Role of Mitochondrial Permeability Transition Pore in Intermittent Hypoxia-Induced Cardiac and Neuronal Protection

  • Galina Vavilova
  • Tatyana Shimanskaya
  • Nataliya StrutynskaEmail author
  • Sergey Talanov
  • Vadim Sagach


We have investigated protective effects of intermittent hypoxic training (IHT) in three experimental models. In experiments on isolated hearts from adult and old guinea pigs, perfused under Langendorff mode, the effect of the intermittent hypoxia on reperfusion injury and activation of mitochondrial permeability transition pore (mPTP) was studied. It was shown that 7-day course of the IHT led to decrease of mitochondrial permeability tran­sition, increased efficiency of the heart in both adult and old animals. Cardiac reperfusion was followed by an increased cardiac contractility and decrease of an oxygen cost of myocardial work. On the heart mitochondria from adult and old rats subjected to IHT, we studied the sensitivity of mPTP opening to its inductor, phenylarsine oxide (PAO). We have found that IHT used in regime II (8% O2 gas mixture) resulted in a twofold decrease as compared with the control in the PAO-induced adult rat heart mitochondria swelling, which was completely abolished in the presence of an inhibitor – cyclosporin A (10–5 mol/l). We have estimated the sensitivity of mPTP opening based on two parameters: alterations of mitochondrial swelling and release of mitochondrial substances (mitochondrial factor). We have demonstrated that old rat heart mitochondria are more sensitive to PAO (that induces the CsA-sensitive mPTP opening and mPTP-dependent release of mitochondrial factor) than adult rat heart mitochondria. Therefore, we have observed protective effect of IHT on PAO-induced mPTP-opening and mPTP-dependent factor release from old rat heart mitochondria. In experiments on the rat hemiparkinsonian model induced by 6-hydroxydopamine (6-OHDA), we have demonstrated that the used IHT course prevented pharmacologically induced unilateral dopaminergic neuronal loss. The most significant neuroprotective effect was observed in case when IHT course carried out prior and after 6-OHDA injection. Prevention of DAergic nigral neurons apoptosis upon the action of 6-OHDA is apparently due to the protective effect of IHT on mPTP opening. By reference to the obtained data, we conclude that IHT, due to its cardio- and neuroprotective effects, can be used as a protective procedure preventing mPTP opening in aging, in a number of chronic pathologies induced by oxidative stress, and also in neurodegenerative diseases.


Mitochondrial Permeability Transition Pore Intermittent Hypoxia Hypoxic Precondition mPTP Opening DAergic Neuron 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.







