LncRNA H19 governs mitophagy and restores mitochondrial respiration in the heart through Pink1/Parkin signaling during obesity.
LncRNA H19 governs mitophagy and restores mitochondrial respiration in the heart through Pink1/Parkin signaling during obesity.
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LncRNA H19 在肥胖期间通过 Pink1/Parkin 信号传导控制线粒体自噬并恢复心脏中的线粒体呼吸
DOI：
10.1038/s41419-021-03821-6
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发表时间：
2021-05-28
影响因子：
9
通讯作者：
Chen YX
中科院分区：
文献类型：
--
作者：
Wang SH;Zhu XL;Wang F;Chen SX;Chen ZT;Qiu Q;Liu WH;Wu MX;Deng BQ;Xie Y;Mai JT;Yang Y;Wang JF;Zhang HF;Chen YX
维持适当的线粒体呼吸功能对于减轻肥胖期间的心脏代谢紊乱至关重要，而线粒体自噬在此过程中起着关键作用。长链非编码RNA H19（H19）对代谢调节至关重要，但其在心脏疾病，线粒体呼吸功能和肥胖期间的线粒体自噬中的作用在很大程度上是未知的。在这项研究中，棕榈酸（PA）处理的H9 c2细胞和Lep−/−小鼠分别在体外和体内研究心脏代谢紊乱。研究了H19对代谢紊乱、线粒体呼吸功能和线粒体自噬的影响。此外，PA，H19，线粒体自噬和呼吸功能的调节机制进行了检查。所测试的模型显示H19表达、呼吸功能以及线粒体数量和体积减少，而线粒体自噬和Pink 1/Parkin信号相关蛋白的表达上调，如使用定量实时PCR、海马线粒体应激测试分析仪、透射电子显微镜、荧光指示剂和蛋白质印迹所示。H19的强制表达有助于呼吸能力和线粒体数量的恢复，同时抑制线粒体自噬和Pink 1/Parkin信号相关蛋白的水平。Pink 1基因敲低也减弱了PA诱导的线粒体自噬，并增加了呼吸能力。RNA pull-down、质谱分析和RNA结合蛋白免疫沉淀实验表明，H19可抑制真核细胞翻译起始因子4A亚型2（eIF 4A 2）与Pink 1 mRNA的结合，从而抑制Pink 1的翻译，减弱线粒体自噬。PA通过上调Dnmt 3b甲基化酶水平显著增加H19启动子区域的甲基化水平，从而抑制H19转录。总的来说，这些发现表明，DNA甲基化介导的H19表达下调在心肌细胞或H9 c2细胞代谢紊乱中起着至关重要的作用，并通过促进线粒体自噬诱导心脏呼吸功能障碍。H19通过限制Pink 1 mRNA翻译来抑制过度的线粒体自噬，从而减轻肥胖期间发生的这种心脏缺陷。
Maintaining proper mitochondrial respiratory function is crucial for alleviating cardiac metabolic disorders during obesity, and mitophagy is critically involved in this process. Long non-coding RNA H19 (H19) is crucial for metabolic regulation, but its roles in cardiac disorders, mitochondrial respiratory function, and mitophagy during obesity are largely unknown. In this study, palmitic acid (PA)-treated H9c2 cell and Lep−/−mice were used to investigate cardiac metabolic disorders in vitro and in vivo, respectively. The effects of H19 on metabolic disorders, mitochondrial respiratory function, and mitophagy were investigated. Moreover, the regulatory mechanisms of PA, H19, mitophagy, and respiratory function were examined. The models tested displayed a reduction in H19 expression, respiratory function and mitochondrial number and volume, while the expression of mitophagy- and Pink1/Parkin signaling-related proteins was upregulated, as indicated using quantitative real-time PCR, Seahorse mitochondrial stress test analyzer, transmission electron microscopy, fluorescence indicators and western blotting. Forced expression of H19 helped to the recoveries of respiratory capacity and mitochondrial number while inhibited the levels of mitophagy- and Pink1/Parkin signaling-related proteins. Pink1 knockdown also attenuated PA-induced mitophagy and increased respiratory capacity. Mechanistically, RNA pull-down, mass spectrometry, and RNA-binding protein immunoprecipitation assays showed that H19 could hinder the binding of eukaryotic translation initiation factor 4A, isoform 2 (eIF4A2) with Pink1 mRNA, thus inhibiting the translation of Pink1 and attenuation of mitophagy. PA significantly increased the methylation levels of the H19 promoter region by upregulation Dnmt3b methylase levels, thereby inhibiting H19 transcription. Collectively, these findings suggest that DNA methylation-mediated the downregulation of H19 expression plays a crucial role in cardiomyocyte or H9c2 cells metabolic disorders and induces cardiac respiratory dysfunction by promoting mitophagy. H19 inhibits excessive mitophagy by limiting Pink1 mRNA translation, thus alleviating this cardiac defect that occurs during obesity.
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