NAD+/SIRT2调控线粒体质量控制在卵巢早衰所致牛卵母细胞成熟障碍中的作用机制

卵巢早衰引起的卵母细胞成熟障碍是高产母牛不孕的根本原因之一。已有研究证实线粒体质量控制缺陷是细胞衰老的关键机制，然而衰老相关信号分子调节卵母细胞成熟的机制尚未阐明。我们前期发现NAD+/SIRT2下调与牛衰老卵母细胞的线粒体功能异常有关，且SIRT2失活阻断了NAD+信号对卵母细胞成熟障碍的改善作用。据此我们首次提出NAD+/SIRT2通过线粒体质量控制调控卵母细胞成熟的新设想。本项目拟从线粒体质量控制的关键生理环节入手，运用靶向过表达、定点突变等手段，明确NAD+/SIRT2介导的线粒体质量控制对衰老卵母细胞成熟的影响；筛选其调节线粒体生物合成与分裂-融合平衡偏移的关键靶蛋白；揭示NAD+/SIRT2影响线粒体自噬的具体环节和分子途径。本研究从去乙酰化调控线粒体质量的全新视角解析NAD+/SIRT2影响衰老卵母细胞成熟的分子机制，为提高衰老卵母细胞成熟质量和延长母牛繁殖年限提供新思路。

The failure of oocyte maturation caused by premature ovarian failure is one of the fundamental causes of infertility in high-yielding cows. Studies have confirmed that mitochondrial quality control defect is the key mechanism of cellular aging, whereas the mechanism by which aging-related signal molecules regulate oocyte maturation has not yet been elucidated. We previously found that the down-regulation of NAD+/SIRT2 is positively correlated with mitochondrial dysfunction, and the beneficial effect of NAD+ signaling on maturation failure is suppressed by SIRT2 inactivity in bovine aging oocytes. Based on these observations, we propose for the first time a new hypothesis that NAD+/SIRT2 regulates oocyte maturation through mitochondrial quality control. This project intends to study the underlying mechanism from the key physiological aspects of mitochondrial quality control. Here, the targeted over-expression and site-directed mutation will be employed to: investigate the effect of NAD+/SIRT2-mediated mitochondrial quality control on the maturation of aging oocytes; screen its key target proteins that regulate mitochondrial biosynthesis and division-fusion balance shift; reveal the specific links and molecular pathways of NAD+/ SIRT2-mediated mitochondrial autophagy. In this study, it will be clarified that the underlying mechanism of NAD+/SIRT2 affecting the maturation of aging oocytes through a new perspective of deacetylation-mediated mitochondrial quality control, and provided new ideas for improving the maturation quality of aged oocytes and prolonging the reproduction period of cows.