Mitochondrial and nuclear DNA base excision repair are affected differently by caloric restriction.
Aging is strongly correlated with the accumulation of oxidative damage in DNA, particularly in mitochondria. Oxidative damage to both mitochondrial and nuclear DNA is repaired by the base excision repair (BER) pathway. The "mitochondrial theory of aging" suggests that aging results from declining mitochondrial function, due to high loads of damage and mutation in mitochondrial DNA (mtDNA). Restriction of caloric intake is the only intervention so far proven to slow the aging rate. However, the molecular mechanisms underlying such effects are still unclear. We used caloric-restricted (CR) mice to investigate whether lifespan extension is associated with changes in mitochondrial BER activities. Mice were divided into two groups, receiving 100% (PF) or 60% (CR) of normal caloric intake, a regime that extends mean lifespan by approximately 40% in CR mice. Mitochondria isolated from CR mice had slightly higher uracil (UDG) and oxoguanine DNA glycosylase (OGG1) activities but marginally lower abasic endonuclease and polymerase gamma gap-filling activities, although these differences were tissue-specific. Uracil-initiated BER synthesis incorporation activities were significantly lower in brain and kidney from CR mice but marginally enhanced in liver. However, nuclear repair synthesis activities were increased by CR, indicating differential regulation of BER in the two compartments. The results indicate that a general up-regulation of mitochondrial BER does not occur in CR.
Stuart
J A
JA
Department of Biology, Brock University, St. Catharines, Ontario, Canada.
Karahalil
B
B
Hogue
B A
BA
Souza-Pinto
N C
NC
Bohr
V A
VA
D000375:Aging / Q000235:genetics; D000818:Animals; D001921:Brain / Q000378:metabolism; D031204:Caloric Restriction; D002467:Cell Nucleus / Q000378:metabolism; D004247:DNA / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage; D045647:DNA Glycosylases / Q000378:metabolism; D000074002:DNA Polymerase gamma; D004260:DNA Repair; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism*; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000032:analysis; D004259:DNA-Directed DNA Polymerase / Q000032:analysis; D007668:Kidney / Q000378:metabolism; D008017:Life Expectancy; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism; D009928:Organ Specificity; D018384:Oxidative Stress; D051981:Uracil-DNA Glycosidase
D004272:DNA, Mitochondrial; D004247:DNA; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; D045647:DNA Glycosylases; C485990:Ogg1 protein, mouse; D051981:Uracil-DNA Glycosidase; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase