title: Mitochondrial DNA exhibits resistance to induced point and deletion mutations.
abstract: The accumulation of somatic mitochondrial DNA (mtDNA) mutations contributes to the pathogenesis of human disease. Currently, mitochondrial mutations are largely considered results of inaccurate processing of its heavily damaged genome. However, mainly from a lack of methods to monitor mtDNA mutations with sufficient sensitivity and accuracy, a link between mtDNA damage and mutation has not been established. To test the hypothesis that mtDNA-damaging agents induce mtDNA mutations, we exposed MutaTMMouse mice to benzo[a]pyrene (B[a]P) or N-ethyl-N-nitrosourea (ENU), daily for 28 consecutive days, and quantified mtDNA point and deletion mutations in bone marrow and liver using our newly developed Digital Random Mutation Capture (dRMC) and Digital Deletion Detection (3D) assays. Surprisingly, our results demonstrate mutagen treatment did not increase mitochondrial point or deletion mutation frequencies, despite evidence both compounds increase nuclear DNA mutations and demonstrated B[a]P adduct formation in mtDNA. These findings contradict models of mtDNA mutagenesis that assert the elevated rate of mtDNA mutation stems from damage sensitivity and abridged repair capacity. Rather, our results demonstrate induced mtDNA damage does not readily convert into mutation. These findings suggest robust mitochondrial damage responses repress induced mutations after mutagen exposure.
authors.affiliation: Translational Research Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA Medical Scientist Training Program, University of Washington School of Medicine, Seattle, WA 98195, USA Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, WA 98195, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Valente
authors.affiliation: Translational Research Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Nolan G
authors.initials: NG
authors.lastname: Ericson
authors.affiliation: Environmental Health Science and Research Bureau, Health Canada, Ottawa, ON K1A 0K9, Canada.
authors.forename: Alexandra S
authors.initials: AS
authors.lastname: Long
authors.affiliation: Environmental Health Science and Research Bureau, Health Canada, Ottawa, ON K1A 0K9, Canada.
authors.forename: Paul A
authors.initials: PA
authors.lastname: White
authors.affiliation: Environmental Health Science and Research Bureau, Health Canada, Ottawa, ON K1A 0K9, Canada francesco.marchetti@canada.ca.
authors.forename: Francesco
authors.initials: F
authors.lastname: Marchetti
authors.affiliation: Translational Research Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, WA 98195, USA Department of Pathology, University of Washington, Seattle, WA 98195, USA Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA jbielas@fredhutch.org.
authors.forename: Jason H
authors.initials: JH
authors.lastname: Bielas
mesh_terms: D000818:Animals; D001564:Benzo(a)pyrene; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000235:genetics; D018736:DNA Adducts / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000235:genetics*; D005038:Ethylnitrosourea; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D016296:Mutagenesis / Q000187:drug effects; D009153:Mutagens / Q000633:toxicity; D017354:Point Mutation / Q000235:genetics*; D017384:Sequence Deletion / Q000235:genetics*
chemical_list: D018736:DNA Adducts; D004272:DNA, Mitochondrial; D009153:Mutagens; D001564:Benzo(a)pyrene; D005038:Ethylnitrosourea