N6-methyladenosine writer METTL3 accelerates the sepsis-induced myocardial injury by regulating m6A-dependent ferroptosis
Abstract Ferroptosis is an iron-dependent and phospholipid peroxidation-mediated cell death, which has been identified to be involved in sepsis-induced injury. However, the in-depth molecular mechanisms of $ N^{6} $-methyladenosine ($ m^{6} $A) and ferroptosis on sepsis-induced myocardial injury are still unclear. Here, in the septic myocardial injury, $ m^{6} $A methyltransferase METTL3 level and methylation level high-expressed in lipopolysaccharide (LPS)-induced cardiomyocytes (H9C2). Functionally, METTL3 silencing repressed the ferroptosis phenotype induced by LPS. Mechanistically, METTL3-mediated $ m^{6} $A methylation on solute carrier family 7 member 11 (SLC7A11) empowered its mRNA with high methylation level. Moreover, YTHDF2 directly bound to the $ m^{6} $A modification sites of SLC7A11 to mediate the mRNA degradation. The $ m^{6} $A modified SLC7A11 mRNA was recognized by YTHDF2, which promoted the decay of SLC7A11 mRNA, consequently up-regulating ferroptosis in sepsis-induced myocardial injury. Together, these findings establish a role of METTL3 in the ferroptosis of LPS-induced cardiomyocytes, and provide potential therapeutic target to treat the sepsis-induced myocardial injury..
| Medienart: |
Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:28 |
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| Enthalten in: |
Apoptosis - 28(2023), 3-4 vom: 16. Jan., Seite 514-524 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Shen, Hao [VerfasserIn] |
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| Links: |
Volltext [lizenzpflichtig] |
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| Anmerkungen: |
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. |
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| doi: |
10.1007/s10495-022-01808-y |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
OLC213452605X |
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| 520 | |a Abstract Ferroptosis is an iron-dependent and phospholipid peroxidation-mediated cell death, which has been identified to be involved in sepsis-induced injury. However, the in-depth molecular mechanisms of $ N^{6} $-methyladenosine ($ m^{6} $A) and ferroptosis on sepsis-induced myocardial injury are still unclear. Here, in the septic myocardial injury, $ m^{6} $A methyltransferase METTL3 level and methylation level high-expressed in lipopolysaccharide (LPS)-induced cardiomyocytes (H9C2). Functionally, METTL3 silencing repressed the ferroptosis phenotype induced by LPS. Mechanistically, METTL3-mediated $ m^{6} $A methylation on solute carrier family 7 member 11 (SLC7A11) empowered its mRNA with high methylation level. Moreover, YTHDF2 directly bound to the $ m^{6} $A modification sites of SLC7A11 to mediate the mRNA degradation. The $ m^{6} $A modified SLC7A11 mRNA was recognized by YTHDF2, which promoted the decay of SLC7A11 mRNA, consequently up-regulating ferroptosis in sepsis-induced myocardial injury. Together, these findings establish a role of METTL3 in the ferroptosis of LPS-induced cardiomyocytes, and provide potential therapeutic target to treat the sepsis-induced myocardial injury. | ||
| 650 | 4 | |a Sepsis | |
| 650 | 4 | |a Myocardial injury | |
| 650 | 4 | |a Ferroptosis | |
| 650 | 4 | |a N | |
| 650 | 4 | |a -methyladenosine | |
| 650 | 4 | |a METTL3 | |
| 700 | 1 | |a Xie, Keliang |4 aut | |
| 700 | 1 | |a Tian, Yikui |4 aut | |
| 700 | 1 | |a Wang, Xiaoye |4 aut | |
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