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26 - The legacy of mitochondrial DNA

from Section 5 - Pathology

Published online by Cambridge University Press:  05 October 2013

By
Helen A.L. Tuppen ,
Mary Herbert  and
Doug M. Turnbull
Edited by
Alan Trounson ,
Roger Gosden  and
Ursula Eichenlaub-Ritter
Helen A.L. Tuppen
Affiliation:
Wellcome Trust Centre for Mitochondrial Research, Institute for Ageing and Health, Newcastle University Medical School, Newcastle-upon-Tyne, UK
Mary Herbert
Affiliation:
Wellcome Trust Centre for Mitochondrial Research, Institute for Ageing and Health, Newcastle University, Bioscience Centre, International Centre for Life, Newcastle-upon-Tyne, UK
Doug M. Turnbull
Affiliation:
Wellcome Trust Centre for Mitochondrial Research, Institute for Ageing and Health, Newcastle University Medical School, Newcastle-upon-Tyne, UK
Alan Trounson
Affiliation:
California Institute for Regenerative Medicine
Roger Gosden
Affiliation:
Center for Reproductive Medicine and Infertility, Cornell University, New York
Ursula Eichenlaub-Ritter
Affiliation:
Universität Bielefeld, Germany
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Summary

Introduction

Present in all nucleated cells, mitochondria are essential subcellular organelles that play a crucial role in several different biochemical processes, including energy production. Mitochondria are believed to be evolutionary relics of ancient bacterial symbionts [1], and an important legacy of this history is the persistence within these organelles of a small genome, termed mitochondrial DNA (mtDNA). MtDNA is the only extranuclear source of DNA in the cell and it follows a different mode of inheritance from nuclear DNA. We highlight the important role of mitochondria in reproduction and why this small molecule of DNA presents so many interesting and important challenges particularly in reproductive biology.

Mitochondrial function

Mitochondria are double-membraned structures which are central to a multitude of biological functions in all nucleated mammalian cells, including the regulation of apoptotic cell death, the control of cytosolic calcium concentration, and the biogenesis of iron–sulfur clusters. Mitochondria are also the primary source of endogenous reactive oxygen species and they house several critical biochemical pathways, including the tricarboxylic acid cycle and part of the urea cycle. However, arguably the most important function of mitochondria is the production of ATP, the energy carrier of the cell, via oxidative phosphorylation (OXPHOS). OXPHOS requires the coordinated activity of five multi-subunit enzyme complexes located in the inner mitochondrial membrane. Electrons, resulting from the oxidation of fat and carbohydrates, are transported along complexes I–IV, thus creating an electrochemical gradient for protons across the inner mitochondrial membrane that drives the synthesis of ATP by complex V (ATP synthase).

Type
Chapter
Information
Biology and Pathology of the Oocyte
Role in Fertility, Medicine and Nuclear Reprograming
 , pp. 306 - 317
Publisher: Cambridge University Press
Print publication year: 2013

