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Biochemistry (Moscow)

, Volume 83, Issue 7, pp 813–830 | Cite as

Involvement of Mitochondria in Neurodegeneration in Multiple Sclerosis

  • M. S. Kozin
  • O. G. Kulakova
  • O. O. Favorova
Review
  • 4 Downloads

Abstract

Functional disruption and neuronal loss followed by progressive dysfunction of the nervous system underlies the pathogenesis of numerous disorders defined as “neurodegenerative diseases”. Multiple sclerosis, a chronic inflammatory demyelinating disease of the central nervous system resulting in serious neurological dysfunctions and disability, is one of the most common neurodegenerative diseases. Recent studies suggest that disturbances in mitochondrial functioning are key factors leading to neurodegeneration. In this review, we consider data on mitochondrial dysfunctions in multiple sclerosis, which were obtained both with patients and with animal models. The contemporary data indicate that the axonal degeneration in multiple sclerosis largely results from the activation of Ca2+-dependent proteases and from misbalance of ion homeostasis caused by energy deficiency. The genetic studies analyzing association of mitochondrial DNA polymorphic variants in multiple sclerosis suggest the participation of mitochondrial genome variability in the development of this disease, although questions of the involvement of individual genomic variants are far from being resolved.

Keywords

neurodegenerative diseases neurodegeneration mitochondria multiple sclerosis haplogroup single nucleotide polymorphism 

