"Cells use sensor pathways compartmentalized in subcellular organelles to recognize stress conditions, including aberrant protein folding, and in response activate gene expression programs aimed at maintaining cell survival and restoring homeostasis. Fine-tuning of the protein-folding environment in organelles like mitochondria is important for adaptive homeostasis and may participate in development of human diseases and ageing. Work in cultured mammalian cells and more recently in Caenorhabditis elegans has highlighted the importance of mechanisms linking perturbations in the protein-folding environment in the mitochondrial matrix to the expression of nuclear genes encoding mitochondrial proteins. This mitochondrial stress pathway is named mitochondrial unfolded protein response. Much of our knowledge regarding the organelle unfolded protein response (UPR) signalling comes from studies of the endoplasmatic reticulum stress response machinery. In contrast, a potential role of mitochondria in UPR pathway is far less defined, and physiologic regulators of this pathway have not been defined.
Here I propose three complementary strategies to identify molecular mechanisms and signalling pathways of the mitochondrial unfolded protein response (UPRmt) under different stress conditions and during ageing. My laboratory has experience in using transgenic mice and C. elegans as experimental tools and both of these powerful model systems will be used in this project.
Specific aims of this proposal are:
Aim 1. To identify specific substrates of UPRmt
Aim 2. To define mechanisms regulating mammalian UPRmt
Aim 3. To elucidate the role of UPRmt signalling in ageing"
Fields of science
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