title: Transmitochondrial embryonic stem cells containing pathogenic mtDNA mutations are compromised in neuronal differentiation.
abstract: OBJECTIVE
  Defects of the mitochondrial genome (mtDNA) cause a series of rare, mainly neurological disorders. In addition, they have been implicated in more common forms of movement disorders, dementia and the ageing process. In order to try to model neuronal dysfunction associated with mitochondrial disease, we have attempted to establish a series of transmitochondrial mouse embryonic stem cells harbouring pathogenic mtDNA mutations.
  
  
  METHODS
  Transmitochondrial embryonic stem cell cybrids were generated by fusion of cytoplasts carrying a variety of mtDNA mutations, into embryonic stem cells that had been pretreated with rhodamine 6G, to prevent transmission of endogenous mtDNA. Cybrids were differentiated into neurons and assessed for efficiency of differentiation and electrophysiological function.
  
  
  RESULTS
  Neuronal differentiation could occur, as indicated by expression of neuronal markers. Differentiation was impaired in embryonic stem cells carrying mtDNA mutations that caused severe biochemical deficiency. Electrophysiological tests showed evidence of synaptic activity in differentiated neurons carrying non-pathogenic mtDNA mutations or in those that caused a mild defect of respiratory activity. Again, however, neurons carrying mtDNA mutations that resulted in severe biochemical deficiency had marked reduction in post-synaptic events.
  
  
  CONCLUSIONS
  Differentiated neurons carrying severely pathogenic mtDNA defects can provide a useful model for understanding how such mutations can cause neuronal dysfunction.
authors: Mitochondrial Research Group, Institute for Ageing and Health, Medical School, Newcastle University, Newcastle upon Tyne, UK.
authors: D M
authors: DM
authors: Kirby
authors: K J
authors: KJ
authors: Rennie
authors: T K
authors: TK
authors: Smulders-Srinivasan
authors: R
authors: R
authors: Acin-Perez
authors: M
authors: M
authors: Whittington
authors: J-A
authors: JA
authors: Enriquez
authors: A J
authors: AJ
authors: Trevelyan
authors: D M
authors: DM
authors: Turnbull
authors: R N
authors: RN
authors: Lightowlers
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D004272:DNA, Mitochondrial / Q000235:genetics*; D004195:Disease Models, Animal; D004579:Electron Transport; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D006822:Hybrid Cells; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000235:genetics / Q000473:pathology*; D028361:Mitochondrial Diseases / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D055495:Neurogenesis; D009474:Neurons / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D009435:Synaptic Transmission
chemical_list: D004272:DNA, Mitochondrial