Stem Cell Reviews and Reports

, Volume 5, Issue 2, pp 140–158 | Cite as

The Relationship Between Pluripotency and Mitochondrial DNA Proliferation During Early Embryo Development and Embryonic Stem Cell Differentiation

  • J. M. Facucho-Oliveira
  • J. C. St. JohnEmail author


Pluripotent blastomeres of mammalian pre-implantation embryos and embryonic stem cells (ESCs) are characterized by limited oxidative capacity and great reliance on anaerobic respiration. Early pre-implantation embryos and undifferentiated ESCs possess small and immature mitochondria located around the nucleus, have low oxygen consumption and express high levels of glycolytic enzymes. However, as embryonic cells and ESCs lose pluripotency and commit to a specific cell fate, the expression of mtDNA transcription and replication factors is upregulated and the number of mitochondria and mtDNA copies/cell increases. Moreover, upon cellular differentiation, mitochondria acquire an elongated morphology with swollen cristae and dense matrices, migrate into wider cytoplasmic areas and increase the levels of oxygen consumption and ATP production as a result of the activation of the more efficient, aerobic metabolism. Since pluripotency seems to be associated with anaerobic metabolism and a poorly developed mitochondrial network and differentiation leads to activation of mitochondrial biogenesis according to the metabolic requirements of the specific cell type, it is hypothesized that reprogramming of somatic cells towards a pluripotent state, by somatic cell nuclear transfer (SCNT), transcription-induced pluripotency or creation of pluripotent cell hybrids, requires acquisition of mitochondrial properties characteristic of pluripotent blastomeres and ESCs.


Mitochondria Mitochondrial DNA Oxidative phosphorylation Pluripotency Embryonic stem cells Pre-implantation embryonic development 



Grant sponsors: this work was supported by British Heart Foundation (PG/04/117) and Fundação para a Ciência e Tecnologia (FCT) Portugal (SFRH/BD/17779/2004).


  1. 1.
    Mitchell, P. (1961). Coupling of phosphorylation to electron and hydrogen transfer by a chemi-osmotic type of mechanism. Nature, 191, 144–148.PubMedCrossRefGoogle Scholar
  2. 2.
    Brown, G. C. (1992). Control of respiration and ATP synthesis in mammalian mitochondria and cells. Biochemical Journal, 284(Pt 1), 1–13.PubMedGoogle Scholar
  3. 3.
    Pfeiffer, T., Schuster, S., & Bonhoeffer, S. (2001). Cooperation and competition in the evolution of ATP-producing pathways. Science, 292, 504–507.PubMedCrossRefGoogle Scholar
  4. 4.
    Cho, Y. M., Kwon, S., Pak, Y. K., et al. (2006). Dynamic changes in mitochondrial biogenesis and antioxidant enzymes during the spontaneous differentiation of human embryonic stem cells. Biochemical and Biophysical Research Communications, 348, 1472–1478.PubMedCrossRefGoogle Scholar
  5. 5.
    St John, J. C., Ramalho-Santos, J., Gray, H. L., et al. (2005). The expression of mitochondrial DNA transcription factors during early cardiomyocyte in vitro differentiation from human embryonic stem cells. Cloning Stem Cells, 7, 141–153.PubMedCrossRefGoogle Scholar
  6. 6.
    Facucho-Oliveira, J. M., Alderson, J., Spikings, E. C., Egginton, S., & St John, J. C. (2007). Mitochondrial DNA replication during differentiation of murine embryonic stem cells. Journal of Cell Science, 120, 4025–4034.PubMedCrossRefGoogle Scholar
  7. 7.
    Chung, S., Dzeja, P. P., Faustino, R. S., Perez-Terzic, C., Behfar, A., & Terzic, A. (2007). Mitochondrial oxidative metabolism is required for the cardiac differentiation of stem cells. Nature Clinical Practice Cardiovascular Medicine, 4(Suppl 1), S60–S67.PubMedCrossRefGoogle Scholar
  8. 8.
    Miller, F. J., Rosenfeldt, F. L., Zhang, C., Linnane, A. W., & Nagley, P. (2003). Precise determination of mitochondrial DNA copy number in human skeletal and cardiac muscle by a PCR-based assay: Lack of change of copy number with age. Nucleic Acids Research, 31, e61.PubMedCrossRefGoogle Scholar
  9. 9.
    Filser, N., Margue, C., & Richter, C. (1997). Quantification of wild-type mitochondrial DNA and its 4.8-kb deletion in rat organs. Biochemical and Biophysical Research Communications, 233, 102–107.PubMedCrossRefGoogle Scholar
  10. 10.
    Erecinska, M., & Silver, I. A. (1989). ATP and brain function. Journal of Cerebral Blood Flow and Metabolism, 9, 2–19.PubMedGoogle Scholar
  11. 11.
    Heineman, F. W., & Balaban, R. S. (1990). Control of mitochondrial respiration in the heart in vivo. Annual Review of Physiology, 52, 523–542.PubMedCrossRefGoogle Scholar
  12. 12.
    Wong-Riley, M. T. (1989). Cytochrome oxidase: An endogenous metabolic marker for neuronal activity. Trends in Neurosciences, 12, 94–101.PubMedCrossRefGoogle Scholar
  13. 13.
    Bjorntorp, P. (1966). The oxidation of fatty acids combined with albumin by isolated rat liver mitochondria. Journal of Biological Chemistry, 241, 1537–1543.PubMedGoogle Scholar
  14. 14.
    Meyerhof, O. (1951). Mechanisms of glycolysis and fermentation. Canadian Journal of Medical Sciences, 29, 63–77.PubMedGoogle Scholar
  15. 15.
    Krebs, H. A., & Johnson, W. A. (1937). Metabolism of ketonic acids in animal tissues. Biochemical Journal, 31, 645–660.PubMedGoogle Scholar
  16. 16.
    Maloney, P. C., Kashket, E. R., & Wilson, T. H. (1974). A protonmotive force drives ATP synthesis in bacteria. Proceedings of the National Academy of Sciences of the United States of America, 71, 3896–3900.PubMedCrossRefGoogle Scholar
  17. 17.
    Anderson, S., Bankier, A. T., Barrell, B. G., et al. (1981). Sequence and organization of the human mitochondrial genome. Nature, 290, 457–465.PubMedCrossRefGoogle Scholar
  18. 18.
    Attardi, G. (1985). Animal mitochondrial DNA: An extreme example of genetic economy. International Review of Cytology, 93, 93–145.PubMedCrossRefGoogle Scholar
  19. 19.
    Clayton, D. A. (1998). Nuclear–mitochondrial intergenomic communication. Biofactors, 7, 203–205.PubMedCrossRefGoogle Scholar
  20. 20.
    Attardi, G., & Schatz, G. (1988). Biogenesis of mitochondria. Annual Review of Cell Biology, 4, 289–333.PubMedCrossRefGoogle Scholar
  21. 21.
    Clayton, D. A. (1982). Replication of animal mitochondrial DNA. Cell, 28, 693–705.PubMedCrossRefGoogle Scholar
  22. 22.
    Anderson, S., de Bruijn, M. H., Coulson, A. R., Eperon, I. C., Sanger, F., & Young, I. G. (1982). Complete sequence of bovine mitochondrial DNA. Conserved features of the mammalian mitochondrial genome. Journal of Molecular Biology, 156, 683–717.PubMedCrossRefGoogle Scholar
  23. 23.
