Abstract
Recent studies reported the important role of autophagy in follicular development. However, the underlying molecular mechanisms remain elusive. In this study, we investigated the effect of follicle-stimulating hormone (FSH) on mouse granulosa cells (MGCs). Results indicated that autophagy was induced by FSH, which is known to be the dominant hormone regulating follicular development and granulosa cell (GC) proliferation. The activation of mammalian target of rapamycin (mTOR), a master regulator of autophagy, was inhibited during the process of MGC autophagy. Moreover, MHY1485 (an agonist of mTOR) significantly suppressed autophagy signaling by activating mTOR. The expression of hypoxia-inducible factor 1-alpha (HIF-1α) was increased after FSH treatment. Blocking hypoxia-inducible factor 1-alpha attenuated autophagy signaling. In vitro, CoCl2-induced hypoxia enhanced cell autophagy and affected the expression of beclin1 and BCL2/adenovirus E1B interacting protein 3 (Bnip3) in the presence of FSH. Knockdown of beclin1 and Bnip3 suppressed autophagy signaling in MGCs. Furthermore, our in vivo study demonstrated that the FSH-induced increase in weight was significantly reduced after effectively inhibiting autophagy with chloroquine, which was correlated with incomplete mitophagy process through the PINK1-Parkin pathway, delayed cell cycle, and reduced cell proliferation rate. In addition, chloroquine treatment decreased inhibin alpha subunit, but enhanced the expression of 3 beta-hydroxysteroid dehydrogenase. Blocking autophagy resulted in a significantly lower percentage of antral and preovulatory follicles after FSH stimulation. In conclusion, our results indicate that FSH induces autophagy signaling in MGCs via HIF-1α. In addition, our results provide evidence that autophagy induced by FSH is related to follicle development and atresia.
Highlights
Macroautophagy is a constitutive, dynamic, evolutionarily conserved catabolic process that involves the degradation and recycling of cellular constituents.[1,2] It maintains cell survival under various forms of stress conditions such as starvation,[3] hypoxia,[4] and interruption of growth signaling.[5]
A proportion of ovarian follicles are removed by atresia prior to maturation in order to promote energy investment and ovulation of viable follicles
Autophagy is closely related with the remodeling of follicle cells during the process of follicular development.[35,36]
Summary
Macroautophagy (hereafter referred to as autophagy) is a constitutive, dynamic, evolutionarily conserved catabolic process that involves the degradation and recycling of cellular constituents.[1,2] It maintains cell survival under various forms of stress conditions such as starvation,[3] hypoxia,[4] and interruption of growth signaling.[5] Autophagy is involved in many physiological and developmental processes such as cell survival, cell death, metabolism, and innate immunity.[6,7,8]. Ovarian follicle atresia is a periodic process by which immature ovarian follicles degenerate and are reabsorbed during the follicular phase of the ovarian cycle. This complicated, dynamic process is triggered by GC apoptosis.[10,11].
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