Multidrug resistance transporter-1 dysfunction perturbs meiosis and Ca2+ homeostasis in oocytes

MDR-1 is a transmembrane ATP-dependent effluxer present in organs that transport a variety of xenobiotics and byproducts. 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 Mdr1 mutant mice produce oocytes characterized by lower quality, with a significant delay in the germinal vesicle (GV) to germinal vesicle breakdown (GVBD) transition, an increased percentage of symmetric divisions, chromosome mis-alignments and a severely altered meiotic spindle shape compared to the wild types. Mutant oocytes exhibit 7000 more single nucleotide polymorphisms (SNPs) in the exomic DNA and twice the amount of mitochondrial DNA 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 towards 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.