    Hiendleder, S., Lewalski, H., Wassmuth, R., & Janke, A. (1998). The complete mitochondrial DNA sequence of the domestic sheep (Ovis aries) and comparison with the other major ovine haplotype. Journal of Molecular Evolution, 47, 441–448.PubMedCrossRefGoogle Scholar
  24. 24.
    Bibb, M. J., Van Etten, R. A., Wright, C. T., Walberg, M. W., & Clayton, D. A. (1981). Sequence and gene organization of mouse mitochondrial DNA. Cell, 26, 167–180.PubMedCrossRefGoogle Scholar
  25. 25.
    Ojala, D., Montoya, J., & Attardi, G. (1981). tRNA punctuation model of RNA processing in human mitochondria. Nature, 290, 470–474.PubMedCrossRefGoogle Scholar
  26. 26.
    Clayton, D. A. (1992). Transcription and replication of animal mitochondrial DNAs. International Review of Cytology, 41, 217–232.CrossRefGoogle Scholar
  27. 27.
    Fisher, R. P., & Clayton, D. A. (1988). Purification and characterization of human mitochondrial transcription factor 1. Molecular and Cellular Biology, 8, 3496–3509.PubMedGoogle Scholar
  28. 28.
    Fisher, R. P., & Clayton, D. A. (1985). A transcription factor required for promoter recognition by human mitochondrial RNA polymerase. Accurate initiation at the heavy- and light-strand promoters dissected and reconstituted in vitro. Journal of Biological Chemistry, 260, 11330–11338.PubMedGoogle Scholar
  29. 29.
    Tiranti, V., Savoia, A., Forti, F., et al. (1997). Identification of the gene encoding the human mitochondrial RNA polymerase (h-mtRPOL) by cyberscreening of the Expressed Sequence Tags database. Human Molecular Genetics, 6, 615–625.PubMedCrossRefGoogle Scholar
  30. 30.
    Falkenberg, M., Gaspari, M., Rantanen, A., Trifunovic, A., Larsson, N. G., & Gustafsson, C. M. (2002). Mitochondrial transcription factors B1 and B2 activate transcription of human mtDNA. Nature Genetics, 31, 289–294.PubMedCrossRefGoogle Scholar
  31. 31.
    McCulloch, V., Seidel-Rogol, B. L., & Shadel, G. S. (2002). A human mitochondrial transcription factor is related to RNA adenine methyltransferases and binds S-adenosylmethionine. Molecular and Cellular Biology, 22, 1116–1125.PubMedCrossRefGoogle Scholar
  32. 32.
    Daga, A., Micol, V., Hess, D., Aebersold, R., & Attardi, G. (1993). Molecular characterization of the transcription termination factor from human mitochondria. Journal of Biological Chemistry, 268, 8123–8130.PubMedGoogle Scholar
  33. 33.
    Shang, J., & Clayton, D. A. (1994). Human mitochondrial transcription termination exhibits RNA polymerase independence and biased bipolarity in vitro. Journal of Biological Chemistry, 269, 29112–29120.PubMedGoogle Scholar
  34. 34.
    Dairaghi, D. J., Shadel, G. S., & Clayton, D. A. (1995). Addition of a 29 residue carboxyl-terminal tail converts a simple HMG box-containing protein into a transcriptional activator. Journal of Molecular Biology, 249, 11–28.PubMedCrossRefGoogle Scholar
  35. 35.
    Parisi, M. A., & Clayton, D. A. (1991). Similarity of human mitochondrial transcription factor 1 to high mobility group proteins. Science, 252, 965–969.PubMedCrossRefGoogle Scholar
  36. 36.
    Shadel, G. S., & Clayton, D. A. (1997). Mitochondrial DNA maintenance in vertebrates. Annual Review of Biochemistry, 66, 409–435.PubMedCrossRefGoogle Scholar
  37. 37.
    McCulloch, V., & Shadel, G. S. (2003). Human mitochondrial transcription factor B1 interacts with the C-terminal activation region of h-mtTFA and stimulates transcription independently of its RNA methyltransferase activity. Molecular and Cellular Biology, 23, 5816–5824.PubMedCrossRefGoogle Scholar
  38. 38.
    Schubot, F. D., Chen, C. J., Rose, J. P., Dailey, T. A., Dailey, H. A., & Wang, B. C. (2001). Crystal structure of the transcription factor sc-mtTFB offers insights into mitochondrial transcription. Protein Science, 10, 1980–1988.PubMedCrossRefGoogle Scholar
  39. 39.
    Gaspari, M., Falkenberg, M., Larsson, N. G., & Gustafsson, C. M. (2004). The mitochondrial RNA polymerase contributes critically to promoter specificity in mammalian cells. EMBO Journal, 23, 4606–4614.PubMedCrossRefGoogle Scholar
  40. 40.
    Fernandez-Silva, P., Martinez-Azorin, F., Micol, V., & Attardi, G. (1997). The human mitochondrial transcription termination factor (mTERF) is a multizipper protein but binds to DNA as a monomer, with evidence pointing to intramolecular leucine zipper interactions. EMBO Journal, 16, 1066–1079.PubMedCrossRefGoogle Scholar
  41. 41.
    Montoya, J., Gaines, G. L., & Attardi, G. (1983). The pattern of transcription of the human mitochondrial rRNA genes reveals two overlapping transcription units. Cell, 34, 151–159.PubMedCrossRefGoogle Scholar
  42. 42.
    Carrodeguas, J. A., Theis, K., Bogenhagen, D. F., & Kisker, C. (2001). Crystal structure and deletion analysis show that the accessory subunit of mammalian DNA polymerase gamma, Pol gamma B, functions as a homodimer. Molecular Cell, 7, 43–54.PubMedCrossRefGoogle Scholar
  43. 43.
    Kaguni, L. S., & Olson, M. W. (1989). Mismatch-specific 3′–5′ exonuclease associated with the mitochondrial DNA polymerase from Drosophila embryos. Proceedings of the National Academy of Sciences of the United States of America, 86, 6469–6473.PubMedCrossRefGoogle Scholar
  44. 44.
    Pinz, K. G., & Bogenhagen, D. F. (1998). Efficient repair of abasic sites in DNA by mitochondrial enzymes. Molecular and Cellular Biology, 18, 1257–1265.PubMedGoogle Scholar
  45. 45.
    Lim, S. E., Longley, M. J., & Copeland, W. C. (1999). The mitochondrial p55 accessory subunit of human DNA polymerase gamma enhances DNA binding, promotes processive DNA synthesis, and confers N-ethylmaleimide resistance. Journal of Biological Chemistry, 274, 38197–38203.PubMedCrossRefGoogle Scholar
  46. 46.
    Xu, B., & Clayton, D. A. (1996). RNA–DNA hybrid formation at the human mitochondrial heavy-strand origin ceases at replication start sites: An implication for RNA–DNA hybrids serving as primers. EMBO Journal, 15, 3135–3143.PubMedGoogle Scholar
  47. 47.
    Xu, B., & Clayton, D. A. (1995). A persistent RNA–DNA hybrid is formed during transcription at a phylogenetically conserved mitochondrial DNA sequence. Molecular and Cellular Biology, 15, 580–589.PubMedGoogle Scholar
  48. 48.