Abbreviations

AP

action potential

BBB

blood–brain barrier

CNS

central nervous system

EAE

experimental autoimmune encephalomyelitis

ETC

electron transport chain

MBP

myelin basic protein

MS

multiple sclerosis

mtDNA

mitochondrial DNA

PPMS

primary progressive multiple sclerosis

RRMS

relapsing-remitting multiple sclerosis

ROS

reactive oxygen species

SNP

single nucleotide polymorphism

SPMS

secondary progressive multiple sclerosis

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References

  1. 1.
    Rafael, H. (2014) Omental transplantation for neurodegen–erative diseases, Am. J. Neurodegener. Dis., 3, 50–63.PubMedPubMedCentralGoogle Scholar
  2. 2.
    Burnside, S. W., and Hardingham, G. E. (2017) Transcriptional regulators of redox balance and other homeostatic processes with the potential to alter neurode–generative disease trajectory, Biochem. Soc. Trans., 45, 1295–1303.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Karussis, D. (2014) The diagnosis of multiple sclerosis and the various related demyelinating syndromes: a critical review, J. Autoimmun., 48–49, 134–142.Google Scholar
  4. 4.
    Ellwardt, E., and Zipp, F. (2014) Molecular mechanisms linking neuroinflammation and neurodegeneration in MS, Exp. Neurol., 262, 8–17.PubMedCrossRefGoogle Scholar
  5. 5.
    Dendrou, C. A., and Fugger, L. (2017) Immunomodula–tion in multiple sclerosis: promises and pitfalls, Curr. Opin. Immunol., 49, 37–43.PubMedCrossRefGoogle Scholar
  6. 6.
    Heidker, R. M., Emerson, M. R., and LeVine, S. M. (2017) Metabolic pathways as possible therapeutic targets for pro–gressive multiple sclerosis, Neural. Regen. Res., 12, 1262–1267.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Garcia–Escudero, V., Martin–Maestro, P., Perry, G., and Avila, J. (2013) Deconstructing mitochondrial dysfunction in Alzheimer disease, Oxid. Med. Cell. Longev., 2013, 162152.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Avetisyan, A. V., Samokhin, A. N., Alexandrova, I. Y., Zinovkin, R. A., Simonyan, R. A., and Bobkova, N. V. (2016) Mitochondrial dysfunction in neocortex and hip–pocampus of olfactory bulbectomized mice, a model of Alzheimer’s disease, Biochemistry (Moscow), 81, 615–623.CrossRefGoogle Scholar
  9. 9.
    Hang, L., Thundyil, J., and Lim, K. L. (2015) Mitochondrial dysfunction and Parkinson disease: a Parkin–AMPK alliance in neuroprotection, Ann. N. Y. Acad. Sci., 1350, 37–47.PubMedCrossRefGoogle Scholar
  10. 10.
    Perfeito, R., Cunha–Oliveira, T., and Rego, A. C. (2013) Reprint of: Revisiting oxidative stress and mitochondrial dysfunction in the pathogenesis of Parkinson disease. Resemblance to the effect of amphetamine drugs of abuse, Free Radic. Biol. Med., 62, 186–201.PubMedCrossRefGoogle Scholar
  11. 11.
    Carri, M. T., D’Ambrosi, N., and Cozzolino, M. (2017) Pathways to mitochondrial dysfunction in ALS pathogene–sis, Biochem. Biophys. Res. Commun., 483, 1187–1193.PubMedCrossRefGoogle Scholar
  12. 12.
    Cozzolino, M., Ferri, A., Valle, C., and Carri, M. T. (2013) Mitochondria and ALS: implications from novel genes and pathways, Mol. Cell. Neurosci., 55, 44–49.PubMedCrossRefGoogle Scholar
  13. 13.
    Polyzos, A. A., and McMurray, C. T. (2017) The chicken or the egg: mitochondrial dysfunction as a cause or conse–quence of toxicity in Huntington’s disease, Mech. Ageing Dev., 161, 181–197.PubMedCrossRefGoogle Scholar
  14. 14.
    Ayala–Pena, S. (2013) Role of oxidative DNA damage in mitochondrial dysfunction and Huntington’s disease pathogenesis, Free Radic. Biol. Med., 62, 102–110.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Dyall, S. D., Brown, M. T., and Johnson, P. J. (2004) Ancient invasions: from endosymbionts to organelles, Science, 304, 253–257.PubMedCrossRefGoogle Scholar
  16. 16.
    Koonin, E. V. (2014) The Logic of Chance: The Nature and Origin of Biological Evolution [in Russian], Tsentrpoligraf, Moscow.Google Scholar
  17. 17.
    Hunt, R. J., and Bateman, J. M. (2017) Mitochondrial ret–rograde signaling in the nervous system, FEBS Lett., 592, 663–678.PubMedCrossRefGoogle Scholar
  18. 18.
    Li, M. X., and Dewson, G. (2015) Mitochondria and apop–tosis: emerging concepts, F1000Prime Rep., 1, 7–42.Google Scholar
  19. 19.
    Rasola, A., and Bernardi, P. (2011) Mitochondrial perme–ability transition in Ca2+–dependent apoptosis and necrosis, Cell Calcium, 50, 222–233.PubMedCrossRefGoogle Scholar
  20. 20.
    Mitra, K. (2013) Mitochondrial fission–fusion as an emerg–ing key regulator of cell proliferation and differentiation, Bioessays, 35, 955–964.PubMedCrossRefGoogle Scholar
