N6-methyladenosine demethylase FTO impairs hepatic ischemia-reperfusion injury via inhibiting Drp1-mediated mitochondrial fragmentation.
N6-methyladenosine demethylase FTO impairs hepatic ischemia-reperfusion injury via inhibiting Drp1-mediated mitochondrial fragmentation.
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N6-甲基腺苷脱甲基酶 FTO 通过抑制 Drp1 介导的线粒体断裂来损害肝缺血再灌注损伤
DOI：
10.1038/s41419-021-03622-x
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发表时间：
2021-05-04
影响因子：
9
通讯作者：
Wang X
中科院分区：
文献类型：
--
作者：
Du YD;Guo WY;Han CH;Wang Y;Chen XS;Li DW;Liu JL;Zhang M;Zhu N;Wang X
尽管N6-甲基腺苷(M6A)在多种生物学过程中具有重要的功能，但其在肝脏中的作用和潜在的调节机制仍未得到很大程度的研究。在本研究中，我们发现脂肪质量和肥胖相关蛋白(FTO，一种m6A去甲基酶)参与了肝脏缺血再灌注损伤(HIRI)时线粒体的功能。我们发现，在HIRI过程中，M6A去甲基酶FTO的表达减少。相反，m6A甲基化RNA水平升高。腺相关病毒介导的肝脏特异性FTO过表达(AAV8-TBG-FTO)可改善HIRI，抑制体内和体外升高的m6A甲基化RNA水平，减轻肝脏氧化应激和线粒体碎裂。此外，动力蛋白相关蛋白1(Drp1)是FTO在HIRI进展过程中的下游靶点。FTO通过使DRp1的mRNA去甲基化，抑制DRp1介导的线粒体断裂，从而发挥保护肝脏的作用。总之，我们的研究结果证明了FTO依赖的肝脏M6A甲基化在HIRI中的功能重要性，并为FTO的治疗机制提供了有价值的见解。
Despite N6-methyladenosine (m6A) is functionally important in various biological processes, its role and the underlying regulatory mechanism in the liver remain largely unexplored. In the present study, we showed that fat mass and obesity-associated protein (FTO, an m6A demethylase) was involved in mitochondrial function during hepatic ischemia–reperfusion injury (HIRI). We found that the expression of m6A demethylase FTO was decreased during HIRI. In contrast, the level of m6A methylated RNA was enhanced. Adeno-associated virus-mediated liver-specific overexpression of FTO (AAV8-TBG-FTO) ameliorated the HIRI, repressed the elevated level of m6A methylated RNA, and alleviated liver oxidative stress and mitochondrial fragmentation in vivo and in vitro. Moreover, dynamin-related protein 1 (Drp1) was a downstream target of FTO in the progression of HIRI. FTO contributed to the hepatic protective effect via demethylating the mRNA of Drp1 and impairing the Drp1-mediated mitochondrial fragmentation. Collectively, our findings demonstrated the functional importance of FTO-dependent hepatic m6A methylation during HIRI and provided valuable insights into the therapeutic mechanisms of FTO.
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影响因子：
64.8
作者：
Shi H;Zhang X;Weng YL;Lu Z;Liu Y;Lu Z;Li J;Hao P;Zhang Y;Zhang F;Wu Y;Delgado JY;Su Y;Patel MJ;Cao X;Shen B;Huang X;Ming GL;Zhuang X;Song H;He C;Zhou T
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Zhou T
METTL14 通过 mRNA m(6)A 修饰抑制造血干/祖细胞分化并促进白血病发生
影响因子：
23.9
作者：
Weng H;Huang H;Wu H;Qin X;Zhao BS;Dong L;Shi H;Skibbe J;Shen C;Hu C;Sheng Y;Wang Y;Wunderlich M;Zhang B;Dore LC;Su R;Deng X;Ferchen K;Li C;Sun M;Lu Z;Jiang X;Marcucci G;Mulloy JC;Yang J;Qian Z;Wei M;He C;Chen J
通讯作者：
Chen J
影响因子：
25.7
作者：
Marrone G;Shah VH;Gracia-Sancho J
通讯作者：
Gracia-Sancho J
R-2HG 通过靶向 FTO/m(6)A/MYC/CEBPA 信号发挥抗肿瘤活性
影响因子：
64.5
作者：
Su R;Dong L;Li C;Nachtergaele S;Wunderlich M;Qing Y;Deng X;Wang Y;Weng X;Hu C;Yu M;Skibbe J;Dai Q;Zou D;Wu T;Yu K;Weng H;Huang H;Ferchen K;Qin X;Zhang B;Qi J;Sasaki AT;Plas DR;Bradner JE;Wei M;Marcucci G;Jiang X;Mulloy JC;Jin J;He C;Chen J
通讯作者：
Chen J
METTL3/m(6)A/miRNA-873-5p 通过调节 Keap1/Nrf2 通路减轻粘菌素诱导的肾损伤中的氧化应激和细胞凋亡
影响因子：
5.6
作者：
Wang, Jian;Ishfaq, Muhammad;Li, Jichang
通讯作者：
Li, Jichang