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）损伤和保护的核心。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传导途径。我们的初步数据表明，UPRmt防止IR损伤，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C.在线虫中，最近描述了UPRmt的中心作用机制：线粒体蛋白毒性应激调节基质输入和随后的ATFS-1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，通过ABC转运蛋白HAF-1阻止基质输入，HAF-1以不确定的方式抑制TIM/TOM活性。相反，ATFS-1运输到细胞核并激活一系列有利于生存的基因。核运输是必要的和足够的保护，这表明进口的ATFS-1到线粒体提供了一个独特的特定的焦点，引发适应。该提案旨在确定普遍定期审议机制保护C。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串扰，这些信号通路也具有保护作用，并将导致鉴定在哺乳动物中与ATFS-1和HAF-1类似的功能性直系同源物。

 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.