Abstract
Reduction of efficiency of oxidative phosphorylation associated with aging and the development of neurodegenerative diseases including Alzheimer’s disease is thought to be linked to the accumulation of deletions in mitochondrial DNA (ΔmtDNA), which are seen as a marker of oxidative damage. Recently, we have shown that mitochondria-targeted antioxidant SkQ1 (10-(6′-plastoquinonyl)decyltriphenylphosphonium) can slow the development of signs of Alzheimer’s disease in senescence-accelerated OXYS rats. The purpose of this study was to explore the relationship between the development of neurodegenerative changes in the brain of OXYS rats and changes in the amount of mtDNA and the 4834-bp mitochondrial DNA deletion (ΔmtDNA4834) as well as the effect of SkQ1. We studied the relative amount of mtDNA and ΔmtDNA4834 in the hippocampus of OXYS and Wistar (control) rats at ages of 1, 2, 6, 10, and 20 days and 3, 6, and 24 months. During the period crucial for manifestation of the signs of accelerated aging of OXYS rats (from 1.5 to 3 months of age), we evaluated the effects of administration of SkQ1 (250 nmol/kg) and vitamin E (670 mmol/kg, reference treatment) on the amount of mtDNA and ΔmtDNA4834 and on the formation of the behavioral feature of accelerated senescence in OXYS rats — passive type of behavior in the open field test. In OXYS rats, the level of ΔmtDNA4834 in the hippocampus is increased compared to the Wistar rats, especially at the stage of completion of brain development in the postnatal period. This level remains elevated not only at the stages preceding the manifestation of the signs of accelerated brain aging and the development of pathological changes linked to Alzheimer’s disease, but also during their progression. However, at age of 24 months, there were no detectable differences between the two strains. SkQ1 treatment reduced the level of ΔmtDNA4834 in the hippocampus of Wistar and OXYS rats and slowed the formation of passive behavior in OXYS rats. These results support the possible use of SkQ1 for prophylaxis of brain aging.
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Abbreviations
- bp:
-
base pairs
- mtDNA:
-
mitochondrial DNA
- ΔmtDNA:
-
deletion in mitochondrial DNA
- ΔmtDNA4834 :
-
4834-bp mitochondrial DNA deletion
- ROS:
-
reactive oxygen species
- SkQ1:
-
antioxidant 10-(6′-plastoquinonyl)decyltriphen-ylphosphonium
References
Morley, J. E., Armbrecht, H. J., Farr, S. A., and Kumar, V. B. (2012) The senescence accelerated mouse (SAMP8) as a model for oxidative stress and Alzheimer’s disease, Biochim. Biophys. Acta, 1822, 650–656.
Li, H., Liu, D., Lu, J., and Bai, Y. (2012) Physiology and pathophysiology of mitochondrial DNA, Adv. Exp. Med. Biol., 942, 39–51.
Kazachkova, N., Ramos, A., Santos, C., and Lima, M. (2013) Mitochondrial DNA damage patterns and aging: revising the evidences for humans and mice, Aging Dis., 4, 337–350.
Zhang, J., Montine, T. J., Smith, M. A., Siedlak, S. L., Gu, G., Robertson, D., and Perry, G. (2002) The mitochondrial common deletion in Parkinson’s disease and related movement disorders, Parkinson. Rel. Disord., 8, 165–170.
Krishnan, K., Ratnaike, T., De Gruyter, H., Jaros, E., and Turnbull, D. (2012) Mitochondrial DNA deletions cause the biochemical defect observed in Alzheimer’s disease, Neurobiol. Aging, 33, 2210–2214.
Stefanova, N. A., Fursova, A. Zh., and Kolosova, N. G. (2010) Behavioral effects induced by mitochondria-targeted antioxidant SkQ1 in Wistar and senescence-accelerated OXYS rats, J. Alzheimers Dis., 21, 479–491.
Stefanova, N. A., Muraleva, N. A., Skulachev, V. P., and Kolosova, N. G. (2014) Alzheimer’s disease-like pathology in senescence-accelerated OXYS rats can be partially retarded with mitochondria-targeted antioxidant SkQ1, J. Alzheimers Dis., 38, 681–694.
Kapay, N. A., Popova, O. V., Isaev, N. K., Stelmashook, E. V., Kondratenko, R. V., Zorov, D. B., Skrebitsky, V. G., and Skulachev, V. P. (2013) Mitochondria-targeted plastoquinone antioxidant SkQ1 prevents amyloid-β-induced impairment of long-term potentiation in rat hippocampal slices, J. Alzheimers Dis., 36, 377–383.
Kolosova, N. G., Stefanova, N. A., Korbolina, E. E., and Fursova, A. Zh. (2014) Senescence-accelerated OXYS rats: a genetic model of premature aging and age-related diseases, Adv. Gerontol., 4, 294–298.
Amstislavskaya, T. G., Maslova, L. N., Gladkikh, D. V., Belousova, I. I., Stefanova, N. A., and Kolosova, N. G. (2010) Effects of the mitochondria-targeted antioxidant SkQ1 on sexually motivated behavior in male rats, Pharmacol. Biochem. Behav., 96, 211–216.
