Abstract
We have examined the role of somatic mitochondrial DNA (mtDNA) mutations in human ageing by quantitating the accumulation of the common 4977 nucleotide pair (np) deletion (mtDNA4977) in the cortex, putamen and cerebellum. A significant increase in the mtDNA4977 deletion was seen in elderly individuals. In the cortex, the deleted to total mtDNA ratio ranged from 0.00023 to 0.012 in 67–77 year old brains and up to 0.034 in subjects over 80. In the putamen, the deletion level ranged from 0.0016 to 0.010 in 67 to 77 years old up to 0.12 in individuals over the age of 80. The cerebellum remained relatively devoid of mtDNA deletions. Similar changes were observed with a different 7436 np deletion. These changes suggest that somatic mtDNA deletions might contribute to the neurological impairment often associated with ageing.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Linnane, A.W., Marzuki, S., Ozawa, T. & Tanaka, M. Mitochondrial DNA mutations as an important contributor to ageing and degenerative diseases. Lancet 3, 642–645 (1989).
Wallace, D.C. Mitochondrial genetics: A paradigm for ageing and degenerative diseases? Science 256, 628–632 (1992).
Wallace, D.C. Diseases of the mitochondrial DNA. Ann. Rev. Biochem. 61, 1175–1212 (1992).
Muller-Hocker, J. Cytochrome-c-oxidase deficient cardiomyocytes in the human heart. Am. J. Pathol. 134, 1167–1173 (1989).
Muller-Hocker, J. Cytochrome c oxidase deficient fibres in the limb muscle and diaphragm of man without muscular disease: An age-related alteration. J. neurol. Sci. 100, 14–21 (1990).
Trounce, I., Byrne, E. & Marzuki, S. Decline in skeletal muscle mitochondrial respiratory chain function: Possible factor in aging. Lancet 1, 637–639 (1989).
Yen, T.C., Chen, Y.S., King, K.L., Yeh, S.H. & Wei, Y.H. Liver mitochondrial respiratory functions decline with age. Biochem. Biophys. Res. Commun. 165, 994–1003 (1989).
Piko, L., Hougham, A.J. & Bulpitt, K.J. Studies of sequence heterogeneity of mitochondrial DNA from rat and mouse tissues: Evidence for an increased frequency of deletions/additions with aging. Mech. ageing Devl. 43, 279–293 (1988).
Katayama, M. et al. Deleted mitochondrial DNA in the skeletal muscle of aged individuals. Biochem. Int. 25, 47–56 (1991).
Yen, T.C., Su, J.H., King, K.L. & Wei, Y.H. Ageing-associated 5 kb deletion in human liver mitochondrial DNA. Biochem. Biophys. Res. Commun. 178, 124–131 (1991).
Zhang, C., Baumer, A., Maxwell, R.J., Linnane, A.W. & Nagley, P. Multiple mitochondrial DNA deletions in an elderly human individual. FEBS Lett. 297, 34–38 (1992).
Cortopassi, G.A. & Arnheim, N. Detection of a specific mitochondrial DNA deletion in tissues of older humans. Nucleic Acid Res. 18, 6927–6933 (1990).
Corral-Debrinski, M. et al. Hypoxemia is associated with mitochondrial DNA damage and gene induction: Implications for cardiac disease. JAMA 266, 1812–1816 (1991).
Corral-Debrinski, M., Shoffner, J.M., Lott, M.T. & Wallace, D.C. Association of mitochondrial DNA damage with ageing and coronary atherosclerotic disease. Mutat. Res. 275, 169–180 (1992).
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).
Miquel, J. & Fleming, J.E. in Free Radicals, Aging, and Degenerative diseases, (eds Johson, J. E. Jr. et al.) 51 (Alan R. LJss, New York, 1986).
Miquel, J. An integrated theory of ageing as the result of mitochondrial DNA mutation in differentiated cells. Arch. Gerontol. Geriatr. 12, 99–117 (1991).
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).
Fukunaga, M. & Yielding, K.L. Fate during cell growth of yeast mitochondria and nuclear DNA after photolytic attachment of the monoazide analog of ethidium. Biochem. Biophys. Res. Commun. 90, 582–586 (1979).
Bandy, B. & Davison, A.J. Mitochondrial mutations may increase oxidative stress: Implications for carcinogenesis and ageing? Mutat. Res. 8, 523–539 (1990).
