Current Genetics

, Volume 48, Issue 1, pp 44–59 | Cite as

Do mitochondria regulate the heat-shock response in Saccharomyces cerevisiae?

  • Eugene G. Rikhvanov
  • Nina N. Varakina
  • Tatyana M. Rusaleva
  • Elena I. Rachenko
  • Dmitry A. Knorre
  • Victor K. Voinikov
Research Article


A mild heat shock induces the synthesis of heat-shock proteins (hsps), which protect cells from damage during more extreme heat exposure. The nature of the signals that induce transcription of heat shock-regulated genes remains conjectural. In this work we studied the role of mitochondria in regulating hsps synthesis in Saccharomyces cerevisiae. The results obtained clearly indicate that a mild heat shock elicits a hyperpolarization of the inner mitochondrial membrane and such an event is one of several signals triggering the chain of reactions that activates the expression of the HSP104 gene and probably the expression of other heat shock-regulated genes in S. cerevisiae. The uncouplers or mitochondrial inhibitors which are capable of dissipating the potential on the inner mitochondrial membrane under particular experimental conditions prevent the synthesis of Hsp104 induced by mild heat shock and thus inhibit the development of induced thermotolerance. It is suggested that cAMP-dependent protein kinase A is participating in the mitochondrial regulation of nuclear genes.


