Increase in Cardiac Ischemia-Reperfusion Injuries in Opa1.sup.+/- Mouse Model

• Published in: PloS one Vol. 11; no. 10; p. e0164066
• Main Authors: Le Page, Sophie, Niro, Marjorie, Fauconnier, Jérémy, Cellier, Laura, Tamareille, Sophie, Gharib, Abdallah, Chevrollier, Arnaud, Loufrani, Laurent, Grenier, Céline, Kamel, Rima, Sarzi, Emmanuelle, Lacampagne, Alain, Ovize, Michel, Henrion, Daniel, Reynier, Pascal, Lenaers, Guy, Mirebeau-Prunier, Delphine, Prunier, Fabrice
• Format: Journal Article
• Language: English
• Published: Public Library of Science 10.10.2016
• Subjects: Analysis; Arrhythmia; Ischemia; Permeability; Proteins
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0164066

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. To investigate whether Opa1 (protein involved in mitochondrial inner-membrane fusion) deficiency affects I/R injuries. We examined mice exhibiting Opa1.sup.delTTAG mutations (Opa1.sup.+/- ), 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.sup.+/- mice. After subjection to I/R, infarct size was significantly greater in Opa1.sup.+/- 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 Ca.sup.2+ uptake, whereas cytosolic Ca.sup.2+ removal from the Na.sup.+ /Ca.sup.2+ exchanger (NCX) was increased, whilst SERCA2a, phospholamban, and NCX protein expression levels were unaffected in Opa1.sup.+/- compared to WT mice. Simultaneous whole-cell patch-clamp recordings of mitochondrial Ca.sup.2+ movements and ventricular action potential (AP) showed impairment of dynamic mitochondrial Ca.sup.2+ uptake and a marked increase in the AP late repolarization phase in conjunction with greater occurrence of arrhythmia in Opa1.sup.+/- mice. Opa1 deficiency was associated with increased sensitivity to I/R, imbalance in dynamic mitochondrial Ca.sup.2+ uptake, and subsequent increase in NCX activity.