Mitochondrial Dynamics in Female Reproduction

项目摘要 线粒体适合度对于它们在不同的细胞和发育过程中的适当功能至关重要。 强有力的证据将线粒体功能障碍与人类生育能力降低联系起来。然而，机制 这些联系的基础，以及这种线粒体缺陷的任何潜在治疗方法是否可以 治疗这些不孕症的病例，仍然未知。线粒体的特征、活动和功能与 通过线粒体融合（mitofusion）和分裂（fistula）调节，统称为线粒体融合（mitofusion）和分裂（mitochondrial fistula）。 动力学来自体细胞的越来越多的证据支持线粒体动力学不仅 使个体线粒体对发育刺激和代谢需求的协调反应成为可能， 还能确保线粒体的健康此外，增加线粒体动力学减少突变 线粒体在果蝇卵母细胞，强烈建议保守的作用，线粒体动力学， 调节线粒体在繁殖中的适应性。在本补充研究的母研究R 01中，我们的目标是 揭示了精原干细胞分化和雄性生殖的新的功能机制 细胞线粒体适应性通过适当平衡的有丝分裂和融合来调节。我们已经生成 一系列转基因小鼠模型来实现这一目标，但只需要雄性小鼠。上 另一方面，已发表的研究表明，线粒体动力学保守地调节哺乳动物 在两性中繁殖，但通过性别特异性机制。每个成熟的卵母细胞含有约 100，000个线粒体，比男性生殖细胞多500倍，这表明非常高的线粒体 需要开展支持女性生殖的活动。条件性基因敲除的研究 女性生殖细胞中的融合或分裂因子确实支持线粒体动力学是不稳定的， 卵巢卵泡储备功能这项补充研究旨在揭示线粒体动力学的作用 在女性生育力和潜在机制方面，与母体R 01在科学上互补。我们将 成本有效地使用来自相同育种过程的雌性突变小鼠用于所提出的实验， 在操作上与父R 01互补。使用线粒体DNA突变小鼠和新的 丝裂融合激动剂，我们将确定对女性生殖和线粒体功能的影响， 通过增强线粒体动力学来适应。研究结果将从根本上推动 线粒体生物学和生殖医学通过揭示基于性别的共性， 哺乳动物生殖的线粒体调节的差异。我们的研究还将为一部小说提供信息， 治疗线粒体功能障碍导致的女性生育能力受损的策略。这项研究的结果将 大力推进与妇女健康有关的生殖研究，响应这一具体目标的呼吁， “性和/或性别影响研究行政补充”，并为 “2019-2023年跨NIH妇女健康研究战略计划”的目标。

PROJECT SUMMARY Mitochondrial fitness is critical for their proper functions in diverse cellular and developmental processes. Strong evidence links mitochondrial dysfunction to reduced fertility in humans. However, the mechanism underlying these connections, and whether any potential treatments of such mitochondrial defects may remedy these infertile cases, remain unknown. Mitochondrial features, activities, and functions are tightly regulated via mitochondrial fusion (mitofusion) and fission, collectively known as mitochondrial dynamics. Accumulating evidence from somatic cells support that mitochondrial dynamics not only enable coordinated responses of individual mitochondria to developmental stimuli and metabolic needs, but also ensure mitochondrial fitness. In addition, increased mitochondrial dynamics reduce mutant mitochondria in Drosophila oocytes, strongly suggesting conserved roles of mitochondrial dynamics in regulating mitochondrial fitness in reproduction. In the parent R01 of this supplement study, we aim to unveil novel functional mechanisms of how spermatogonial stem cell differentiation and male germ cell mitochondrial fitness are regulated by properly balanced mitofusion and fission. We have generated a series of genetically modified mouse models to achieve this goal but will only need male mice. On the other hand, published studies suggest that mitochondrial dynamics conservatively regulate mammalian reproduction in both sexes but via sex-specific mechanisms. Each mature oocyte contains about 100,000 mitochondria, 500-fold more than male germ cells, suggesting that very high mitochondrial activities are needed to support female reproduction. Studies with conditional knockouts of either pro- fusion or fission factors in female germ cells indeed support that mitochondrial dynamics are dispensable for ovarian follicular reserve. This supplement study aims to unveil the role of mitochondria dynamics in female fertility and underlying mechanisms, scientifically complementary to the parent R01. We will cost-efficiently use female mutant mice from the same breeding process for the proposed experiments, operationally complementary to the parent R01. Using mitochondrial DNA mutator mice and novel mitofusion agonists, we will determine the functional impacts on female reproduction and mitochondrial fitness by augmented mitochondrial dynamics. Study findings will fundamentally advance research in both mitochondrial biology and reproductive medicine by revealing sex-based commonalities and differences in the mitochondrial regulation of mammalian reproduction. Our study will also inform a novel strategy to treat impaired female fertility due to mitochondrial dysfunction. Findings from this study will significantly advance reproductive research related to women’s health, answering the call of this specific “Administrative Supplement for Research on Sex and/or Gender Influences” and serving well the strategic goals of the “2019-2023 Trans-NIH Strategic Plan for Women’s Health Research”.