MicroRNA-20b Promotes Cardiac Hypertrophy by the Inhibition of Mitofusin 2-Mediated Inter-organelle Ca2+ Cross-Talk
MicroRNA-20b Promotes Cardiac Hypertrophy by the Inhibition of Mitofusin 2-Mediated Inter-organelle Ca2+ Cross-Talk
复制标题
MicroRNA-20b 通过抑制 Mitofusin 2 介导的细胞器间 Ca2 串扰促进心脏肥大
DOI：
10.1016/j.omtn.2020.01.017
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发表时间：
2020-03-06
影响因子：
8.8
通讯作者：
Zhang, Rong
中科院分区：
文献类型：
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作者：
Qiu, Yue;Cheng, Rongchao;Zhang, Rong
微小RNA（miRNA）和线粒体融合蛋白2（Mfn2）在心肌肥大的发展过程中具有重要作用，但在肥大条件下，与肌浆网和线粒体之间钙处理相关的靶向关系及机制尚未明确。利用动物/细胞肥大模型和先进技术评估了Mfn2的表达、Mfn2介导的细胞器间钙信号交流以及miRNA - 20b（miR - 20b）的靶向调控。结果表明，在肥大条件下，根据靶向结合情况，Mfn2表达下调，miR - 20b表达上调。我们的数据显示，miR - 20b诱导心肌肥大，而重组腺相关病毒载体9（rAAV9）-抗miR - 20b或miR - 20b反义抑制剂（AMO - 20b）可逆转这一作用。观察到miR - 20b对Mfn2表达/功能以及线粒体ATP合成具有有害作用，rAAV9 - 抗miR - 20b或AMO - 20b可逆转这种作用。通过荧光素酶报告基因实验和miRNA掩蔽实验证实了miR - 20b对Mfn2的靶向调控。重要的是，精胺激活线粒体钙单向转运体（MCU）使细胞质钙进入线粒体增加，表现为组胺介导的线粒体钙释放增强，这表明miR - 20b介导的Mfn2信号通路损害了线粒体对细胞质钙的再摄取/缓冲能力，从而通过钙信号通路导致细胞质钙超载和心肌肥大。总之，促肥大的miR - 20b通过下调Mfn2以及削弱线粒体的缓冲能力导致细胞质钙超载，在心肌肥大过程中发挥关键作用。
MicroRNA (miRNA) and mitofusin-2 (Mfn2) are important in the development of cardiac hypertrophy, but the target relationship and mechanism associated with Ca2+ handling between SR and mitochondria under hypertrophic condition is not established. Mfn2 expression, Mfn2-mediated interorganelle Ca2+ cross-talk, and target regulation by miRNA-20b (miR-20b) were evaluated using animal/cellular hypertrophic models with state-of-the-art techniques. The results demonstrated that Mfn2 was downregulated and miR-20b was upregulated upon the target binding profile under hypertrophic condition. Our data showed that miR-20b induced cardiac hypertrophy that was reversed by recombinant adeno-associated virus vector 9 (rAAV9)-anti-miR-20b or miR-20b antisense inhibitor (AMO-20b). The deleterious action of miR-20b on Mfn2 expression/function and mitochondrial ATP synthesis was observed and reversed by rAAV9-anti-miR-20b or AMO-20b. The targeted regulation of miR-20b on Mfn2 was confirmed by luciferase reporter and miRNA-masking. Importantly, the facts that mitochondrial calcium uniporter (MCU) activation by Spermine increased the cytosolic Ca2+ into mitochondria, manifested as enhanced histamine-mediated Ca2+ release from mitochondrial, suggesting that Ca2+ reuptake/buffering capability of mitochondria to cytosolic Ca2+ is injured by miR-20b-mediated Mfn2 signaling, by which leads cytosolic Ca2+ overload and cardiac hypertrophy through Ca2+ signaling pathway. In conclusion, pro-hypertonic miR-20b plays crucial roles in cardiac hypertrophy through downregulation of Mfn2 and cytosolic Ca2+ overload by weakening the buffering capability of mitochondria.