The Jak/Stat Pathway and Mitochondrial Function

描述（由申请人提供）：Stat转录因子在控制参与免疫应答、细胞转化和维持体内平衡的基因表达中起关键作用。该实验室发表的结果表明，在线粒体中存在一个Stat3库（mitoStat3），它在细胞和心脏组织中起着控制细胞呼吸的作用。初步结果表明，表达Stat3靶向心脏线粒体的转基因小鼠表明，转基因蛋白可以保护心脏免受缺血引起的电子传递链复合体I活性降低、线粒体活性氧（ROS）的产生和线粒体细胞色素C的释放。本提案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抑制编码电子传递链组分的核rna的转录。似乎Stat1的作用可能会对抗Stat3在线粒体稳态调节中的作用，以及它们对细胞生长和炎症的相反作用。我们提出实验来确定mitoStat3在急性和慢性心脏损伤模型中对该转录因子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，我们将研究在Stat1-/-背景下，线粒体靶向Stat3转基因是否显示出增强的保护作用。这些研究的完成将阐明一个由Stat3在细胞核和线粒体中的位置所调节的线粒体-核信号网络。

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.