title: Reactive oxygen species stimulate mitochondrial allele segregation toward homoplasmy in human cells.
abstract: Mitochondria that contain a mixture of mutant and wild-type mitochondrial (mt) DNA copies are heteroplasmic. In humans, homoplasmy is restored during early oogenesis and reprogramming of somatic cells, but the mechanism of mt-allele segregation remains unknown. In budding yeast, homoplasmy is restored by head-to-tail concatemer formation in mother cells by reactive oxygen species (ROS)-induced rolling-circle replication and selective transmission of concatemers to daughter cells, but this mechanism is not obvious in higher eukaryotes. Here, using heteroplasmic m.3243A > G primary fibroblast cells derived from MELAS patients treated with hydrogen peroxide (H2O2), we show that an optimal ROS level promotes mt-allele segregation toward wild-type and mutant mtDNA homoplasmy. Enhanced ROS level reduced the amount of intact mtDNA replication templates but increased linear tandem multimers linked by head-to-tail unit-sized mtDNA (mtDNA concatemers). ROS-triggered mt-allele segregation correlated with mtDNA-concatemer production and enabled transmission of multiple identical mt-genome copies as a single unit. Our results support a mechanism by which mt-allele segregation toward mt-homoplasmy is mediated by concatemers.
authors.affiliation: Chemical Genetics Laboratory, RIKEN, Saitama 351-0198, Japan Japan Agency for Medical Research and Development-Core Research for Evolutional Science and Technology, Tokyo 100-0004 Japan ling@postman.riken.go.jp tshibata@postman.riken.go.jp.
authors.forename: Feng
authors.initials: F
authors.lastname: Ling
authors.affiliation: Chemical Genetics Laboratory, RIKEN, Saitama 351-0198, Japan Japan Agency for Medical Research and Development-Core Research for Evolutional Science and Technology, Tokyo 100-0004 Japan.
authors.forename: Rong
authors.initials: R
authors.lastname: Niu
authors.affiliation: Japan Agency for Medical Research and Development-Core Research for Evolutional Science and Technology, Tokyo 100-0004 Japan Department of Mental Retardation and Birth Defect Research, National Center of Neurology and Psychiatry, Tokyo 187-8502, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Hatakeyama
authors.affiliation: Japan Agency for Medical Research and Development-Core Research for Evolutional Science and Technology, Tokyo 100-0004 Japan Department of Mental Retardation and Birth Defect Research, National Center of Neurology and Psychiatry, Tokyo 187-8502, Japan.
authors.forename: Yu-Ichi
authors.initials: Y
authors.lastname: Goto
authors.affiliation: Japan Agency for Medical Research and Development-Core Research for Evolutional Science and Technology, Tokyo 100-0004 Japan Cellular and Molecular Biology Laboratory, RIKEN, Saitama 351-0198, Japan ling@postman.riken.go.jp tshibata@postman.riken.go.jp.
authors.forename: Takehiko
authors.initials: T
authors.lastname: Shibata
authors.affiliation: Chemical Genetics Laboratory, RIKEN, Saitama 351-0198, Japan Japan Agency for Medical Research and Development-Core Research for Evolutional Science and Technology, Tokyo 100-0004 Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Yoshida
mesh_terms: D000483:Alleles; D020090:Chromosome Segregation; D004261:DNA Replication / Q000502:physiology; D004272:DNA, Mitochondrial / Q000235:genetics* / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D050259:Genes, Mitochondrial; D054629:Genome, Mitochondrial; D006801:Humans; D017241:MELAS Syndrome / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism*; D009154:Mutation; D061251:Primary Cell Culture; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D004272:DNA, Mitochondrial; D017382:Reactive Oxygen Species