Somatic mitochondrial DNA mutations in cortex and substantia nigra in aging and Parkinson's disease
- PMID: 14675733
- DOI: 10.1016/s0197-4580(03)00037-x
Somatic mitochondrial DNA mutations in cortex and substantia nigra in aging and Parkinson's disease
Abstract
Oxidative damage to mitochondrial DNA (mtDNA) increases with age in the brain and can induce G:C to T:A and T:A to G:C point mutations. Though rare at any particular site, multiple somatic mtDNA mutations induced by oxidative damage or by other mechanisms may accumulate with age in the brain and thus could play a role in aging and neurodegenerative diseases. However, no prior study has quantified the total burden of mtDNA point mutation subtypes in the brain. Using a highly sensitive cloning and sequencing strategy, we find that the aggregate levels of G:C to T:A and T:A to G:C transversions and of all point mutations increase with age in the frontal cortex (FCtx). In the substantia nigra (SN), the aggregate levels of point mutations in young controls are similar to the levels in the SN or FCtx of elderly subjects. Extrapolation from our data suggests an average of 2.7 (FCtx) to 3.2 (SN) somatic point mutations per mitochondrial genome in elderly subjects. There were no significant differences between Parkinson's disease (PD) patients and age-matched controls in somatic mutation levels. These results indicate that individually rare mtDNA point mutations reach a high aggregate burden in FCtx and SN of elderly subjects.
Comment in
-
Response to Simon et al.Acta Neuropathol Commun. 2017 Apr 29;5(1):34. doi: 10.1186/s40478-017-0434-8. Acta Neuropathol Commun. 2017. PMID: 28454558 Free PMC article. No abstract available.
Similar articles
-
High aggregate burden of somatic mtDNA point mutations in aging and Alzheimer's disease brain.Hum Mol Genet. 2002 Jan 15;11(2):133-45. doi: 10.1093/hmg/11.2.133. Hum Mol Genet. 2002. PMID: 11809722
-
Mitochondrial DNA deletions/rearrangements in parkinson disease and related neurodegenerative disorders.J Neuropathol Exp Neurol. 2002 Jul;61(7):634-9. doi: 10.1093/jnen/61.7.634. J Neuropathol Exp Neurol. 2002. PMID: 12125742
-
Accumulation of mitochondrial DNA deletions within dopaminergic neurons triggers neuroprotective mechanisms.Brain. 2013 Aug;136(Pt 8):2369-78. doi: 10.1093/brain/awt196. Brain. 2013. PMID: 23884809
-
Detrimental deletions: mitochondria, aging and Parkinson's disease.Bioessays. 2006 Oct;28(10):963-7. doi: 10.1002/bies.20471. Bioessays. 2006. PMID: 16998822 Review.
-
Mechanism of somatic mitochondrial DNA mutations associated with age and diseases.Biochim Biophys Acta. 1995 May 24;1271(1):177-89. doi: 10.1016/0925-4439(95)00026-z. Biochim Biophys Acta. 1995. PMID: 7599206 Review.
Cited by
-
Mechanisms linking mtDNA damage and aging.Free Radic Biol Med. 2015 Aug;85:250-8. doi: 10.1016/j.freeradbiomed.2015.05.005. Epub 2015 May 13. Free Radic Biol Med. 2015. PMID: 25979659 Free PMC article. Review.
-
Do somatic mitochondrial DNA mutations contribute to Parkinson's disease?Parkinsons Dis. 2011;2011:659694. doi: 10.4061/2011/659694. Epub 2011 Apr 27. Parkinsons Dis. 2011. PMID: 21603185 Free PMC article.
-
Mitochondrial DNA oxidative damage and repair in aging and Alzheimer's disease.Antioxid Redox Signal. 2013 Jun 20;18(18):2444-57. doi: 10.1089/ars.2012.5039. Epub 2012 Dec 7. Antioxid Redox Signal. 2013. PMID: 23216311 Free PMC article. Review.
-
The unusual amino acid L-ergothioneine is a physiologic cytoprotectant.Cell Death Differ. 2010 Jul;17(7):1134-40. doi: 10.1038/cdd.2009.163. Epub 2009 Nov 13. Cell Death Differ. 2010. PMID: 19911007 Free PMC article.
-
The mitochondrial impairment, oxidative stress and neurodegeneration connection: reality or just an attractive hypothesis?Trends Neurosci. 2008 May;31(5):251-6. doi: 10.1016/j.tins.2008.02.008. Epub 2008 Apr 9. Trends Neurosci. 2008. PMID: 18403030 Free PMC article. Review.
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Medical