期刊
REDOX BIOLOGY
卷 18, 期 -, 页码 138-157出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.redox.2018.07.004
关键词
Melatonin; Autophagic death; FOXO1; Granulosa cells; Oxidative damage; Antioxidation-independent
资金
- National Natural Science Foundation of China [31630072, 31601939]
- Key Project of Chinese National Programs for Fundamental Research and Development (973 program) [2014CB138502]
- Natural Science Foundation of Jiangsu Province [BK20150664]
- Fundamental Research Funds for the Central Universities [KJQN201705]
- China Postdoctoral Science Special Foundation [2016T90476]
- China Postdoctoral Science Foundation [2015M581818]
- Jiangsu Planned Projects for Postdoctoral Research Funds [1501047A]
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-mediated deacetylation of FOXO1 and its interaction with ATG proteins, as well as the inhibition of autophagic death in GCs suffering oxidative stress. These findings reveal a brand new mechanism of melatonin in defense against oxidative damage to GCs by repressing FOXO1, which may be a potential therapeutic target for anovulatory disorders.
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