Melatonin protects mouse granulosa cells against oxidative damage by inhibiting FOXO1-mediated autophagy: Implication of an antioxidation-independent mechanism

作者：Ming Shen, Yan Cao, Yi Jiang, Yinghui Wei, Honglin Liu · 发表于：Redox Biology · 年份：2018 · DOI：10.1016/j.redox.2018.07.004 · 被引用次数：174 · 研究领域：Birth, Development, and Health、Dietary Effects on Health、Genetics, Aging, and Longevity in Model Organisms

Oxidative stress has been described as a prime driver of granulosa cell (GCs) death during follicular atresia. Increasing evidence suggests potential roles of melatonin in protecting GCs from oxidative injury, though the underlying mechanisms remain largely undetermined. Here we first proposed that the inhibition of autophagy through some novel regulators contributes to melatonin-mediated GCs survival under conditions of oxidative stress. Oxidant-induced loss of GCs viability was significantly reduced after melatonin administration, which was correlated with attenuated autophagic signals upon oxidative stimulation both in vivo and in vitro. Compared with melatonin treatment, suppression of autophagy displayed similar preventive effect on GCs death during oxidative stress, but melatonin provided no additional protection in GCs pretreated with autophagy inhibitors. Notably, we found that melatonin-directed regulation of autophagic death was independent of its antioxidation/radical scavenging ability. Further investigations identified FOXO1 as a critical downstream effector of melatonin in promoting GCs survival from oxidative stress-induced autophagy. Specifically, suppression of FOXO1 via the melatonin-phosphatidylinositol 3-kinase (PI3K)-AKT axis not only improved GCs resistance to oxidative stress, but also abolished the autophagic response, from genes expression to the formation of autophagic vacuoles. Moreover, the activation of SIRT1 signaling was required for melatonin-m...