Heat shock Mitochondria Hsp104 regulation 


  1. Ahn SG, Thiele DJ (2003) Redox regulation of mammalian heat shock factor 1 is essential for Hsp gene activation and protection from stress. Genes Dev 17:516–528CrossRefPubMedGoogle Scholar
  2. Ananthan J, Goldberg AL, Voellmy R (1986) Abnormal proteins serve as eukaryotic stress signals and trigger the activation of heat shock genes. Science 232:522–524PubMedGoogle Scholar
  3. Appleby RD, Porteous WK, Hughes G, James AM, Shannon D, Wei YH, Murphy MP (1999) Quantitation and origin of the mitochondrial membrane potential in human cells lacking mitochondrial DNA. Eur J Biochem 262:108–116Google Scholar
  4. Ashburner M, Bonner JJ (1979) The induction of gene activity in Drosophilia by heat shock. Cell 17:241–254CrossRefPubMedGoogle Scholar
  5. Barrett MJ, Alones V, Wang KX, Phan L, Swerdlow RH (2004) Mitochondria-derived oxidative stress induces a heat shock protein response. J Neurosci Res 78:420–439CrossRefPubMedGoogle Scholar
  6. Boutibonnes P, Bisson V, Thammavongs B, Hartke A, Panoff JM, Benachour A, Auffray Y (1995) Induction of thermotolerance by chemical agents in Lactococcus lactis subsp. lactis IL1403. Int J Food Microbiol 25:83–94CrossRefPubMedGoogle Scholar
  7. Boy-Marcotte E, Lagniel G, Perrot M, Bussereau F, Boudsocq A, Jacquet M, Labarre J (1999) The heat shock response in yeast: differential regulations and contributions of the Msn2p/Msn4p and Hsf1p regulons. Mol Microbiol 33:274–283Google Scholar
  8. Cameron S, Levin L, Zoller M, Wigler M (1988) cAMP-independent control of sporulation, glycogen metabolism, and heat shock resistance in S. cerevisiae. Cell 53:555–566CrossRefPubMedGoogle Scholar
  9. Chandel NS, Schumacker PT (1999) Cells depleted of mitochondrial DNA (ρo) yield insight into physiological mechanisms. FEBS Lett 454:173–176CrossRefPubMedGoogle Scholar
  10. Chen XJ, Clark-Walker GD (1999) α and β subunits of F1-ATPase are required for survival of petite mutants in Saccharomyces cerevisiae. Mol Gen Genet 262:898–908CrossRefPubMedGoogle Scholar
  11. Cheng L, Piper PW (1994) Weak acid preservatives block the heat shock response and heat-shock-element-directed lacZ expression of low pH Saccharomyces cerevisiae cultures, an inhibitory action partially relieved by respiratory deficiency. Microbiology 140:1085–1096Google Scholar
  12. Currie S, Tufts BL, Moyes CD (1999) Influence of bioenergetic stress on heat shock protein gene expression in nucleated red blood cells of fish. Am J Physiol 276:R990–R996PubMedGoogle Scholar
  13. Dupont CH, Mazat JP, Guerin B (1985) The role of adenine nucleotide translocation in the energization of the inner membrane of mitochondria isolated from ρ+ and ρ0 strains of Saccharomyces cerevisiae. Biochem Biophys Res Commun 132:1116–1123CrossRefPubMedGoogle Scholar
  14. Elia G, De Marco A, Rossi A, Santoro MG (1996) Inhibition of HSP70 expression by calcium ionophore A23187 in human cells. An effect independent of the acquisition of DNA-binding activity by the heat shock transcription factor. J Biol Chem 271:16111–16118Google Scholar
  15. Fukunaga M, Mizuguchi Y, Yielding LW, Yielding KL (1984) Petite induction in Saccharomyces cerevisiae by ethidium analogs. Action on mitochondrial genome. Mutat Res 127:15–21PubMedGoogle Scholar
  16. Gabai VL, Sherman MY (2002) Invited review: interplay between molecular chaperones and signaling pathways in survival of heat shock. J Appl Physiol 92:1743–1748PubMedGoogle Scholar
  17. Garreau H, Hasan RN, Renault G, Estruch F, Boy-Marcotte E, Jacquet M (2000) Hyperphosphorylation of Msn2p and Msn4p in response to heat shock and the diauxic shift is inhibited by cAMP in Saccharomyces cerevisiae. Microbiology 146:2113–2120Google Scholar
  18. Gasch AP (2003) The environmental stress response: a common yeast response to diverse environmental. In: Hohmann S, Mager PWH (eds) Topics in current genetics: yeast stress responses, vol 1. Springer, Berlin Heidelberg New York, pp 11–70Google Scholar
  19. Gasser SM, Daum G, Schatz G (1982) Import of proteins into mitochondria. Energy-dependent uptake of precursors by isolated mitochondria. J Biol Chem 257:13034–13041Google Scholar
  20. Giraud MF, Velours J (1997) The absence of the mitochondrial ATP synthase δ subunit promotes a slow growth phenotype of rho yeast cells by a lack of assembly of the catalytic sector F1. Eur J Biochem 245:813–818Google Scholar
  21. Gorman AM, Heavey B, Creagh E, Cotter TG, Samali A (1999) Antioxidant-mediated inhibition of the heat shock response leads to apoptosis. FEBS Lett 445:98–102CrossRefPubMedGoogle Scholar
  22. Görner W, Durchschlag E, Martinez-Pastor MT, Estruch F, Ammerer G, Hamilton B, Ruis H, Schuller C (1998) Nuclear localization of the C2H2 zinc finger protein Msn2p is regulated by stress and protein kinase A activity. Genes Dev 12:586–597PubMedGoogle Scholar
