Grant: Master's Award: Canada Graduate Scholarships

There are 1,158 nuclear-encoded proteins destined for the mitochondria, all of which must be transported through protein import machinery (PIM). Protein import through the mitochondria involves the linearization of protein in the cytosol to allow for passage through the translocons of the mitochondrial membranes. Once in the mitochondria, it is refolded into a functional conformation. Under stress, this process may be impaired and the protein may undergo misfolding or improper assembly. To combat this accumulation there is a compartment specific response termed the mitochondrial unfolded protein response (UPRmt). The UPRmt consists of chaperones and proteases that are responsible for either refolding or degrading misfolded proteins respectively. This quality control mechanism is well described in C. elegans, where the degradation of misfolded proteins results in an accumulation of peptides, which are then exported into the cytosol. These peptides serve as a retrograde signal to promote the upregulation of protective genes, and a shift for glycolysis. To date, advances have not been made in a mammalian model, and so there is a need to investigate the relationship between protein import, UPRmt and the retrograde signals involved. We will use an in-vivo knockdown of TIM23 in a murine model, and we hypothesize that this downregulation will cause a sufficient stress to activate the UPRmt allowing us to investigate the interaction and the retrograde signals involved. We intend to use a modified version of studying protein import to examine the role of peptide efflux in a mammalian model. Future work will use exercise to rescue the defect in protein import and assess how this will effect peptide emission and retrograde signaling to the nucleus.