Semin Reprod Med 2015; 33(06): 401-409
DOI: 10.1055/s-0035-1567821
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Mitochondrial DNA Assessment to Determine Oocyte and Embryo Viability

Elpida Fragouli
1   Reprogenetics UK, Oxford, United Kingdom
,
Dagan Wells
1   Reprogenetics UK, Oxford, United Kingdom
2   Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Oxford, United Kingdom
› Author Affiliations
Further Information

Publication History

Publication Date:
13 November 2015 (online)

Abstract

Mitochondria are the key regulators of multiple vital cellular processes, including apoptosis, calcium homeostasis, and the generation of ATP via the metabolic pathway known as oxidative phosphorylation. Unlike other cellular organelles, mitochondria contain one or more copies of their own genome (mtDNA). The mtDNA encodes a total of 13 genes with critical functions in cellular metabolism. The energy required to support the normal progress of preimplantation embryo development is provided in the form of ATP generated by the mitochondria. It has been suggested that cellular bioenergetic capacity and suboptimal levels of mitochondria-generated ATP could contribute to a variety of embryo developmental defects, and therefore adversely affect in vitro fertilization success rates. During this review, we discuss the role of mitochondria and their genome during oogenesis and early embryo development. We also assess whether analysis of mitochondria and their genome could be used as biomarkers to determine oocyte quality and embryo viability.