Cyclosporin A




Intermittent hypoxia training


Index Veragut


Left ventricle pressure


Mitochondrial permeability transition pore


Nitric oxide


Oxygen cost of myocardial work




Phenylarsine oxide


Parkinson’s disease


Reactive oxygen species


  1. 1.
    Andrew R, Watson DG, Best SA. The determination of hydroxydopamines and other trace amines in the urine of parkinsonian patients and normal controls. Neurochem Res. 1993;18:1175–7.PubMedCrossRefGoogle Scholar
  2. 2.
    Argaud L, Gateau-Roesch O, Muntean D, et al. Specific inhibition of the mitochondrial permeability transition prevents lethal reperfusion injury. J Mol Cell Cardiol. 2005;38:367–74.PubMedCrossRefGoogle Scholar
  3. 3.
    Bertuglia S. Intermittent hypoxia modulates nitric oxide-dependent vasodilation and capillary perfusion during ischemia-reperfusion-induced damage. Am J Physiol. 2008;294:H1914–22.Google Scholar
  4. 4.
    Bowling AC, Beal MF. Bioenergetic and oxidative stress in neurodegenerative diseases. Life Sci. 1995;56:1151–71.PubMedCrossRefGoogle Scholar
  5. 5.
    Burtscher M, Pachinger O, Ehrenbourg I, et al. Intermittent hypoxia increases exercise tolerance in elderly men with and without coronary artery disease. Int J Cardiol. 2004;96:247–54.PubMedCrossRefGoogle Scholar
  6. 6.
    Cassarino DS, Bennett Jr JP. An evaluation of the role of mitochondria in neurodegenerative diseases: mitochondrial mutations and oxidative pathology, protective nuclear responses, and cell death in neurodegeneration. Brain Res Rev. 1999;29:1–25.PubMedCrossRefGoogle Scholar
  7. 7.
    Chorna SV, Talanov SO, Strutynska NA, et al. The functional state of the rat heart during ischemia-reperfusion, the sensitivity of calcium-induced NO-dependent mitochondrial permeability transition pore opening and the uncoupling protein 3 expression under long exercise training. Fiziol Zh. 2010;56:13–21 [In Ukrainian].Google Scholar
  8. 8.
    Crompton M. Mitochondria and aging: a role for the permeability transition? Aging Cell. 2004;3:3–6.PubMedCrossRefGoogle Scholar
  9. 9.
    Curtius HC, Wolfensberger M, Steinmann B, et al. Mass fragmentography of dopamine and 6-hydroxydopamine. Application to the determination of dopamine in human brain biopsies from the caudate nucleus. J Chromatogr. 1974;99:529–40.PubMedCrossRefGoogle Scholar
  10. 10.
    El’chaninova SA, Smagina IV, Koreniak NA, et al. The influence of interval hypoxic training on lipid peroxidation and antioxidant enzyme activity. Fiziol Cheloveka. 2003;29:72–5 [In Russian].PubMedGoogle Scholar
  11. 11.
    Feng J, Lucchinetti E, Ahuja P, et al. Isoflurane postconditioning prevents opening of the mitochondrial permeability transition pore through inhibition of glycogen synthase kinase 3beta. Anesthesiology. 2005;103:987–95.PubMedCrossRefGoogle Scholar
  12. 12.
    Griffiths E, Halestrap A. Mitochondrial non-specific pores remain closed during cardiac ischemia but open upon reperfusion. Biochem J. 1995;307:93–8.PubMedGoogle Scholar
  13. 13.
    Halestrap AP. A pore way to die: the role of mitochondria in reperfusion injury and cardioprotection. Biochem Soc Trans. 2010;38:841–60.PubMedCrossRefGoogle Scholar
  14. 14.
    Halestrap AP, Clarke SJ, Javadov SA. Mitochondrial permeability transition pore opening during myocardial reperfusion - a target for cardioprotection. Cardiovasc Res. 2004;61:372–85.PubMedCrossRefGoogle Scholar
  15. 15.
    Halestrap AP, Pasdois P. The role of the mitochondrial permeability transition pore in heart disease. Biochim Biophys Acta. 2009;1787:1402–15.PubMedCrossRefGoogle Scholar
  16. 16.
