The Jak/Stat Pathway and Mitochondrial Function

描述(申请人提供)：Stat转录因子在控制免疫反应相关基因的表达、细胞转化和维持动态平衡方面发挥关键作用。该实验室发表的结果表明，在线粒体(MitoStat3)中有一个STAT3池，它在细胞和心脏组织中发挥控制细胞呼吸的功能。用表达靶向心脏线粒体的STAT3的转基因小鼠的初步结果表明，转基因蛋白保护心脏免受缺血引起的电子传递链复合体I活性下降、线粒体产生活性氧物种(ROS)和线粒体释放细胞色素C的影响。这项研究的初步结果还定义了STAT1作为线粒体基因表达抑制因子的新功能。此外，STAT1还抑制编码电子传递链组成部分的核RNA的转录。看来，STAT1的作用可能拮抗STAT3调节线粒体动态平衡的作用，以及它们众所周知的对细胞生长和炎症的相反作用。有人建议进行实验，以确定mitoStat3对该转录因子在急性和慢性心脏损伤模型中的心脏保护作用的贡献。由于STAT1抑制线粒体转录导致线粒体功能下降的机制似乎与mitoStat3的作用相反，我们将检查线粒体靶向STAT3转基因在STAT1-/-背景下是否显示出增强的保护作用。这些研究的完成将阐明一个线粒体-核信号网络，该网络受STAT3‘S定位于细胞核和线粒体的调控。 公共卫生相关性：心脏病是美国死亡和发病的主要原因之一。转录因子STAT3在维持正常心脏功能方面起着重要作用，无论是在小鼠还是在人类中，STAT3的缺失都会导致严重的心脏功能障碍，特别是在应激条件下。在这项提案中，我们将确定位于线粒体中并调节氧化代谢的一小部分STAT3对心脏功能的贡献，目的是更好地了解STAT3如何调节呼吸，提供一个可以操纵的新靶点，以在心脏病发作等应激条件下维持心脏健康。

DESCRIPTION (provided by applicant): The Stat transcription factors play pivotal roles in controlling the expression of genes involved in immune responses, cell transformation and maintaining homeostasis. Published results from this lab demonstrate that there is a pool of Stat3 that is localized in the mitochondria (mitoStat3) where it functions to control cellular respiration both in cells and in cardiac tissue. Preliminary results with a transgenic mice that express Stat3 that is targeted heart mitochondria indicate that it the transgenic protein protects hearts from ischemia induced decreases in the activity of complex I of the electron transport chain, production of reactive oxygen species (ROS) from mitochondria and release of cytochrome C from the mitochondria. Preliminary results in this proposal also define a new function of Stat1 as a repressor of mitochondrial gene expression. In addition, Stat1 represses the transcription of nuclear RNAs that encode components of the electron transport chain. It appears that the actions of Stat1 might antagonize the effects of Stat3 in regulation of mitochondrial homeostasis as well as their well knows opposing actions on cell growth and inflammation. Experiments are proposed to define the contribution of mitoStat3 to the cardio-protective effects of this transcription factor in acute and chronic models of heart injury. Since the mechanisms by which Stat1 represses mitochondrial transcription leading to decreased mitochondria function appear to oppose the effects of mitoStat3, we will examine if mitochondrial targeted Stat3 transgenes show enhanced protection in a Stat1-/- background. Completion of these studies will elucidate a mitochondria-nuclear signaling network that is regulated by Stat3's location in the both the nucleus and mitochondria. PUBLIC HEALTH RELEVANCE: Heart disease is one of the primary causes of mortality and morbidity in the United States. The transcription factor Stat3 plays a major role in maintaining normal heart function, and loss of Stat3 either in mice or humans causes severe cardiac dysfunction, especially under conditions of stress. In this proposal we will determine the contribution to heart function of a small pool of Stat3 that is located in the mitochondria and regulates oxidative metabolism, with the goal of better understanding of how Stat3 regulates respiration, providing a new target that can be the manipulated to maintain cardiac health under conditions of stress such as heart attacks.