Marked changes in mitochondrial DNA deletion levels in Alzheimer brains
Abstract
Levels of the common 4977 nucleotide pair (np) mitochondrial DNA (mtDNA) deletion (mtDNA4977) were quantitated in the cortex, putamen, and cerebellum of patients with Alzheimer disease (AD) and compared to age-matched controls. Although cerebellum deletion levels were comparably low in AD patients and controls of all ages, cortical deletion levels were clearly different. The levels of mtDNA deletions in control brains started low, but rose markedly after age 75, while those of AD patients started high and declined to low levels by age 80. Choosing age 75 to arbitrarily delineate between younger and older subjects, younger patients had 15 times more mtDNA deletions than younger controls, while older patients had one-fifth the deletion level of older controls. Younger AD patients also had fourfold more deletions than older AD patients. These results support the hypothesis that OXPHOS defects resulting from somatic mtDNA mutations may play a role in AD pathophysiology.
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Mitochondrial DNA damage has been described in an AD brain, in which base deletions correlate with complex IV deficiency in an AD hippocampus.
“which has been described in an AD brain [169,170] in which base deletions correlate with complex IV deficiency in an AD hippocampus [171].”
From Mitochondrial Oxidative and Nitrosative Stress and Alzheimer Disease (2020) · cites this paper as [169]
MtDNA from AD subject brains exhibits excess oxidative damage and deletions.
“MtDNA from AD subject brains exhibits excess oxidative damage and deletions [47, 102-105].”
From The Alzheimer’s disease mitochondrial cascade hypothesis: progress and perspectives (2014) · cites this paper as [103]
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“Enhanced oxidative damage has been associated with increased levels of the common mtDNA deletion as well, although this finding has not been corroborated [26,40].”
BackgroundUnderstanding aging: revealing order out of chaos
Dufour, É., & Larsson, N. (2004) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2004.04.020 · Cited by 101 · see citing works
Mitochondria in Alzheimer's disease and their potential role in Alzheimer's proteostasis
Weidling, I. W., & Swerdlow, R. H. (2020) · Experimental Neurology · doi:10.1016/j.expneurol.2020.113321 · Cited by 100 · see citing works
“This is in contrast to age-matched control brains, which accumulate the common deletion to a greater extent beyond age 75 (Corral-Debrinski et al., 1994; Hamblet and Castora, 1997).”
ResultGenes and the Environment in Neurodegeneration
Coppedè, F., Mancuso, M., Siciliano, G., Migliore, L., & Murri, L. (2006) · Bioscience Reports · doi:10.1007/s10540-006-9028-6 · Cited by 99 · see citing works
Mechanisms of Mitochondrial DNA Repair in Mammals
Zinovkina, L. A. (2018) · Biochemistry (Moscow) · doi:10.1134/s0006297918030045 · Cited by 97 · see citing works
Mitochondrial DNA deletions cause the biochemical defect observed in Alzheimer’s disease
Krishnan, K. J., Ratnaike, T. E., De Gruyter, H. L. M., Jaros, E., & Turnbull, D. M. (2012) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2011.08.009 · Cited by 95 · see citing works
Conditional Targeting of the DNA Repair Enzyme hOGG1 into Mitochondria*
Rachek, L., Grishko, V., Musiyenko, S. I., Kelley, M., Ledoux, S., & Wilson, G. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m208770200 · Cited by 97 · see citing works
Deschamps, V., Barberger‐Gateau, P., Peuchant, E., & Orgogozo, J. M. (2001) · Neuroepidemiology · doi:10.1159/000054752 · Cited by 91 · see citing works
Mitochondrial Oxidative and Nitrosative Stress and Alzheimer Disease
Butterfield, D. A., & Boyd-Kimball, D. (2020) · Antioxidants · doi:10.3390/antiox9090818 · Cited by 85 · see citing works
“Mitochondrial oxidative stress is increased by the consumption of excess calories and, in turn, it leads to mitochondrial DNA damage [120], which has been described in an AD brain [169,170] in which base deletions correlate with complex IV deficiency in an AD hippocampus [171].”
