title: Mitochondrial oxidative stress can lead to nuclear hypermutability.
abstract: Reactive oxygen species (ROS) are generated in mitochondria and are thought to be important in aging, carcinogenesis, and the development of other pathologies. We now provide direct experimental evidence linking mitochondrial ROS generation to the induction of nuclear DNA damage and subsequent mutagenesis of a chromosomal gene. Specifically, we demonstrate that the mev-1 mutant of Caenorhabditis elegans has elevated levels of oxidative damage in its chromosomal DNA. This mutant was shown previously to overproduce ROS in its mitochondria. We also show that mutation frequencies were higher in the mev-1 mutant under hypoxia than in the wild type strain. By extension, these data imply that mitochondrially derived ROS mutate other genes, including tumor suppressor genes and oncogenes. We propose that this three-step process (mitochondrial ROS --> nuclear DNA damage --> mutation) contributes to aging and age-associated diseases.
authors.affiliation: Biology Department, Texas Christian University, Fort Worth, TX 76129, USA. p.hartman@tcu.edu
authors.forename: Phil
authors.initials: P
authors.lastname: Hartman
authors.forename: Rebecca
authors.initials: R
authors.lastname: Ponder
authors.forename: Herng-Hsiang
authors.initials: HH
authors.lastname: Lo
authors.forename: Naoaki
authors.initials: N
authors.lastname: Ishii
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000375:Aging / Q000235:genetics / Q000502:physiology; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics; D002467:Cell Nucleus / Q000235:genetics* / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000235:genetics; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000032:analysis / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D016296:Mutagenesis; D009153:Mutagens / Q000032:analysis / Q000378:metabolism; D009154:Mutation / Q000502:physiology*; D018384:Oxidative Stress / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics
chemical_list: D029742:Caenorhabditis elegans Proteins; D004268:DNA-Binding Proteins; D009153:Mutagens; D017382:Reactive Oxygen Species; D014157:Transcription Factors; C075059:fem-3 protein, C elegans; C073702:skn-1 protein, C elegans; D000080242:8-Hydroxy-2'-Deoxyguanosine; D004247:DNA; D003849:Deoxyguanosine