N6-methyladenosine writer METTL3 accelerates the sepsis-induced myocardial injury by regulating m6A-dependent ferroptosis
N6-methyladenosine writer METTL3 accelerates the sepsis-induced myocardial injury by regulating m6A-dependent ferroptosis
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N6-甲基腺苷作家 METTL3 通过调节 m6A 依赖性铁死亡加速脓毒症引起的心肌损伤
DOI：
10.1007/s10495-022-01808-y
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发表时间：
2023-01-16
期刊：
影响因子：
7.2
通讯作者：
Wang, Xiaoye
中科院分区：
文献类型：
--
作者：
Shen, Hao;Xie, Keliang;Wang, Xiaoye
铁凋亡是一种铁依赖性和磷脂过氧化介导的细胞死亡，已被确定参与脓毒症诱导的损伤。然而，N6-甲基腺苷（m6 A）和铁凋亡在脓毒症诱导的心肌损伤中的深入分子机制仍不清楚。在此，在脓毒性心肌损伤中，m6 A甲基转移酶L3水平和甲基化水平在脂多糖（LPS）诱导的心肌细胞（H9 C2）中高表达。在功能上，胃L3沉默抑制LPS诱导的铁凋亡表型。从机制上讲，在溶质载体家族7成员11（SLC 7A 11）上，胃L3介导的m6 A甲基化使其mRNA具有高甲基化水平。此外，YTHDF 2直接结合到SLC 7A 11的m6 A修饰位点，介导mRNA降解。m6 A修饰的SLC 7A 11 mRNA可被YTHDF 2识别，促进SLC 7A 11 mRNA的降解，从而上调脓毒症心肌损伤中的铁凋亡。这些发现共同确立了胃L3在LPS诱导的心肌细胞铁凋亡中的作用，并为治疗脓毒症诱导的心肌损伤提供了潜在的治疗靶点。
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 N6-methyladenosine (m6A) and ferroptosis on sepsis-induced myocardial injury are still unclear. Here, in the septic myocardial injury, m6A 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 m6A methylation on solute carrier family 7 member 11 (SLC7A11) empowered its mRNA with high methylation level. Moreover, YTHDF2 directly bound to the m6A modification sites of SLC7A11 to mediate the mRNA degradation. The m6A 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.