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Mosaicism for a specific somatic mitochondrial DNA mutation in adult human brain

Nature Genetics volume 2, pages 318–323 (1992)Cite this article

Abstract

The levels of a specific mitochondrial DNA deletion (mtDNA4977) measured in 12 brain regions of 6 normal adults 39 to 82 years old exhibited striking variation among anatomical locations. Comparisons of the same region among individuals showed an increase of mtDNA4977 with age. The three regions with the highest levels, caudate, putamen and substantia nigra, are characterized by a high dopamine metabolism. The breakdown of dopamine by mitochondrial MAO produces H2O2 which can lead to oxygen radical formation. We suggest that mtDNA4977 may be the “tip of the iceberg” of the spectrum of somatic mutations produced by oxidative damage.

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References

  1. Shoffner, J.M. & Wallace, D.C. Oxidative phosphorylation diseases. Disorders of two genomes. Adv. hum. Genet. 19, 267–330 (1990).

    Article  CAS  Google Scholar 

  2. Harding, A.E. Neurological disease and mitochondrial genes. Trends Neurosci. 14, 132–138 (1991).

    Article  CAS  Google Scholar 

  3. Moraes, C.T., Schon, E.A. & DiMauro, S. Mitochondrial Diseases: Toward a Rational Classification in Current Neurology Vol 11 (ed. Appel, S. H.) 83–120 (Mosby-Year Book, St. Louis, 1991).

    Google Scholar 

  4. Ballinger, S.W. et al. Maternally transmitted diabetes and deafness associated with a 10.4 kb mitochondrial DNA deletion. Nature Genet. 1, 11–15 (1992).

    Article  CAS  Google Scholar 

  5. Holt, I.J., Harding, A.E. & Morgan-Hughes, J.A. Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies. Nature 331, 717–719 (1988).

    Article  CAS  Google Scholar 

  6. Schon, E.A. et al. A direct repeat is a hotspot for large-scale deletion of human mitochondrial DNA. Science 244, 346–349 (1989).

    Article  CAS  Google Scholar 

  7. Shoffner, J.M. et al. Spontaneous Kearns-Sayre/chronic external opthalmoplegia plus syndrome associated with a mitochondrial deletion: a slip-replication model and metabolic therapy. Proc. natn. Acad. Sci. U.S.A. 86, 7952–7956 (1989).

    Article  CAS  Google Scholar 

  8. Cortopassi, G.A. & Arnheim, N. Detection of a specific mitochondrial DNA deletion in tissues of older individuals. Nucl. Acids Res. 18, 6927–6933 (1990).

    Article  CAS  Google Scholar 

  9. Corral-Debrinski, M. et al. Hypoxemia is associated with mitochondrial DNA damage and gene induction. Implications for cardiac disease. JAMA 266, 1812–1816 (1991).

    Article  CAS  Google Scholar 

  10. Ozawa, T. et al. Multiple mitochondrial DNA deletions exist in cardiomyocytes of patients with hypertrophic or dilated cardiomyopathy. Biochem. Biophys. Res. Commun. 170, 830–836 (1990).

    Article  CAS  Google Scholar 

  11. Hattori, K. et al. Age dependent increase in deleted mitochondrial DNA in the human heart: Possible contributory factor to presbycardia. Am. Heart J. 121, 1735–1742 (1991).

    Article  CAS  Google Scholar 

  12. Cortopassi, G.A., Pasinetti, G. & Arnheim, N. Mosaicism for levels of a somatic mutation of mitochondrial DNA in different brain regions and its implication for neurological disease. In Progress in Parkinson's Disease Research II (eds Hefti, F. & Weiner, W.J.) (Futura Publishing, Mount Kisco, New York, 1992).

    Google Scholar 

  13. Cortopassi, G.A., Shibata, D., Soong, N.-W. & Arnheim, N. A pattern of accumulation of a somatic deletion of mitochondrial DNA in aging human tissues. Proc. natn. Acad. Sci. U.S.A. 89, 7370–7374 (1992).

