Is there a Relationship between Conditions Associated with Chronic Hypoxia, the Mitochondria, and Neurodegenerative Diseases, Such as Alzheimer’s Disease?

  • Carl. R. Merril
  • Steve Zullo
  • Hossein Ghanbari
Part of the GWUMC Department of Biochemistry and Molecular Biology Annual Spring Symposia book series (GWUN)


The central nervous system (CNS) is extremely sensitive to hypoxia, as neuronal cells require a high rate of energy metabolism to maintain transmembrane potentials. As these cells normally rely on aerobic mitochondrial metabolism to generate the required energy, a lack of oxygen results in a shift toward the anaerobic utilization of glucose. Such a metabolic shift may result in a cascade of potentially deleterious events beginning with an increased production of lactic acid and a decreased rate of ATP production.1 Increased lactic acid concentrations may cause a decrease in cellular pH, followed by the release of iron and the reaction of ferrous ions with hydrogen peroxide to produce hydroxyl radicals. A decrease in ATP may adversely affect DNA replication, transcription,2 and mRNA translation. In addition, the levels of inter-cellular calcium will increase as the ATP dependent calcium ion pump mechanism fails. Increased calcium levels can activate: endonucleases, nitric oxide synthetase, phospholipases and proteases. All of the above alterations in cellular metabolism may result in damage to the cellular DNA, particularly the mitochondrial DNA (Figure 1).