    Walberg, M. W., & Clayton, D. A. (1981). Sequence and properties of the human KB cell and mouse L cell D-loop regions of mitochondrial DNA. Nucleic Acids Research, 9, 5411–5421.PubMedCrossRefGoogle Scholar
  49. 49.
    Takamatsu, C., Umeda, S., Ohsato, T., et al. (2002). Regulation of mitochondrial D-loops by transcription factor A and single-stranded DNA-binding protein. EMBO Reports, 3, 451–456.PubMedCrossRefGoogle Scholar
  50. 50.
    Korhonen, J. A., Gaspari, M., & Falkenberg, M. (2003). TWINKLE Has 5′–>3′ DNA helicase activity and is specifically stimulated by mitochondrial single-stranded DNA-binding protein. Journal of Biological Chemistry, 278, 48627–48632.PubMedCrossRefGoogle Scholar
  51. 51.
    Hoke, G. D., Pavco, P. A., Ledwith, B. J., & Van Tuyle, G. C. (1990). Structural and functional studies of the rat mitochondrial single strand DNA binding protein P16. Archives of Biochemistry and Biophysics, 282, 116–124.PubMedCrossRefGoogle Scholar
  52. 52.
    Korhonen, J. A., Pham, X. H., Pellegrini, M., & Falkenberg, M. (2004). Reconstitution of a minimal mtDNA replisome in vitro. EMBO Journal, 23, 2423–2429.PubMedCrossRefGoogle Scholar
  53. 53.
    Lee, D. Y., & Clayton, D. A. (1996). Properties of a primer RNA–DNA hybrid at the mouse mitochondrial DNA leading-strand origin of replication. Journal of Biological Chemistry, 271, 24262–24269.PubMedCrossRefGoogle Scholar
  54. 54.
    Alam, T. I., Kanki, T., Muta, T., et al. (2003). Human mitochondrial DNA is packaged with TFAM. Nucleic Acids Research, 31, 1640–1645.PubMedCrossRefGoogle Scholar
  55. 55.
    Seidel-Rogol, B. L., McCulloch, V., & Shadel, G. S. (2003). Human mitochondrial transcription factor B1 methylates ribosomal RNA at a conserved stem-loop. Nature Genetics, 33, 23–24.PubMedCrossRefGoogle Scholar
  56. 56.
    Longley, M. J., Prasad, R., Srivastava, D. K., Wilson, S. H., & Copeland, W. C. (1998). Identification of 5′-deoxyribose phosphate lyase activity in human DNA polymerase gamma and its role in mitochondrial base excision repair in vitro. Proceedings of the National Academy of Sciences of the United States of America, 95, 12244–12248.PubMedCrossRefGoogle Scholar
  57. 57.
    Kaufman, B. A., Durisic, N., Mativetsky, J. M., et al. (2007). The mitochondrial transcription factor TFAM coordinates the assembly of multiple DNA molecules into nucleoid-like structures. Molecular Biology of the Cell, 18, 3225–3236.PubMedCrossRefGoogle Scholar
  58. 58.
    Ohgaki, K., Kanki, T., Fukuoh, A., et al. (2007). The C-terminal tail of mitochondrial transcription factor a markedly strengthens its general binding to DNA. Journal of Biochemistry, 141, 201–211.PubMedCrossRefGoogle Scholar
  59. 59.
    Larsson, N. G., Oldfors, A., Holme, E., & Clayton, D. A. (1994). Low levels of mitochondrial transcription factor A in mitochondrial DNA depletion. Biochemical and Biophysical Research Communications, 200, 1374–1381.PubMedCrossRefGoogle Scholar
  60. 60.
    Seidel-Rogol, B. L., & Shadel, G. S. (2002). Modulation of mitochondrial transcription in response to mtDNA depletion and repletion in HeLa cells. Nucleic Acids Research, 30, 1929–1934.PubMedCrossRefGoogle Scholar
  61. 61.
    Longley, M. J., Nguyen, D., Kunkel, T. A., & Copeland, W. C. (2001). The fidelity of human DNA polymerase gamma with and without exonucleolytic proofreading and the p55 accessory subunit. Journal of Biological Chemistry, 276, 38555–38562.PubMedCrossRefGoogle Scholar
  62. 62.
    Spelbrink, J. N., Toivonen, J. M., Hakkaart, G. A., et al. (2000). In vivo functional analysis of the human mitochondrial DNA polymerase POLG expressed in cultured human cells. Journal of Biological Chemistry, 275, 24818–24828.PubMedCrossRefGoogle Scholar
  63. 63.
    Pinz, K. G., & Bogenhagen, D. F. (2006). The influence of the DNA polymerase gamma accessory subunit on base excision repair by the catalytic subunit. DNA Repair (Amst), 5, 121–128.CrossRefGoogle Scholar
  64. 64.
    DiMauro, S., & Schon, E. A. (2003). Mitochondrial respiratory-chain diseases. New England Journal of Medicine, 348, 2656–2668.PubMedCrossRefGoogle Scholar
  65. 65.
    De Vivo, D. C., & DiMauro, S. (1990). Mitochondrial defects of brain and muscle. Biology of the Neonate, 58(Suppl 1), 54–69.PubMedGoogle Scholar
  66. 66.
    Wallace, D. C. (1992). Diseases of the mitochondrial DNA. Annu Rev Biochem, 61, 1175–1212.PubMedCrossRefGoogle Scholar
  67. 67.
    Van Goethem, G., Dermaut, B., Lofgren, A., Martin, J. J., & Van Broeckhoven, C. (2001). Mutation of POLG is associated with progressive external ophthalmoplegia characterized by mtDNA deletions. Nature Genetics, 28, 211–212.PubMedCrossRefGoogle Scholar
  68. 68.
    Graziewicz, M. A., Longley, M. J., Bienstock, R. J., Zeviani, M., & Copeland, W. C. (2004). Structure–function defects of human mitochondrial DNA polymerase in autosomal dominant progressive external ophthalmoplegia. Nature Structural & Molecular Biology, 11, 770–776.CrossRefGoogle Scholar
  69. 69.
    Naviaux, R. K., Nyhan, W. L., Barshop, B. A., et al. (1999). Mitochondrial DNA polymerase gamma deficiency and mtDNA depletion in a child with Alpers’ syndrome. Annals of Neurology, 45, 54–58.PubMedCrossRefGoogle Scholar
  70. 70.
    Van Goethem, G., Luoma, P., Rantamaki, M., et al. (2004). POLG mutations in neurodegenerative disorders with ataxia but no muscle involvement. Neurology, 63, 1251–1257.PubMedGoogle Scholar
  71. 71.
    Rovio, A. T., Marchington, D. R., Donat, S., et al. (2001). Mutations at the mitochondrial DNA polymerase (POLG) locus associated with male infertility. Nature Genetics, 29, 261–262.PubMedCrossRefGoogle Scholar
  72. 72.
    Trifunovic, A., Wredenberg, A., Falkenberg, M., et al. (2004). Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature, 429, 417–423.PubMedCrossRefGoogle Scholar
  73. 73.
    Chan, S. S., Longley, M. J., & Copeland, W. C. (2005). The common A467T mutation in the human mitochondrial DNA polymerase (POLG) compromises catalytic efficiency and interaction with the accessory subunit. Journal of Biological Chemistry, 280, 31341–31346.PubMedCrossRefGoogle Scholar
  74. 74.
