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.
There are striking similarities in how stress is dealt with in the genetic model organism C. elegans and in mammals, including their response to ischemia (low oxygen). Recently, a novel signaling pathway has been identified in C. elegans that senses stress in the energy producing organelles of the cell (the mitochondria) and communicates that stress to the nucleus, where adaptive changes are initiated. Our focus is to dissect the role of these various signaling proteins in integrating the mitochondrial stress response to ischemia, in both C. elegans and mice. The results of this research are likely to be broadly relevant, as the ability of mitochondria to adapt to stress is central to cell viability in a variety of different physiologic and disease states.
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