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

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 indepth analysis of LONP1 will be crucial for elucidating the mechanisms underlying premature ovarian insufficiency. Copyright (C) 2021 The Author(s). Published by Elsevier B.V.

Automated summary

Using conditional oocyte Lonp1-knockout mice, RNA sequencing (RNA-seq) and Co-IP/LC-MS technology, the functions of LONP1 in mammalian oogenesis were analyzed. It was found that the conditional knockout of Lonp1 in mouse oocytes impairs follicular development, causes progressive oocyte death, ovarian reserve loss, and infertility. In addition, women with pathogenic variants of LONP1 lack large antral follicles (>10 mm) in the ovaries, are infertile and present premature ovarian insufficiency.