Enhanced axonal response of mitochondria to demyelination offers neuroprotection: implications for multiple sclerosis
Creators: name: Licht-Mayer, Simon
name: Campbell, Graham R.
name: Canizares, Marco
name: Mehta, Arpan R.
name: Gane, Angus B.
name: McGill, Katie
name: Ghosh, Aniket
name: Fullerton, Alexander
name: Menezes, Niels
name: Dean, Jasmine
name: Dunham, Jordon
name: Al-Azki, Sarah
name: Pryce, Gareth
name: Zandee, Stephanie
name: Zhao, Chao
name: Kipp, Markus
name: Smith, Kenneth J.
name: Baker, David
name: Altmann, Daniel
name: Anderton, Stephen M.
name: Kap, Yolanda S.
name: Laman, Jon D.
name: Hart, Bert A.‘T
name: Rodriguez, Moses
name: Watzlawick, Ralf
name: Schwab, Jan M.
name: Carter, Roderick
name: Morton, Nicholas
name: Zagnoni, Michele
name: Franklin, Robin J. M.
name: Mitchell, Rory
name: Fleetwood-Walker, Sue
name: Lyons, David A.
name: Chandran, Siddharthan
name: Lassmann, Hans
name: Trapp, Bruce D.
name: Mahad, Don J.
Publisher: name: Apollo - University of Cambridge Repository
Year: 2020
Subjects: Original Paper
Multiple sclerosis
Mitochondria
Demyelination and neuroprotection

description: Funder: Wellcome Trust; doi: http://dx.doi.org/10.13039/100004440
description: Funder: Medical Research Foundation; doi: http://dx.doi.org/10.13039/501100009187
description: Funder: National Multiple Sclerosis Society; doi: http://dx.doi.org/10.13039/100000890
description: Funder: Multiple Sclerosis Society; doi: http://dx.doi.org/10.13039/501100000381
description: Funder: National Institutes of Health; doi: http://dx.doi.org/10.13039/100000002
description: 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.