1 Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology and Key Laboratory of Assisted Reproduction, Ministry of Education, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital , Beijing, China .
2 Yunnan Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology , Kunming, China .
Antioxid Redox Signal. 2019 Feb 1;30(4):542-559. doi: 10.1089/ars.2017.7151. Epub 2018 Apr 13.
The mechanisms coordinating maturation with an environment-driven metabolic shift, a critical step in determining the developmental potential of human in vitro maturation (IVM) oocytes, remain to be elucidated. Here we explored the key genes regulating human oocyte maturation using single-cell RNA sequencing and illuminated the compensatory mechanism from a metabolic perspective by analyzing gene expression.
Three key genes that encode CoA-related enzymes were screened from the RNA sequencing data. Two of them, ACAT1 and HADHA, were closely related to the regulation of substrate production in the Krebs cycle. Dysfunction of the Krebs cycle was induced by decreases in the activity of specific enzymes. Furthermore, the activator of these enzymes, the calcium concentration, was also decreased because of the failure of influx of exogenous calcium. Although release of endogenous calcium from the endoplasmic reticulum and mitochondria met the requirement for maturation, excessive release resulted in aneuploidy and developmental incompetence. High nicotinamide nucleotide transhydrogenase expression induced NADPH dehydrogenation to compensate for the NADH shortage resulting from the dysfunction of the Krebs cycle. Importantly, high NADP levels activated DPYD to enhance the repair of DNA double-strand breaks to maintain euploidy.
The present study shows for the first time that exposure to the in vitro environment can lead to the decline of energy metabolism in human oocytes during maturation but that a compensatory action maintains their developmental competence.
In vitro maturation of human oocytes is mediated through a cascade of competing and compensatory actions driven by genes encoding enzymes.
协调成熟与环境驱动的代谢转变的机制，这是决定人类体外成熟（IVM）卵母细胞发育潜力的关键步骤，其机制仍有待阐明。在这里，我们使用单细胞 RNA 测序探索了调节人类卵母细胞成熟的关键基因，并从代谢角度分析基因表达阐明了补偿机制。
从 RNA 测序数据中筛选出编码 CoA 相关酶的三个关键基因。其中两个，ACAT1 和 HADHA，与克雷布斯循环中底物产生的调节密切相关。特定酶活性降低会导致克雷布斯循环功能障碍。此外，由于外源性钙流入失败，这些酶的激活剂——钙浓度也降低了。尽管内质网和线粒体释放内源性钙以满足成熟的要求，但过量的钙释放会导致非整倍体和发育无能。高烟酰胺核苷酸转氢酶表达诱导 NADPH 脱氢酶以补偿克雷布斯循环功能障碍导致的 NADH 短缺。重要的是，高 NADP 水平激活 DPYD 以增强 DNA 双链断裂的修复，从而维持整倍体。
本研究首次表明，体外环境暴露会导致人类卵母细胞在成熟过程中能量代谢下降，但补偿作用可维持其发育能力。
人类卵母细胞的体外成熟是由编码酶的基因驱动的一系列竞争和补偿作用介导的。
