Mitochondrial changes within axons in multiple sclerosis
Open accessAbstract
Multiple sclerosis is the most common cause of non-traumatic neurological impairment in young adults. An energy deficient state has been implicated in the degeneration of axons, the pathological correlate of disease progression, in multiple sclerosis. Mitochondria are the most efficient producers of energy and play an important role in calcium homeostasis. We analysed the density and function of mitochondria using immunohistochemistry and histochemistry, respectively, in chronic active and inactive lesions in progressive multiple sclerosis. As shown before in acute pattern III and Balo's lesions, the mitochondrial respiratory chain complex IV activity is reduced despite the presence of mitochondria in demyelinated axons with amyloid precursor protein accumulation, which are predominantly located at the active edge of chronic active lesions. Furthermore, the strong non-phosphorylated neurofilament (SMI32) reactivity was associated with a significant reduction in complex IV activity and mitochondria within demyelinated axons. The complex IV defect associated with axonal injury may be mediated by soluble products of innate immunity, as suggested by an inverse correlation between complex IV activity and macrophage/microglial density in chronic lesions. However, in inactive areas of chronic multiple sclerosis lesions the mitochondrial respiratory chain complex IV activity and mitochondrial mass, judged by porin immunoreactivity, are increased within approximately half of large (>2.5 microm diameter) chronically demyelinated axons compared with large myelinated axons in the brain and spinal cord. The axon-specific mitochondrial docking protein (syntaphilin) and phosphorylated neurofilament-H were increased in chronic lesions. The lack of complex IV activity in a proportion of Na(+)/K(+) ATPase alpha-1 positive demyelinated axons supports axonal dysfunction as a contributor to neurological impairment and disease progression. Furthermore, in vitro studies show that inhibition of complex IV augments glutamate-mediated axonal injury (amyloid precursor protein and SMI32 reactivity). Our findings have important implications for both axonal degeneration and dysfunction during the progressive stage of multiple sclerosis.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Oxidative damage and mitochondrial dysfunction are key features of MS pathology.
“Oxidative damage and mitochondrial dysfunction are key features of MS pathology [277,278,279,280].”
From Ageing, Cellular Senescence and Neurodegenerative Disease (2018) · cites this paper as [280]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Axonal transection in the lesions of multiple sclerosis
Trapp, B. D., Peterson, J., Ransohoff, R. M., Rudick, R., Mörk, S., & Bö, L. (1998) · New England Journal of Medicine · doi:10.1056/nejm199801293380502 · Cited by 4,029 · see citing works
Mitochondrial DNA mutations in human disease
Taylor, R. W., & Turnbull, D. M. (2005) · Nature Reviews Genetics · doi:10.1038/nrg1606 · Cited by 1,866 · see citing works
Self-citationMitochondrial Respiratory-Chain Diseases
DiMauro, S., & Schon, E. A. (2003) · New England Journal of Medicine · doi:10.1056/nejmra022567 · Cited by 1,650 · see citing works
Axonal damage in acute multiple sclerosis lesions
Ferguson, B. (1997) · Brain · doi:10.1093/brain/120.3.393 · Cited by 1,532 · see citing works
Mitochondrial metabolism of reactive oxygen species
Andreyev, A. Y., Kushnareva, Y. E., & Starkov, A. A. (2005) · Biochemistry (Moscow) · doi:10.1007/s10541-005-0102-7 · Cited by 1,336 · see citing works
Microdomains of Intracellular Ca2+: Molecular Determinants and Functional Consequences
Rizzuto, R., & Pozzan, T. (2005) · Physiological Reviews · doi:10.1152/physrev.00004.2005 · Cited by 1,201 · see citing works