BackgroundOxidative Stress and the Aging Brain
Vila, J., Gemma, C., Bachstetter, A. D., & Bickford, P. C. (2007) · Frontiers in neuroscience · doi:10.1201/9781420005523.ch15 · Cited by 88 · see citing works
Dopaminergic midbrain neurons are the prime target for mitochondrial DNA deletions
Bender, A., Schwarzkopf, R.-M., McMillan, A., Krishnan, K. J., Rieder, G., Neumann, M., Elstner, M., Turnbull, D. M., & Klopstock, T. (2008) · Journal of Neurology · doi:10.1007/s00415-008-0892-9 · Cited by 88 · see citing works
“Underlining the importance of such single cell approaches, the reported deletion levels are much higher than those of previous studies which investigated tissue homogenates rather than individual neurons [9, 20].”
BackgroundResultMitochondrial Abnormalities in Alzheimer’s Disease
Silva, D. F., Selfridge, J. E., Lu, J., E, L., Cardoso, S. M., & Swerdlow, R. H. (2012) · Advances in Pharmacology · doi:10.1016/b978-0-12-394816-8.00003-9 · Cited by 86 · see citing works
“Other studies using different approaches have also found that relative to control brains, AD brains contain increased amounts of the 5 kDa deletion (Corral-Debrinski et al., 1994; Hamblet & Castora, 1997).”
ResultKukreja, L., Kujoth, G. C., Prolla, T. A., LEUVEN, F. V., & Vassar, R. J. (2014) · Molecular Neurodegeneration · doi:10.1186/1750-1326-9-16 · Cited by 86 · see citing works
“Compared to age-matched controls, AD patients have significantly higher levels of mitochondrial DNA (mtDNA) deletions in large vulnerable neurons of the hippocampus and neocortex [7,8].”
BackgroundMaternal transmission of Alzheimer's disease: prodromal metabolic phenotype and the search for genes
Mosconi, L., Berti, V., Swerdlow, R. H., Pupi, A., Duara, R., & de Leon, M. (2010) · Human Genomics · doi:10.1186/1479-7364-4-3-170 · Cited by 85 · see citing works
Alzheimer’s disease: as it was in the beginning
Kozlov, S. O., Afonin, A. М., Evsyukov, I., & Бондаренко, А. Б. (2017) · Reviews in the Neurosciences · doi:10.1515/revneuro-2017-0006 · Cited by 84 · see citing works
Swerdlow, R. H. (2020) · International review of neurobiology · doi:10.1016/bs.irn.2020.01.008 · Cited by 88 · see citing works
Lott, I. T. (2011) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2011.12.010 · Cited by 82 · see citing works
Abnormal Mitochondrial Dynamics—A Novel Therapeutic Target for Alzheimer's Disease?
Su, B., Wang, X., Bonda, D., Perry, G. L., Smith, M. A., & Zhu, X. (2010) · Molecular Neurobiology · doi:10.1007/s12035-009-8095-7 · Cited by 82 · see citing works
“In this regard, it is notable that accumulation of damaged or mutant mtDNA is almost an invariant feature of all neurodegenerative diseases [5, 6, 87–92].”
- Authors
- Corral-Debrinski, M., Horton, T., Lott, M. T., Shoffner, J. M., McKee, A. C., Beal, M. F., Graham, B. H., & Wallace, D. C.
- Affiliations
- Harvard University (US)
- Venue
- Genomics
- Publisher
- Elsevier BV
- Published
- 1994-09
- Volume
- 23
- Issue
- 2
- Pages
- 471-476
- ISSN
- 0888-7543 (ISSN-L)
- OpenAlex
- W2060626022
- Cited by
- 309
- References
- 0
- Citations by year
- 2026: 8 · 2025: 6 · 2024: 11 · 2023: 8 · 2022: 24 · 2021: 6 · 2020: 15 · 2019: 13 · 2018: 13 · 2017: 8 · 2016: 4 · 2015: 9 · 2014: 8 · 2013: 13 · 2012: 10
- FWCI
- 2.15
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Genomics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5f32ca009329-02)
- National Institute on Aging (P30AG010130, 1P30AG10130)
- National Cancer Institute (CA09329)
- National Center for Research Resources (M01-RR00039, M01RR000039)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- mitochondrial DNA deletions, Alzheimer's disease, somatic mtDNA mutations, brain aging, cortical mitochondria, putamen, cerebellum
- MeSH terms
- Age Factors, Aged, Aged, 80 and over, Alzheimer Disease, Cerebellum, Cerebral Cortex, DNA Damage, DNA, Mitochondrial, Female, Humans, Male, Middle Aged, Oxidative Phosphorylation, Putamen, Tissue Distribution, Sequence Deletion
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