title: Mitochondrial respiratory dysfunction disturbs neuronal and cardiac lineage commitment of human iPSCs.
abstract: Mitochondrial diseases are genetically heterogeneous and present a broad clinical spectrum among patients; in most cases, genetic determinants of mitochondrial diseases are heteroplasmic mitochondrial DNA (mtDNA) mutations. However, it is uncertain whether and how heteroplasmic mtDNA mutations affect particular cellular fate-determination processes, which are closely associated with the cell-type-specific pathophysiology of mitochondrial diseases. In this study, we established two isogenic induced pluripotent stem cell (iPSC) lines each carrying different proportions of a heteroplasmic m.3243A>G mutation from the same patient; one exhibited apparently normal and the other showed most likely impaired mitochondrial respiratory function. Low proportions of m.3243A>G exhibited no apparent molecular pathogenic influence on directed differentiation into neurons and cardiomyocytes, whereas high proportions of m.3243A>G showed both induced neuronal cell death and inhibited cardiac lineage commitment. Such neuronal and cardiac maturation defects were also confirmed using another patient-derived iPSC line carrying quite high proportion of m.3243A>G. In conclusion, mitochondrial respiratory dysfunction strongly inhibits maturation and survival of iPSC-derived neurons and cardiomyocytes; our presenting data also suggest that appropriate mitochondrial maturation actually contributes to cellular fate-determination processes during development.
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.
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: Yasuha
authors.initials: Y
authors.lastname: Ono
authors.affiliation: Medical Genome Center, National Center of Neurology and Psychiatry, Tokyo 187-8551, Japan.
authors.forename: Miyuki
authors.initials: M
authors.lastname: Kanazawa
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.|Medical Genome Center, National Center of Neurology and Psychiatry, Tokyo 187-8551, Japan.
authors.forename: Yu-Ichi
authors.initials: YI
authors.lastname: Goto
mesh_terms: D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage / Q000235:genetics; D004272:DNA, Mitochondrial / Q000235:genetics*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D028361:Mitochondrial Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology
chemical_list: D004272:DNA, Mitochondrial