Mitoguardin-1/2调控生殖内分泌和排卵及其参与原发性卵巢功能不全的发病机制研究

Premature ovarian insufficiency(POI) is one of the most common reproductive endocrine diseases with life-changing ovarian dysfunction, defective ovulation and amenorrhea. It affected about 1% women by the age of 40 physically and psychologically, while the genetic factors remain to be elucidated. Recently, our group found the novel mitochondria dynamics regulating genes Miga1/2 which could mediate mitochondria fusion through Mito-PLD. Miga1/2 knockout led to mitochondria fragmentation and disruption of mitochondria functions, which led to ovulation defect and finally subfertility in female mice. Further results showed that Miga1/2 express significantly in mouse ovary granulosa cells of growing follicle and corpus luteum, granulosa cells secreted progesterone was greatly decreased after Miga1/2 knockout. While the insufficiency of progesterone is the leading cause of infertility and premature ovarian insufficiency. Thus, Miga1/2 are more likely to affect hormone synthesis or secretion in ovary granulosa cells and cause ovary failure. This project is to detect the mitochondrial morphology, structure and function in ovary granulosa cells of Miga1/2 knockout mouse, elucidate the functional mechanism of Miga1/2 in ovarian endocrine and ovulation, and finally illuminate the involving pathogenesis of POI using clinical cases.

原发性卵巢功能不全（POI）是育龄妇女中常见的一种卵巢功能逐渐衰竭，且具有排卵障碍性闭经的生殖内分泌疾病，该疾病影响了将近1%育龄女性的身心健康，但其遗传致病因素尚不清楚。本研究组近期发现新线粒体动态调节基因Miga1/2 能够通过Mito-PLD介导线粒体融合，而Miga1/2 敲除后能够导致线粒体形态碎片化、线粒体功能受损并导致雌性小鼠排卵障碍，最终生育力下降。进一步研究发现Miga1/2在卵巢窦卵泡和黄体颗粒细胞中均有显著表达，而在Miga1/2敲除小鼠中孕酮产生水平大大下降。而孕酮不足是直接导致不孕和POI的元凶，因此Miga1/2极有可能调节了卵巢颗粒细胞中相关激素的合成并导致卵巢功能衰竭。本项目将利用Miga1/2敲除小鼠检测卵巢颗粒细胞中线粒体形态结构以及功能，阐明Miga1/2在卵巢内分泌中的作用机制，最终通过临床病例验证Miga1/2参与POI的发病机制。

卵巢颗粒细胞是介导卵泡发育、排卵及生殖内分泌功能的主要场所，与卵巢功能具有密切联系。线粒体在卵巢颗粒细胞功能中发挥重要调控作用，但线粒体在细胞中处于一个不断融合与分裂的动态变化过程中，线粒体在不同时期颗粒细胞中的具体作用也不同。本项目主要研究了线粒体动态调节基因Miga1/2在小鼠中敲除后对卵巢颗粒细胞线粒体形态结构以及功能的影响，在小鼠卵泡发育过程中对颗粒细胞内分泌功能的作用及参与卵巢功能不全的发病机制。研究证实了线粒体动态调节基因Miga1/2分别或同时敲除后对不同时期的卵巢颗粒细胞中线粒体形态结构及功能均造成一定损伤，从而诱导大量卵泡闭锁并造成颗粒细胞中排卵障碍、黄体期颗粒细胞孕酮分泌功能缺陷，从而导致卵巢功能不全。该项目阐明了线粒体动态调节基因Miga1/2在卵巢颗粒细胞内分泌功能及卵泡发育中的关键作用，为原发性卵巢功能不全的诊治提供研究依据。

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