In pre-clinical study fetal hypoxia caused autophagy and mitochondrial impairment in ovary granulosa cells mitigated by melatonin supplement

文献类型： 外文期刊

第一作者： Zhang, Luyao

作者： Zhang, Luyao;Liu, Kexiong;Liu, Zhiqiang;Hou, Jian;Hou, Yunpeng;Zhang, Luyao;Jia, Gongxue;Tao, Haiping;Jia, Gongxue;Tao, Haiping;Jia, Gongxue;Fu, Xiangwei;Fu, Xiangwei

作者机构：

关键词： Autophagic cell death; Energy production impairment; Fetal-hypoxic expose; Mitochondrial dysfunction; PI3K/Akt/FoxO pathway; Melatonin

期刊名称：JOURNAL OF ADVANCED RESEARCH （ 影响因子：13.0； 五年影响因子：11.6 ）

ISSN： 2090-1232

年卷期： 2024 年 64 卷

页码：

收录情况： SCI

摘要： Introduction: Fetal hypoxia has long-term effects on postnatal reproductive functions and the mitochondrial impairments of ovarian granulosa cells may be one of the causes. Melatonin applied to mitigate mitochondrial dysfunction and autophagy in mammalian cells has been reported. However, the potential mechanisms by which fetal hypoxia damages reproductive function in neonatal female mice and the melatonin effects on this problem remain unclear. Objectives: This research aimed to explore the mechanism that fetal hypoxia damages reproductive function in neonatal female mice and attempt to improve the reproductive function by treating with melatonin in vivo and in vitro. . Methods: We established a fetal hypoxia model and confirmed that fetal hypoxia affects ovarian function by inducing GC excessive autophagy. Transcriptomic analysis, gene interference, cell immunofluorescence, immunohistochemistry and western blot were conducted to explore and verify the underlying mechanisms in mice GCs and KGN cells. Finally, melatonin treatment was executed on hypoxia-treated mice GCs and KGN cells and melatonin injection to fetal-hypoxia-treated mice to determine its effect. Results: The results of in vitro experiments found that fetal hypoxia led to mitochondrial dysfunction in ovarian GCs causing autophagic cell death. And the PI3K/Akt/FoxO pathway mediated the occurrence of this process by transcriptome analysis of ovarian GCs from normal and fetal hypoxia mice, which was further verified in mice GCs and KGN cells. Additionally, melatonin administration prevented autophagic injuries and mitochondrial impairments in hypoxia-treated mice GCs and KGN cells. Meanwhile, in vivo experiments by melatonin injection ameliorated oxidative stress of ovary in fetal-hypoxiatreated mice and improved their low fertility. Conclusion: Our data found that fetal hypoxia causes ovarian GCs excessive autophagy leading to low fertility in neonatal female mice and mitigated by melatonin. These results provide a potential therapy for hypoxic stress-related reproductive disorders. (c) 2024 The Authors. Published by Elsevier B.V. on behalf of Cairo University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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