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Malena, Adriana (2008) Mitochondrial DNA heteroplasmy in muscle cybrids harbouring A3243G Melas mutation. [Tesi di dottorato]

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Abstract (inglese)

The maternally inherited mitochondrial DNA (mtDNA) A3243G point mutation, in tRNALeu(UUR) gene is associated with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), but it has also been detected in other pathologies, such as cardiomyopathy, maternally inherited diabetes with deafness (MIDD) and progressive external ophtalmoplegia (PEO). Despite the knowledge of the genetic defect that impairs mitochondrial protein synthesis and thereby compromises respiration, a complete understanding of the pathogenesis of MELAS remains elusive. Every cell contains multiple copies of mtDNA and in cells and tissues of patients with this syndrome, mutant and wild-type mtDNA molecules coexist (heteroplasmy).
Clinical status of human mitochondrial disorders associated with heteroplasmic mtDNA mutations is greatly dependent on the residual amount of wild-type mtDNA molecules. No clinical symptoms or biochemical respiratory chain defects are detected above a relatively low threshold of wild-type mtDNA proportion. A "selective advantage" or "dominant factor" of mutant mtDNA molecules is known. In this work we aimed to: i) verify different conditions able to modify the percentage of mutant mtDNA in vitro; ii) try to understand why mutant mtDNA molecules had a selective advantage in cultured muscle cells.
At first heteroplasmic cybrids with a muscular nuclear background harbouring MELAS mutation (RD cybrids) have been established. Different growth regimes (antioxidant supplementation, creatine, uridine, low glucose) were tested to verify an influence on percentage of MELAS mutation, but all failed.
In this work we substantiated the greater survival of muscular heteroplasmic 83% and 92% MELAS cybrids compared to homoplasmic 0% and 99% cells, in energetic stress conditions (5mM glucose instead of 25mM glucose). Physiological, biochemical and molecular analysis indicated that cells with an intermediate mutant load presented an increase of their bioenergetic anaerobic and aerobic pathways. This probably helps the cells to better survive in energetic stress as shown by growth rate and RCR values, concomitant to a reduced ROS generation.
Mitochondrial fusion was favoured through the downregulation of Drp1 and hFis1, proteins involved in mitochondrial fission, using RNAi method. Surprisingly mitochondrial fusion determined the increase of mutant mtDNA molecules in some clones. This result shows that mitochondrial fusion favours mutant mtDNA molecules that are dominant on wild-type in a muscle nuclear background.

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Tipo di EPrint:Tesi di dottorato
Relatore:Vergani, Lodovica
Dottorato (corsi e scuole):Ciclo 20 > Scuole per il 20simo ciclo > SCIENZE MEDICHE, CLINICHE E SPERIMENTALI > NEUROSCIENZE
Data di deposito della tesi:Gennaio 2008
Anno di Pubblicazione:Gennaio 2008
Parole chiave (italiano / inglese):MELAS, cybrids, heteroplasmy, mitochondrial DNA
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/26 Neurologia
Struttura di riferimento:Dipartimenti > Dipartimento di Neuroscienze
Codice ID:725
Depositato il:08 Ott 2008
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1. Wallace DC (1999) Mitochondrial diseases in man and mouse. Science 283:1482-1488 Cerca con Google

2. Gray MW, Burger G, Lang BF (1999) Mitochondrial evolution. Science 283:1476-1481 Cerca con Google

3. Ernster L, Schatz G (1981) Mitochondria: a historical review. J Cell Biol 91:227s-255s Cerca con Google

4. Duchen MR (2004) Mitochondria in health and disease: perspectives on a new mitochondrial biology. Mol Aspects Med 25:365-451 Cerca con Google

5. Chipuk JE, Bouchier-Hayes L, Green DR (2006) Mitochondrial outer membrane permeabilization during apoptosis: the innocent bystander scenario. Cell Death Differ 13:1396-1402 Cerca con Google

6. Frey TG, Mannella CA (2000) The internal structure of mitochondria. Trends Biochem Sci 25:319-324 Cerca con Google

7. Scheffler IE (2001) Mitochondria make a come back. Adv Drug Deliv Rev 49:3-26 Cerca con Google

8. Zeviani M, Di DS (2004) Mitochondrial disorders. Brain 127:2153-2172 Cerca con Google

9. Smeitink J, van den HL, DiMauro S (2001) The genetics and pathology of oxidative phosphorylation. Nat Rev Genet 2:342-352 Cerca con Google

10. Carroll J, Fearnley IM, Shannon RJ, Hirst J, Walker JE (2003) Analysis of the subunit composition of complex I from bovine heart mitochondria. Mol Cell Proteomics 2:117-126 Cerca con Google

11. Saraste M (1999) Oxidative phosphorylation at the fin de siecle. Science 283:1488-1493 Cerca con Google

12. Di DS (2000) Disorders related to mitochondrial membranes: pathology of the respiratory chain and neurodegeneration. J Inherit Metab Dis 23:247-263 Cerca con Google

13. Poyton RO, McEwen JE (1996) Crosstalk between nuclear and mitochondrial genomes. Annu Rev Biochem 65:563-607 Cerca con Google

