FSH protects mouse granulosa cells from oxidative damage by repressing mitophagy
Ming Shen1, Yi Jiang1, Zhiqiang Guan1
1College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China.
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.
Insights
Follicle-stimulating hormone (FSH) protects granulosa cells from oxidative stress by inhibiting mitophagy, a key pathway in cell death. This discovery reveals a novel mechanism for FSH in preserving ovarian cell survival.
Area of Science:
- Reproductive Biology
- Cellular Biology
- Endocrinology
Background:
- Oxidative stress contributes to granulosa cell (GC) death during follicular atresia.
- Follicle-stimulating hormone (FSH) is known to protect GCs from oxidative injury, but the mechanism is unclear.
Purpose of the Study:
- To elucidate the mechanism by which FSH protects granulosa cells from oxidative stress-induced death.
- To investigate the role of mitophagy in FSH-mediated GC survival.
Main Methods:
- FSH treatment of GCs under oxidative stress conditions.
- Assessment of GC viability and mitophagy activation.
- Inhibition of mitophagy using specific inhibitors.
- RNA interference (RNAi) to knockdown PINK1 expression.
- Analysis of PINK1 and Parkin protein levels and localization.
Main Results:
- FSH treatment significantly reduced oxidative stress-induced GC death by inhibiting mitophagy.
- FSH suppressed the induction of PINK1 and subsequent Parkin translocation to mitochondria.
- Blocking mitophagy alone provided protection, but FSH did not offer additional benefit when mitophagy was already inhibited.
- Knockdown of PINK1 confirmed the involvement of the FSH-PINK1-Parkin-mitophagy pathway in GC survival.
Conclusions:
- FSH protects granulosa cells from oxidative damage by inhibiting PINK1-Parkin-mediated mitophagy.
- This study identifies a novel role for FSH in regulating mitophagy and promoting GC survival under oxidative stress.
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