Chronic Hypoxia Lactic Acid Concentration Parkinson Disease Patient Nitric Oxide Synthetase Increase Calcium Level 
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  1. 1.
    M.F. Beal, Does impairment of energy metabolism result in excitotoxic neuronal death in neurodegenerative illnesses? Ann. Neurol. 31:119–130 (1992).PubMedCrossRefGoogle Scholar
  2. 2.
    T. Kadowaki and Y. Kitagawa, Hypoxic depression of mitochondrial mRNA levels in HeLa cell, Experimental Cell Res. 192:243–247 (1991).CrossRefGoogle Scholar
  3. 3.
    C. Richter, J.-W. Park, and B.N. Ames, Normal oxidative damage to mitochondrial and nuclear DNA is extensive, Proc. natn. Acad. Sci. U.S.A. 85:6465–6467 (1988).CrossRefGoogle Scholar
  4. 4.
    K.P. Gupta, K.L. van Golen, E. Randerath, and K. Randerath, Age-dependent covalent DNA alterations (I-compounds) in rat liver mitochondrial DNA, Mut. Res. 237:17–27 (1990).CrossRefGoogle Scholar
  5. 5.
    D.C. Wallace, Diseases of the mitochondrial DNA, Annu. Rev. Biochem. 61:1175–1212 (1992).PubMedCrossRefGoogle Scholar
  6. 6.
    M. Corral-Debrinski, G. Stepien, J.M. Shoffner, M.T. Lott, K. Kanter, and D.C. Wallace, Hypoxemia is associated with mitochondrial DNA damage and gene induction, JAMA 266:1812–1816 (1991).PubMedCrossRefGoogle Scholar
  7. 7.
    K. Hattori, M. Tanaka, S. Sugiyama, T. Obayashi, I. Takayki, T. Satake, H. Yoshihiro, J. Asai, M. Nagano, and T. Ozawa, Age-dependent increase in deleted mitochondrial DNA in the human heart: possible contributory factor to presbycardia. Am. heart J. 121:1735–1742 (1991).PubMedCrossRefGoogle Scholar
  8. 8.
    C.R. Merril, S. Zullo, H. Ghanbari, M.M. Herman, J.E. Kleinman, L.B. Bigelow, J.J. Bartko, and D.J. Sabourin, Possible relationship between hypoxia and brain mitochondrial DNA deletions, Manuscript submitted for publication.Google Scholar
  9. 9.
    D.L. Sparks, H. Liu, S.W. Scheff, C.M. Coyne, and J.C. Hunsaker, Temporal sequence of plaque formation in the cerebral cortex of non-demented individuals, J. Neuropath. Exp. Neurol. 52:135–142 (1993).PubMedCrossRefGoogle Scholar
  10. 10.
    M.K. Aronson, W.L. Ooi, H. Morgenstern, A. Hafner, D. Masur, H. Crystal, W.H. Frishman, D. Fisher, and R. Katzman, Women, myocardial infarction, and dementia in the very old, Neurol. 40:1102–1106 (1990).CrossRefGoogle Scholar
  11. 11.
    D.L. Sparks, S.W. Scheff, J.C. Hunsaker, III, H. Liu, T. Landers, and D.R. Gross, Induction of Alzheimer-like β-Amyloid immunoreactivity in the brains of rabbits with dietary cholesterol, Exp. Neurol. 126:88–94 (1994).PubMedCrossRefGoogle Scholar
  12. 12.
    W.J. Strittmatter, A.M. Saunders, D.E. Schmechel, M. Pericak-Vance, I. Enchild, G.S. Salvesen, and A.D. Roses, Apolipoprotein E: high-avidity binding to β-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer’s disease, Proc. natn. Acad. Sci. U.S.A. 90:1977–1981 (1993).CrossRefGoogle Scholar
  13. 13.
    J. Davignon, R.E. Gregg, and C.F. Sing, Apolipoprotein E polymorphism and atherosclerosis, Atherosclerosis. 8:1–21 (1988).Google Scholar
  14. 14.
    D.M. Hallman, E. Boerwinkle, N. Saha, C. Sandhozer, H.J. Menzel, A. Caazar, and G. Utermann, The apolipoprotein E polymorphism: A comparison of allele frequencies and effects in nine populations, Am. J. Hum. Genet. 49:338–349 (1991).PubMedGoogle Scholar
  15. 15.
    A.M. Cumming and F. Robertson, Polymorphism at the apoprotein-E locus in relation to risk of coronary disease, Clin. Genet. 25:310–318 (1984).PubMedCrossRefGoogle Scholar
  16. 16.
    T. Kuusi, M.S. Nieminen, C. Ehnholm, H. Yki-Järvinen, M. Valle, E.A. Nikkilä, and M.-R. Taskinen, Apoprotein E polymorphism and coronary artery disease: Increased prevalence of apolipoprotein E-4 in angiographically verified coronary patients, Atherosclerosis. 9:237–241 (1988).Google Scholar
  17. 17.
    G.D. Schellenberg, T.D. Bird, E.M. Wijsman, H.T. Orr, L. Anderson, E. Nemens, J.A. White, L. Bonnycastle, J.L. Weber, M.E. Alonso, H. Potter, L.L. Heston, and G.M. Martin, Genetic linkage evidence for a familial Alzheimer’s disease locus on chromosome 14, Science. 258:668–671 (1992).PubMedCrossRefGoogle Scholar
  18. 18.
    A. Goate, M.-C. Chartier-Harlin, M. Mullan, J. Brown, F. Crawford, L. Fidani, L. Giuffra, A. Haynes, N. Irving, L. James, R. Mant, P. Newton, K. Rooke, P. Roques, C. Talbot, M. Pericak-Vance, A. Roses, R. Williamson, M. Rossor, M. Owen, and J. Hardy, Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature. 349:704–706 (1991).PubMedCrossRefGoogle Scholar
  19. 19.
    F.-H. Lin, R. Lin, H.M. Wisniewski, Y.-W. Hwang, I. Grundke-Iqbal, G. Healy-Louie, and K. Iqbal, Detection of point mutations in codon 331 of mitochondrial NADH dehydrogenase subunit 2 in Alzheimer’s brains, Biochem. Biophys. Res. Comm. 182:238–246 (1992).PubMedCrossRefGoogle Scholar
  20. 20.
    V. Petruzzella, X. Chen, and E.A. Schon, Is a point mutation in the mitochondrial ND2 gene associated with Alzheimer’s disease? Biochem. Biophys. Res. Comm. 186:490–497 (1992).CrossRefGoogle Scholar
  21. 21.
    F.-H. Lin, and R. Lin, A comparison of single nucleotide primer extension with mispairing PCR-RFLP in detecting a point mutation, Biochem. Biophys. Res. Comm. 189:1202–1206 (1992).PubMedCrossRefGoogle Scholar
  22. 22.
    J.M. Shoffner, M.D. Brown, A. Torroni, M.T. Lott, M.F Cabell, S.S. Mirra, M.F. Beal, C.-C. Yang, M. Gearing, R. Salvo, R.L. Watts, J.L. Juncos, L.A. Hansen, B.J. Crain, M. Fayad, C.L. Reckord, and D.C. Wallace, Mitochondrial DNA variants observed in Alzheimer’s disease and Parkinson disease patients, Genomics. 17:171–184 (1993).PubMedCrossRefGoogle Scholar
  23. 23.
    M. Corral-Debrinski, T. Horton, M.T. Lott, J.M. Shoffner, A.C. McKee, M.F. Beal, B.H. Graham, and D.C. Wallace, Marked changes in mitochondrial DNA deletion levels in Alzheimer brains, Genomics. 23:471–476 (1994).PubMedCrossRefGoogle Scholar
  24. 24.
    N.-W. Soong, D.R. Hinton, G. Cortopassi, and N. Arnheim, Mosaicism for a specific somatic mitochondrial DNA mutation in adult human brain, Nature Genet. 2:318–323 (1992).PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1996

Authors and Affiliations

  • Carl. R. Merril
    • 1
  • Steve Zullo
    • 1
  • Hossein Ghanbari
    • 2
  1. 1.Laboratory of Biochemical GeneticsNIMH, NIH, NIMH Neuroscience Center at Saint ElizabethsUSA
  2. 2.Nymox Corp.Johnson CityUSA

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