title: In vivo levels of mitochondrial hydrogen peroxide increase with age in mtDNA mutator mice.
abstract: In mtDNA mutator mice, mtDNA mutations accumulate leading to a rapidly aging phenotype. However, there is little evidence of oxidative damage to tissues, and when analyzed ex vivo, no change in production of the reactive oxygen species (ROS) superoxide and hydrogen peroxide by mitochondria has been reported, undermining the mitochondrial oxidative damage theory of aging. Paradoxically, interventions that decrease mitochondrial ROS levels in vivo delay onset of aging. To reconcile these findings, we used the mitochondria-targeted mass spectrometry probe MitoB to measure hydrogen peroxide within mitochondria of living mice. Mitochondrial hydrogen peroxide was the same in young mutator and control mice, but as the mutator mice aged, hydrogen peroxide increased. This suggests that the prolonged presence of mtDNA mutations in vivo increases hydrogen peroxide that contributes to an accelerated aging phenotype, perhaps through the activation of pro-apoptotic and pro-inflammatory redox signaling pathways.
authors.affiliation: MRC Mitochondrial Biology Unit, Wellcome Trust/MRC Building, Cambridge, CB2 0XY, UK.
authors.forename: Angela
authors.initials: A
authors.lastname: Logan
authors.forename: Irina G
authors.initials: IG
authors.lastname: Shabalina
authors.forename: Tracy A
authors.initials: TA
authors.lastname: Prime
authors.forename: Sebastian
authors.initials: S
authors.lastname: Rogatti
authors.forename: Anastasia V
authors.initials: AV
authors.lastname: Kalinovich
authors.forename: Richard C
authors.initials: RC
authors.lastname: Hartley
authors.forename: Ralph C
authors.initials: RC
authors.lastname: Budd
authors.forename: Barbara
authors.initials: B
authors.lastname: Cannon
authors.forename: Michael P
authors.initials: MP
authors.lastname: Murphy
mesh_terms: D000375:Aging / Q000097:blood / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D016207:Cytokines / Q000097:blood; D004272:DNA, Mitochondrial / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009154:Mutation / Q000235:genetics*; D009943:Organophosphorus Compounds / Q000494:pharmacology
chemical_list: D016207:Cytokines; D004272:DNA, Mitochondrial; D008070:Lipopolysaccharides; C558697:MItoB compound; D009943:Organophosphorus Compounds; D006861:Hydrogen Peroxide
keywords: MitoB; hydrogen peroxide; mitochondria; mitochondrial DNA; mtDNA mutator mice