The Role of the Mitochondrial UPR in Ischemic Protection

 描述(由申请人提供)：线粒体是缺血再灌注(IR)损伤和保护的中心。线粒体未折叠蛋白反应(UPRmt)是一种响应线粒体功能障碍和蛋白毒性应激的信号通路。我们的初步数据表明，UPRmt对IR损伤具有保护作用，这与线粒体伴侣基因、ROS解毒机制和糖酵解能力的上调一致。在遗传模式生物秀丽线虫中，UPRmt的核心作用机制最近被描述为：线粒体蛋白毒性应激调节基质输入和随后的ATFS-1的降解，ATFS-1是一种具有双靶向基序的bZip转录因子。在温和的蛋白毒性应激条件下，通过ABC转运蛋白HAF-1以一种未知的方式抑制Tim/TOM活性，阻止基质输入。相反，ATFS-1与细胞核进行通讯，并激活支持生存的基因库。核贩运对于保护来说既是必要的，也是充分的，这表明将ATFS-1导入线粒体为引发适应提供了一个独特的特定焦点。这项建议旨在确定UPRmt保护线虫的机制，并将这些发现转化为哺乳动物心脏模型。我们的方法将包括定义与其他信号通路的机械性串扰，这些信号通路也是保护性的，并将导致识别在哺乳动物中表现类似的功能同源基因，如ATFS-1和HAF-1。

 DESCRIPTION (provided by applicant): Mitochondria are central to ischemia-reperfusion (IR) injury and protection. The mitochondrial unfolded protein response (UPRmt) is a signaling pathway that responds to mitochondrial dysfunction and proteotoxic stress. Our preliminary data suggests that the UPRmt protects against IR injury, consistent with up-regulation of mitochondrial chaperone genes, ROS detoxification machinery, and glycolytic capacity. In the genetic model organism C. elegans, the UPRmt's central mechanism of action has recently been described: mitochondrial proteotoxic stress regulates the matrix import and subsequent degradation of ATFS-1, a bZip transcription factor with dual targeting motifs. Under conditions of mild proteotoxic stress, matrix import is prevented through an ABC transport protein, HAF-1, acting in an undefined manner to suppress TIM/TOM activity. ATFS-1 instead traffics to the nucleus and activates a pro-survival repertoire of genes. Nuclear trafficking is both necessary and sufficient for protection, suggesting that the import of ATFS-1 into mitochondria provides a uniquely specific focal point for eliciting adaptation. This proposal aims to identify mechanisms through which the UPRmt protects C. elegans and to translate these findings to a mammalian cardiac model. Our approach will include defining mechanistic crosstalk with other signaling pathways that are also protective and will result in the identification of functional orthologs tha perform similarly in mammals as ATFS-1 and HAF-1.