Mitochondrial disorders in neuromuscular pathology

Introduction. With the advent of new drugs — analogues of mitochondrial metabolites, the widespread introduction into practice of research methods for assessing the function of mitochondria in patients with neurological pathology and other diseases becomes relevant.

Study aim. To determine the change in the intracellular activity of mitochondrial enzymes (succinate dehydrogenase, α -glycerophosphate dehydrogenase, glutamate dehydrogenase, lactate dehydrogenase) in case of neuromuscular diseases.

Materials and methods. We examined 74patients with neuromuscular diseases. The activity of 4 mitochondrial enzymes involved in carbohydrate metabolism (lactate dehydrogenase), amino acid metabolism (glutamate dehydrogenase), fatty acids (α -glycerophosphate dehydrogenase), and mitochondrial respiratory chain complex II (succinate dehydrogenase) was evaluated. For a cytochemical study of the activity of mitochondrial enzymes in peripheral blood lymphocytes, the method proposed by A.G.E. Pearse as modified by R.P. Narcissov.

Results. The greatest changes were revealed in cases with myotonic dystrophy: statistically significant decreases in the average activity value of all studied enzymes (р <0.05).In cases with hereditary motor-sensory neuropathy of type I the activity of succinate dehydrogenase and glutamate dehydrogenase is reduced (р <0.05), in cases with type II there are deviations in the activity indicators of mitochondrial enzymes, more pronounced compared with type I, but not statistically significant (p >0.05). In patients with myasthenia gravis, a decrease in the activity of α -glycerophosphate dehydrogenase and glutamate dehydrogenase (p <0.05) was noted. Average values of succinate dehydrogenase and lactate dehydrogenase activity indicators were also reduced (p >0.05). In cases with Landusi-Dejerine myopathy the activity of succinate dehydrogenase, α -glycerophosphate dehydrogenase and glutamate dehydrogenase were reduced, of which only for α -glycerophosphate    dehydrogenase p <0.05. In the analysis of each case in groups of patients with the studied pathology, it was shown that in addition to patients with myotonic dystrophy, in which all patients decreased the activity of succinate dehydrogenase, α -glycerophosphate dehydrogenase and glutamate dehydrogenase, in other cases, in some patients, the studied enzyme activity did not change.

Conclusion. There are methods for studying these metabolites in plasma. The activity of mitochondrial enzymes is also examined. In cases with neuromuscular diseases, there are violations of the mitochondria. Therefore, it is necessary to consider such patients as metabolic patients and prescribe metabolic, antioxidant therapy to them.

1. Afshin-Majd S., Bashiri K., Kiasalari Z. et al. Acetyl-l-carnitine protects dopaminergic nigrostriatal pathway in 6-hydroxydopamine-mduced model of Parkinson’s disease in the rat. Biomed Pharmacother 2017;89:1-9. DOI: 10.1016/j.biopha.2017.02.007. PMID: 28199883.

2. Yoritaka A., Kawajiri S., Yamamoto Y. et al. Randomized, double-blind, placebo-controlled pilot trial of reduced coenzyme Q10 for Parkinson’s disease. Parkinsonism Relat Disord 2015;21(8):911-6. DOI: 10.1016/j.parkreldis.2015.05.022. PMID: 26054881.

3. Li Z., Wang P., Yu Z. et al. The effect of creatine and coenzyme q10 combination therapy on mild cognitive impairment in Parkinson’s disease. Eur Neurol 2015;73(3—4):205—11. DOI: 10.1159/000377676. PMID: 25792086.

4. Joshi A.U., Ebert A.E., Haileselassie B., Mochly-Rosen D. Drp1/Fis1-mediated mitochondrial fragmentation leads to lysosomal dysfunction in cardiac models of Huntington’s disease. J Mol Cell Cardiol 2019;127:125-33. DOI: 10.1016/j.yjmcc.2018.12.004.

5. Zhou Z., Austin G.L., Young L.E.A. et al. Mitochondrial metabolism in major neurological diseases. Cells 2018;23(12):pii: E229. DOI: 10.3390/cells7120229. Review. PMID: 30477120.

6. Gautam M., Jara J.H., Kocak N. et al. Mitochondria, ER, and nuclear membrane defects reveal early mechanisms for upper motor neuron vulnerability with respect to TDP-43 pathology. Acta Neuropathol 2019;137(1):47-69. DOI: 10.1007/s00401-018-1934-8. PMID: 30450515.

7. Lu M.H., Zhao X.Y., Yao P.P., Xu D.E., Ma Q.H. The Mitochondrion: A Potential Therapeutic Target for Alzheimer’s Disease. Neurosci Bull 2018;34(6):1127—30. DOI: 10.1007/s12264-018-0310-y.

