Research Paper Volume 14, Issue 5 pp 2335—2347
Decrease in ovarian reserve through the inhibition of SIRT1-mediated oxidative phosphorylation
- 1 Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200011, China
- 2 Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200090, China
Received: December 20, 2021 Accepted: February 24, 2022 Published: March 11, 2022https://doi.org/10.18632/aging.203942
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Copyright: © 2022 Guo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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.