    Longley, M. J., Clark, S., Yu Wai Man, C., et al. (2006). Mutant POLG2 disrupts DNA polymerase gamma subunits and causes progressive external ophthalmoplegia. American Journal of Human Genetics, 78, 1026–1034.PubMedCrossRefGoogle Scholar
  75. 75.
    Poulton, J., Morten, K., Freeman-Emmerson, C., et al. (1994). Deficiency of the human mitochondrial transcription factor h-mtTFA in infantile mitochondrial myopathy is associated with mtDNA depletion. Human Molecular Genetics, 3, 1763–1769.PubMedCrossRefGoogle Scholar
  76. 76.
    Siciliano, G., Mancuso, M., Pasquali, L., Manca, M. L., Tessa, A., & Iudice, A. (2000). Abnormal levels of human mitochondrial transcription factor A in skeletal muscle in mitochondrial encephalomyopathies. Neurological Sciences, 21, S985–S987.PubMedCrossRefGoogle Scholar
  77. 77.
    Sorensen, L., Ekstrand, M., Silva, J. P., et al. (2001). Late-onset corticohippocampal neurodepletion attributable to catastrophic failure of oxidative phosphorylation in MILON mice. Journal of Neuroscience, 21, 8082–8090.PubMedGoogle Scholar
  78. 78.
    Dufour, E., Terzioglu, M., Sterky, F. H., et al. (2008). Age-associated mosaic respiratory chain deficiency causes trans-neuronal degeneration. Human Molecular Genetics, 17, 1418–1426.PubMedCrossRefGoogle Scholar
  79. 79.
    Wallace, D. C., Singh, G., Lott, M. T., et al. (1988). Mitochondrial DNA mutation associated with Leber’s hereditary optic neuropathy. Science, 242, 1427–1430.PubMedCrossRefGoogle Scholar
  80. 80.
    Fryer, A., Appleton, R., Sweeney, M. G., Rosenbloom, L., & Harding, A. E. (1994). Mitochondrial DNA 8993 (NARP) mutation presenting with a heterogeneous phenotype including ‘cerebral palsy’. Archives of Disease in Childhood, 71, 419–422.PubMedCrossRefGoogle Scholar
  81. 81.
    Clark, K. M., Taylor, R. W., Johnson, M. A., et al. (1999). An mtDNA mutation in the initiation codon of the cytochrome C oxidase subunit II gene results in lower levels of the protein and a mitochondrial encephalomyopathy. American Journal of Human Genetics, 64, 1330–1339.PubMedCrossRefGoogle Scholar
  82. 82.
    Holt, I. J., Harding, A. E., Petty, R. K., & Morgan-Hughes, J. A. (1990). A new mitochondrial disease associated with mitochondrial DNA heteroplasmy. American Journal of Human Genetics, 46, 428–433.PubMedGoogle Scholar
  83. 83.
    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.PubMedCrossRefGoogle Scholar
  84. 84.
    Shoffner, J. M., Lott, M. T., Lezza, A. M., Seibel, P., Ballinger, S. W., & Wallace, D. C. (1990). Myoclonic epilepsy and ragged-red fiber disease (MERRF) is associated with a mitochondrial DNA tRNA(Lys) mutation. Cell, 61, 931–937.PubMedCrossRefGoogle Scholar
  85. 85.
    Hanna, M. G., Nelson, I. P., Morgan-Hughes, J. A., & Harding, A. E. (1995). Impaired mitochondrial translation in human myoblasts harbouring the mitochondrial DNA tRNA lysine 8344 A–>G (MERRF) mutation: Relationship to proportion of mutant mitochondrial DNA. Journal of the Neurological Sciences, 130, 154–160.PubMedCrossRefGoogle Scholar
  86. 86.
    Nishigaki, Y., Tadesse, S., Bonilla, E., et al. (2003). A novel mitochondrial tRNA(Leu(UUR)) mutation in a patient with features of MERRF and Kearns–Sayre syndrome. Neuromuscular Disorders, 13, 334–340.PubMedCrossRefGoogle Scholar
  87. 87.
    Torroni, A., Cruciani, F., Rengo, C., et al. (1999). The A1555G mutation in the 12S rRNA gene of human mtDNA: Recurrent origins and founder events in families affected by sensorineural deafness. American Journal of Human Genetics, 65, 1349–1358.PubMedCrossRefGoogle Scholar
  88. 88.
    Schon, E. A., Rizzuto, R., Moraes, C. T., Nakase, H., Zeviani, M., & DiMauro, S. (1989). A direct repeat is a hotspot for large-scale deletion of human mitochondrial DNA. Science, 244, 346–349.PubMedCrossRefGoogle Scholar
  89. 89.
    Boulet, L., Karpati, G., & Shoubridge, E. A. (1992). Distribution and threshold expression of the tRNA(Lys) mutation in skeletal muscle of patients with myoclonic epilepsy and ragged-red fibers (MERRF). American Journal of Human Genetics, 51, 1187–1200.PubMedGoogle Scholar
  90. 90.
    Debray, F. G., Lambert, M., Chevalier, I., et al. (2007). Long-term outcome and clinical spectrum of 73 pediatric patients with mitochondrial diseases. Pediatrics, 119, 722–733.PubMedCrossRefGoogle Scholar
  91. 91.
    Richter, C., Park, J. W., & Ames, B. N. (1988). Normal oxidative damage to mitochondrial and nuclear DNA is extensive. Proceedings of the National Academy of Sciences of the United States of America, 85, 6465–6467.PubMedCrossRefGoogle Scholar
  92. 92.
    Wallace, D. C., Ye, J. H., Neckelmann, S. N., Singh, G., Webster, K. A., & Greenberg, B. D. (1987). Sequence analysis of cDNAs for the human and bovine ATP synthase beta subunit: Mitochondrial DNA genes sustain seventeen times more mutations. Current Genetics, 12, 81–90.PubMedCrossRefGoogle Scholar
  93. 93.
    Shoubridge, E. A., & Wai, T. (2007). Mitochondrial DNA and the mammalian oocyte. Current Topics in Developmental Biology, 77, 87–111.PubMedCrossRefGoogle Scholar
  94. 94.
    Fan, W., Waymire, K. G., Narula, N., et al. (2008). A mouse model of mitochondrial disease reveals germline selection against severe mtDNA mutations. Science, 319, 958–962.PubMedCrossRefGoogle Scholar
  95. 95.
    Stewart, J. B., Freyer, C., Elson, J. L., et al. (2008). Strong purifying selection in transmission of mammalian mitochondrial DNA. PLoS Biology, 6, e10.PubMedCrossRefGoogle Scholar
  96. 96.
    Pelton, T. A., Bettess, M. D., Lake, J., Rathjen, J., & Rathjen, P. D. (1998). Developmental complexity of early mammalian pluripotent cell populations in vivo and in vitro. Reproduction, Fertility and Development, 10, 535–549.CrossRefGoogle Scholar
  97. 97.
    Johnson, B. V., Rathjen, J., & Rathjen, P. D. (2006). Transcriptional control of pluripotency: Decisions in early development. Current Opinion in Genetics & Development, 16, 447–454.CrossRefGoogle Scholar
  98. 98.
