Upregulation of Oxidative Phosphorylation Genes in Cumulus Cells of The Polycystic Ovary Syndrome Patients with or without Insulin Resistance

Document Type : Original Article

Authors

1 Applied Biotechnology Research Center, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran

2 Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran

3 International Faculty, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran

4 Department of Embryology, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran

5 Department of Biology, Faculty of Basic Sciences, Shahed University, Tehran, Iran

6 Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran

10.22074/cellj.2024.2006763.1357

Abstract

Objective: The relationship between oxidative stress (OS), insulin resistance (IR), and polycystic ovary syndrome
(PCOS) is an important medical issue in human reproduction. Some of the oxidative phosphorylation (OXPHOS) genes
have been previously studied in granulosa and muscle cells of PCOS patients. Cumulus cells (CCs) remain close to the
oocyte even after ovulation. This research has been designed to compare the expression of OXPHOS genes in CCs of
PCOS, with or without insulin resistance.
Materials and Methods: In this experimental study, patients were included in PCOS insulin-resistant, PCOS insulinsensitive
(IS), and control (fertile women with male infertility history) groups. The expression of NCF2, TXNIP, UCP2,
NDUFB6, ATP5H, COX7C, NDUFA3, SDHA, and SDHB was studied by real-time polymerase chain reaction (PCR),a
and normalization was performed considering HPRT1 and CYC1 as reference genes. One-way ANOVA and Tukey test
were used for data analysis.
Results: The results showed that the expression of NCF2, TXNIP, UCP2, and ATP5H was significantly higher in the
IR group than IS and control groups (P<0.01). NDUFB6 showed the highest expression in the IS group, which was
significantly different from other groups (P<0.01). The other genes of interest, except COX7C, were observed with the
most transcriptional levels in the IS group, although there was no significant difference for those genes.
Conclusion: Altered expression of genes involved in mitochondrial function compared to the control group in CCs
of both IR and IS categories of the PCOS patients suggests that alteration in OXPHOS genes can contribute to the
pathophysiology of PCOS.

