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Journal of Assisted Reproduction and Genetics

, Volume 35, Issue 10, pp 1821–1830 | Cite as

Respirometric reserve capacity of cumulus cell mitochondria correlates with oocyte maturity

  • Sharon H. Anderson
  • Michael J. Glassner
  • Andrey Melnikov
  • Gary Friedman
  • Zulfiya Orynbayeva
Reproductive Physiology and Disease

Abstract

Purpose

Oocyte competence is critical in success of assisted reproduction. Metabolic signaling between oocyte and cumulus cells within the cumulus-oocyte complex procure oocyte development. This study evaluated the relationship between respirometric activity of cumulus cells and maturity of corresponding oocytes.

Methods

In prospective cohort study, 20 women of age 28–42 undergoing IVF procedure were involved. To evaluate oocyte maturity, the cumulus cells from individual oocytes were assessed flow cytometrically by double labeling of cells with mitochondria specific dyes. The respirometric stress analysis using ATPase inhibitor oligomycin was applied to assess mitochondria metabolic abnormalities.

Results

The cumulus cells from each of 327 oocytes were analyzed. The respirometric index of cumulus cells (O′R) strongly correlates with maternal ovarian reserve, showing to be higher in patients with higher AMH (p < 0.0017). Cumulus cells from immature oocytes had severe mitochondria deficiency, i.e., low O′R, than those from mature oocytes (p < 0.02). No significant difference in respirometric capacity was found between cumulus cells associated with good vs poor-quality embryos.

Conclusions

The oocyte maturity is potentially related to the mitochondria activity of cumulus cells.

Keywords

Cumulus cells Oocytes Energy metabolism Respiration Mitochondria membrane potential 

Notes

Acknowledgments

The authors are thankful to Saniya Ossikbayeva for her excellent technical assistance. The support of EMD Serono, Inc. to the Main Line Fertility Center is appreciated. The sponsor has no involvement in experimental design, experimental performance, data analysis, and manuscript generation.

Compliance with ethical standards

Conflict of interest

Michael Glassner is a founding partner and the medical director at the Main Line Fertility Center. Other authors have no conflicts of interest to declare.

