Functions and Kinetics of Mitochondrial Fusion and Fission in the Axon: a Quantitative Study

In eukaryotic cells, mitochondria form a dynamic interconnected network to respond to changing needs at different subcellular locations. A fundamental yet unanswered question regarding this network is whether, and if so how, local fusion and fission of individual mitochondria affect their global distribution. To address this question, we developed high-resolution computational image analysis techniques to examine the relations between mitochondrial fusion/fission and spatial distribution within the axon of Drosophila larval neurons. We found that stationary and moving mitochondria underwent fusion and fission regularly but followed different spatial distribution patterns and exhibited different morphology. Disruption of inner membrane fusion by dOpa1 knockdown not only increased the spatial density of stationary and moving mitochondria but also changed their spatial distribution and morphology differentially. We found that changes to the spatial distribution of axonal mitochondria under dOpa1 knockdown could not be fully accounted for by changes to their motility but, instead, resulted from the disruption of inner membrane fusion. To understand the complex dynamic behavior of axonal mitochondria observed in our experimental studies quantitatively and at the mechanistic level, we built experimental data driven computational models. We found that the stationary mitochondria were composed of two morphologically different populations, which were generated by fusion/fission and long pause, respectively. Furthermore, computational modeling confirmed our experimental findings that motility and morphological dynamics of mitochondria synergistically regulated their spatial distribution in the axon. Together, our data revealed that stationary mitochondria within the axon interconnected with moving mitochondria through fusion and fission and that fusion between individual mitochondria mediated their global distribution.