AARS2-catalyzed lactylation induces follicle development and premature ovarian insufficiency
Abstract Lactate, a metabolite which is elevated in various developmental and pathological processes, exerts its signal through alanyl tRNA synthetases (AARS)-catalyzed protein lactylation. Herein, we report that elevated lactate and gain-of-function mitochondrial AARS (AARS2) mutations-induced hype...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-04-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-025-02501-0 |
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| author | Zhi-Ling Zhang Shu-Ting Ren Wan-Jie Yang Xiao-Wen Xu Shi-Min Zhao Ke-Fei Fang Yan Lin Yi-Yuan Yuan Xiao-Jin Zhang Yun-Qin Chen Wei Xu |
| author_facet | Zhi-Ling Zhang Shu-Ting Ren Wan-Jie Yang Xiao-Wen Xu Shi-Min Zhao Ke-Fei Fang Yan Lin Yi-Yuan Yuan Xiao-Jin Zhang Yun-Qin Chen Wei Xu |
| author_sort | Zhi-Ling Zhang |
| collection | DOAJ |
| description | Abstract Lactate, a metabolite which is elevated in various developmental and pathological processes, exerts its signal through alanyl tRNA synthetases (AARS)-catalyzed protein lactylation. Herein, we report that elevated lactate and gain-of-function mitochondrial AARS (AARS2) mutations-induced hyper-lactylation promotes premature ovarian insufficiency (POI). Serum lactate is elevated in POI patients. POI-driving AARS2 mutations gain lactyltransferase activity. AARS2 lactylates and inactivates carnitine palmitoyl transferase 2 (CPT2), resulting in FFA accumulation that activates peroxisome proliferator-activated receptor γ (PPARγ), and potentiates follicle-stimulating hormone (FSH) to initiate follicle development. These, in synergy with the anabolites accumulation effects of AARS2, promoted lactylation-induced PDHA1 inactivation promote granular cell (GC) proliferation and primordial follicle development. GC-specific AARS2 overexpression does not affect primordial follicle number but speed up follicle depletion. AARS2 ablation or lactylation-inhibiting β-alanine treatments can prevent folliculogenesis and POI traits in mouse. These findings reveal that lactate signal drives follicle development, and inhibiting lactate signal could treat/prevent POI. |
| format | Article |
| id | doaj-art-64b9ca9bedbd4c53bf4fb029714a17d1 |
| institution | DOAJ |
| issn | 2058-7716 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj-art-64b9ca9bedbd4c53bf4fb029714a17d12025-08-20T02:55:31ZengNature Publishing GroupCell Death Discovery2058-77162025-04-0111111610.1038/s41420-025-02501-0AARS2-catalyzed lactylation induces follicle development and premature ovarian insufficiencyZhi-Ling Zhang0Shu-Ting Ren1Wan-Jie Yang2Xiao-Wen Xu3Shi-Min Zhao4Ke-Fei Fang5Yan Lin6Yi-Yuan Yuan7Xiao-Jin Zhang8Yun-Qin Chen9Wei Xu10Obstetrics & Gynecology Hospital of Fudan University, State Key Laboratory of Genetic and Development of Complex Phenotypes, and Institutes of Biomedical Sciences, Fudan UniversityObstetrics & Gynecology Hospital of Fudan University, State Key Laboratory of Genetic and Development of Complex Phenotypes, and Institutes of Biomedical Sciences, Fudan UniversityObstetrics & Gynecology Hospital of Fudan University, State Key Laboratory of Genetic and Development of Complex Phenotypes, and Institutes of Biomedical Sciences, Fudan UniversityObstetrics & Gynecology Hospital of Fudan University, State Key Laboratory of Genetic and Development of Complex Phenotypes, and Institutes of Biomedical Sciences, Fudan UniversityObstetrics & Gynecology Hospital of Fudan University, State Key Laboratory of Genetic and Development of Complex Phenotypes, and Institutes of Biomedical Sciences, Fudan UniversityObstetrics & Gynecology Hospital of Fudan University, State Key Laboratory of Genetic and Development of Complex Phenotypes, and Institutes of Biomedical Sciences, Fudan UniversityObstetrics & Gynecology Hospital of Fudan University, State Key Laboratory of Genetic and Development of Complex Phenotypes, and Institutes of Biomedical Sciences, Fudan UniversityObstetrics & Gynecology Hospital of Fudan University, State Key Laboratory of Genetic and Development of Complex Phenotypes, and Institutes of Biomedical Sciences, Fudan UniversityObstetrics & Gynecology Hospital of Fudan University, State Key Laboratory of Genetic and Development of Complex Phenotypes, and Institutes of Biomedical Sciences, Fudan UniversityShanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan UniversityObstetrics & Gynecology Hospital of Fudan University, State Key Laboratory of Genetic and Development of Complex Phenotypes, and Institutes of Biomedical Sciences, Fudan UniversityAbstract Lactate, a metabolite which is elevated in various developmental and pathological processes, exerts its signal through alanyl tRNA synthetases (AARS)-catalyzed protein lactylation. Herein, we report that elevated lactate and gain-of-function mitochondrial AARS (AARS2) mutations-induced hyper-lactylation promotes premature ovarian insufficiency (POI). Serum lactate is elevated in POI patients. POI-driving AARS2 mutations gain lactyltransferase activity. AARS2 lactylates and inactivates carnitine palmitoyl transferase 2 (CPT2), resulting in FFA accumulation that activates peroxisome proliferator-activated receptor γ (PPARγ), and potentiates follicle-stimulating hormone (FSH) to initiate follicle development. These, in synergy with the anabolites accumulation effects of AARS2, promoted lactylation-induced PDHA1 inactivation promote granular cell (GC) proliferation and primordial follicle development. GC-specific AARS2 overexpression does not affect primordial follicle number but speed up follicle depletion. AARS2 ablation or lactylation-inhibiting β-alanine treatments can prevent folliculogenesis and POI traits in mouse. These findings reveal that lactate signal drives follicle development, and inhibiting lactate signal could treat/prevent POI.https://doi.org/10.1038/s41420-025-02501-0 |
| spellingShingle | Zhi-Ling Zhang Shu-Ting Ren Wan-Jie Yang Xiao-Wen Xu Shi-Min Zhao Ke-Fei Fang Yan Lin Yi-Yuan Yuan Xiao-Jin Zhang Yun-Qin Chen Wei Xu AARS2-catalyzed lactylation induces follicle development and premature ovarian insufficiency Cell Death Discovery |
| title | AARS2-catalyzed lactylation induces follicle development and premature ovarian insufficiency |
| title_full | AARS2-catalyzed lactylation induces follicle development and premature ovarian insufficiency |
| title_fullStr | AARS2-catalyzed lactylation induces follicle development and premature ovarian insufficiency |
| title_full_unstemmed | AARS2-catalyzed lactylation induces follicle development and premature ovarian insufficiency |
| title_short | AARS2-catalyzed lactylation induces follicle development and premature ovarian insufficiency |
| title_sort | aars2 catalyzed lactylation induces follicle development and premature ovarian insufficiency |
| url | https://doi.org/10.1038/s41420-025-02501-0 |
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