Grant: CIHR Fellowship

Dysfunctional mitochondria can be extremely damaging to the cells they inhabit and are implicated in multiple neurodegenerative diseases. To combat dysfunction, mitochondria have evolved several lines of quality control. One is the mitochondrial unfolded protein response (UPRmt), which when activated will up regulate genes to mitigate stress. If the organelle is damaged beyond repair it will be eliminated by mitophagy. Multiple stressors, including misfolded protein accumulation in mitochondria activate these responses. Both pathways require a reduction of mitochondrial protein import. How misfolded proteins lead to decreased import has yet to be determined, but would be a step toward understanding the mechanisms that regulate these pathways. I hypothesize that the presence of misfolded proteins in the matrix leads to decreased mitochondrial import due to protease mediated degradation of proteins within the import complex. The experiments I have proposed should reveal how these pathways are regulated and will identify therapeutic targets to treat neurodegenerative disease.