TY - JOUR
T1 - Enhanced axonal response of mitochondria to demyelination offers neuroprotection
T2 - implications for multiple sclerosis
AU - Licht-Mayer, Simon
AU - Campbell, Graham R.
AU - Canizares, Marco
AU - Mehta, Arpan R.
AU - Gane, Angus B.
AU - McGill, Katie
AU - Ghosh, Aniket
AU - Fullerton, Alexander
AU - Menezes, Niels
AU - Dean, Jasmine
AU - Dunham, Jordon
AU - Al-Azki, Sarah
AU - Pryce, Gareth
AU - Zandee, Stephanie
AU - Zhao, Chao
AU - Kipp, Markus
AU - Smith, Kenneth J.
AU - Baker, David
AU - Altmann, Daniel
AU - Anderton, Stephen M.
AU - Kap, Yolanda S.
AU - Laman, Jon D.
AU - Hart, Bert A.‘t
AU - Rodriguez, Moses
AU - Watzlawick, Ralf
AU - Schwab, Jan M.
AU - Carter, Roderick
AU - Morton, Nicholas
AU - Zagnoni, Michele
AU - Franklin, Robin J. M.
AU - Mitchell, Rory
AU - Fleetwood-Walker, Sue
AU - Lyons, David A.
AU - Chandran, Siddharthan
AU - Lassmann, Hans
AU - Trapp, Bruce D.
AU - Mahad, Don J.
PY - 2020/8/1
Y1 - 2020/8/1
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.
AB - 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.
KW - demyelination and neuroprotection
KW - mitochondria
KW - multiple sclerosis
UR - http://www.scopus.com/inward/record.url?scp=85086705011&partnerID=8YFLogxK
U2 - 10.1007/s00401-020-02179-x
DO - 10.1007/s00401-020-02179-x
M3 - Article
AN - SCOPUS:85086705011
SN - 0001-6322
VL - 140
SP - 143
EP - 167
JO - Acta Neuropathologica
JF - Acta Neuropathologica
IS - 2
ER -