Effect of Moderate Hypoxia/Reoxygenation on Mitochondrial Adaptation to Acute Severe Hypoxia


In an experimental model, it was shown that repetitive periods of hypoxia/reoxygenation (H/R) [5 cycles of 5 min hypoxia (12% O2 in N2) followed by 15 min normoxia, daily for three weeks] attenuated basal and stimulated in vitro lipid peroxidation, as well as H2O2 production in liver and brain mitochondria of rats exposed to acute severe hypoxia. Adaptation to moderate H/R enhanced in mitochondria the production and activity of reactive oxygen species scavengers, such as glutathione, manganese superoxide dismutase, glutathione peroxidase, and glutathione-S-transferase. It was demonstrated that the maintenance of GSH-redox cycle by activation of glutathione reductase and NADP+-dependent isocitrate dehydrogenase is an integral part of the biochemical adaptive mechanism of oxidative tolerance to new damaging factor. Brain mitochondria showed more sensitivity to oxidative stress than liver mitochondria, and long-lasting sessions of H/R affect differentially their pro-/antioxidant homeostasis.


  1. 1.

    Anderson, M. (1985) Determination of glutathione and glutathione disulfide in biological samples. Methods Enzymol. 113, 548–551.

    CAS  Article  Google Scholar 

  2. 2.

    Arkhipenko, Yu., Sazontova, T. G. (1995) Mechanisms of the cardioprotective effect of a diet enriched n-3 polyunsaturated fatty acids. Pathophysiology 2, 131–140.

    CAS  Article  Google Scholar 

  3. 3.

    Arrigo, A. P. (1999) Gene expression and the thiol redox state. Free Radic. Biol. Med. 27, 936–944.

    CAS  Article  Google Scholar 

  4. 4.

    Barja, G., Lopez Torres, M., Perez Campo, R., Rojas, C., Cadenas, S., Prat, J., Pamplona, R. (1994) Dietary vitamin C decreases endogenous protein oxidative damage, malondialdehyde, and lipid peroxidation and maintains fatty acid unsaturation in the guinea pig liver. Free Radic. Biol. Med. 17, 105–115.

    CAS  Article  Google Scholar 

  5. 5.

    Basford, R. E. (1967) Preparation and properties of brain mitochondria. Methods Enzymol. 10, 96–100.

    CAS  Article  Google Scholar 

  6. 6.

    Bell, E., Emerling, B., Chandel, N. (2005) Mitochondrial regulation of oxygen sensing. Mitochondrion 5, 322–332.

    CAS  Article  Google Scholar 

  7. 7.

    Buege, J., Aust, S. (1978) Microsomal lipid peroxidation. Methods Enzymol. LII, 302–308.

    Article  Google Scholar 

  8. 8.

    Carlberg, I., Mannervik, B. (1985) Glutathione Reductase. Methods Enzymol. 113, 484–490.

    CAS  Article  Google Scholar 

  9. 9.

    Chandel, N., Budinger, S. (2007) The cellular basis for diverse responses to oxygen. Free Radic. Biol. Med. 42, 165–174.

    CAS  Article  Google Scholar 

  10. 10.

    Clanton, T. L., Klawitter, P. (2001) Physiological and genomic consequences of intermittent hypoxia. Invited review: Adaptive responses of skeletal muscle to intermittent hypoxia: the known and the unknown. J. Appl. Physiol. 90, 2476–2487.

    CAS  Article  Google Scholar 

  11. 11.

    Dickinson, D. A., Forman, H. J. (2002) Cellular glutathione and thiols metabolism. Biochem. Pharmacol. 4, 1019–1026.

    Article  Google Scholar 

  12. 12.

    Faraci, F., Didion, S. (2004) Vascular protection: superoxide dismutase isoforms in the vessel wall. Arterioscler. Thromb. Vasc. Biol. 24, 1367–1373.

    CAS  Article  Google Scholar 

  13. 13.

    Gonchar, O. (2005) Muscle fiber specific antioxidative system adaptation to swim training in rats: influence of intermittent hypoxia. J. Sport Sci. Med. 4, 160–169.

    Google Scholar 

  14. 14.

    Gonchar, O., Rozova, K. (2007) Effects of different modes of interval hypoxic training on morphological characteristics and antioxidant status of heart and lung tissues. Bull. Exp. Biol. Med. 144, 249–252.

    CAS  Article  Google Scholar 

  15. 15.

