Affiliation:
1. The Innovation Centre of Ministry of Education for Development and Diseases the Second Affiliated Hospital School of Medicine South China University of Technology Guangzhou China
2. Department of Physiology Baotou Medical College Baotou China
Abstract
AbstractBackgroundMutations in several translation initiation factors are closely associated with premature ovarian insufficiency (POI), but the underlying pathogenesis remains largely unknown.Methods and resultsWe generated eukaryotic translation initiation factor 5 (Eif5) conditional knockout mice aiming to investigate the function of eIF5 during oocyte growth and follicle development. Here, we demonstrated that Eif5 deletion in mouse primordial and growing oocytes both resulted in the apoptosis of oocytes within the early‐growing follicles. Further studies revealed that Eif5 deletion in oocytes downregulated the levels of mitochondrial fission‐related proteins (p‐DRP1, FIS1, MFF and MTFR) and upregulated the levels of the integrated stress response‐related proteins (AARS1, SHMT2 and SLC7A1) and genes (Atf4, Ddit3 and Fgf21). Consistent with this, Eif5 deletion in oocytes resulted in mitochondrial dysfunction characterized by elongated form, aggregated distribution beneath the oocyte membrane, decreased adenosine triphosphate content and mtDNA copy numbers, and excessive accumulation of reactive oxygen species (ROS) and mitochondrial superoxide. Meanwhile, Eif5 deletion in oocytes led to a significant increase in the levels of DNA damage response proteins (γH2AX, p‐CHK2 and p‐p53) and proapoptotic proteins (PUMA and BAX), as well as a significant decrease in the levels of anti‐apoptotic protein BCL‐xL.ConclusionThese findings indicate that Eif5 deletion in mouse oocytes results in the apoptosis of oocytes within the early‐growing follicles via mitochondrial fission defects, excessive ROS accumulation and DNA damage. This study provides new insights into pathogenesis, genetic diagnosis and potential therapeutic targets for POI.Key points
Eif5 deletion in oocytes leads to arrest in oocyte growth and follicle development.
Eif5 deletion in oocytes impairs the translation of mitochondrial fission‐related proteins, followed by mitochondrial dysfunction.
Depletion of Eif5 causes oocyte apoptosis via ROS accumulation and DNA damage response pathway.
Funder
National Key Research and Development Program of China
National Natural Science Foundation of China
Natural Science Foundation of Inner Mongolia Autonomous Region