title: Down-regulation of OPA1 alters mouse mitochondrial morphology, PTP function, and cardiac adaptation to pressure overload.
abstract: OBJECTIVE
  The optic atrophy 1 (OPA1) protein is an essential protein involved in the fusion of the mitochondrial inner membrane. Despite its high level of expression, the role of OPA1 in the heart is largely unknown. We investigated the role of this protein in Opa1(+/-) mice, having a 50% reduction in OPA1 protein expression in cardiac tissue.
  
  
  RESULTS
  In mutant mice, cardiac function assessed by echocardiography was not significantly different from that of the Opa1(+/+). Electron and fluorescence microscopy revealed altered morphology of the Opa1(+/-) mice mitochondrial network; unexpectedly, mitochondria were larger with the presence of clusters of fused mitochondria and altered cristae. In permeabilized mutant ventricular fibres, mitochondrial functional properties were maintained, but direct energy channelling between mitochondria and myofilaments was weakened. Importantly, the mitochondrial permeability transition pore (PTP) opening in isolated permeabilized cardiomyocytes and in isolated mitochondria was significantly less sensitive to mitochondrial calcium accumulation. Finally, 6 weeks after transversal aortic constriction, Opa1(+/-) hearts demonstrated hypertrophy almost two-fold higher (P< 0.01) than in wild-type mice with altered ejection fraction (decrease in 43 vs. 22% in Opa1(+/+) mice, P< 0.05).
  
  
  CONCLUSIONS
  These results suggest that, in adult cardiomyocytes, OPA1 plays an important role in mitochondrial morphology and PTP functioning. These properties may be critical for cardiac function under conditions of chronic pressure overload.
authors.affiliation: INSERM, U-769, Faculté de Pharmacie, Université Paris-Sud, 5 rue J-B Clément, F-92296 Châtenay-Malabry,  France.
authors.forename: Jerome
authors.initials: J
authors.lastname: Piquereau
authors.forename: Fanny
authors.initials: F
authors.lastname: Caffin
authors.forename: Marta
authors.initials: M
authors.lastname: Novotova
authors.forename: Alexandre
authors.initials: A
authors.lastname: Prola
authors.forename: Anne
authors.initials: A
authors.lastname: Garnier
authors.forename: Philippe
authors.initials: P
authors.lastname: Mateo
authors.forename: Dominique
authors.initials: D
authors.lastname: Fortin
authors.forename: Le Ha
authors.initials: le H
authors.lastname: Huynh
authors.forename: Valérie
authors.initials: V
authors.lastname: Nicolas
authors.forename: Marcel V
authors.initials: MV
authors.lastname: Alavi
authors.forename: Catherine
authors.initials: C
authors.lastname: Brenner
authors.forename: Renée
authors.initials: R
authors.lastname: Ventura-Clapier
authors.forename: Vladimir
authors.initials: V
authors.lastname: Veksler
authors.forename: Frédéric
authors.initials: F
authors.lastname: Joubert
mesh_terms: D000220:Adaptation, Biological; D000818:Animals; D015536:Down-Regulation; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D033681:Mitochondrial Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D024101:Mitochondrial Proteins / Q000235:genetics / Q000502:physiology; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism; D029241:Optic Atrophy, Autosomal Dominant / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D010539:Permeability; D011312:Pressure
chemical_list: D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D024101:Mitochondrial Proteins; D020558:GTP Phosphohydrolases; C498809:Opa1 protein, mouse