Age-associated oxygen damage and mutations in mitochondrial DNA in human hearts.
Some mutations in mitochondrial DNA (mtDNA) causing a number of neuromuscular diseases are suggested to arise spontaneously during the life of an individual. To substantiate the extent and the rate of these somatic mutations, mtDNA specimens from post-mortem human heart muscles of subjects in differing age groups were hydrolyzed. 8-Hydroxy-deoxyguanosine (8-OH-dG), a hydroxyl-radical adduct of deoxyguanosine, in mtDNA, was quantitatively determined using a micro high-performance liquid chromatography/mass spectrometry system. In each specimen, the mtDNA with a 7.4 kilo base-pair deletion was quantified by the kinetic polymerase chain reaction method. In association with age, the 8-OH-dG content accumulated exponentially up to 1.5% with a correlative increase in the content of the deleted mtDNA up to 7%. Clear correlation between the 8-OH-dG content in mtDNA and the population of mtDNA with a deletion (r = 0.93, P < 0.01) gives insight into the mechanism for the generation of a large deletion. These results indicate that accumulation of somatically acquired oxygen damage together with age-associated mutations in mtDNA which lead to bioenergetic deficiency and the heart muscle weakness are inevitable in human life.
Hayakawa
M
M
Department of Biomedical Chemistry, Faculty of Medicine, University of Nagoya, Japan.
Hattori
K
K
Sugiyama
S
S
Ozawa
T
T
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics*; D001483:Base Sequence; D002851:Chromatography, High Pressure Liquid; D004249:DNA Damage; D004272:DNA, Mitochondrial / Q000235:genetics* / Q000302:isolation & purification; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000032:analysis; D005260:Female; D006321:Heart / Q000502:physiology*; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D008929:Mitochondria, Heart / Q000502:physiology; D008957:Models, Genetic; D008969:Molecular Sequence Data; D010100:Oxygen / Q000633:toxicity*; D017354:Point Mutation; D017384:Sequence Deletion
D004272:DNA, Mitochondrial; D000080242:8-Hydroxy-2'-Deoxyguanosine; D003849:Deoxyguanosine; D010100:Oxygen