References

  1. 1.
    Kovalevsky G, Patrizio P. High rates of embryo wastage with use of assisted reproductive technology: a look at the trends between 1995 and 2001 in the United States. Fertil Steril. 2005;84(2):325–30.  https://doi.org/10.1016/j.fertnstert.2005.04.020.CrossRefPubMedGoogle Scholar
  2. 2.
    te Velde ER, Pearson PL. The variability of female reproductive ageing. Hum Reprod Update. 2002;8(2):141–54.CrossRefGoogle Scholar
  3. 3.
    Wu LL, Dunning KR, Yang X, Russell DL, Lane M, Norman RJ, et al. High-fat diet causes lipotoxicity responses in cumulus-oocyte complexes and decreased fertilization rates. Endocrinology. 2010;151(11):5438–45.  https://doi.org/10.1210/en.2010-0551.CrossRefPubMedGoogle Scholar
  4. 4.
    Colton SA, Humpherson PG, Leese HJ, Downs SM. Physiological changes in oocyte-cumulus cell complexes from diabetic mice that potentially influence meiotic regulation. Biol Reprod. 2003;69(3):761–70.  https://doi.org/10.1095/biolreprod.102.013649.CrossRefPubMedGoogle Scholar
  5. 5.
    Sanchez T, Seidler EA, Gardner DK, Needleman D, Sakkas D. Will noninvasive methods surpass invasive for assessing gametes and embryos? Fertil Steril. 2017;108(5):730–7.  https://doi.org/10.1016/j.fertnstert.2017.10.004.CrossRefPubMedGoogle Scholar
  6. 6.
    Dumesic DA, Meldrum DR, Katz-Jaffe MG, Krisher RL, Schoolcraft WB. Oocyte environment: follicular fluid and cumulus cells are critical for oocyte health. Fertil Steril. 2015;103(2):303–16.  https://doi.org/10.1016/j.fertnstert.2014.11.015.CrossRefPubMedGoogle Scholar
  7. 7.
    Silvestre F, Boni R, Fissore RA, Tosti E. Ca2+ signaling during maturation of cumulus-oocyte complex in mammals. Mol Reprod Dev. 2011;78(10–11):744–56.  https://doi.org/10.1002/mrd.21332.CrossRefPubMedGoogle Scholar
  8. 8.
    Su YQ, Sugiura K, Wigglesworth K, O'Brien MJ, Affourtit JP, Pangas SA, et al. Oocyte regulation of metabolic cooperativity between mouse cumulus cells and oocytes: BMP15 and GDF9 control cholesterol biosynthesis in cumulus cells. Development. 2008;135(1):111–21.  https://doi.org/10.1242/dev.009068.CrossRefPubMedGoogle Scholar
  9. 9.
    Downs SM, Mastropolo AM. The participation of energy substrates in the control of meiotic maturation in murine oocytes. Dev Biol. 1994;162(1):154–68.  https://doi.org/10.1006/dbio.1994.1075.CrossRefPubMedGoogle Scholar
  10. 10.
    Behrman HR, Preston SL, Pellicer A, Parmer TG. Oocyte maturation is regulated by modulation of the action of FSH in cumulus cells. Prog Clin Biol Res. 1988;267:115–35.PubMedGoogle Scholar
  11. 11.
    Lolicato F, Brouwers JF, de Lest CH, Wubbolts R, Aardema H, Priore P, et al. The cumulus cell layer protects the bovine maturing oocyte against fatty acid-induced lipotoxicity. Biol Reprod. 2015;92(1):16.  https://doi.org/10.1095/biolreprod.114.120634.CrossRefPubMedGoogle Scholar
  12. 12.
    Sugiura K, Su YQ, Diaz FJ, Pangas SA, Sharma S, Wigglesworth K, et al. Oocyte-derived BMP15 and FGFs cooperate to promote glycolysis in cumulus cells. Development. 2007;134(14):2593–603.  https://doi.org/10.1242/dev.006882.CrossRefPubMedGoogle Scholar
  13. 13.
    Sanchez-Lazo L, Brisard D, Elis S, Maillard V, Uzbekov R, Labas V, et al. Fatty acid synthesis and oxidation in cumulus cells support oocyte maturation in bovine. Mol Endocrinol. 2014;28(9):1502–21.  https://doi.org/10.1210/me.2014-1049.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Miao YL, Liu XY, Qiao TW, Miao DQ, Luo MJ, Tan JH. Cumulus cells accelerate aging of mouse oocytes. Biol Reprod. 2005;73(5):1025–31.  https://doi.org/10.1095/biolreprod.105.043703.CrossRefPubMedGoogle Scholar
  15. 15.
    Ikeda S, Imai H, Yamada M. Apoptosis in cumulus cells during in vitro maturation of bovine cumulus-enclosed oocytes. Reproduction. 2003;125(3):369–76.CrossRefGoogle Scholar
  16. 16.
    Lee KS, Joo BS, Na YJ, Yoon MS, Choi OH, Kim WW. Cumulus cells apoptosis as an indicator to predict the quality of oocytes and the outcome of IVF-ET. J Assist Reprod Genet. 2001;18(9):490–8.CrossRefGoogle Scholar
  17. 17.
    Dumesic DA, Guedikian AA, Madrigal VK, Phan JD, Hill DL, Alvarez JP, et al. Cumulus cell mitochondrial resistance to stress in vitro predicts oocyte development during assisted reproduction. J Clin Endocrinol Metab. 2016;101(5):2235–45.  https://doi.org/10.1210/jc.2016-1464.CrossRefPubMedGoogle Scholar