14. Nass MM (1966) The circularity of mitochondrial DNA. Proc Natl Acad Sci U S A 56:1215-1222 Cerca con Google

15. Goto Y (2001) Clinical and molecular studies of mitochondrial disease. J Inherit Metab Dis 24:181-188 Cerca con Google

16. Reynier P, May-Panloup P, Chretien MF, Morgan CJ, Jean M, Savagner F, Barriere P, Malthiery Y (2001) Mitochondrial DNA content affects the fertilizability of human oocytes. Mol Hum Reprod 7:425-429 Cerca con Google

17. Fernandez-Silva P, Enriquez JA, Montoya J (2003) Replication and transcription of mammalian mitochondrial DNA. Exp Physiol 88:41-56 Cerca con Google

18. Lightowlers RN, Chinnery PF, Turnbull DM, Howell N (1997) Mammalian mitochondrial genetics: heredity, heteroplasmy and disease. Trends Genet 13:450-455 Cerca con Google

19. Jacobs LJ, de WG, Geraedts JP, de C, I, Smeets HJ (2006) The transmission of OXPHOS disease and methods to prevent this. Hum Reprod Update 12:119-136 Cerca con Google

20. Ames BN (1989) Endogenous oxidative DNA damage, aging, and cancer. Free Radic Res Commun 7:121-128 Cerca con Google

21. Richter C, Park JW, Ames BN (1988) Normal oxidative damage to mitochondrial and nuclear DNA is extensive. Proc Natl Acad Sci U S A 85:6465-6467 Cerca con Google

22. Shibata T, Ling F (2007) DNA recombination protein-dependent mechanism of homoplasmy and its proposed functions. Mitochondrion 7:17-23 Cerca con Google

23. Poulton J, Marchington DR (2002) Segregation of mitochondrial DNA (mtDNA) in human oocytes and in animal models of mtDNA disease: clinical implications. Reproduction 123:751-755 Cerca con Google

24. Sato A, Endo H, Umetsu K, Sone H, Yanagisawa Y, Saigusa A, Aita S, Kagawa Y (2003) Polymorphism, heteroplasmy, mitochondrial fusion and diabetes. Biosci Rep 23:313-337 Cerca con Google

25. Battersby BJ, Loredo-Osti JC, Shoubridge EA (2003) Nuclear genetic control of mitochondrial DNA segregation. Nat Genet 33:183-186 Cerca con Google

26. Yoneda M, Chomyn A, Martinuzzi A, Hurko O, Attardi G (1992) Marked replicative advantage of human mtDNA carrying a point mutation that causes the MELAS encephalomyopathy. Proc Natl Acad Sci U S A 89:11164-11168 Cerca con Google

27. Dunbar DR, Moonie PA, Jacobs HT, Holt IJ (1995) Different cellular backgrounds confer a marked advantage to either mutant or wild-type mitochondrial genomes. Proc Natl Acad Sci U S A 92:6562-6566 Cerca con Google

28. Yoneda M, Miyatake T, Attardi G (1994) Complementation of mutant and wild-type human mitochondrial DNAs coexisting since the mutation event and lack of complementation of DNAs introduced separately into a cell within distinct organelles. Mol Cell Biol 14:2699-2712 Cerca con Google

29. Nakada K, Inoue K, Ono T, Isobe K, Ogura A, Goto YI, Nonaka I, Hayashi JI (2001) Inter-mitochondrial complementation: Mitochondria-specific system preventing mice from expression of disease phenotypes by mutant mtDNA. Nat Med 7:934-940 Cerca con Google

30. Hoppins S, Lackner L, Nunnari J (2007) The machines that divide and fuse mitochondria. Annu Rev Biochem 76:751-780 Cerca con Google

31. Rube DA, van der Bliek AM (2004) Mitochondrial morphology is dynamic and varied. Mol Cell Biochem 256-257:331-339 Cerca con Google

32. Chen H, Chan DC (2005) Emerging functions of mammalian mitochondrial fusion and fission. Hum Mol Genet 14 Spec No. 2:R283-R289 Cerca con Google

33. Praefcke GJ, McMahon HT (2004) The dynamin superfamily: universal membrane tubulation and fission molecules? Nat Rev Mol Cell Biol 5:133-147 Cerca con Google

34. Klockow B, Tichelaar W, Madden DR, Niemann HH, Akiba T, Hirose K, Manstein DJ (2002) The dynamin A ring complex: molecular organization and nucleotide-dependent conformational changes. EMBO J 21:240-250 Cerca con Google

35. Hinshaw JE (2000) Dynamin and its role in membrane fission. Annu Rev Cell Dev Biol 16:483-519 Cerca con Google

36. Muhlberg AB, Warnock DE, Schmid SL (1997) Domain structure and intramolecular regulation of dynamin GTPase. EMBO J 16:6676-6683 Cerca con Google

37. Smirnova E, Shurland DL, Ryazantsev SN, van der Bliek AM (1998) A human dynamin-related protein controls the distribution of mitochondria. J Cell Biol 143:351-358 Cerca con Google

38. Smirnova E, Griparic L, Shurland DL, van der Bliek AM (2001) Dynamin-related protein Drp1 is required for mitochondrial division in mammalian cells. Mol Biol Cell 12:2245-2256 Cerca con Google