McCord, J.M. Free radicals and myocardial ischemia : overview and outlook. Free Rad. Biol. Med. 4, 9–14 (1988).
Drayer, B.P., Burger, P. & Darwin, R. Magnetic resonance imaging of brain iron. Am. J. Neuroradiol. 7, 373–380 (1986).
Drayer, B.P. Imaging of the ageing brain Part I. Normal findings. Radiology 166, 785–796 (1988).
Goldstein, S. & Reivich, M. Cerebral blood flow and metabolism in ageing and dementia. Clin. Neuropharm. 14, S34–S44 (1991).
Chawluk, J.B., Alavi, A. & Jamieson, D.G. Changes in local cerebral glucose metabolism with normal ageing: the effect of cardiovascular and systemic health factors. J. Cereb. Blood Flow Metab. 7, S411 (1987).
Ditter, S.M. & Mirra, S.S. Neuropathological and clinical features of Parkinson's disease in Alzheimer's diseases patients. Neurology 37, 754–760 (1987).
Mirra, S.S. et al. The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part II. Standardization of the neuropathological assessment of Alzheimer's disease. Neurology 41, 479–486 (1991).
Wallace, D.C., Lott, M.T., Torroni, A. & Shoffner, J.M. Report of the committee on human mitochondrial DNA. Cytogenet. Cell Genet. 58, 1103–1123 (1991).
Shoffner, J.M. et al. Spontaneous Kearns-Sayre/chronic external ophthalmoplegia plus syndrome is associated with a mtDNA deletion: A slip-replication model and metabolic therapy. Proc. natn. Acad. Sci. U.S.A. 86, 7952–7956 (1989).
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).
McGeer, P.L., McGeer, E.G. & Suzuki, J.S. ageing and extrapyramidal function. Arch. Neurol. 34, 33–35 (1977).
Morris, J.C. & McManus, D.Q. The neurology of ageing: Normal versus pathological changes. Geriatrics 46, 47–54 (1991).
Ames, B.N. Endogenous DNA damage as related to cancer and aging. Mutat. Res. 214, 41–46 (1989).
Harman, D. in Free radical ageing and degenerative diseases. (eds Johson J.E., Jr. et al.) 3–49 (Alan R. Liss, New York, 1986).
Frackowiak, R.S.J., Wise, R.J.S., Gibbs, J.M. & Jones, T. Positron emission tomographic studies in ageing and cerebrovascular disease at Hammersmith Hospital. Ann. Neurol. 15, S112–S118 (1984).
Yamaguchi, T., Kanno, I. & Vermura, K. Reduction in regional cerebral metabolic rate of oxygen during human aging. Stroke 17i, 220–228 (1986).
Yoshii, F. et al. Sensitivity of cerebral glucose metabolism, to age, gender, brain volume, brain atrophy and cerebrovascular risk factors. J. Cereb. Blood Flow Met. 8, 654–661 (1988).
Parker, W.D. Cytochrome oxidase deficiency in Alzheimer's disease. Annal. N. Y. Acad. Sci. 640, 59–64 (1992).
Evans, D.A. et al. Prevalence of Alzheimer's disease in a community population of older persons. Higher than previously reported. JAMA 262, 2551–2556 (1989).
Sokal, R.R. & Rohlf, F.J. in Biometry: The principles and pratice of statistics in biological research (eds Ralph, E. et al.) 387–400 (Freeman, San Francisco, 1969).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Corral-Debrinski, M., Horton, T., Lott, M. et al. Mitochondrial DNA deletions in human brain: regional variability and increase with advanced age. Nat Genet 2, 324–329 (1992). https://doi.org/10.1038/ng1292-324
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/ng1292-324
This article is cited by
-
The mitochondrial DNA common deletion as a potential biomarker of cancer-associated fibroblasts from skin basal and squamous cell carcinomas
Scientific Reports (2024)
-
Cellular and Molecular Responses to Mitochondrial DNA Deletions in Kearns-Sayre Syndrome: Some Underlying Mechanisms
Molecular Neurobiology (2024)
-
Mitochondria: how eminent in ageing and neurodegenerative disorders?
Human Cell (2022)
-
Mitochondrial links between brain aging and Alzheimer’s disease
Translational Neurodegeneration (2021)
-
Age-related mitochondrial alterations in brain and skeletal muscle of the YAC128 model of Huntington disease
npj Aging and Mechanisms of Disease (2021)