METTL3 regulates autophagy of hypoxia-induced cardiomyocytes by targeting ATG7
Abstract N6-methyladenosine (m6A) mRNA modification is the most common mRNA internal modification in eukaryotes, which participates in a variety of biological processes. However, the role of m6A methylation in regulating autophagy induced by ischemia and hypoxia remains to be widely investigated. He...
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| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-02-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-025-02320-3 |
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| _version_ | 1832571982497972224 |
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| author | Linnan Li Hao Cheng Yufei Zhou Di Zhao Xiaoxue Zhang Yajun Wang Jianying Ma Junbo Ge |
| author_facet | Linnan Li Hao Cheng Yufei Zhou Di Zhao Xiaoxue Zhang Yajun Wang Jianying Ma Junbo Ge |
| author_sort | Linnan Li |
| collection | DOAJ |
| description | Abstract N6-methyladenosine (m6A) mRNA modification is the most common mRNA internal modification in eukaryotes, which participates in a variety of biological processes. However, the role of m6A methylation in regulating autophagy induced by ischemia and hypoxia remains to be widely investigated. Here, we investigated the impact of METTL3, a key m6A methyltransferase, on the autophagy regulation in ischemic and hypoxic cardiomyocytes, as well as in mice following acute myocardial infarction (AMI). METTL3 negatively regulated autophagy in cardiomyocytes under ischemia and hypoxia conditions. Silencing METTL3 enhanced autophagy and mitigated cardiomyocyte injury, whereas overexpression of METTL3 exerted the opposite effect. Mechanistically, METTL3 methylated ATG7 mRNA, a crucial autophagy-related gene, leads to the recruitment of the m6A-binding protein YTHDF2. Subsequently, YTHDF2 facilitated the degradation of ATG7 mRNA, consequently inhibiting autophagy and exacerbating cellular damage. Our study shed light on the pivotal role of METTL3-mediated m6A modification in the regulation of autophagy during AMI, providing novel insights into the functional significance of m6A methylation and its regulatory mechanisms. |
| format | Article |
| id | doaj-art-1a6ad991321a4e9c8338305a6dc03b56 |
| institution | Kabale University |
| issn | 2058-7716 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj-art-1a6ad991321a4e9c8338305a6dc03b562025-02-02T12:08:49ZengNature Publishing GroupCell Death Discovery2058-77162025-02-0111111310.1038/s41420-025-02320-3METTL3 regulates autophagy of hypoxia-induced cardiomyocytes by targeting ATG7Linnan Li0Hao Cheng1Yufei Zhou2Di Zhao3Xiaoxue Zhang4Yajun Wang5Jianying Ma6Junbo Ge7Department of Cardiology, Zhongshan Hospital, Shanghai Institute of Cardiovascular Diseases, Fudan UniversityDepartment of Cardiology, Zhongshan Hospital, Shanghai Institute of Cardiovascular Diseases, Fudan UniversityDepartment of Cardiology, Zhongshan Hospital, Shanghai Institute of Cardiovascular Diseases, Fudan UniversityDepartment of Cardiology, Zhongshan Hospital, Shanghai Institute of Cardiovascular Diseases, Fudan UniversityDepartment of Cardiology, Zhongshan Hospital, Shanghai Institute of Cardiovascular Diseases, Fudan UniversityDepartment of Pulmonary and Critical Care Medicine, Zhongshan Hospital, Fudan UniversityDepartment of Cardiology, Zhongshan Hospital, Shanghai Institute of Cardiovascular Diseases, Fudan UniversityDepartment of Cardiology, Zhongshan Hospital, Shanghai Institute of Cardiovascular Diseases, Fudan UniversityAbstract N6-methyladenosine (m6A) mRNA modification is the most common mRNA internal modification in eukaryotes, which participates in a variety of biological processes. However, the role of m6A methylation in regulating autophagy induced by ischemia and hypoxia remains to be widely investigated. Here, we investigated the impact of METTL3, a key m6A methyltransferase, on the autophagy regulation in ischemic and hypoxic cardiomyocytes, as well as in mice following acute myocardial infarction (AMI). METTL3 negatively regulated autophagy in cardiomyocytes under ischemia and hypoxia conditions. Silencing METTL3 enhanced autophagy and mitigated cardiomyocyte injury, whereas overexpression of METTL3 exerted the opposite effect. Mechanistically, METTL3 methylated ATG7 mRNA, a crucial autophagy-related gene, leads to the recruitment of the m6A-binding protein YTHDF2. Subsequently, YTHDF2 facilitated the degradation of ATG7 mRNA, consequently inhibiting autophagy and exacerbating cellular damage. Our study shed light on the pivotal role of METTL3-mediated m6A modification in the regulation of autophagy during AMI, providing novel insights into the functional significance of m6A methylation and its regulatory mechanisms.https://doi.org/10.1038/s41420-025-02320-3 |
| spellingShingle | Linnan Li Hao Cheng Yufei Zhou Di Zhao Xiaoxue Zhang Yajun Wang Jianying Ma Junbo Ge METTL3 regulates autophagy of hypoxia-induced cardiomyocytes by targeting ATG7 Cell Death Discovery |
| title | METTL3 regulates autophagy of hypoxia-induced cardiomyocytes by targeting ATG7 |
| title_full | METTL3 regulates autophagy of hypoxia-induced cardiomyocytes by targeting ATG7 |
| title_fullStr | METTL3 regulates autophagy of hypoxia-induced cardiomyocytes by targeting ATG7 |
| title_full_unstemmed | METTL3 regulates autophagy of hypoxia-induced cardiomyocytes by targeting ATG7 |
| title_short | METTL3 regulates autophagy of hypoxia-induced cardiomyocytes by targeting ATG7 |
| title_sort | mettl3 regulates autophagy of hypoxia induced cardiomyocytes by targeting atg7 |
| url | https://doi.org/10.1038/s41420-025-02320-3 |
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