Optimizing mitochondrial maintenance in extended neuronal projections

Abstract

AbstractNeurons rely on localized mitochondria to fulfill spatially heterogeneous metabolic demands. Mitochondrial aging occurs on timescales shorter than the neuronal lifespan, necessitating transport of fresh material from the soma. Maintaining an optimal distribution of healthy mitochondria requires an interplay between a stationary pool localized to sites of high metabolic demand and a motile pool capable of delivering new material. Interchange between these pools can occur via transient fusion / fission events or by halting and restarting entire mitochondria. Our quantitative model of neuronal mitostasis identifies key parameters that govern steady-state mitochondrial health at discrete locations. Very infrequent exchange between stationary and motile pools optimizes this system. Exchange via transient fusion allows for robust maintenance, which can be further improved by selective recycling through mitophagy. These results provide a framework for quantifying how perturbations in organelle transport and interactions affect mitochondrial homeostasis in neurons, a key aspect underlying many neurodegenerative disorders.Author summaryNeurons contain long projections termed axons and dendrites and a small central body that is responsible for much of cellular biosynthesis. Mitochondria, the energy hubs of a cell, are synthesized in the soma and actively transported to distant sites of high energy demand. Given the extreme distances between these sites and the soma, maintaining distal mitochondrial health poses a substantial challenge. Defects in mitochondrial transport and maintenance are associated with several neurological disorders.Fortunately, mitochondria stationed at distant sites can be ‘serviced’ by passing mitochondria that emerge from the soma and move around the neuron, as well as through low levels of local protein synthesis. We develop mathematical models for two strategies of mitochondrial maintenance: one with direct protein exchange between moving and stationary mitochondria (‘Space Station’) and the other with moving mitchondria occasionally replacing stationary ones at the demand sites (‘Changing of the Guard’). We find that only a few servicing events and a small motile pool form optimal conditions for maintaining mitochondrial health. The system can be improved further by selectively removing and recycling some unhealthy mitochondria. Our results are consistent with observations of mitochondrial behavior in neurons and form a basis for future quantitative study of mitochondrial maintenance.