The Role of the Mitochondrial UPR in Ischemic Protection

 描述（由申请人提供）：线粒体对于缺血再灌注（IR）损伤和保护至关重要。线粒体未折叠蛋白反应（UPRmt）是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 可以防止 IR 损伤，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。在遗传模型生物体秀丽隐杆线虫中，UPRmt 的中心作用机制最近被描述为：线粒体蛋白毒性应激调节 ATFS-1 的基质输入和随后的降解，ATFS-1 是一种具有双重靶向基序的 bZip 转录因子。在轻度蛋白毒性应激条件下，ABC 转运蛋白 HAF-1 会阻止基质输入，HAF-1 以不确定的方式发挥作用，抑制 TIM/TOM 活性。相反，ATFS-1 会转运至细胞核并激活一系列促生存的基因。核运输对于保护来说既是必要的也是充分的，这表明 ATFS-1 进入线粒体为引发适应提供了一个独特的特定焦点。该提案旨在确定 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同样具有保护性的信号通路的机械串扰，并将导致鉴定出在哺乳动物中与 ATFS-1 和 HAF-1 表现相似的功能直向同源物。

 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.