Functional integrity of mitochondrial genomes in human platelets and autopsied brain tissues from elderly patients with Alzheimer's disease.
To determine whether pathogenic mutations in mtDNA are involved in phenotypic expression of Alzheimer's disease (AD), the transfer of mtDNA from elderly patients with AD into mtDNA-less (rho0) HeLa cells was carried out by fusion of platelets or synaptosomal fractions of autopsied brain tissues with rho0 HeLa cells. The results showed that mtDNA in postmortem brain tissue survives for a long time without degradation and could be rescued in rho0 HeLa cells. Next, the cybrid clones repopulated with exogenously imported mtDNA from patients with AD were used for examination of respiratory enzyme activity and transfer of mtDNA with the pathogenic mutations that induce mitochondrial dysfunction. The presence of the mutated mtDNA was restricted to brain tissues and their cybrid clones that formed with synaptosomes as mtDNA donors, whereas no cybrid clones that isolated with platelets as mtDNA donors had detectable mutated mtDNA. However, biochemical analyses showed that all cybrid clones with mtDNA imported from platelets or brain tissues of patients with AD restored mitochondrial respiration activity to almost the same levels as those of cybrid clones with mtDNA from age-matched normal controls, suggesting functional integrity of mtDNA in both platelets and brain tissues of elderly patients with AD. These observations warrant the reassessment of the conventional concept that the accumulation of pathogenic mutations in mtDNA throughout the aging process is responsible for the decrease of mitochondrial respiration capacity with age and with the development of age-associated neurodegenerative diseases.
Ito
S
S
Institute of Biological Sciences, University of Tsukuba, Ibaraki 305-8572, Japan.
Ohta
S
S
Nishimaki
K
K
Kagawa
Y
Y
Soma
R
R
Kuno
S Y
SY
Komatsuzaki
Y
Y
Mizusawa
H
H
Hayashi
J
J
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000097:blood / Q000235:genetics* / Q000473:pathology; D001344:Autopsy; D001792:Blood Platelets / Q000737:chemistry / Q000473:pathology*; D001921:Brain / Q000473:pathology*; D001923:Brain Chemistry; D004272:DNA, Mitochondrial / Q000235:genetics*; D003576:Electron Transport Complex IV / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005917:Globus Pallidus / Q000737:chemistry / Q000473:pathology; D006367:HeLa Cells; D006801:Humans; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D012016:Reference Values; D013378:Substantia Nigra / Q000737:chemistry / Q000473:pathology; D013574:Synaptosomes / Q000737:chemistry / Q000473:pathology; D014162:Transfection
D004272:DNA, Mitochondrial; D003576:Electron Transport Complex IV