Circadian Clock Genes REV-ERBs Inhibits Granulosa Cells Apoptosis by Regulating Mitochondrial Biogenesis and Autophagy in Polycystic Ovary Syndrome.

Xue Xue,Songguo Xue,Lihua Sun,Caixia Zhang,Rongxiang Wang,Hui Tian,Qiuju Chen,Shaorong Gao,Yu Liu,Hongjuan Ye

doi:10.3389/fcell.2021.658112

Abstract

Polycystic ovary syndrome (PCOS) is an endocrinopathy with complex pathophysiology that is a common cause of anovulatory infertility in women. Although the disruption of circadian rhythms is indicated in PCOS, the role of the clock in the etiology of these pathologies has yet to be appreciated. The nuclear receptors REV-ERBα and REV-ERBβ are core modulators of the circadian clock and participate in the regulation of a diverse set of biological functions. However, in PCOS, the expression of REV-ERBs and their effects remain unclear. Here, we demonstrate that the levels of REV-ERBα and REV-ERBβ expression were lower in the granulosa cells of PCOS patients than in control subjects. In vitro, we found that the overexpression of REV-ERBα and REV-ERBβ, and their agonist SR9009, promoted the expression of mitochondrial biosynthesis genes PGC-1α, NRF1, and TFAM and inhibited autophagy in KGN cells. Our results also indicate that REV-ERBα and REV-ERBβ can inhibit apoptosis in granulosa cells and promote proliferation. Importantly, the REV-ERB agonist SR9009 ameliorates abnormal follicular development by promoting mitochondrial biosynthesis and inhibiting autophagy in a mouse PCOS model. This allows us to speculate that SR9009 has potential as a therapeutic agent for the treatment of PCOS.

Highlights

Polycystic ovary syndrome (PCOS) is a common endocrinopathy with complex pathophysiology that can result in anovulatory infertility in women (Tanbo et al, 2018; Khan et al, 2019; Dehghani Firoozabadi et al, 2020)
To determine if the expression of REV-ERBs was altered in PCOS, we first determined the level of REV-ERBs expression in the granulosa cells of patients with PCOS compared to control subjects
These results indicate that down-regulated REVERBs may be associated with apoptosis in the granulosa cells of patients with PCOS

Summary

INTRODUCTION

Polycystic ovary syndrome (PCOS) is a common endocrinopathy with complex pathophysiology that can result in anovulatory infertility in women (Tanbo et al, 2018; Khan et al, 2019; Dehghani Firoozabadi et al, 2020). Studies have shown that reduced mitochondrial biosynthesis promotes cell apoptosis (Diebold et al, 2015; Zhang et al, 2017; Wood Dos Santos et al, 2018) Another key player that plays an important role in follicular development is the autophagy pathway. A study indicated that one such biological clock genes, BMAL1 (a cell-autonomous circadian clock oscillator) is highly downregulated in Granulosa cells (GCs) of PCOS patients, when compared to the non-PCOS group (Zhang et al, 2016) Another key circadian rhythm regulator is nuclear receptors REV-ERBα and REV-ERBβ (Bugge et al, 2012). Other studies have indicated that REV-ERB agonists display anticancer properties by inhibiting lipogenesis and autophagy (Stujanna et al, 2017; Sulli et al, 2018) These studies imply that REV-ERBs may play a role in PCOS through the regulation of mitochondrial biogenesis and autophagy in granulocytes, the exact mechanism requires further study. We investigated the expression of REV-ERBs in follicular granulocytes from PCOS patients and elucidated the influence of the REV-ERBs and REV-ERB agonist, SR9009, on mitochondrial biosynthesis, and autophagy in KGN cells and in PCOS animal models

MATERIALS AND METHODS

RESULTS

DISCUSSION

ETHICS STATEMENT