Keywords

Main Subjects

References

  1. Zhang J, Bao Y, Zhou X, Zheng L. Polycystic ovary syndrome and mitochondrial dysfunction. Reprod Biol Endocrinol. 2019; 17(1): 67.
  2. Azziz R, Carmina E, Chen Z, Dunaif A, Laven JS, Legro RS, et al. Polycystic ovary syndrome. Nat Rev Dis Primers. 2016; 2: 16057.
  3. He X, Zeng H, Chen ST, Roman RJ, Aschner JL, Didion S, et al. Endothelial specific SIRT3 deletion impairs glycolysis and angiogenesis and causes diastolic dysfunction. J Mol Cell Cardiol. 2017; 112: 104-113.
  4. Zuo T, Zhu M, Xu W. Roles of oxidative stress in polycystic ovary syndrome and cancers. Oxid Med Cell Longev. 2016; 2016: 8589318.
  5. Liu Q, Xie YJ, Qu LH, Zhang MX, Mo ZC. Dyslipidemia involvement in the development of polycystic ovary syndrome. Taiwan J ObstetGynecol. 2019; 58(4): 447-453. 6. Zhu J, Thompson CB. Metabolic regulation of cell growth and proliferation. Nat Rev Mol Cell Biol. 2019; 20(7): 436-450.
  6. 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.
  7. von Mengden L, Klamt F, Smitz J. Redox biology of human cumulus cells: basic concepts, impact on oocyte quality, and potential clinical use. Antioxid Redox Signal. 2020; 32(8): 522-535.
  8. 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): 805-810.
  9. Montgomery MK, Turner N. Mitochondrial dysfunction and insulin resistance: an update. Endocr Connect. 2015; 4(1): R1-R15.
  10. Bruce CR, Risis S, Babb JR, Yang C, Kowalski GM, Selathurai A, et al. Overexpression of sphingosine kinase 1 prevents ceramide accumulation and ameliorates muscle insulin resistance in high-fat diet--fed mice. Diabetes. 2012; 61(12): 3148-3155.
  11. Özer A, Bakacak M, Kıran H, Ercan Ö, Köstü B, Kanat-Pektaş M, et al. Increased oxidative stress is associated with insulin resistance and infertility in polycystic ovary syndrome. Ginekol Pol. 2016; 87(11): 733-738.
  12. Steiner AZ, Jukic AM. Impact of female age and nulligravidity on fecundity in an older reproductive age cohort. Fertil Steril. 2016; 105(6): 1584-1588. e1.
  13. Hassani F, Oryan S, Eftekhari-Yazdi P, Bazrgar M, Moini A, Nasiri N, et al. Downregulation of extracellular matrix and cell adhesion molecules in cumulus cells of infertile polycystic ovary syndrome women with and without insulin resistance. Cell J. 2019; 21(1): 35- 42.
  14. Ma F, Qiao L, Yue H, Xie S, Zhou X, Jiang M, et al. Homeostasis model assessment-insulin resistance (HOMA-IR), a key role for assessing the ovulation function in polycystic ovary syndrome (PCOS) patients with insulin resistance. Endocr J. 2008; 55(5): 943-945.
  15. Reinecke F, Smeitink JA, van der Westhuizen FH. OXPHOS gene expression and control in mitochondrial disorders. Biochim Biophys Acta. 2009; 1792(12): 1113-1121.
  16. Schmittgen TD, Livak KJ. Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc. 2008; 3(6): 1101-1108.
  17. Labarta E, de Los Santos MJ, Escribá MJ, Pellicer A, Herraiz S. Mitochondria as a tool for oocyte rejuvenation. Fertil Steril. 2019; 111(2): 219-226.
  18. Ruegsegger GN, Creo AL, Cortes TM, Dasari S, Nair KS. Altered mitochondrial function in insulin-deficient and insulin-resistant states. J Clin Invest. 2018; 128(9): 3671-3681.
  19. Shkolnik K, Tadmor A, Ben-Dor S, Nevo N, Galiani D, Dekel N. Reactive oxygen species are indispensable in ovulation. Proc Natl Acad Sci USA. 2011; 108(4): 1462-1467.
  20. Liu Q, Li Y, Feng Y, Liu C, Ma J, Li Y, et al. Single-cell analysis of differences in transcriptomic profiles of oocytes and cumulus cells at GV, MI, MII stages from PCOS patients. Sci Rep. 2016; 6: 39638.
  21. Gao Y, Zou Y, Wu G, Zheng L. Oxidative stress and mitochondrial dysfunction of granulosa cells in polycystic ovarian syndrome. Front Med (Lausanne). 2023; 10: 1193749.
  22. Zhang Q, Ren J, Wang F, Pan M, Cui L, Li M, et al. Mitochondrial and glucose metabolic dysfunctions in granulosa cells induce impaired oocytes of polycystic ovary syndrome through Sirtuin 3. Free Radic Biol Med. 2022; 187: 1-16.