 
  • References

  • 1 May-Panloup P, Chrétien MF, Jacques C, Vasseur C, Malthièry Y, Reynier P. Low oocyte mitochondrial DNA content in ovarian insufficiency. Hum Reprod 2005; 20 (3) 593-597
  • 2 St John JC, Facucho-Oliveira J, Jiang Y, Kelly R, Salah R. 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
  • 3 Dumollard R, Carroll J, Duchen MR, Campbell K, Swann K. Mitochondrial function and redox state in mammalian embryos. Semin Cell Dev Biol 2009; 20 (3) 346-353
  • 4 Anderson S, Bankier AT, Barrell BG , et al. Sequence and organization of the human mitochondrial genome. Nature 1981; 290 (5806) 457-465
  • 5 Ashley MV, Laipis PJ, Hauswirth WW. Rapid segregation of heteroplasmic bovine mitochondria. Nucleic Acids Res 1989; 17 (18) 7325-7331
  • 6 Bartmann AK, Salata Romao G, da Silveira Ramos E , et al. Why do older women have poor implantation rates? A possible role of the mitochondria. JARG 2004; 21: 79-83
  • 7 Marchington DR, Macaulay V, Hartshorne GM, Barlow D, Poulton J. Evidence from human oocytes for a genetic bottleneck in an mtDNA disease. Am J Hum Genet 1998; 63 (3) 769-775
  • 8 Wai T, Ao A, Zhang X, Cyr D, Dufort D, Shoubridge EA. The role of mitochondrial DNA copy number in mammalian fertility. Biol Reprod 2010; 83 (1) 52-62
  • 9 Jansen RP. Germline passage of mitochondria: quantitative considerations and possible embryological sequelae. Hum Reprod 2000; 15 (Suppl. 02) 112-128
  • 10 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) 116-125
  • 11 Van Blerkom J. Mitochondrial function in the human oocyte and embryo and their role in developmental competence. Mitochondrion 2011; 11 (5) 797-813
  • 12 Houghton FD. Energy metabolism of the inner cell mass and trophectoderm of the mouse blastocyst. Differentiation 2006; 74 (1) 11-18
  • 13 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) 415-424
  • 14 Fragouli E, Alfarawati S, Spath K , et al. The origin and impact of embryonic aneuploidy. Hum Genet 2013; 132 (9) 1001-1013
  • 15 Wells D, Kaur K, Grifo J , et al. Clinical utilisation of a rapid low-pass whole genome sequencing technique for the diagnosis of aneuploidy in human embryos prior to implantation. J Med Genet 2014; 51 (8) 553-562
  • 16 Yang Z, Liu J, Collins GS , et al. Selection of single blastocysts for fresh transfer via standard morphology assessment alone and with array CGH for good prognosis IVF patients: results from a randomized pilot study. Mol Cytogenet 2012; 5 (1) 24
  • 17 Forman EJ, Upham KM, Cheng M , et al. Comprehensive chromosome screening alters traditional morphology-based embryo selection: a prospective study of 100 consecutive cycles of planned fresh euploid blastocyst transfer. Fertil Steril 2013; 100 (3) 718-724
  • 18 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) 231-236
  • 19 Motta PM, Nottola SA, Makabe S, Heyn R. Mitochondrial morphology in human fetal and adult female germ cells. Hum Reprod 2000; 15 (Suppl. 02) 129-147
  • 20 Dumollard R, Duchen M, Carroll J. The role of mitochondrial function in the oocyte and embryo. Curr Top Dev Biol 2007; 77: 21-49
  • 21 Van Blerkom J. Development of human embryos to the hatched blastocyst stage in the presence or absence of a monolayer of Vero cells. Hum Reprod 1993; 8 (9) 1525-1539
  • 22 Sathananthan AH, Trounson AO. Mitochondrial morphology during preimplantational human embryogenesis. Hum Reprod 2000; 15 (Suppl. 02) 148-159
  • 23 Steuerwald N, Barritt JA, Adler R , et al. Quantification of mtDNA in single oocytes, polar bodies and subcellular components by real-time rapid cycle fluorescence monitored PCR. Zygote 2000; 8 (3) 209-215
  • 24 Reynier P, May-Panloup P, Chrétien MF , et al. Mitochondrial DNA content affects the fertilizability of human oocytes. Mol Hum Reprod 2001; 7 (5) 425-429
  • 25 Chan CC, Liu VW, Lau EY, Yeung WS, Ng EH, Ho PC. Mitochondrial DNA content and 4977 bp deletion in unfertilized oocytes. Mol Hum Reprod 2005; 11 (12) 843-846
  • 26 Murakoshi Y, Sueoka K, Takahashi K , et al. Embryo developmental capability and pregnancy outcome are related to the mitochondrial DNA copy number and ooplasmic volume. J Assist Reprod Genet 2013; 30 (10) 1367-1375
  • 27 Pikó L, Taylor KD. Amounts of mitochondrial DNA and abundance of some mitochondrial gene transcripts in early mouse embryos. Dev Biol 1987; 123 (2) 364-374
