Mitochondrial abnormality in ovarian granulosa cells of patients with polycystic ovary syndrome

Xie,Congcong; Xie,Congcong; Lu,Hui; Lu,Hui; Zhang,Xiujia; Zhang,Xiujia; An,Zhuo; An,Zhuo; Chen,Tong; Chen,Tong; Yu,Wenbo; Yu,Wenbo; Wang,Shusong; Wang,Shusong; Shang,Dandan; Shang,Dandan; Wang,Xueying; Wang,Xueying

doi:10.3892/mmr.2023.13150

Mitochondrial abnormality in ovarian granulosa cells of patients with polycystic ovary syndrome

Authors:
- Congcong Xie
- Hui Lu
- Xiujia Zhang
- Zhuo An
- Tong Chen
- Wenbo Yu
- Shusong Wang
- Dandan Shang
- Xueying Wang
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Affiliations: Hebei Key Laboratory of Reproductive Medicine, Hebei Reproductive Health Hospital, Hebei Institute of Reproductive Health Science and Technology, Shijiazhuang, Hebei 050071, P.R. China, Department of Biochemistry and Molecule Biology, Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China
Published online on: December 18, 2023 https://doi.org/10.3892/mmr.2023.13150
Article Number: 27
Copyright: © Xie et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The quality of oocytes in patients with polycystic ovary syndrome (PCOS) decreases, which is closely related to the function of oocytes' mitochondria. If mitochondrial dysfunction is involved in PCOS, it is likely to affect the function of cumulus cells. However, the mechanism of mitochondrial dysfunction remains unclear. In the present study, granulosa cells were collected from women attending the Hebei Reproductive Health Hospital and were divided into the normal ovarian reserve group (CON group) and the PCOS group. The mitochondrial ultrastructure was observed by transmission electron microscope, and the mitochondrial function was determined by detecting the ATP content, reactive oxygen species levels, the number of mitochondria and the mitochondrial membrane potential. Additionally, western blotting was used to compare the expression levels of mitochondrial kinetic protein, the related channel protein, between the two groups. In the present study, it was found that patients with PCOS had abnormal granulosa cell morphology, increased mitochondrial abnormalities, decreased mitochondrial function and disturbed mitochondrial dynamics. In addition, the silent information regulator 1/phosphorylated‑AMP‑activated protein kinase/peroxisome proliferator‑activated receptor‑γ coactivator 1α pathway expression was decreased, and it was hypothesized that the decreased mitochondrial mass in the PCOS group was associated with it.