  21. 21.
    Zhang, Z. W., Cheng, J., Xu, F., Chen, Y. E., Du, J. B., Yuan, M., Zhu, F., Xu, X. C., and Yuan, S. (2011) Red blood cell extrudes nucleus and mitochondria against oxidative stress, IUBMB Life, 63, 560–565.PubMedCrossRefGoogle Scholar
  22. 22.
    Uranova, N., Orlovskaya, D., Vikhreva, O., Zimina, I., Kolomeets, N., Vostrikov, V., and Rachmanova, V. (2001) Electron microscopy of oligodendroglia in severe mental illness, Brain Res. Bull., 55, 597–610.PubMedCrossRefGoogle Scholar
  23. 23.
    Duran, H. E., Simsek–Duran, F., Oehninger, S. C., Jones, H. W., Jr., and Castora, F. J. (2011) The association of reproductive senescence with mitochondrial quantity, func–tion, and DNA integrity in human oocytes at different stages of maturation, Fertil. Steril., 96, 384–388.PubMedCrossRefGoogle Scholar
  24. 24.
    Michel, S., Wanet, A., De Pauw, A., Rommelaere, G., Arnould, T., and Renard, P. (2012) Crosstalk between mito–chondrial (dys)function and mitochondrial abundance, J. Cell Physiol., 227, 2297–2310.PubMedCrossRefGoogle Scholar
  25. 25.
    Rodriguez–Enriquez, S., Kai, Y., Maldonado, E., Currin, R. T., and Lemasters, J. J. (2009) Roles of mitophagy and the mitochondrial permeability transition in remodeling of cultured rat hepatocytes, Autophagy, 5, 1099–1106.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Friedman, J. R., and Nunnari, J. (2014) Mitochondrial form and function, Nature, 505, 335–343.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Mazunin, I. O., Volodko, N. V., Starikovskaya, E. B., and Sukernik, R. I. (2010) Mitochondrial genome and human mitochondrial diseases, Mol. Biol., 44, 755–772.CrossRefGoogle Scholar
  28. 28.
    Anderson, S., Bankier, A. T., Barrell, B. G., de Bruijn, M. H., Coulson, A. R., Drouin, J., Eperon, I. C., Nierlich, D. P., Roe, B. A., Sanger, F., Schreier, P. H., Smith, A. J., Staden, R., and Young, I. G. (1981) Sequence and organi–zation of the human mitochondrial genome, Nature, 290, 457–465.PubMedCrossRefGoogle Scholar
  29. 29.
    Reed, J. C. (1998) Bcl–2 family proteins, Oncogene, 17, 3225–3236.PubMedCrossRefGoogle Scholar
  30. 30.
    Wang, X. (2001) The expanding role of mitochondria in apoptosis, Genes Dev., 15, 2922–2933.PubMedGoogle Scholar
  31. 31.
    Tait, S. W., and Green, D. R. (2010) Mitochondria and cell death: outer membrane permeabilization and beyond, Nat. Rev. Mol. Cell Biol., 11, 621–632.PubMedCrossRefGoogle Scholar
  32. 32.
    Pena–Blanco, A., and Garcia–Saez, A. J. (2017) Bax, Bak and beyond–mitochondrial performance in apoptosis, FEBS J., 285, 416–431.Google Scholar
  33. 33.
    Hamacher–Brady, A., and Brady, N. R. (2015) Bax/Bak–dependent, Drp1–independent targeting of Smac X–linked inhibitor of apoptosis protein (XIAP) into inner mitochondr–ial compartments counteracts Smac/DIABLO–dependent effector caspase activation, J. Biol. Chem., 290, 22005–22018.PubMedGoogle Scholar
  34. 34.
    Vande Walle, L., Lamkanfi, M., and Vandenabeele, P. (2008) The mitochondrial serine protease HtrA2/Omi: an overview, Cell Death Differ., 15, 453–460.PubMedCrossRefGoogle Scholar
  35. 35.
    Jang, D. S., Penthala, N. R., Apostolov, E. O., Wang, X., Crooks, P. A., and Basnakian, A. G. (2014) Novel cytopro–tective inhibitors for apoptotic endonuclease G, DNA Cell Biol., 34, 92–100.PubMedCrossRefGoogle Scholar
  36. 36.
    Ding, Z. J., Chen, X., Tang, X. X., Wang, X., Song, Y. L., Chen, X. D., Wang, J., Wang, R. F., Mi, W. J., Chen, F. Q., and Qiu, J. H. (2015) Apoptosis–inducing factor and cal–pain upregulation in glutamate–induced injury of rat spiral ganglion neurons, Mol. Med. Rep., 12, 1685–1692.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Bender, T., and Martinou, J. C. (2013) Where killers meet–permeabilization of the outer mitochondrial membrane during apoptosis, Cold Spring Harb. Perspect. Biol., 5, a011106.Google Scholar
  38. 38.
    Suhaili, S. H., Karimian, H., Stellato, M., Lee, T. H., and Aguilar, M. I. (2017) Mitochondrial outer membrane per–meabilization: a focus on the role of mitochondrial mem–brane structural organization, Biophys. Rev., 9, 443–457.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Zamzami, N., and Kroemer, G. (2001) The mitochondrion in apoptosis: how Pandora’s box opens, Nat. Rev. Mol. Cell. Biol., 2, 67–71.PubMedCrossRefGoogle Scholar
  40. 40.
    Joseph, S. K., and Hajnoczky, G. (2007) IP3 receptors in cell survival and apoptosis: Ca2+ release and beyond, Apoptosis, 12, 951–968.PubMedCrossRefGoogle Scholar