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References

Margulis, L.Symbiosis and evolution. Sci Am 1971; 225(2): 48–57.CrossRefGoogle ScholarPubMed
Anderson, S, Bankier, AT, Barrell, BG, et al. Sequence and organization of the human mitochondrial genome. Nature 1981; 290(5806): 457–65.CrossRefGoogle ScholarPubMed
Andrews, RM, Kubacka, I, Chinnery, PF, et al. Reanalysis and revision of the Cambridge reference sequence for human mitochondrial DNA. Nat Genet 1999; 23(2): 147.CrossRefGoogle ScholarPubMed
Mokranjac, D, Neupert, W.Protein import into mitochondria. Biochem Soc Trans 2005; 33(Pt 5): 1019–23.CrossRefGoogle ScholarPubMed
Ojala, D, Montoya, J, Attardi, G.tRNA punctuation model of RNA processing in human mitochondria. Nature 1981; 290(5806): 470–4.CrossRefGoogle ScholarPubMed
Bogenhagen, D, Clayton, DA.Mouse L cell mitochondrial DNA molecules are selected randomly for replication throughout the cell cycle. Cell 1977; 11(4): 719–27.CrossRefGoogle ScholarPubMed
Holt, IJ.Mitochondrial DNA replication and repair: all a flap. Trends Biochem Sci 2009; 34(7): 358–65.CrossRefGoogle Scholar
Fish, J, Raule, N, Attardi, G.Discovery of a major D-loop replication origin reveals two modes of human mtDNA synthesis. Science 2004; 306(5704): 2098–101.CrossRefGoogle Scholar
Graziewicz, MA, Longley, MJ, Copeland WC. DNA polymerase gamma in mitochondrial DNA replication and repair. Chem Rev 2006; 106(2): 383–405.CrossRefGoogle ScholarPubMed
Korhonen, JA, Pham, XH, Pellegrini, M, et al. Reconstitution of a minimal mtDNA replisome in vitro. EMBO J 2004; 23(12): 2423–9.CrossRefGoogle ScholarPubMed
Rossmanith, W.Of P and Z: mitochondrial tRNA processing enzymes. Biochim Biophys Acta 2012; 1819(9–10): 1017–26.CrossRefGoogle Scholar
Holt, IJ, He, J, Mao, CC, et al. Mammalian mitochondrial nucleoids: organizing an independently minded genome. Mitochondrion 2007; 7(5): 311–21.CrossRefGoogle ScholarPubMed
Bereiter-Hahn, J.Behavior of mitochondria in the living cell. Int Rev Cytol 1990; 122: 1–63.CrossRefGoogle ScholarPubMed
Sathananthan, AH, Trounson, AO.Mitochondrial morphology during preimplantational human embryogenesis. Hum Reprod 2000; 15 Suppl 2: 148–59.CrossRefGoogle ScholarPubMed
Jansen, RP.Germline passage of mitochondria: quantitative considerations and possible embryological sequelae. Hum Reprod 2000; 15 Suppl 2: 112–28.CrossRefGoogle ScholarPubMed
Piko, L, Matsumoto, L.Number of mitochondria and some properties of mitochondrial DNA in the mouse egg. Dev Biol 1976; 49(1): 1–10.CrossRefGoogle ScholarPubMed
Wilding, M, Coppola, G, Dale, B, et al. Mitochondria and human preimplantation embryo development. Reproduction 2009; 137(4): 619–24.CrossRefGoogle ScholarPubMed
Van Blerkom, J.Mitochondrial function in the human oocyte and embryo and their role in developmental competence. Mitochondrion 2011; 11(5): 797–813.CrossRefGoogle ScholarPubMed
Larsson, NG, Wang, J, Wilhelmsson, H, et al. Mitochondrial transcription factor A is necessary for mtDNA maintenance and embryogenesis in mice. Nat Genet 1998; 18(3): 231–6.CrossRefGoogle ScholarPubMed
St John, JC, Facucho-Oliveira, J, Jiang, Y, et al. Mitochondrial DNA transmission, replication and inheritance: a journey from the gamete through the embryo and into offspring and embryonic stem cells. Hum Reprod Update 2010; 16(5): 488–509.CrossRefGoogle ScholarPubMed
Wilding, M, Dale, B, Marino, M, et al. Mitochondrial aggregation patterns and activity in human oocytes and preimplantation embryos. Hum Reprod 2001; 16(5): 909–17.CrossRefGoogle ScholarPubMed
Cao, L, Shitara, H, Horii, T, et al. The mitochondrial bottleneck occurs without reduction of mtDNA content in female mouse germ cells. Nat Genet 2007; 39(3): 386–90.CrossRefGoogle ScholarPubMed
Cree, LM, Samuels, DC, de Sousa Lopes, SC, et al. A reduction of mitochondrial DNA molecules during embryogenesis explains the rapid segregation of genotypes. Nat Genet 2008; 40(2): 249–54.CrossRefGoogle ScholarPubMed
Wai, T, Teoli, D, Shoubridge, EA.The mitochondrial DNA genetic bottleneck results from replication of a subpopulation of genomes. Nat Genet 2008; 40(12): 1484–8.CrossRefGoogle ScholarPubMed
Bogenhagen, DF.Does mtDNA nucleoid organization impact aging? Exp Gerontol 2010; 45(7–8): 473–7.CrossRefGoogle ScholarPubMed
