Iain Scott, PhD

Mitochondria are ubiquitous organelles, playing a vital role in bioenergetics, metabolite biosynthesis and overall cellular homeostasis. Their activity needs to be tightly regulated, as evidenced by the growing number of pathologies in which mitochondrial dysfunction is a causative factor. Mitochondria are highly susceptible to environmental stresses, with overnutrition being a particular problem in the developed world. A high caloric intake leads to a surge in available acetyl-CoA (the final breakdown product of fats, carbohydrates and proteins in the mitochondria), which cannot be utilized for energetic or synthetic purposes. This excess acetyl-CoA is instead used as the substrate for acetylation (a post-translational modification of lysine residues), which acts to reduce the activity of a vast number of mitochondrial metabolic enzymes. Our work focuses on the intrinsic mechanisms that regulate mitochondrial protein acetylation, and how this fundamental alteration affects organelle function at the cellular and tissue level. In particular, we are interested in the coordination between acetylation levels and mitophagy, a quality control mechanism that mediates the removal of dysfunctional mitochondrial organelles. We have recently discovered that GCN5L1, a mitochondrial protein that promotes lysine acetylation, regulates the transcriptional machinery of mitophagy. Our future work will aim to elucidate the pathways that link nutritional inputs, GCN5L1-mediated lysine acetylation, and mitochondrial quality control systems. These findings will then be translated into studies involving metabolically-relevant disease models, such as heart failure and diabetes, in order to achieve a better understanding of the role played by dysfunctional mitochondria in these processes.