title: Mitochondrial respiratory dysfunction caused by a heteroplasmic mitochondrial DNA mutation blocks cellular reprogramming.
abstract: Mitochondrial dysfunction caused by pathogenic mutations in mitochondrial tRNA genes emerges only when mutant mitochondrial DNA (mtDNA) proportions exceed intrinsic pathogenic thresholds; however, little is known about the actual proportions of mutant mtDNA that can affect particular cellular lineage-determining processes. Here, we mainly focused on the effects of mitochondrial respiratory dysfunction caused by m.3243A>G heteroplasmy in MT-TL1 gene on cellular reprogramming. We found that generation of induced pluripotent stem cells (iPSCs) was drastically depressed only by high proportions of mutant mtDNA (≥ 90% m.3243A>G), and these proportions were strongly associated with the degree of induced mitochondrial respiratory dysfunction. Nevertheless, all established iPSCs, even those carrying ∼ 100% m.3243A>G, exhibited an embryonic stem cell-like pluripotent state. Therefore, our findings clearly demonstrate that loss of physiological integrity in mitochondria triggered by mutant mtDNA constitute a roadblock to cellular rejuvenation, but do not affect the maintenance of the pluripotent state.
authors.affiliation: Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo 187-8502, Japan, AMED-CREST, Japan Agency for Medical Research and Development, Tokyo 100-0004, Japan.
authors.forename: Mutsumi
authors.initials: M
authors.lastname: Yokota
authors.affiliation: Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo 187-8502, Japan, AMED-CREST, Japan Agency for Medical Research and Development, Tokyo 100-0004, Japan hideyuki@ncnp.go.jp goto@ncnp.go.jp.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Hatakeyama
authors.affiliation: Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo 187-8502, Japan.
authors.forename: Saki
authors.initials: S
authors.lastname: Okabe
authors.affiliation: Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo 187-8502, Japan.
authors.forename: Yasuha
authors.initials: Y
authors.lastname: Ono
authors.affiliation: Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo 187-8502, Japan, Medical Genome Center, National Center of Neurology and Psychiatry, Tokyo 187-8551, Japan and AMED-CREST, Japan Agency for Medical Research and Development, Tokyo 100-0004, Japan hideyuki@ncnp.go.jp goto@ncnp.go.jp.
authors.forename: Yu-ichi
authors.initials: Y
authors.lastname: Goto
mesh_terms: D065150:Cellular Reprogramming / Q000235:genetics*; D004272:DNA, Mitochondrial / Q000235:genetics*; D005260:Female; D006801:Humans; D057026:Induced Pluripotent Stem Cells; D008297:Male; D028361:Mitochondrial Diseases / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D012343:RNA, Transfer / Q000235:genetics / Q000378:metabolism
chemical_list: D004272:DNA, Mitochondrial; D012343:RNA, Transfer