    Article  CAS  Google Scholar 

  14. Ikebe, S.-i. et al. Increase of deleted mitochondrial DNA in the striatum in Parkinson's disease and senescence. Biochem. Biophys. Res. Commun. 170, 1044–1048 (1990).

    Article  CAS  Google Scholar 

  15. Chelly, J., Kaplan, J.C., Maire, P., Gautron, S. & Kahn, A. Transcription of the Dystrophin Gene in Human Muscle and Non-Muscle Tissues. Nature 333, 858–860 (1988).

    Article  CAS  Google Scholar 

  16. Lubin, M., Elashoff, J.D., Wang, S.-J., Rotter, J. & Toyoda, H. Precise Gene Dosage Determination by Polymerase Chain Reaction: Theory, Methodology and Statistical Approach. Molec. cell. Probes 5, 307–317 (1991).

    Article  CAS  Google Scholar 

  17. Sokal, R.R. & Rohlf, F.J. Biometry 2nd edn (Freeman, New York, 1981).

    Google Scholar 

  18. Gross, N.J., Getz, G.S. & Rabinowitz, M. Apparent turnover of mtDNA and mitochondrial phospholipids in the tissues of the rat. J. biol. Chem. 244, 1552–1562 (1969).

    CAS  PubMed  Google Scholar 

  19. Menzies, R.A. & Gold, P.H. The turnover of mitochondria in a variety of tissues of young adult and aged rats. J. biol. Chem. 246, 2425–2429 (1971).

    CAS  PubMed  Google Scholar 

  20. Harman, D. The biological clock: the mitochondria? J. Amer. Ger. Soc. 20, 145–147 (1972).

    Article  CAS  Google Scholar 

  21. Harman, D. The aging process. Proc. natn. Acad. Sci. U.S.A. 78, 7124–7128 (1981).

    Article  CAS  Google Scholar 

  22. Miquel, J., Economos, A.C., Fleming, J. & Johnson, J.E., Jr. Mitochondrial role in cell aging. Exp. Gerontol. 15, 575–591 (1982).

    Article  Google Scholar 

  23. Richter, C., Park, J.-W. & Ames, B.N. Normal oxidative damage to mitochondrial and nuclear DNA is extensive. Proc. natn. Acad. Sci. U.S.A. 85, 6465–6467 (1988).

    Article  CAS  Google Scholar 

  24. Bandy, B. & Davison, A.J. Mitochondrial mutations may increase oxidative stress: implications for carcinogenesis and aging? Free Rad. Biol. Med. 8, 523–539 (1990).

    Article  CAS  Google Scholar 

  25. Wallace, D.C. Mitochondrial genetics: a paradigm for aging and degenerative diseases? Science 256, 628–632 (1992).

    Article  CAS  Google Scholar 

  26. Gupta, K.P., van Golen, K.L., Randerath, E. & Randerath, K. Age-dependent covalent DNA alterations (I-compounds) in rat liver mitochondrial DNA. Mut. Res. 237, 17–27 (1990).

    Article  CAS  Google Scholar 

  27. Harding, A.E. & Morgan-Hughes, J.A. Deletions of muscle mitochondrial DNA in mitochondrial myopathies: sequence analysis and possible mechanisms. Nucl. Acids Res. 17, 4465–4469 (1989).

    Article  Google Scholar 

  28. Mita, S. et al. Recombination via flanking direct repeats is a major cause of large scale deletions of human mitochondrial DNA. Nucl. Acids Res. 18, 561–567 (1990).

    Article  CAS  Google Scholar 

  29. Johns, D.R., Rutledge, S.L., Stine, O.C. & Hurko, O. Directly repeated sequences associated with pathogenic mitochondrial DNA deletions. Proc. natn. Acad. Sci U.S.A. 86, 8059–8062 (1989).

    Article  CAS  Google Scholar 

  30. Phelps, M.E., Mazziotta, J.C. & Huang, S.C. Study of cerebral function with positron computed tomography. J. Cereb. Blood Flow Met. 2, 113–162 (1982).