Giles, RE, Blanc, H, Cann, HM, et al. Maternal inheritance of human mitochondrial DNA. Proc Natl Acad Sci USA 1980; 77(11): 6715–19.CrossRefGoogle ScholarPubMed
Ramalho-Santos, J, Varum, S, Amaral, S, et al. Mitochondrial functionality in reproduction: from gonads and gametes to embryos and embryonic stem cells. Hum Reprod Update 2009; 15(5): 553–72.CrossRefGoogle ScholarPubMed
Sutovsky, P, Moreno, RD, Ramalho-Santos, J, et al. Ubiquitin tag for sperm mitochondria. Nature 1999; 402(6760): 371–2.CrossRefGoogle ScholarPubMed
Nishimura, Y, Yoshinari, T, Naruse, K, et al. Active digestion of sperm mitochondrial DNA in single living sperm revealed by optical tweezers. Proc Natl Acad Sci USA 2006; 103(5): 1382–7.CrossRefGoogle ScholarPubMed
Al Rawi, S, Louvet-Vallee, S, Djeddi, A, et al. Postfertilization autophagy of sperm organelles prevents paternal mitochondrial DNA transmission. Science 2011; 334(6059): 1144–7.CrossRefGoogle ScholarPubMed
Sato, M, Sato, K.Degradation of paternal mitochondria by fertilization-triggered autophagy in C. elegans embryos. Science 2011; 334(6059): 1141–4.CrossRefGoogle ScholarPubMed
Manfredi, G, Thyagarajan, D, Papadopoulou, LC, et al. The fate of human sperm-derived mtDNA in somatic cells. Am J Hum Genet 1997; 61(4): 953–60.CrossRefGoogle ScholarPubMed
Schwartz, M, Vissing, J.Paternal inheritance of mitochondrial DNA. N Engl J Med 2002; 347(8): 576–80.CrossRefGoogle ScholarPubMed
Taylor, RW, McDonnell, MT, Blakely, EL, et al. Genotypes from patients indicate no paternal mitochondrial DNA contribution. Ann Neurol 2003; 54(4): 521–4.CrossRefGoogle ScholarPubMed
Filosto, M, Mancuso, M, Vives-Bauza, C, et al. Lack of paternal inheritance of muscle mitochondrial DNA in sporadic mitochondrial myopathies. Ann Neurol 2003; 54(4): 524–6.CrossRefGoogle ScholarPubMed
Sutovsky, P, Van Leyen, K, McCauley, T, et al. Degradation of paternal mitochondria after fertilization: implications for heteroplasmy, assisted reproductive technologies and mtDNA inheritance. Reprod Biomed Online 2004; 8(1): 24–33.CrossRefGoogle ScholarPubMed
Lewin, R.The unmasking of mitochondrial Eve. Science 1987; 238(4823): 24–6.CrossRefGoogle ScholarPubMed
Holt, IJ, Harding, AE, Morgan-Hughes, JA.Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies. Nature 1988; 331(6158): 717–19.CrossRefGoogle ScholarPubMed
Wallace, DC, Singh, G, Lott, MT, et al. Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy. Science 1988; 242(4884): 1427–30.CrossRefGoogle ScholarPubMed
Tuppen, HA, Blakely, EL, Turnbull, DM, et al. Mitochondrial DNA mutations and human disease. Biochim Biophys Acta 2010; 1797(2): 113–28.CrossRefGoogle ScholarPubMed
Schaefer, AM, McFarland, R, Blakely, EL, et al. Prevalence of mitochondrial DNA disease in adults. Ann Neurol 2008; 63(1): 35–9.CrossRefGoogle ScholarPubMed
Manwaring, N, Jones, MM, Wang, JJ, et al. Population prevalence of the MELAS A3243G mutation. Mitochondrion 2007; 7(3): 230–3.CrossRefGoogle ScholarPubMed
Elliott, HR, Samuels, DC, Eden, JA, et al. Pathogenic mitochondrial DNA mutations are common in the general population. Am J Hum Genet 2008; 83(2): 254–60.CrossRefGoogle ScholarPubMed
Carling, PJ, Cree, LM, Chinnery, PF.The implications of mitochondrial DNA copy number regulation during embryogenesis. Mitochondrion 2011; 11(5): 686–92.CrossRefGoogle ScholarPubMed
Freyer, C, Cree, LM, Mourier, A, et al. Variation in germline mtDNA heteroplasmy is determined prenatally but modified during subsequent transmission. Nat Genet 2012; 44(11): 1282–5.CrossRefGoogle ScholarPubMed
Stewart, JB, Freyer, C, Elson, JL, et al. Strong purifying selection in transmission of mammalian mitochondrial DNA. PLoS Biol 2008; 6(1): e10.CrossRefGoogle ScholarPubMed
Monnot, S, Gigarel, N, Samuels, DC, et al. Segregation of mtDNA throughout human embryofetal development: m.3243A>G as a model system. Hum Mutat 2011; 32(1): 116–25.CrossRefGoogle ScholarPubMed
Steffann, J, Frydman, N, Gigarel, N, et al. Analysis of mtDNA variant segregation during early human embryonic development: a tool for successful NARP preimplantation diagnosis. J Med Genet 2006; 43(3): 244–7.CrossRefGoogle ScholarPubMed
Craven, L, Elson, JL, Irving, L, et al. Mitochondrial DNA disease: new options for prevention. Hum Mol Genet 2011; 20(R2): R168–74.CrossRefGoogle Scholar
McGrath, J, Solter, D.Nuclear transplantation in the mouse embryo by microsurgery and cell fusion. Science 1983; 220(4603): 1300–2.CrossRefGoogle ScholarPubMed
