EVALUATION OF THE MITOCHONDRIA RESPIROMETRIC FUNCTION IN THE CONDITIONS OF PATHOLOGIES OF VARIOUS GENESES


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Abstract

The aim of the paper is to assess the change in the mitochondrial respirometric function under conditions of various pathologies.Materials and methods. The study was performed on male Wistar rats. Experimental focal cerebral ischemia, traumatic brain injury, coronary occlusive myocardial infarction and muscle dysfunction were used as pathological models. Focal ischemia was reproduced by the method of irreversible thermocoagulation of the middle cerebral artery. Traumatic brain injury was modeled by the method of free fall of the load. Experimental myocardial infarction was reproduced by ligating the descending branch of the left coronary artery. Muscle dysfunction was modeled by the method of «forced swimming with a 20% burden». The respiratory function of mitochondria was assessed by the method of respirometry by the change in oxygen consumption when introducing mitochondrial respiration into the medium: Oligomycin, Rotenone and FCCP. Additionally, we evaluated the intensity of the glycolysis process and the activity of respiratory complexes I, II, IV and V. In order to comprehensively assess the respiratory function, an ELISA study was conducted to determine the concentration of ATP, mitochondrial ATP synthetase, cytochrome C oxidase and NADP-Oxidase 4.Results. In the course of the study it was established that under conditions of experimental cerebral ischemia, traumatic brain injury, myocardial infarction and muscle dysfunction, the ATP-generating ability of mitochondria the maximum breathing and respiratory capacity deteriorated, herby the decrease in overall respiratory function was accompanied by an increase in glycolysis, which was uncompensated, as well as dysfunction of mitochondrial complexes I, II, IV and V, confirmed by an increase in NADPH oxidase 4 activity and a decrease in cytochrome C oxidases and ATP synthetase. As a result, the observed changes in mitochondrial respiration function contributed to a decrease in ATP concentration under conditions of cerebral ischemia - by 3.2 times (p <0.05), traumatic brain injury – by 2.6 times (p <0.05), myocardial infarction – by 1.8 times (p <0.05) and muscle dysfunction – by 4 times (p <0.05).Conclusion. Basing on the data obtained, we can assume that in conditions of cerebral ischemia, traumatic brain injury, myocardial infarction and muscle dysfunction, there is deterioration of the mitochondrial respirometric function with inhibition of ATP synthesis and increased glycolysis.

About the authors

A. V. Voronkov

Pyatigorsk Medical and Pharmaceutical Institute – branch of Volgograd State Medical University

Email: prohor77@mail.ru

D. I. Pozdnyakov

Pyatigorsk Medical and Pharmaceutical Institute – branch of Volgograd State Medical University

Email: pozdniackow.dmitry@yandex.ru

S. A. Nigaryan

Pyatigorsk Medical and Pharmaceutical Institute – branch of Volgograd State Medical University

Email: 79682650210@yandex.ru

E. I. Khouri

Pyatigorsk Medical and Pharmaceutical Institute – branch of Volgograd State Medical University

Email: elena.belova@hotmail.ru

K. A. Miroshnichenko

Pyatigorsk Medical and Pharmaceutical Institute – branch of Volgograd State Medical University

Email: K220436@yandex.ru

A. V. Sosnovskaya

Pyatigorsk Medical and Pharmaceutical Institute – branch of Volgograd State Medical University