39. Yoon Y, Pitts KR, McNiven MA (2001) Mammalian dynamin-like protein DLP1 tubulates membranes. Mol Biol Cell 12:2894-2905 Cerca con Google

40. Fukushima NH, Brisch E, Keegan BR, Bleazard W, Shaw JM (2001) The GTPase effector domain sequence of the Dnm1p GTPase regulates self-assembly and controls a rate-limiting step in mitochondrial fission. Mol Biol Cell 12:2756-2766 Cerca con Google

41. Jahani-Asl A, Slack RS (2007) The phosphorylation state of Drp1 determines cell fate. EMBO Rep 8:912-913 Cerca con Google

42. Ingerman E, Perkins EM, Marino M, Mears JA, McCaffery JM, Hinshaw JE, Nunnari J (2005) Dnm1 forms spirals that are structurally tailored to fit mitochondria. J Cell Biol 170:1021-1027 Cerca con Google

43. Cerveny KL, Tamura Y, Zhang Z, Jensen RE, Sesaki H (2007) Regulation of mitochondrial fusion and division. Trends Cell Biol 17:563-569 Cerca con Google

44. Chang CR, Blackstone C (2007) Cyclic AMP-dependent protein kinase phosphorylation of Drp1 regulates its GTPase activity and mitochondrial morphology. J Biol Chem 282:21583-21587 Cerca con Google

45. Karbowski M, Neutzner A, Youle RJ (2007) The mitochondrial E3 ubiquitin ligase MARCH5 is required for Drp1 dependent mitochondrial division. J Cell Biol 178:71-84 Cerca con Google

46. Harder Z, Zunino R, McBride H (2004) Sumo1 conjugates mitochondrial substrates and participates in mitochondrial fission. Curr Biol 14:340-345 Cerca con Google

47. Di BA, Ouyang J, Lee HY, Catic A, Ploegh H, Gill G (2006) The SUMO-specific protease SENP5 is required for cell division. Mol Cell Biol 26:4489-4498 Cerca con Google

48. Wasiak S, Zunino R, McBride HM (2007) Bax/Bak promote sumoylation of DRP1 and its stable association with mitochondria during apoptotic cell death. J Cell Biol 177:439-450 Cerca con Google

49. Arnoult D, Rismanchi N, Grodet A, Roberts RG, Seeburg DP, Estaquier J, Sheng M, Blackstone C (2005) Bax/Bak-dependent release of DDP/TIMM8a promotes Drp1-mediated mitochondrial fission and mitoptosis during programmed cell death. Curr Biol 15:2112-2118 Cerca con Google

50. Yoon Y, Krueger EW, Oswald BJ, McNiven MA (2003) The mitochondrial protein hFis1 regulates mitochondrial fission in mammalian cells through an interaction with the dynamin-like protein DLP1. Mol Cell Biol 23:5409-5420 Cerca con Google

51. Mozdy AD, McCaffery JM, Shaw JM (2000) Dnm1p GTPase-mediated mitochondrial fission is a multi-step process requiring the novel integral membrane component Fis1p. J Cell Biol 151:367-380 Cerca con Google

52. James DI, Parone PA, Mattenberger Y, Martinou JC (2003) hFis1, a novel component of the mammalian mitochondrial fission machinery. J Biol Chem 278:36373-36379 Cerca con Google

53. Suzuki M, Jeong SY, Karbowski M, Youle RJ, Tjandra N (2003) The solution structure of human mitochondria fission protein Fis1 reveals a novel TPR-like helix bundle. J Mol Biol 334:445-458 Cerca con Google

54. Suzuki M, Neutzner A, Tjandra N, Youle RJ (2005) Novel structure of the N terminus in yeast Fis1 correlates with a specialized function in mitochondrial fission. J Biol Chem 280:21444-21452 Cerca con Google

55. Karren MA, Coonrod EM, Anderson TK, Shaw JM (2005) The role of Fis1p-Mdv1p interactions in mitochondrial fission complex assembly. J Cell Biol 171:291-301 Cerca con Google

56. Yu T, Fox RJ, Burwell LS, Yoon Y (2005) Regulation of mitochondrial fission and apoptosis by the mitochondrial outer membrane protein hFis1. J Cell Sci 118:4141-4151 Cerca con Google

57. Tieu Q, Nunnari J (2000) Mdv1p is a WD repeat protein that interacts with the dynamin-related GTPase, Dnm1p, to trigger mitochondrial division. J Cell Biol 151:353-366 Cerca con Google

58. Cerveny KL, Jensen RE (2003) The WD-repeats of Net2p interact with Dnm1p and Fis1p to regulate division of mitochondria. Mol Biol Cell 14:4126-4139 Cerca con Google

59. Tieu Q, Okreglak V, Naylor K, Nunnari J (2002) The WD repeat protein, Mdv1p, functions as a molecular adaptor by interacting with Dnm1p and Fis1p during mitochondrial fission. J Cell Biol 158:445-452 Cerca con Google

60. Naylor K, Ingerman E, Okreglak V, Marino M, Hinshaw JE, Nunnari J (2006) Mdv1 interacts with assembled dnm1 to promote mitochondrial division. J Biol Chem 281:2177-2183 Cerca con Google

