Skip to main content
SpringerLink
Log in

Variability of the Mitochondrial Genome and Development of the Primary Progressing form of Multiple Sclerosis

  • GENOMICS. TRANSCRIPTOMICS
  • Published:
Molecular Biology Aims and scope Submit manuscript

Abstracts

Recently, it has been shown that dysfunction of mitochondria is an important component of the molecular mechanisms of the development of many neurodegenerative diseases. These include multiple sclerosis, a chronic autoimmune and neurodegenerative disease of the central nervous system, which is characterized by clinical heterogeneity. The role of genetic variability of mitochondrial DNA in the development of various clinical forms of multiple sclerosis is poorly understood. The aim of present study was to analyze the association of ten mitochondrial DNA single nucleotide polymorphisms and the nine most common European mitochondrial haplogroups (H, J, K, U, T, I, V, W and X) with a severe and relatively rare multiple sclerosis disease form—primary progressive multiple sclerosis. 110 patients with primary progressive multiple sclerosis and 406 healthy controls were enrolled in the study, all ethnic Russians. For the first time association of the m.12308*G (rs2853498) variant (P = 0.024) and haplogroup U (P = 0.0004, passes the adjustment for multiple comparisons: Pcorr = 0.0076) with primary progressive multiple sclerosis was shown. Comparison of these data with the results of our previous study [1], that was focused on the role of mitochondrial genome variability in susceptibility to the most common form of multiple sclerosis, relapsing-remitting multiple sclerosis, leads to the conclusion that two different mitochondrial haplogroups, U and J, are involved in the development of two different clinical forms of multiple sclerosis. The results may contribute to the identification of new targets for the treatment of primary progressive multiple sclerosis, for which there is no effective pathogenetic treatment at the moment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

REFERENCES

  1. Kozin M.S., Kulakova O.G., Kiselev I.S., Balanovsky O.P., Boyko A.N., Favorova O.O. 2018. Variants of mitochondrial genome and risk of multiple sclerosis development in Russians. Acta Naturae.10 (4), 79–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Sawcer S., Franklin R.J.M., Ban M. 2014. Multiple sclerosis genetics. Lancet Neurol.13 (7), 700–709.

    Article  CAS  PubMed  Google Scholar 

  3. Boyko A., Smirnova N., Petrov S., Gusev E. 2016. Epidemiology of MS in Russia: A historical review. Mult. Scler. Demyelinat. Disord. 1, 13.

    Article  Google Scholar 

  4. Huitema M.J.D., Schenk G.J. 2018. Insights into the mechanisms that may clarify obesity as a risk factor for multiple sclerosis. Curr. Neurol. Neurosci. Rep. 18 (4), 18.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Sand I.B.K., Lublin F.D. 2013. Diagnosis and differential diagnosis of multiple sclerosis. Continuum (Minneap. Minn.). 19 (4), 922–943.

    Google Scholar 

  6. Koch M., Kingwell E., Rieckmann P., Tremlett H. 2009. The natural history of primary progressive multiple sclerosis. Neurology. 73 (23), 1996–2002.

    Article  PubMed  Google Scholar 

  7. IMSGC. 2019. Peripheral immune cells and microglia in susceptibility. Science. 365 (6460), eaav7188.

  8. IMSGC. 2011. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature.476 (7359), 214–219.

    Article  Google Scholar 

  9. Martinelli-Boneschi F., Esposito F., Brambilla P., Lindström E., Lavorgna G., Stankovich J., Rodegher M., Capra R., Ghezzi A., Coniglio G., Colombo B., Sorosina M., Martinelli V., Booth D., Oturai A.B., et al. 2012. A Genome-Wide Association Study in progressive multiple sclerosis. Mult. Scler. 18 (10), 1384–1394.

