Optimizing mitochondrial maintenance in extended neuronal projections.

Elena F. Koslover,Anamika Agrawal,Daniel A. Beard

doi:10.1371/journal.pcbi.1009073

Elena F. Koslover, Anamika Agrawal + Show 1 more

Open Access

https://doi.org/10.1371/journal.pcbi.1009073

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Abstract

Neurons 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.

Highlights

Mammalian neurons, with their complex and elongated architecture, pose a unique challenge for the delivery and maintenance of cellular components
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’)

Summary

Introduction

With their complex and elongated architecture, pose a unique challenge for the delivery and maintenance of cellular components Their relatively small cell body (soma) contains the nucleus and is responsible for synthesizing all the mRNA transcripts and a large portion of the proteins delivered to distal regions [1, 2]. Neurons rely on packaging components into vesicular organelles or RNA-protein granules, which are actively transported by molecular motors moving along microtubule tracks to the most distant regions of the cell. Such long-distance transport is critical for neuronal growth and repair [9,10,11], synapse formation and function [12,13,14], and synaptic plasticity [15, 16]. Perpetual delivery through transport from the cell body is required to replenish degraded components and maintain neuronal function

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