61. Griffin EE, Graumann J, Chan DC (2005) The WD40 protein Caf4p is a component of the mitochondrial fission machinery and recruits Dnm1p to mitochondria. J Cell Biol 170:237-248 Cerca con Google

62. Karbowski M, Jeong SY, Youle RJ (2004) Endophilin B1 is required for the maintenance of mitochondrial morphology. J Cell Biol 166:1027-1039 Cerca con Google

63. Niemann A, Ruegg M, La P, V, Schenone A, Suter U (2005) Ganglioside-induced differentiation associated protein 1 is a regulator of the mitochondrial network: new implications for Charcot-Marie-Tooth disease. J Cell Biol 170:1067-1078 Cerca con Google

64. Messerschmitt M, Jakobs S, Vogel F, Fritz S, Dimmer KS, Neupert W, Westermann B (2003) The inner membrane protein Mdm33 controls mitochondrial morphology in yeast. J Cell Biol 160:553-564 Cerca con Google

65. Tondera D, Czauderna F, Paulick K, Schwarzer R, Kaufmann J, Santel A (2005) The mitochondrial protein MTP18 contributes to mitochondrial fission in mammalian cells. J Cell Sci 118:3049-3059 Cerca con Google

66. Sesaki H, Southard SM, Yaffe MP, Jensen RE (2003) Mgm1p, a dynamin-related GTPase, is essential for fusion of the mitochondrial outer membrane. Mol Biol Cell 14:2342-2356 Cerca con Google

67. Santel A, Fuller MT (2001) Control of mitochondrial morphology by a human mitofusin. J Cell Sci 114:867-874 Cerca con Google

68. Chen H, Detmer SA, Ewald AJ, Griffin EE, Fraser SE, Chan DC (2003) Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development. J Cell Biol 160:189-200 Cerca con Google

69. Cipolat S, Martins de BO, Dal ZB, Scorrano L (2004) OPA1 requires mitofusin 1 to promote mitochondrial fusion. Proc Natl Acad Sci U S A 101:15927-15932 Cerca con Google

70. Kijima K, Numakura C, Izumino H, Umetsu K, Nezu A, Shiiki T, Ogawa M, Ishizaki Y, Kitamura T, Shozawa Y, Hayasaka K (2005) Mitochondrial GTPase mitofusin 2 mutation in Charcot-Marie-Tooth neuropathy type 2A. Hum Genet 116:23-27 Cerca con Google

71. Baloh RH, Schmidt RE, Pestronk A, Milbrandt J (2007) Altered axonal mitochondrial transport in the pathogenesis of Charcot-Marie-Tooth disease from mitofusin 2 mutations. J Neurosci 27:422-430 Cerca con Google

72. Detmer SA, Chan DC (2007) Complementation between mouse Mfn1 and Mfn2 protects mitochondrial fusion defects caused by CMT2A disease mutations. J Cell Biol 176:405-414 Cerca con Google

73. Cereghetti GM, Scorrano L (2006) The many shapes of mitochondrial death. Oncogene 25:4717-4724 Cerca con Google

74. Youle RJ, Karbowski M (2005) Mitochondrial fission in apoptosis. Nat Rev Mol Cell Biol 6:657-663 Cerca con Google

75. Karbowski M, Lee YJ, Gaume B, Jeong SY, Frank S, Nechushtan A, Santel A, Fuller M, Smith CL, Youle RJ (2002) Spatial and temporal association of Bax with mitochondrial fission sites, Drp1, and Mfn2 during apoptosis. J Cell Biol 159:931-938 Cerca con Google

76. Eura Y, Ishihara N, Oka T, Mihara K (2006) Identification of a novel protein that regulates mitochondrial fusion by modulating mitofusin (Mfn) protein function. J Cell Sci 119:4913-4925 Cerca con Google

77. Hajek P, Chomyn A, Attardi G (2007) Identification of a novel mitochondrial complex containing mitofusin 2 and stomatin-like protein 2. J Biol Chem 282:5670-5681 Cerca con Google

78. Griparic L, van der Wel NN, Orozco IJ, Peters PJ, van der Bliek AM (2004) Loss of the intermembrane space protein Mgm1/OPA1 induces swelling and localized constrictions along the lengths of mitochondria. J Biol Chem 279:18792-18798 Cerca con Google

79. Meeusen S, DeVay R, Block J, Cassidy-Stone A, Wayson S, McCaffery JM, Nunnari J (2006) Mitochondrial inner-membrane fusion and crista maintenance requires the dynamin-related GTPase Mgm1. Cell 127:383-395 Cerca con Google

80. McQuibban GA, Saurya S, Freeman M (2003) Mitochondrial membrane remodelling regulated by a conserved rhomboid protease. Nature 423:537-541 Cerca con Google

81. Herlan M, Vogel F, Bornhovd C, Neupert W, Reichert AS (2003) Processing of Mgm1 by the rhomboid-type protease Pcp1 is required for maintenance of mitochondrial morphology and of mitochondrial DNA. J Biol Chem 278:27781-27788 Cerca con Google

