Association between mitochondrial SIRTs (SIRT3, SIRT4, and SIRT5) and PCOS

Abstract

Polycystic ovary syndrome (PCOS) is a complex endocrine and metabolic disorder with unclear pathogenesis. Increasing evidence suggests that oxidative stress and mitochondrial dysfunction contribute to PCOS development. Sirtuins (SIRTs), especially mitochondrial SIRTs (SIRT3, SIRT4, and SIRT5), are critical regulators of mitochondrial metabolism, energy homeostasis, and oxidative stress, and may be involved in the pathophysiology of PCOS. However, their specific roles remain controversial. We hypothesize that the dysregulation of mitochondrial SIRTs contributes to PCOS by promoting mitochondrial dysfunction and oxidative stress. To test this hypothesis, we enrolled patients from the Reproductive Medicine Center of the Affiliated Hospital of Youjiang Medical University for Nationalities, with PCOS patients assigned to the experimental group and non-PCOS patients to the control group. We collected peripheral blood mononuclear cells and follicular fluid granulosa cells (GCs) from the two groups of patients, and used PCR to detect the expression of SIRTs, oxidative stress indexes, and mitochondrial function indexes. The correlation between the expression of SIRTs and the expression of oxidative stress and mitochondrial function indicators, as well as the clinical parameters of PCOS was investigated using Pearson or Spearman correlation analysis. The results showed that the expression of SIRT3 and SIRT5 was significantly lower in mononuclear cells and GCs of PCOS patients (P < 0.05), and there was no significant difference in the expression of SIRT4 (P > 0.05). In GCs of PCOS patients, higher SIRT3 expression was associated with lower levels of age, androgen (T), fasting insulin and insulin resistance index (HOMA-IR) (P < 0.05); while higher SIRT5 expression was associated with lower levels of fasting insulin and HOMA-IR (P < 0.05). In addition, oxidative stress-related indicator (CAT) and mitochondrial function indicator (MTTFA) were significantly downregulated in PCOS patients (P < 0.05). Notably, the expression levels of SIRT3 and SIRT5 were significantly positively correlated with the expression levels of CAT and MTTFA (P < 0.05). ELISA results indicated the levels of SIRT3 and SIRT5 proteins in the follicular fluid of PCOS were also significantly reduced. In conclusion, our results suggest that SIRT3 and SIRT5 downregulation contributes to the development of PCOS by mediating mitochondrial dysfunction and oxidative stress, providing new therapeutic targets and potential strategies for PCOS treatment.

Keywords: Pathogenesis; Polycystic ovary syndrome; SIRT3; SIRT4; SIRT5.

Fig. 1

The expression levels of SIRT3 and SIRT5 were decreased in peripheral blood mononuclear cells and GCs from patients with PCOS. (A–C) The relative expression levels of SIRT3, SIRT4, and SIRT5 were analyzed in peripheral blood mononuclear cells from women with PCOS (n = 103) and control subjects (n = 102). (D, E) The relative expression levels of SIRT3 and SIRT5 were analyzed in GCs from women with PCOS (n = 106) and control subjects (n = 102)

Fig. 2

Expression levels of SIRT3 and SIRT5 mRNA in GCs from different PCOS subgroups. (A, D) Comparison of SIRT3, SIRT5 expression levels in Control, obe-Control, PCOS and obe-PCOS. (B, E) Comparison of SIRT3, SIRT5 expression levels in Control, IR-PCOS and NIR-PCOS. (C, F) Comparison of SIRT3, SIRT5 expression levels in Control, HA-PCOS and NHA-PCOS

Fig. 3

The relative expression levels of SIRT3 and SIRT5 were correlated with clinical characteristics in both PCOS and Control groups. (A–D) The associations between SIRT3 expression and age, T, FINS, and HOMA-IR were examined in both the control group and the PCOS group. (E–F) The associations between SIRT5 expression and FINS and HOMA-IR were examined in both the control group. Statistical analysis was conducted using Pearson’s correlation test. The control group is represented by blue dots, while the PCOS group is represented by red dots

Fig. 4

The expression levels of CAT and MTTFA were decreased in GCs from patients with PCOS and the relative expression levels of SIRT3 and SIRT5 were correlated with the expression of CAT and MTTFA in both control women and PCOS patients. (A–B) The relative expression levels of CAT and MTTFA were analyzed in GCs from women with PCOS (n = 106) and control subjects (n = 102). (C–D) Correlation between SIRT3 expression levels and CAT and MTTFA expression levels. (E–F) Correlation between SIRT5 expression levels and CAT and MTTFA expression levels

Fig. 5

The protein abundance levels of SIRT3, SIRT5, CAT, and MTTFA were decreased in follicular fluid from patients with PCOS, and the protein levels of SIRT3 and SIRT5 were correlated with the protein levels of CAT and MTTFA in both control women and PCOS patients. (A–D) The protein abundance levels of SIRT3, SIRT5, CAT, and MTTFA were analyzed in follicular fluid from women with PCOS (n = 20) and control subjects (n = 21). (E–F) Correlation between SIRT3 protein levels and CAT and MTTFA protein levels. (G–H) Correlation between SIRT5 protein levels and CAT and MTTFA protein levels