Neroev, V. V., Archipova, M. M., Bakeeva, L. E., Fursova, A. Zh., Grigorian, E. N., Grishanova, A. Yu., Iomdina, E. N., Ivashchenko, Zh. N., Katargina, L. A., Khoroshilova-Maslova, I. P., Kilina, O. V., Kolosova, N. G., Kopenkin, E. P., Korshunov, S. S., Kovaleva, N. A., Novikova, Yu. P., Philippov, P. P., Pilipenko, D. I., Robustova, O. V., Saprunova, V. B., Senin, I. I., Skulachev, M. V., Sotnikova, L. F., Stefanova, N. A., Tikhomirova, N. K., Tsapenko, I. V., Shchipanova, A. I., Zinovkin, R. A., and Skulachev, V. P. (2008) Mitochondria-targeted plastoquinone derivatives as tools to interrupt execution of the aging program. 4. Agerelated eye disease. SkQ1 returns vision to blind animals, Biochemistry (Moscow), 73, 1317–1328.
Skulachev, V. P., Anisimov, V. N., Antonenko, Y. N., Bakeeva, L. E., Chernyak, B. V., Erichev, V. P., Filenko, O. F., Kalinina, N. I., Kapelko, V. I., Kolosova, N. G., Kopnin, B. P., Korshunova, G. A., Lichinitser, M. R., Obukhova, L. A., Pasyukova, E. G., Pisarenko, O. I., Roginsky, V. A., Ruuge, E. K., Senin, I. I., Severina, I. I., Skulachev, M. V., Spivak, I. M., Tashlitsky, V. N., Tkachuk, V. A., Vyssokikh, M. Y., Yaguzhinsky, L. S., and Zorov, D. B. (2009) An attempt to prevent senescence: a mitochondrial approach, Biochim. Biophys. Acta, 1787, 437–461.
Vays, V. B., Eldarov, C. M., Vangely, I. M., Kolosova, N. G., Bakeeva, L. E., and Skulachev, V. P. (2014) Antioxidant SkQ1 delays sarcopenia-associated damage of mitochondrial ultrastructure, Aging (Albany, NY), 6, 140–148.
Saprunova, V. B., Lelekova, M. A., Kolosova, N. G., and Bakeeva, L. E. (2012) SkQ1 slows development of age-dependent destructive processes in retina and vascular layer of eyes of Wistar and OXYS rats, Biochemistry (Moscow), 77, 648–658.
Markovets, A. M., Fursova, A. Z., and Kolosova, N. G. (2011) Therapeutic action of the mitochondria-targeted antioxidant SkQ1 on retinopathy in OXYS rats linked with improvement of VEGF and PEDF gene expression, PLoS One, 6, e21682.
Kolosova, N. G., Stefanova, N. A., Muraleva, N. A., and Skulachev, V. P. (2012) The mitochondria-targeted antioxidant SkQ1 but not N-acetylcysteine reverses aging-related biomarkers in rats, Aging (Albany, NY), 4, 686–694.
Stefanova, N. A., Kozhevnikova, O. S., Vitovtov, A. O., Maksimova, K. Y., Logvinov, S. V., Rudnitskaya, E. A., Korbolina, E. E., Muraleva, N. A., and Kolosova, N. G. (2014) Senescence-accelerated OXYS rats: a model of agerelated cognitive decline with relevance to abnormalities in Alzheimer disease, Cell Cycle, 13, 898–909.
Kolosova, N. G., Shcheglova, T. V., Sergeeva, S. V., and Loskutova, L. V. (2006) Long-term antioxidant supplementation attenuates oxidative stress markers and cognitive deficits in senescent-accelerated OXYS rats, Neurobiol. Aging, 27, 1289–1297.
Meissner, C., Bruse, P., Mohamed, S. A., Schulz, A., Warnk, H., Storm, T., and Oehmichen, M. (2008) The 4977 bp deletion of mitochondrial DNA in human skeletal muscle, heart and different areas of the brain: a useful biomarker or more, Exp. Gerontol., 43, 645–652.
Gadaleta, M. N., Rainaldi, G., Lezza, A. M., Milella, F., Fracasso, F., and Cantatore, P. (1992) Mitochondrial DNA copy number and mitochondrial DNA deletion in adult and senescent rats, Mutat. Res., 275, 181–193.
DiMauro, S., Tanji, K., Bonilla, E., Pallotti, F., and Schon, E. (2002) Mitochondrial abnormalities in muscle and other aging cells: classification, causes, and effects, Muscle Nerve, 26, 597–607.
Chen, T. F., Chiu, M. J., Huang, C. T., Tang, M. C., Wang, S. J., Wang, C. C., and Huang, R. F. (2011) Changes in dietary folate intake differentially affect oxidized lipid and mitochondrial DNA damage in various brain regions of rats in the absence/presence of intracerebroventricularly injected amyloid β-peptide challenge, Br. J. Nutr., 105, 1294–1302.
Edris, W., Burgett, B., Colin, O., and Filburn, C. (1994) Detection and quantitation by competitive PCR of an ageassociated increase in a 4.8-kb deletion in rat mitochondrial DNA, Mutat. Res., 316, 69–78.
