Grant: DRA : Canada Graduate Research Scholarship - Doctoral Program (CGRS D)

Our cells comprise a collection of macromolecules and organelles that work together to maintain cellular function and health. As these components age, or in times of stress when the cell needs to conserve energy and metabolites, these components are recycled to meet cellular demands through a process called autophagy. This process begins with the formation of a double-membrane package called the autophagosome which is subsequently delivered to the "cellular incinerator" known as the lysosome where the waste can be recycled. Autophagy can function in two ways: non-selective bulk degradation or targeted selective degradation. When autophagy is impaired, toxic materials accumulate in our cells and can cause diseases including neurodegenerative disorders, cancer, and immunodeficiencies. EPG5 is a protein critical for proper autophagosome-lysosome fusion. Mutations in EPG5 result in a severe disorder called Vici Syndrome that's characterized by neurodegeneration and immunodeficiency. How these mutations affect EPG5 function and lead to the broad symptoms observed in Vici syndrome is not fully understood. Based on recent work from our lab, we hypothesize that EPG5 is involved in not only bulk autophagic degradation, but also in the selective degradation of our cells' energy-producing organelle, the mitochondria, and that defective mitochondrial turnover due to EPG5 malfunction contributes to Vici syndrome. My proposed research aims to understand EPG5's role in the autophagic degradation of mitochondria, identify how EPG5 is recruited to the site of mitochondrial autophagy, and leverage cells from patients with Vici Syndrome to understand the effects of EPG5-related mutations on mitochondrial degradation and its role in Vici syndrome. Altogether, understanding how EPG5 coordinates mitochondrial autophagy will give us a better understanding of the disease mechanisms associated with Vici syndrome and provide insight into potential therapeutics for this devastating disorder.