    Hausenloy DJ, Yellon DM, Mani-Babu S, et al. Preconditioning protects by inhibiting the mitochondrial permeability transition. Am J Physiol. 2004;287:H841–9.Google Scholar
  17. 17.
    Jung ME, Simpkins JW, Wilson AM, et al. Intermittent hypoxia conditioning prevents behavioral deficit and brain oxidative stress in ethanol-withdrawn rats. J Appl Physiol. 2008;105:510–7.PubMedCrossRefGoogle Scholar
  18. 18.
    Kolchinskaya AZ, Cyganova TN, Ostapenko LA. Normobaric intermittent hypoxic training in medicine and sport. Moscow: Medicine; 2003 [In Russian].Google Scholar
  19. 19.
    Leeuwenburgh C, Phaneuf S. Cytochrome c release from mitochondria in the aging hear: a possible mechanism for apoptosis with age. Am J Physiol Regul Integr Comp Physiol. 2002;282:R423–30.PubMedGoogle Scholar
  20. 20.
    Lesnefsky EJ, Hoppel CL. Ischemia-reperfusion injury in the aged heart: role of the mitochondria. Arch Biochem Biophys. 2003;420:287–97.PubMedCrossRefGoogle Scholar
  21. 21.
    Lin AM, Chen CF, Ho LT. Neuroprotective effect of intermittent hypoxia on iron-induced oxidative injury in rat brain. Exp Neurol. 2002;176:328–35.PubMedCrossRefGoogle Scholar
  22. 22.
    Malyshev IY, Manuhina EB. Stress, adaptation and nitric oxide. Biochemistry. 1998;67:992–1006 [In Russian].Google Scholar
  23. 23.
    Meerson FZ. Essentials of adaptive medicine: protective effects of adaptation, hypoxia. Moscow: Hypoxia Medical LTD; 1994.Google Scholar
  24. 24.
    Mochizuki H, Goto K, Mori H, et al. Histochemical detection of apoptosis in Parkinson’s disease. J Neurol Sci. 1996;137:120–3.PubMedCrossRefGoogle Scholar
  25. 25.
    Mochizuki H, Mori H, Mizuno Y. Apoptosis in neurodegenerative disorders. J Neural Transm. 1997;50:125–40.CrossRefGoogle Scholar
  26. 26.
    Nadtochiy SM, Bohuslavs’kyĭ AI, Sagach VF. Determination of the stable mitochondrial factor in vivo. Fiziol Zh. 2003;49:25–30 [In Ukrainian].Google Scholar
  27. 27.
    Nadtochiy SM, Nauduri D, Shimanskaya TV, et al. Purine release: a protective signaling mechanism of the mitochondrial permeability transition pore in ischemia. Fiziol Zh. 2008;54:5–14.PubMedGoogle Scholar
  28. 28.
    Naghshin J, McGaffin KR, Witham WG, et al. Chronic intermittent hypoxia increases left ventricular contractility in C57BL/6J mice. J Appl Physiol. 2009;107:787–93.PubMedCrossRefGoogle Scholar
  29. 29.
    Nazareth W, Yafei N, Crompton M. Inhibition of anoxia-induced injury in heart myocytes by cyclosporin A. J Mol Cell Cardiol. 1991;23:1351–4.PubMedCrossRefGoogle Scholar
  30. 30.
    Park AM, Suzuki YJ. Effects of intermittent hypoxia on oxidative stress-induced myocardial damage in mice. J Appl Physiol. 2007;102:1806–14.PubMedCrossRefGoogle Scholar
  31. 31.
    Pilar Valle M, García-Godos F, Woolcott OO, et al. Improvement of myocardial perfusion in coronary patients after intermittent hypobaric hypoxia. J Nucl Cardiol. 2006;13:69–74.PubMedCrossRefGoogle Scholar
  32. 32.
    Prabhakar NR, Kumar GK. Oxidative stress in the systemic and ­cellular responses to intermittent hypoxia. Biol Chem. 2004;385:217–21.PubMedCrossRefGoogle Scholar
  33. 33.
    Prabhakar NR, Kumar GK, Nanduri J. Intermittent hypoxia augments acute hypoxic sensing via HIF-mediated ROS. Respir Physiol Neurobiol. 2010;174:230–4.PubMedCrossRefGoogle Scholar
  34. 34.
    Prabhakar NR, Peng YJ, Kumar GK, et al. Long-term regulation of carotid body function: acclimatization and adaptation. Adv Exp Med Biol. 2009;648:307–17.PubMedCrossRefGoogle Scholar
  35. 35.
    Rasola A, Sciacovelli M, Pantic B, et al. Signal transduction to the permeability transition pore. FEBS Lett. 2010;584:1989–96.PubMedCrossRefGoogle Scholar