  • 28 Thundathil J, Filion F, Smith LC. Molecular control of mitochondrial function in preimplantation mouse embryos. Mol Reprod Dev 2005; 71 (4) 405-413
  • 29 Spikings EC, Alderson J, St John JC. Regulated mitochondrial DNA replication during oocyte maturation is essential for successful porcine embryonic development. Biol Reprod 2007; 76 (2) 327-335
  • 30 Tyynismaa H, Suomalainen A. Mouse models of mtDNA replication diseases. Methods 2010; 51 (4) 405-410
  • 31 Spelbrink JN, Li FY, Tiranti V , et al. Human mitochondrial DNA deletions associated with mutations in the gene encoding Twinkle, a phage T7 gene 4-like protein localized in mitochondria. Nat Genet 2001; 28 (3) 223-231
  • 32 Korhonen JA, Gaspari M, Falkenberg M. TWINKLE Has 5′ -> 3′ DNA helicase activity and is specifically stimulated by mitochondrial single-stranded DNA-binding protein. J Biol Chem 2003; 278 (49) 48627-48632
  • 33 Bogenhagen DF, Rousseau D, Burke S. The layered structure of human mitochondrial DNA nucleoids. J Biol Chem 2008; 283 (6) 3665-3675
  • 34 Seo AY, Joseph AM, Dutta D, Hwang JC, Aris JP, Leeuwenburgh C. New insights into the role of mitochondria in aging: mitochondrial dynamics and more. J Cell Sci 2010; 123 (Pt 15): 2533-2542
  • 35 Satoh M, Kuroiwa T. Organization of multiple nucleoids and DNA molecules in mitochondria of a human cell. Exp Cell Res 1991; 196 (1) 137-140
  • 36 Brown TA, Tkachuk AN, Shtengel G , et al. Superresolution fluorescence imaging of mitochondrial nucleoids reveals their spatial range, limits, and membrane interaction. Mol Cell Biol 2011; 31 (24) 4994-5010
  • 37 Sandalinas M, Márquez C, Munné S. Spectral karyotyping of fresh, non-inseminated oocytes. Mol Hum Reprod 2002; 8 (6) 580-585
  • 38 Kuliev A, Cieslak J, Ilkevitch Y, Verlinsky Y. Chromosomal abnormalities in a series of 6,733 human oocytes in preimplantation diagnosis for age-related aneuploidies. Reprod Biomed Online 2003; 6 (1) 54-59
  • 39 Pellestor F, Andréo B, Arnal F, Humeau C, Demaille J. Maternal aging and chromosomal abnormalities: new data drawn from in vitro unfertilized human oocytes. Hum Genet 2003; 112 (2) 195-203
  • 40 Fragouli E, Wells D, Thornhill A , et al. Comparative genomic hybridization analysis of human oocytes and polar bodies. Hum Reprod 2006; 21 (9) 2319-2328
  • 41 Fragouli E, Escalona A, Gutiérrez-Mateo C , et al. Comparative genomic hybridization of oocytes and first polar bodies from young donors. Reprod Biomed Online 2009; 19 (2) 228-237
  • 42 Fragouli E, Katz-Jaffe M, Alfarawati S , et al. Comprehensive chromosome screening of polar bodies and blastocysts from couples experiencing repeated implantation failure. Fertil Steril 2010; 94 (3) 875-887
  • 43 Eichenlaub-Ritter U, Wieczorek M, Lüke S, Seidel T. Age related changes in mitochondrial function and new approaches to study redox regulation in mammalian oocytes in response to age or maturation conditions. Mitochondrion 2011; 11 (5) 783-796
  • 44 Chen X, Prosser R, Simonetti S, Sadlock J, Jagiello G, Schon EA. Rearranged mitochondrial genomes are present in human oocytes. Am J Hum Genet 1995; 57 (2) 239-247
  • 45 Cummins JM. Fertilization and elimination of the paternal mitochondrial genome. Hum Reprod 2000; 15 (Suppl. 02) 92-101
  • 46 Hsu AL, Townsend PM, Oehninger S, Castora FJ. Endometriosis may be associated with mitochondrial dysfunction in cumulus cells from subjects undergoing in vitro fertilization-intracytoplasmic sperm injection, as reflected by decreased adenosine triphosphate production. Fertil Steril 2015; 103 (2) 347-352.e1
  • 47 Boucret L, Chao de la Barca JM, Morinière C , et al. Relationship between diminished ovarian reserve and mitochondrial biogenesis in cumulus cells. Hum Reprod 2015; 30 (7) 1653-1664
  • 48 Puigserver P, Wu Z, Park CW, Graves R, Wright M, Spiegelman BM. A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell 1998; 92 (6) 829-839
  • 49 Wu Z, Puigserver P, Andersson U , et al. Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell 1999; 98 (1) 115-124
  • 50 Duran HE, Simsek-Duran F, Oehninger SC, Jones Jr HW, Castora FJ. The association of reproductive senescence with mitochondrial quantity, function, and DNA integrity in human oocytes at different stages of maturation. Fertil Steril 2011; 96 (2) 384-388
