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Current Genetics

, Volume 64, Issue 1, pp 199–214 | Cite as

The influence of mitochondrial dynamics on mitochondrial genome stability

  • Christopher T. Prevost
  • Nicole Peris
  • Christina Seger
  • Deanna R. Pedeville
  • Kathryn Wershing
  • Elaine A. SiaEmail author
  • Rey A. L. SiaEmail author
Original Article

Abstract

Mitochondria are dynamic organelles that fuse and divide. These changes alter the number and distribution of mitochondrial structures throughout the cell in response to developmental and metabolic cues. We have demonstrated that mitochondrial fission is essential to the maintenance of mitochondrial DNA (mtDNA) under changing metabolic conditions in wild-type Saccharomyces cerevisiae. While increased loss of mtDNA integrity has been demonstrated for dnm1-∆ fission mutants after growth in a non-fermentable carbon source, we demonstrate that growth of yeast in different carbon sources affects the frequency of mtDNA loss, even when the carbon sources are fermentable. In addition, we demonstrate that the impact of fission on mtDNA maintenance during growth in different carbon sources is neither mediated by retrograde signaling nor mitophagy. Instead, we demonstrate that mitochondrial distribution and mtDNA maintenance phenotypes conferred by loss of Dnm1p are suppressed by the loss of Sod2p, the mitochondrial matrix superoxide dismutase.

Keywords

Mitochondria Mitochondrial DNA (mtDNA) Genome instability Mitochondrial dynamics Mitochondrial genome 

Notes

Acknowledgements

E.A.S and R.A.S research was supported by National Science Foundation Grants, MCB0841857 and MCB1243428. E.A.S. and C.T.P. received additional support from University of Rochester Pump Primer Grant, OP212588.

Supplementary material

294_2017_717_MOESM1_ESM.pdf (12.1 mb)
Supplementary material 1 (PDF 12366 kb)

