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.
在一项对17例特发性非梗阻性无精子症（iNOA）患者的单细胞转录组测序分析发现，其中7例患者的精原细胞中，多个翻译起始因子表达下调（其中包括 EIF5）。该研究发现，雄性小鼠睾丸生殖细胞中eIF5 mRNA和蛋白水平显著高于体细胞（间质细胞和支持细胞）。综上所述，为探究eIF5在精子发生中的功能及机制，我们通过繁殖 Eif5 fl/fl 与 Stra8-Cre小鼠，构建了雄性生殖细胞 Eif5条件性敲除小鼠。雄性生殖细胞中 Eif5的缺失导致SOX3 +精原祖细胞和KIT +分化型精原细胞数量减少，最终引发严重的减数分裂缺陷和雄性不育。进一步分析表明， Eif5缺失会降低泛素化、自噬及DNA修复相关基因的翻译，导致SOX3 +精原祖细胞内质网应激升高和DNA修复缺陷。这些变化共同引发了DNA损伤及细胞凋亡，最终导致精子发生障碍和雄性不育。该研究揭示了eIF5在精子发生中的关键作用，为因 EIF5及其它翻译起始因子功能缺陷引发的iNOA提供了潜在治疗策略和理论参考。.
Keywords: DNA repair; Endoplasmic reticulum stress; Male infertility; eIF5.