82. Sesaki H, Dunn CD, Iijima M, Shepard KA, Yaffe MP, Machamer CE, Jensen RE (2006) Ups1p, a conserved intermembrane space protein, regulates mitochondrial shape and alternative topogenesis of Mgm1p. J Cell Biol 173:651-658 Cerca con Google

83. Frezza C, Cipolat S, Martins de BO, Micaroni M, Beznoussenko GV, Rudka T, Bartoli D, Polishuck RS, Danial NN, De SB, Scorrano L (2006) OPA1 controls apoptotic cristae remodeling independently from mitochondrial fusion. Cell 126:177-189 Cerca con Google

84. Cipolat S, Rudka T, Hartmann D, Costa V, Serneels L, Craessaerts K, Metzger K, Frezza C, Annaert W, D'Adamio L, Derks C, Dejaegere T, Pellegrini L, D'Hooge R, Scorrano L, De SB (2006) Mitochondrial rhomboid PARL regulates cytochrome c release during apoptosis via OPA1-dependent cristae remodeling. Cell 126:163-175 Cerca con Google

85. Ishihara N, Fujita Y, Oka T, Mihara K (2006) Regulation of mitochondrial morphology through proteolytic cleavage of OPA1. EMBO J 25:2966-2977 Cerca con Google

86. Duvezin-Caubet S, Jagasia R, Wagener J, Hofmann S, Trifunovic A, Hansson A, Chomyn A, Bauer MF, Attardi G, Larsson NG, Neupert W, Reichert AS (2006) Proteolytic processing of OPA1 links mitochondrial dysfunction to alterations in mitochondrial morphology. J Biol Chem 281:37972-37979 Cerca con Google

87. Frey TG, Renken CW, Perkins GA (2002) Insight into mitochondrial structure and function from electron tomography. Biochim Biophys Acta 1555:196-203 Cerca con Google

88. Olichon A, Baricault L, Gas N, Guillou E, Valette A, Belenguer P, Lenaers G (2003) Loss of OPA1 perturbates the mitochondrial inner membrane structure and integrity, leading to cytochrome c release and apoptosis. J Biol Chem 278:7743-7746 Cerca con Google

89. Zeviani M, Carelli V (2007) Mitochondrial disorders. Curr Opin Neurol 20:564-571 Cerca con Google

90. Zeviani M, Spinazzola A, Carelli V (2003) Nuclear genes in mitochondrial disorders. Curr Opin Genet Dev 13:262-270 Cerca con Google

91. Zeviani M, Carelli V (2003) Mitochondrial disorders. Curr Opin Neurol 16:585-594 Cerca con Google

92. Mollers M, Maniura-Weber K, Kiseljakovic E, Bust M, Hayrapetyan A, Jaksch M, Helm M, Wiesner RJ, von Kleist-Retzow JC (2005) A new mechanism for mtDNA pathogenesis: impairment of post-transcriptional maturation leads to severe depletion of mitochondrial tRNASer(UCN) caused by T7512C and G7497A point mutations. Nucleic Acids Res 33:5647-5658 Cerca con Google

93. Mita S, Schmidt B, Schon EA, DiMauro S, Bonilla E (1989) Detection of "deleted" mitochondrial genomes in cytochrome-c oxidase-deficient muscle fibers of a patient with Kearns-Sayre syndrome. Proc Natl Acad Sci U S A 86:9509-9513 Cerca con Google

94. Barkovich AJ, Good WV, Koch TK, Berg BO (1993) Mitochondrial disorders: analysis of their clinical and imaging characteristics. AJNR Am J Neuroradiol 14:1119-1137 Cerca con Google

95. Shoffner JM, Lott MT, Voljavec AS, Soueidan SA, Costigan DA, Wallace DC (1989) Spontaneous Kearns-Sayre/chronic external ophthalmoplegia plus syndrome associated with a mitochondrial DNA deletion: a slip-replication model and metabolic therapy. Proc Natl Acad Sci U S A 86:7952-7956 Cerca con Google

96. Shanske S, Tang Y, Hirano M, Nishigaki Y, Tanji K, Bonilla E, Sue C, Krishna S, Carlo JR, Willner J, Schon EA, DiMauro S (2002) Identical mitochondrial DNA deletion in a woman with ocular myopathy and in her son with pearson syndrome. Am J Hum Genet 71:679-683 Cerca con Google

97. Chen X, Prosser R, Simonetti S, Sadlock J, Jagiello G, Schon EA (1995) Rearranged mitochondrial genomes are present in human oocytes. Am J Hum Genet 57:239-247 Cerca con Google

98. Finsterer J (2007) Genetic, pathogenetic, and phenotypic implications of the mitochondrial A3243G tRNALeu(UUR) mutation. Acta Neurol Scand 116:1-14 Cerca con Google

99. Hirano M, Ricci E, Koenigsberger MR, Defendini R, Pavlakis SG, DeVivo DC, DiMauro S, Rowland LP (1992) Melas: an original case and clinical criteria for diagnosis. Neuromuscul Disord 2:125-135 Cerca con Google

100. Dubeau F, De SN, Zifkin BG, Arnold DL, Shoubridge EA (2000) Oxidative phosphorylation defect in the brains of carriers of the tRNAleu(UUR) A3243G mutation in a MELAS pedigree. Ann Neurol 47:179-185 Cerca con Google

