Oocyte-specific knockout of eIF2B subunits causes apoptosis of mouse oocytes within the early growing follicles via DNA damage and mitochondrial dysfunction.

Mutations in several translation initiation factors are closely associated with premature ovarian insufficiency (POI). In this study, we demonstrated that the conditional knockout of eukaryotic translation initiation factor 2B (eIF2B) subunits Eif2b2, Eif2b3, Eif2b4 or Eif2b5, but not Eif2b1, in mouse oocytes of primordial follicles caused oocyte apoptosis within the early growing follicles. Integrative Ribo-seq and RNA-seq analysis revealed the upregulation of integrated stress response- and DNA damage-related genes, and the downregulation of oocyte development-related genes in Eif2b4-cKO oocytes. Then, further research indicated that the depletion of Eif2b4 in oocytes resulted in mitochondrial dysfunctions characterized by decreased mitochondrial membrane potential, mtDNA copy numbers, and ATP content, along with excessive accumulation of reactive oxygen species (ROS). At the same time, the depletion of Eif2b4 in oocytes resulted in the increased levels of DNA damage response (DDR) proteins (NBS1, p-ATM, p-CHK2, and p53) and proapoptotic protein BAX, as well as the decreased levels of DNA damage repair protein Polβ and anti-apoptotic protein BCL-xL. Collectively, these findings indicate that the depletion of eIF2B subunits in mouse oocytes leads to oocyte apoptosis within the early growing follicles by DNA damage and mitochondrial dysfunction. This study provides new insights into the pathogenesis and genetic diagnosis of POI.