    Article  CAS  Google Scholar 

  31. Gerfen, C.R. The neostriatal mosaic: multiple levels of compartmental organization in the basal ganglia. Ann. Rev. Neurosci. 15, 285–320 (1992).

    Article  CAS  Google Scholar 

  32. Bjorklund, A. & Lindvall, O. Dopamine containing systems in the CNS. In Handbook of Chemical Neuroanatomy Vol 2i (eds Bjorklund, A. & Hokfelt, T.) 55–122 (Elsevier, 1984).

    Google Scholar 

  33. Westlund, K.N., Denney, R.M., Rose, R.M. & Abell, C.W. Distinct monoamine oxidase A and B populations in primate brain. Neuroscience 25, 439–456 (1988).

    Article  CAS  Google Scholar 

  34. Goldstein, M. & Lieberman, A. The role of the regulatory enzymes of catecholamine synthesis in Parkinson's disease. Neurology 42, 8–12 (1992).

    CAS  PubMed  Google Scholar 

  35. Riederer, P. et al. Distribution of iron in different brain regions and subcellular compartments in Parkinson's disease. Ann. Neuro. 32, S101–S104 (1992).

    Article  CAS  Google Scholar 

  36. Bulpitt, K.J. & Piko, L. Variation in the frequency of complex forms of mitochondrial DNA in different brain regions of senescent mice. Brain Research 300, 41–48 (1984).

    Article  CAS  Google Scholar 

  37. Linnane, A.W., Marzuki, S., Ozawa, T. & Tanaka, M. Hypothesis: Mitochondrial DNA mutation as an important contributor to aging and degenerative diseases. Lancet, i, 642–645 (1989).

    Article  Google Scholar 

  38. Muller-Hocker Mitochondria and Aging. J. Brain Pathology 2, 149–158 (1992).

    Article  CAS  Google Scholar 

  39. Trounce, I., Byrne, E. & Marzuki, S. Decline in skeletal muscle mitochondrial respiratory chain function: possible factor in aging. Lancet i, 637–639 (1989).

    Article  Google Scholar 

  40. De Keyser, J., Ebinger, G. & Vauquelin, G. Age related changes in the human nigrostriatal dopaminergic system. Ann. Neurol. 27, 157–161 (1990).

    Article  CAS  Google Scholar 

  41. Terry, R.D., DeTeresa, R. & Hansen, L.A. Neocortical cell counts in normal human adult aging. Ann. Neurol. 21, 530–539 (1987).

    Article  CAS  Google Scholar 

  42. Coleman, P.D. & Flood, D.G. Neuron numbers and dendritic extent in normal aging and Alzheimer's disease. Neurobiol. Aging 8, 521–545 (1987).

    Article  CAS  Google Scholar 

  43. Przedborski, S. et al. Transgenic mice with increased Cu/Zn-superoxide dismutase activity are resistant to N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity. J. Neurosci. 12, 1658–1667 (1992).

    Article  CAS  Google Scholar 

  44. Jenner, P. What process causes nigral cell death in Parkinson's disease? Neurol. Clin. 19, 387–403 (1992).

    Article  Google Scholar 

  45. Anderson, S. et al. Sequence and organization of the human mitochondrial genome. Nature 290, 457–465 (1981).

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Molecular Biology Section, University of Southern California, Los Angeles, California, 90089-1340, USA

    Nay Wei Soong & Norman Arnheim

  2. Department of Pathology, USC School of Medicine, Los Angeles, California, 90033, USA

    David R. Hinton

  3. Institute for Toxicology, University of Southern California, 1985 Zonal Ave, Los Angeles, California, 90033, USA

    Gino Cortopassi

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  1. Nay Wei Soong
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  2. David R. Hinton
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  3. Gino Cortopassi
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  4. Norman Arnheim
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Wei Soong, N., Hinton, D., Cortopassi, G. et al. Mosaicism for a specific somatic mitochondrial DNA mutation in adult human brain. Nat Genet 2, 318–323 (1992). https://doi.org/10.1038/ng1292-318

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