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

Idiopathic non-obstructive azoospermia (iNOA) is associated with reduced expression of multiple eukaryotic translation initiation factors (EIFs) in spermatogonia, including eukaryotic translation initiation factor 5 (EIF5). The present study revealed that eIF5 mRNA and protein levels were markedly higher in male mouse (Mus musculus) germ cells than in Leydig or Sertoli cells. Thus, to define the role of eIF5 in spermatogenesis, Eif5 conditional knockout (cKO) mice were generated by crossing Eif5^fl/fl mice with Stimulated by retinoic acid 8 (Stra8)-Cre mice. Loss of Eif5 in male germ cells reduced both SRY-box transcription factor 3 (SOX3)⁺ progenitor spermatogonia and Kit proto-oncogene receptor tyrosine kinase (KIT)⁺ differentiating spermatogonia, leading to severe meiotic failure and complete male infertility. Mechanistically, Eif5 deficiency impaired translation of genes involved in ubiquitination, autophagy, and DNA repair, which, in turn, triggered excessive endoplasmic reticulum (ER) stress and compromised DNA repair in SOX3⁺ progenitor spermatogonia. These defects promoted DNA damage and subsequent apoptosis, resulting in progressive germ cell depletion and sterility. Collectively, these findings highlight the essential role of eIF5 in spermatogenesis and offer a potential therapeutic strategy for iNOA associated with reduced expression of EIF5 and other translation initiation factors.