Melatonin attenuates Drp1-mediated excessive mitochondrial fission through SIRT1 upregulation in granulosa cells of PCOS

Background Mitochondrial dysfunction in granulosa cells (GCs) has been implicated in the pathogenesis of polycystic ovary syndrome (PCOS). Our previous studies showed that melatonin alleviated mitochondrial dysfunction by upregulating SIRT1 (NAD-dependent deacetylase sirtuin-1) expression. Dynamin-related protein 1 (Drp1) mediated mitochondrial fission is critical for maintaining intact mitochondrial function. While, whether mitochondrial fission contributes to mitochondrial dysfunction in the GCs of PCOS, and whether melatonin ameliorates mitochondrial impairment through the suppression of excessive fission remain unclear. Results In this study, transmission electron microscopy showed that the mitochondria were overly divided and tended to be fragmented, while the average mitochondrial area and the aspect ratio (AR) were decreased in the GCs of PCOS patients and dihydrotestosterone (DHT)-induced PCOS-like mice, which indicated excessive mitochondrial fission in PCOS GCs. Meanwhile, the expression of mitochondrial Drp1 in the KGN cells treated with DHT and in DHT-induced PCOS mice was significantly increased. In vivo and in vitro studies showed that melatonin treatment decreased the level of Drp1, while increasing the values of the average mitochondrial area and AR. Simultaneously, the mitochondrial ROS expression was down-regulated, and the mitochondrial membrane potential was up-regulated under the melatonin treatment, demonstrating melatonin may ameliorate excessive mitochondrial fission to improve the mitochondrial dysfunction in the GCs of PCOS. Furthermore, melatonin treatment upregulated SIRT1 expression, however, silencing SIRT1 mRNA attenuated its protective effect against Drp1. Conclusions Melatonin potentially attenuates excessive mitochondrial fission mediated by Drp1, through the upregulation of SIRT1 in GCs. This finding suggests that mitochondrial fission may represent a novel therapeutic target for PCOS treatment.