Vol 71, No 2 (2020)
Original paper
Published online: 2020-01-22

open access

Page views 3536
Article views/downloads 1940
Get Citation

Connect on Social Media

Connect on Social Media

The effects of mitochondrial dysfunction on energy metabolism switch by HIF-1α signalling in granulosa cells of polycystic ovary syndrome

Jing Wang1, Xiaohua Wu1
Pubmed: 32096549
Endokrynol Pol 2020;71(2):134-145.

Abstract

Background: This study aimed to determine the effects of mitochondrial dysfunction on energy metabolism of granulosa cells (GCs) and the competence of oocytes in polycystic ovary syndrome (PCOS).

Material and methods: A total of 107 patients who underwent controlled ovarian hyperstimulation (COH) were enrolled. The clinical outcomes of patients with and without PCOS under in vitro fertilisation-embryo transfer (IVF-ET) were compared. Human primary GCs were exposed to mitochondrial and glycolysis inhibitors. Then, the related indicators of mitochondrial activity and glycometabolism were compared with controls. The viability of GCs after mitochondrial inhibitors was also determined.

Results: In PCOS patients, the number of retrieved oocytes significantly increased, but the high-quality embryos, available embryos, and high-quality blastocyst formation obviously decreased (p < 0.05). Furthermore, the mitochondrial membrane potential, adenosine triphosphate (ATP) content, mitochondrial DNA (mtDNA) copy number, and HIF-1α mRNA levels in GCs decreased, while the levels of reactive oxygen species increased (p < 0.05). Mitochondrial inhibitors reduced the mitochondrial function, but increased the HIF-1α, GLUT1, LDHA, and PFKP gene expression. Glucose consumption gradually increased at 24, 48, and 72 hours of GC culture after CCCP treatment, and the viability of cells tested by CCK-8 increased (p < 0.05).

Conclusion: GCs are dependent on mitochondrial respiration and glycolysis for energy provision. Mitochondrial dysfunction accompanied by abnormal glycolysis was observed in PCOS patients, which affects the switch of energy from metabolic to glycolytic. The failure of transformation to glycolysis and low HIF-1a expression in GCs during the development of follicles might be correlated with the low oocyte competence of PCOS. 

Article available in PDF format

View PDF Download PDF file

References

  1. McCartney C, Marshall J. Polycystic Ovary Syndrome. N Engl J Med. 2016; 375(1): 54–64.
  2. Qiao J. Pay more attention to ethnic differences in polycystic ovary syndrome phenotypic expression. Chin Med J (Engl). 2013; 126(11): 2003–2006.
  3. Sirmans SM, Pate KA. Epidemiology, diagnosis, and management of polycystic ovary syndrome. Clin Epidemiol. 2013; 6: 1–13.
  4. Qiao J, Feng HL. Extra- and intra-ovarian factors in polycystic ovary syndrome: impact on oocyte maturation and embryo developmental competence. Hum Reprod Update. 2011; 17(1): 17–33.
  5. Heijnen EM, Eijkemans MJC, Hughes EG, et al. A meta-analysis of outcomes of conventional IVF in women with polycystic ovary syndrome. Hum Reprod Update. 2006; 12(1): 13–21.
  6. Vartanyan EV, Tsaturova KA, Devyatova EA, et al. Improvement in quality of oocytes in polycystic ovarian syndrome in programs of in vitro fertilization. Gynecol Endocrinol. 2017; 33(sup1): 8–11.
  7. Fair T. Mammalian oocyte development: checkpoints for competence. Reprod Fertil Dev. 2010; 22(1): 13–20.
  8. Franks S, McCarthy MI, Hardy K. Development of polycystic ovary syndrome: involvement of genetic and environmental factors. Int J Androl. 2006; 29(1): 278–85; discussion 286.
  9. Chronowska E. High-throughput analysis of ovarian granulosa cell transcriptome. Biomed Res Int. 2014; 2014: 213570.
  10. Combelles CMH, Holick EA, Paolella LJ, et al. Profiling of superoxide dismutase isoenzymes in compartments of the developing bovine antral follicles. Reproduction. 2010; 139(5): 871–881.
  11. Sutton-McDowall ML, Gilchrist RB, Thompson JG. The pivotal role of glucose metabolism in determining oocyte developmental competence. Reproduction. 2010; 139(4): 685–695.
  12. Downs SM, Mosey JL, Klinger J. Fatty acid oxidation and meiotic resumption in mouse oocytes. Mol Reprod Dev. 2009; 76(9): 844–853.
  13. Wu LLY, Dunning KR, Yang X, et al. High-fat diet causes lipotoxicity responses in cumulus-oocyte complexes and decreased fertilization rates. Endocrinology. 2010; 151(11): 5438–5445.
  14. Yang X, Wu LL, Chura LR, et al. Exposure to lipid-rich follicular fluid is associated with endoplasmic reticulum stress and impaired oocyte maturation in cumulus-oocyte complexes. Fertil Steril. 2012; 97(6): 1438–1443.
  15. Jakimiuk AJ, Weitsman SR, Navab A, et al. Luteinizing hormone receptor, steroidogenesis acute regulatory protein, and steroidogenic enzyme messenger ribonucleic acids are overexpressed in thecal and granulosa cells from polycystic ovaries. J Clin Endocrinol Metab. 2001; 86(3): 1318–1323.
  16. Shiratsuki S, Hara T, Munakata Y, et al. Low oxygen level increases proliferation and metabolic changes in bovine granulosa cells. Mol Cell Endocrinol. 2016; 437: 75–85.
  17. Stefano GB, Kream RM. Glycolytic Coupling to Mitochondrial Energy Production Ensures Survival in an Oxygen Rich Environment. Med Sci Monit. 2016; 22: 2571–2575.
  18. Stark H, Fichtner M, König R, et al. Causes of upregulation of glycolysis in lymphocytes upon stimulation. A comparison with other cell types. Biochimie. 2015; 118: 185–194.
  19. Laganà AS, Rossetti P, Buscema M, et al. Metabolism and Ovarian Function in PCOS Women: A Therapeutic Approach with Inositols. Int J Endocrinol. 2016; 2016: 6306410.
  20. González F, Rote NS, Minium J, et al. Reactive oxygen species-induced oxidative stress in the development of insulin resistance and hyperandrogenism in polycystic ovary syndrome. J Clin Endocrinol Metab. 2006; 91(1): 336–340.
  21. Reddy TV, Govatati S, Deenadayal M, et al. Impact of mitochondrial DNA copy number and displacement loop alterations on polycystic ovary syndrome risk in south Indian women. Mitochondrion. 2019; 44: 35–40.