Male germ cells-specific deletion of eukaryotic translation initiation factor 5 causes apoptosis of mouse progenitor spermatogonia by DNA repair defects and sustained endoplasmic reticulum stress

Eukaryotic translation initiation factor 5 (eIF5) promotes protein translation by regulating the ternary complex (TC) of eIF2•GTP•Met-tRNAi. A previous study showed that eIF5 is closely associated with testicular germ cell tumors (TGCTs). However, the role of eIF5 in mouse spermatogenesis remains unclear. Our study found that eIF5 is highly expressed in the cytoplasm of germ cells compared to other cells in the mouse testis. To explore the role and mechanism of eIF5 in mouse spermatogenesis, we generated Eif5 conditional knockout mice by crossing Eif5fl/fl mice with Stra8-Cre mice. The deletion of Eif5 in male germ cells caused a reduction of progenitor spermatogonia and differentiating spermatogonia, eventually leading to the failure of meiosis initiation and male infertility. Further investigations demonstrated that the deletion of Eif5 in progenitor spermatogonia led to decreased cell proliferation, increased ROS level, DNA damage and apoptosis. These observed phenotypes can be attributed to decreased protein translation efficiency in DNA repair, ubiquitination, autophagy-related genes, and increased protein translation efficiency of endoplasmic reticulum stress-related genes. These findings underscore the indispensable role of eIF5 in the proliferation and differentiation of mouse progenitor spermatogonia.