  18. 18.
    Bentov Y, Yavorska T, Esfandiari N, Jurisicova A, Casper RF. The contribution of mitochondrial function to reproductive aging. J Assist Reprod Genet. 2011;28(9):773–83.  https://doi.org/10.1007/s10815-011-9588-7.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Wu LL, Russell DL, Norman RJ, Robker RL. Endoplasmic reticulum (ER) stress in cumulus-oocyte complexes impairs pentraxin-3 secretion, mitochondrial membrane potential (DeltaPsi m), and embryo development. Mol Endocrinol. 2012;26(4):562–73.  https://doi.org/10.1210/me.2011-1362.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Schatten H, Sun QY, Prather R. The impact of mitochondrial function/dysfunction on IVF and new treatment possibilities for infertility. Reprod Biol Endocrinol : RB&E. 2014;12:111.  https://doi.org/10.1186/1477-7827-12-111.CrossRefGoogle Scholar
  21. 21.
    Chappel S. The role of mitochondria from mature oocyte to viable blastocyst. Obstet Gynecol Int. 2013;2013:183024–10.  https://doi.org/10.1155/2013/183024.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Galluzzi L, Kepp O, Trojel-Hansen C, Kroemer G. Mitochondrial control of cellular life, stress, and death. Circ Res. 2012;111(9):1198–207.  https://doi.org/10.1161/CIRCRESAHA.112.268946.CrossRefPubMedGoogle Scholar
  23. 23.
    Goldenthal MJ, Marin-Garcia J. Mitochondrial signaling pathways: a receiver/integrator organelle. Mol Cell Biochem. 2004;262(1–2):1–16.CrossRefGoogle Scholar
  24. 24.
    Gardner DK, Lane M, Stevens J, Schoolcraft WB. Noninvasive assessment of human embryo nutrient consumption as a measure of developmental potential. Fertil Steril. 2001;76(6):1175–80.CrossRefGoogle Scholar
  25. 25.
    Ramakrishna R, Edwards JS, McCulloch A, Palsson BO. Flux-balance analysis of mitochondrial energy metabolism: consequences of systemic stoichiometric constraints. Am J Physiol Regul Integr Comp Physiol. 2001;280(3):R695–704.CrossRefGoogle Scholar
  26. 26.
    Dalton CM, Szabadkai G, Carroll J. Measurement of ATP in single oocytes: impact of maturation and cumulus cells on levels and consumption. J Cell Physiol. 2014;229(3):353–61.  https://doi.org/10.1002/jcp.24457.CrossRefPubMedGoogle Scholar
  27. 27.
    Collins Y, Chouchani ET, James AM, Menger KE, Cocheme HM, Murphy MP. Mitochondrial redox signalling at a glance. J Cell Sci. 2012;125(Pt 4):801–6.  https://doi.org/10.1242/jcs.098475.CrossRefPubMedGoogle Scholar
  28. 28.
    Lenaz G. Role of mitochondria in oxidative stress and ageing. Biochim Biophys Acta. 1998;1366(1–2):53–67.CrossRefGoogle Scholar
  29. 29.
    Bing YZ, Hirao Y, Iga K, Che LM, Takenouchi N, Kuwayama M, et al. In vitro maturation and glutathione synthesis of porcine oocytes in the presence or absence of cysteamine under different oxygen tensions: role of cumulus cells. Reprod Fertil Dev. 2002;14(3–4):125–31.CrossRefGoogle Scholar
  30. 30.
    Tatemoto H, Sakurai N, Muto N. Protection of porcine oocytes against apoptotic cell death caused by oxidative stress during in vitro maturation: role of cumulus cells. Biol Reprod. 2000;63(3):805–10.CrossRefGoogle Scholar
  31. 31.
    Kaya A, Gerashchenko MV, Seim I, Labarre J, Toledano MB, Gladyshev VN. Adaptive aneuploidy protects against thiol peroxidase deficiency by increasing respiration via key mitochondrial proteins. Proc Natl Acad Sci U S A. 2015;112(34):10685–90.  https://doi.org/10.1073/pnas.1505315112.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Assou S, Haouzi D, Mahmoud K, Aouacheria A, Guillemin Y, Pantesco V, et al. A non-invasive test for assessing embryo potential by gene expression profiles of human cumulus cells: a proof of concept study. Mol Hum Reprod. 2008;14(12):711–9.  https://doi.org/10.1093/molehr/gan067.CrossRefPubMedGoogle Scholar
  33. 33.
    Setterfield K, Williams AJ, Donald J, Thorburn DR, Kirby DM, Trounce I, et al. Flow cytometry in the study of mitochondrial respiratory chain disorders. Mitochondrion. 2002;1(5):437–45.CrossRefGoogle Scholar
  34. 34.
    Matteucci E, Manzini S, Ghimenti M, Consani C, Giampietro O. Rapid flow cytometric method for measuring mitochondrial membrane potential, respiratory burst activity, and intracellular thiols of human blood leukocytes. Open Chem Biom Methods. 2009;2:65–8.CrossRefGoogle Scholar
  35. 35.
