, Volume 48, Issue 2, pp 97–106 | Cite as

Structural/Functional Modifications in the Mitochondria of Brainstem Cells in Rat Offspring Subjected to Prenatal Hypoxia

  • E. V. Rozova
  • V. I. Pokhylko
  • N. G. Sydoryak
  • M. G. Dubovaya

We examined changes in the morphofunctional state of the mitochondria (MCh) and immunohistochemical peculiarities of brainstem neurons in rat offspring exposed to experimental prenatal (intrauterine) hypoxia of different severity, moderate and strong. This was provided by exposure of pregnant females to O2/N2 respiratory mixtures containing 12 and 7% O2, respectively. Experimental groups included 20 one-month-old rats (offspring of 9 females, control and subjected to hypoxia). We estimated the ultrastructural characteristics of the MCh and also expression of the CD95 APO-1/Fas and Bcl-2 genes modulating the intensity of apoptosis and mitoptosis in these cells. Severe intrauterine hypoxia resulted in the development of structural distress in the MCh of brainstem cells; all stages of MCh degradation, from swelling to complete dissipation, were observed. Juvenile forms of these organelles were absent. Mosaic-like destruction of myelin with manifestations of edema was observed. After the moderate prenatal hypoxia, about half of the changes in the MCh ultrastructure could be qualified as directed toward an increase in the compensatory capabilities of the MCh apparatus. In rats after moderate hypoxic influence, levels of expression of the CD95 APO-1/Fas and Bcl-2 genes were indicative of a greater readiness of the neurons to apoptosis and decrease in the probability to inhibition of the respective MCh pathway in brainstem neurocites. At the same time, the MCh and neurocites of animals subjected to severe intrauterine hypoxia demonstrated decreased trends toward mitoptosis and apoptosis, respectively. The obtained results characterizing the effects of intrauterine hypoxia of different levels on the formation of structural/functional changes in the MCh of brainstem cells can be taken into account in the process of development of novel approaches to the treatment of MCh diseases.


