Melatonin Ameliorates PINK1/Parkin-Mediated Mitophagy by Enhancing SIRT1 Expression in Granulosa Cells of Polycystic Ovary Syndrome Patients

Background: Mitochondrial injury in granulosa cells (GCs) is associated with the pathogenesis of polycystic ovary syndrome (PCOS). However, the protective effects of melatonin against mitochondrial injury in the GCs of PCOS remain unclear. Methods: GCs from PCOS patients and dihydrotestosterone (DHT)-treated KGN cells were used to investigate molecular mechanisms in vitro. A DHT-induced PCOS mouse model was established to examine the roles of melatonin in granulosa cells. Findings: Enhanced PINK1/Parkin-mediated mitophagy, injury to mitochondria and decreased levels of SIRT1 expression were observed in the GCs of the PCOS patients and the DHT-treated KGN cells. DHT-induced PCOS mice also showed enhanced mitophagy, decreased SIRT1 expression, an increased number of antral follicles and elevated serum testosterone and LH levels. Melatonin treatment increased the level of SIRT1 expression and ameliorated the mitochondrial function and PCOS phenotype in vitro and vivo. Knocking down SIRT1 mRNA inhibited the protective effect of melatonin. Interpretation: Melatonin protects against mitochondrial injury in GCs by enhancing SIRT1 expression to inhibit PINK1/Parkin-mediated mitophagy. Funding Statement: This study was supported by the National Natural Science Foundation of China (81571504, 81771537) and Natural Science Foundation of Jiangsu Province (BK20181117, LGY2018002). Declaration of Interests: The authors have no conflicts of interest to disclose. Ethics Approval Statement: This study received ethical approval from the Medical Ethics Committee of Affiliated Drum Tower Hospital of Nanjing University Medical School. All of the methods described here were carried out following the guidelines and regulations approved by the Medical Ethics Committee of Affiliated Drum Tower Hospital of Nanjing University Medical School. Our study conformed to the Declaration of Helsinki. All mice procedures were performed according to the guidelines of the Animal Research Institute Committee.