101. Chinnery PF, Howell N, Lightowlers RN, Turnbull DM (1997) Molecular pathology of MELAS and MERRF. The relationship between mutation load and clinical phenotypes. Brain 120 ( Pt 10):1713-1721 Cerca con Google

102. Goto Y, Nonaka I, Horai S (1990) A mutation in the tRNA(Leu)(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies. Nature 348:651-653 Cerca con Google

103. DiMauro S (2004) Mitochondrial diseases. Biochim Biophys Acta 1658:80-88 Cerca con Google

104. Bentlage HA, Attardi G (1996) Relationship of genotype to phenotype in fibroblast-derived transmitochondrial cell lines carrying the 3243 mutation associated with the MELAS encephalomyopathy: shift towards mutant genotype and role of mtDNA copy number. Hum Mol Genet 5:197-205 Cerca con Google

105. Park H, Davidson E, King MP (2003) The pathogenic A3243G mutation in human mitochondrial tRNALeu(UUR) decreases the efficiency of aminoacylation. Biochemistry 42:958-964 Cerca con Google

106. Chomyn A, Enriquez JA, Micol V, Fernandez-Silva P, Attardi G (2000) The mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episode syndrome-associated human mitochondrial tRNALeu(UUR) mutation causes aminoacylation deficiency and concomitant reduced association of mRNA with ribosomes. J Biol Chem 275:19198-19209 Cerca con Google

107. Jacobs HT, Holt IJ (2000) The np 3243 MELAS mutation: damned if you aminoacylate, damned if you don't. Hum Mol Genet 9:463-465 Cerca con Google

108. Suzuki T, Suzuki T, Wada T, Saigo K, Watanabe K (2002) Taurine as a constituent of mitochondrial tRNAs: new insights into the functions of taurine and human mitochondrial diseases. EMBO J 21:6581-6589 Cerca con Google

109. Yasukawa T, Kirino Y, Ishii N, Holt IJ, Jacobs HT, Makifuchi T, Fukuhara N, Ohta S, Suzuki T, Watanabe K (2005) Wobble modification deficiency in mutant tRNAs in patients with mitochondrial diseases. FEBS Lett 579:2948-2952 Cerca con Google

110. Yasukawa T, Suzuki T, Ueda T, Ohta S, Watanabe K (2000) Modification defect at anticodon wobble nucleotide of mitochondrial tRNAs(Leu)(UUR) with pathogenic mutations of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes. J Biol Chem 275:4251-4257 Cerca con Google

111. Yasukawa T, Suzuki T, Ishii N, Ohta S, Watanabe K (2001) Wobble modification defect in tRNA disturbs codon-anticodon interaction in a mitochondrial disease. EMBO J 20:4794-4802 Cerca con Google

112. Chomyn A, Martinuzzi A, Yoneda M, Daga A, Hurko O, Johns D, Lai ST, Nonaka I, Angelini C, Attardi G (1992) MELAS mutation in mtDNA binding site for transcription termination factor causes defects in protein synthesis and in respiration but no change in levels of upstream and downstream mature transcripts. Proc Natl Acad Sci U S A 89:4221-4225 Cerca con Google

113. Lehtinen SK, Hance N, El MA, Juhola MK, Juhola KM, Karhu R, Spelbrink JN, Holt IJ, Jacobs HT (2000) Genotypic stability, segregation and selection in heteroplasmic human cell lines containing np 3243 mutant mtDNA. Genetics 154:363-380 Cerca con Google

114. Shoffner JM, Lott MT, Lezza AM, Seibel P, Ballinger SW, Wallace DC (1990) Myoclonic epilepsy and ragged-red fiber disease (MERRF) is associated with a mitochondrial DNA tRNA(Lys) mutation. Cell 61:931-937 Cerca con Google

115. Wallace DC, Zheng XX, Lott MT, Shoffner JM, Hodge JA, Kelley RI, Epstein CM, Hopkins LC (1988) Familial mitochondrial encephalomyopathy (MERRF): genetic, pathophysiological, and biochemical characterization of a mitochondrial DNA disease. Cell 55:601-610 Cerca con Google

116. Austin SA, Vriesendorp FJ, Thandroyen FT, Hecht JT, Jones OT, Johns DR (1998) Expanding the phenotype of the 8344 transfer RNAlysine mitochondrial DNA mutation. Neurology 51:1447-1450 Cerca con Google

117. Holt IJ, Harding AE, Petty RK, Morgan-Hughes JA (1990) A new mitochondrial disease associated with mitochondrial DNA heteroplasmy. Am J Hum Genet 46:428-433 Cerca con Google

118. onisi-Vici C, Seneca S, Zeviani M, Fariello G, Rimoldi M, Bertini E, De ML (1998) Fulminant Leigh syndrome and sudden unexpected death in a family with the T9176C mutation of the mitochondrial ATPase 6 gene. J Inherit Metab Dis 21:2-8 Cerca con Google