    Article  PubMed  Google Scholar 

  10. Kiselev I., Bashinskaya V., Baulina N., Kozin M., Popova E., Boyko A., Favorova O., Kulakova O. 2019. Genetic differences between primary progressive and relapsing-remitting multiple sclerosis: the impact of immune-related genes variability. Mult. Scler. Relat. Disord.29, 130–136.

    Article  PubMed  Google Scholar 

  11. Campbell G., Mahad D.J. 2018. Mitochondrial dysfunction and axon degeneration in progressive multiple sclerosis. FEBS Lett. 592 (7), 1113–1121.

    Article  CAS  PubMed  Google Scholar 

  12. Kozin M.S., Kulakova O.G., Favorova O.O. 2018. Involvement of mitochondria in neurodegeneration in multiple sclerosis. Biochemistry (Moscow). 83 (7), 813–830.

    CAS  PubMed  Google Scholar 

  13. Tranah G.J., Santaniello A., Caillier S.J., D’Alfonso S., Boneschi F.M., Hauser S.L., Oksenberg J.R. 2015. Mitochondrial DNA sequence variation in multiple sclerosis. Neurology.85 (4), 325–330.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Hudson G., Gomez-Duran A., Wilson I.J., Chinnery P.F. 2014. Recent mitochondrial DNA mutations increase the risk of developing common late-onset human diseases. PLoS Genet.10 (5), e1004369.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Giacalone G., Clarelli F., Osiceanu A.M., Guaschino C., Brambilla P., Sorosina M., Liberatore G., Zauli A., Esposito F., Rodegher M., Ghezzi A., Galimberti D., Patti F., Barizzone N., Guerini F., et al. 2015. Analysis of genes, pathways and networks involved in disease severity and age at onset in primary-progressive multiple sclerosis. Mult. Scler.21 (11), 1431–1442.

    Article  CAS  PubMed  Google Scholar 

  16. Polman C.H., Reingold S.C., Banwell B., Clanet M., Cohen J.A., Filippi M., Fujihara K., Havrdova E., Hutchinson M., Kappos L., Lublin F.D., Montalban X., O’Connor P., Sandberg-Wollheim M., Thompson A.J., et al. 2011. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann. Neurol.69 (2), 292–302.

    Article  PubMed  PubMed Central  Google Scholar 

  17. van Oven M., Kayser M. 2009. Updated comprehensive phylogenetic tree of global human mitochondrial DNA variation. Hum. Mutat. 30 (2), E386–E394.

    Article  PubMed  Google Scholar 

  18. Zifa E., Daniil Z., Skoumi E., Stavrou M., Papadimitriou K., Terzenidou M., Kostikas K., Bagiatis V., Gourgoulianis K.I., Mamuris Z. 2012. Mitochondrial genetic background plays a role in increasing risk to asthma. Mol. Biol. Rep.39 (4), 4697–4708.

    Article  CAS  PubMed  Google Scholar 

  19. Gaur R.K. 2014. Amino acid frequency distribution among eukaryotic proteins. IIOAB J.5 (2), 6–11.

    Google Scholar 

  20. Pulkes T., Sweeney M.G., Hanna M.G. 2000. Increased risk of stroke in patients with the A12308G polymorphism in mitochondria. Lancet. 356 (9247), 2068–2069.

    Article  CAS  PubMed  Google Scholar 

  21. Schulmann A., Ryu E., Goncalves V., Rollins B., Christiansen M., Frye M.A., Biernacka J., Vawter M.P. 2019. Novel complex interactions between mitochondrial and nuclear DNA in schizophrenia and bipolar disorder. Mol. Neuropsychiatry. 5 (1), 13–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Covarrubias D., Bai R.K., Wong L.J.C., Leal S.M. 2008. Mitochondrial DNA variant interactions modify breast cancer risk. J. Hum. Genet.53 (10), 924–928.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. van der Walt J.M, Dementieva Y.A., Martin E.R., Scott W.K., Nicodemus K.K., Kroner C.C., Welsh-Bohmer K.A., Saunders A.M., Roses A.D., Small G.W., Schmechel D.E., Doraiswamy P.M., Gilbert J.R., Haines J.L., Vance J.M., Pericak-Vance M.A. 2004. Analysis of European mitochondrial haplogroups with Alzheimer disease risk. Neurosci. Lett.365 (1), 28–32.