    Lovell-Badge, R. (2001). The future for stem cell research. Nature, 414, 88–91.PubMedCrossRefGoogle Scholar
  99. 99.
    Surani, M. A., Hayashi, K., & Hajkova, P. (2007). Genetic and epigenetic regulators of pluripotency. Cell, 128, 747–762.PubMedCrossRefGoogle Scholar
  100. 100.
    Martin, G. R. (1981). Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proceedings of the National Academy of Sciences of the United States of America, 78, 7634–7638.PubMedCrossRefGoogle Scholar
  101. 101.
    Thomson, J. A., Itskovitz-Eldor, J., Shapiro, S. S., et al. (1998). Embryonic stem cell lines derived from human blastocysts. Science, 282, 1145–1147.PubMedCrossRefGoogle Scholar
  102. 102.
    Palmieri, S. L., Peter, W., Hess, H., & Scholer, H. R. (1994). Oct-4 transcription factor is differentially expressed in the mouse embryo during establishment of the first two extraembryonic cell lineages involved in implantation. Developments in Biologicals, 166, 259–267.CrossRefGoogle Scholar
  103. 103.
    Avilion, A. A., Nicolis, S. K., Pevny, L. H., Perez, L., Vivian, N., & Lovell-Badge, R. (2003). Multipotent cell lineages in early mouse development depend on SOX2 function. Genes & Development, 17, 126–140.CrossRefGoogle Scholar
  104. 104.
    Scholer, H. R., Hatzopoulos, A. K., Balling, R., Suzuki, N., & Gruss, P. (1989). A family of octamer-specific proteins present during mouse embryogenesis: Evidence for germline-specific expression of an Oct factor. EMBO Journal, 8, 2543–2550.PubMedGoogle Scholar
  105. 105.
    Nichols, J., Zevnik, B., Anastassiadis, K., et al. (1998). Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4. Cell, 95, 379–391.PubMedCrossRefGoogle Scholar
  106. 106.
    Chambers, I., Colby, D., Robertson, M., et al. (2003). Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells. Cell, 113, 643–655.PubMedCrossRefGoogle Scholar
  107. 107.
    Mitsui, K., Tokuzawa, Y., Itoh, H., et al. (2003). The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells. Cell, 113, 631–642.PubMedCrossRefGoogle Scholar
  108. 108.
    Niwa, H., Miyazaki, J., & Smith, A. G. (2000). Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells. Nature Genetics, 24, 372–376.PubMedCrossRefGoogle Scholar
  109. 109.
    Li, J., Pan, G., Cui, K., Liu, Y., Xu, S., & Pei, D. (2007). A dominant-negative form of mouse SOX2 induces trophectoderm differentiation and progressive polyploidy in mouse embryonic stem cells. Journal of Biological Chemistry, 282, 19481–19492.PubMedCrossRefGoogle Scholar
  110. 110.
    Hay, D. C., Sutherland, L., Clark, J., & Burdon, T. (2004). Oct-4 knockdown induces similar patterns of endoderm and trophoblast differentiation markers in human and mouse embryonic stem cells. Stem Cells, 22, 225–235.PubMedCrossRefGoogle Scholar
  111. 111.
    Hough, S. R., Clements, I., Welch, P. J., & Wiederholt, K. A. (2006). Differentiation of mouse embryonic stem cells after RNA interference-mediated silencing of OCT4 and Nanog. Stem Cells, 24, 1467–1475.PubMedCrossRefGoogle Scholar
  112. 112.
    Fong, H., Hohenstein, K. A., & Donovan, P. J. (2008). Regulation of self-renewal and pluripotency by Sox2 in human embryonic stem cells. Stem Cells, 26, 1931–1938.PubMedCrossRefGoogle Scholar
  113. 113.
    Bortvin, A., Eggan, K., Skaletsky, H., et al. (2003). Incomplete reactivation of Oct4-related genes in mouse embryos cloned from somatic nuclei. Development, 130, 1673–1680.PubMedCrossRefGoogle Scholar
  114. 114.
    Buhr, N., Carapito, C., Schaeffer, C., Kieffer, E., Van Dorsselaer, A., & Viville, S. (2008). Nuclear proteome analysis of undifferentiated mouse embryonic stem and germ cells. Electrophoresis, 29, 2381–2390.PubMedCrossRefGoogle Scholar
  115. 115.
    Cinelli, P., Casanova, E. A., Uhlig, S., et al. (2008). Expression profiling in transgenic FVB/N embryonic stem cells overexpressing STAT3. BMC Developmental Biology, 8, 57.PubMedCrossRefGoogle Scholar
  116. 116.
    Poulton, J., Macaulay, V., & Marchington, D. R. (1998). Mitochondrial genetics ‘98 is the bottleneck cracked? American Journal of Human Genetics, 62, 752–757.PubMedCrossRefGoogle Scholar
  117. 117.
    Chen, X., Prosser, R., Simonetti, S., Sadlock, J., Jagiello, G., & Schon, E. A. (1995). Rearranged mitochondrial genomes are present in human oocytes. American Journal of Human Genetics, 57, 239–247.PubMedGoogle Scholar
  118. 118.
    Jansen, R. P., & de Boer, K. (1998). The bottleneck: Mitochondrial imperatives in oogenesis and ovarian follicular fate. Molecular and Cellular Endocrinology, 145, 81–88.PubMedCrossRefGoogle Scholar
  119. 119.
    Cao, L., Shitara, H., Horii, T., et al. (2007). The mitochondrial bottleneck occurs without reduction of mtDNA content in female mouse germ cells. Nature Genetics, 39, 386–390.PubMedCrossRefGoogle Scholar
  120. 120.
    Piko, L., & Taylor, K. D. (1987). Amounts of mitochondrial DNA and abundance of some mitochondrial gene transcripts in early mouse embryos. Developments in Biologicals, 123, 364–374.CrossRefGoogle Scholar
  121. 121.
    Cree, L. M., Samuels, D. C., de Sousa Lopes, S. C., et al. (2008). A reduction of mitochondrial DNA molecules during embryogenesis explains the rapid segregation of genotypes. Nature Genetics, 40, 249–254.PubMedCrossRefGoogle Scholar
  122. 122.
    Reynier, P., May-Panloup, P., Chretien, M. F., et al. (2001). Mitochondrial DNA content affects the fertilizability of human oocytes. Molecular Human Reproduction, 7, 425–429.PubMedCrossRefGoogle Scholar
  123. 123.
    Santos, T. A., El Shourbagy, S., & St John, J. C. (2006). Mitochondrial content reflects oocyte variability and fertilization outcome. Fertility and Sterility, 85, 584–591.PubMedCrossRefGoogle Scholar
  124. 124.
    Steuerwald, N., Barritt, J. A., Adler, R., et al. (2000). Quantification of mtDNA in single oocytes, polar bodies and subcellular components by real-time rapid cycle fluorescence monitored PCR. Zygote, 8, 209–215.PubMedCrossRefGoogle Scholar
  125. 125.
    El Shourbagy, S. H., Spikings, E. C., Freitas, M., & St John, J. C. (2006). Mitochondria directly influence fertilisation outcome in the pig. Reproduction, 131, 233–245.PubMedCrossRefGoogle Scholar
  126. 126.
