Decrease in ovarian reserve through the inhibition of SIRT1-mediated oxidative phosphorylation.

Lu Guo,Weigui Wang,Xiaocheng Liu,Hua Chen,Chao Gu,Bin Li

doi:10.18632/aging.203942

Abstract

Objective: To establish an oxidative stress-induced model of premature ovarian insufficiency (POI) and to explore the effect of SIRT1 and mitochondrial oxidative phosphorylation on the ovarian reserve.Methods: Mice were treated with intraperitoneal injections of 3-nitropropionic acid (3-NPA) at different doses and for different time periods to induce a model of POI. Subsequently, the efficiency of each regimen was evaluated. The expression of SIRT1 in ovarian tissue was examined. Then, SIRT1 was knocked down in human luteinized granulosa cells (GCs), and its function and related receptor and gene expression were examined. Finally, a SIRT1 antagonist and agonist were used to explore the effects of SIRT1 on ovarian function in vivo and on the change in mitochondrial oxidative phosphorylation complexes (OXPHOS).Results: Decreases in ovarian reserve were successfully induced through the intraperitoneal injection of 40 mg/kg 3-NPA for 3 weeks, and SIRT1 was down-regulated in the model group. The knockdown of SIRT1 impaired the estrogen synthesis capacity of human GCs and decreased the expression of related genes. 3-NPA and SIRT1 antagonist Ex-527 decreased ovarian function and inhibited OXPHOS. In contrast, the SIRT1 agonist resveratrol promoted the recovery of ovarian function in the model group and improved OXPHOS. Additionally, P53, CASPASE 3, and BAX were down-regulated and BCL2 was up-regulated in the 3-NPA and Ex-527 groups; opposite trends were observed after resveratrol treatment.Conclusions: The intraperitoneal injection of 40 mg/kg 3-NPA for 3 weeks could effectively induce POI. The increase in oxidative stress inhibited SRIT1 and mitochondrial oxidative phosphorylation, inducing follicular apoptosis.

Highlights

With the delay in female childbearing age and the initiation of the three-child policy, more and more attention has been paid to problems associated with ovarian aging
Mice were treated with intraperitoneal injections of 3-nitropropionic acid (3-NPA) at different doses and for different time periods to induce a model of premature ovarian insufficiency (POI)
Decreases in ovarian reserve were successfully induced through the intraperitoneal injection of 40 mg/kg 3-NPA for 3 weeks, and SIRT1 was down-regulated in the model group

Summary

INTRODUCTION

With the delay in female childbearing age and the initiation of the three-child policy, more and more attention has been paid to problems associated with ovarian aging. Premature ovarian insufficiency (POI) is a common cause of early menopause, affecting about 1-2% of women of childbearing age [1]. Elevated levels of oxidative stress are considered to be the main cause of decline in oocyte quality [2]. Oxidative stress, which is related to mitochondrial dysfunction — a cause of ovarian aging — is considered as an important contributor to premature ovarian insufficiency (POI) [3]. Decreased SIRT1 levels were shown to cause mitochondrial dysfunction by increasing oxidative stress and DNA damage, leading to infertility [7]. The relationship between SIRT1 and mitochondrial oxidative phosphorylation in POI models has so far remained unclear. This study aimed to establish a 3-NPAinduced model of POI and to explore the role of SIRT1 and oxidative phosphorylation in this process

RESULTS

DISCUSSION

Findings

MATERIALS AND METHODS