Center for Human Genome Research, The Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Cardio-X Institute, Huazhong University of Science and Technology, Wuhan, 430074, Hubei Province, PR China.
Hubei Provincial Key Laboratory of Occurrence and Intervention of Kidney Diseases, Medical College, Hubei Polytechnic University, Huangshi, Hubei Province, PR China.
Biochim Biophys Acta Mol Basis Dis. 2022 Sep 1;1868(9):166429. doi: 10.1016/j.bbadis.2022.166429. Epub 2022 May 6.
Our earlier studies identified MOG1 as a Nav1.5-binding protein that promotes Nav1.5 intracellular trafficking to plasma membranes. Genetic studies have identified MOG1 variants responsible for cardiac arrhythmias. However, the physiological functions of MOG1 in vivo remain incompletely characterized. In this study, we generated Mog1 knockout (Mog1) mice. Mog1 mice did not develop spontaneous arrhythmias at the baseline, but exhibited a prolongation of QRS duration. Mog1 mice treated with isoproterenol (ISO), but not with flecainide, exhibited an increased risk of arrhythmias and even sudden death. Mog1 mice had normal cardiac morphology, however, LV systolic dysfunction was identified and associated with an increase in ventricular fibrosis. Whole-cell patch-clamping and Western blotting analysis clearly demonstrated the normal cardiac expression and function of Nav1.5 in Mog1 mice. Further RNA-seq and iTRAQ analysis identified critical pathways and genes, including extracellular matrix (Mmp2), gap junction (Gja1), and mitochondrial components that were dysregulated in Mog1 mice. RT-qPCR, Western blotting, and immunofluorescence assays revealed reduced cardiac expression of Gja1 in Mog1 mice. Dye transfer assays confirmed impairment of gap-junction function; Cx43 gap-junction enhancer ZP123 decreased arrhythmia inducibility in ISO-treated Mog1 mice. Transmission electron microscopy analysis revealed abnormal sarcomere ultrastructure and altered mitochondrial morphology in Mog1 mice. Mitochondrial dynamics was found to be disturbed, and associated with a trend toward increased mitochondrial fusion in Mog1 mice. Meanwhile, the level of ATP supply was increased in the hearts of Mog1 mice. These results indicate that MOG1 plays an important role in cardiac electrophysiology and cardiac contractile function.
我们之前的研究确定 MOG1 是一种与 Nav1.5 结合的蛋白，可促进 Nav1.5 向质膜的细胞内转运。遗传研究已经确定了导致心律失常的 MOG1 变体。然而，MOG1 在体内的生理功能仍不完全清楚。在这项研究中，我们生成了 Mog1 敲除（Mog1）小鼠。Mog1 小鼠在基线时没有自发发生心律失常，但 QRS 持续时间延长。用异丙肾上腺素（ISO）处理 Mog1 小鼠，但不用氟卡尼处理，会增加心律失常甚至猝死的风险。Mog1 小鼠的心脏形态正常，但左心室收缩功能障碍，伴心室纤维化增加。全细胞膜片钳和 Western blot 分析清楚地表明 Mog1 小鼠心脏中 Nav1.5 的表达和功能正常。进一步的 RNA-seq 和 iTRAQ 分析确定了关键途径和基因，包括细胞外基质（Mmp2）、间隙连接（Gja1）和线粒体成分，这些在 Mog1 小鼠中失调。RT-qPCR、Western blot 和免疫荧光分析显示 Mog1 小鼠心脏中 Gja1 的表达减少。染料转移实验证实了间隙连接功能受损；Cx43 间隙连接增强剂 ZP123 降低了 ISO 处理的 Mog1 小鼠心律失常的易感性。透射电镜分析显示 Mog1 小鼠肌节超微结构异常，线粒体形态改变。发现线粒体动力学紊乱，与 Mog1 小鼠中线粒体融合增加的趋势有关。同时，Mog1 小鼠心脏中的 ATP 供应水平增加。这些结果表明 MOG1 在心脏电生理和心脏收缩功能中起重要作用。