    Spikings, E. C., Alderson, J., & John, J. C. (2007). Regulated mitochondrial DNA replication during oocyte maturation is essential for successful porcine embryonic development. Biology of Reproduction, 76, 327–335.PubMedCrossRefGoogle Scholar
  127. 127.
    Kaneda, H., Hayashi, J., Takahama, S., Taya, C., Lindahl, K. F., & Yonekawa, H. (1995). Elimination of paternal mitochondrial DNA in intraspecific crosses during early mouse embryogenesis. Proceedings of the National Academy of Sciences of the United States of America, 92, 4542–4546.PubMedCrossRefGoogle Scholar
  128. 128.
    May-Panloup, P., Vignon, X., Chretien, M. F., et al. (2005). Increase of mitochondrial DNA content and transcripts in early bovine embryogenesis associated with upregulation of mtTFA and NRF1 transcription factors. Reproductive Biology and Endocrinology, 3, 65.PubMedCrossRefGoogle Scholar
  129. 129.
    Thundathil, J., Filion, F., & Smith, L. C. (2005). Molecular control of mitochondrial function in preimplantation mouse embryos. Molecular Reproduction and Development, 71, 405–413.PubMedCrossRefGoogle Scholar
  130. 130.
    McConnell, J. M., & Petrie, L. (2004). Mitochondrial DNA turnover occurs during preimplantation development and can be modulated by environmental factors. Reproductive Biomedicine Online, 9, 418–424.PubMedGoogle Scholar
  131. 131.
    Van Blerkom, J., Davis, P., Mathwig, V., & Alexander, S. (2002). Domains of high-polarized and low-polarized mitochondria may occur in mouse and human oocytes and early embryos. Human Reproduction, 17, 393–406.PubMedCrossRefGoogle Scholar
  132. 132.
    Van Blerkom, J., Davis, P. W., & Lee, J. (1995). ATP content of human oocytes and developmental potential and outcome after in-vitro fertilization and embryo transfer. Human Reproduction, 10, 415–424.PubMedGoogle Scholar
  133. 133.
    Stojkovic, M., Machado, S. A., Stojkovic, P., et al. (2001). Mitochondrial distribution and adenosine triphosphate content of bovine oocytes before and after in vitro maturation: Correlation with morphological criteria and developmental capacity after in vitro fertilization and culture. Biology of Reproduction, 64, 904–909.PubMedCrossRefGoogle Scholar
  134. 134.
    Van Blerkom, J., Sinclair, J., & Davis, P. (1998). Mitochondrial transfer between oocytes: Potential applications of mitochondrial donation and the issue of heteroplasmy. Human Reproduction, 13, 2857–2868.PubMedGoogle Scholar
  135. 135.
    Ma, J., Svoboda, P., Schultz, R. M., & Stein, P. (2001). Regulation of zygotic gene activation in the preimplantation mouse embryo: Global activation and repression of gene expression. Biology of Reproduction, 64, 1713–1721.PubMedCrossRefGoogle Scholar
  136. 136.
    Bolton, V. N., Oades, P. J., & Johnson, M. H. (1984). The relationship between cleavage, DNA replication, and gene expression in the mouse 2-cell embryo. Journal of Embryology and Experimental Morphology, 79, 139–163.PubMedGoogle Scholar
  137. 137.
    Bowles, E. J., Lee, J. H., Alberio, R., et al. (2007). Contrasting effects of in vitro fertilization and nuclear transfer on the expression of mtDNA replication factors. Genetics, 176, 1511–1526.PubMedCrossRefGoogle Scholar
  138. 138.
    Crosby, I. M., Gandolfi, F., & Moor, R. M. (1988). Control of protein synthesis during early cleavage of sheep embryos. Journal of Reproduction and Fertility, 82, 769–775.PubMedGoogle Scholar
  139. 139.
    Jarrell, V. L., Day, B. N., & Prather, R. S. (1991). The transition from maternal to zygotic control of development occurs during the 4-cell stage in the domestic pig, Sus scrofa: Quantitative and qualitative aspects of protein synthesis. Biology of Reproduction, 44, 62–68.PubMedCrossRefGoogle Scholar
  140. 140.
    Piko, L., & Matsumoto, L. (1976). Number of mitochondria and some properties of mitochondrial DNA in the mouse egg. Developments in Biologicals, 49, 1–10.CrossRefGoogle Scholar
  141. 141.
    Wilding, M., Dale, B., Marino, M., et al. (2001). Mitochondrial aggregation patterns and activity in human oocytes and preimplantation embryos. Human Reproduction, 16, 909–917.PubMedCrossRefGoogle Scholar
  142. 142.
    Stern, S., Biggers, J. D., & Anderson, E. (1971). Mitochondria and early development of the mouse. Journal of Experimental Zoology, 176, 179–191.PubMedCrossRefGoogle Scholar
  143. 143.
    Houghton, F. D., Thompson, J. G., Kennedy, C. J., & Leese, H. J. (1996). Oxygen consumption and energy metabolism of the early mouse embryo. Molecular Reproduction and Development, 44, 476–485.PubMedCrossRefGoogle Scholar
  144. 144.
    Trimarchi, J. R., Liu, L., Porterfield, D. M., Smith, P. J., & Keefe, D. L. (2000). Oxidative phosphorylation-dependent and -independent oxygen consumption by individual preimplantation mouse embryos. Biology of Reproduction, 62, 1866–1874.PubMedCrossRefGoogle Scholar
  145. 145.
    Houghton, F. D. (2006). Energy metabolism of the inner cell mass and trophectoderm of the mouse blastocyst. Differentiation, 74, 11–18.PubMedCrossRefGoogle Scholar
  146. 146.
    Guest, D. J., & Allen, W. R. (2007). Expression of cell-surface antigens and embryonic stem cell pluripotency genes in equine blastocysts. Stem Cells and Development, 16, 789–796.PubMedCrossRefGoogle Scholar
  147. 147.
    Baharvand, H., & Matthaei, K. I. (2003). The ultrastructure of mouse embryonic stem cells. Reproductive Biomedicine Online, 7, 330–335.PubMedCrossRefGoogle Scholar
  148. 148.
    Bavister, B. D. (2006). The mitochondrial contribution to stem cell biology. Reproduction, Fertility and Development, 18, 829–838.CrossRefGoogle Scholar
  149. 149.
    Batten, B. E., Albertini, D. F., & Ducibella, T. (1987). Patterns of organelle distribution in mouse embryos during preimplantation development. American Journal of Anatomy, 178, 204–213.PubMedCrossRefGoogle Scholar
  150. 150.
    Squirrell, J. M., Schramm, R. D., Paprocki, A. M., Wokosin, D. L., & Bavister, B. D. (2003). Imaging mitochondrial organization in living primate oocytes and embryos using multiphoton microscopy. Microscopy and Microanalysis, 9, 190–201.PubMedCrossRefGoogle Scholar
  151. 151.
    Spikings, E. C. (2007). Mitochondrial DNA replication in pre-implantation embryonic development. Ph.D. thesis, University of Birmingham, UK, p. 191.Google Scholar
  152. 152.
    Kondoh, H., Lleonart, M. E., Nakashima, Y., et al. (2007). A high glycolytic flux supports the proliferative potential of murine embryonic stem cells. Antioxidants & Redox Signalling, 9, 293–299.CrossRefGoogle Scholar
  153. 153.
