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

Simon Licht-Mayer, Graham R. Campbell, Marco Canizares, Arpan R Mehta, Angus B Gane, Katie McGill, Aniket Ghosh, Alexander Fullerton, Niels Menezes, Jasmine Dean, Jordon Dunham, Sarah Al-Azki, Gareth Pryce, Stephanie Zandee, Chao Zhao, Markus Kipp, Kenneth J Smith, David Baker, Daniel Altmann, Stephen M. AndertonYolanda S. Kap, Jon D. Laman, Bert A. 't Hart, Moses Rodriguez, Ralf Watzlawick, Jan M. Schwab, Roderick Carter, Nicholas Morton, Michele Zagnoni, Robin J.M. Franklin, Rory Mitchell, Sue Fleetwood-Walker, David A. Lyons, Siddharthan Chandran, Hans Lassmann, Bruce D. Trapp, Don J. Mahad (Lead / Corresponding author)

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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.

Original languageEnglish
Pages (from-to)143-167
Number of pages25
JournalActa Neuropathologica
Issue number2
Early online date22 Jun 2020
Publication statusPublished - Aug 2020


  • Multiple sclerosis
  • Mitochondria
  • Demyelination and neuroprotection


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