MIGA1/2Promote Mitochondria Fusion And Are Essential For Female Mouse Fertility

Mitochondria provide energy for cells, mediate cell apoptosis and the synthesis of steroids hormones, which are the most important for cells and individual organisms’ metabolism. While mitochondrial functions especially for the oocyte meiosis by mitochondria dynamics still lack of clarification.We firstly confirmed the mitochondrial fusion function of Migal/2in HeLa cells by RNAi and other methods. Then it was analyzed in MEFs of Migal-/-, Miga2-/-and Migal/2-/-mice, it was found mitochondria in these MEFs lost tubular or netty morphology, and turned to fragmented shape with decreased mitochondrial membrane potential, enhanced ROS level, broken mitochondria cristae and low ATP production, which indicated the dysfunction of mitochondria.Physiologically, these mice could survive but with a great decrease in fertility of females rather than in males. It was observed that the number of the ovulated oocytes decreased in the females. However, the ovulated oocytes often degenerated without polarbodies and the mitochondria clustered into blocks, with mitochondrial membrane potential decreased, ROS increased, mtDNA copy number and ATP content reduced. In addition, aneuploidy in the chromosomes of MII oocytes might contribute to the ovulation defect and oocytes degeneration. Following the development of the early embryos from zygotes to blastcysts, partial of them were degenerated or retarded, indicating a low competence of the original oocytes.Furthermore, there were oocytes detained in ovary follicles even after injection of hCG for48h in Migal/2-/-mice, which indicated the destruction of the ovulation mechanism. Additionally, the progesterone level decreased in mice serum, in accordance with that in granulosa cells (GCs) cultured in vitro. It was also found FSH/LH targeted genes were widely down regulated after FSK/PMA treated for2h in Migal/2-/-GCs through RT-PCR, which was responsible for the low level of progesterone and the ovulation defect. Finally, it was found in the GCs large amount of cells happened to be apoptotic, and these cells were also found decreased in mitochondrial membrane potential (MMP), ATP production and mtDNA copy number. Interestingly, FSK/PMA treatment for2h could increase the activity of MMP and reduce the level of ROS in GCs. It was different from that in HeLa cells that RNAi of Migal/2could hardly induce cell apoptosis, suggesting that it might specially induce apoptosis in GCs after Migal/2knockown or knockout.In summary, Migal/2could not only regulate mitochondria fusion, but also regulate mitochondria activity and cell metabolisms, providing energy for oocyte growth and reproductive endocrinology to maintain oocyte quality and ovulation.