The DOI matches its Crossref record; 70 of the 71 references it cites were found in a registry or an index.
High aggregate burden of somatic mtDNA point mutations in aging and Alzheimer's disease brain
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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“Evidence indicates age-related mtDNA changes do in fact occur within the human brain.”
From Brain aging, Alzheimer's disease, and mitochondria (2011) · cites this paper as [110]
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1 retracted
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Mitochondrial Dysfunction and Oxidative Stress in Neurodegenerative Diseases
Lin, M. T., & Beal, M. F. (2006) · Nature · doi:10.1038/nature05292 · Cited by 6,455
Self-citationOxidative stress and mitochondrial dysfunction in Alzheimer’s disease
Wang, X., Wang, W., Li, L., Perry, G., Lee, H.-G., & Zhu, X. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2013.10.015 · Cited by 1,357
Mitochondria dysfunction in the pathogenesis of Alzheimer’s disease: Recent advances.
Wang, W., Zhao, F., Ma, X., Perry, G., & Zhu, X. (2020) · Molecular Neurodegeneration · doi:10.1186/s13024-020-00376-6 · Cited by 1,274
Detection of ultra-rare mutations by next-generation sequencing
Schmitt, M. W., Kennedy, S. R., Salk, J. J., Fox, E. J., Hiatt, J. B., & Loeb, L. A. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1208715109 · Cited by 1,047
Reddy, P. H., & Beal, M. F. (2008) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2007.12.002 · Cited by 975
Metadata
- 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
- 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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