Mitochondrial dysfunction as a cause of axonal degeneration in multiple sclerosis patients
Dutta, R., McDonough, J., Yin, X., Peterson, J. W., Chang, A., Torres, T., Gudz, T. I., Macklin, W. B., Lewis, D., Fox, R., et al. (2006) · Annals of Neurology · doi:10.1002/ana.20736 · Cited by 881 · see citing works
Axon degeneration mechanisms: Commonality amid diversity
Coleman, M. (2005) · Nature reviews. Neuroscience · doi:10.1038/nrn1788 · Cited by 819 · see citing works
The axonal transport of mitochondria
Hollenbeck, P. J., & Saxton, W. M. (2005) · Journal of Cell Science · doi:10.1242/jcs.02745 · Cited by 771 · see citing works
CNS energy metabolism as related to function
Ames, A. (2000) · Brain Research Reviews · doi:10.1016/s0165-0173(00)00038-2 · Cited by 663 · see citing works
Kang, J.-S., Tian, J.-H., Pan, P.-Y., Zald, P., Li, C., Deng, C., & Sheng, Z.-H. (2008) · Cell · doi:10.1016/j.cell.2007.11.024 · Cited by 598 · see citing works
The role of nitric oxide in multiple sclerosis
Smith, K. J., & Lassmann, H. (2002) · The Lancet Neurology · doi:10.1016/s1474-4422(02)00102-3 · Cited by 531 · see citing works
Self-citationPathogenesis of axonal and neuronal damage in multiple sclerosis
Dutta, R., & Trapp, B. (2007) · Neurology · doi:10.1212/01.wnl.0000275229.13012.32 · Cited by 450 · see citing works
Craner, M. J., Newcombe, J., Black, J. A., Hartle, C., Cuzner, M. L., & Waxman, S. G. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0402765101 · Cited by 446 · see citing works
Vos, K. J. D., Chapman, A. L., Tennant, M. E., Manser, C., Tudor, E. L., Lau, K., Brownlees, J., Ackerley, S., Shaw, P. J., McLoughlin, D. M., et al. (2007) · Human Molecular Genetics · doi:10.1093/hmg/ddm226 · Cited by 420 · see citing works
Mitochondrial defects in acute multiple sclerosis lesions
Mahad, D., Ziabreva, I., Lassmann, H., & Turnbull, D. (2008) · Brain · doi:10.1093/brain/awn105 · Cited by 406 · see citing works
Self-citationAxonal conduction and injury in multiple sclerosis: the role of sodium channels
Waxman, S. G. (2006) · Nature reviews. Neuroscience · doi:10.1038/nrn2023 · Cited by 398 · see citing works
Lu, F., Selak, M. A., O'Connor, J. J., Croul, S. E., Lorenzana, C., Butunoi, C., & Kálmán, B. (2000) · Journal of the Neurological Sciences · doi:10.1016/s0022-510x(00)00343-9 · Cited by 331 · see citing works
Redford, E. (1997) · Brain · doi:10.1093/brain/120.12.2149 · Cited by 329 · see citing works
Caldwell, P. C., Hodgkin, A. L., Keynes, R. D., & Shaw, T. I. (1960) · The Journal of Physiology · doi:10.1113/jphysiol.1960.sp006509 · Cited by 321 · see citing works
Electrically active axons degenerate when exposed to nitric oxide
Smith, K. J., Kapoor, R., Hall, S. M., & Davies, M. (2001) · Annals of Neurology · doi:10.1002/ana.96 · Cited by 320 · see citing works
General mechanisms of axonal damage and its prevention
Stys, P. K. (2005) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2005.03.031 · Cited by 314 · see citing works
Staging of multiple sclerosis (MS) lesions: pathology of the time frame of MS
van der Valk, P., & Groot, C. J. A. D. (2000) · Neuropathology and Applied Neurobiology · doi:10.1046/j.1365-2990.2000.00217.x · Cited by 304 · see citing works
Lesion genesis in a subset of patients with multiple sclerosis: a role for innate immunity?
Marik, C., Felts, P. A., Bauer, J., Lassmann, H., & Smith, K. J. (2007) · Brain · doi:10.1093/brain/awm236 · Cited by 292 · see citing works
Self-citationTakeuchi, H., Mizuno, T., Zhang, G., Wang, J., Kawanokuchi, J., Kuno, R., & Suzumura, A. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m413863200 · Cited by 285 · cited 3× · see citing works
“Furthermore, the inhibition of complex IV is recognized in microglia induced neuritic beading, in vitro (Takeuchi et al., 2005).”
