| The mitochondrial morphology is a dynamic property that is controlled by the relative rates of two opposing processes: mitochondrial fusion and fission. Mitochondrial fusion and fission events are collectively termed mitochondrial dynamics. The study of mitochondrial dynamics has undergone great advances in the past few years and it is now clear that mitochondrial dynamics play a critical role in mitochondrial function. As a result, mitochondrial dynamics is particularly important in cells that have a special dependence on mitochondrial function. Mitochondria within pancreatic β-cells play a critical role in glucose-stimulated insulin secretion. Increasing evidence strongly suggests that defects in mitochondrial function are involved in the pathology of type 2 diabetes. It is not yet known what significance mitochondrial dynamics has on β-cell physiology. The objectives of this dissertation were to investigate the role of mitochondrial dynamics in β-cell function and dysfunction. We found that β-cells do undergo mitochondrial dynamics which is significantly hindered in an in vitro model of type 2 diabetes, referred to as glucolipotoxicity. By knocking down the rate-limiting protein in mitochondrial fission, FIS-1, we were able to restore mitochondrial dynamics and reduce glucolipotoxicity-induced β-cell apoptosis. We next proceeded to test the role of mitochondrial fission in β-cell and mitochondrial function under normal physiological conditions. We found that reduced mitochondrial fission caused a significant reduction in mitochondrial respiration and insulin secretion. Furthermore we found reduced mitochondrial autophagy due to the knockdown in mitochondrial fission. This suggests that the detrimental effects of reduced mitochondrial fission may partly be due to impairment in mitochondrial autophagy, a pathway critical to mitochondrial turnover. The results presented in this dissertation are the first to demonstrate mitochondrial dynamics in β-cells and highlight its significance in β-cell physiology and dysfunction. |