  23. Grably MR, Stanhill A, Tell O, Engelberg D (2002) HSF and Msn2/4p can exclusively or cooperatively activate the yeast HSP104 gene. Mol Microbiol 44:21–35Google Scholar
  24. Groot GS, Kovac L, Schatz G (1971) Promitochondria of anaerobically grown yeast. V. Energy transfer in the absence of an electron transfer chain. Proc Natl Acad Sci USA 68:308–311PubMedGoogle Scholar
  25. Käppeli O (1986) Regulation of carbon metabolism in Saccharomyces cerevisiae and related yeasts. Adv Microb Physiol 28:181–209PubMedGoogle Scholar
  26. Kominsky DJ, Brownson MP, Updike DL, Thorsness PE (2002) Genetic and biochemical basis for viability of yeast lacking mitochondrial genomes. Genetics 162:1595–1604PubMedGoogle Scholar
  27. Kovacova V, Irmlerova J, Kovac L (1968) Oxidative phosphorylatiion in yeast. IV. Combination of a nuclear mutation affecting oxidative phosphorylation with cytoplasmic mutation to respiratory deficiency. Biochim Biophys Acta 162:157–163PubMedGoogle Scholar
  28. Kuzmin EV, Karpova OV, Elthon TE, Newton KJ (2004) Mitochondrial respiratory deficiencies signal up-regulation of genes for heat shock proteins. J Biol Chem 279:20672–20677Google Scholar
  29. Lee K, Kang S, Lindquist S (1998) 13C NMR studies of metabolic pathways regulated by HSP104 in Saccharomyces cerevisiae. Bull Korean Chem Soc 19:295–299Google Scholar
  30. Lee S, Carlson T, Christian N, Lea K, Kedzie J, Reilly JP, Bonner JJ (2000) The yeast heat shock transcription factor changes conformation in response to superoxide and temperature. Mol Biol Cell 11:1753–1764PubMedGoogle Scholar
  31. Lefebvre-Legendre L, Balguerie A, Duvezin-Caubet S, Giraud MF, Slonimski PP, Di Rago JP (2003) F1-catalysed ATP hydrolysis is required for mitochondrial biogenesis in Saccharomyces cerevisiae growing under conditions where it cannot respire. Mol Microbiol 47:1329–1339CrossRefPubMedGoogle Scholar
  32. Li B, Liu HT, Sun DY, Zhou RG (2004) Ca2+ and calmodulin modulate DNA-binding activity of maize heat shock transcription factor in vitro. Plant Cell Physiol 45:627–634CrossRefPubMedGoogle Scholar
  33. Lindquist S, Kim G (1996) Heat-shock protein 104 expression is sufficient for thermotolerance in yeast. Proc Natl Acad Sci USA 93:5301–5306CrossRefPubMedGoogle Scholar
  34. Loiseau D, Chevrollier A, Douay O, Vavasseur F, Renier G, Reynier P, Malthiery Y, Stepien G (2002) Oxygen consumption and expression of the adenine nucleotide translocator in cells lacking mitochondrial DNA. Exp Cell Res 278:12–18CrossRefPubMedGoogle Scholar
  35. Ludovico P, Sansonetty F, Corte-Real M (2001) Assessment of mitochondrial membrane potential in yeast cell populations by flow cytometry. Microbiology 147:3335–3343Google Scholar
  36. Martinez-Pastor MT, Marchler G, Schuller C, Marchler-Bauer A, Ruis H, Estruch F (1996) The Saccharomyces cerevisiae zinc finger proteins Msn2p and Msn4p are required for transcriptional induction through the stress response element (STRE). EMBO J 15:2227–2235PubMedGoogle Scholar
  37. Massie MR, Lapoczka EM, Boggs KD, Stine KE, White GE (2003) Exposure to the metabolic inhibitor sodium azide induces stress protein expression and thermotolerance in the nematode Caenorhabditis elegans. Cell Stress Chaperones 8:1–7CrossRefPubMedGoogle Scholar
  38. Mitchel RE, Morrison DP (1983) Assessment of the role of oxygen and mitochondria in heat shock induction of radiation and thermal resistance in Saccharomyces cerevisiae. Radiat Res 96:113–117PubMedGoogle Scholar
  39. Moraitis C, Curran BP (2004) Reactive oxygen species may influence the heat shock response and stress tolerance in the yeast Saccharomyces cerevisiae. Yeast 21:313–323CrossRefPubMedGoogle Scholar
  40. Noshiro A, Purwin C, Laux M, Nicolay K, Scheffers WA, Holzer H (1987) Mechanism of stimulation of endogenous fermentation in yeast by carbonyl cyanide m-chlorophenylhydrazone. J Biol Chem 262:14154–14157Google Scholar
  41. Parsell DA, Lindquist S (1993) The function of heat-shock proteins in stress tolerance: degradation and reactivation of damaged proteins. Annu Rev Genet 27:437–496Google Scholar
  42. Piper PW (1993) Molecular events associated with acquisition of heat tolerance by the yeast Saccharomyces cerevisiae. FEMS Microbiol Rev 11:339–355CrossRefPubMedGoogle Scholar
  43. Pozniakovsky AI, Knorre DA, Markova OV, Hyman AA, Skulachev VP, Severin FF (2005) Role of mitochondria in the pheromone- and amiodarone-induced programmed death of yeast. J Cell Biol 168:257–269CrossRefPubMedGoogle Scholar
  44. Rikhvanov EG, Varakina NN, Rusaleva TM, Rachenko EI, Voinikov VK (2002) Sodium azide reduces the thermotolerance of respiratively grown yeasts. Curr Microbiol 45:394–399CrossRefPubMedGoogle Scholar
