Age-dependent decline of DNA repair activity for oxidative lesions in rat brain mitochondria.
Endogenous oxidative damage to brain mitochondrial DNA and mitochondrial dysfunction are contributing factors in aging and in the pathogenesis of a number of neurodegenerative diseases. In this study, we characterized the regulation of base-excision-repair (BER) activity, the predominant repair mechanism for oxidative DNA lesions, in brain mitochondria as the function of age. Mitochondrial protein extracts were prepared from rat cerebral cortices at the ages of embryonic day 17 (E17) or postnatal 1-, 2-, and 3-weeks, or 5- and 30-months. The total BER activity and the activity of essential BER enzymes were examined in mitochondria using in vitro DNA repair assay employing specific repair substrates. Mitochondrial BER activity showed marked age-dependent declines in the brain. The levels of overall BER activity were highest at E17, gradually decreased thereafter, and reached to the lowest at the age of 30-month ( approximately 80% reduction). The decline of overall BER activity with age was attributed to the decreased expression of repair enzymes such as 8-OHdG glycosylase and DNA polymerase-gamma and, consequently, the reduced activity at the steps of lesion-base incision, DNA repair synthesis and DNA ligation in the BER pathway. These results strongly suggest that the decline in BER activity may be an important mechanism contributing to the age-dependent accumulation of oxidative DNA lesions in brain mitochondria.
Chen
Dexi
D
Department of Neurology, Pittsburgh Institute for Neurodegenerative Disorders, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
Cao
Guodong
G
Hastings
Teresa
T
Feng
Yiqin
Y
Pei
Wei
W
O'Horo
Cristine
C
Chen
Jun
J
D000375:Aging / Q000502:physiology*; D000818:Animals; D001483:Base Sequence / Q000235:genetics; D001921:Brain / Q000503:physiopathology*; D011088:DNA Ligases / Q000378:metabolism; D000074002:DNA Polymerase gamma; D004260:DNA Repair / Q000502:physiology*; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D043382:DNA-Formamidopyrimidine Glycosylase; D008928:Mitochondria / Q000502:physiology*; D024101:Mitochondrial Proteins / Q000502:physiology; D008969:Molecular Sequence Data; D009699:N-Glycosyl Hydrolases / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D024101:Mitochondrial Proteins; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; D009699:N-Glycosyl Hydrolases; D043382:DNA-Formamidopyrimidine Glycosylase; D011088:DNA Ligases