Sato, A, Kono, T, Nakada, K, et al. Gene therapy for progeny of mito-mice carrying pathogenic mtDNA by nuclear transplantation. Proc Natl Acad Sci USA 2005; 102(46): 16765–70.CrossRefGoogle ScholarPubMed
Craven, L, Tuppen, HA, Greggains, GD, et al. Pronuclear transfer in human embryos to prevent transmission of mitochondrial DNA disease. Nature 2010; 465(7294): 82–5.CrossRefGoogle ScholarPubMed
Tachibana, M, Sparman, M, Sritanaudomchai, H, et al. Mitochondrial gene replacement in primate offspring and embryonic stem cells. Nature 2009; 461(7262): 367–72.CrossRefGoogle ScholarPubMed
Downs, SM.The influence of glucose, cumulus cells, and metabolic coupling on ATP levels and meiotic control in the isolated mouse oocyte. Dev Biol 1995; 167(2): 502–12.CrossRefGoogle ScholarPubMed
Sutton-McDowall, ML, Gilchrist, RB, Thompson, JG.The pivotal role of glucose metabolism in determining oocyte developmental competence. Reproduction 2010; 139(4): 685–95.CrossRefGoogle ScholarPubMed
Johnson, MT, Freeman, EA, Gardner, DK, et al. Oxidative metabolism of pyruvate is required for meiotic maturation of murine oocytes in vivo. Biol Reprod 2007; 77(1): 2–8.CrossRefGoogle ScholarPubMed
Van Blerkom, J, Davis, PW, Lee, J.ATP content of human oocytes and developmental potential and outcome after in-vitro fertilization and embryo transfer. Hum Reprod 1995; 10(2): 415–24.CrossRefGoogle ScholarPubMed
Reynier, P, May-Panloup, P, Chretien, MF, et al. Mitochondrial DNA content affects the fertilizability of human oocytes. Mol Hum Reprod 2001; 7(5): 425–9.CrossRefGoogle ScholarPubMed
Copeland, WC.Inherited mitochondrial diseases of DNA replication. Ann Rev Med 2008; 59: 131–46.CrossRefGoogle ScholarPubMed
May-Panloup, P, Chretien, MF, Jacques, C, et al. Low oocyte mitochondrial DNA content in ovarian insufficiency. Hum Reprod 2005; 20(3): 593–7.CrossRefGoogle ScholarPubMed
Zeng, HT, Ren, Z, Yeung, WS, et al. Low mitochondrial DNA and ATP contents contribute to the absence of birefringent spindle imaged with PolScope in in vitro matured human oocytes. Hum Reprod 2007; 22(6): 1681–6.CrossRefGoogle ScholarPubMed
Wai, T, Ao, A, Zhang, X, et al. The role of mitochondrial DNA copy number in mammalian fertility. Biol Reprod 2010; 83(1): 52–62.CrossRefGoogle ScholarPubMed
Sauer, MV, Paulson, RJ, Lobo, RA.A preliminary report on oocyte donation extending reproductive potential to women over 40. N Engl J Med 1990; 323(17): 1157–60.CrossRefGoogle ScholarPubMed
Steuerwald, NM, Bermudez, MG, Wells, D, et al. Maternal age-related differential global expression profiles observed in human oocytes. Reprod Biomed Online 2007; 14(6): 700–8.CrossRefGoogle ScholarPubMed
Trifunovic, A, Larsson, NG.Mitochondrial dysfunction as a cause of ageing. J Intern Med 2008; 263(2): 167–78.CrossRefGoogle ScholarPubMed
Muller-Hocker, J, Schafer, S, Weis, S, et al. Morphological-cytochemical and molecular genetic analyses of mitochondria in isolated human oocytes in the reproductive age. Mol Hum Reprod 1996; 2(12): 951–8.CrossRefGoogle ScholarPubMed
Tarin, JJ, Vendrell, FJ, Ten, J, et al. The oxidizing agent tertiary butyl hydroperoxide induces disturbances in spindle organization, c-meiosis, and aneuploidy in mouse oocytes. Mol Hum Reprod 1996; 2(12): 895–901.CrossRefGoogle ScholarPubMed
Zhang, X, Wu, XQ, Lu, S, Guo, YL, Ma, X.Deficit of mitochondria-derived ATP during oxidative stress impairs mouse MII oocyte spindles. Cell Res 2006; 16: 841–50. .CrossRefGoogle ScholarPubMed
Seifer, DB, DeJesus, V, Hubbard, K.Mitochondrial deletions in luteinized granulosa cells as a function of age in women undergoing in vitro fertilization. Fertil Steril 2002; 78(5): 1046– 8.CrossRefGoogle ScholarPubMed
Tsai, HD, Hsieh, YY, Hsieh, JN, et al. Mitochondria DNA deletion and copy numbers of cumulus cells associated with in vitro fertilization outcomes. J Reprod Med 2010; 55(11–12): 491–7.Google ScholarPubMed
St John, JC.Transmission, inheritance and replication of mitochondrial DNA in mammals: implications for reproductive processes and infertility. Cell Tissue Res 2012; 349(3): 795–808.CrossRefGoogle ScholarPubMed
Tarin, JJ, Perez-Albala, S, Cano, A.Cellular and morphological traits of oocytes retrieved from aging mice after exogenous ovarian stimulation. Biol Reprod 2001; 65(1): 141–50.CrossRefGoogle ScholarPubMed

