Multidrug resistance transporter-1 dysfunction perturbs meiosis and Ca2+ homeostasis in oocytes.
Multidrug resistance transporter-1 dysfunction perturbs meiosis and Ca2+ homeostasis in oocytes.
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DOI：
10.1530/rep-22-0192
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发表时间：
2023-01-01
期刊：
影响因子：
3.8
通讯作者：
Brayboy, Lynae M.
中科院分区：
文献类型：
--
作者：
Nabi, Dalileh;Bosi, Davide;Gupta, Neha;Thaker, Nidhi;Fissore, Rafael;Brayboy, Lynae M.
卵母细胞质量仍然是生殖过程中最重要也是最未解决的问题。我们的数据显示，在小鼠模型中，多药耐药转运体和卵母细胞线粒体参与了决定卵母细胞质量的过程。多药耐药转运蛋白-1(MDR-1)是一种跨膜的ATP依赖的外排出物，存在于器官中，运输各种外源物质和副产物。本课题组以前的研究结果表明，该转运蛋白也存在于卵母细胞线粒体膜上，其突变导致线粒体内稳态异常。考虑到这些细胞器在雌配子中的重要性，我们评估了mdr-1功能障碍对小鼠卵母细胞质量的影响，特别是减数分裂纺锤体组织、非整倍体、钙稳态、ATP产生和mtDNA突变。我们的结果表明，与野生型相比，年轻的mdr1a突变小鼠产生的卵母细胞质量较低，生发泡到生发泡的破裂转变明显延迟，对称分裂比例增加，染色体错位，减数分裂纺锤体形状严重改变。与野生型卵母细胞相比，突变卵母细胞外显体DNA中的SNPs增加了7000个，线粒体DNA(MtDNA)SNPs的数量增加了一倍。Ca~(2+)分析表明，MDR-1突变卵母细胞不能管理钙存储内容和对几种刺激的振荡反应，而ATP定量分析表明，突变卵母细胞与野生型相比有降低ATP水平的趋势。最后，与野生型相比，1年龄突变卵巢表达的SIRT1、SIRT3、SIRT5、SIRT6和SIRT7的水平较低。这些结果共同强调了MDR-1在线粒体生理学中的重要性，并强调了MDR-1对卵母细胞质量和卵巢老化的影响。
Oocyte quality remains the most important and unsolved issue in reproduction. Our data show that multidrug resistance transporters and oocyte mitochondria are involved in determining oocyte quality in a mouse model. Multidrug resistance transporter-1 (MDR-1) is a transmembrane ATP-dependent effluxer present in organs that transport a variety of xenobiotics and by-products. Previous findings by our group demonstrated that this transporter is also present in the oocyte mitochondrial membrane and that its mutation led to abnormal mitochondrial homeostasis. Considering the importance of these organelles in the female gamete, we assessed the impact of MDR-1 dysfunction on mouse oocyte quality, with a particular focus on the meiotic spindle organization, aneuploidies, Ca2+ homeostasis, ATP production and mtDNA mutations. Our results demonstrate that young Mdr1a mutant mice produce oocytes characterized by lower quality, with a significant delay in the germinal vesicle to germinal vesicle breakdown transition, an increased percentage of symmetric divisions, chromosome misalignments and a severely altered meiotic spindle shape compared to the wild types. Mutant oocytes exhibit 7000 more SNPs in the exomic DNA and twice the amount of mitochondrial DNA (mtDNA) SNPs compared to the wild-type ones. Ca2+ analysis revealed the inability of MDR-1 mutant oocytes to manage Ca2+ storage content and oscillations in response to several stimuli, and ATP quantification shows that mutant oocytes trend toward lower ATP levels compared to wild types. Finally, 1-year-old mutant ovaries express a lower amount of SIRT1, SIRT3, SIRT5, SIRT6 and SIRT7 compared to wild-type levels. These results together emphasize the importance of MDR-1 in mitochondrial physiology and highlight the influence of MDR-1 on oocyte quality and ovarian aging.