Axonal loss in multiple sclerosis: a pathological survey of the corticospinal and sensory tracts
DeLuca, G. C. (2004) · Brain · doi:10.1093/brain/awh118 · Cited by 255 · see citing works
The Distribution of Mitochondrial Activity in Relation to Optic Nerve Structure
Bristow, E. (2002) · Archives of Ophthalmology · doi:10.1001/archopht.120.6.791 · Cited by 243 · see citing works
Kirkinezos, I. G., Bacman, S. R., Hernandez, D., Oca‐Cossio, J., Arias, L. J., Pérez‐Pinzón, M. A., Bradley, W. G., & Moraes, C. T. (2005) · Journal of Neuroscience · doi:10.1523/jneurosci.3829-04.2005 · Cited by 200 · see citing works
Disability as an outcome in MS clinical trials
Ebers, G. C., Heigenhauser, L., Däumer, M., Lederer, C., & Noseworthy, J. H. (2008) · Neurology · doi:10.1212/01.wnl.0000313034.46883.16 · Cited by 180 · see citing works
Mechanisms of Mitochondria-Neurofilament Interactions
Wagner, O. I., Lifshitz, J., Janmey, P. A., Lindén, M., McIntosh, T. K., & Leterrier, J. F. (2003) · Journal of Neuroscience · doi:10.1523/jneurosci.23-27-09046.2003 · Cited by 179 · see citing works
Barron, M. J. (2004) · British Journal of Ophthalmology · doi:10.1136/bjo.2003.027664 · Cited by 164 · see citing works
Mitochondrial biogenesis in the axons of vertebrate peripheral neurons
Amiri, M., & Hollenbeck, P. J. (2008) · Developmental Neurobiology · doi:10.1002/dneu.20668 · Cited by 161 · see citing works
Hevner, R. F., Liu, S., & Wong‐Riley, M. T. T. (1995) · Neuroscience · doi:10.1016/0306-4522(94)00514-6 · Cited by 147 · see citing works
Qi, X., Lewin, A. S., Sun, L., Hauswirth, W. W., & Guy, J. R. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m603717200 · Cited by 142 · see citing works
Membranes, Myelin, and the Pathophysiology of Multiple Sclerosis
Waxman, S. G. (1982) · New England Journal of Medicine · doi:10.1056/nejm198206243062505 · Cited by 142 · see citing works
Reversal of a mitochondrial DNA defect in human skeletal muscle
Clark, K. M., Bindoff, L. A., Lightowlers, R. N., Andrews, R. M., Griffiths, P. G., Johnson, M. A., Brierley, E. J., & Turnbull, D. M. (1997) · Nature Genetics · doi:10.1038/ng0797-222 · Cited by 141 · see citing works
Self-citationSodium Channels and Multiple Sclerosis: Roles in Symptom Production, Damage and Therapy
Smith, K. J. (2007) · Brain Pathology · doi:10.1111/j.1750-3639.2007.00066.x · Cited by 123 · see citing works
Ultrastructural concomitants of anoxic injury and early post-anoxic recovery in rat optic nerve
Waxman, S. G., Black, J. A., Stys, P. K., & Ransom, B. R. (1992) · Brain Research · doi:10.1016/0006-8993(92)90806-k · Cited by 116 · see citing works
Imaging correlates of decreased axonal Na + /K + ATPase in chronic multiple sclerosis lesions
Young, E. A., Fowler, C. D., Kidd, G. J., Chang, A., Rudick, R. A., Fisher, E., & Trapp, B. D. (2008) · Annals of Neurology · doi:10.1002/ana.21381 · Cited by 111 · see citing works
Increased axonal mitochondrial activity as an adaptation to myelin deficiency in the Shiverer mouse
Andrews, H., White, K., Thomson, C. E., Edgar, J. M., Bates, D., Griffiths, I. R., Turnbull, D. M., & Nichols, P. P. (2006) · Journal of Neuroscience Research · doi:10.1002/jnr.20842 · Cited by 104 · see citing works
Self-citationSodium Channel Expression Within Chronic Multiple Sclerosis Plaques
Black, J., Newcombe, J., Trapp, B., & Waxman, S. (2007) · Journal of Neuropathology and Experimental Neurology · doi:10.1097/nen.0b013e3181462841 · Cited by 92 · see citing works
Na+-Dependent Sources of Intra-Axonal Ca2+Release in Rat Optic Nerve duringIn VitroChemical Ischemia
Nikolaeva, M. A., Mukherjee, B., & Stys, P. K. (2005) · Journal of Neuroscience · doi:10.1523/jneurosci.2003-05.2005 · Cited by 88 · see citing works
The Ionic Basis of Nervous Conduction
Hodgkin, A. L. (1964) · Science · doi:10.1126/science.145.3637.1148 · Cited by 88 · see citing works
Clements, R. J., McDonough, J. A., & Freeman, E. J. (2008) · Experimental Brain Research · doi:10.1007/s00221-008-1317-9 · Cited by 73 · see citing works