References

  1. Abeliovich H, Zarei M, Rigbolt KT, Youle RJ, Dengjel J (2013) Involvement of mitochondrial dynamics in the segregation of mitochondrial matrix proteins during stationary phase mitophagy. Nat Commun 4:2789CrossRefPubMedPubMedCentralGoogle Scholar
  2. Archer SL (2013) Mitochondrial dynamics—mitochondrial fission and fusion in human disease. N Engl J Med 369:2236–2251CrossRefPubMedGoogle Scholar
  3. Bianchi NO, Bianchi MS, Richard SM (2001) Mitochondrial genome instability in human cancers. Mutat Res 488:9–23CrossRefPubMedGoogle Scholar
  4. Bleazard W, McCaffery JM, King EJ, Bale S, Mozy A et al (1999) The dynamin-related GTPase Dnm1 regulates mitochondrial fission in yeast. Nat Cell Biol 1:298–304CrossRefPubMedPubMedCentralGoogle Scholar
  5. Cox RT, Spradling AC (2009) clueless, a conserved Drosophila gene required for mitochondrial subcellular localization, interacts genetically with parkin. Dis Model Mech 9–10:490–499CrossRefGoogle Scholar
  6. Defontaine A, Lecocq FM, Hallet JN (1991) A rapid miniprep method for the preparation of yeast mitochondrial DNA. Nucleic Acids Res 19:185CrossRefPubMedPubMedCentralGoogle Scholar
  7. Dengjel J, Abeliovich H (2017) Roles of mitophagy in cellular physiology and development. Cell Tissue Res 367:95–109CrossRefPubMedGoogle Scholar
  8. Dimmer KS, Fritz S, Fuchs F, Messerschmitt M, Weinback N et al (2002) Genetic basis of mitochondrial function and morphology in Saccharomyces cerevisiae. Mol Biol Cell 13:847–853CrossRefPubMedPubMedCentralGoogle Scholar
  9. Dimmer KS, Jakobs S, Vogel F, Altmann K, Westermann B (2005) Mdm31 and Mdm32 are inner membrane proteins required for maintenance of mitochondrial shape and stability of mitochondrial DNA nucleoids in yeast. J Cell Biol 168:103–115CrossRefPubMedPubMedCentralGoogle Scholar
  10. Doudican NA, Song B, Shadel GS, Doetsch PW (2005) Oxidative DNA damage causes mitochondrial genomic instability in Saccharomyces cerevisiae. Mol Cell Biol 25:5196–5204CrossRefPubMedPubMedCentralGoogle Scholar
  11. Dujon B (1981) Mitochondrial genetics and functions. In: Strathern JN, Jones EW, Broach JR (eds) Molecular biology of the yeast Saccharomyces: life cycle and inheritance. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, pp 505–635Google Scholar
  12. Dunn B, Wobbe CR (2001) Preparation of protein extracts from yeast. Curr Protoc Mol Biol. doi: 10.1002/0471142727.mb1313s23
  13. Epstein CB, Waddle JA, Hale WT, Dave V, Thornton J et al (2001) Genome-wide responses to mitochondrial dysfunction. Mol Biol Cell 12:297–308CrossRefPubMedPubMedCentralGoogle Scholar
  14. Fendt SM, Sauer U (2010) Transcriptional regulation of respiration in yeast metabolizing differently repressive carbon substrates. BMC Syst Biol 4:12CrossRefPubMedPubMedCentralGoogle Scholar
  15. Fields SD, Conrad MN, Clarke M (1998) The S. cerevisiae CLU1 and D. discoideum, cluA genes are functional homologues that influence mitochondrial morphology and distribution. J Cell Sci 111:1717–1727PubMedGoogle Scholar
  16. Fields SD, Arana Q, Heuser J, Clark M (2002) Mitochondrial membrane dynamics are altered in cluA- mutants of Dictyostelium. J Muscle Res Cell Motil 23:829–838CrossRefPubMedGoogle Scholar
  17. Friedman JR, Mourier A, Yamada J, McCaffery JM, Nunnari J (2015) MICOS coordinates with respiratory complexes and lipids to establish mitochondrial inner membrane architecture. Elife. doi: 10.7554/eLife.07739
  18. Guaragnella N, Zdralevic M, Lattanzio P, Marzulli D, Pracheil T et al (2013) Yeast growth in raffinose results in resistance to acetic-acid induced programmed cell death mostly due to the activation of the mitochondrial retrograde pathway. Biochem Biophys Acta 1833:2765–2774CrossRefPubMedGoogle Scholar
  19. Hanekamp T, Thorsness MK, Rebbapragada I, Fishe EM, Seebart C et al (2002) Maintenance of mitochondrial morphology is linked to maintenance of the mitochondrial genome in Saccharomyces cerevisiae. Genetics 162:1147–1156PubMedPubMedCentralGoogle Scholar
  20. Hermann GJ, Thatcher JW, Mills JP, Hales KG, Fuller MT et al (1998) Mitochondrial fusion in yeast requires the transmembrane GTPase Fzo1p. J Cell Biol 143:359–373CrossRefPubMedPubMedCentralGoogle Scholar
