TY  - JOUR
SP  - 143
UR  - http://dx.doi.org/10.1007/s00401-020-02179-x
TI  - Enhanced axonal response of mitochondria to demyelination offers neuroprotection: implications for multiple sclerosis
KW  - Multiple sclerosis
KW  - 
Mitochondria
KW  - 
Demyelination and neuroprotection
ID  - discovery10105161
N1  - Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
JF  - Acta Neuropathologica
EP  - 167
AV  - public
N2  - 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.
PB  - SPRINGER
Y1  - 2020/06/22/
VL  - 140
A1  - Licht-Mayer, S
A1  - Campbell, GR
A1  - Canizares, M
A1  - Mehta, AR
A1  - Gane, AB
A1  - McGill, K
A1  - Ghosh, A
A1  - Fullerton, A
A1  - Menezes, N
A1  - Dean, J
A1  - Dunham, J
A1  - Al-Azki, S
A1  - Pryce, G
A1  - Zandee, S
A1  - Zhao, C
A1  - Kipp, M
A1  - Smith, KJ
A1  - Baker, D
A1  - Altmann, D
A1  - Anderton, SM
A1  - Kap, YS
A1  - Laman, JD
A1  - 't Hart, BA
A1  - Rodriguez, M
A1  - Watzlawick, R
A1  - Schwab, JM
A1  - Carter, R
A1  - Morton, N
A1  - Zagnoni, M
A1  - Franklin, RJM
A1  - Mitchell, R
A1  - Fleetwood-Walker, S
A1  - Lyons, DA
A1  - Chandran, S
A1  - Lassmann, H
A1  - Trapp, BD
A1  - Mahad, DJ
ER  -