Eif4enif1 haploinsufficiency disrupts oocyte mitochondrial dynamics and leads to subfertility

Abstract

ABSTRACT Infertility affects couples worldwide. Premature ovarian insufficiency (POI) refers to loss of ovarian function before 40 years of age and is a contributing factor to infertility. Several case studies have reported dominant-inherited POI symptoms in families with heterozygous EIF4ENIF1 (4E-T) mutations. However, the effects of EIF4ENIF1 haploinsufficiency have rarely been studied in animal models to reveal the underlying molecular changes related to infertility. Here, we demonstrate that Eif4enif1 haploinsufficiency causes mouse subfertility, impairs oocyte maturation and partially arrests early embryonic development. Using dual-omic sequencing, we observed that Eif4enif1 haploinsufficiency significantly altered both transcriptome and translatome in mouse oocytes, by which we further revealed oocyte mitochondrial hyperfusion and mitochondria-associated ribonucleoprotein domain distribution alteration in Eif4enif1-deficient oocytes. This study provides new insights into the molecular mechanisms underlying clinical fertility failure and new avenues to pursue new therapeutic targets to address infertility.