Mitochondrial Dynamics in Female Reproduction

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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”.