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

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.

The role of oxidative stress in ovarian aging: a review

“…Sirt1 deletion in oocytes led to reduced oocyte quality, the inhibition of oocyte division, and increased OS damage during the embryonic period, ultimately causing negative effects on pregnancy outcome [ 165 ]. The knockdown of Sirt1 in granulosa cells was found to impair E 2 synthesis and secretion and significantly reduce the expression of E 2 -related receptors (ESR, FSHR and AMHR2) [ 166 ]. In addition, Sirt1 mediates the activation of peroxisome proliferator-activated receptor gamma coactivator l-alpha (PGC1α), further promoting mitochondrial biogenesis and oxidative phosphorylation during primordial follicle activation [ 167 ].…”

Identification of the active ingredients and pharmacological effects of Kuntai capsules in the treatment of primary ovarian insufficiency: A review

“…Moreover, it is increasingly believed that oxidative stress may contribute to POI pathogenesis. [38] Patients with POI have increased plasma levels of advanced oxidation protein products, which induce reactive oxygen species generation, resulting in the inhibition of ovarian granulosa cell proliferation, which could lead to the occurrence of POI in vivo. [39] Some antioxidants, such as melatonin, resveratrol, and dehydroepiandrosterone have considerable beneficial effects on the ovarian reserve by reducing oxidative stress.…”

Transcriptome profiling of equine ovarian cortex during foetal and adult stages

“…Thermogenesis is essential for warm‐blooded animals to ensure normal cellular and physiological function under conditions of environmental challenge, and oestrogen can increase sympathetic nerve activity in brown adipose tissue, resulting in thermogenesis (Martinez de Morentin et al., 2014; Sievers et al., 2022; Steiner & Berry, 2022). Oestrogen‐related receptor α regulates genes involved in fatty acid oxidation and oxidative phosphorylation in muscle (Kitamura et al., 2020), and the increase in oxidative stress inhibits mitochondrial oxidative phosphorylation and induces follicular apoptosis (Guo et al., 2022). Efficient thermogenesis and oxidative phosphorylation may meet the needs of this period, when oogonia and primordial follicles begin to appear in the central region of the ovary (Barreto et al., 2018).…”