Lactylation of Mitochondrial Adenosine Triphosphate Synthase Subunit Alpha Regulates Vascular Remodeling and Progression of Aortic Dissection
Aortic dissection (AD) is a cardiovascular disorder with a high mortality rate. Lysine Lactylation (Kla), a novel posttranslational modification, critically regulates inflammation, tumors, and cardiovascular diseases. However, its specific role in AD pathogenesis remains unexplored. Using modificati...
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American Association for the Advancement of Science (AAAS)
2025-01-01
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| Online Access: | https://spj.science.org/doi/10.34133/research.0799 |
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| author | Tao Yu Xiaolu Li Chao Wang Yanyan Yang Xiuxiu Fu Tianxiang Li Wentao Wang Xiangyu Liu Xiaoxin Jiang Ding Wei Jian-Xun Wang |
| author_facet | Tao Yu Xiaolu Li Chao Wang Yanyan Yang Xiuxiu Fu Tianxiang Li Wentao Wang Xiangyu Liu Xiaoxin Jiang Ding Wei Jian-Xun Wang |
| author_sort | Tao Yu |
| collection | DOAJ |
| description | Aortic dissection (AD) is a cardiovascular disorder with a high mortality rate. Lysine Lactylation (Kla), a novel posttranslational modification, critically regulates inflammation, tumors, and cardiovascular diseases. However, its specific role in AD pathogenesis remains unexplored. Using modification omics, we conducted a macroscopic analysis of the occurrence of extensive lactylation modification in aortic dissection and identified extensive lactylation, particularly in the adenosine triphosphatase activity pathway. Among these proteins, adenosine triphosphate (ATP) synthase F1 subunit α (ATP5F1A), a subunit in the ATP synthase complex, exhibited pronounced lactylation at the K531, catalyzed by sirtuin 3 (Sirt3). Through site-directed mutagenesis (K531R/K531E), we validated the key mechanism of lactylation activation at the K531 site of ATP5F1A and the regulatory enzymes. Functionally, K531 lactylation impairs ATP synthase activity, elevates reactive oxygen species generation, reduces ATP generation, and induces mitochondrial structural abnormalities. These effects ultimately contribute to the phenotypic transformation of human aortic vascular smooth muscle cells and enhanced synthesis and secretion of matrix metalloproteinases. In addition, we assessed the potential therapeutic effect of lactylation inhibition in aortic dissection using a mouse model and a drug based in vivo lactate alteration strategy. In conclusion, targeting the lactate–Sirt3–ATP5F1A axis represents a promising therapeutic strategy for blocking the progression of aortic dissection. |
| format | Article |
| id | doaj-art-af6bc9b631834f31bcff38f28548108f |
| institution | DOAJ |
| issn | 2639-5274 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | American Association for the Advancement of Science (AAAS) |
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| spelling | doaj-art-af6bc9b631834f31bcff38f28548108f2025-08-20T03:05:35ZengAmerican Association for the Advancement of Science (AAAS)Research2639-52742025-01-01810.34133/research.0799Lactylation of Mitochondrial Adenosine Triphosphate Synthase Subunit Alpha Regulates Vascular Remodeling and Progression of Aortic DissectionTao Yu0Xiaolu Li1Chao Wang2Yanyan Yang3Xiuxiu Fu4Tianxiang Li5Wentao Wang6Xiangyu Liu7Xiaoxin Jiang8Ding Wei9Jian-Xun Wang10Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao 266021, People’s Republic of China.Department of Cardiac Ultrasound, The Affiliated hospital of Qingdao University, Qingdao 266000, People’s Republic of China.Department of Cardiovascular Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China.Department of Immunology, School of Basic Medicine, Qingdao University, Qingdao 266071, China.Department of Cardiac Ultrasound, The Affiliated hospital of Qingdao University, Qingdao 266000, People’s Republic of China.Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao 266021, People’s Republic of China.Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao 266021, People’s Republic of China.Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao 266021, People’s Republic of China.Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao 266021, People’s Republic of China.Department of General Medicine, The Affiliated Hospital of Qingdao University, Qingdao 266000, People’s Republic of China.Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao 266021, People’s Republic of China.Aortic dissection (AD) is a cardiovascular disorder with a high mortality rate. Lysine Lactylation (Kla), a novel posttranslational modification, critically regulates inflammation, tumors, and cardiovascular diseases. However, its specific role in AD pathogenesis remains unexplored. Using modification omics, we conducted a macroscopic analysis of the occurrence of extensive lactylation modification in aortic dissection and identified extensive lactylation, particularly in the adenosine triphosphatase activity pathway. Among these proteins, adenosine triphosphate (ATP) synthase F1 subunit α (ATP5F1A), a subunit in the ATP synthase complex, exhibited pronounced lactylation at the K531, catalyzed by sirtuin 3 (Sirt3). Through site-directed mutagenesis (K531R/K531E), we validated the key mechanism of lactylation activation at the K531 site of ATP5F1A and the regulatory enzymes. Functionally, K531 lactylation impairs ATP synthase activity, elevates reactive oxygen species generation, reduces ATP generation, and induces mitochondrial structural abnormalities. These effects ultimately contribute to the phenotypic transformation of human aortic vascular smooth muscle cells and enhanced synthesis and secretion of matrix metalloproteinases. In addition, we assessed the potential therapeutic effect of lactylation inhibition in aortic dissection using a mouse model and a drug based in vivo lactate alteration strategy. In conclusion, targeting the lactate–Sirt3–ATP5F1A axis represents a promising therapeutic strategy for blocking the progression of aortic dissection.https://spj.science.org/doi/10.34133/research.0799 |
| spellingShingle | Tao Yu Xiaolu Li Chao Wang Yanyan Yang Xiuxiu Fu Tianxiang Li Wentao Wang Xiangyu Liu Xiaoxin Jiang Ding Wei Jian-Xun Wang Lactylation of Mitochondrial Adenosine Triphosphate Synthase Subunit Alpha Regulates Vascular Remodeling and Progression of Aortic Dissection Research |
| title | Lactylation of Mitochondrial Adenosine Triphosphate Synthase Subunit Alpha Regulates Vascular Remodeling and Progression of Aortic Dissection |
| title_full | Lactylation of Mitochondrial Adenosine Triphosphate Synthase Subunit Alpha Regulates Vascular Remodeling and Progression of Aortic Dissection |
| title_fullStr | Lactylation of Mitochondrial Adenosine Triphosphate Synthase Subunit Alpha Regulates Vascular Remodeling and Progression of Aortic Dissection |
| title_full_unstemmed | Lactylation of Mitochondrial Adenosine Triphosphate Synthase Subunit Alpha Regulates Vascular Remodeling and Progression of Aortic Dissection |
| title_short | Lactylation of Mitochondrial Adenosine Triphosphate Synthase Subunit Alpha Regulates Vascular Remodeling and Progression of Aortic Dissection |
| title_sort | lactylation of mitochondrial adenosine triphosphate synthase subunit alpha regulates vascular remodeling and progression of aortic dissection |
| url | https://spj.science.org/doi/10.34133/research.0799 |
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