MTG1在心力衰竭发生中的分子机制

MTG1（Mitochondrial GTPases 1） is a key protease that assembles mitochondrial large ribosomal subunit, affecting cell oxidation and energy metabolism. Previous studies have demonstrated that ROS could activate MAPK and mitochondrial splenic protein Drp1 through phosphorylation, inducing cell autophagy and death. However, the role of MTG1 in heart failure remains unknown. Our laboratory funded by NSFC focuses on the mechanism of heart failure for long periods of time. We recently found that mouse MTG1 knockout increased stress overload induced heart failure, and MTG1 overexpression improved heart failure. However, the main mechanism is still unclear. Accordingly, we hypothesized that MTG1 gene mutation was involved in the progression of heart failure through mitochondrial ROS / MAPK / Drp1 loop. We will elucidate the role and molecular mechanism of MTG1 in the development of heart failure systematically from 3 aspects: (1) To determine the role of MTG1 in mitochondrial ROS, MAPK and mitochondrial splitting and fusion. (2) To elucidate the molecular mechanism of MTG1 on mitochondrial ROS, MAPK and the Drp1 loop in the progression of heart failure using specific inhibitors. (3) To explore the therapeutic target of mitochondrial MTG1 gene mutation. This study will elucidate the molecular mechanism of MTG1 in the development of heart failure, and provide novel ideas in the prevention and treatment for heart failure.

MTG1（Mitochondrial GTPases 1）是组装线粒体核糖体大亚基的关键蛋白酶，影响细胞氧化与能量代谢；既往研究认为ROS可激活MAPK与线粒体分裂蛋白Drp1，介导细胞自噬与死亡等；然而，MTG1在心衰领域的研究尚处空白。我们课题组在NSFC资助下，长期聚焦心衰的机制研究；最近发现小鼠MTG1基因敲除加重压力负荷诱导的心衰，而MTG1过表达改善心衰，但机制不清。据此，我们假设MTG1基因突变通过线粒体ROS/MAPK/Drp1环路参与心衰的发生发展。本课题拟从三个方面阐述MTG1在心衰发生中的分子机制：①研究MTG1在线粒体ROS、MAPK与线粒体分裂及融合中的作用；②利用特异性抑制剂，阐明MTG1通过线粒体ROS、MAPK与Drp1环路调控心衰发生的分子机制；③探索线粒体基因突变在心衰防治中的药物靶点。本课题将阐明MTG1在心衰发生中的分子机制，为心衰防治提供新的思路。

大多数线粒体蛋白质在细胞核中编码并在细胞质/内质网核糖体上翻译，而线粒体DNA编码的蛋白质在线粒体核糖体上翻译。线粒体GTPases 1（MTG1）调节线粒体核糖体组装和翻译，但其对心脏应激适应的影响尚不清楚。前期我们发现在扩张型心肌病患者的心脏和暴露于压力超负荷（AB）的小鼠中MTG1显著升高。为了研究MTG1在心肌肥大和心力衰竭中的作用，在培养的心肌细胞和AB小鼠模型中进行了MTG1功能丧失/获得的研究。MTG1 shRNA和腺病毒过度表达研究表明，MTG1表达可减轻血管紧张素II诱导的培养心肌细胞肥大，而MTG1 KO小鼠在基础条件下未表现出明显的心衰表型。与WT小鼠相比，MTG1缺乏显著加剧AB诱导的心肌肥厚、肥大应激标记物的表达、纤维化和LV功能障碍。相反，转基因心肌MTG1表达减弱AB诱导的心肌肥厚和左室功能障碍。在机制上，MTG1在压力超负荷期间保留线粒体呼吸链复合物活性，从而进一步减弱ROS的产生。此外，我们证明MTG1过表达组TAK1、P38和JNK1/2活性下调。重要的是，用N-乙酰半胱氨酸（NAC）抑制氧化应激可降低MTG1 KO至WT水平的肥大。因此，我们的研究表明MTG1通过保护线粒体功，减少氧化应激和下游TAK1应激信号传导来保护压力超负荷诱导的心肌肥厚和功能障碍。