Petzold, A., Gveric, D. O., Groves, M., Schmierer, K., Grant, D., Chapman, M. D., Keir, G., Cuzner, L., & Thompson, E. J. (2008) · Experimental Neurology · doi:10.1016/j.expneurol.2008.06.008 · Cited by 68 · see citing works
Ions, energy and axonal injury: towards a molecular neurology of multiple sclerosis
Waxman, S. G. (2006) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2006.03.001 · Cited by 67 · see citing works
Variations in Mitochondrial DNA Copy Numbers in MS Brains
Blokhin, A., Vyshkina, T., Komoly, S., et al. (2008) · Journal of Molecular Neuroscience · doi:10.1007/s12031-008-9115-1 · Cited by 65 · see citing works
VONKLEISTRETZOW, J., Hornig‐Do, H., Schauen, M., Eckertz, S., DINH, T., STASSEN, F., Lottmann, N., Bust, M., Galunska, B. T., & Wielckens, K. (2007) · Experimental Cell Research · doi:10.1016/j.yexcr.2007.04.015 · Cited by 59 · see citing works
INCREASED DIAMETER OF DEMYELINATED AXONS IN CHRONIC MULTIPLE SCLEROSIS OF THE SPINAL CORD
SHINTAKU, M., HIRANO, A., & LLENA, J. F. (1988) · Neuropathology and Applied Neurobiology · doi:10.1111/j.1365-2990.1988.tb01341.x · Cited by 33 · see citing works
Axonal dysfunction in chronic multiple sclerosis: Meltdown in the membrane
Waxman, S. G. (2008) · Annals of Neurology · doi:10.1002/ana.21361 · Cited by 29 · see citing works
Wei, J., Guo, H., & Kuo, P. C. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.168.9.4721 · Cited by 23 · see citing works
Flagged first, then by citations
Research works printed but not linked: 3
- Compston A McAlpine’s Multiple Sclerosis 2005 Vol. 1 Churchill Livingstone London
- Hildebrand C Waxman SG Regional node-like membrane specializations in non-myelinated Brain Research 1983 258 23 32 24010160
- Kornek B Storch MK Weissert R Wallstroem E Stefferl A Olsson T Multiple sclerosis and chronic autoimmune encephalomyelitis: a comparative quantitative study of axonal injury in active, inactive, and remyelinated lesions Am J Pathol 2000 157 267 76 10880396 PMC1850217
Cited by
Sorted by citations
Progressive multiple sclerosis: pathology and pathogenesis
Lassmann, H., van Horssen, J., & Mahad, D. (2012) · Nature Reviews Neurology · doi:10.1038/nrneurol.2012.168 · Cited by 1,033 · see citing works
Self-citationMitochondrial optic neuropathies—Disease mechanisms and therapeutic strategies
Yu-Wai-Man, P., Griffiths, P. G., & Chinnery, P. F. (2011) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2010.11.002 · Cited by 633 · see citing works
Fischer, M. T., Sharma, R., Lim, J. L., Haider, L., Frischer, J. M., Drexhage, J., Mahad, D., Bradl, M., van Horssen, J., & Lassmann, H. (2012) · Brain · doi:10.1093/brain/aws012 · Cited by 507 · see citing works
Self-citationAgeing, Cellular Senescence and Neurodegenerative Disease
Kritsilis, M., V. Rizou, S., Koutsoudaki, P. N., Evangelou, K., Gorgoulis, V. G., & Papadopoulos, D. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19102937 · Cited by 448 · see citing works
Progressive multiple sclerosis: from pathophysiology to therapeutic strategies
Faissner, S., Plemel, J. R., Gold, R., & Yong, V. W. (2019) · Nature Reviews Drug Discovery · doi:10.1038/s41573-019-0035-2 · Cited by 459 · see citing works
Inflammation, demyelination, and degeneration — Recent insights from MS pathology
Stadelmann, C., Wegner, C., & Brück, W. (2011) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2010.07.007 · Cited by 276 · see citing works
The many roads to mitochondrial dysfunction in neuroimmune and neuropsychiatric disorders
Morris, G., & Berk, M. (2015) · BMC Medicine · doi:10.1186/s12916-015-0310-y · Cited by 245 · see citing works
Jamwal, S., Blackburn, J. K., & Elsworth, J. D. (2021) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2020.107705 · Cited by 236 · see citing works
Mechanisms of white matter damage in multiple sclerosis
Lassmann, H. (2014) · Glia · doi:10.1002/glia.22597 · Cited by 191 · see citing works
Self-citationMechanisms of Neurodegeneration and Axonal Dysfunction in Progressive Multiple Sclerosis
Correale, J., Marrodan, M., & Ysrraelit, M. C. (2019) · Biomedicines · doi:10.3390/biomedicines7010014 · Cited by 167 · see citing works
Food, Nutrigenomics, and Neurodegeneration—Neuroprotection by What You Eat!
