How do neurons maintain mitochondrial homeostasis in vivo?

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Project Summary Mitochondria are critical for neuronal function and must be reliably distributed throughout the entire neuron. To maintain healthy, properly distributed mitochondria, neurons must coordinate mitochondrial dynamics, including motility, fission and fusion, and degradation, over space and time. The broad goal of this proposal is to define mechanisms for spatiotemporal control of mitochondrial dynamics in neurons in vivo. To that end, we will employ an innovative in vivo imaging approach to measure mitochondrial dynamics in well-defined motion vision neurons in Drosophila. By combining our in vivo measurements with mathematical modeling, we will gain mechanistic insight into how neurons maintain mitochondrial homeostasis at the systems level. We propose three specific aims. In Aim 1 we will determine how neurons maintain steady-state mitochondrial distribution patterns despite high levels of mitochondrial motility within complex neuronal morphologies. Specifically, we will test the hypothesis that neuronal architectures are optimized for the robust self- organization of specific mitochondrial localization patterns. We will use experimental measurements of in vivo mitochondrial motility and neuronal branching patterns to develop a quantitative model linking large-scale mitochondrial distributions to branch scaling rules. We will test this model by predicting mitochondrial localization patterns from experimental measurements of neuronal architecture across morphologically and functionally diverse Drosophila visual system neurons. We will then test our model predictions by comparing to ground truth measurements of mitochondrial distributions in EM datasets. In Aim 2 we will investigate how proper spatiotemporal control of mitochondrial fission and fusion contributes to the maintenance of healthy mitochondria in distal axons and dendrites. We will test the hypothesis that neurons optimize fission and fusion rates to both maximize complementation across mitochondria and ensure efficient delivery of newly- synthesized mitochondrial proteins to distal axons and dendrites. Finally, in Aim 3 we will probe the relationship between neuronal activity and mitophagy rates in neurons in vivo. Altogether, this proposal promises to provide a critical mechanistic framework for understanding how neurons regulate mitochondrial movement, fission and fusion, and degradation to maintain healthy, properly distributed mitochondrial populations in vivo, providing new insight into the molecular and cellular basis for neurodegenerative diseases.