The mitochondrial protease LONP1 maintains oocyte development and survival by suppressing nuclear translocation of AIFM1 in mammals
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...
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Elsevier
2022-01-01
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| Series: | EBioMedicine |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396421005843 |
| _version_ | 1818753117708091392 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Xiaoqiang Sheng |
| collection | DOAJ |
| description | 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). |
| first_indexed | 2024-12-18T05:02:16Z |
| format | Article |
| id | doaj.art-6414280ea097432dbe4509e4efe22b30 |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-12-18T05:02:16Z |
| publishDate | 2022-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-6414280ea097432dbe4509e4efe22b302022-12-21T21:20:07ZengElsevierEBioMedicine2352-39642022-01-0175103790The mitochondrial protease LONP1 maintains oocyte development and survival by suppressing nuclear translocation of AIFM1 in mammalsXiaoqiang Sheng0Chuanming Liu1Guijun Yan2Guangyu Li3Jingyu Liu4Yanjun Yang5Shiyuan Li6Zhongxun Li7Jidong Zhou8Xin Zhen9Yang Zhang10Zhenyu Diao11Yali Hu12Chuanhai Fu13Bin Yao14Chaojun Li15Yu Cao16Bin Lu17Zhongzhou Yang18Yingying Qin19Haixiang Sun20Lijun Ding21Center 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, ChinaCenter 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, ChinaCenter 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, ChinaCenter 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, ChinaCenter 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, ChinaDepartment of Obstetrics and Gynecology, the Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, ChinaCenter 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, ChinaCenter 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, ChinaCenter 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, ChinaCenter 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, ChinaCenter 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, ChinaCenter 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, ChinaCenter 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, ChinaSchool of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, ChinaThe Reproductive Medical Center, Nanjing Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu 210002, ChinaState Key Laboratory of Pharmaceutical Biotechnology, Medical School of Nanjing University & Model Animal Research Center, Nanjing University, Nanjing, Jiangsu 210093, ChinaInstitute 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, ChinaProtein Quality Control and Diseases Laboratory, Attardi Institute of Mitochondrial Biomedicine, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, ChinaState 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 ChinaCenter 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.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.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).http://www.sciencedirect.com/science/article/pii/S2352396421005843MitochondriaLONP1AIFM1Oocyte developmentOocyte survivalPremature ovarian insufficiency |
| spellingShingle | 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 The mitochondrial protease LONP1 maintains oocyte development and survival by suppressing nuclear translocation of AIFM1 in mammals EBioMedicine Mitochondria LONP1 AIFM1 Oocyte development Oocyte survival Premature ovarian insufficiency |
| title | The mitochondrial protease LONP1 maintains oocyte development and survival by suppressing nuclear translocation of AIFM1 in mammals |
| title_full | The mitochondrial protease LONP1 maintains oocyte development and survival by suppressing nuclear translocation of AIFM1 in mammals |
| title_fullStr | The mitochondrial protease LONP1 maintains oocyte development and survival by suppressing nuclear translocation of AIFM1 in mammals |
| title_full_unstemmed | The mitochondrial protease LONP1 maintains oocyte development and survival by suppressing nuclear translocation of AIFM1 in mammals |
| title_short | The mitochondrial protease LONP1 maintains oocyte development and survival by suppressing nuclear translocation of AIFM1 in mammals |
| title_sort | mitochondrial protease lonp1 maintains oocyte development and survival by suppressing nuclear translocation of aifm1 in mammals |
| topic | Mitochondria LONP1 AIFM1 Oocyte development Oocyte survival Premature ovarian insufficiency |
| url | http://www.sciencedirect.com/science/article/pii/S2352396421005843 |
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