119. Carelli V, Baracca A, Barogi S, Pallotti F, Valentino ML, Montagna P, Zeviani M, Pini A, Lenaz G, Baruzzi A, Solaini G (2002) Biochemical-clinical correlation in patients with different loads of the mitochondrial DNA T8993G mutation. Arch Neurol 59:264-270 Cerca con Google

120. Tiranti V, Chariot P, Carella F, Toscano A, Soliveri P, Girlanda P, Carrara F, Fratta GM, Reid FM, Mariotti C, . (1995) Maternally inherited hearing loss, ataxia and myoclonus associated with a novel point mutation in mitochondrial tRNASer(UCN) gene. Hum Mol Genet 4:1421-1427 Cerca con Google

121. Hutchin TP, Cortopassi GA (2000) Mitochondrial defects and hearing loss. Cell Mol Life Sci 57:1927-1937 Cerca con Google

122. Howell N, Mackey DA (1998) Low-penetrance branches in matrilineal pedigrees with Leber hereditary optic neuropathy. Am J Hum Genet 63:1220-1224 Cerca con Google

123. Wallace DC, Singh G, Lott MT, Hodge JA, Schurr TG, Lezza AM, Elsas LJ, Nikoskelainen EK (1988) Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy. Science 242:1427-1430 Cerca con Google

124. Chinnery PF, Turnbull DM (2001) Epidemiology and treatment of mitochondrial disorders. Am J Med Genet 106:94-101 Cerca con Google

125. Estivill X, Govea N, Barcelo E, Badenas C, Romero E, Moral L, Scozzri R, D'Urbano L, Zeviani M, Torroni A (1998) Familial progressive sensorineural deafness is mainly due to the mtDNA A1555G mutation and is enhanced by treatment of aminoglycosides. Am J Hum Genet 62:27-35 Cerca con Google

126. DiMauro S, Davidzon G (2005) Mitochondrial DNA and disease. Ann Med 37:222-232 Cerca con Google

127. King MP, Attardi G (1989) Human cells lacking mtDNA: repopulation with exogenous mitochondria by complementation. Science 246:500-503 Cerca con Google

128. King MP, Attardi G (1996) Isolation of human cell lines lacking mitochondrial DNA. Methods Enzymol 264:304-313 Cerca con Google

129. Chomyn A, Lai ST, Shakeley R, Bresolin N, Scarlato G, Attardi G (1994) Platelet-mediated transformation of mtDNA-less human cells: analysis of phenotypic variability among clones from normal individuals--and complementation behavior of the tRNALys mutation causing myoclonic epilepsy and ragged red fibers. Am J Hum Genet 54:966-974 Cerca con Google

130. Khan SM, Smigrodzki RM, Swerdlow RH (2007) Cell and animal models of mtDNA biology: progress and prospects. Am J Physiol Cell Physiol 292:C658-C669 Cerca con Google

131. Vergani L, Prescott AR, Holt IJ (2000) Rhabdomyosarcoma rho(0) cells: isolation and characterization of a mitochondrial DNA depleted cell line with 'muscle-like' properties. Neuromuscul Disord 10:454-459 Cerca con Google

132. D'Autreaux B, Toledano MB (2007) ROS as signalling molecules: mechanisms that generate specificity in ROS homeostasis. Nat Rev Mol Cell Biol 8:813-824 Cerca con Google

133. Bunik VI, Schloss JV, Pinto JT, Gibson GE, Cooper AJ (2007) Enzyme-catalyzed side reactions with molecular oxygen may contribute to cell signaling and neurodegenerative diseases. Neurochem Res 32:871-891 Cerca con Google

134. Hansford RG, Hogue BA, Mildaziene V (1997) Dependence of H2O2 formation by rat heart mitochondria on substrate availability and donor age. J Bioenerg Biomembr 29:89-95 Cerca con Google

135. Cross AR, Jones OT (1991) Enzymic mechanisms of superoxide production. Biochim Biophys Acta 1057:281-298 Cerca con Google

136. Berridge MV, Tan AS (2000) Cell-surface NAD(P)H-oxidase: relationship to trans-plasma membrane NADH-oxidoreductase and a potential source of circulating NADH-oxidase. Antioxid Redox Signal 2:277-288 Cerca con Google

137. Morel Y, Barouki R (1999) Repression of gene expression by oxidative stress. Biochem J 342 Pt 3:481-496 Cerca con Google

138. Ischiropoulos H, Beckman JS (2003) Oxidative stress and nitration in neurodegeneration: cause, effect, or association? J Clin Invest 111:163-169 Cerca con Google

139. Mates JM, Sanchez-Jimenez F (1999) Antioxidant enzymes and their implications in pathophysiologic processes. Front Biosci 4:D339-D345 Cerca con Google

140. Fridovich I (1995) Superoxide radical and superoxide dismutases. Annu Rev Biochem 64:97-112 Cerca con Google

141. Balendiran GK, Dabur R, Fraser D (2004) The role of glutathione in cancer. Cell Biochem Funct 22:343-352 Cerca con Google

142. Rhee SG (2006) Cell signaling. H2O2, a necessary evil for cell signaling. Science 312:1882-1883 Cerca con Google

143. Pizzorno G, Cao D, Leffert JJ, Russell RL, Zhang D, Handschumacher RE (2002) Homeostatic control of uridine and the role of uridine phosphorylase: a biological and clinical update. Biochim Biophys Acta 1587:133-144 Cerca con Google

