Cited by 366Mitochondrial Function and PathologyGenetics, Aging, and Longevity in Model OrganismsAlzheimer's disease research and treatments

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High aggregate burden of somatic mtDNA point mutations in aging and Alzheimer's disease brain

Lin, M. T.·2002·Human Molecular Genetics

DOI 10.1093/hmg/11.2.133

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Abstract

The mitochondrial theory of aging proposes that mitochondrial DNA (mtDNA) accumulates mutations with age, and that these mutations contribute to physiological decline in aging and degenerative diseases. Although a great deal of indirect evidence supports this hypothesis, the aggregate burden of mtDNA mutations, particularly point mutations, has not been systematically quantified in aging or neurodegenerative disorders. Therefore, we directly assessed the aggregate burden of brain mtDNA point mutations in 17 subjects with Alzheimer's disease (AD), 10 elderly control subjects and 14 younger control subjects, using a PCR-cloning-sequencing strategy. We found that brain mtDNA from elderly subjects had a higher aggregate burden of mutations than brain mtDNA from younger subjects. The average aggregate mutational burden in elderly subjects was 2 x 10(-4) mutations/bp. The bulk of these mutations were individually rare point mutations, 60% of which changed an amino acid. Control experiments ensure that these results were not due to artifacts arising from PCR error, mistaken identification of nuclear pseudogenes or ex vivo oxidation. Cytochrome oxidase activity correlated negatively with increasing mutational burden. These findings significantly bolster the mitochondrial theory of aging.

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RETRACTED: Mutations in mitochondrial cytochrome c oxidase genes segregate with late-onset Alzheimer disease
Davis, R. E., Miller, S., Herrnstadt, C., Ghosh, S. S., Fahy, E., Shinobu, L. A., Galasko, D., Thal, L. J., Beal, M. F., Howell, N., et al. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.9.4526 · Cited by 341
Retracted
Molecular cloning: A laboratory manual
Deininger, P. L. (1990) · Analytical Biochemistry · doi:10.1016/0003-2697(90)90595-z · Cited by 84,684
Sequence and organization of the human mitochondrial genome
Anderson, S., Bankier, A. T., Barrell, B. G., de Bruijn, M. H. L., Coulson, A. R., Drouin, J., Eperon, I. C., Nierlich, D. P., Roe, B. A., Sanger, F., et al. (1981) · Nature · doi:10.1038/290457a0 · Cited by 9,740
Oxidants, antioxidants, and the degenerative diseases of aging.
Ames, B. N., Shigenaga, M. K., & Hagen, T. M. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.17.7915 · Cited by 5,958
Reanalysis and revision of the Cambridge reference sequence for human mitochondrial DNA
Andrews, R. M., Kubacka, I., Chinnery, P. F., Lightowlers, R. N., Turnbull, D. M., & Howell, N. (1999) · Nature Genetics · doi:10.1038/13779 · Cited by 3,337
Oxidative damage and mitochondrial decay in aging.
Shigenaga, M. K., Hagen, T. M., & Ames, B. N. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.23.10771 · Cited by 2,055
8-Hydroxyguanine, an abundant form of oxidative DNA damage, causes G-T and A-C substitutions.
Cheng, K. C., Cahill, D. S., Kasai, H., Nishimura, S., & Loeb, L. A. (1992) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)48474-8 · Cited by 1,844
Oxidative damage to mitochondrial DNA is increased in Alzheimer’s disease
Mecocci, P., MacGarvey, U., & Beal, M. F. (1994) · Annals of Neurology · doi:10.1002/ana.410360510 · Cited by 1,037
Mitochondrial DNA mutations as an important contributor to ageing and degenerative diseases
Linnane, A., Ozawa, T., Marzuki, S., & Tanaka, M. (1989) · The Lancet · doi:10.1016/s0140-6736(89)92145-4 · Cited by 983
Mitochondrial DNA deletions in human brain: regional variability and increase with advanced age
Corral-Debrinski, M., Horton, T., Lott, M. T., Shoffner, J. M., Flint Beal, M., & Wallace, D. C. (1992) · Nature Genetics · doi:10.1038/ng1292-324 · Cited by 890

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Authors: Lin, M. T.
Affiliations: Cornell University (US)
Corresponding author: Lin, M. T.
Venue: Human Molecular Genetics
Publisher: Oxford University Press (OUP)
Published: 2002-01-01
Volume: 11
Issue: 2
Pages: 133-145
ISSN: 0964-6906 (ISSN-L)
1460-2083
DOI: 10.1093/hmg/11.2.133
OpenAlex: W2148641357
Cited by: 366
References: 71
Citations by year: 2026: 3 · 2025: 4 · 2024: 12 · 2023: 12 · 2022: 17 · 2021: 19 · 2020: 15 · 2019: 13 · 2018: 21 · 2017: 8 · 2016: 20 · 2015: 15 · 2014: 11 · 2013: 13 · 2012: 20
FWCI: 6.60
Type: journal article
Language: en
Open access: closed
Locations: Human Molecular Genetics (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health (5k08ns001971-03, 5k08ag000798-03)
National Institute on Aging (K08-AG00798)
National Institute of Neurological Disorders and Stroke (K08 NS01971)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
Keywords: mitochondrial DNA, somatic mtDNA mutations, point mutations, aging, Alzheimer's disease, mitochondrial theory of aging, brain, cytochrome oxidase activity, neurodegeneration
MeSH terms: Adult, Aged, Aged, 80 and over, Aging, Alzheimer Disease, Brain, Child, Cloning, Molecular, Electron Transport Complex IV, DNA, Mitochondrial, Female, Humans, Infant, Male, Middle Aged, Molecular Sequence Data, Pseudogenes, Polymerase Chain Reaction, Point Mutation, Sequence Analysis, DNA

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High aggregate burden of somatic mtDNA point mutations in aging and Alzheimer's disease brain

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