  41. 41.
    Shoshan–Barmatz, V., Krelin, Y., and Shteinfer–Kuzmine, A. (2018) VDAC1 functions in Ca2+ homeostasis and cell life and death in health and disease, Cell Calcium, 69, 81–100.PubMedCrossRefGoogle Scholar
  42. 42.
    De Stefani, D., Patron, M., and Rizzuto, R. (2015) Structure and function of the mitochondrial calcium uni–porter complex, Biochim. Biophys. Acta, 1853, 2006–2011.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Palty, R., Silverman, W. F., Hershfinkel, M., Caporale, T., Sensi, S. L., Parnis, J., Nolte, C., Fishman, D., Shoshan–Barmatz, V., Herrmann, S., Khananshvili, D., and Sekler, I. (2010) NCLX is an essential component of mitochondri–al Na+/Ca2+ exchange, Proc. Natl. Acad. Sci. USA, 107, 436–441.PubMedCrossRefGoogle Scholar
  44. 44.
    De Stefani, D., Rizzuto, R., and Pozzan, T. (2016) Enjoy the trip: calcium in mitochondria back and forth, Annu. Rev. Biochem., 85, 161–192.PubMedCrossRefGoogle Scholar
  45. 45.
    Glancy, B., and Balaban, R. S. (2012) Role of mitochondr–ial Ca2+ in the regulation of cellular energetics, Biochemistry, 51, 2959–2973.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Holt, I. J., and Reyes, A. (2012) Human mitochondrial DNA replication, Cold Spring Harb. Perspect. Biol., 4; doi: 10.1101/cshperspect.a012971.Google Scholar
  47. 47.
    Gusev, E. I., Zavalishin, I. A., and Boiko, A. N. (2004) Multiple Sclerosis and Other Demyelinating Diseases [in Russian], Miklosh, Moscow.Google Scholar
  48. 48.
    Zavalishin, I. A., Piradov, M. A., Boiko, A. N., Nikitin, S. S., and Peresedova, A. V. (2014) Autoimmune Diseases in Neurology. Clinical Guidebook [in Russian], Zdorov’e Cheloveka, Moscow.Google Scholar
  49. 49.
    Steinman, L. (2001) Multiple sclerosis: a two–stage disease, Nat. Immunol., 2, 762–764.PubMedCrossRefGoogle Scholar
  50. 50.
    Cunningham, C. (2013) Microglia and neurodegeneration: the role of systemic inflammation, Glia, 61, 71–90.PubMedCrossRefGoogle Scholar
  51. 51.
    Von Budingen, H. C., Bar–Or, A., and Zamvil, S. S. (2011) B–cells in multiple sclerosis: connecting the dots, Curr. Opin. Immunol., 23, 713–720.CrossRefGoogle Scholar
  52. 52.
    Bjartmar, C., Wujek, J. R., and Trapp, B. D. (2003) Axonal loss in the pathology of MS: consequences for understand–ing the progressive phase of the disease, J. Neurol. Sci., 206, 165–171.PubMedCrossRefGoogle Scholar
  53. 53.
    Bruck, W. (2005) The pathology of multiple sclerosis is the result of focal inflammatory demyelination with axonal damage, J. Neurol., 5, 3–9.CrossRefGoogle Scholar
  54. 54.
    Howe, C. L. (2008) Immunological aspects of axon injury in multiple sclerosis, Curr. Top. Microbiol. Immunol., 318, 93–131.PubMedGoogle Scholar
  55. 55.
    Pfueller, C. F., Brandt, A. U., Schubert, F., Bock, M., Walaszek, B., Waiczies, H., Schwenteck, T., Dorr, J., Bellmann–Strobl, J., Mohr, C., Weinges–Evers, N., Ittermann, B., Wuerfel, J. T., and Paul, F. (2011) Metabolic changes in the visual cortex are linked to retinal nerve fiber layer thinning in multiple sclerosis, PLoS One, 6, e18019.Google Scholar
  56. 56.
    Funfschilling, U., Supplie, L. M., Mahad, D., Boretius, S., Saab, A. S., Edgar, J., Brinkmann, B. G., Kassmann, C. M., Tzvetanova, I. D., Mobius, W., Diaz, F., Meijer, D., Suter, U., Hamprecht, B., Sereda, M. W., Moraes, C. T., Frahm, J., Goebbels, S., and Nave, K. A. (2012) Glycolytic oligodendrocytes maintain myelin and long–term axonal integrity, Nature, 485, 517–521.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Frischer, J. M., Bramow, S., Dal–Bianco, A., Lucchinetti, C. F., Rauschka, H., Schmidbauer, M., Laursen, H., Sorensen, P. S., and Lassmann, H. (2009) The relation between inflammation and neurodegeneration in multiple sclerosis brains, Brain, 132, 1175–1189.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    DeLuca, G. C., Ebers, G. C., and Esiri, M. M. (2004) Axonal loss in multiple sclerosis: a pathological survey of the corticospinal and sensory tracts, Brain, 127, 1009–1018.PubMedCrossRefGoogle Scholar
  59. 59.
    Friese, M. A., Schattling, B., and Fugger, L. (2014) Mechanisms of neurodegeneration and axonal dysfunction in multiple sclerosis, Nat. Rev. Neurol., 10, 225–238.PubMedCrossRefGoogle Scholar
  60. 60.
    Mahad, D. H., Trapp, B. D., and Lassmann, H. (2015) Pathological mechanisms in progressive multiple sclerosis, Lancet Neurol., 14, 183–193.PubMedCrossRefGoogle Scholar
  61. 61.