  21. Ishihara T, Ban-Ishihara R, Maeda M, Matusnaga Y, Ichimura A et al (2015) Dynamics of mitochondrial DNA nucleoids regulated by mitochondrial fission is essential for maintenance of homogeneously active mitochondria during neonatal heart development. Mol Cell Biol 35:211–223CrossRefPubMedGoogle Scholar
  22. Kajander O, Karhunen PJ, Jacobs HT (2002) The relationship between somatic mtDNA rearrangements, human heart disease and aging. Hum Mol Genet 11:317–324CrossRefPubMedGoogle Scholar
  23. Kalifa L, Beutner G, Phadnis N, Sheu SS, Sia EA (2009) Evidence for a role of FEN1 in maintaining mitochondrial DNA integrity. DNA Repair (Amst) 8:1242–1249CrossRefGoogle Scholar
  24. Kanki T, Wang K, Baba M, Bartholomew CR, Lynch-Day MA et al (2009a) A genomic screen for yeast mutants defective in selective mitochondrial autophagy. Mol Biol Cell 20:4730–4738CrossRefPubMedPubMedCentralGoogle Scholar
  25. Kanki T, Wang K, Cao Y, Baba M, Klionsky DJ (2009b) Atg32 is a mitochondrial protein that confers selectivity during mitophagy. Dev Cell 17:98–109CrossRefPubMedPubMedCentralGoogle Scholar
  26. Kanki T, Furukawa K, Yamashita S (2015) Mitophagy in yeast: molecular mechanisms and physiological role. Biochim Biophys Acta 1853:2756–2765CrossRefPubMedGoogle Scholar
  27. Lang A, Peter ATJ, Kornmann B (2015) ER-mitochondria contact sites in yeast: beyond the myth of ERMES. Curr Opin Cell Biol 35:7–12CrossRefPubMedGoogle Scholar
  28. Lea DE, Coulson CA (1949) The distribution of the numbers of mutants in bacterial populations. J Genet 49:264–285CrossRefPubMedGoogle Scholar
  29. Liao X, Butow RA (1993) RTG1 and RTG2: two yeast genes required for a novel path of communication from mitochondria to the nucleus. Cell 72:61–71CrossRefPubMedGoogle Scholar
  30. Liesa M, Palacin M, Zorzano A (2009) Mitochondrial dynamics in health and disease. Physiol Rev 89:799–845CrossRefPubMedGoogle Scholar
  31. Logan DC, Scott I, Tobin AK (2003) The genetic control of plant mitochondrial morphology and dynamics. Plant J 36:500–509CrossRefPubMedGoogle Scholar
  32. Miyakawa I, Nobundo S, Shigeyuki K, Soichi N, Tsuneyoshi K (1987) Isolation of morphologically intact mitochondrial nucleoids from the yeast, Saccharomyces cerevisiae. J. Cell Sci 88:431–439PubMedGoogle Scholar
  33. Miyakawa I, Fumoto S, Kuroiwa T, Sando N (1995) Characterization of DNA-binding proteins involved in the assembly of mitochondrial nucleoids from the yeast, Saccharomyces cerevisiae. Plant Cell Physiol 36:1179–1188PubMedGoogle Scholar
  34. Muller M, Lu K, Reichert AS (2015) Mitophagy and mitochondrial dynamics in Saccharomyces cerevisiae. Biochim Biophys Acta 1853:2766–2774CrossRefPubMedGoogle Scholar
  35. Murley A, Lackner LL, Osman C, West M, Voeltz GK et al (2013) ER-associated mitochondrial division links the distribution of mitochondria and mitochondrial DNA in yeast. eLife 2:e00422CrossRefPubMedPubMedCentralGoogle Scholar
  36. Newman SM, Zelenaya-Troitskaya O, Perlman PS, Butow RA (1996) Analysis of mitochondrial DNA nucleoids in wild-type and a mutant strain of Saccharomyces cerevisiae that lacks the mitochondrial HMG-box protein Abf2p. Nucleic Acids Res 24:386–393CrossRefPubMedPubMedCentralGoogle Scholar
  37. Nunnari J, Suomalainen A (2012) Mitochondria: in sickness and in health. Cell 748:1145–1159CrossRefGoogle Scholar
  38. Odoardi F, Rana M, Broccolini A, Mirabella M, Modoni A et al (2003) Pathogenic role of mtDNA duplications in mitochondrial diseases associated with mtDNA deletions. Am J Med Genet 118A:247–254CrossRefPubMedGoogle Scholar
  39. Okamoto K, Kondo-Okamoto N, Ohsumi Y (2009) A landmark protein essential for mitophagy: Atg32 recruits the autophagic machinery to mitochondria. Autophagy 5:1203–1205CrossRefPubMedGoogle Scholar
  40. Osman C, Noriega TR, Okreglak V, Fung JC, Walter P (2015) Integrity of the yeast mitocondrial genome, but not its distribution and inheritance, relies on mitochondrial fission and fusion. Proc Natl Acad Sci USA 112:E947–E956CrossRefPubMedPubMedCentralGoogle Scholar