    Fischer, B., & Bavister, B. D. (1993). Oxygen tension in the oviduct and uterus of rhesus monkeys, hamsters and rabbits. Journal of Reproduction and Fertility, 99, 673–679.PubMedGoogle Scholar
  154. 154.
    Ezashi, T., Das, P., & Roberts, R. M. (2005). Low O2 tensions and the prevention of differentiation of hES cells. Proceedings of the National Academy of Sciences of the United States of America, 102, 4783–4788.PubMedCrossRefGoogle Scholar
  155. 155.
    Lonergan, T., Brenner, C., & Bavister, B. (2006). Differentiation-related changes in mitochondrial properties as indicators of stem cell competence. Journal of Cellular Physiology, 208, 149–153.PubMedCrossRefGoogle Scholar
  156. 156.
    Piccoli, C., Ria, R., Scrima, R., et al. (2005). Characterization of mitochondrial and extra-mitochondrial oxygen consuming reactions in human hematopoietic stem cells. Novel evidence of the occurrence of NAD(P)H oxidase activity. Journal of Biological Chemistry, 280, 26467–26476.PubMedCrossRefGoogle Scholar
  157. 157.
    Chen, C. T., Shih, Y. R., Kuo, T. K., Lee, O. K., & Wei, Y. H. (2008). Coordinated changes of mitochondrial biogenesis and antioxidant enzymes during osteogenic differentiation of human mesenchymal stem cells. Stem Cells, 26, 960–968.PubMedCrossRefGoogle Scholar
  158. 158.
    Niwa, H. (2001). Molecular mechanism to maintain stem cell renewal of ES cells. Cell Structure and Function, 26, 137–148.PubMedCrossRefGoogle Scholar
  159. 159.
    Boyer, L. A., Lee, T. I., Cole, M. F., et al. (2005). Core transcriptional regulatory circuitry in human embryonic stem cells. Cell, 122, 947–956.PubMedCrossRefGoogle Scholar
  160. 160.
    Sauer, H., & Wartenberg, M. (2005). Reactive oxygen species as signaling molecules in cardiovascular differentiation of embryonic stem cells and tumor-induced angiogenesis. Antioxidants & Redox Signalling, 7, 1423–1434.CrossRefGoogle Scholar
  161. 161.
    Leahy, A., Xiong, J. W., Kuhnert, F., & Stuhlmann, H. (1999). Use of developmental marker genes to define temporal and spatial patterns of differentiation during embryoid body formation. Journal of Experimental Zoology, 284, 67–81.PubMedCrossRefGoogle Scholar
  162. 162.
    Hance, N., Ekstrand, M. I., & Trifunovic, A. (2005). Mitochondrial DNA polymerase gamma is essential for mammalian embryogenesis. Human Molecular Genetics, 14, 1775–1783.PubMedCrossRefGoogle Scholar
  163. 163.
    Larsson, N. G., Wang, J., Wilhelmsson, H., et al. (1998). Mitochondrial transcription factor A is necessary for mtDNA maintenance and embryogenesis in mice. Nature Genetics, 18, 231–236.PubMedCrossRefGoogle Scholar
  164. 164.
    Hondares, E., Mora, O., Yubero, P., et al. (2006). Thiazolidinediones and rexinoids induce peroxisome proliferator-activated receptor–coactivator (PGC)-1alpha gene transcription: An autoregulatory loop controls PGC-1alpha expression in adipocytes via peroxisome proliferator-activated receptor-gamma coactivation. Endocrinology, 147, 2829–2838.PubMedCrossRefGoogle Scholar
  165. 165.
    Scarpulla, R. C. (2002). Transcriptional activators and coactivators in the nuclear control of mitochondrial function in mammalian cells. Gene, 286, 81–89.PubMedCrossRefGoogle Scholar
  166. 166.
    Scarpulla, R. C. (1997). Nuclear control of respiratory chain expression in mammalian cells. Journal of Bioenergetics and Biomembranes, 29, 109–119.PubMedCrossRefGoogle Scholar
  167. 167.
    Scarpulla, R. C. (2008). Transcriptional paradigms in mammalian mitochondrial biogenesis and function. Physiological Reviews, 88, 611–638.PubMedCrossRefGoogle Scholar
  168. 168.
    Gaemers, I. C., Van Pelt, A. M., Themmen, A. P., & De Rooij, D. G. (1998). Isolation and characterization of all-trans-retinoic acid-responsive genes in the rat testis. Molecular Reproduction and Development, 50, 1–6.PubMedCrossRefGoogle Scholar
  169. 169.
    Berdanier, C. D., Everts, H. B., Hermoyian, C., & Mathews, C. E. (2001). Role of vitamin A in mitochondrial gene expression. Diabetes Research and Clinical Practice, 54(Suppl 2), S11–S27.PubMedCrossRefGoogle Scholar
  170. 170.
    Demonacos, C. V., Karayanni, N., Hatzoglou, E., Tsiriyiotis, C., Spandidos, D. A., & Sekeris, C. E. (1996). Mitochondrial genes as sites of primary action of steroid hormones. Steroids, 61, 226–232.PubMedCrossRefGoogle Scholar
  171. 171.
    Wrutniak, C., Cassar-Malek, I., Marchal, S., et al. (1995). A 43-kDa protein related to c-Erb A alpha 1 is located in the mitochondrial matrix of rat liver. Journal of Biological Chemistry, 270, 16347–16354.PubMedCrossRefGoogle Scholar
  172. 172.
    Sharova, L. V., Sharov, A. A., Piao, Y., et al. (2007). Global gene expression profiling reveals similarities and differences among mouse pluripotent stem cells of different origins and strains. Developments in Biologicals, 307, 446–459.CrossRefGoogle Scholar
  173. 173.
    Bain, G., Ray, W. J., Yao, M., & Gottlieb, D. I. (1996). Retinoic acid promotes neural and represses mesodermal gene expression in mouse embryonic stem cells in culture. Biochemical and Biophysical Research Communications, 223, 691–694.PubMedCrossRefGoogle Scholar
  174. 174.
    Gajovic, S., St-Onge, L., Yokota, Y., & Gruss, P. (1997). Retinoic acid mediates Pax6 expression during in vitro differentiation of embryonic stem cells. Differentiation, 62, 187–192.PubMedGoogle Scholar
  175. 175.
    Bibel, M., Richter, J., Schrenk, K., et al. (2004). Differentiation of mouse embryonic stem cells into a defined neuronal lineage. Nature Neuroscience, 7, 1003–1009.PubMedCrossRefGoogle Scholar
  176. 176.
    Nordin, N., Li, M., & Mason, J. O. (2008). Expression profiles of Wnt genes during neural differentiation of mouse embryonic stem cells. Cloning Stem Cells, 10, 37–48.PubMedCrossRefGoogle Scholar
  177. 177.
    Huo, L., & Scarpulla, R. C. (2001). Mitochondrial DNA instability and peri-implantation lethality associated with targeted disruption of nuclear respiratory factor 1 in mice. Molecular and Cellular Biology, 21, 644–654.PubMedCrossRefGoogle Scholar
  178. 178.
    Spitkovsky, D., Sasse, P., Kolossov, E., et al. (2004). Activity of complex III of the mitochondrial electron transport chain is essential for early heart muscle cell differentiation. FASEB Journal, 18, 1300–1302.PubMedGoogle Scholar
  179. 179.