Virmani, A., Pinto, L., Binienda, Z., & Ali, S. (2013) · Molecular Neurobiology · doi:10.1007/s12035-013-8498-3 · Cited by 137 · see citing works
Clinical features of MS associated with Leber hereditary optic neuropathy mtDNA mutations
Pfeffer, G., Burke, A., Yu-Wai-Man, P., Compston, D. A. S., & Chinnery, P. F. (2013) · Neurology · doi:10.1212/01.wnl.0000437308.22603.43 · Cited by 122 · see citing works
Axonal degeneration as a therapeutic target in the CNS
Lingor, P., Koch, J. C., Tönges, L., & Bähr, M. (2012) · Cell and Tissue Research · doi:10.1007/s00441-012-1362-3 · Cited by 119 · see citing works
Mechanisms of neurodegeneration shared between multiple sclerosis and Alzheimer’s disease
Lassmann, H. (2011) · Journal of Neural Transmission · doi:10.1007/s00702-011-0607-8 · Cited by 112 · see citing works
Self-citationNijland, P. G., Witte, M. E., van het Hof, B., van der Pol, S., Bauer, J., Lassmann, H., van der Valk, P., de Vries, H. E., & van Horssen, J. (2014) · Acta Neuropathologica Communications · doi:10.1186/s40478-014-0170-2 · Cited by 96 · see citing works
Self-citationvan Hameren, G., Campbell, G., Deck, M., Berthelot, J., Gautier, B., Quintana, P., Chrast, R., & Tricaud, N. (2019) · Acta Neuropathologica Communications · doi:10.1186/s40478-019-0740-4 · Cited by 83 · see citing works
Self-citationDiagnosis and Management of Progressive Multiple Sclerosis
Macaron, G., & Ontaneda, D. (2019) · Biomedicines · doi:10.3390/biomedicines7030056 · Cited by 70 · see citing works
Expression of Translocator Protein and [18F]-GE180 Ligand Uptake in Multiple Sclerosis Animal Models
Nack, A., Brendel, M., Nedelcu, J., Daerr, M., Nyamoya, S., Beyer, C., Focke, C., Deussing, M., Hoornaert, C., Ponsaerts, P., et al. (2019) · Cells · doi:10.3390/cells8020094 · Cited by 43 · see citing works
The emerging neuroprotective role of mitochondrial uncoupling protein-2 in traumatic brain injury
Normoyle, K. P., Kim, M., Farahvar, A., Llano, D., Jackson, K., & Wang, H. (2015) · Translational Neuroscience · doi:10.1515/tnsci-2015-0019 · Cited by 36 · see citing works
- Authors
- Mahad, D. J., Ziabreva, I., Campbell, G., Lax, N., White, K., Hanson, P. S., Lassmann, H., & Turnbull, D. M.
- Affiliations
- Newcastle University (GB)
- Medical University of Vienna (AT)
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2009-03-17
- Volume
- 132
- Issue
- 5
- Pages
- 1161-1174
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- PMC
- PMC3605917
- OpenAlex
- W2149515432
- Cited by
- 454
- References
- 51
- Citations by year
- 2026: 13 · 2025: 14 · 2024: 18 · 2023: 17 · 2022: 20 · 2021: 27 · 2020: 21 · 2019: 34 · 2018: 32 · 2017: 27 · 2016: 20 · 2015: 40 · 2014: 34 · 2013: 27 · 2012: 38
- FWCI
- 25.20
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Brain (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- Newcastle University ePrints (Newcastle Univesity)
- Funders
- Wellcome Trust (078415, 074454)
- Multiple Sclerosis Society
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Keywords
- multiple sclerosis, axonal degeneration, demyelination, axons, amyloid precursor protein, neurofilaments, innate immunity, porin, syntaphilin, Na+/K+-ATPase, chronic active lesions, disease progression
- MeSH terms
- Adult, Aged, Aged, 80 and over, Animals, Autopsy, Axons, Brain, Cells, Cultured, Chronic Disease, Electron Transport Complex IV, Female, Humans, Immunohistochemistry, Male, Microscopy, Electron, Middle Aged, Mitochondria, Multiple Sclerosis, Spinal Cord, Blotting, Western, Glutamic Acid, Sodium Azide, Electron Transport Complex II, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
