Neuronal Energetics: Mitochondrial Distribution and The Phosphagen System

The relationship between neuronal function and energy metabolism is a field of intense inquiry and while bioenergetic per se are well understood, we lack a good understanding of the ways in which these mechanisms overcome the challenges presented by the unique morphology of neurons and their volatile energy demands. Here we examined the extent to which these challenges can be met through strategic mitochondrial placement and the support of a phosphagen system.
We examined fluctuations in energy demand of Drosophila larval motor neurons utilizing a combination of computational modeling and empirical analysis, and uncovered a neglected aspect of cellular energy metabolism that appears to accommodate the stress of highly volatile energy demands. Our findings highlight a reliance on the phosphagen system to buffer against rapid changes in the rate of ATP consumption induced by burst firing. The knockdown of a key element in the phosphagen system of invertebrates, arginine kinase, revealed a suppression of the mitochondrial proton motive force, and a more rapid decline in the presynaptic ATP/ADP ratio during burst firing. The knock down of arginine kinase also revealed metabolic shifts that indicated a compensatory increase in glycolysis, but, surprisingly, few consequences for either presynaptic Ca2+ handling or neurotransmission. In a final effort to ensure that we were imposing a metabolic load adequate to challenge these motor neurons, we developed an ex vivo calcium clearance assay and in vivo locomotor performance assay – currently in their final stages of validation.