    Campbell, K. H., McWhir, J., Ritchie, W. A., & Wilmut, I. (1996). Sheep cloned by nuclear transfer from a cultured cell line. Nature, 380, 64–66.PubMedCrossRefGoogle Scholar
  180. 180.
    White, K. L., Bunch, T. D., Mitalipov, S., & Reed, W. A. (1999). Establishment of pregnancy after the transfer of nuclear transfer embryos produced from the fusion of argali (Ovis ammon) nuclei into domestic sheep (Ovis aries) enucleated oocytes. Cloning, 1, 47–54.PubMedCrossRefGoogle Scholar
  181. 181.
    Wilmut, I., Schnieke, A. E., McWhir, J., Kind, A. J., & Campbell, K. H. (1997). Viable offspring derived from fetal and adult mammalian cells. Nature, 385, 810–813.PubMedCrossRefGoogle Scholar
  182. 182.
    Yang, L., Chavatte-Palmer, P., Kubota, C., et al. (2005). Expression of imprinted genes is aberrant in deceased newborn cloned calves and relatively normal in surviving adult clones. Molecular Reproduction and Development, 71, 431–438.PubMedCrossRefGoogle Scholar
  183. 183.
    Cummins, J. M., Wakayama, T., & Yanagimachi, R. (1997). Fate of microinjected sperm components in the mouse oocyte and embryo. Zygote, 5, 301–308.PubMedCrossRefGoogle Scholar
  184. 184.
    Sutovsky, P., Moreno, R. D., Ramalho-Santos, J., Dominko, T., Simerly, C., & Schatten, G. (1999). Ubiquitin tag for sperm mitochondria. Nature, 402, 371–372.PubMedCrossRefGoogle Scholar
  185. 185.
    St John, J. C., Lloyd, R. E., Bowles, E. J., Thomas, E. C., & El Shourbagy, S. (2004). The consequences of nuclear transfer for mammalian foetal development and offspring survival. A mitochondrial DNA perspective. Reproduction, 127, 631–641.PubMedCrossRefGoogle Scholar
  186. 186.
    Gaertig, J., Kiersnowska, M., & Iftode, F. (1988). Induction of cybrid strains of Tetrahymena thermophila by electrofusion. Journal of Cell Science, 89(Pt 2), 253–261.PubMedGoogle Scholar
  187. 187.
    Steinborn, R., Schinogl, P., Wells, D. N., Bergthaler, A., Muller, M., & Brem, G. (2002). Coexistence of Bos taurus and B. indicus mitochondrial DNAs in nuclear transfer-derived somatic cattle clones. Genetics, 162, 823–829.PubMedGoogle Scholar
  188. 188.
    St John, J. C., Moffatt, O., & D’Souza, N. (2005). Aberrant heteroplasmic transmission of mtDNA in cloned pigs arising from double nuclear transfer. Molecular Reproduction and Development, 72, 450–460.PubMedCrossRefGoogle Scholar
  189. 189.
    McCreath, K. J., Howcroft, J., Campbell, K. H., Colman, A., Schnieke, A. E., & Kind, A. J. (2000). Production of gene-targeted sheep by nuclear transfer from cultured somatic cells. Nature, 405, 1066–1069.PubMedCrossRefGoogle Scholar
  190. 190.
    Takeda, K., Akagi, S., Kaneyama, K., et al. (2003). Proliferation of donor mitochondrial DNA in nuclear transfer calves (Bos taurus) derived from cumulus cells. Molecular Reproduction and Development, 64, 429–437.PubMedCrossRefGoogle Scholar
  191. 191.
    Inoue, K., Ogonuki, N., Yamamoto, Y., et al. (2004). Tissue-specific distribution of donor mitochondrial DNA in cloned mice produced by somatic cell nuclear transfer. Genesis, 39, 79–83.PubMedCrossRefGoogle Scholar
  192. 192.
    Lloyd, R. E., Lee, J. H., Alberio, R., et al. (2006). Aberrant nucleo-cytoplasmic cross-talk results in donor cell mtDNA persistence in cloned embryos. Genetics, 172, 2515–2527.PubMedCrossRefGoogle Scholar
  193. 193.
    Shi, W., Zakhartchenko, V., & Wolf, E. (2003). Epigenetic reprogramming in mammalian nuclear transfer. Differentiation, 71, 91–113.PubMedCrossRefGoogle Scholar
  194. 194.
    Fulka, H., St John, J. C., Fulka, J., & Hozak, P. (2008). Chromatin in early mammalian embryos: Achieving the pluripotent state. Differentiation, 76, 3–14.PubMedGoogle Scholar
  195. 195.
    Barthelemy, C., Ogier de Baulny, H., Diaz, J., et al. (2001). Late-onset mitochondrial DNA depletion: DNA copy number, multiple deletions, and compensation. Annals of Neurology, 49, 607–617.PubMedCrossRefGoogle Scholar
  196. 196.
    Robin, E. D., & Wong, R. (1988). Mitochondrial DNA molecules and virtual number of mitochondria per cell in mammalian cells. Journal of Cellular Physiology, 136, 507–513.PubMedCrossRefGoogle Scholar
  197. 197.
    Shmookler Reis, R. J., & Goldstein, S. (1983). Mitochondrial DNA in mortal and immortal human cells. Genome number, integrity, and methylation. Journal of Biological Chemistry, 258, 9078–9085.PubMedGoogle Scholar
  198. 198.
    King, W. A., Shepherd, D. L., Plante, L., Lavoir, M. C., Looney, C. R., & Barnes, F. L. (1996). Nucleolar and mitochondrial morphology in bovine embryos reconstructed by nuclear transfer. Molecular Reproduction and Development, 44, 499–506.PubMedCrossRefGoogle Scholar
  199. 199.
    Takahashi, K., & Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell, 126, 663–676.PubMedCrossRefGoogle Scholar
  200. 200.
    Yamanaka, S. (2007). Strategies and new developments in the generation of patient-specific pluripotent stem cells. Cell Stem Cell, 1, 39–49.PubMedCrossRefGoogle Scholar
  201. 201.
    Takahashi, K., Tanabe, K., Ohnuki, M., et al. (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell, 131, 861–872.PubMedCrossRefGoogle Scholar
  202. 202.
    Do, J. T., & Scholer, H. R. (2004). Nuclei of embryonic stem cells reprogram somatic cells. Stem Cells, 22, 941–949.PubMedCrossRefGoogle Scholar
  203. 203.
    Cowan, C. A., Atienza, J., Melton, D. A., & Eggan, K. (2005). Nuclear reprogramming of somatic cells after fusion with human embryonic stem cells. Science, 309, 1369–1373.PubMedCrossRefGoogle Scholar
  204. 204.
    Do, J. T., & Scholer, H. R. (2005). Comparison of neurosphere cells with cumulus cells after fusion with embryonic stem cells: Reprogramming potential. Reproduction, Fertility and Development, 17, 143–149.CrossRefGoogle Scholar

Copyright information

© Springer Science + Business Media 2009

Authors and Affiliations

  1. 1.The Mitochondrial and Reproductive Genetics Group, Clinical Sciences Research Institute, Warwick Medical SchoolUniversity of WarwickWarwickUK

Personalised recommendations