    Article  CAS  PubMed  Google Scholar 

  24. Rollins B., Martin M.V., Sequeira P.A., Moon E.A., Morgan L.Z., Watson S.J., Schatzberg A., Akil H., Myers R.M., Jones E.G., Wallace D.C., Bunney W.E., Vawter M.P. 2009. Mitochondrial variants in schizophrenia, bipolar disorder, and major depressive disorder. PLoS One. 4 (3), e4913.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Ban M., Elson J., Walton A., Turnbull D., Compston A., Chinnery P., Sawcer S. 2008. Investigation of the role of mitochondrial DNA in multiple sclerosis susceptibility. PLoS One. 3 (8), e2891.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Sun D., Wei Y., Zheng H.X., Jin L., Wang J. 2019. Contribution of mitochondrial DNA variation to chronic disease in East Asian populations. Front. Mol. Biosci. 6, 128.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Gómez-Durán A., Pacheu-Grau D., López-Gallardo E., Díez-Sánchez C., Montoya J., López-Pérez M.J., Ruiz-Pesini E. 2010. Unmasking the causes of multifactorial disorders: OXPHOS differences between mitochondrial haplogroups. Hum. Mol. Genet. 19 (17), 3343–3353.

    Article  PubMed  Google Scholar 

  28. Iwanowski P., Losy J. 2015. Immunological differences between classical phenothypes of multiple sclerosis. J. Neurol. Sci.349 (1–2), 10–14.

    Article  CAS  PubMed  Google Scholar 

Download references

ACKNOWLEDGMENTS

The authors are deeply grateful to the neurologists N.N. Babicheva, L.I. Volkova, A.V. Karaeva, D.S. Kasatkin, D.S. Korobko, N.A. Malkova, S.A. Sivertseva, N.N. Spirina, N.N. Spirin, E.L. Turova, and F.A. Khabirov for participating in the formation of a group of PPMS patients.

Funding

This work was supported by the government contract AAAA-A19-119042590026-5.

Author information

Authors and Affiliations

  1. Pirogov Russian National Research Medical University, 117997, Moscow, Russia

    M. S. Kozin, O. G. Kulakova, I. S. Kiselev, A. N. Boyko & O. O. Favorova

  2. Federal Center for the Brain and Neurotechnologies, 117997, Moscow, Russia

    M. S. Kozin & A. N. Boyko

Authors
  1. M. S. Kozin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. O. G. Kulakova
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. I. S. Kiselev
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A. N. Boyko
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. O. O. Favorova
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M. S. Kozin.

Ethics declarations

Conflict of interest. The authors report no potential conflict of interest.

Statement of compliance with standards of research involving humans as subjects. All procedures performed in this work comply with the ethical standards of the institutional committee for research ethics and the 1964 Helsinki Declaration and its subsequent changes or comparable ethical standards. Written consent was obtained from all participants in the experiments.

Additional information

Abbreviations: CI, confidence interval; PCR, polymerase chain reaction; PCR-RFLP, PCR-restriction fragment length polymorphism analysis; OR, odds ratio; MS, multiple sclerosis; PPMS, primary progressive MS; RRMS, relapsing-remitting MS; GWAS, Genome Wide Association Study; SNP, single nucleotide polymorphism.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kozin, M.S., Kulakova, O.G., Kiselev, I.S. et al. Variability of the Mitochondrial Genome and Development of the Primary Progressing form of Multiple Sclerosis. Mol Biol 54, 535–540 (2020). https://doi.org/10.1134/S0026893320040081

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S0026893320040081

Keywords:

Search

Navigation