title: Activation of peroxisome proliferator-activated receptor pathway stimulates the mitochondrial respiratory chain and can correct deficiencies in patients' cells lacking its components.
abstract: BACKGROUND
  The mitochondrial respiratory chain (RC) disorders are the largest group of inborn errors of metabolism and still remain without treatment in most cases.
  
  
  OBJECTIVE
  We tested whether bezafibrate, a drug acting as a peroxisome proliferator-activated receptor (PPAR) agonist, could stimulate RC capacities.
  
  
  METHODS
  Fibroblasts or myoblasts from controls or patients deficient in complex I (CI), complex III (CIII), or complex IV (CIV) were cultured with or without bezafibrate.
  
  
  METHODS
  Enzyme activities, mRNA and protein expression, and respiration rates were measured.
  
  
  RESULTS
  In control cells, bezafibrate increased the CI, CIII, and CIV enzyme activities (+42 to +52%), as well as RC mRNAs (+40 to +120%) and RC protein levels (+50 to +150%). Nine of 14 patient cell lines tested exhibited a significant increase in the activity of the deficient RC complex after bezafibrate treatment (+46 to +133%), and full pharmacological correction could be achieved in seven cell lines. Similar effects were obtained using a PPARdelta agonist. These changes were related to a drug-induced increase in the mutated mRNAs and RC protein levels. Finally, the molecular mechanisms by which the PPAR pathway could induce the expression of genes encoding structural subunits or ancillary proteins of the RC apparatus, leading to stimulate the activity and protein levels of RC complex, likely involved the PPARgamma coactivator-1alpha.
  
  
  CONCLUSIONS
  This study suggests a rationale for a possible correction of moderate RC disorders due to mutations in nuclear genes, using existing drugs, and brings new insights into the role of PPAR in the regulation of the mitochondrial RC in human cells.
authors.affiliation: Université Paris Descartes, Centre National de la Recherche Scientifique Unité Propre de Recherche 9078, Faculté Necker-Enfants Malades, 75015 Paris, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Bastin
authors.forename: Flore
authors.initials: F
authors.lastname: Aubey
authors.forename: Agnès
authors.initials: A
authors.lastname: Rötig
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Fatima
authors.initials: F
authors.lastname: Djouadi
mesh_terms: D001629:Bezafibrate / Q000494:pharmacology* / Q000627:therapeutic use; D002478:Cells, Cultured; D004579:Electron Transport / Q000187:drug effects*; D042967:Electron Transport Complex I / Q000172:deficiency*; D014450:Electron Transport Complex III / Q000172:deficiency*; D003576:Electron Transport Complex IV / Q000032:analysis*; D005786:Gene Expression Regulation / Q000187:drug effects; D006360:Heat-Shock Proteins / Q000235:genetics; D006801:Humans; D028361:Mitochondrial Diseases / Q000188:drug therapy* / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics
chemical_list: D006360:Heat-Shock Proteins; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D047492:Peroxisome Proliferator-Activated Receptors; D014157:Transcription Factors; D003576:Electron Transport Complex IV; D042967:Electron Transport Complex I; D014450:Electron Transport Complex III; D001629:Bezafibrate