Abstract
Multiple sclerosis (MS), which results in damage of the white matter at multiple foci, poses a far-reaching public health problem in view of the burden it imposes on the affected young and middle-aged. Some previous data suggested that roles could be played in the demyelinization of the white matter of the brain by the malfunctioning of the mitochondria and mitochondria-associated reactive oxygen species. In this context, we hypothesized that the finely tuned dynamic stability of the mitochondrial membrane potential (MMP), which is the main mirror of the functional state of the mitochondria, is essential for the intact nature of the glia cells in the brain. Setting out from this, our aim in this study was to examine how the rs10807344 and rs2270450 genetic variants of mitochondrial uncoupling protein 4 (mUCP4) can give rise to the development of MS, since mUCP4 is presumed to be of great importance in the regulation of the MMP and cellular energy metabolism. The clinical and genetic data on 120 relapsing-remitting MS patients and 250 neuroimaging alteration-free subjects were analyzed. The rs10807344 CC genotype proved to exert a protective effect against the occurrence of MS (neuroimaging alteration-free controls, 58%; MS group, 33%; P < 0.0000089; OR, 0.32; 95% CI: 0.2–0.56, P < 0.005). The present findings indirectly raise the possibility that a shift or imbalance in the finally regulated MMP plays a role in the development of MS.
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References
Bencsik, K., Rajda, C., Fuvesi, J., Klivenyi, P., Jardanhazy, T., Torok, M., et al. (2001). The prevalence of multiple sclerosis, distribution of clinical forms of the disease and functional status of patients in Csongrad County, Hungary. European Neurology, 46, 206–209.
Karg, E., Klivenyi, P., Bencsik, K., Turi, S., & Vecsei, L. (2003). Alpha-tocopherol and NADPH in the erythrocytes and plasma of multiple sclerosis patients. Effect of interferon-beta-1b treatment. European Neurology, 50, 215–219.
Komoly, S., Hudson, L. D., Webster, H. D., & Bondy, C. A. (1992). Insulin-like growth factor I gene expression is induced in astrocytes during experimental demyelination. Proceedings of the National Academy of Sciences of the United States of America, 89, 1894–1898.
Kurtzke, J. F. (1993). Rating neurologic impairment in multiple sclerosis: An expanded disability status scale (EDDS). Neurology, 33, 1442–1452.
Liu, D., Chan, S. L., de Souza-Pinto, N. C., Slevin, J. R., Wersto, R. P., Zhan, M., et al. (2006). Mitochondrial UCP4 mediates an adaptive shift in energy metabolism and increases the resistance of neurons to metabolic and oxidative stress. Neuromolecular Medicine, 8, 389–414.
Mattson, M. P., & Liu, D. (2003). Mitochondrial potassium channels and uncoupling proteins in synaptic plasticity and neuronal cell death. Biochemical and Biophysical Research Communications, 9, 539–549.
McDonald, W. I., Compston, A., Edan, G., Goodkin, D., Hartung, H. P., Lublin, F. D., et al. (2001). Recommended diagnostic criteria for multiple sclerosis: Guidelines from the International Panel on the Diagnosis of Multiple Sclerosis. Annals of Neurology, 50, 121–127.
Miller, D. H., Barkof, F., Berry, I., Kappos, L., Scotti, S., & Thompson, A. J. (1991). Magnetic resonance imaging in monitoring the treatment of multiple sclerosis: Concerted action guidelines. Journal of Neurology, Neurosurgery and Psychiatry, 54, 683–688.
Miller, S. A., Dykes, D. D., & Polesky, H. F. (1988). A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Research, 16, 1215–1218.
Otaegui, D., Saenz, A., Ruiz-Martinez, J., Olaskoaga, J., & López de Munain, A. (2007). UCP2 and mitochondrial haplogroups as a multiple sclerosis risk factor. Multiple Sclerosis, 13(4), 454–458.
Poser, C. M., Paty, D. W., Scheimberg, L., McDonald, W. I., Davis, F. A., Ebers, G. C., et al. (1983). New diagnostic criteria for multiple sclerosis: Guidelines for research protocols. Annals of Neurology, 13, 227–231.
Szolnoki, Z. (2007). Pathomechanism of leukoaraiosis: Molecular bridge between the genetic, biochemical, and clinical processes (a mitochondrial hypothesis). Neuromolecular Medicine, 9, 21–33.
Szolnoki, Z., Kondacs, A., Mandi, Y., & Somogyvari, F. (2007a). A genetic variant in cytoskeleton motors amplifies susceptibility to leukoaraiosis in hypertensive smokers: Gene-environmental interactions behind vascular white matter demyelinization. Journal of Molecular Neuroscience, 33, 173–179.
Szolnoki, Z., Kondacs, A., Mandi, Y., & Somogyvari, F. (2007b). A cytoskeleton motor protein genetic variant may exert a protective effect on the occurrence of multiple sclerosis: The janus face of the kinesin light-chain 1 56836CC genetic variant. Neuromolecular Medicine, 9, 335–339.
Thompson, A. J., Montalban, X., Barkhof, F., et al. (2000). Diagnostic criteria for primary progressive multiple sclerosis: A position paper. Annals of Neurology, 47, 831–835.
Tintoré, M., Rovira, A., Martinez, M. J., et al. (2000). Isolated demyelinating syndromes: Comparison of different MR imaging criteria to predict conversion clinically definite multiple sclerosis. American Journal of Neuroradiology, 21, 702–706.
Vogler, S., Goedde, R., Miterski, B., Gold, R., Kroner, A., Koczan, D., et al. (2005). Association of a common polymorphism in the promoter of UCP2 with susceptibility to multiple sclerosis. Journal of Molecular Medicine, 83(10), 806–811.
Vogler, S., Pahnke, J., Rousset, S., Ricquier, D., Moch, H., Miroux, B., et al. (2006). Uncoupling protein 2 has protective function during experimental autoimmune encephalomyelitis. American Journal of Pathology, 168(5), 1570–1575.
Yasuno, K., Ando, S., Misumi, S., Makino, S., Kulski, J. K., Muratake, T., et al. (2007). Synergistic association of mitochondrial uncoupling protein (UCP) genes with schizophrenia. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics, 144B(2), 250–253.
Yoon, Y., Park, B. L., Cha, M. H., Kim, K. S., Cheong, H. S., Choi, Y. H., et al. (2007). Effects of genetic polymorphisms of UCP2 and UCP3 on very low calorie diet-induced body fat reduction in Korean female subjects. Biochemical and Biophysical Research Communications, 359(3), 451–456.
Yu, X., Wieczorek, S., Franke, A., Yin, H., Pierer, M., Sina, C., et al. (2009). Association of UCP2 -866 G/A polymorphism with chronic inflammatory diseases. doi:10.1038/gene.2009.29.
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Szolnoki, Z., Kondacs, A., Mandi, Y. et al. A Homozygous Genetic Variant of Mitochondrial Uncoupling Protein 4 Exerts Protection Against the Occurrence of Multiple Sclerosis. Neuromol Med 11, 101–105 (2009). https://doi.org/10.1007/s12017-009-8071-4
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DOI: https://doi.org/10.1007/s12017-009-8071-4