ENERGETIC REGULATION OF CARDIAC ION CHANNELS

为了提供持续的ATP供应，心肌细胞含有数千个线粒体，这可能是一种 氧化应激的来源，并容易受到氧化应激的损害。我们发现，心肌线粒体的组织形式为 振荡器的网络，其耦合和同步度受活性氧物种的影响 (ROS)。在病理条件下，例如缺血-再灌流，ROS产生增加或 清除ROS的能力下降，导致线粒体内膜崩溃或振荡 在整个细胞中，以及在心肌合体中的细胞团中。通过这种方式，线粒体 功能障碍会产生器官水平的异质性，从而显著改变电生理和 心脏的收缩特性，我们已经确定了心脏的稳定性 靶向线粒体苯二氮卓类药物的线粒体内膜电位 受体可以预防缺血后心律失常，减少缺血再灌注损伤，我们有 提示特定的内膜阴离子通道(IMAC)是ROS的主要靶标，不依赖于 经典渗透率转换孔(PTP)。在目前的提案中，我们寻求1)识别关键蛋白质 用分子方法研究线粒体ROS诱导ROS释放的机制 在分离的细胞和线粒体中的实验，2)确定主要的生化途径负责 清除心肌线粒体中的ROS及其对接近线粒体临界点的影响，3) 通过细胞的氧化还原状态阐明线粒体到核的通讯机制，以及4) 继续开发和扩展我们的兴奋-收缩耦合的集成计算模型， 线粒体能量学，以及ROS诱导的ROS释放到组织水平，以了解线粒体 心脏疾病中心律失常和收缩功能障碍的起源。

In order to provide a continuous supply of ATP, heart cells contain thousands of mitochondria, which may be a source of, and subject to damage by, oxidative stress. We have found that cardiac mitochondria are organized as a network of oscillators, whose degree of coupling and synchronization is influenced by reactive oxygen species (ROS). Under pathological conditions, e.g. ischemia-reperfusion, either an increase in ROS production, or a decrease in the capacity to scavenge ROS, results in the collapse or oscillation of mitochondrial inner membrane potential throughout the cell, and in clusters of cells in the myocardial syncytium. In this way, mitochondrial dysfunction scales to produce organ level heterogeneity that significantly alters the electrophysiological and contractile properties ofthe heart Over the prior award period, we have established that stabilization of mitochondrial inner membrane potential by pharmacological agents targeting mitochondrial benzodiazepine receptors can prevent post-ischemic arrhythmias and decrease ischemia-reperfusion injury and we have suggested that a specific inner membrane anion channel (IMAC) was the primary target of ROS, independent of the classical permeability transition pore (PTP). In the present proposal we seek 1) to identify the key proteins implicated in the mechanism of mitochondrial ROS-induced ROS release using molecular methods and experiments in isolated cells and mitochondria, 2) to define the main biochemical pathways responsible for scavenging ROS in cardiac mitochondria and their impact on the approach to mitochondrial criticality, 3) to elucidate the mechanisms of mitochondrial-to-nuclear communication via the redox status ofthe cell, and 4) to continue to develop and expand our integrated computational models of excitation-contraction coupling, mitochondrial energetics, and ROS-induced ROS release to the tissue level to understand the mitochondrial origin of cardiac arrhythmias and contractile dysfunction in heart disease.