Differential age-related changes in mitochondrial DNA repair activities in mouse brain regions.
Aging in the brain is characterized by increased susceptibility to neuronal loss and functional decline, and mitochondrial DNA (mtDNA) mutations are thought to play an important role in these processes. Due to the proximity of mtDNA to the main sites of mitochondrial free radical generation, oxidative stress is a major source of DNA mutations in mitochondria. The base excision repair (BER) pathway removes oxidative lesions from mtDNA, thereby constituting an important mechanism to avoid accumulation of mtDNA mutations. The complexity of the brain implies that exposure and defence against oxidative stress varies among brain regions and hence some regions may be particularly prone to accumulation of mtDNA damages. In the current study we investigated the efficiency of the BER pathway throughout the murine lifespan in mitochondria from cortex and hippocampus, regions that are central in mammalian cognition, and which are severely affected during aging and in neurodegenerative diseases. A regional specific regulation of mitochondrial DNA repair activities was observed with aging. In cortical mitochondria, DNA glycosylase activities peaked at middle-age followed by a significant drop at old age. However, only minor changes were observed in hippocampal mitochondria during the whole lifespan of the animals. Furthermore, DNA glycosylase activities were lower in hippocampal than in cortical mitochondria. Mitochondrial AP endonuclease activity increased in old animals in both brain regions. Our data suggest an important regional specific regulation of mitochondrial BER during aging.
Gredilla
Ricardo
R
Danish Center of Molecular Gerontology, University of Aarhus, Department of Molecular Biology, Aarhus C, Denmark.
Garm
Christian
C
Holm
Rikke
R
Bohr
Vilhelm A
VA
Stevnsner
Tinna
T
D000375:Aging; D000818:Animals; D001921:Brain / Q000033:anatomy & histology / Q000502:physiology*; D045647:DNA Glycosylases / Q000235:genetics / Q000378:metabolism; D004260:DNA Repair / Q000502:physiology*; D004272:DNA, Mitochondrial / Q000502:physiology*; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000235:genetics / Q000378:metabolism; D034921:Lamin Type B / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D013116:Spinal Cord / Q000502:physiology; D050995:Voltage-Dependent Anion Channel 1 / Q000378:metabolism
D004272:DNA, Mitochondrial; D034921:Lamin Type B; D024101:Mitochondrial Proteins; D050995:Voltage-Dependent Anion Channel 1; D045647:DNA Glycosylases; C481347:Neil1 protein, mouse; C485990:Ogg1 protein, mouse; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase