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

Abstract

Introduction: 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-1a 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-1a, 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.