# Enhanced axonal response of mitochondria to demyelination offers neuroprotection: implications for multiple sclerosis

## TL;DR

The study shows that increasing mitochondria in axons after demyelination protects neurons, offering a new strategy for treating multiple sclerosis.

## Contribution

The study identifies a novel neuroprotective mechanism involving enhanced mitochondrial transport to demyelinated axons.

## Key findings

- Mitochondria move from the cell body to demyelinated axons, termed the axonal response of mitochondria to demyelination (ARMD).
- Enhancing ARMD protects acutely demyelinated axons from degeneration.
- Promoting mitochondrial dynamics in complex IV deficient neurons preserves axons after demyelination.

## Abstract

Axonal loss is the key pathological substrate of neurological disability in demyelinating disorders, including multiple sclerosis (MS). However, the consequences of demyelination on neuronal and axonal biology are poorly understood. The abundance of mitochondria in demyelinated axons in MS raises the possibility that increased mitochondrial content serves as a compensatory response to demyelination. Here, we show that upon demyelination mitochondria move from the neuronal cell body to the demyelinated axon, increasing axonal mitochondrial content, which we term the axonal response of mitochondria to demyelination (ARMD). However, following demyelination axons degenerate before the homeostatic ARMD reaches its peak. Enhancement of ARMD, by targeting mitochondrial biogenesis and mitochondrial transport from the cell body to axon, protects acutely demyelinated axons from degeneration. To determine the relevance of ARMD to disease state, we examined MS autopsy tissue and found a positive correlation between mitochondrial content in demyelinated dorsal column axons and cytochrome c oxidase (complex IV) deficiency in dorsal root ganglia (DRG) neuronal cell bodies. We experimentally demyelinated DRG neuron-specific complex IV deficient mice, as established disease models do not recapitulate complex IV deficiency in neurons, and found that these mice are able to demonstrate ARMD, despite the mitochondrial perturbation. Enhancement of mitochondrial dynamics in complex IV deficient neurons protects the axon upon demyelination. Consequently, increased mobilisation of mitochondria from the neuronal cell body to the axon is a novel neuroprotective strategy for the vulnerable, acutely demyelinated axon. We propose that promoting ARMD is likely to be a crucial preceding step for implementing potential regenerative strategies for demyelinating disorders.

The online version of this article (10.1007/s00401-020-02179-x) contains supplementary material, which is available to authorized users.