Abstract
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).
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
M.F. Beal, Does impairment of energy metabolism result in excitotoxic neuronal death in neurodegenerative illnesses? Ann. Neurol. 31:119–130 (1992).
T. Kadowaki and Y. Kitagawa, Hypoxic depression of mitochondrial mRNA levels in HeLa cell, Experimental Cell Res. 192:243–247 (1991).
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).
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).
D.C. Wallace, Diseases of the mitochondrial DNA, Annu. Rev. Biochem. 61:1175–1212 (1992).
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).
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).
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.
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).
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).
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).
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).
J. Davignon, R.E. Gregg, and C.F. Sing, Apolipoprotein E polymorphism and atherosclerosis, Atherosclerosis. 8:1–21 (1988).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1996 Springer Science+Business Media New York
About this chapter
Cite this chapter
Merril, C.R., Zullo, S., Ghanbari, H. (1996). Is there a Relationship between Conditions Associated with Chronic Hypoxia, the Mitochondria, and Neurodegenerative Diseases, Such as Alzheimer’s Disease?. In: Fiskum, G. (eds) Neurodegenerative Diseases. GWUMC Department of Biochemistry and Molecular Biology Annual Spring Symposia. Springer, Boston, MA. https://doi.org/10.1007/978-1-4899-0209-2_23
Download citation
DOI: https://doi.org/10.1007/978-1-4899-0209-2_23
Publisher Name: Springer, Boston, MA
Print ISBN: 978-1-4899-0211-5
Online ISBN: 978-1-4899-0209-2
eBook Packages: Springer Book Archive