8. Civiletto G., Dogan S.A., Cerutti R. et al. Rapamycin rescues mitochondrial myopathy via coordinated activation of autophagy and lysosomal biogenesis. EMBO Mol Med 2018;10(11):pii:e8799. DOI: 10.15252/emmm.201708799. PMID: 30309855.

9. Van Giau V., An S.S.A., Hulme J.P. Mitochondrial therapeutic interventions in Alzheimer’s disease. J Neurol Sci 2018;395:62-70. DOI: 10.1016/j.jns.2018.09.033. PMID: 30292965.

10. Ranganathan S., Harmison G.G., Meyertholen K. et al. Mitochondrial abnormalities in spinal and bulbar muscular atrophy. Hum Mol Genet 2009;18(1):27—42. DOI 10.1093/hmg/ddv561. PMID:29931346.

11. McClelland C., Manousakis G., Lee M.S. Progressive External Ophthalmoplegia. Curr Neurol Neurosci Rep 2016;16(6):53. DOI: 10.1007/s11910-016-0652-7. PMID:29938308.

12. Santacatterina F., Chamorro M., de Arenas C.N. et al. Quantitative analysis of proteins of metabolism by reverse phase protein microarrays identifies potential biomarkers of rare neuromuscular diseases. J Transl Med 2015;13:65. DOI: 10.1186/s12967-016-0904-y. PMID:29929550.

13. Singh I., Faruq M., Padma M.V. et al. Investigation of mitochondrial DNA variations among Indian Friedreich’s ataxia (FRDA) patients. Mitochondrion 2015;25:1-5. DOI: 10.1016/j.mito. PMID:26321457.

14. Clarke J.T. A clinical guide to inherited metabolic disease. Cambridge: University press, 2010. P. 338. DOI: 10.1017/CBO9780511544682.

15. Sure V.N., Sakamuri S.S.V.P., Sperling J.A. et al. A novel high-throughput assay for respiration in isolated brain microvessels reveals impaired mitochondrial function in the aged mice. Geroscience 2018;40(4):365-75. DOI: 10.1007/s11357-018-0037-8. PMID: 30074132.

16. Donnino M.W., Liu X., Andersen L. et al. Characterization of mitochondrial injury after cardiac arrest (COMICA). Resuscitation 2017;113:56-62. DOI: 10.1016/j.resuscitation.2016.12.029. PMID: 28126408.

17. Kim A.Y., Jeong K.H., Lee J.H. et al. Glutamate dehydrogenase as a neuroprotective target against brain ischemia and reperfusion. Neuroscience 2017;340: 487-500. DOI: 10.1016/j.neuroscience.2016.11.007. PMID: 27845178.

18. Orozco-Ibarra M., Garcia-Morales J., Calvo-Silva FJ. et al. Striatal mitochondria response to 3-nitropropionic acid and fish oil treatment. Nutr Neurosci 2018;21(2):132-42. DOI: 10.1080/1028415X.2016.1237074. PMID: 27682807.

19. Ahmed Alamoudi W., Ahmad F., Acharya S. et al. A simplified colorimetric method for rapid detection of cell viability and toxicity in adherent cell culture systems. J BUON 2018;23(5):1505-13. PMID: 30570879.

20. Qadri R., Namdeo M., Behari M. et al. Alterations in mitochondrial membrane potential in peripheral blood mononuclear cells in Parkinson’s disease: potential for a novel biomarker. Restor Neurol Neurosci 2018;36(6):719—27. DOI: 10.3233/RNN-180852. PMID: 30282380.

21. Monzio C.G., Kleiner G., Bordoni A. et al. Mitochondrial dysfunction in fibroblasts of multiple system atrophy. Biochim Biophys Acta Mol Basis Dis 2018;1864(12):3588—97. DOI: 10.1016/j.bbadis.2018.09.018. PMID: 30254015.

22. Kurbatova O.V., Surkov A.N., Namazova-Baranova L.S. et al. Mitochondrial dysfunction in children with hepatic forms of glycogen disease. Vestnik rossiyskoy akademii edicinckih nauk = Bulletin of the Russian Academy of Medical Sciences 2014;69(7—8):78—84. (In Russ.).

23. Jones A.J., Hirst J. A spectrophotometric coupled enzyme assay to measure the activity of succinate dehydrogenase. Anal Biochem 2013;442(1):19—23. DOI: 10.1016/j.ab.2013.07.018. PMID:23886887.

24. Botman D., Tigchelaar W., Van Noorden C.J. Determination of glutamate dehydrogenase activity and its kinetics in mouse tissues using metabolic mapping (quantitative enzyme histochemistry). J Histochem Cytochem 2014;62(11): 802-12. DOI: 10.1369/0022155414549071. PMID: 25124006.