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  • The legacy of mitochondrial DNA
    • By Helen A.L. Tuppen, Wellcome Trust Centre for Mitochondrial Research, Institute for Ageing and Health, Newcastle University Medical School, Newcastle-upon-Tyne, UK, Mary Herbert, Wellcome Trust Centre for Mitochondrial Research, Institute for Ageing and Health, Newcastle University, Bioscience Centre, International Centre for Life, Newcastle-upon-Tyne, UK, Doug M. Turnbull, Wellcome Trust Centre for Mitochondrial Research, Institute for Ageing and Health, Newcastle University Medical School, Newcastle-upon-Tyne, UK
  • Edited by Alan Trounson, Roger Gosden, Ursula Eichenlaub-Ritter, Universität Bielefeld, Germany
  • Book: Biology and Pathology of the Oocyte
  • Online publication: 05 October 2013
  • Chapter DOI: https://doi.org/10.1017/CBO9781139135030.027
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  • The legacy of mitochondrial DNA
    • By Helen A.L. Tuppen, Wellcome Trust Centre for Mitochondrial Research, Institute for Ageing and Health, Newcastle University Medical School, Newcastle-upon-Tyne, UK, Mary Herbert, Wellcome Trust Centre for Mitochondrial Research, Institute for Ageing and Health, Newcastle University, Bioscience Centre, International Centre for Life, Newcastle-upon-Tyne, UK, Doug M. Turnbull, Wellcome Trust Centre for Mitochondrial Research, Institute for Ageing and Health, Newcastle University Medical School, Newcastle-upon-Tyne, UK
  • Edited by Alan Trounson, Roger Gosden, Ursula Eichenlaub-Ritter, Universität Bielefeld, Germany
  • Book: Biology and Pathology of the Oocyte
  • Online publication: 05 October 2013
  • Chapter DOI: https://doi.org/10.1017/CBO9781139135030.027
Available formats
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Save book to Google Drive

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Google Drive.

  • The legacy of mitochondrial DNA
    • By Helen A.L. Tuppen, Wellcome Trust Centre for Mitochondrial Research, Institute for Ageing and Health, Newcastle University Medical School, Newcastle-upon-Tyne, UK, Mary Herbert, Wellcome Trust Centre for Mitochondrial Research, Institute for Ageing and Health, Newcastle University, Bioscience Centre, International Centre for Life, Newcastle-upon-Tyne, UK, Doug M. Turnbull, Wellcome Trust Centre for Mitochondrial Research, Institute for Ageing and Health, Newcastle University Medical School, Newcastle-upon-Tyne, UK
  • Edited by Alan Trounson, Roger Gosden, Ursula Eichenlaub-Ritter, Universität Bielefeld, Germany
  • Book: Biology and Pathology of the Oocyte
  • Online publication: 05 October 2013
  • Chapter DOI: https://doi.org/10.1017/CBO9781139135030.027
Available formats
×