Somatic mitochondrial DNA mutations in single neurons and glia

Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA.
Neurobiology of Aging (Impact Factor: 5.01). 11/2005; 26(10):1343-55. DOI: 10.1016/j.neurobiolaging.2004.11.008
Source: PubMed


Somatic mitochondrial DNA (mtDNA) point mutations reach high levels in the brain. However, the cell types that accumulate mutations and the patterns of mutations within individual cells are not known. We have quantified somatic mtDNA mutations in 28 single neurons and in 18 single glia from post-mortem human substantia nigra of six control subjects. Both neurons and glia contain mtDNA with somatic mutations. Single neurons harbor a geometric mean (95% CI) of 200.3 (152.9-262.4) somatic mtDNA point mutations per million base pairs, compared to 133.8 (97.5-184.9) for single glia (p=0.0251). If mutations detected multiple times in the same cell are counted only once, the mean mutation level per million base pairs remains elevated in single neurons (146.9; 124.0-174.2) compared to single glia (100.5; 81.5-126.5; p=0.009). Multiple distinct somatic point mutations are present in different cells from the same subject. Most of these mutations are individually present at low levels (less than 10-20% of mtDNA molecules), but with high aggregate mutation levels, particularly in neurons. These mutations may contribute to changes in brain function during normal aging and neurodegenerative disorders.

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    • "Mitochondrial DNA (mtDNA) mutations and mitochondrial dysfunction are thought to play an important role in the aging process (Barja, 2004; Cantuti-Castelvetri et al., 2005; Kujoth et al., 2007); and increased levels of oxidative modifications and mutations in mtDNA occur in the brain during normal aging (Beal, 2005; Melov, 2004; Vermulst et al., 2007) and in AD (Gabbita et al., 1998; Morocz et al., 2002). Base excision repair (BER) is the primary DNA repair pathway for small DNA modifications caused by alkylation, deamination or oxidation in nuclei and mitochondria and it has been described to play a major role in the development and maintenance of the central nervous system (CNS) (Weissman et al., 2007a). "
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