title: Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases.
abstract: As regulators of bioenergetics in the cell and the primary source of endogenous reactive oxygen species (ROS), dysfunctional mitochondria have been implicated for decades in the process of aging and age-related diseases. Mitochondrial DNA (mtDNA) is replicated and repaired by nuclear-encoded mtDNA polymerase γ (Pol γ) and several other associated proteins, which compose the mtDNA replication machinery. Here, we review evidence that errors caused by this replication machinery and failure to repair these mtDNA errors results in mtDNA mutations. Clonal expansion of mtDNA mutations results in mitochondrial dysfunction, such as decreased electron transport chain (ETC) enzyme activity and impaired cellular respiration. We address the literature that mitochondrial dysfunction, in conjunction with altered mitochondrial dynamics, is a major driving force behind aging and age-related diseases. Additionally, interventions to improve mitochondrial function and attenuate the symptoms of aging are examined.
authors.affiliation: Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
authors.forename: Karen L
authors.initials: KL
authors.lastname: DeBalsi
authors.affiliation: Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
authors.forename: Kirsten E
authors.initials: KE
authors.lastname: Hoff
authors.affiliation: Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA. Electronic address: copelan1@niehs.nih.gov.
authors.forename: William C
authors.initials: WC
authors.lastname: Copeland
mesh_terms: D000375:Aging / Q000235:genetics / Q000378:metabolism; D004261:DNA Replication; D004272:DNA, Mitochondrial / Q000235:genetics / Q000502:physiology; D050259:Genes, Mitochondrial / Q000235:genetics; D006801:Humans; D008928:Mitochondria / Q000235:genetics*; D016296:Mutagenesis / Q000502:physiology*; D009154:Mutation; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D004272:DNA, Mitochondrial; D017382:Reactive Oxygen Species
keywords: Age-related diseases; Aging; DNA polymerase gamma; Mitochondrial DNA mutations; MtDNA replication; POLG