    Halliwell, B., Gutteridge, J. M. C. (1999) Free Radicals in Biology and Medicine. Oxford University Press, Oxford.

    Google Scholar 

  16. 16.

    Huwiler, M., Kohler, H. (1984) Pseudo-catalytic degradation of hydrogen peroxide in the lactoperoxidase/ H2O2/iodide system. Eur. J. Biochem. 141, 69–74.

    CAS  Article  Google Scholar 

  17. 17.

    Jezek, P., Hlavata, L. (2005) Mitochondria in homeostasis of reactive oxygen species in cell, tissues, and organism. Int. J. Biochem. & Cell Biol. 37, 2478–2503.

    CAS  Article  Google Scholar 

  18. 18.

    Jo, S., Son, M., Koh, H., Lee, S., Song, I., Kim, Y., Lee, Y., Jeong, K., Kim, W., Park, J., Song, B., Huhe, T. (2001) Control of mitochondrial redox balance and cellular defense against oxidative damage by mitochondrial NADP+-dependent isocitrate dehydrogenase. J. Biol. Chem. 276, 16168–16176.

    CAS  Article  Google Scholar 

  19. 19.

    Jonson, D., Lardy, H. (1967) Isolation of liver and kidney mitochondria. Methods Enzymol. 10, 94–96.

    Article  Google Scholar 

  20. 20.

    Li, C., Jackson, R. M. (2002) Reactive species mechanisms of cellular hypoxia-reoxygenation injury. Am. J. Physiol. 282 (Cell Physiol.), C227–C241.

    CAS  Article  Google Scholar 

  21. 21.

    Lin, A., Chen, C. F., Ho, L. T. (2002) Neuroprotective effect of intermittent hypoxia on iron-induced injury in rat brain. Exp. Neurology 178, 328–335.

    Article  Google Scholar 

  22. 22.

    Lukyanova, L. D. (2005) Novel approach to the understanding of molecular mechanisms of adaptation to hypoxia. In: Hargens, A., Takeda, N., Singal, P. (eds) Adaptation Biology and Medicine. Current Concepts, New Delhi: Narosa, pp. 1–19.

    Google Scholar 

  23. 23.

    Maiti Panchanan, Shashi B. Singh, Alpesh K. Sharma, Muthuraju, S., Pratul, K., Banerjee, Ilavazhagan, G. (2006) Hypobaric hypoxia induces oxidative stress in rat brain. Neurochem. Int. 49, 709–716.

    Article  Google Scholar 

  24. 24.

    Misra, H., Fridovich, I. (1972) The role of superoxide anion in the autoxidation of epinephrine and a simple assay superoxide dismutase. J. Biol. Chem. 247, 3170–3175.

    CAS  Google Scholar 

  25. 25.

    Putilina, F. (1982) The NADP+-dependent isocitrate dehydrogenase activity determination. Methods Biochem. 1, 174–176.

    Google Scholar 

  26. 26.

    Rotruck, J. T., Pope, A. L., Ganther, H. E., Swanson, A. B. (1973) Selenium: biochemical role as a component of glutathione peroxidase. Science 179, 588–590.

    CAS  Article  Google Scholar 

  27. 27.

    Warholm, M., Guthenberg, C., Bahr, C., Mannervik, B. (1985) Glutathione transferases from human liver. Methods Enzymol. 113, 499–501.

    CAS  Article  Google Scholar 

  28. 28.

    Waypa, G. B., Schumacker, P. T. (2005) Hypoxic pulmonary vasoconstriction: redox events in oxygen sensing. J. Appl. Physiol. 98, 404–414.

    CAS  Article  Google Scholar 

  29. 29.

    Zhu, W.-Z., Xie, Y., Chen, L., Yang, H.-T., Zhou, Z.-N. (2006) Intermittent high altitude hypoxia inhibits opening of mitochondrial permeability transition pores against reperfusion injury. J. Mol. Cell Cardiol. 40, 96–106.

    CAS  Article  Google Scholar 

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Correspondence to Olga Gonchar.

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Gonchar, O., Mankovskaya, I. Effect of Moderate Hypoxia/Reoxygenation on Mitochondrial Adaptation to Acute Severe Hypoxia. BIOLOGIA FUTURA 60, 185–194 (2009). https://doi.org/10.1556/ABiol.60.2009.2.6

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  • Hypoxia/reoxygenation
  • mitochondria
  • oxidative stress
  • antioxidative defense
  • adaptation