Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT, 06510, USA.
AgCenter, School of Animal Sciences, Louisiana State University, Baton Rouge, LA, 70803, USA.
Cell Death Dis. 2019 Jul 22;10(8):560. doi: 10.1038/s41419-019-1799-3.
Mitochondria are dynamic organelles that continually adapt their structure through fusion and fission in response to changes in their bioenergetic environment. Targeted deletion of mitochondrial fusion protein mitofusin1 (MFN1) in oocytes resulted in female infertility associated with failure to achieve oocyte maturation. Oocyte-granulosa cell communication was impaired, and cadherins and connexins were downregulated, resulting in follicle developmental arrest at the secondary follicle stage. Deletion of MFN1 in oocytes resulted in mitochondrial dysfunction and altered mitochondrial dynamics, as well as accumulation of ceramide, which contributed to increased apoptosis and a reproductive phenotype that was partially rescued by treatment with ceramide synthesis inhibitor myriocin. Absence of MFN1 and resulting apoptotic cell loss also caused depletion of ovarian follicular reserve, and a phenotype consistent with accelerated female reproductive aging.
线粒体是动态细胞器，可通过融合和裂变来不断适应其生物能量环境的变化而调整其结构。卵母细胞中线粒体融合蛋白 MFN1 的靶向缺失导致女性不孕，这与卵母细胞成熟失败有关。卵母细胞-颗粒细胞的通讯受到损害，钙粘蛋白和连接蛋白下调，导致卵泡在次级卵泡阶段发育停滞。卵母细胞中 MFN1 的缺失导致线粒体功能障碍和线粒体动力学改变，以及神经酰胺的积累，这导致细胞凋亡增加，生殖表型部分通过使用神经酰胺合成抑制剂米诺环素得到挽救。MFN1 的缺失和由此导致的凋亡细胞丢失也导致卵巢卵泡储备耗竭，并表现出与加速女性生殖衰老一致的表型。
