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

Licht-Mayer, Simon and Campbell, Graham R. and Canizares, Marco and Mehta, Arpan R. and Gane, Angus B. and McGill, Katie and Ghosh, Aniket and Fullerton, Alexander and Menezes, Niels and Dean, Jasmine and Dunham, Jordon and Al-Azki, Sarah and Pryce, Gareth and Zandee, Stephanie and Zhao, Chao and Kipp, Markus and Smith, Kenneth J. and Baker, David and Altmann, Daniel and Anderton, Stephen M. and Kap, Yolanda S. and Laman, Jon D. and Hart, Bert A.‘t and Rodriguez, Moses and Watzlawick, Ralf and Schwab, Jan M. and Carter, Roderick and Morton, Nicholas and Zagnoni, Michele and Franklin, Robin J. M. and Mitchell, Rory and Fleetwood-Walker, Sue and Lyons, David A. and Chandran, Siddharthan and Lassmann, Hans and Trapp, Bruce D. and Mahad, Don J. (2020) Enhanced axonal response of mitochondria to demyelination offers neuroprotection : implications for multiple sclerosis. Acta Neuropathologica, 140 (2). pp. 143-167. ISSN 0001-6322

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    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.