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1	Aversa A, La Vignera S, Rago R, Gambineri A, Nappi RE, Calogero AE and Ferlin A: Fundamental concepts and novel aspects of polycystic ovarian syndrome: Expert consensus resolutions. Front Endocrinol (Lausanne). 11:5162020. View Article : Google Scholar : PubMed/NCBI
2	Gleicher N, Darmon S, Patrizio P and Barad DH: Reconsidering the polycystic ovary syndrome (PCOS). Biomedicines. 10:15052022. View Article : Google Scholar : PubMed/NCBI
3	Liu X, Wang L, Zuo X, Li C and Teng Y: Women with PCOS with a history of early pregnancy loss show a higher risk of gestational diabetes mellitus. Int J Gen Med. 14:6409–6416. 2021. View Article : Google Scholar : PubMed/NCBI
4	Sayutti N, Abu MA and Ahmad MF: PCOS and role of cumulus gene expression in assessing oocytes quality. Front Endocrinol (Lausanne). 13:8438672022. View Article : Google Scholar : PubMed/NCBI
5	Richani D, Dunning KR, Thompson JG and Gilchrist RB: Metabolic co-dependence of the oocyte and cumulus cells: essential role in determining oocyte developmental competence. Hum Reprod Update. 27:27–47. 2021. View Article : Google Scholar : PubMed/NCBI
6	Kirillova A, Smitz JEJ, Sukhikh GT and Mazunin I: The role of mitochondria in oocyte maturation. Cells. 10:24842021. View Article : Google Scholar : PubMed/NCBI
7	Li W, Cao J, Wang X, Zhang Y, Sun Q, Jiang Y, Yao J, Li C, Wang Y and Wang W: Ferruginol restores SIRT1-PGC-1α-mediated mitochondrial biogenesis and fatty acid oxidation for the treatment of DOX-induced cardiotoxicity. Front Pharmacol. 12:7738342021. View Article : Google Scholar : PubMed/NCBI
8	Tian F, Li Q, Shi L, Li J, Shi M, Zhu Y, Li H and Ge RS: In utero bisphenol AF exposure causes fetal Leydig cell dysfunction and induces multinucleated gonocytes by generating oxidative stress and reducing the SIRT1/PGC1α signals. Toxicol Appl Pharmacol. 447:1160692022. View Article : Google Scholar : PubMed/NCBI
9	Zhao Y, Zhang J, Zheng Y, Zhang Y, Zhang XJ, Wang H, Du Y, Guan J, Wang X and Fu J: NAD⁺ improves cognitive function and reduces neuroinflammation by ameliorating mitochondrial damage and decreasing ROS production in chronic cerebral hypoperfusion models through Sirt1/PGC-1α pathway. J Neuroinflammation. 18:2072021. View Article : Google Scholar : PubMed/NCBI
10	Tian L, Cao W, Yue R, Yuan Y, Guo X, Qin D, Xing J and Wang X: Pretreatment with Tilianin improves mitochondrial energy metabolism and oxidative stress in rats with myocardial ischemia/reperfusion injury via AMPK/SIRT1/PGC-1 alpha signaling pathway. J Pharmacol Sci. 139:352–360. 2019. View Article : Google Scholar : PubMed/NCBI
11	Chandrasekaran K, Anjaneyulu M, Choi J, Kumar P, Salimian M, Ho CY and Russell JW: Role of mitochondria in diabetic peripheral neuropathy: Influencing the NAD⁺-dependent SIRT1-PGC-1α-TFAM pathway. Int Rev Neurobiol. 145:177–209. 2019. View Article : Google Scholar : PubMed/NCBI
12	Kalliora C, Kyriazis ID, Oka SI, Lieu MJ, Yue Y, Area-Gomez E, Pol CJ, Tian Y, Mizushima W, Chin A, et al: Dual peroxisome-proliferator-activated-receptor-α/γ activation inhibits SIRT1-PGC1α axis and causes cardiac dysfunction. JCI Insight. 5:e1295562019. View Article : Google Scholar : PubMed/NCBI
13	Emidio GD, Placidi M, Rea F, Rossi G, Falone S, Cristiano L, Nottola S, D'Alessandro AM, Amicarelli F, Palmerini MG and Tatone C: Methylglyoxal-dependent glycative stress and deregulation of SIRT1 functional network in the ovary of PCOS mice. Cells. 9:2092020. View Article : Google Scholar : PubMed/NCBI
14	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
15	He Y, Lu Y, Zhu Q, Wang Y, Lindheim SR, Qi J, Li X, Ding Y, Shi Y, Wei D, et al: Influence of metabolic syndrome on female fertility and in vitro fertilization outcomes in PCOS women. Am J Obstet Gynecol. 221:138.e1–138.e12. 2019. View Article : Google Scholar : PubMed/NCBI
16	Gong Y, Luo S, Fan P, Zhu H, Li Y and Huang W: Growth hormone activates PI3K/Akt signaling and inhibits ROS accumulation and apoptosis in granulosa cells of patients with polycystic ovary syndrome. Reprod Biol Endocrinol. 18:1212020. View Article : Google Scholar : PubMed/NCBI
17	Guijarro LG, Sanmartin-Salinas P, Pérez-Cuevas E, Toledo-Lobo MV, Monserrat J, Zoullas S, Sáez MA, Álvarez-Mon MA, Bujan J, Noguerales-Fraguas F, et al: Actinomycin D arrests cell cycle of hepatocellular carcinoma cell lines and induces p53-dependent cell death: A study of the molecular mechanism involved in the protective effect of IRS-4. Pharmaceuticals (Basel). 14:8452021. View Article : Google Scholar : PubMed/NCBI
18	Patil K, Shinde G, Hinduja I and Mukherjee S: Compromised cumulus-oocyte complex matrix organization and expansion in women with PCOS. Reprod Sci. 29:836–848. 2022. View Article : Google Scholar : PubMed/NCBI
19	Yefimova MG, Lefevre C, Bashamboo A, Eozenou C, Burel A, Lavault MT, Meunier AC, Pimentel C, Veau S, Neyroud AS, et al: Granulosa cells provide elimination of apoptotic oocytes through unconventional autophagy-assisted phagocytosis. Hum Reprod. 35:1346–1362. 2020. View Article : Google Scholar : PubMed/NCBI