Nicklas, J., Brooks, E., Hunter, T., Single, R., and Branda, R. (2004) Development of a quantitative PCR (TaqMan) assay for relative mitochondrial DNA copy number and the common mitochondrial DNA deletion in the rat, Environ. Mol. Mutagen., 44, 313–320.
Kowald, A., and Kirkwood, T. B. (2013) Mitochondrial mutations and aging: random drift is insufficient to explain the accumulation of mitochondrial deletion mutants in short-lived animals, Aging Cell, 12, 728–731.
Kowald, A., Dawson, M., and Kirkwood, T. B. (2014) Mitochondrial mutations and ageing: can mitochondrial deletion mutants accumulate via a size based replication advantage, J. Theor. Biol., 340, 111–118.
Nadasi, E., Melegh, B., Seress, L., and Kosztolanyi, G. (2004) Mitochondrial DNA deletions in newborn brain samples, Orv. Hetil., 145, 1321–1325.
Kim, W. R., and Sun, W. (2011) Programmed cell death during postnatal development of the rodent nervous system, Dev. Growth Differ., 53, 225–235.
Walton, N. M., Shin, R., Tajinda, K., Heusner, C. L., Kogan, J. H., Miyake, S., Chen, Q., Tamura, K., and Matsumoto, M. (2012) Adult neurogenesis transiently generates oxidative stress, PLoS One, 7, e35264.
Gerschutz, A., Heinsen, H., Grunblatt, E., Wagner, A. K., Bartl, J., Meissner, C., Fallgatter, A. J., Al-Sarraj, S., Troakes, C., Ferrer, I., Arzberger, T., Deckert, J., Riederer, P., Fischer, M., Tatschner, T., and Monoranu, C. M. (2013) Neuron-specific mitochondrial DANN deletion levels in sporadic Alzheimer’s disease, Curr. Alzheimer Res., 10, 1041–1046.
Sergeeva, S., Bagryanskaya, E., Korbolina, E., and Kolosova, N. (2006) Development of behavioral dysfunctions in accelerated-senescence OXYS rats is associated with early postnatal alterations in brain phosphate metabolism, Exp. Gerontol., 41, 141–150.
Kolosova, N. G., Shcheglova, T. V., Amstislavskaya, T. G., and Loskutova, L. V. (2003) Comparative analysis of LPO products in brain structures of Wistar and OXYS rats of different age, Bull. Exp. Biol. Med., 135, 593–596.
Shabalina, I. G., Kolosova, N. G., Grishanova, A. Yu., Solovyov, V. N., Salganik, R. I., and Solovyova, N. A. (1995) Oxidative phosphorylation activity, F0F1-ATPase, and cytochrome content in liver mitochondria of rats with inherited hyperproduction of free radicals, Biochemistry (Moscow), 60, 1563–1568.
Kolosova, N. G., Aydagulova, S. V., Nepomnyashchikh, G. I., Shabalina, I. G., and Shalbueva, N. I. (2001) Dynamics of structural-functional changes in hepatocyte mitochondria of prematurely aging OXYS rats, Bull. Eksp. Biol. Med., 132, 235–240.
Skulachev, V. P., Antonenko, Y. N., Cherepanov, D. A., Chernyak, B. V., Izyumov, D. S., Khailova, L. S., Klishin, S. S., Korshunova, G. A., Lyamzaev, K. G., Pletjushkina, O. Y., Roginsky, V. A., Rokitskaya, T. I., Severin, F. F., Severina, I. I., Simonyan, R. A., Skulachev, M. V., Sumbatyan, N. V., Sukhanova, E. I., Tashlitsky, V. N., Trendeleva, T. A., Vyssokikh, M. Y., and Zvyagilskaya, R. A. (2010) Prevention of cardiolipin oxidation and fatty acid cycling as two antioxidant mechanisms of cationic derivatives of plastoquinone (SkQs), Biochim. Biophys. Acta, 1797, 878–889.
Plotnikov, E. Y., Silachev, D. N., Jankauskas, S. S., Rokitskaya, T. I., Chupyrkina, A. A., Pevzner, I. B., Zorova, L. D., Isaev, N. K., Antonenko, Y. N., Skulachev, V. P., and Zorov, D. B. (2012) Mild uncoupling of respiration and phosphorylation as a mechanism providing nephro- and neuroprotective effects of penetrating cations of the SkQ family, Biochemistry (Moscow), 77, 1029–1037.
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Original Russian Text © P. S. Loshchenova, O. I. Sinitsyna, L. A. Fedoseeva, N. A. Stefanova, N. G. Kolosova, 2015, published in Biokhimiya, 2015, Vol. 80, No. 5, pp. 707–715.
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Loshchenova, P.S., Sinitsyna, O.I., Fedoseeva, L.A. et al. Influence of antioxidant SkQ1 on accumulation of mitochondrial DNA deletions in the hippocampus of senescence-accelerated OXYS rats. Biochemistry Moscow 80, 596–603 (2015). https://doi.org/10.1134/S0006297915050120
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DOI: https://doi.org/10.1134/S0006297915050120