title: Mitochondrial DNA mutations activate the mitochondrial apoptotic pathway and cause dilated cardiomyopathy.
abstract: OBJECTIVE
  To determine whether low frequency mitochondrial DNA (mtDNA) mutations are pathogenic.
  
  
  METHODS
  We studied mice that express a proofreading-deficient mitochondrial DNA polymerase in the heart and develop cardiac mtDNA mutations.
  
  
  RESULTS
  At 4 weeks of age, when point mutation levels had risen to on average two per mitochondrial genome, these mice developed severe dilated cardiomyopathy. Interstitial fibrosis first became apparent at 4 weeks of age and progressed with age. Sporadic myocytic death occurred in all regions of the heart, apparently due to apoptosis as assessed by histological analysis and TUNEL staining. The frequency of TUNEL-positive cells peaked at 4-5 weeks of age and then gradually declined. While mitochondrial respiratory function, ultrastructure, and number remained normal, cytochrome c was released from mitochondria, a known apoptotic signal.
  
  
  CONCLUSIONS
  mtDNA mutations therefore are pathogenic, and seem to trigger apoptosis through the mitochondrial pathway.
authors.affiliation: Department of Molecular Microbiology and Immunology, Saint Louis University Health Sciences Center, 1402 South Grand Boulevard, St. Louis, MO 63104, USA.
authors.forename: Dekui
authors.initials: D
authors.lastname: Zhang
authors.forename: Justin L
authors.initials: JL
authors.lastname: Mott
authors.forename: Patricia
authors.initials: P
authors.lastname: Farrar
authors.forename: Jan S
authors.initials: JS
authors.lastname: Ryerse
authors.forename: Shin-Wen
authors.initials: SW
authors.lastname: Chang
authors.forename: Melissa
authors.initials: M
authors.lastname: Stevens
authors.forename: Grace
authors.initials: G
authors.lastname: Denniger
authors.forename: Hans Peter
authors.initials: HP
authors.lastname: Zassenhaus
mesh_terms: D000818:Animals; D017209:Apoptosis; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000473:pathology; D003574:Cytochrome c Group / Q000378:metabolism; D004272:DNA, Mitochondrial; D005355:Fibrosis; D020287:In Situ Nick-End Labeling; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D008929:Mitochondria, Heart / Q000235:genetics* / Q000378:metabolism; D009206:Myocardium / Q000473:pathology; D017354:Point Mutation
chemical_list: D003574:Cytochrome c Group; D004272:DNA, Mitochondrial