20	Lai Q, Xiang W, Li Q, Zhang H, Li Y, Zhu G, Xiong C and Jin L: Oxidative stress in granulosa cells contributes to poor oocyte quality and IVF-ET outcomes in women with polycystic ovary syndrome. Front Med. 12:518–524. 2018. View Article : Google Scholar : PubMed/NCBI
21	Zhang Q, Ren J, Wang F, Pan M, Cui L, Li M and Qu F: Mitochondrial and glucose metabolic dysfunctions in granulosa cells induce impaired oocytes of polycystic ovary syndrome through Sirtuin 3. Free Radic Biol Med. 187:1–16. 2022. View Article : Google Scholar : PubMed/NCBI
22	Chiang JL, Shukla P, Pagidas K, Ahmed NS, Karri S, Gunn DD, Hurd WW and Singh KK: Mitochondria in ovarian aging and reproductive longevity. Ageing Res Rev. 63:1011682020. View Article : Google Scholar : PubMed/NCBI
23	Guijarro LG, Cano-Martínez D, Toledo-Lobo MV, Ruiz-Llorente L, Chaparro M, Guerra I, Iborra M, Cabriada JL, Bujanda L, Taxonera C, et al: Evaluation of AIF-1 (allograft inflammatory factor-1) as a biomarker of Crohn's disease severity. Biomedicines. 10:7272022. View Article : Google Scholar : PubMed/NCBI
24	Adhikari D, Lee IW, Yuen WS and Carroll J: Oocyte mitochondria-key regulators of oocyte function and potential therapeutic targets for improving fertility. Biol Reprod. 106:366–377. 2022. View Article : Google Scholar : PubMed/NCBI
25	Zhao S, Heng N, Wang H, Wang H, Zhang H, Gong J, Hu Z and Zhu H: Mitofusins: From mitochondria to fertility. Cell Mol Life Sci. 79:3702022. View Article : Google Scholar : PubMed/NCBI
26	Liu Y, Han M, Li X, Wang H, Ma M, Zhang S, Guo Y, Wang S, Wang Y, Duan N, et al: Age-related changes in the mitochondria of human mural granulosa cells. Hum Reprod. 32:2465–2473. 2017. View Article : Google Scholar : PubMed/NCBI
27	Maremanda KP, Sundar IK and Rahman I: Role of inner mitochondrial protein OPA1 in mitochondrial dysfunction by tobacco smoking and in the pathogenesis of COPD. Redox Biol. 45:1020552021. View Article : Google Scholar : PubMed/NCBI
28	Chen L, Liu B, Qin Y, Li A, Gao M, Liu H and Gong G: Mitochondrial fusion protein Mfn2 and its role in heart failure. Front Mol Biosci. 8:6812372021. View Article : Google Scholar : PubMed/NCBI
29	Yapa NMB, Lisnyak V, Reljic B and Ryan MT: Mitochondrial dynamics in health and disease. FEBS Lett. 595:1184–1204. 2021. View Article : Google Scholar : PubMed/NCBI
30	Kalia R, Wang RY, Yusuf A, Thomas PV, Agard DA, Shaw JM and Frost A: Structural basis of mitochondrial receptor binding and constriction by DRP1. Nature. 558:401–405. 2018. View Article : Google Scholar : PubMed/NCBI
31	Kim HK, Jeon J, Song IS, Heo HJ, Jeong SH, Long LT, Thu VT, Ko TH, Kim M, Kim N, et al: Tetrahydrobiopterin enhances mitochondrial biogenesis and cardiac contractility via stimulation of PGC1α signaling. Biochim Biophys Acta Mol Basis Dis. 1865:1655242019. View Article : Google Scholar : PubMed/NCBI
32	Hao L, Zhong W, Dong H, Guo W, Sun X, Zhang W, Yue R, Li T, Griffiths A, Ahmadi AR, et al: ATF4 activation promotes hepatic mitochondrial dysfunction by repressing NRF1-TFAM signalling in alcoholic steatohepatitis. Gut. 70:1933–1945. 2021. View Article : Google Scholar : PubMed/NCBI
33	Sun L, Tian H, Xue S, Ye H, Xue X, Wang R, Liu Y, Zhang C, Chen Q and Gao S: Circadian clock genes REV-ERBs inhibits granulosa cells apoptosis by regulating mitochondrial biogenesis and autophagy in polycystic ovary syndrome. Front Cell Dev Biol. 9:6581122021. View Article : Google Scholar : PubMed/NCBI
34	Safaei Z, Bakhshalizadeh S, Nasr-Esfahani MH, Akbari Sene A, Najafzadeh V, Soleimani M and Shirazi R: Vitamin D3 affects mitochondrial biogenesis through mitogen-activated protein kinase in polycystic ovary syndrome mouse model. J Cell Physiol. 235:6113–6126. 2020. View Article : Google Scholar : PubMed/NCBI
35	Wang C, Liu T, Tong Y, Cui R, Qu K, Liu C and Zhang J: Ulinastatin protects against acetaminophen-induced liver injury by alleviating ferroptosis via the SIRT1/NRF2/HO-1 pathway. Am J Transl Res. 13:6031–6042. 2021.PubMed/NCBI
36	Jalgaonkar MP, Parmar UM, Kulkarni YA and Oza MJ: SIRT1-FOXOs activity regulates diabetic complications. Pharmacol Res. 175:1060142022. View Article : Google Scholar : PubMed/NCBI
37	Guo A, Li K and Xiao Q: Fibroblast growth factor 19 alleviates palmitic acid-induced mitochondrial dysfunction and oxidative stress via the AMPK/PGC-1α pathway in skeletal muscle. Biochem Biophys Res Commun. 526:1069–1076. 2020. View Article : Google Scholar : PubMed/NCBI
38	Ortega MA, De Leon-Oliva D, Garcia-Montero C, Fraile-Martinez O, Boaru DL, Del Val Toledo Lobo M, García-Tuñón I, Royuela M, García-Honduvilla N, Bujan J, et al: Understanding HAT1: A comprehensive review of noncanonical roles and connection with disease. Genes (Basel). 14:9152023. View Article : Google Scholar : PubMed/NCBI
39	Wang ZH, Bao XG, Hu JJ, Shen SB, Xu GH and Wu YL: Nicotinamide riboside enhances endothelial precursor cell function to promote refractory wound healing through mediating the Sirt1/AMPK pathway. Front Pharmacol. 12:6715632021. View Article : Google Scholar : PubMed/NCBI