Wang Weiyong, Liu Huiyu, Liu Shuang, Hao Tiantian, Wei Ying, Wei Hongwei, Zhou Wenjun, Zhang Xiaodan, Hao Xiaoqiong, Zhang Meijia
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.
Department of Physiology, Baotou Medical College, Baotou, China.
Clin Transl Med. 2024 Aug;14(8):e1791. doi: 10.1002/ctm2.1791.
Mutations in several translation initiation factors are closely associated with premature ovarian insufficiency (POI), but the underlying pathogenesis remains largely unknown.
We 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.
These 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.
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.
几种翻译起始因子的突变与卵巢早衰（POI）密切相关，但其潜在发病机制仍 largely 未知。
我们构建了真核翻译起始因子 5（Eif5）条件性敲除小鼠，旨在研究 eIF5 在卵母细胞生长和卵泡发育过程中的功能。在此，我们证明小鼠原始卵泡和生长卵泡中的 Eif5 缺失均导致早期生长卵泡内的卵母细胞凋亡。进一步研究表明，卵母细胞中 Eif5 的缺失下调了线粒体分裂相关蛋白（p-DRP1、FIS1、MFF 和 MTFR）的水平，上调了整合应激反应相关蛋白（AARS1、SHMT2 和 SLC7A1）和基因（Atf4、Ddit3 和 Fgf21）的水平。与此一致，卵母细胞中 Eif5 的缺失导致线粒体功能障碍，其特征为形态拉长、在卵母细胞膜下聚集分布、三磷酸腺苷含量和线粒体 DNA 拷贝数减少，以及活性氧（ROS）和线粒体超氧化物的过度积累。同时，卵母细胞中 Eif5 的缺失导致 DNA 损伤反应蛋白（γH2AX、p-CHK2 和 p-p53）和促凋亡蛋白（PUMA 和 BAX）水平显著升高，以及抗凋亡蛋白 BCL-xL 水平显著降低。
这些发现表明，小鼠卵母细胞中 Eif5 的缺失通过线粒体分裂缺陷、ROS 过度积累和 DNA 损伤导致早期生长卵泡内的卵母细胞凋亡。本研究为 POI 的发病机制、基因诊断和潜在治疗靶点提供了新的见解。
卵母细胞中 Eif5 的缺失导致卵母细胞生长和卵泡发育停滞。卵母细胞中 Eif5 的缺失损害线粒体分裂相关蛋白的翻译，随后导致线粒体功能障碍。Eif5 的缺失通过 ROS 积累和 DNA 损伤反应途径导致卵母细胞凋亡。
