Optimizing mitochondrial maintenance in extended neuronal projections

Abstract

Neurons rely on localized mitochondria to fulfill spatially heterogeneous metabolic demands. Mi-tochondrial 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, an key aspect underlying many neurodegenerative disorders.

Computation of the mitochondrial age distribution along the axon length

“…Unlike [22], we assumed that mitochondria that reenter the motile state are not split evenly between the anterograde and retrograde components. Rather, the portion of mitochondria that reenter the anterograde component is given by  and the portion of mitochondria that reenter the retrograde component is given by   1   (see Fig.…”

“…(1)-( 9) with zero initial conditions in all compartments and proceeded until the solution reached steady-state. a We estimated 1 soma j  using the formula suggested in [22],…”

“…, where s N is an average number of stops that a mitochondrion makes during a back and forth journey in the axon [22].…”

“…An initial population of 150 unfused mitochondria was simulated. Recent research [22] developed models for two maintenance models of mitochondria, one that assumed the exchange of mitochondrial proteins between moving and stationary mitochondria due to mitochondrial fusion and fission, and the other that assumed occasional replacement of stationary mitochondria with new ones, arriving from the soma.…”