    Rottenberg H, Wu S. Quantitative assay by flow cytometry of the mitochondrial membrane potential in intact cells. Biochim Biophys Acta. 1998;1404(3):393–404.CrossRefGoogle Scholar
  36. 36.
    Gregori G, Denis M, Lefevre D, Beker B. A flow cytometric approach to assess phytoplankton respiration. Methods Cell Sci. 2002;24(1–3):99–106.CrossRefGoogle Scholar
  37. 37.
    Panov A, Orynbayeva Z. Bioenergetic and antiapoptotic properties of mitochondria from cultured human prostate cancer cell lines PC-3, DU145 and LNCaP. PLoS One. 2013;8(8):e72078.  https://doi.org/10.1371/journal.pone.0072078.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Nicholls DG, Darley-Usmar VM, Wu M, Jensen PB, Rogers GW, Ferrick DA. Bioenergetic profile experiment using C2C12 myoblast cells. J Vis Exp : JoVE. 2010(46). doi: https://doi.org/10.3791/2511.
  39. 39.
    Nicholls DG. Mitochondrial membrane potential and aging. Aging Cell. 2004;3(1):35–40.CrossRefGoogle Scholar
  40. 40.
    Barbakadze L, Kristesashvili J, Khonelidze N, Tsagareishvili G. The correlations of anti-mullerian hormone, follicle-stimulating hormone and antral follicle count in different age groups of infertile women. Int J Fertil Steril. 2015;8(4):393–8.PubMedPubMedCentralGoogle Scholar
  41. 41.
    Xie HL, Wang YB, Jiao GZ, Kong DL, Li Q, Li H, et al. Effects of glucose metabolism during in vitro maturation on cytoplasmic maturation of mouse oocytes. Sci Rep. 2016;6:20764.  https://doi.org/10.1038/srep20764.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Reynier P, May-Panloup P, Chretien MF, Morgan CJ, Jean M, Savagner F, et al. Mitochondrial DNA content affects the fertilizability of human oocytes. Mol Hum Reprod. 2001;7(5):425–9.CrossRefGoogle Scholar
  43. 43.
    Zeng HT, Ren Z, Yeung WS, Shu YM, Xu YW, Zhuang GL, 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.  https://doi.org/10.1093/humrep/dem070.CrossRefPubMedGoogle Scholar
  44. 44.
    May-Panloup P, Boucret L, Chao de la Barca JM, Desquiret-Dumas V, Ferre-L’Hotellier V, Moriniere C, et al. Ovarian ageing: the role of mitochondria in oocytes and follicles. Hum Reprod Update. 2016;22(6):725–43.  https://doi.org/10.1093/humupd/dmw028.CrossRefPubMedGoogle Scholar
  45. 45.
    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):347–52 e1.  https://doi.org/10.1016/j.fertnstert.2014.11.002.CrossRefPubMedGoogle Scholar
  46. 46.
    Pacella-Ince L, Zander-Fox DL, Lan M. Mitochondrial SIRT3 and its target glutamate dehydrogenase are altered in follicular cells of women with reduced ovarian reserve or advanced maternal age. Hum Reprod. 2014;29(7):1490–9.  https://doi.org/10.1093/humrep/deu071.CrossRefPubMedGoogle Scholar
  47. 47.
    Van Blerkom J, Davis P. Mitochondrial signaling and fertilization. Mol Hum Reprod. 2007;13(11):759–70.  https://doi.org/10.1093/molehr/gam068.CrossRefPubMedGoogle Scholar
  48. 48.
    Panov A, Orynbayeva Z. Determination of mitochondrial metabolic phenotype through investigation of the intrinsic inhibition of succinate dehydrogenase. Anal Biochem. 2017;552:30–7.  https://doi.org/10.1016/j.ab.2017.10.010.CrossRefPubMedGoogle Scholar
  49. 49.
    Starkov AA. The role of mitochondria in reactive oxygen species metabolism and signaling. Ann N Y Acad Sci. 2008;1147:37–52.  https://doi.org/10.1196/annals.1427.015.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Pesta D, Gnaiger E. High-resolution respirometry: OXPHOS protocols for human cells and permeabilized fibers from small biopsies of human muscle. Methods Mol Biol. 2012;810:25–58.  https://doi.org/10.1007/978-1-61779-382-0_3.CrossRefPubMedGoogle Scholar
  51. 51.
    Yuan YQ, Van Soom A, Leroy JL, Dewulf J, Van Zeveren A, de Kruif A, et al. Apoptosis in cumulus cells, but not in oocytes, may influence bovine embryonic developmental competence. Theriogenology. 2005;63(8):2147–63.  https://doi.org/10.1016/j.theriogenology.2004.09.054.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Main Line Fertility CenterBryn MawrUSA
  2. 2.Department of Obstetrics and GynecologyDrexel University College of MedicinePhiladelphiaUSA
  3. 3.DatalogicTelfordUSA
  4. 4.Department of Electrical and Computer EngineeringDrexel UniversityPhiladelphiaUSA
  5. 5.Department of SurgeryDrexel University College of MedicinePhiladelphiaUSA

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