Low mutational burden of individual acquired mitochondrial DNA mutations in brain.
Neurons may be particularly susceptible to oxidative damage, which has been proposed to induce somatic mutations, particularly in mitochondrial DNA (mtDNA). Therefore, acquired mtDNA mutations might preferentially accumulate in the brain and could play a role in aging and neurodegenerative disorders. Recently, a somatic T to G mtDNA mutation at noncoding nucleotide position 414 was reported in fibroblasts specifically from elderly subjects, with mutational burdens of up to 50%. We screened for this mutation in brain-derived mtDNA from 8 Alzheimer's disease patients, 27 Parkinson's disease patients, 4 multiple system atrophy patients, and 44 controls using up to three RFLP analyses. A total of 73 of these subjects were over the age of 65. The 414 mutation was absent in all cases. Next, individual mtDNA fragments from 6 elderly subjects were cloned, and a total of 70 clones were sequenced. The 414 mutation was absent in all clones, though occasional sequence variations were identified at other sites in single clones. The 414 mutation also was absent in blood (n = 6) and fibroblasts (n = 11) from elderly subjects. Our data suggest that it is rare for any one particular acquired mtDNA mutation to reach levels in the brain that are functionally significant. This does not exclude the possibility that the cumulative burden of multiple, individually rare, acquired mutations impairs mitochondrial function.
Simon
D K
DK
Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02115, USA. dsimon1@caregroup.harvard.edu
Lin
M T
MT
Ahn
C H
CH
Liu
G J
GJ
Gibson
G E
GE
Beal
M F
MF
Johns
D R
DR
D000368:Aged; D000375:Aging / Q000235:genetics; D000544:Alzheimer Disease / Q000235:genetics; D001769:Blood; D001927:Brain Diseases / Q000235:genetics*; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial / Q000235:genetics*; D005347:Fibroblasts; D005787:Gene Frequency / Q000235:genetics; D006801:Humans; D018384:Oxidative Stress; D017354:Point Mutation; D012150:Polymorphism, Restriction Fragment Length
D004272:DNA, Mitochondrial