25. Gao M., Liu W., Chen Y., Zhang W. Cytochrome oxidase and succinate dehydrogenase double staining method in mitochondrial myopathy. Zhonghua Bing Li Xue Za Zhi 2015;44(3):208-9. PMID: 2626876.

26. Kollberg G., Melberg A., Holme E., Oldfors A. Transient restoration of succinate dehydrogenase activity after rhabdomyolysis in iron-sulphur cluster deficiency myopathy. Neuromuscul Disord 2011;21(2):115-20. DOI: 10.1016/j.nmd.2010.11.010. PMID: 21196119.

27. Gimenes A.C., Bravo D.M., Napolis L.M. et al. Effect of L-carnitine on exercise performance in patients with mitochondrial myopathy. Braz J Med Biol Res 2015;48(4):354—62. DOI: 10.1590/1414-431X20165247. PMID: 9924138.

28. Nicolson G.L. Mitochondrial dysfunction and chronic disease: treatment with natural supplements. Altern Ther Health Med 2014;20(1):18—25. DOI: 10.2307/2700127. PMID: 29859509.

29. Kato K., Mizota T., Hirota K., Fukuda K. Successful perioperative management of a patient with primary systemic carnitine deficiency: a case report. J Anesth 2013;27(1):141—2. DOI:10.1093/bja/ael103. PMID: 29938387.

30. Han L.S., Ye J., Qiu WJ. et al. Primary carnitine deficiency in 17 patients: diagnosis, treatment and follow up. Zhonghua Er Ke Za Zhi 2012;50(6):405—9. DOI: 10.3760/cma.j.issn.0578-1310. PMID: 29902860.

31. LoMauro A., D’Angelo M.G., Aliverti A. Assessment and management of respiratory function in patients with Duchenne muscular dystrophy: current and emerging options. Ther Clin Risk Manag 2015;11:1475-88. DOI: 10.2147/TCRM.S87876. PMID: 29928125.

32. Mercuri E., Muntoni F. Efficacy of idebenone in Duchenne muscular dystrophy. Lancet 2015;385(9979):1704—6. DOI: 10.1016/S0140-6736(16)00562-6. PMID: 29937195.

33. Buyse G.M., Voit T., Schara U. et al. DELOS Study Group. Efficacy of idebenone on respiratory function in patients with Duchenne muscular dystrophy not using glucocorticoids (DELOS): a double-blind randomised placebo-controlled phase 3 trial. Lancet 2015;385(9979):1748—57. DOI: 10.1016/S0140-6736(16)00562-6. PMID: 29937195.

34. Luk’yanova L.D., Kirova Yu.I., Germanova E.L. The role of succinate in the regulation of urgent expression of HIF-1A in hypoxia. B’yulleten’ eksperimental’noy biologii i meditcinj = Bulletin of Experimental Biology and Medicine 2017;164(9):273—9. (In Russ.).

35. Lukyanova L.D., Kirova Y.I. Mito-chondria-cjntrolled signaling mechanisms of brain protection in hypoxia. Frontiers in Neuroscience 2015;9(OCT):320. DOI: 10.3389/fnins.2015.00320. PMID: 26483619.

36. Lukyanova L.D., Kirova Y.I., Germanova E.L. Energotropic effect of intermittent hypoxia: role of succindt-depend signaling. Intermittent Hypoxia and Human Diseases London, 2012. P. 239—252.

37. Vlodavetc D.V., Belousova E.D., Sukhorukov V.S., Kharlamov D.A. A method for the treatment of congenital structural myopathies and congenital muscular dystrophies by correcting secondary mitochondrial changes. Abstr. diss. ... cand. med. sciences. Moscow, 2009. 28 p. (In Russ.).

38. Stvolinsky S., Boldyrev A., Toropova K. et al. Carnosine and its(S)-Trolox™ derivative protect animals against oxidative stress. Amino Acids 2012;43:165—70. DOI: 10.1007/s00726-012-1256-4. PMID: 22389054.

39. Stvolinsky S.L., Bulygina E.R., Fedorova T.N. et al. Biological activity of novel synthetic derivatives of carnosine. Cellular and Molecular Neurobiology 2010;30(3):395—404. DOI: 10.1007/s10571-009-9462-7. PMID: 19798566.

40. Fedorova T.N., Stvolinskiy S.L., Kulikova O.I. et al. The effectiveness of the neuroprotective effect of carnosine in the composition of nanoliposomes and S-trolox-carnosine under conditions of oxidative stress in vitro and in vivo. Annaly klinicheskoy i eksperimentalnoy nevrologii = Annals of Clinical and Experimental Neurology 2016;10(1):47—52. (In Russ.).

41. Grinio L.P. The role of carnosine in muscle pathology. Voprosy biologicheskoy, meditcinskoy i farmactevticheskoy khimii = Questions of biological, medical and pharmaceutical chemistry 2011;10:62—7. (In Russ.).