rat offspring brainstem cells prenatal (intrauterine) hypoxia mitochondria (MCh) genes CD95 APO-1/Fas and Bcl-2 electron microscopy immunohistochemistry 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    E. L. Germanova, Disorders of Energy Metabolism in Hypoxia and their Correction using a Succinate-Containing Compound, Proxinin, Thesis Cand. Biol. Sci., Moscow (2008).Google Scholar
  2. 2.
    L. D. Luk’yanova, “Modern problems of adaptation to hypoxia. Signal mechanisms and their role in systemic regulation,” Patol. Fiziol. Eksp. Terap., No. 1, 3-19 (2011).Google Scholar
  3. 3.
    T. K. Znamens’ka, V. I. Pokhil’ko, O. M. Kovalyova, et al., “Changes in neurocytes of the brainstem in rats under conditions of an experimental model of hypoxia and at neuroprotective cortrection,” Likar. Sprava, No. 3/4, 75-84 (2009).Google Scholar
  4. 4.
    Yu. I. Barnashev, Perinatal Neurology, Triada-X, Moscow (2001).Google Scholar
  5. 5.
    D. A. Rossignol and J. J. Bradstreet, “Evidence of mitochondrial dysfunction in autism and implications for treatment,” Am. Biochem. Biotechnol., 4, No. 2, 208-217 (2008).CrossRefGoogle Scholar
  6. 6.
    6. L. Palmieri and A. M. Persico, “Mitochondrial dysfunction in autism spectrum disorders: cause or effect?” Biochim. Biophys. Acta, 1797, Nos. 6/7, 1130-1137 (2010).CrossRefPubMedGoogle Scholar
  7. 7.
    M. Dhar-Mascareno and J. M. Castramo, “Hypoxia–reoxygenation-induced mitochondrial damage and apoptosis in human endothelial cells,” Free Radical Biol. Med., 38, No. 10, 1548-1554 (2005).CrossRefGoogle Scholar
  8. 8.
    A. A. Selin, N. V. Lobysheva, O. N. Vorontsova, et al., “Mechanisms of effect of glycine as a protector in disorders of the energetics in brain tissues under conditions of hypoxia,” Byul. Eksperim. Biol. Med., 153, No. 1, 52-55 (2012).Google Scholar
  9. 9.
    Yu. A. Vladimirov, “Biological membranes and nonprogrammed cell death,” Soros. Obrazovat. Zh., 6, No. 9, 2-9 (2000).Google Scholar
  10. 10.
    10. Yu. V. Sudakova, L. Ye. Bakeyeva, and V. G. Tsyplenkova, “Energy-dependent ultrastructural changes in the mitochondria of human cardiomyocytes in alcohol lesion of the heart,” Arkh. Patol., 61, No. 2, 15-20 (1999).Google Scholar
  11. 11.
    N. P. Chesnokova, Ye. V. Ponukalina, and M. N. Bizenkova, “Molecular/cellular mechanisms of cytotoxic effects of hypoxia. Pathogenesis of hypoxic necrobiosis,” Sovrem. Naukoyemk. Tekhnol., No. 7, 32-40 (2006).Google Scholar
  12. 12.
    T. K. Znamens’ka, V. I. Pokhil’ko, O. M. Kovalyova, et al., “Morphofunctional changes in the mitochondria of brainstem neurocytes of rats under conditions of an experimental model of hypoxia and their correction by cerebrocourin and lipin,” Perinatol. Pediatr., 28, No. 4, 83-86 (2006).Google Scholar
  13. 13.
    K. M. Reznikov, “General mechanisms of the formation of the responses of an organism to the action of environmental factors,” in Applied Informational Aspects of Medicine, Vol. 1, B. I. Voronezh (1998), pp. 4-9.Google Scholar
  14. 14.
    14. Yu. V. Sudakova,.Ye. Bakeyeva, and V. G. Tsyplenkova, “Destructive changes of mitochondria in human cardiomyocytes in alcohol lesion of the heart,” Arkh. Patol., 61, No. 9, 19-23 (1999).Google Scholar
  15. 15.
    M. Karbowski and R. J. Youle, “Dynamics of mitochondrial morphology in healthy cells and during apoptosis,” Cell Death Differ., 10, No. 10, 870-880 (2003).CrossRefPubMedGoogle Scholar
  16. 16.
    R. Almini, T. J. Levy, B. H. Han, et al, “BDNF protects against spatial memory deficit following neonatal hypoxia-ischemia,” Exp. Neurol., 166, No. 1, 99-114 (2000).CrossRefGoogle Scholar
  17. 17.
    I. Z. Pinigina, Structural Characteristics of the Brainstem Nuclei of Albino Rats within Postnatal Ontogenesis in the Norm and after Intrauterine Hypoxia, Thesis Cand. Med. Sci., Tyumen’ (2009). 18. A. D. Nozdrachev, Anatomy of the Rat, Lan’, St. Petersburg (2001).Google Scholar
  18. 18.
    A. D. Nozdrachev, Anatomy of the Rat, Lan’, St. Petersburg (2001).Google Scholar
  19. 19.
    B. I. Pokhil’ko and K. V. Rozova, “Morphological changes in the mitochondrial membranes of neurocytes in rat offspring under conditions of an experimental model of hypoxia,” Visn. Ukr. Med. Stomat. Akad., 9, No. 2, 109-112 (2009).Google Scholar
  20. 20.
    Secondary Tissue Hypoxia, A. Z. Kolchinskaya (ed.), Naukova Dumka, Kyiv (1983).Google Scholar
  21. 21.
    V. Ya. Karupu, Electron Microscopy, Vyshcha Shkola, Kyiv (1984).Google Scholar
  22. 22.
    K. Tashke, Introduction to Quantitative Cyto-Histological Morphology, Publ. House of Acad. Soc. Rep. Romania, Bucharest (1980).Google Scholar
  23. 23.