  23. Kaur S, Archer KJ, Devi MG, Kriplani A, Strauss JF 3rd, Singh R. Differential gene expression in granulosa cells from polycystic ovary syndrome patients with and without insulin resistance: identification of susceptibility gene sets through network analysis. J Clin Endocrinol Metab. 2012; 97(10): E2016-E2021.
  24. Chen Y, Ma L, Ge Z, Pan Y, Xie L. Key genes associated with nonalcoholic fatty liver disease and polycystic ovary syndrome. Front Mol Biosci. 2022; 9: 888194.
  25. Duarte AI, Sadowska-Bartosz I, Karkucinska-Wieckowska A, Lebiedzinska- Arciszewska M, Palmeira CM, Rolo AP, et al. A metabolic and mitochondrial angle on aging. In: Oliveira PJ, Malva JO, editors. Aging. Academic Press; 2023; 175-256.
  26. Pecqueur C, Alves-Guerra C, Ricquier D, Bouillaud F. UCP2, a metabolic sensor coupling glucose oxidation to mitochondrial metabolism? IUBMB Life. 2009; 61(7): 762-767.
  27. Huang L, Liang A, Li T, Lei X, Chen X, Liao B, et al. Mogroside V improves follicular development and ovulation in young-adult PCOS rats induced by letrozole and high-fat diet through promoting glycolysis. Front Endocrinol (Lausanne). 2022; 13: 838204.
  28. Liu Y, Jiang H, He LY, Huang WJ, He XY, Xing FQ. Abnormal expression of uncoupling protein-2 correlates with CYP11A1 expression in polycystic ovary syndrome. Reprod Fertil Dev. 2011; 23(4): 520-526.
  29. Zeber-Lubecka N, Kulecka M, Suchta K, Dąbrowska M, Ciebiera M, Hennig EE. Association of mitochondrial variants with the joint occurrence of polycystic ovary syndrome and hashimoto’s thyroiditis. Antioxidants (Basel). 2023; 12(11): 1983.
  30. Tan ALM, Langley SR, Tan CF, Chai JF, Khoo CM, Leow MK, et al. Ethnicity-specific skeletal muscle transcriptional signatures and their relevance to insulin resistance in Singapore. J Clin Endocrinol Metab. 2019; 104(2): 465-486.
  31. Ling C, Poulsen P, Simonsson S, Rönn T, Holmkvist J, Almgren P, et al. Genetic and epigenetic factors are associated with expression of respiratory chain component NDUFB6 in human skeletal muscle. J Clin Invest. 2007; 117(11): 3427-3435.
  32. Skov V, Glintborg D, Knudsen S, Jensen T, Kruse TA, Tan Q, et al. Reduced expression of nuclear-encoded genes involved in mitochondrial oxidative metabolism in skeletal muscle of insulinresistant women with polycystic ovary syndrome. Diabetes. 2007; 56(9): 2349-2355.
  33. Kim C, Moon J, Kang B, Moon S. Serum testosterone and free testosterone levels may be negatively correlated with mitochondrial function of granulosa cells in women with polycystic ovary syndrome. Fertil Steril. 2018; 110(4): e245-e246.
  34. Nilsson E, Benrick A, Kokosar M, Krook A, Lindgren E, Källman T, et al. Transcriptional and epigenetic changes influencing skeletal muscle metabolism in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2018; 103(12): 4465-4477.
  35. Cui P, Hu W, Ma T, Hu M, Tong X, Zhang F, et al. Long-term androgen excess induces insulin resistance and non-alcoholic fatty liver disease in PCOS-like rats. J Steroid Biochem Mol Biol. 2021; 208: 105829.
  36. Li J, Yue Z, Xiong W, Sun P, You K, Wang J. TXNIP overexpression suppresses proliferation and induces apoptosis in SMMC7221 cells through ROS generation and MAPK pathway activation. Oncol Rep. 2017; 37(6): 3369-3376.
  37. Ogboo BC, Grabovyy UV, Maini A, Scouten S, van der Vliet A, Mattevi A, et al. Architecture of the NADPH oxidase family of enzymes. Redox Biol. 2022; 52: 102298.
  38. Xu Q, Xing H, Wu J, Chen W, Zhang N. miRNA-141 induced pyroptosis in intervertebral disk degeneration by targeting ROS generation and activating TXNIP/NLRP3 signaling in nucleus pulpous cells. Front Cell Dev Biol. 2020; 8: 871.
  39. Wu P, Chen J, Chen J, Tao J, Wu S, Xu G, et al. Trimethylamine N-oxide promotes apoE-/- mice atherosclerosis by inducing vascular endothelial cell pyroptosis via the SDHB/ROS pathway. J Cell Physiol. 2020; 235(10): 6582-6591.

Files

Share

How to cite

Statistics