The mitochondrial protease LONP1 maintains oocyte development and survival by suppressing nuclear translocation of AIFM1 in mammals
Xiaoqiang Sheng,
Chuanming Liu,
Guijun Yan,
Guangyu Li,
Jingyu Liu,
Yanjun Yang,
Shiyuan Li,
Zhongxun Li,
Jidong Zhou,
Xin Zhen,
Yang Zhang,
Zhenyu Diao,
Yali Hu,
Chuanhai Fu,
Bin Yao,
Chaojun Li,
Yu Cao,
Bin Lu,
Zhongzhou Yang,
Yingying Qin,
Haixiang Sun,
Lijun Ding
Affiliations
Xiaoqiang Sheng
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
Chuanming Liu
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
Guijun Yan
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
Guangyu Li
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
Jingyu Liu
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
Yanjun Yang
Department of Obstetrics and Gynecology, the Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China
Shiyuan Li
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
Zhongxun Li
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
Jidong Zhou
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
Xin Zhen
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
Yang Zhang
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
Zhenyu Diao
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
Yali Hu
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
Chuanhai Fu
School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China
Bin Yao
The Reproductive Medical Center, Nanjing Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu 210002, China
Chaojun Li
State Key Laboratory of Pharmaceutical Biotechnology, Medical School of Nanjing University & Model Animal Research Center, Nanjing University, Nanjing, Jiangsu 210093, China
Yu Cao
Institute of Precision Medicine, The Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200125, China; Department of Orthopaedics, Shanghai Key Laboratory of Orthopaedic Implant, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
Bin Lu
Protein Quality Control and Diseases Laboratory, Attardi Institute of Mitochondrial Biomedicine, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
Zhongzhou Yang
State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University Medical School, Nanjing, Jiangsu 210093 China
Yingying Qin
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; Corresponding author.
Haixiang Sun
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; Corresponding authors at: 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.
Lijun Ding
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; Clinical Center for Stem Cell Research, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210008, China; State Key Laboratory of Analytic Chemistry for Life Science, Nanjing University, Nanjing, Jiangsu 210093, China; Corresponding authors at: 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.
Summary: 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).