  • 51 Kitagawa T, Suganuma N, Nawa A , et al. Rapid accumulation of deleted mitochondrial deoxyribonucleic acid in postmenopausal ovaries. Biol Reprod 1993; 49 (4) 730-736
  • 52 Keefe DL, Niven-Fairchild T, Powell S, Buradagunta S. Mitochondrial deoxyribonucleic acid deletions in oocytes and reproductive aging in women. Fertil Steril 1995; 64 (3) 577-583
  • 53 Konstantinidis M, Alfarawati S, Hurd D , et al. Simultaneous assessment of aneuploidy, polymorphisms, and mitochondrial DNA content in human polar bodies and embryos with the use of a novel microarray platform. Fertil Steril 2014; 102 (5) 1385-1392
  • 54 de Boer KA, Jansen RP, Leigh DA , et al. O-165 quantification of mtDNA copy number in the human secondary oocyte. Hum Reprod 1999; 14 (9) 2419
  • 55 Gianaroli L, Luiselli D, Crivello AM , et al. Mitochondrial DNA analysis and numerical chromosome condition in human oocytes and polar bodies. Mol Hum Reprod 2015; 21 (1) 46-57
  • 56 Kenney MC, Chwa M, Atilano SR , et al. Mitochondrial DNA variants mediate energy production and expression levels for CFH, C3 and EFEMP1 genes: implications for age-related macular degeneration. PLoS ONE 2013; 8 (1) e54339
  • 57 Marcuello A, Martínez-Redondo D, Dahmani Y , et al. Human mitochondrial variants influence on oxygen consumption. Mitochondrion 2009; 9 (1) 27-30
  • 58 Cohen J, Scott R, Alikani M , et al. Ooplasmic transfer in mature human oocytes. Mol Hum Reprod 1998; 4 (3) 269-280
  • 59 Barritt J, Willadsen S, Brenner C, Cohen J. Cytoplasmic transfer in assisted reproduction. Hum Reprod Update 2001; 7 (4) 428-435
  • 60 Harvey AJ, Gibson TC, Quebedeaux TM, Brenner CA. Impact of assisted reproductive technologies: a mitochondrial perspective of cytoplasmic transplantation. Curr Top Dev Biol 2007; 77: 229-249
  • 61 St John J. The control of mtDNA replication during differentiation and development. Biochim Biophys Acta 2014; 1840 (4) 1345-1354
  • 62 Chappel S. The role of mitochondria from mature oocyte to viable blastocyst. Obstet Gynecol Int 2013; 2013: 183024
  • 63 Braude P, Bolton V, Moore S. Human gene expression first occurs between the four- and eight-cell stages of preimplantation development. Nature 1988; 332 (6163) 459-461
  • 64 El Shourbagy SH, Spikings EC, Freitas M, St John JC. Mitochondria directly influence fertilisation outcome in the pig. Reproduction 2006; 131 (2) 233-245
  • 65 Harvey A, Gibson T, Lonergan T, Brenner C. Dynamic regulation of mitochondrial function in preimplantation embryos and embryonic stem cells. Mitochondrion 2011; 11 (5) 829-838
  • 66 Van Blerkom J. Mitochondria as regulatory forces in oocytes, preimplantation embryos and stem cells. Reprod Biomed Online 2008; 16 (4) 553-569
  • 67 Barnett DK, Clayton MK, Kimura J, Bavister BD. Glucose and phosphate toxicity in hamster preimplantation embryos involves disruption of cellular organization, including distribution of active mitochondria. Mol Reprod Dev 1997; 48 (2) 227-237
  • 68 Lane M, Bavister BD. Calcium homeostasis in early hamster preimplantation embryos. Biol Reprod 1998; 59 (4) 1000-1007
  • 69 Squirrell JM, Lane M, Bavister BD. Altering intracellular pH disrupts development and cellular organization in preimplantation hamster embryos. Biol Reprod 2001; 64 (6) 1845-1854
  • 70 Leese HJ. Quiet please, do not disturb: a hypothesis of embryo metabolism and viability. BioEssays 2002; 24 (9) 845-849
  • 71 Stigliani S, Anserini P, Venturini PL, Scaruffi P. Mitochondrial DNA content in embryo culture medium is significantly associated with human embryo fragmentation. Hum Reprod 2013; 28 (10) 2652-2660
  • 72 Stigliani S, Persico L, Lagazio C, Anserini P, Venturini PL, Scaruffi P. Mitochondrial DNA in Day 3 embryo culture medium is a novel, non-invasive biomarker of blastocyst potential and implantation outcome. Mol Hum Reprod 2014; 20 (12) 1238-1246
  • 73 Fragouli E, Spath K, Alfarawati S , et al. Altered levels of mitochondrial DNA are associated with female age, aneuploidy, and provide an independent measure of embryonic implantation potential. PLoS Genet 2015; 11 (6) e1005241
  • 74 Tan Y, Yin X, Zhang S , et al. Clinical outcome of preimplantation genetic diagnosis and screening using next generation sequencing. Gigascience 2014; 3 (1) 30
  • 75 Diez-Juan A, Rubio C, Marin C , et al. Mitochondrial DNA content as a viability score in human euploid embryos: less is better. Fertil Steril 2015; 104 (3) 534-541.e1