乙醛脱氢酶2通过调控线粒体DNA甲基化修饰影响心肌缺血后的线粒体功能

Mitochondrial dysfunction induced by ischemia dampens the function of cardiomyocytes, which mainly accounts for energy depletion in heart failure. Mitochondria are half-autonomous organelles, containing an independent coding system. The proteins coded by mitochondrial DNA play an important role in oxidative phosphorylation. Recent studies reported that the mitochondrial DNA could be modified by methylation. However, it reminas unclear whether it exists in cardiomyocytes which contains abundant mitochondria, let alone its pathophysiological significance in heart disesases. Our present results revealed that DNA methylated transferase 1 (DNMT1) was abundantly expressed in cardiomyocytes which could modify mitochondrial DNA, and its expression dynamically changed according to the degree of myocardial ischemia. More importantly, as a protective factor in myocardium, ALDH2 deletion could inhibit the mitochondrial translocation of DNMT1. Therefore, we speculate that ALDH2 may regulate cardiomyocyte function during myocardial ischemia by regulating mitochondrial DNA methylation modification. We intend to use ALDH2 knockout mice to explore the effect of signal transmission between mitochondria and nuclear genes on the epigenetic modification status of mitochondrial DNA during myocardial ischemia, and to expolre the potential intervention targets to improve mitochondrial dysfunction and the pathogenesis of heart failure.

缺血引起的线粒体功能障碍严重影响心肌细胞功能，是心衰能量耗竭的主要原因。线粒体是一个半自主性细胞器，具有独立编码系统，自身编码蛋白在线粒体氧化磷酸化产能中扮演着重要的角色。最近的研究发现线粒体DNA存在甲基化修饰，但这种甲基化修饰在线粒体丰富的心肌细胞中是否存在以及相关的病理生理学意义尚不明确。我们近期的研究结果证实，心肌细胞线粒体表达丰富的DNA甲基化转移酶1（DNMT1）能够甲基化修饰DNA，并且随着心肌缺血程度呈动态变化。更重要的是，作为心肌保护分子，乙醛脱氢酶2（ALDH2）的缺失会抑制DNMT1的线粒体转位，我们推测，心肌缺血时ALDH2能够通过调控线粒体DNA甲基化修饰影响心肌细胞功能。我们拟运用ALDH2敲除小鼠探索心肌缺血时线粒体与核基因之间信号传递引起的线粒体DNA表观修饰变化，从而寻找有效的干预靶点纠正线粒体功能失调从而改善心衰表型。

线粒体作为心肌细胞信号网络中心和能量代谢中心，在心肌功能的维护中扮演着重要的角色。线粒体作为半自主性细胞器，本研究从其独立的编码系统切入，通过解析线粒体DNA的甲基化修饰特点，解释了心肌缺血过程中线粒体DNA甲基化变化机制。此外，研究充分探讨了乙醛脱氢酶2(ALDH2)作为心肌保护分子，通过调控线粒体甲基化酶DNMT1的线粒体转位对线粒体自身编码蛋白影响的表观修饰作用机制。该项研究探讨了心肌缺血时线粒体与核基因之间信号传递引起的线粒体DNA表观修饰变化，以及改变化的主要调节因子。研究证实ALDH2有望被作为有效的干预靶点以纠正线粒体功能失调从而改善心衰表型。