  41. Otsuga D, Keegan BR, Brisch E, Thatcher JW, Hermann GJ et al (1998) The dynamin-related GTPase, Dnm1p, controls mitochondrial morphology in yeast. J Cell Biol 143:333–349CrossRefPubMedPubMedCentralGoogle Scholar
  42. Phadnis N, Sia RA, Sia EA (2005) Analysis of repeat-mediated deletions in the mitochondrial genome of Saccharomyces cerevisiae. Genetics 171:1549–1559CrossRefPubMedPubMedCentralGoogle Scholar
  43. Rampelt H, Zerbes RM, van der Laan M, Pfanner N (2017) Role of the mitochondrial contact site and cristae organizing system in membrane architecture and dynamics. Biochim Biophys Acta 1864:737–746CrossRefPubMedGoogle Scholar
  44. Shintani T, Huang WP, Stromhaug PE, Klionsky DJ (2002) Mechanism of cargo selection in the cytoplasm to vacuole targeting pathway. Dev Cell 3:825–837CrossRefPubMedPubMedCentralGoogle Scholar
  45. Shoubridge EA (2001) Nuclear genetic defects of oxidative phosphorylation. Hum Mol Genet 10:2277–2284CrossRefPubMedGoogle Scholar
  46. Sia EA, Butler CA, Dominska M, Greenwell P, Fox TD et al (2000) Analysis of microsatellite mutations in the mitochondrial DNA of Saccharomyces cerevisae. Proc Natl Acad Sci USA 97:250–255CrossRefPubMedPubMedCentralGoogle Scholar
  47. Solans A, Zambrano A, Rodriguez M, Barrientos A (2006) Cytotoxicity of a mutant huntingtin fragment in yeast involves early alterations in mitochondrial OXPHOS complexes II and III. Hum Mol Genet 15:3063–3081CrossRefPubMedGoogle Scholar
  48. Sor F, Fukuhara H (1982) Identification of two erythromycin resistance mutations in the mitochondrial gene coding for the large ribosomal RNA in yeast. Nucleic Acids Res 10:6571–6577CrossRefPubMedPubMedCentralGoogle Scholar
  49. Steele DF, Butler CA, Fox TD (1996) Expression of a recoded nuclear gene inserted into yeast mitochondrial DNA is limited by mRNA-specific translational activation. Proc Natl Acad Sci USA 93:5253–5257CrossRefPubMedPubMedCentralGoogle Scholar
  50. Stein A, Kalifa L, Sia EA (2015) Members of the RAD52 epistasis group contribute to mitochondrial homologous recombination and double-strand break repair in Saccharomyces cerevisiae. PLoS Genet 11:e1005664CrossRefPubMedPubMedCentralGoogle Scholar
  51. Trifunovic A, Wredenberg A, Falkenberg M, Spelbrink JN, Rovio AT et al (2004) Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature 429:417–421CrossRefPubMedGoogle Scholar
  52. Vornlocher HP, Hanachi P, Ribeiro S, Hershey JWB (1999) A 110-Kilodalton subunit of translation initiation factor eIF3 and an associated 135-kilodalton protein are encoded by the Saccharomyces cerevisiae TIF32 and TIF31 genes. J Biol Chem 274:16802–16812CrossRefPubMedGoogle Scholar
  53. Wagener J (2016) Regulation of mitochondrial inner membrane fusion: divergent evolution with similar solutions? Curr Genet 62:291–294CrossRefPubMedGoogle Scholar
  54. Wai T, Langer T (2016) Mitochondrial dynamics and metabolic regulation. Trends Endocrin Metab 27:105–117CrossRefGoogle Scholar
  55. Williamson DH (1976) Packaging and recombination of mitochondrial DNA in vegetatively growing cells. In: Bandlow W, Schweyen RJ, Thomas DY, Wolf TK, Kaudewitz F (eds) Genetics, biogenesis and bioenergetics of mitochondria. Walter de Gruyter, Berlin, pp 99–115Google Scholar
  56. Zeviani M, Spinazzola A, Carelli V (2003) Nuclear genes in mitochondrial disorders. Curr Opin Genet Dev 13:262–270CrossRefPubMedGoogle Scholar
  57. Zhao J, Lendahl U, Nister M (2013) Regulation of mitochondrial dynamics: convergences and divergences between yeast and vertebrates. Cell Mol Life Sci 70:951–976CrossRefPubMedGoogle Scholar
  58. Zhu Q, Hulen D, Liu T, Clarke M (1997) The cluA-mutant of Dictyostelium identifies a novel class of proteins required for dispersion of mitochondria. Proc Natl Acad Sci 94:7308–7313CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Christopher T. Prevost
    • 1
    • 2
  • Nicole Peris
    • 2
  • Christina Seger
    • 2
  • Deanna R. Pedeville
    • 2
  • Kathryn Wershing
    • 2
  • Elaine A. Sia
    • 1
    Email author
  • Rey A. L. Sia
    • 2
    Email author
  1. 1.Department of BiologyUniversity of RochesterRochesterUSA
  2. 2.Department of Biology, The College at BrockportState University of New YorkBrockportUSA

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