144. Connolly GP, Duley JA (1999) Uridine and its nucleotides: biological actions, therapeutic potentials. Trends Pharmacol Sci 20:218-225 Cerca con Google

145. Connolly GP, Simmonds HA, Duley JA (1996) Pyrimidines and CNS regulation. Trends Pharmacol Sci 17:106-107 Cerca con Google

146. Aussedat J (1983) Effect of uridine supply on glycogen resynthesis after ischaemia in the isolated perfused rat heart. Cardiovasc Res 17:145-151 Cerca con Google

147. Hultman E, Soderlund K, Timmons JA, Cederblad G, Greenhaff PL (1996) Muscle creatine loading in men. J Appl Physiol 81:232-237 Cerca con Google

148. Klivenyi P, Ferrante RJ, Matthews RT, Bogdanov MB, Klein AM, Andreassen OA, Mueller G, Wermer M, Kaddurah-Daouk R, Beal MF (1999) Neuroprotective effects of creatine in a transgenic animal model of amyotrophic lateral sclerosis. Nat Med 5:347-350 Cerca con Google

149. Vergani L, Malena A, Sabatelli P, Loro E, Cavallini L, Magalhaes P, Valente L, Bragantini F, Carrara F, Leger B, Poulton J, Russell AP, Holt IJ (2007) Cultured muscle cells display defects of mitochondrial myopathy ameliorated by anti-oxidants. Brain 130:2715-2724 Cerca con Google

150. Rychahou PG, Jackson LN, Farrow BJ, Evers BM (2006) RNA interference: mechanisms of action and therapeutic consideration. Surgery 140:719-725 Cerca con Google

151. Hannon GJ, Rossi JJ (2004) Unlocking the potential of the human genome with RNA interference. Nature 431:371-378 Cerca con Google

152. Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116:281-297 Cerca con Google

153. Taylor RW, Chinnery PF, Turnbull DM, Lightowlers RN (1997) Selective inhibition of mutant human mitochondrial DNA replication in vitro by peptide nucleic acids. Nat Genet 15:212-215 Cerca con Google

154. Heddi A, Stepien G, Benke PJ, Wallace DC (1999) Coordinate induction of energy gene expression in tissues of mitochondrial disease patients. J Biol Chem 274:22968-22976 Cerca con Google

155. Patterson MK, Jr. (1979) Measurement of growth and viability of cells in culture. Methods Enzymol 58:141-152 Cerca con Google

156. King MP, Attadi G (1996) Mitochondria-mediated transformation of human rho(0) cells. Methods Enzymol 264:313-334 Cerca con Google

157. Ling KH, Lardy H (1959) p 306 Cerca con Google

158. Kornberg A (1955) Lactic dehydrogenase of muscle. pp 441-443 Cerca con Google

159. King TE, Howard RL (1967) pp 52-58 Cerca con Google

160. Angelini C, Bresolin N, Pegolo G, Bet L, Rinaldo P, Trevisan C, Vergani L (1986) Childhood encephalomyopathy with cytochrome c oxidase deficiency, ataxia, muscle wasting, and mental impairment. Neurology 36:1048-1052 Cerca con Google

161. Srere PA (1969) Citrate synthase. pp 3-5 Cerca con Google

162. Moraes CT, Ricci E, Bonilla E, DiMauro S, Schon EA (1992) The mitochondrial tRNA(Leu(UUR)) mutation in mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS): genetic, biochemical, and morphological correlations in skeletal muscle. Am J Hum Genet 50:934-949 Cerca con Google

163. Laemmli UK (1970) Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227:680-685 Cerca con Google

164. Lee S, Jeong SY, Lim WC, Kim S, Park YY, Sun X, Youle RJ, Cho H (2007) Mitochondrial fission and fusion mediators, hFis1 and OPA1, modulate cellular senescence. J Biol Chem 282:22977-22983 Cerca con Google

165. Benard G, Bellance N, James D, Parrone P, Fernandez H, Letellier T, Rossignol R (2007) Mitochondrial bioenergetics and structural network organization. J Cell Sci 120:838-848 Cerca con Google

166. WARBURG O (1956) On the origin of cancer cells. Science 123:309-314 Cerca con Google

167. Xu RH, Pelicano H, Zhou Y, Carew JS, Feng L, Bhalla KN, Keating MJ, Huang P (2005) Inhibition of glycolysis in cancer cells: a novel strategy to overcome drug resistance associated with mitochondrial respiratory defect and hypoxia. Cancer Res 65:613-621 Cerca con Google

168. Galluzzi L, Larochette N, Zamzami N, Kroemer G (2006) Mitochondria as therapeutic targets for cancer chemotherapy. Oncogene 25:4812-4830 Cerca con Google

169. Carew JS, Huang P (2002) Mitochondrial defects in cancer. Mol Cancer 1:9 Cerca con Google

170. Maiuri MC, Zalckvar E, Kimchi A, Kroemer G (2007) Self-eating and self-killing: crosstalk between autophagy and apoptosis. Nat Rev Mol Cell Biol 8:741-752 Cerca con Google

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