Mitochondrial dynamics: regulation mechanisms and physiologic impact.

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The morphological state of mitochondria has been linked to energy production, cell health and apoptosis. Mitochondrial shape is widely ascribed to a balance between mitochondrial fission and fusion. However it is underappreciated that they are morphologically pliable organelles that change their shape without undergoing fission. They exhibit reversible "rounding", which results in shorter organelles, a process we refer to as remodelling. We will explore the regulatory mechanisms and functional significance of mitochondrial remodelling in astrocytes. The central thesis is that mitochondrial remodelling is a critical process in the regulation of mitochondrial morphology and therefore cellular homeostasis.Our previous NSERC funded research was the first to quantitatively differentiate between mitochondrial fission and remodelling. We reported that mitochondrial remodelling is the predominant process in calcium-induced mitochondrial shape-change. We also demonstrated that regulation of the processes are mechanistically distinct; fission, but not remodelling is blocked by calcineurin inhibitors. This mechanistic distinction is supported by our paper in which we show that remodelling, not fission, is blocked by antioxidants. The current proposal extends these findings by examining the specific impact of remodelling on cellular physiology, exploring the mechanisms of remodelling, and examining the specific role of remodelling in mitochondrial quality control.Specific objectives:I. Investigate the molecular mechanisms of mitochondrial remodelling. We have shown previously that intracellular calcium, ROS, and molecular motors, all implicated in modulating mitochondrial motility, have critical roles in regulating mitochondrial morphology through remodelling. Our preliminary data implicates GSK3 in the mechanism of remodelling. The specific mechanisms by which ROS signalling regulates remodelling will be examined by assessing the protein targets of oxidative signalling induced remodelling and examining the role of GSK3. II. Examine the cellular impact of mitochondrial remodelling. Mitochondrial remodelling will be induced as we have reported previously or by the GSK3 inhibitor. We will examine the cellular and mitochondrial impact of remodelling; specifically ATP production, ROS generation, calcium homeostasis, the impact on the mitochondrial inner and outer membranes, as well as the effect on the cristae. III. Investigate the role of mitochondrial remodelling in mitophagy. We hypothesise that remodelling is a key initial event in mitochondrial mitophagy. By selectively inducing or blocking mitochondrial remodelling, we will investigate the relationship between remodelling and organelle recycling. These experiments will yield insights into the functional importance of mitochondrial remodelling and regulation of mitochondrial dynamics.