    Ye. R. Polosukhina, A. Yu. Baryshnikova, and Yu. V. Shishkin, “Examination of expression of the apoptosis-mediating gene Fas(APO-1/CD95) using monoclonal antibodies,” Gematol. Transfuziol., No. 4, 3-6 (2000).Google Scholar
  24. 24.
    E. Kondo, S. Nakamura, C. Milliman, et al., “Detection of bcl-2 protein and bcl-2 messenger RNA in normal and neoplastic lymphoid tissues by immunohistochemistry and in situ hybridization,” Blood, 80, No. 8, 2044-2051 (1992).PubMedGoogle Scholar
  25. 25.
    G. Siciliano, L. Volpi, S. Piazza et al., “Functional diagnostics in mitochondrial diseases,” Biosci. Rep., 27, Nos. 1/3, 53-67 (2007).CrossRefPubMedGoogle Scholar
  26. 26.
    I. F. Belenichev, V. I. Cherniy, Yu. M. Kolesnik, et al., Rational Neuroprotection, Publ. House of A. Yu. Zaslavskii, Donetsk (2009).Google Scholar
  27. 27.
    Yu. E. Vel’tishchev, Locus and Importance of Disorders of the Organism’s Bioenergetics in Pathology in Childhood. Clinical and Pathogenetic Problems of Disorders of Cellular Bioenergetics (Mitochondrial Pathology), Meditsina, Moscow (1999).Google Scholar
  28. 28.
    V. N. Zalesskii and N. V. Velikaya, “Mechanisms of cytotoxic effects of active oxygen molecules and the development of apoptosis,” Sovrem. Probl. Toksikol., No. 1, 11-17 (2003).Google Scholar
  29. 29.
    V. N. Manskikh, “Morphological techniques of verification and quantitative estimation of apoptosis,” Byul. Sibirsk. Med., No. 1, 63-70 (2004).Google Scholar
  30. 30.
    Ye. V. Rozova, “Changes in the morphofunctional state of the mitochondria in cells of pulmonary and heart tissues of rats in hypoxia of different genesis,” Zh. Akad. Med. Nauk Ukr., 14, No. 4, 752-765 (2008).Google Scholar
  31. 31.
    V. Yu. Polyakov, M. Yu. Sukhomlinova, and D. Fais, “How the mitochondria fuse with each other, fragment, and divide,” Biokhimya, 68, No. 8, 1026-1039 (2003).Google Scholar
  32. 32.
    V. P. Skulachev, L. E. Bakeeva, B. V. Cherniyak, et al., “Thread-grain transition of mitochondrial reticulum as a step of mitoptosis and apoptosis,” Mol. Cell Biochem., 256-257, Nos. 1/2, 341-358 (2004).CrossRefPubMedGoogle Scholar
  33. 33.
    Ye. V. Vladimirskaya, “Mechanisms of cell apoptotic death,” Gematol. Transfuziol., 47, No. 2, 35-40 (2002).Google Scholar
  34. 34.
    M. Muschen, U. Warskulat and M. W. Beckmann, “Defining CD95 as a tumor suppressor gene,” J. Mol. Med., 78, No. 6, 312-325 (2000).CrossRefPubMedGoogle Scholar
  35. 35.
    S. V. Ryzhov and V. V. Novikov, “Molecular mechanisms of the apoptotic processes,” Ros. Bioter. Zh., 1, No. 3, 5-11 (2002).Google Scholar
  36. 36.
    R. C. Budd, “Death receptors couple to both cell proliferation and apoptosis,” J. Clin. Invest., 109, No. 4, 437-442 (2002).CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    T. S. Zaporozhets, K. V. Maystrovskii, V. G. Rapovka, et al., “Role of T-cell dysfunction in the development of atherosclerosis in lower-limb vessels and possibilities for its correction,” Tikhookean. Med. Zh., No. 3, 100-105 (2009).Google Scholar
  38. 38.
    H. Walczak and P. H. Krammer, “The CD95 (APO-1/Fas) and the TRAIL (APO-2L) apoptosis system,” Exp. Cell Res., 256, No. 1, 58-66 (2000).CrossRefPubMedGoogle Scholar
  39. 39.
    A. V. Akleyev, L. Yu. Krestinina, T. A. Varfolomeyeva, et al., “Adaptive capabilities of blood lymphocytes in inhabitants of the Southern Urals subjected to chronic irradiation,” Radiats. Biol. Radioekol., 44, No. 4, 426-431 (2004).Google Scholar
  40. 40.
    I. A. Bondarchuk, “Analysis of the role of DNA reparation, regulation of the cellular cycle, and apoptosis in the radiation-induced adaptive response of mammalian cells,” Radiats. Biol. Radioekol., 43, No. 1, 19-28 (2003).Google Scholar
  41. 41.
    G. D. Zasukhina, “Mechanisms of defense of human cells related to the genetic polymorphism,” Radiats. Biol. Radioekol., 45, No. 4, 520-535 (2005).Google Scholar
  42. 42.
    A. A. Yarilin, “Apoptosis: Nature of the phenomenon and its role in the norm and pathology,” in Urgent Problems of Pathophysiology, B. B. Moroz ed., Meditsina, Moscow (2001), pp. 13-56.Google Scholar
  43. 43.
    S. Parikh, R. Saneto, M. J. Faulk et al., “A modern approach to the treatment of mitochondrial disease,” Curr. Treat. Options Neurol., 11, No. 6, 414-430 (2009).CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • E. V. Rozova
    • 1
  • V. I. Pokhylko
    • 2
  • N. G. Sydoryak
    • 3
  • M. G. Dubovaya
    • 1
  1. 1.Bogomolets Institute of Physiolgoy of the NAS of UkraineKyivUkraine
  2. 2.Ukrainian Medical Stomatological Academy, Ministry of Public Health of UkrainePoltavaUkraine
  3. 3.Interdepartmental Research Laboratory of Medical/Biological Monitoring of the Bogdan Khmel’nitskii Melitopol’ State Pedagogical University and Tavrida State Agrotechnical AcademyMelitopol’Ukraine

Personalised recommendations