Male germ cell-specific deletion of Eif5 causes the apoptosis of mouse progenitor spermatogonia by excessive endoplasmic reticulum stress and defective DNA repair

Downregulation of eukaryotic translation initiation factors (EIFs) in spermatogonia was found in the idiopathic non-obstructive azoospermia (iNOA) patients, including EIF5. In this study, we revealed that the mRNA and protein levels of eIF5 were higher in male mouse germ cells than in Leydig cells and Sertoli cells. Thus, we generated Eif5 conditional knockout mice by crossing Eif5fl/fl mice with Stra8-Cre mice to investigate the function and mechanism of eIF5 in spermatogenesis. The deletion of Eif5 in male germ cells decreased the number of SOX3+ progenitor spermatogonia and KIT+ differentiating spermatogonia, ultimately causing severe meiosis defects and male sterility. Further analysis revealed that Eif5 deletion decreased the translation of genes related to ubiquitination, autophagy and DNA repair, resulting in excessive endoplasmic reticulum (ER) stress and defective DNA repair in SOX3+ progenitor spermatogonia. All of these caused DNA damage and subsequent apoptosis, thereby reducing germ cell number and causing sterility. Our findings highlight the essential role of eIF5 in spermatogenesis and offer a potential therapeutic strategy for iNOA patients caused by the low expression of translation initiation factor(s).