    Dutta, R., McDonough, J., Yin, X., Peterson, J., Chang, A., Torres, T., Gudz, T., Macklin, W. B., Lewis, D. A., Fox, R. J., Rudick, R., Mirnics, K., and Trapp, B. D. (2006) Mitochondrial dysfunction as a cause of axonal degenera–tion in multiple sclerosis patients, Ann. Neurol., 59, 478–489.PubMedCrossRefGoogle Scholar
  62. 62.
    Campbell, G. R., Worrall, J. T., and Mahad, D. J. (2014) The central role of mitochondria in axonal degeneration in multiple sclerosis, Mult. Scler., 20, 1806–1813.PubMedCrossRefGoogle Scholar
  63. 63.
    Mahad, D., Ziabreva, I., Lassmann, H., and Turnbull, D. (2008) Mitochondrial defects in acute multiple sclerosis lesions, Brain, 131, 1722–1735.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Witte, M. E., Bo, L., Rodenburg, R. J., Belien, J. A., Musters, R., Hazes, T., Wintjes, L. T., Smeitink, J. A., Geurts, J. J., de Vries, H. E., van der Valk, P., and van Horssen, J. (2009) Enhanced number and activity of mito–chondria in multiple sclerosis lesions, J. Pathol., 219, 193–204.PubMedCrossRefGoogle Scholar
  65. 65.
    Campbell, G. R., Ziabreva, I., Reeve, A. K., Krishnan, K. J., Reynolds, R., Howell, O., Lassmann, H., Turnbull, D. M., and Mahad, D. J. (2011) Mitochondrial DNA dele–tions and neurodegeneration in multiple sclerosis, Ann. Neurol., 69, 481–492.PubMedCrossRefGoogle Scholar
  66. 66.
    McDonough, J., Dutta, R., Gudz, T., Foell, S., Mirnics, K., and Trapp, B. D. (2003) Decreases in GABA and Mitochondrial Genes Are Implicated in MS Neuronal Pathology through Microarray Analysis of Postmortem MS Cortex, 213.12, Abstracts of the 33rd Ann. Meet. of Society for Neuroscience, New Orleans, LA.Google Scholar
  67. 67.
    Witte, M. E., Nijland, P. G., Drexhage, J. A., Gerritsen, W., Geerts, D., van Het Hof, B., Reijerkerk, A., de Vries, H. E., van der Valk, P., and van Horssen, J. (2013) Reduced expression of PGC–1α partly underlies mito–chondrial changes and correlates with neuronal loss in multiple sclerosis cortex, Acta Neuropathol., 125, 231–243.PubMedCrossRefGoogle Scholar
  68. 68.
    Pandit, A., Vadnal, J., Houston, S., Freeman, E., and McDonough, J. (2009) Impaired regulation of electron transport chain subunit genes by nuclear respiratory factor 2 in multiple sclerosis, J. Neurol. Sci., 279, 14–20.PubMedCrossRefGoogle Scholar
  69. 69.
    Choi, I. Y., Lee, P., Adany, P., Hughes, A. J., Belliston, S., Denney, D. R., and Lynch, S. G. (2018) In vivo evidence of oxidative stress in brains of patients with progressive multi–ple sclerosis, Mult. Scler., 24, 1029–1038.PubMedCrossRefGoogle Scholar
  70. 70.
    Feng, J., Tao, T., Yan, W., Chen, C. S., and Qin, X. (2014) Curcumin inhibits mitochondrial injury and apoptosis from the early stage in EAE mice, Oxid. Med. Cell. Longev., 2014, 728751.PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Prinz, J., Karacivi, A., Stormanns, E. R., Recks, M. S., and Kuerten, S. (2016) Correction: time–dependent progres–sion of demyelination and axonal pathology in MP4–induced experimental autoimmune encephalomyelitis, PLoS One, 11, e0155197.Google Scholar
  72. 72.
    Recks, M. S., Stormanns, E. R., Bader, J., Arnhold, S., Addicks, K., and Kuerten, S. (2013) Early axonal damage and progressive myelin pathology define the kinetics of CNS histopathology in a mouse model of multiple sclero–sis, Clin. Immunol., 149, 32–45.PubMedCrossRefGoogle Scholar
  73. 73.
    Sadeghian, M., Mastrolia, V., Rezaei Haddad, A., Mosley, A., Mullali, G., Schiza, D., Sajic, M., Hargreaves, I., Heales, S., Duchen, M. R., and Smith, K. J. (2016) Mitochondrial dysfunction is an important cause of neuro–logical deficits in an inflammatory model of multiple scle–rosis, Sci. Rep., 6, 33249.PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Talla, V., Yu, H., Chou, T. H., Porciatti, V., Chiodo, V., Boye, S. L., Hauswirth, W. W., Lewin, A. S., and Guy, J. (2013) NADH–dehydrogenase type–2 suppresses irre–versible visual loss and neurodegeneration in the EAE ani–mal model of MS, Mol. Ther., 21, 1876–1888.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Talla, V., Koilkonda, R., Porciatti, V., Chiodo, V., Boye, S. L., Hauswirth, W. W., and Guy, J. (2015) Complex I sub–unit gene therapy with NDUFA6 ameliorates neurodegen–eration in EAE, Invest. Ophthalmol. Vis. Sci., 56, 1129–1140.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Fetisova, E., Chernyak, B., Korshunova, G., Muntyan, M., and Skulachev, V. (2017) Mitochondria–targeted antioxi–dants as a prospective therapeutic strategy for multiple scle–rosis, Curr. Med. Chem., 24, 2086–2114.PubMedCrossRefGoogle Scholar
