title: Molecular pathomechanisms and cell-type-specific disease phenotypes of MELAS caused by mutant mitochondrial tRNA(Trp).
abstract: BACKGROUND
  Numerous pathogenic mutations responsible for mitochondrial diseases have been identified in mitochondrial DNA (mtDNA)-encoded tRNA genes. In most cases, however, the detailed molecular pathomechanisms and cellular pathophysiology of these mtDNA mutations -how such genetic defects determine the variation and the severity of clinical symptoms in affected individuals- remain unclear. To investigate the molecular pathomechanisms and to realize in vitro recapitulation of mitochondrial diseases, intracellular mutant mtDNA proportions must always be considered.
  
  
  RESULTS
  We found a disease-causative mutation, m.5541C>T heteroplasmy in MT-TW gene, in a patient exhibiting mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) with multiple organ involvement. We identified the intrinsic molecular pathomechanisms of m.5541C>T. This mutation firstly disturbed the translation machinery of mitochondrial tRNA(Trp) and induced mitochondrial respiratory dysfunction, followed by severely injured mitochondrial homeostasis. We also demonstrated cell-type-specific disease phenotypes using patient-derived induced pluripotent stem cells (iPSCs) carrying ~100 % mutant m.5541C>T. Significant loss of terminally differentiated iPSC-derived neurons, but not their stem/progenitor cells, was detected most likely due to serious mitochondrial dysfunction triggered by m.5541C>T; in contrast, m.5541C>T did not apparently affect skeletal muscle development.
  
  
  CONCLUSIONS
  Our iPSC-based disease models would be widely available for understanding the "definite" genotype-phenotype relationship of affected tissues and organs in various mitochondrial diseases caused by heteroplasmic mtDNA mutations, as well as for further drug discovery applications.
authors: Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, 187-8502, Japan. hideyuki@ncnp.go.jp.|AMED-CREST, Japan Agency for Medical Research and Development, Chiyoda-ku, Tokyo, 100-0004, Japan. hideyuki@ncnp.go.jp.
authors: Hideyuki
authors: H
authors: Hatakeyama
authors: Department of Child Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Kodaira, Tokyo, 187-8551, Japan.
authors: Ayako
authors: A
authors: Katayama
authors: Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, 187-8502, Japan.|Department of Child Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Kodaira, Tokyo, 187-8551, Japan.
authors: Hirofumi
authors: H
authors: Komaki
authors: Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, 187-8502, Japan.|Medical Genome Center, National Center of Neurology and Psychiatry, Kodaira, Tokyo, 187-8551, Japan.
authors: Ichizo
authors: I
authors: Nishino
authors: Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, 187-8502, Japan. goto@ncnp.go.jp.|AMED-CREST, Japan Agency for Medical Research and Development, Chiyoda-ku, Tokyo, 100-0004, Japan. goto@ncnp.go.jp.|Department of Child Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Kodaira, Tokyo, 187-8551, Japan. goto@ncnp.go.jp.|Medical Genome Center, National Center of Neurology and Psychiatry, Kodaira, Tokyo, 187-8551, Japan. goto@ncnp.go.jp.
authors: Yu-Ichi
authors: Y
authors: Goto
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D001921:Brain / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D002648:Child; D002950:Citrate (si)-Synthase / Q000378:metabolism; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects / Q000502:physiology; D017241:MELAS Syndrome / Q000235:genetics* / Q000473:pathology*; D008297:Male; D008564:Membrane Potentials / Q000235:genetics; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D032446:Myoblasts / Q000378:metabolism; D009474:Neurons / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D012364:RNA, Transfer, Trp / Q000235:genetics*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D004272:DNA, Mitochondrial; D024101:Mitochondrial Proteins; D012333:RNA, Messenger; D012364:RNA, Transfer, Trp; D014157:Transcription Factors; D000255:Adenosine Triphosphate; D002950:Citrate (si)-Synthase