  45. Rikhvanov EG, Rachenko EI, Varakina NN, Rusaleva TM, Borovskii GB, Voinikov VK (2004) The induction of Saccharomyces cerevisiae Hsp104 synthesis by heat shock is controlled by mitochondria. Russ J Genet 40:341–347CrossRefGoogle Scholar
  46. Salvioli S, Dobrucki J, Moretti L, Troiano L, Fernandez MG, Pinti M, Pedrazzi J, Franceschi C, Cossarizza A (2000) Mitochondrial heterogeneity during staurosporine-induced apoptosis in HL60 cells: analysis at the single cell and single organelle level. Cytometry 40:189–197CrossRefPubMedGoogle Scholar
  47. Sanchez Y, Lindquist S (1990) HSP104 required for induced thermotolerance. Science 248:1112–1115PubMedGoogle Scholar
  48. Sanchez Y, Taulien J, Borkovich KA, Lindquist S (1992) Hsp104 is required for tolerance to many forms of stress. EMBO J 11:2357–2364PubMedGoogle Scholar
  49. Sanchez Y, Parsell DA, Taulien J, Vogel JL, Craig EA, Lindquist S (1993) Genetic evidence for a functional relationship between Hsp104 and Hsp70. J Bacteriol 175:6484–6491PubMedGoogle Scholar
  50. Scaduto RC Jr, Grotyohann LW (1999) Measurement of mitochondrial membrane potential using fluorescent rhodamine derivatives. Biophys J 76:469–477Google Scholar
  51. Schmitt AP, McEntee K (1996) Msn2p, a zinc finger DNA-binding protein, is the transcriptional activator of the multistress response in Saccharomyces cerevisiae. Proc Natl Acad Sci USA 93:5777–5782CrossRefPubMedGoogle Scholar
  52. Skulachev VP (1996) Role of uncoupled and non-coupled oxidations in maintenance of safely low levels of oxygen and its one-electron reductants. Q Rev Biophys 29:169–202PubMedGoogle Scholar
  53. Smith A, Ward MP, Garrett S (1998) Yeast PKA represses Msn2p/Msn4p-dependent gene expression to regulate growth, stress response and glycogen accumulation. EMBO J 17:3556–3564CrossRefPubMedGoogle Scholar
  54. Sugiyama K, Izawa S, Inoue Y (2000) The Yap1p-dependent induction of glutathione synthesis in heat shock response of Saccharomyces cerevisiae. J Biol Chem 275:15535–15540Google Scholar
  55. Thevelein JM, Winde JH de (1999) Novel sensing mechanisms and targets for the cAMP-protein kinase A pathway in the yeast Saccharomyces cerevisiae. Mol Microbiol 33:904–918Google Scholar
  56. Thevelein JM, Beullens M, Honshoven F, Hoebeeck G, Detremerie K, Hollander JA den, Jans AW (1987) Regulation of the cAMP level in the yeast Saccharomyces cerevisiae: intracellular pH and the effect of membrane depolarizing compounds. J Gen Microbiol 133:2191–2196Google Scholar
  57. Toda T, Uno I, Ishikawa T, Powers S, Kataoka T, Broek D, Cameron S, Broach J, Matsumoto K, Wigler M (1985) In yeast, RAS proteins are controlling elements of adenylate cyclase. Cell 40:27–36CrossRefPubMedGoogle Scholar
  58. Trott A, Morano KA (2003) The yeast response to heat shock. In: Hohmann S, Mager PWH (eds) Topics in current genetics: yeast stress responses, vol 1. Springer, Berlin Heidelberg, New York, pp 71–119Google Scholar
  59. Trotter EW, Kao CM, Berenfeld L, Botstein D, Petsko GA, Gray JV (2002) Misfolded proteins are competent to mediate a subset of the responses to heat shock in Saccharomyces cerevisiae. J Biol Chem 277:44817–44825Google Scholar
  60. Tzagoloff A, Myers AM (1986) Genetics of mitochondrial biogenesis. Annu Rev Biochem 55:249–285CrossRefPubMedGoogle Scholar
  61. Varela JCS, Praekelt UM, Meacock PA, Planta RJ, Mager WH (1995) The Saccharomyces cerevisiae HSP12 gene is activated by the high-osmolarity glycerol pathway and negatively regulated by protein kinase. Mol Cell Biol 15:6232–6245PubMedGoogle Scholar
  62. Webb JL (1963) Enzyme and metabolic inhibitor, vol 1. General principles of inhibition. Academic, New York, pp 782–784Google Scholar
  63. Weber J, Senior AE (1998) Effects of the inhibitors azide, dicyclohexylcarbodiimide, and aurovertin on nucleotide binding to the three F1-ATPase catalytic sites measured using specific tryptophan probes. J Biol Chem 273:33210–33215Google Scholar
  64. Weitzel G, Pilatus U, Rensing L (1987) The cytoplasmic pH, ATP content and total protein synthesis rate during heat-shock protein inducing treatments in yeast. Exp Cell Res 170:64–79CrossRefPubMedGoogle Scholar
  65. Wieser R, Adam G, Wagner A, Schuller C, Marchler G, Ruis H, Krawiec Z, Bilinski T (1991) Heat shock factor-independent heat control of transcription of the CTT1 gene encoding the cytosolic catalase T of Saccharomyces cerevisiae. J Biol Chem 266:12406–12411Google Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Eugene G. Rikhvanov
    • 1
  • Nina N. Varakina
    • 1
  • Tatyana M. Rusaleva
    • 1
  • Elena I. Rachenko
    • 1
  • Dmitry A. Knorre
    • 2
  • Victor K. Voinikov
    • 1
  1. 1.Siberian Institute of Plant Physiology and Biochemistry, Siberian DivisionRussian Academy of SciencesIrkutskRussia
  2. 2.A.N. Belozersky Institute of Physico-Chemical BiologyMoscow State UniversityMoscowRussia

Personalised recommendations