eprintid: 10105161 rev_number: 14 eprint_status: archive userid: 608 dir: disk0/10/10/51/61 datestamp: 2020-07-16 10:23:47 lastmod: 2021-09-22 22:05:57 status_changed: 2020-07-16 10:23:47 type: article metadata_visibility: show creators_name: Licht-Mayer, S creators_name: Campbell, GR creators_name: Canizares, M creators_name: Mehta, AR creators_name: Gane, AB creators_name: McGill, K creators_name: Ghosh, A creators_name: Fullerton, A creators_name: Menezes, N creators_name: Dean, J creators_name: Dunham, J creators_name: Al-Azki, S creators_name: Pryce, G creators_name: Zandee, S creators_name: Zhao, C creators_name: Kipp, M creators_name: Smith, KJ creators_name: Baker, D creators_name: Altmann, D creators_name: Anderton, SM creators_name: Kap, YS creators_name: Laman, JD creators_name: 't Hart, BA creators_name: Rodriguez, M creators_name: Watzlawick, R creators_name: Schwab, JM creators_name: Carter, R creators_name: Morton, N creators_name: Zagnoni, M creators_name: Franklin, RJM creators_name: Mitchell, R creators_name: Fleetwood-Walker, S creators_name: Lyons, DA creators_name: Chandran, S creators_name: Lassmann, H creators_name: Trapp, BD creators_name: Mahad, DJ title: Enhanced axonal response of mitochondria to demyelination offers neuroprotection: implications for multiple sclerosis ispublished: pub divisions: UCL divisions: B02 divisions: C07 divisions: D07 divisions: F87 keywords: Multiple sclerosis, Mitochondria, Demyelination and neuroprotection note: 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/. 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. date: 2020-06-22 date_type: published publisher: SPRINGER official_url: http://dx.doi.org/10.1007/s00401-020-02179-x oa_status: green full_text_type: pub language: eng primo: open primo_central: open_green verified: verified_manual elements_id: 1793987 doi: 10.1007/s00401-020-02179-x lyricists_name: Smith, Kenneth lyricists_id: KJSMI17 actors_name: Flynn, Bernadette actors_id: BFFLY94 actors_role: owner full_text_status: public publication: Acta Neuropathologica volume: 140 pagerange: 143-167 pages: 25 citation: Licht-Mayer, S; Campbell, GR; Canizares, M; Mehta, AR; Gane, AB; McGill, K; Ghosh, A; ... Mahad, DJ; + view all <#> Licht-Mayer, S; Campbell, GR; Canizares, M; Mehta, AR; Gane, AB; McGill, K; Ghosh, A; Fullerton, A; Menezes, N; Dean, J; Dunham, J; Al-Azki, S; Pryce, G; Zandee, S; Zhao, C; Kipp, M; Smith, KJ; Baker, D; Altmann, D; Anderton, SM; Kap, YS; Laman, JD; 't Hart, BA; Rodriguez, M; Watzlawick, R; Schwab, JM; Carter, R; Morton, N; Zagnoni, M; Franklin, RJM; Mitchell, R; Fleetwood-Walker, S; Lyons, DA; Chandran, S; Lassmann, H; Trapp, BD; Mahad, DJ; - view fewer <#> (2020) Enhanced axonal response of mitochondria to demyelination offers neuroprotection: implications for multiple sclerosis. Acta Neuropathologica , 140 pp. 143-167. 10.1007/s00401-020-02179-x <https://doi.org/10.1007/s00401-020-02179-x>. Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/10105161/1/Licht-Mayer2020_Article_EnhancedAxonalResponseOfMitoch.pdf