FSH protects mouse granulosa cells from oxidative damage by repressing mitophagy.

Ming Shen,Shao-Chen Sun,Honglin Liu,Yi Jiang,Zhiqiang Guan,Yan Cao

doi:10.1038/srep38090

Abstract

Oxidative stress has been implicated in triggering granulosa cell (GC) death during follicular atresia. Recent studies suggested that follicle-stimulating hormone (FSH) has a pivotal role in protecting GCs from oxidative injury, although the exact mechanism remains largely unknown. Here, we report that FSH promotes GC survival by inhibiting oxidative stress-induced mitophagy. The loss of GC viability caused by oxidative stress was significantly reduced after FSH treatment, which was correlated with impaired activation of mitophagy upon oxidative stress. Compared with FSH treatment, blocking mitophagy displayed approximate preventive effect on oxidative stress-induced GC death, but FSH did not further restore viability of cells pretreated with mitophagy inhibitor. Importantly, FSH suppressed the induction of serine/threonine kinase PINK1 during oxidative stress. This inhibited the mitochondrial translocation of the E3 ligase Parkin, which is required for the subsequent clearance of mitochondria, and ultimately cell death via mitophagy. In addition, knocking down PINK1 using RNAi confirmed the role of the FSH-PINK1-Parkin-mitophagy pathway in regulating GC survival under oxidative conditions. These findings introduce a novel physiological function of FSH in protecting GCs against oxidative damage by targeting PINK1-Parkin-mediated mitophagy.

Highlights

Oxidative stress has been implicated in triggering granulosa cell (GC) death during follicular atresia
Immunofluorescence staining using anti-light chain 3 (LC3) antibodies revealed that treating GCs with Follicle stimulating hormone (FSH) strongly attenuated the oxidative stress-induced expression of LC3 (Supplementary Fig. 1 and Fig. 1A), which was colocalized with the acidic autophagic vacuoles (Supplementary Fig. 1)
The ability of FSH to inhibit autophagy was demonstrated by monitoring GCs that had been transfected with a vector expressing GFP-LC3

Summary

Introduction

Oxidative stress has been implicated in triggering granulosa cell (GC) death during follicular atresia. Recent studies have provided evidence that other forms of programmed cell death (PCD) such as autophagy can be activated, mainly in GCs, during follicular atresia[15,16]. These observations were further supported by reports that GC death could be induced by oxidized LDL (oxLDL)-dependent lectin-type oxLDL receptor (LOX1)-activated autophagy[17,18]. Obese women with high levels of oxLDL displayed increased oxidative stress in the ovaries, which led to a higher rate of anovulatory infertility[17] This raises the question of whether the ability of FSH to protect against oxidative damage is related to the suppression of autophagic GC death. Several forms of autophagy that lead to the degradation of specific organelles have been described, including ribophagy for ribosome-targeted degradation[19], mitophagy for mitochondria-targeted degradation[20], pexophagy www.nature.com/scientificreports/

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Conclusion