  36. 36.
    Rudyk OV, Vavilova HL, Strutyns’ka NA, et al. Sensitivity of phenylarsineoxide-induced mitochondrial permeability transition pore opening in the heart of old rats during intermittent hypoxic training. Fiziol Zh. 2004;50:29–37 [In Ukrainian].PubMedGoogle Scholar
  37. 37.
    Sagach VF, Dmitrieva AV, Bubnova IuO, et al. Diagnostics method of myocardium ischemia-reperfusion injury and the mitochondrial permeability transition pore opening. 2007; Patent of utility model № 26385. Bul.№15 of 25.09.2007.Google Scholar
  38. 38.
    Sagach VF, Dmytrieva AV, Bubnova IuO, et al. Using marker of the mitochondrial pore opening in diagnostics of patients with myocardial ischemic lesions. Fiziol Zh. 2009;55:12–8 [In Ukrainian].Google Scholar
  39. 39.
    Sagach VF, Maksymenko VB, Dmytrieva AV, et al. Early marker of myocardial injury of the ischemia-reperfused heart in dogs and during operations with artificial circulation in humans. Fiziol Zh. 2006;52:3–8 [In Ukrainian].Google Scholar
  40. 40.
    Sagach VF, Shimanskaya TV, Nadtochiy SM. Protection of heart from reperfusion injury and ineffective oxygen consumption by inhibitors of the mitochondrial permeability transition pore. Fiziol Zh. 2002;48:3–9 [In Ukrainian].Google Scholar
  41. 41.
    Sagach VF, Shimanskaya TV, Nadtochiy SM. Factor, released under the isolated heart reperfusion may be the marker of the opening the mitochondrial permeability transition pore. Fiziol Zh. 2003;49:7–13 [In Ukrainian].Google Scholar
  42. 42.
    Sagach VF, Vavilova HL, Rudyk OV, et al. Release of unidentified mitochondrial substance – evidence for mitochondrial permeability transition pore opening in heart mitochondria of rats. Fiziol Zh. 2003;49:3–12 [In Ukrainian].Google Scholar
  43. 43.
    Sagach VF, Vavilova HL, Strutynska NA, et al. Effect of inductors and inhibitors of the mitochondrial permeability transition pore on its opening and release of unidentified mitochondrial factor. Fiziol Zh. 2003;49:3–12 [In Ukrainian].Google Scholar
  44. 44.
    Sagach VF, Vavilova HL, Strutynska NA, et al. The aging-related increase of sensitivity of the mitochondrial permeability transition pore opening to inductors in rat heart. Fiziol Zh. 2004;50:49–63 [In Ukrainian].Google Scholar
  45. 45.
    Schapira AH, Gu M, Taanman JW, et al. Mitochondria in the etiology and pathogenesis of Parkinson’s disease. Ann Neurol. 1998;44:S89–98.PubMedGoogle Scholar
  46. 46.
    Schulz JB, Matthews RT, Klockgether T, et al. The role of mitochondrial dysfunction and neuronal nitric oxide in animal models of neurodegenerative diseases. Mol Cell Biochem. 1997;174:193–7.PubMedCrossRefGoogle Scholar
  47. 47.
    Serebrovs’ka TV, Kurgaliuk NM, Nosar VI, et al. Intermittent hypoxic training with exogenous nitric oxide improves rat liver mitochondrial oxidation and phosphorylation during acute hypoxia. Fiziol Zh. 2001;47:85–92 [In Ukrainian].PubMedGoogle Scholar
  48. 48.
    Serebrovskaya TV, Vavilova GL, Rudyk OV, et al. Different ­regimen of intermittent hypoxia training (IHT) as modulator of ­mitochondrial membrane permeability transition pore in rat heart. In: Mitochondrial physiology. MiP2005, Schröcken, Vorarlberg, Austria, p.29–30.Google Scholar
  49. 49.
    Sharp FR, Ran R, Lu A, et al. Hypoxic preconditioning protects against ischemic brain injury. NeuroRx. 2004;1:26–35.PubMedCrossRefGoogle Scholar
  50. 50.
    Shimanskaya T, Dobrovolsky F, Vavilova G, et al. NO-dependent modulation of the sensitivity of the mitochondrial permeability transition pore opening under ischemia-reperfusion of the isolated heart. I M Sechenov Physiol J. 2009;95:28–37 [In Russian].Google Scholar