Email: 88misi88@yandex.ru

E. A. Olokhova

Krasnoyarsk State Medical University n. a V.F. Voyno-Yasenetsky

Email: tabletka@yandex.ru

References

  1. Lerner C.A., Sundar I.K., Rahman I. Mitochondrial redox system, dynamics, and dysfunction in lung inflammaging and COPD // Int J Biochem Cell Biol. – 2016. – Vol. 81 (Pt В). – P. 294–306. doi: 10.1016/j.biocel.2016.07.026.
  2. Zielonka J., Joseph J., Sikora A., et al.MitochondriaTargeted Triphenylphosphonium-Based Compounds: Syntheses, Mechanisms of Action, and Therapeutic and Diagnostic Applications // Chem Rev. – 2017. – Vol. 117, №15. – P. 10043–10120. doi: 10.1021/acs.chemrev.7b00042.
  3. Menges S., Minakaki G., Schaefer P.M., et al. Alpha-synuclein prevents the formation of spherical mitochondria and apoptosis under oxidative stress // Sci Rep. – 2017. – Vol. 7. – P. 42942. doi: 10.1038/srep42942.
  4. Zorov D.B., Juhaszova M., Sollott S.J. Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release // Physiol Rev. – 2014. – Vol. 94, №3. – P. 909–950. doi: 10.1152/physrev.00026.2013.
  5. Bergman O., Ben-Shachar D. Mitochondrial Oxidative Phosphorylation System (OXPHOS) Deficits in Schizophrenia: Possible Interactions with Cellular Processes // Can J Psychiatry. – 2016. – Vol. 61, №8. – P. 457–469. doi: 10.1177/0706743716648290.
  6. Alston C.L., Rocha M.C., Lax N.Z., Turnbull D.M., Taylor R.W. The genetics and pathology of mitochondrial disease // J Pathol. – 2017. – Vol. 241, №2. – P. 236–250. doi: 10.1002/path.4809
  7. Chinnery P.F. Mitochondrial disease in adults: what’s old and what’s new? // EMBO Mol Med. – 2015. – Vol. 7, №12. – P. 1503–1512. doi: 10.15252/emmm.201505079.
  8. O-Uchi J., Ryu S.Y., Jhun B.S., Hurst S., Sheu S.S. Mitochondrial ion channels/transporters as sensors and regulators of cellular redox signaling // Antioxid Redox Signal. – 2014. – Vol. 21, №6. – P. 987–1006. doi: 10.1089/ars.2013.5681.
  9. Di Meo S., Reed T.T., Venditti P., Victor V.M. Role of ROS and RNS Sources in Physiological and Pathological Conditions // Oxid Med Cell Longev. – 2016. – Vol. 2016. – P. 1245049. doi: 10.1155/2016/1245049.
  10. Ferrari D., Stepczynska A., Los M., Wesselborg S., Schulze-Osthoff K. Differential regulation and ATP requirement for caspase-8 and caspase-3 activation during CD95- and anticancer drug-induced apoptosis // J Exp Med. – 1998. – Vol. 188, №5. – P. 979–984.
  11. Khacho M., Tarabay M., Patten D. Acidosis overrides oxygen deprivation to maintain mitochondrial function and cell survival // Nat Commun. – 2014. – Т. 5. doi: 10.1038/ncomms4550.
  12. Bederson J.B., Pitts L.H., Tsuji M., Nishimura M.C., Davis R.L., Bartkowski H. Rat middle cerebral artery occlusion: evaluation of the model and development of a neurologic examination // Stroke. – 1986. – Vol. 17, №3. – P. 472–476.
  13. Воронков А.В., Калашникова С.А., Хури Е.И., Поздняков Д.И. Моделирование черепно-мозговой травмы в условиях эксперимента у крыс // Современные проблемы науки и образования. – 2016. – № 1. URL: http://www.science-education.ru/ru/article/view?id=25242.
  14. Воронков А.В., Поздняков Д.И., Воронкова М.П. Комплексная валидационная оценка нового методического подхода к изучению физического и психоэмоционального перенапряжения в эксперименте // Фундаментальные исследования. – 2015. – №1–5. – С. 915–919.
  15. Сисакян А.С., Оганян В.А., Семерджян A.Б., Петросян М.В., Сисакян С.А., Гуревич М.А. Влияние фактора ангиогенеза на морфофункциональное состояние миокарда у крыс при экспериментальном инфаркте миокарда // Российский кардиоло-гический журнал. – 2008. – Т. 13, № 2. – С. 63–66.
