线粒体蛋白酶 LONP1 通过抑制 AIFM1 的核转位来维持哺乳动物卵母细胞的发育和存活。

The mitochondrial protease LONP1 maintains oocyte development and survival by suppressing nuclear translocation of AIFM1 in mammals.

机构信息

Center for Reproductive Medicine, Department of Obstetrics and Gynecology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, 321 Zhongshan Rd., Nanjing, Jiangsu 210008, China; Center for Molecular Reproductive Medicine, Nanjing University, Nanjing, Jiangsu 210008, China.

Center for Reproductive Medicine, National Research Center for Assisted Reproductive Technology and Reproductive Genetics, The Key Laboratory of Reproductive Endocrinology (Shandong University), Ministry of Education, Shandong University, Jinan, Shangdong 250021, China.

出版信息

EBioMedicine. 2022 Jan;75:103790. doi: 10.1016/j.ebiom.2021.103790. Epub 2021 Dec 30.

DOI:10.1016/j.ebiom.2021.103790

PMID:34974310

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8733232/

Abstract

BACKGROUND

Oogenesis is a fundamental process of human reproduction, and mitochondria play crucial roles in oocyte competence. Mitochondrial ATP-dependent Lon protease 1 (LONP1) functions as a critical protein in maintaining mitochondrial and cellular homeostasis in somatic cells. However, the essential role of LONP1 in maintaining mammalian oogenesis is far from elucidated.

METHODS

Using conditional oocyte Lonp1-knockout mice, RNA sequencing (RNA-seq) and coimmunoprecipitation/liquid chromatography-mass spectrometry (Co-IP/LC-MS) technology, we analysed the functions of LONP1 in mammalian oogenesis.

FINDINGS

Conditional knockout of Lonp1 in mouse oocytes in both the primordial and growing follicle stages impairs follicular development and causes progressive oocyte death, ovarian reserve loss, and infertility. LONP1 directly interacts with apoptosis inducing factor mitochondria-associated 1 (AIFM1), and LONP1 ablation leads to the translocation of AIFM1 from the cytoplasm to the nucleus, causing apoptosis in mouse oocytes. In addition, women with pathogenic variants of LONP1 lack large antral follicles (>10 mm) in the ovaries, are infertile and present premature ovarian insufficiency.

INTERPRETATION

We demonstrated the function of LONP1 in regulating oocyte development and survival, and in-depth analysis of LONP1 will be crucial for elucidating the mechanisms underlying premature ovarian insufficiency.

FUNDING

This work was supported by grants from the National Key Research and Development Program of China (2018YFC1004701), the National Nature Science Foundation of China (82001629, 81871128, 81571391, 81401166, 82030040), the Jiangsu Province Social Development Project (BE2018602), the Jiangsu Provincial Medical Youth Talent (QNRC2016006), the Youth Program of the Natural Science Foundation of Jiangsu Province (BK20200116) and Jiangsu Province Postdoctoral Research Funding (2021K277B).

摘要

背景

卵子发生是人类生殖的基本过程，线粒体在卵母细胞功能中起着至关重要的作用。线粒体 ATP 依赖性 Lon 蛋白酶 1（LONP1）作为一种关键蛋白，在维持体细胞中线粒体和细胞内稳态方面发挥着重要作用。然而，LONP1 在维持哺乳动物卵子发生中的基本作用还远未阐明。

方法

使用条件性卵母细胞 Lonp1 敲除小鼠、RNA 测序（RNA-seq）和免疫共沉淀/液相色谱-质谱联用（Co-IP/LC-MS）技术，我们分析了 LONP1 在哺乳动物卵子发生中的功能。

结果

在原始卵泡和生长卵泡阶段，条件性敲除小鼠卵母细胞中的 Lonp1 会损害卵泡发育并导致卵母细胞渐进性死亡、卵巢储备丧失和不孕。LONP1 与凋亡诱导因子线粒体相关蛋白 1（AIFM1）直接相互作用，LONP1 缺失导致 AIFM1 从细胞质易位到细胞核，导致小鼠卵母细胞凋亡。此外，患有 LONP1 致病变异的女性卵巢中缺乏大的窦卵泡（>10mm），不孕且出现卵巢早衰。

解释

我们证明了 LONP1 在调节卵母细胞发育和存活中的作用，深入分析 LONP1 将对阐明卵巢早衰的机制至关重要。

资助

本工作得到国家重点研发计划（2018YFC1004701）、国家自然科学基金（82030040、81871128、81571391、81401166、82030040）、江苏省社会发展项目（BE2018602）、江苏省医学青年人才项目（QNRC2016006）、江苏省自然科学基金青年项目（BK20200116）和江苏省博士后科研资助计划（2021K277B）的资助。