  51. 51.
    Singh S, Kumar S, Dikshit M. Involvement of the mitochondrial apoptotic pathway and nitric oxide synthase in dopaminergic neuronal death induced by 6-hydroxydopamine and lipopolysaccharide. Redox Rep. 2010;15:115–22.PubMedCrossRefGoogle Scholar
  52. 52.
    Talanov SA, Oleshko NN, Tkachenko MN, et al. Pharmacoprotective influences on different links of the mechanism underlying 6-hydroxydopamine-induced degeneration of nigro-striatal dopaminergic neurons. Neurophysiology. 2006;38:150–6.Google Scholar
  53. 53.
    Talanov SA, Sahach VF. Antioxidants prevent experimental hemiparkinsonism in rats. Fiziol Zh. 2008;54:23–9 [In Ukrainian].PubMedGoogle Scholar
  54. 54.
    Talanov SA, Timoshchuk SV, Rudyk OV, et al. An increased sensitivity of the mitochondrial permeability transition pore to calcium in the heart of rats with chronic deficiency of nigrostriatal dopamine. Fiziol Zh. 2009;55:3–8 [In Ukrainian].PubMedGoogle Scholar
  55. 55.
    Talanov SO, Sahach VF, Oleshko MM, et al. Inhibitors of mitochondrial permeability transition pore prevent apoptosis of dopaminergic neurons in the mesencephalon. Fiziol Zh. 2006;52:13–8 [In Ukrainian].PubMedGoogle Scholar
  56. 56.
    Tatton WG, Chalmers-Redman RM, Ju WY, et al. Apoptosis in neurodegenerative disorders: potential for therapy by modifying gene transcription. J Neural Transm Suppl. 1997;49:245–68.PubMedGoogle Scholar
  57. 57.
    Vannucci RC, Towfighi J, Vannucci SJ. Hypoxic preconditioning and hypoxic-ischemic brain damage in the immature rat: pathologic and metabolic correlates. J Neurochem. 1998;71:1215–20.PubMedCrossRefGoogle Scholar
  58. 58.
    Vavilova GL, Serebrovskaya TV, Rudyk OV, et al. Influence of the intermittent hypoxia training on the sensitivity of phenylarsineoxide-induced mitochondrial permeability transition pore in rat heart. Fiziol Zh. 2005;51:3–12 [In Ukrainian].PubMedGoogle Scholar
  59. 59.
    Wang T, Liu YY, Yang N, et al. Relationship of oxidative DNA damage and expression of mitochondrial apoptotic proteins in rat striatum induced by 6-hydroxydopamine. Zhonghua Yi Xue Za Zhi. 2010;90:2074–7 [In Chinese].PubMedGoogle Scholar
  60. 60.
    Yuan G, Adhikary G, McCormick AA, et al. Role of oxidative stress in intermittent hypoxia-induced immediate early gene activation in PC12 cells. J Physiol. 2004;157:773–83.CrossRefGoogle Scholar
  61. 61.
    Zamzami N, Susin SA, Marchetti P, et al. Mitochondrial control of nuclear apoptosis. J Exp Med. 1996;183:1533–44.PubMedCrossRefGoogle Scholar
  62. 62.
    Zhu W-Z, Xie Y, Chen L, et al. Intermittent high altitude hypoxia inhibits opening of mitochondrial permeability transition pores against reperfusion injury. J Mol Cell Cardiol. 2006;40:96–106.PubMedCrossRefGoogle Scholar
  63. 63.
    Zorov DB, Filburn CR, Klotz LO, et al. Reactive oxygen species (ROS)-induced ROS release: a new phenomenon accompanying induction of the mitochondrial permeability transition in cardiac myocytes. J Exp Med. 2000;192:1001–14.PubMedCrossRefGoogle Scholar
  64. 64.
    Zorov DB, Juhaszova M, Yaniv Y, et al. Regulation and pharmacology of the mitochondrial permeability transition pore. Cardiovasc Res. 2009;83:213–25.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag London 2012

Authors and Affiliations

  • Galina Vavilova
    • 1
  • Tatyana Shimanskaya
    • 1
  • Nataliya Strutynska
    • 1
    Email author
  • Sergey Talanov
    • 1
  • Vadim Sagach
    • 1
  1. 1.Department of Blood Circulation, Bogomoletz Institute of PhysiologyNational Academy of Sciences of UkraineKievUkraine

Personalised recommendations