Nucleic Acids Research, Vol 27, Issue 8 1935-1942, Copyright © 1999 by Oxford University Press
NC Souza-Pinto, DL Croteau, EK Hudson, RG Hansford and VA Bohr
The mitochondrial theory of aging postulates that organisms age due to the
accumulation of DNA damage and mutations in the multiple mitochondrial
genomes, leading to mitochondrial dysfunction. Among the wide variety of
DNA damage, 8-oxo-deoxyguanosine (8-oxo-dG) has received the most attention
due to its mutagenicity and because of the possible correlation between its
accumulation and pathological processes like cancer, degenerative diseases
and aging. Although still controversial, many studies show that 8-oxo-dG
accumulates with age in the mitochondrial (mt) DNA. However, little is
known about the processing of this lesion and no study has yet examined
whether mtDNA repair changes with age. Here, we report the first study on
age-related changes in mtDNA repair, accomplished by assessing the cleavage
activity of mitochondrial extracts towards an 8-oxo-dG-containing
substrate. In this study, mitochondria obtained from rat heart and liver
were used. We find that this enzymatic activity is higher in 12 and 23
month-old rats than in 6 month-old rats, in both liver and heart extracts.
These mitochondrial extracts also cleave oligonucleotides containing a U:A
mismatch, at the uracil position, reflecting the combined action of
mitochondrial uracil DNA glycosylase (mtUDG) and mitochondrial
apurinic/apyrimidinic (AP) endonucleases. The mtUDG activity did not change
with age in liver mitochondria, but there was a small increase in activity
from 6 to 23 months in rat heart extracts, after normalization to citrate
synthase activity. Endonuclease G activity, measured by a plasmid
relaxation assay, did not show any age- associated change in liver, but
there was a significant decrease from 6 to 23 months in heart mitochondria.
Our results suggest that the mitochondrial capacity to repair 8-oxo-dG, the
main oxidative base damage suggested to accumulate with age in mtDNA, does
not decrease, but rather increases with age. The specific increase in
8-oxo-dG endonuclease activity, rather than a general up-regulation of DNA
repair in mitochondria, suggests an induction of the 8-oxo-dG-specific
repair pathway with age.
ARTICLES
Age-associated increase in 8-oxo-deoxyguanosine glycosylase/AP lyase activity in rat mitochondria
Laboratory of Molecular Genetics, Box 1, National Institute on Aging, National Institutes of Health,5600 Nathan Shock Drive, Baltimore, MD 21224, USA.
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