10.1074/jbc.271.21.12275. [DOI] [PubMed] [Google Scholar]
  34. Longo V. D., Liou L. L., Valentine J. S., Gralla E. B. Mitochondrial superoxide decreases yeast survival in stationary phase. Arch Biochem Biophys. 1999 May 1;365(1):131–142. doi: 10.1006/abbi.1999.1158. [DOI] [PubMed] [Google Scholar]
  35. Longo V. D. Mutations in signal transduction proteins increase stress resistance and longevity in yeast, nematodes, fruit flies, and mammalian neuronal cells. Neurobiol Aging. 1999 Sep-Oct;20(5):479–486. doi: 10.1016/s0197-4580(99)00089-5. [DOI] [PubMed] [Google Scholar]
  36. Martínez-Pastor M. T., Marchler G., Schüller C., Marchler-Bauer A., Ruis H., Estruch F. The Saccharomyces cerevisiae zinc finger proteins Msn2p and Msn4p are required for transcriptional induction through the stress response element (STRE). EMBO J. 1996 May 1;15(9):2227–2235. [PMC free article] [PubMed] [Google Scholar]
  37. Mikus M. D., Petes T. D. Recombination between genes located on nonhomologous chromosomes in Saccharomyces cerevisiae. Genetics. 1982 Jul-Aug;101(3-4):369–404. doi: 10.1093/genetics/101.3-4.369. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Morano K. A., Thiele D. J. The Sch9 protein kinase regulates Hsp90 chaperone complex signal transduction activity in vivo. EMBO J. 1999 Nov 1;18(21):5953–5962. doi: 10.1093/emboj/18.21.5953. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Morris J. Z., Tissenbaum H. A., Ruvkun G. A phosphatidylinositol-3-OH kinase family member regulating longevity and diapause in Caenorhabditis elegans. Nature. 1996 Aug 8;382(6591):536–539. doi: 10.1038/382536a0. [DOI] [PubMed] [Google Scholar]
  40. Mueller D. M. Arginine 328 of the beta-subunit of the mitochondrial ATPase in yeast is essential for protein stability. J Biol Chem. 1988 Apr 25;263(12):5634–5639. [PubMed] [Google Scholar]
  41. Okado-Matsumoto A., Fridovich I. Subcellular distribution of superoxide dismutases (SOD) in rat liver: Cu,Zn-SOD in mitochondria. J Biol Chem. 2001 Aug 15;276(42):38388–38393. doi: 10.1074/jbc.M105395200. [DOI] [PubMed] [Google Scholar]
  42. Pedruzzi I., Bürckert N., Egger P., De Virgilio C. Saccharomyces cerevisiae Ras/cAMP pathway controls post-diauxic shift element-dependent transcription through the zinc finger protein Gis1. EMBO J. 2000 Jun 1;19(11):2569–2579. doi: 10.1093/emboj/19.11.2569. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Poon W. W., Barkovich R. J., Hsu A. Y., Frankel A., Lee P. T., Shepherd J. N., Myles D. C., Clarke C. F. Yeast and rat Coq3 and Escherichia coli UbiG polypeptides catalyze both O-methyltransferase steps in coenzyme Q biosynthesis. J Biol Chem. 1999 Jul 30;274(31):21665–21672. doi: 10.1074/jbc.274.31.21665. [DOI] [PubMed] [Google Scholar]
  44. RACKER E. Spectrophotometric measurements of the enzymatic formation of fumaric and cis-aconitic acids. Biochim Biophys Acta. 1950 Jan;4(1-3):211–214. doi: 10.1016/0006-3002(50)90026-6. [DOI] [PubMed] [Google Scholar]
  45. Roberts R. L., Mösch H. U., Fink G. R. 14-3-3 proteins are essential for RAS/MAPK cascade signaling during pseudohyphal development in S. cerevisiae. Cell. 1997 Jun 27;89(7):1055–1065. doi: 10.1016/s0092-8674(00)80293-7. [DOI] [PubMed] [Google Scholar]
  46. Ruis H., Schüller C. Stress signaling in yeast. Bioessays. 1995 Nov;17(11):959–965. doi: 10.1002/bies.950171109. [DOI] [PubMed] [Google Scholar]
  47. Sinclair D. A., Mills K., Guarente L. Accelerated aging and nucleolar fragmentation in yeast sgs1 mutants. Science. 1997 Aug 29;277(5330):1313–1316. doi: 10.1126/science.277.5330.1313. [DOI] [PubMed] [Google Scholar]
  48. Sinclair D., Mills K., Guarente L. Aging in Saccharomyces cerevisiae. Annu Rev Microbiol. 1998;52:533–560. doi: 10.1146/annurev.micro.52.1.533. [DOI] [PubMed] [Google Scholar]
  49. Smith A., Ward M. P., Garrett S. Yeast PKA represses Msn2p/Msn4p-dependent gene expression to regulate growth, stress response and glycogen accumulation. EMBO J. 1998 Jul 1;17(13):3556–3564. doi: 10.1093/emboj/17.13.3556. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Thevelein J. M., de Winde J. H. Novel sensing mechanisms and targets for the cAMP-protein kinase A pathway in the yeast Saccharomyces cerevisiae. Mol Microbiol. 1999 Sep;33(5):904–918. doi: 10.1046/j.1365-2958.1999.01538.x. [DOI] [PubMed] [Google Scholar]
  51. Toda T., Cameron S., Sass P., Wigler M. SCH9, a gene of Saccharomyces cerevisiae that encodes a protein distinct from, but functionally and structurally related to, cAMP-dependent protein kinase catalytic subunits. Genes Dev. 1988 May;2(5):517–527. doi: 10.1101/gad.2.5.517. [DOI] [PubMed] [Google Scholar]
  52. Toda T., Uno I., Ishikawa T., Powers S., Kataoka T., Broek D., Cameron S., Broach J., Matsumoto K., Wigler M. In yeast, RAS proteins are controlling elements of adenylate cyclase. Cell. 1985 Jan;40(1):27–36. doi: 10.1016/0092-8674(85)90305-8. [DOI] [PubMed] [Google Scholar]
  53. Werner-Washburne M., Braun E. L., Crawford M. E., Peck V. M. Stationary phase in Saccharomyces cerevisiae. Mol Microbiol. 1996 Mar;19(6):1159–1166. doi: 10.1111/j.1365-2958.1996.tb02461.x. [DOI] [PubMed] [Google Scholar]
  54. Werner-Washburne M., Braun E., Johnston G. C., Singer R. A. Stationary phase in the yeast Saccharomyces cerevisiae. Microbiol Rev. 1993 Jun;57(2):383–401. doi: 10.1128/mr.57.2.383-401.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Zambrano M. M., Kolter R. GASPing for life in stationary phase. Cell. 1996 Jul 26;86(2):181–184. doi: 10.1016/s0092-8674(00)80089-6. [DOI] [PubMed] [Google Scholar]

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