title: Addressing RNA integrity to determine the impact of mitochondrial DNA mutations on brain mitochondrial function with age.
abstract: Mitochondrial DNA (mtDNA) mutations can result in mitochondrial dysfunction, but emerging experimental data question the fundamental role of mtDNA mutagenesis in age-associated mitochondrial impairment. The multicopy nature of mtDNA renders the impact of a given mtDNA mutation unpredictable. In this study, we compared mtDNA stability and mtRNA integrity during normal aging. Seven distinct sites in mouse brain mtDNA and corresponding mtRNA were analyzed. Accumulation of mtDNA mutations during aging was highly site-specific. The variation in mutation frequencies overrode the age-mediated increase by more than 100-fold and aging generally did not influence mtDNA mutagenesis. Errors introduced by mtRNA polymerase were also site-dependent and up to two hundred-fold more frequent than mtDNA mutations, and independent of mtDNA mutation frequency. We therefore conclude that mitochondrial transcription fidelity limits the impact of mtDNA mutations.
authors.affiliation: Department of Medical Biochemistry, Oslo University Hospital, University of Oslo, Oslo, Norway; Department of Microbiology, Oslo University Hospital, University of Oslo, Oslo, Norway.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Medical Biochemistry, Oslo University Hospital, University of Oslo, Oslo, Norway; Department of Microbiology, Oslo University Hospital, University of Oslo, Oslo, Norway.
authors.forename: Katja
authors.initials: K
authors.lastname: Scheffler
authors.affiliation: Department of Clinical Molecular Biology and Laboratory Sciences (EpiGen), Division of Medicine, Akershus University Hospital and University of Oslo, Lørenskog, Norway.
authors.forename: Ying
authors.initials: Y
authors.lastname: Esbensen
authors.affiliation: Department of Medical Biochemistry, Oslo University Hospital, University of Oslo, Oslo, Norway; Department of Microbiology, Oslo University Hospital, University of Oslo, Oslo, Norway.
authors.forename: Janne M
authors.initials: JM
authors.lastname: Strand
authors.affiliation: Max Planck Institute for Biology of Ageing, Cologne, Germany.
authors.forename: James B
authors.initials: JB
authors.lastname: Stewart
authors.affiliation: Department of Medical Biochemistry, Oslo University Hospital, University of Oslo, Oslo, Norway; Department of Microbiology, Oslo University Hospital, University of Oslo, Oslo, Norway.
authors.forename: Magnar
authors.initials: M
authors.lastname: Bjørås
authors.affiliation: Department of Medical Biochemistry, Oslo University Hospital, University of Oslo, Oslo, Norway.
authors.forename: Lars
authors.initials: L
authors.lastname: Eide
mesh_terms: D000375:Aging / Q000235:genetics*; D000818:Animals; D001921:Brain / Q000166:cytology* / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000235:genetics*; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism*; D016296:Mutagenesis; D009154:Mutation; D059645:Mutation Rate; D012313:RNA / Q000235:genetics*; D000077278:RNA, Mitochondrial; D014158:Transcription, Genetic / Q000235:genetics
chemical_list: D004272:DNA, Mitochondrial; D000077278:RNA, Mitochondrial; D012313:RNA