  77. 77.
    Mao, P., Manczak, M., Shirendeb, U. P., and Reddy, P. H. (2013) MitoQ, a mitochondria–targeted antioxidant, delays disease progression and alleviates pathogenesis in an exper–imental autoimmune encephalomyelitis mouse model of multiple sclerosis, Biochim. Biophys. Acta, 1832, 2322–2231.PubMedCrossRefGoogle Scholar
  78. 78.
    Acs, P., Selak, M. A., Komoly, S., and Kalman, B. (2013) Distribution of oligodendrocyte loss and mitochondrial toxicity in the cuprizone–induced experimental demyelina–tion model, J. Neuroimmunol., 262, 128–131.PubMedCrossRefGoogle Scholar
  79. 79.
    Faizi, M., Salimi, A., Seydi, E., Naserzadeh, P., Kouhnavard, M., Rahimi, A., and Pourahmad, J. (2016) Toxicity of cuprizone a Cu2+ chelating agent on isolated mouse brain mitochondria: a justification for demyelina–tion and subsequent behavioral dysfunction, Toxicol. Mech. Methods, 26, 276–283.PubMedCrossRefGoogle Scholar
  80. 80.
    Andrews, H., White, K., Thomson, C., Edgar, J., Bates, D., Griffiths, I., Turnbull, D., and Nichols, P. (2006) Increased axonal mitochondrial activity as an adaptation to myelin deficiency in the Shiverer mouse, J. Neurosci. Res., 83, 1533–1539.PubMedCrossRefGoogle Scholar
  81. 81.
    Readhead, C., Popko, B., Takahashi, N., Shine, H. D., Saavedra, R. A., Sidman, R. L., and Hood, L. (1987) Expression of a myelin basic protein gene in transgenic Shiverer mice: correction of the dysmyelinating phenotype, Cell, 48, 703–712.PubMedCrossRefGoogle Scholar
  82. 82.
    Lassmann, H., and van Horssen, J. (2015) Oxidative stress and its impact on neurons and glia in multiple sclerosis lesions, Biochim. Biophys. Acta, 1862, 506–510.PubMedCrossRefGoogle Scholar
  83. 83.
    Broadwater, L., Pandit, A., Clements, R., Azzam, S., Vadnal, J., Sulak, M., Yong, V. W., Freeman, E. J., Gregory, R. B., and McDonough, J. (2011) Analysis of the mito–chondrial proteome in multiple sclerosis cortex, Biochim. Biophys. Acta, 1812, 630–641.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Waxman, S. G. (2006) Ions, energy and axonal injury: towards a molecular neurology of multiple sclerosis, Trends Mol. Med., 12, 192–195.PubMedCrossRefGoogle Scholar
  85. 85.
    Saab, A. S., Tzvetanova, I. D., and Nave, K. A. (2013) The role of myelin and oligodendrocytes in axonal energy metabolism, Curr. Opin. Neurobiol., 23, 1065–1072.PubMedCrossRefGoogle Scholar
  86. 86.
    Campbell, G., and Mahad, D. J. (2018) Mitochondrial dysfunction and axon degeneration in progressive multiple sclerosis, FEBS Lett., 592, 1113–1121.PubMedCrossRefGoogle Scholar
  87. 87.
    Trapp, B. D., and Stys, P. K. (2009) Virtual hypoxia and chronic necrosis of demyelinated axons in multiple sclero–sis, Lancet Neurol., 8, 280–291.PubMedCrossRefGoogle Scholar
  88. 88.
    Kiryu–Seo, S., Ohno, N., Kidd, G. J., Komuro, H., and Trapp, B. D. (2010) Demyelination increases axonal sta–tionary mitochondrial size and the speed of axonal mito–chondrial transport, J. Neurosci., 30, 6658–6666.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Mahad, D. J., Ziabreva, I., Campbell, G., Lax, N., White, K., Hanson, P. S., Lassmann, H., and Turnbull, D. M. (2009) Mitochondrial changes within axons in multiple sclerosis, Brain, 132, 1161–1174.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Zambonin, J. L., Zhao, C., Ohno, N., Campbell, G. R., Engeham, S., Ziabreva, I., Schwarz, N., Lee, S. E., Frischer, J. M., Turnbull, D. M., Trapp, B. D., Lassmann, H., Franklin, R. J., and Mahad, D. J. (2011) Increased mitochondrial content in remyelinated axons: implications for multiple sclerosis, Brain, 134, 1901–1913.PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Tsutsui, S., and Stys, P. K. (2013) Metabolic injury to axons and myelin, Exp. Neurol., 246, 26–34.PubMedCrossRefGoogle Scholar
  92. 92.
    Favorova, O. O., Bashinskaya, V. V., Kulakova, O. O., Favorov, A. V., and Boiko, A. N. (2014) A genome–wide search for associations as an approach for analyzing the genetic architecture of polygenic diseases exemplified by multiple sclerosis, Mol. Biol., 48, 573–586.CrossRefGoogle Scholar
  93. 93.
    Oksenberg, J. R. (2013) Decoding multiple sclerosis: an update on genomics and future directions, Expert. Rev. Neurother., 13, 11–19.PubMedCrossRefGoogle Scholar
  94. 94.
    Lin, R., Charlesworth, J., van der Mei, I., and Taylor, B. V. (2012) The genetics of multiple sclerosis, Pract. Neurol., 12, 279–288.PubMedCrossRefGoogle Scholar
  95. 95.
    Baranzini, S. E., and Oksenberg, J. R. (2017) The genetics of multiple sclerosis: from 0 to 200 in 50 years, Trends Genet., 33, 960–970.PubMedCrossRefGoogle Scholar
  96. 96.
    Bashinskaya, V. V., Kulakova, O. G., Boyko, A. N., Favorov, A. V., and Favorova, O. O. (2015) A review of genome–wide association studies for multiple sclerosis: classical and hypothesis–driven approaches, Hum. Genet., 134, 1143–1162.PubMedCrossRefGoogle Scholar
  97. 97.
    Joo, J. H., Dorsey, F. C., Joshi, A., Hennessy–Walters, K. M., Rose, K. L., McCastlain, K., Zhang, J., Iyengar, R., Jung, C. H., Suen, D. F., Steeves, M. A., Yang, C. Y., Prater, S. M., Kim, D. H., Thompson, C. B., Youle, R. J., Ney, P. A., Cleveland, J. L., and Kundu, M. (2015) Hsp90–Cdc37 chaperone complex regulates Ulk1–and Atg13–mediated mitophagy, Mol. Cell, 43, 572–585.CrossRefGoogle Scholar
  98. 98.
    Soleimanpour, S. A., Gupta, A., Bakay, M., Ferrari, A. M., Groff, D. N., Fadista, J., Spruce, L. A., Kushner, J. A., Groop, L., Seeholzer, S. H., Kaufman, B. A., Hakonarson, H., and Stoffers, D. A. (2014) The diabetes susceptibility gene Clec16a regulates mitophagy, Cell, 157, 1577–1590.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Morrish, F., and Hockenbery, D. (2014) MYC and mito–chondrial biogenesis, Cold Spring Harb. Perspect. Med., 4, a014225.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Hagenbuchner, J., and Ausserlechner, M. J. (2013) Mitochondria and FOXO3: breath or die, Front. Physiol., 4, 1–10.CrossRefGoogle Scholar
  101. 101.
    Rui, Y., and Mercedes, R. (2016) Mitochondrial Stat3, the need for design thinking, Int. J. Biol. Sci., 12, 532–544.CrossRefGoogle Scholar
  102. 102.
    Lill, C. M. (2014) Recent advances and future challenges in the genetics of multiple sclerosis, Front. Neurol., 5, 130.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Pinto, M., and Moraes, C. T. (2014) Mitochondrial genome changes and neurodegenerative diseases, Biochim. Biophys. Acta, 1842, 1198–1207.PubMedCrossRefGoogle Scholar
  104. 104.
    Kennedy, S. R., Salk, J. J., Schmitt, M. W., and Loeb, L. A. (2013) Ultra–sensitive sequencing reveals an age–related increase in somatic mitochondrial mutations that are inconsistent with oxidative damage, PLoS Genet., 9, e1003794.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Payne, B. A., Wilson, I. J., Yu–Wai–Man, P., Coxhead, J., Deehan, D., Horvath, R., Taylor, R. W., Samuels, D. C., Santibanez–Koref, M., and Chinnery, P. F. (2013) Universal heteroplasmy of human mitochondrial DNA, Hum. Mol. Genet., 22, 384–390.PubMedCrossRefGoogle Scholar
  106. 106.
    Pakendorf, B., and Stoneking, M. (2005) Mitochondrial DNA and human evolution, Annu. Rev. Genomics Hum. Genet., 6, 165–183.PubMedCrossRefGoogle Scholar
  107. 107.
    Kalman, B., Li, S., Chatterjee, D., O’Connor, J., Voehl, M. R., Brown, M. D., and Alder, H. (1999) Large scale screening of the mitochondrial DNA reveals no pathogen–ic mutations but a haplotype associated with multiple scle–rosis in Caucasians, Acta Neurol. Scand., 99, 16–25.PubMedCrossRefGoogle Scholar
  108. 108.
    Houshmand, M., Sanati, M. H., Babrzadeh, F., Ardalan, A., Teimori, M., Vakilian, M., Akuchekian, M., Farhud, D., and Lotfi, J. (2005) Population screening for asso–ciation of mitochondrial haplogroups BM, J, K and M with multiple sclerosis: interrelation between haplo–group J and MS in Persian patients, Mult. Scler., 11, 728–730.CrossRefGoogle Scholar
  109. 109.
    Hassani–Kumleh, H., Houshmand, M., Panahi, M. S., Riazi, G. H., Sanati, M. H., Gharagozli, K., and Ghabaee, M. (2006) Mitochondrial D–loop variation in Persian multiple sclerosis patients: K and A haplogroups as a risk factor, Cell Mol. Neurobiol., 26, 119–125.PubMedCrossRefGoogle Scholar
  110. 110.
    Vyshkina, T., Sylvester, A., Sadiq, S., Bonilla, E., Canter, J. A., Perl, A., and Kalman, B. (2008) Association of com–mon mitochondrial DNA variants with multiple sclerosis and systemic lupus erythematosus, Clin. Immunol., 129, 31–35.PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Yu, X., Koczan, D., Sulonen, A. M., Akkad, D. A., Kroner, A., Comabella, M., Costa, G., Corongiu, D., Goertsches, R., Camina–Tato, M., Thiesen, H. J., Nyland, H. I., Mork, S. J., Montalban, X., Rieckmann, P., Marrosu, M. G., Myhr, K. M., Epplen, J. T., Saarela, J., and Ibrahim, S. M. (2008) mtDNA nt13708A variant increases the risk of multiple sclerosis, PLoS One, 3, e1530.Google Scholar
  112. 112.
    Venkateswaran, S., Zheng, K., Sacchetti, M., Gagne, D., Arnold, D. L., Sadovnick, A. D., Scherer, S. W., Banwell, B., Bar–Or, A., and Simon, D. K. (2011) Mitochondrial DNA haplogroups and mutations in children with acquired central demyelination, Neurology, 76, 774–780.PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Tranah, G. J., Santaniello, A., Caillier, S. J., D’Alfonso, S., Martinelli Boneschi, F., Hauser, S. L., and Oksenberg, J. R. (2015) Mitochondrial DNA sequence variation in multiple sclerosis, Neurology, 85, 325–330.PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Otaegui, D., Saenz, A., Martinez–Zabaleta, M., Villoslada, P., Fernandez–Manchola, I., Alvarez de Arcaya, A., Emparanza, J. I., and Lopez de Munain, A. (2004) Mitochondrial haplogroups in Basque multiple sclerosis patients, Mult. Scler., 10, 532–535.PubMedCrossRefGoogle Scholar
  115. 115.
    Mihailova, S. M., Ivanova, M. I., Quin, L. M., and Naumova, E. J. (2007) Mitochondrial DNA variants in Bulgarian patients affected by multiple sclerosis, Eur. J. Neurol., 14, 44–47.PubMedCrossRefGoogle Scholar
  116. 116.
    Kalman, B., Lublin, F. D., and Alder, H. (1996) Characterization of the mitochondrial DNA in patients with multiple sclerosis, J. Neurol. Sci., 140, 75–84.PubMedCrossRefGoogle Scholar
  117. 117.
    Taylor, R. W., Chinnery, P. F., Bates, M. J., Jackson, M. J., Johnson, M. A., Andrews, R. M., and Turnbull, D. M. (1998) A novel mitochondrial DNA point mutation in the tRNA(Ile) gene: studies in a patient presenting with chronic progressive external ophthalmoplegia and multiple sclerosis, Biochem. Biophys. Res. Commun., 243, 47–51.PubMedCrossRefGoogle Scholar
  118. 118.
    Slee, M., Finkemeyer, J., Krupa, M., Raghupathi, R., Gardner, J., Blumbergs, P., Agzarian, M., and Thyagarajan, D. (2011) A novel mitochondrial DNA dele–tion producing progressive external ophthalmoplegia asso–ciated with multiple sclerosis, J. Clin. Neurosci., 18, 1318–1324.PubMedCrossRefGoogle Scholar
  119. 119.
    Wilichowski, E., Ohlenbusch, A., and Hanefeld, F. (1998) Characterization of the mitochondrial genome in child–hood multiple sclerosis. II. Multiple sclerosis without optic neuritis and LHON–associated genes, Neuropediatrics, 29, 307–312.PubMedCrossRefGoogle Scholar
  120. 120.
    Kalman, B., Lublin, F. D., and Alder, H. (1995) Mitochondrial DNA mutations in multiple sclerosis, Mult. Scler., 1, 32–36.PubMedCrossRefGoogle Scholar
  121. 121.
    Poursadegh Zonouzi, A., Ghorbian, S., Abkar, M., Poursadegh Zonouzi, A. A., and Azadi, A. (2014) Mitochondrial complex I gene variations; as a potential genetic risk factor in pathogenesis of multiple sclerosis, J. Neurol. Sci., 345, 220–223.PubMedCrossRefGoogle Scholar
  122. 122.
    Andalib, S., Talebi, M., Sakhinia, E., Farhoudi, M., Sadeghi–Bazargani, H., and Gjedde, A. (2015) Mitochondrial DNA T4216C and A4917G variations in multiple sclerosis, J. Neurol. Sci., 356, 55–60.PubMedCrossRefGoogle Scholar
  123. 123.
    Mayr–Wohlfart, U., Paulus, C., Henneberg, A., and Rodel, G. (1996) Mitochondrial DNA mutations in mul–tiple sclerosis patients with severe optic involvement, Acta. Neurol. Scand., 94, 167–171.PubMedCrossRefGoogle Scholar
  124. 124.
    Andalib, S., Emamhadi, M., Yousefzadeh–Chabok, S., Salari, A., Sigaroudi, A. E., and Vafaee, M. S. (2016) MtDNA T4216C variation in multiple sclerosis: a system–atic review and meta–analysis, Acta Neurol. Belg., 116, 439–443.PubMedCrossRefGoogle Scholar
  125. 125.
    Andalib, S., Talebi, M., Sakhinia, E., Farhoudi, M., Sadeghi–Bazargani, H., Masoudian, N., Vafaee, M. S., and Gjedde, A. (2017) No evidence of association between optic neuritis and secondary LHON mtDNA mutations in patients with multiple sclerosis, Mitochondrion, 36, 182–185.PubMedCrossRefGoogle Scholar
  126. 126.
    Andalib, S., Talebi, M., Sakhinia, E., Farhoudi, M., Sadeghi–Bazargani, H., and Gjedde, A. (2015) Lack of association between mitochondrial DNA G15257A and G15812A variations and multiple sclerosis, J. Neurol. Sci., 356, 102–106.PubMedCrossRefGoogle Scholar
  127. 127.
    Hudson, G., Gomez–Duran, A., Wilson, I. J., and Chinnery, P. F. (2014) Recent mitochondrial DNA muta–tions increase the risk of developing common late–onset human diseases, PLoS Genet., 10, e1004369.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Pleiades Publishing, Ltd. 2018

Authors and Affiliations

  • M. S. Kozin
    • 1
    • 2
  • O. G. Kulakova
    • 1
    • 2
  • O. O. Favorova
    • 1
    • 2
  1. 1.Pirogov Russian National Research Medical UniversityMoscowRussia
  2. 2.National Medical Research Center of CardiologyMoscowRussia

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