title: Increase in Cardiac Ischemia-Reperfusion Injuries in Opa1+/- Mouse Model.
abstract: BACKGROUND
  Recent data suggests the involvement of mitochondrial dynamics in cardiac ischemia/reperfusion (I/R) injuries. Whilst excessive mitochondrial fission has been described as detrimental, the role of fusion proteins in this context remains uncertain.
  
  
  OBJECTIVE
  To investigate whether Opa1 (protein involved in mitochondrial inner-membrane fusion) deficiency affects I/R injuries.
  
  
  RESULTS
  We examined mice exhibiting Opa1delTTAG mutations (Opa1+/-), showing 70% Opa1 protein expression in the myocardium as compared to their wild-type (WT) littermates. Cardiac left-ventricular systolic function assessed by means of echocardiography was observed to be similar in 3-month-old WT and Opa1+/- mice. After subjection to I/R, infarct size was significantly greater in Opa1+/- than in WTs both in vivo (43.2±4.1% vs. 28.4±3.5%, respectively; p<0.01) and ex vivo (71.1±3.2% vs. 59.6±8.5%, respectively; p<0.05). No difference was observed in the expression of other main fission/fusion protein, oxidative phosphorylation, apoptotic markers, or mitochondrial permeability transition pore (mPTP) function. Analysis of calcium transients in isolated ventricular cardiomyocytes demonstrated a lower sarcoplasmic reticulum Ca2+ uptake, whereas cytosolic Ca2+ removal from the Na+/Ca2+ exchanger (NCX) was increased, whilst SERCA2a, phospholamban, and NCX protein expression levels were unaffected in Opa1+/- compared to WT mice. Simultaneous whole-cell patch-clamp recordings of mitochondrial Ca2+ movements and ventricular action potential (AP) showed impairment of dynamic mitochondrial Ca2+ uptake and a marked increase in the AP late repolarization phase in conjunction with greater occurrence of arrhythmia in Opa1+/- mice.
  
  
  CONCLUSIONS
  Opa1 deficiency was associated with increased sensitivity to I/R, imbalance in dynamic mitochondrial Ca2+ uptake, and subsequent increase in NCX activity.
authors.affiliation: Institut MITOVASC, Université Angers, CHU Angers, Angers, France.|Laboratoire Cardioprotection Remodelage et Thrombose, Angers, France.|Service de Cardiologie, CHU Angers, Angers, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Le Page
authors.affiliation: Institut MITOVASC, Université Angers, CHU Angers, Angers, France.|Laboratoire Cardioprotection Remodelage et Thrombose, Angers, France.|Service de Cardiologie, CHU Angers, Angers, France.
authors.forename: Marjorie
authors.initials: M
authors.lastname: Niro
authors.affiliation: INSERM U1046, Université Montpellier I et II, Montpellier, France.
authors.forename: Jérémy
authors.initials: J
authors.lastname: Fauconnier
authors.affiliation: Institut MITOVASC, Université Angers, CHU Angers, Angers, France.|Laboratoire Cardioprotection Remodelage et Thrombose, Angers, France.
authors.forename: Laura
authors.initials: L
authors.lastname: Cellier
authors.affiliation: Institut MITOVASC, Université Angers, CHU Angers, Angers, France.|Laboratoire Cardioprotection Remodelage et Thrombose, Angers, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Tamareille
authors.affiliation: INSERM UMR 1060, CarMeN, Lyon, France.
authors.forename: Abdallah
authors.initials: A
authors.lastname: Gharib
authors.affiliation: Institut MITOVASC, Université Angers, CHU Angers, Angers, France.|INSERM UMR_S1083, CNRS UMR_C6214, BNMI, Angers, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Chevrollier
authors.affiliation: Institut MITOVASC, Université Angers, CHU Angers, Angers, France.|INSERM UMR_S1083, CNRS UMR_C6214, BNMI, Angers, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Loufrani
authors.affiliation: Institut MITOVASC, Université Angers, CHU Angers, Angers, France.|INSERM UMR_S1083, CNRS UMR_C6214, BNMI, Angers, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Grenier
authors.affiliation: Institut MITOVASC, Université Angers, CHU Angers, Angers, France.|Laboratoire Cardioprotection Remodelage et Thrombose, Angers, France.
authors.forename: Rima
authors.initials: R
authors.lastname: Kamel
authors.affiliation: Institut des Neurosciences de Montpellier, INSERM U1051, Université Montpellier I et II, Montpellier, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Sarzi
authors.affiliation: INSERM U1046, Université Montpellier I et II, Montpellier, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Lacampagne
authors.affiliation: INSERM UMR 1060, CarMeN, Lyon, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Ovize
authors.affiliation: Institut MITOVASC, Université Angers, CHU Angers, Angers, France.|INSERM UMR_S1083, CNRS UMR_C6214, BNMI, Angers, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Henrion
authors.affiliation: Institut MITOVASC, Université Angers, CHU Angers, Angers, France.|INSERM UMR_S1083, CNRS UMR_C6214, BNMI, Angers, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Reynier
authors.affiliation: Institut MITOVASC, Université Angers, CHU Angers, Angers, France.|INSERM UMR_S1083, CNRS UMR_C6214, BNMI, Angers, France.
authors.forename: Guy
authors.initials: G
authors.lastname: Lenaers
authors.affiliation: Institut MITOVASC, Université Angers, CHU Angers, Angers, France.|INSERM UMR_S1083, CNRS UMR_C6214, BNMI, Angers, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Mirebeau-Prunier
authors.affiliation: Institut MITOVASC, Université Angers, CHU Angers, Angers, France.|Laboratoire Cardioprotection Remodelage et Thrombose, Angers, France.|Service de Cardiologie, CHU Angers, Angers, France.
authors.forename: Fabrice
authors.identifier: http://orcid.org/0000-0002-6637-1141
authors.initials: F
authors.lastname: Prunier
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D004195:Disease Models, Animal; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D008929:Mitochondria, Heart / Q000235:genetics / Q000378:metabolism*; D063154:Mitochondrial Dynamics; D033681:Mitochondrial Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism
chemical_list: D018398:Homeodomain Proteins; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; C107836:Tlx2 protein, mouse; D020558:GTP Phosphohydrolases; C498809:Opa1 protein, mouse; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium