Acetate ameliorates ovarian mitochondrial dysfunction in letrozole-induced polycystic ovarian syndrome rat model by improving mitofusin-2

Abstract

Androgen excess and metabolic abnormality largely contribute to the pathogenesis of polycystic ovarian syndrome (PCOS), which primarily precipitates ovarian dysfunction and infertility in reproductive-age women. Impaired mitochondrial function and epigenetic alteration have been linked to the development of PCOS. However, it is unknown whether acetate would exert a therapeutic effect on ovarian mitochondrial dysfunction in PCOS. Herein, the study hypothesized that acetate reverses ovarian mitochondrial dysfunction in experimental PCOS rat model, possibly through modulation of mitofusin-2 (MFn2). Eight-week-old female Wistar rats were randomized into four groups (n = 5). Induction of PCOS was performed by 1 mg/kg letrozole (p.o.), administered for 21 days. Thereafter, the rats were treated with acetate (200 mg/kg; p.o.) for 6 weeks. The PCOS rats demonstrated androgen excess, multiple ovarian cysts, elevated anti-mullerian hormone and leptin and decreased SHBG, adiponectin and 17-β estradiol with corresponding increase in ovarian transforming growth factor-β1. Additionally, inflammation (tumor growth factor and nuclear factor-kB), elevated caspase-6, decreased hypoxia-inducible factor-1α and elevated histone deacetylase-2 (HDAC2) were observed in the ovaries of PCOS rats, while mitochondrial abnormality with evidence of decreased adenosine triphosphate synthase and MFn2 was observed in rats with PCOS. Treatment with acetate reversed the alterations. The present results collectively suggest that acetate ameliorates ovarian mitochondrial abnormality, a beneficial effect that is accompanied by MFn2 with consequent normalization of reproductive-endocrine profile and ovarian function. Perhaps, the present data provide hope for PCOS individuals that suffer infertility.

Keywords: Androgen; HDAC2; Infertility; Mitochondrial dysfunction; Mitofusin-2; PCOS.

Fig. 1

Sodium acetate’s impact on testosterone (a), 17β-estradiol (b), anti-mullerian hormone (c), sex hormone binding globulin (d), and ovarian histology (e) in experimental PCOS rats. Data are expressed with mean ± SD, n = 5. (*p < 0.05 vs control, #p < 0.05 vs PCOS). Polycystic ovarian syndrome (PCOS); control (CONT); sodium acetate (SATE); anti-mullerian hormone (AMH); sex hormone binding globulin (SHBG)

Fig. 2

Sodium acetate’s impact on plasma leptin (a), adiponectin (b), and transforming growth factor-β1 (c) in experimental PCOS rats. Data are expressed with mean ± SD, n = 5. (*p < 0.05 vs control, #p < 0.05 vs PCOS). Polycystic ovarian syndrome (PCOS); control (CONT); sodium acetate (SATE); transforming growth factor-β1 (TGF-β1)

Fig. 3

Sodium acetate’s impact on ovarian TNF-α (a), NF-kB (b), Caspase-6 (c), and HIF-1α (d) in experimental PCOS rats. Data are expressed with mean ± SD, n = 5. (*p < 0.05 vs control, #p < 0.05 vs PCOS). Polycystic ovarian syndrome (PCOS); Control (CONT); sodium acetate (SATE); tumor necrosis factor-α (TNF-α); nuclear factor-kappaB (NF-kB); hypoxia inducible factor-1α (HIF-1 α)

Fig. 4

Sodium acetate’s impact on ovarian mitochondrial ATP synthase (a), mitofusin-2 (b), and HDAC2 (C) in experimental PCOS rats. Data are expressed with mean ± SD, n = 5. (*p < 0.05 vs control, #p < 0.05 vs PCOS). Polycystic ovarian syndrome (PCOS); control (CONT); sodium acetate (SATE); adenosine triphosphate (ATP); mitofusin-2 (MFn2); histone deacetylase-2 (HDAC2)