Regulating Mitochondrial Fission for Arrhythmia Prevention

描述（由申请人提供）：新出现的证据强调了心脏线粒体作为兴奋性和心律失常的中枢调节因子的潜在作用。近年来，线粒体越来越被认为是一种高度动态的细胞器，可以融合和分裂。这些形态学变化是由复杂的融合和分裂事件引起的，对于胚胎发育、神经元可塑性、细胞凋亡和钙信号传导是必不可少的。线粒体融合和分裂之间的平衡的破坏导致高度互连的线粒体网络（有利于融合）或异常碎片化的线粒体（有利于分裂）。我们对这些对立过程的基本理解最近通过鉴定调节线粒体动力学的关键蛋白质而得到了推进。对R21的提议特别感兴趣的是动力蛋白相关蛋白（DRP 1），它是保守的动力蛋白GTdR超家族的成员，控制大多数细胞类型（包括心肌细胞）中的线粒体分裂。DRP 1的功能重要性通过以下事实强调：DRP 1的过表达导致线粒体片段化促进细胞死亡，而DRP 1的沉默或化学抑制减弱该过程。迄今为止，DRP 1在心血管疾病发病机制中的作用很少受到关注。尽管最近的研究结果表明线粒体分裂与细胞凋亡之间存在机械联系，但DRP 1表达/功能改变对调节心律失常易感性的潜在影响仍然完全未知。这个R21建议的中心租户是，DRP 1介导的线粒体分裂的调节是一个主要的决定因素的胚胎发生。在这个项目中，我们将使用药理学和基因为基础的方法来调节心脏中的DRP 1的功能和表达。我们将确定是否改变线粒体形态/结构调节急性（目标1）和慢性（目标2）氧化应激下心律失常的发生。这些研究的完成将揭示一个潜在的新型线粒体靶点，用于心律失常的预防。

DESCRIPTION (provided by applicant): Emerging evidence highlights the potential role of cardiac mitochondria as central regulators of excitability and arrhythmias. In recent years, mitochondria have been increasingly recognized as highly dynamic organelles that fuse and divide. These morphological changes, caused by complex fusion and fission events, are essential for embryonic development, neuronal plasticity, apoptosis, and calcium signaling. Disruption of the balance between mitochondrial fusion and fission results in either highly interconnected mitochondrial networks (favoring fusion) or abnormally fragmented mitochondria (favoring fission). Our fundamental understanding of these opposing processes was recently advanced by the identification of key proteins that regulate mitochondrial dynamics. Of particular interest to this R21 proposal is the dynamin related protein (DRP1), a member of the conserved dynamin GTPase superfamily, which controls mitochondrial fission in most cell types, including cardiomyocytes. The functional importance of DRP1 is underscored by the fact that overexpression of DRP1 resulting in fragmented mitochondria promotes cell death whereas silencing or chemical inhibition of DRP1 attenuates this process. To date, the role of DRP1 in the pathogenesis of cardiovascular disorders has received very little attention. Despite recent findings that mechanistically link mitochondrial fission to apoptosis, the potential implications o altered DRP1 expression/function for modulating arrhythmia susceptibility remain completely unknown. The central tenant of this R21 proposal is that DRP1 mediated regulation of mitochondrial fission is a major determinant of arrhythmogenesis. In this project we will use pharmacological and gene based approaches to modulate the function and expression of DRP1 in the heart. We will determine if altered mitochondrial morphometry/structure modulates the genesis of arrhythmias under acute (Aim 1) and chronic (Aim 2) oxidative stresses. Completion of these studies will reveal a potentially novel mitochondrial target for arrhythmia prevention.