  16. Patel S.P., Sullivan P.G., Pandya J.D et al. N-acetylcysteine amide preserves mitochondrial bioenergetics and improves functional recovery following spinal trauma // Exp Neurol. – 2014. – Vol. 257. – P. 95–105. doi: 10.1016/j.expneurol.2014.04.026.
  17. Redmann M., Benavides G.A., Wani W.Y. et al. Methods for assessing mitochondrial quality control mechanisms and cellular consequences in cell culture // Redox Biol. – 2018. – Vol. 17. – P. 59–69. https://doi.org/10.1016/j.redox.2018.04.005.
  18. Picard M., Wallace D.C., Burelle Y. The rise of mitochondria in medicine // Mitochondrion. – 2016. – Vol. 30. – P. 105–116. doi: 10.1016/j.mito.2016.07.003.
  19. Lesnefsky E.J., Chen Q., Hoppel C.L. Mitochondrial Metabolism in Aging Heart // Circ Res. – 2016. – Vol. 118, №10. – P. 1593–1611. doi: 10.1161/CIRCRESAHA.116.307505.
  20. Cai Q., Tammineni P. Mitochondrial Aspects of Synaptic Dysfunction in Alzheimer’s Disease // J Alzheimers Dis. – 2017. – Vol. 57, №4. – P. 1087– 1103. doi: 10.3233/JAD-160726.
  21. Boengler K., Kosiol M., Mayr M., Schulz R., Rohrbach S. Mitochondria and ageing: role in heart, skeletal muscle and adipose tissue // J Cachexia Sarcopenia Muscle. – 2017. – Vol. 8, №3. – P. 349– 369. doi: 10.1002/jcsm.12178.
  22. Choudhury A.R., Singh K.K. Mitochondrial determinants of cancer health disparities // Semin Cancer Biol. – 2017. – Vol. 47. – P. 125–146. doi: 10.1016/j.semcancer.2017.05.001.
  23. Szeto H.H., Birk A.V. Serendipity and the discovery of novel compounds that restore mitochondrial plasticity // Clin PharmacolTher. – 2014. – Vol. 96, №6. – P. 672–683. doi: 10.1038/clpt.2014.174.
  24. Dranka B.P., Benavides G.A., Diers A.R., Giordano S., Zelickson B.R., Reily C., Zou L., Chatham J.C., Hill B.G., Zhang J., Landar A., Darley-Usmar VM. Assessing bioenergetic function in response to oxidative stress by metabolic profiling // Free Radic Biol Med. – 2011. – Vol. 51. – P. 1621–1635. doi: 10.1016/j.freeradbiomed.2011.08.005.
  25. Salabei J.K., Gibb A.A., Hill B.G. Comprehensive measurement of respiratory activity in permeabilized cells using extracellular flux analysis // Nat Protoc. – 2014. – Vol. 9, №2. – P. 421–438. doi: 10.1038/nprot.2014.018
  26. Kim Y.M, Kim S.J, Tatsunami R., Yamamura H., Fukai T., Ushio-Fukai M. ROS-induced ROS release orchestrated by Nox4, Nox2, and mitochondria in VEGF signaling and angiogenesis // Am J Physiol Cell Physiol. – 2017. – Vol. 312, №6. – P. C749– C764. doi: 10.1152/ajpcell.00346.2016.
  27. Shanmugasundaram K., Nayak B.K., Friedrichs W.E., Kaushik D., Rodriguez R., Block K. NOX4 functions as a mitochondrial energetic sensor coupling cancer metabolic reprogramming to drug resistance // Nat Commun. – 2017. – Vol. 8, №1. – P. 997. doi: 10.1038/s41467-017-01106-1.
  28. Smith M.R., Vayalil P.K., Zhou F., et al. Mitochondrial thiol modification by a targeted electrophile inhibits metabolism in breast adenocarcinoma cells by inhibiting enzyme activity and protein levels // Redox Biol. – 2016. – Vol. 8. – P. 136–148. doi: 10.1016/j.redox.2016.01.002.

Copyright (c) 2019 Voronkov A.V., Pozdnyakov D.I., Nigaryan S.A., Khouri E.I., Miroshnichenko K.A., Sosnovskaya A.V., Olokhova E.A.

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This work is licensed under a Creative Commons Attribution 4.0 International License.
 

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