Intracellular Trafficking and the Metabolic Regulation of Cardiovascular Health

Mitochondrial dysfunction is associated with the development and progression of heart failure, cardiomyopathy and other vascular abnormalities like diabetic microvascular disease and atherosclerosis. Recent evidence suggests that increasing mitochondrial quality can improve cardiac function and prevent further deterioration of cardiovascular diseases. Using H9C2 cardiomyocytes, primary endothelial cells, and rat hearts, we standardized various assays that query the role of two quality control pathways, mitochondria-derived vesicle (MDV) formation and actin cages around damaged mitochondria. Mitochondria-derived vesicles act as a first line of defence transporting damaged and unfolded mitochondrial proteins to lysosomes for degradation. Actin cages are also formed around damaged mitochondria to prevent its refusion with the network. We hope to further characterize this pathway to understand cargo selectivity, vesicle generation, trafficking routes and destinations of MDVs.

We will characterize the role of actin regulators of the RhoGTPase family in modulating actin cage formation around mitochondria. Our study will highlight novel ways to modulate mitochondrial health in cardiomyocytes and endothelial cells. We are further keen on applying our understanding of mitochondrial quality control to a cerebrovascular disease called Moyamoya disease. This disease is found to be prevalent in people of Asian descent and its pathogenesis remains unclear. In close collaboration with the Neurovascular surgeon Dr. Jayanand Sudhir we will develop novel protocols to examine arterial wall stenosis that characterises this disease.