Journal
PLOS ONE
Volume 11, Issue 10, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0164066
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Funding
- French Ministry of Education and Research
- Federation Francaise de Cardiologie
- Fondation de France and Fondation pour la Recherche Medicale
- University of Angers
- University Hospital of Angers
- French region Pays de la Loire and Angers Loire Metropole
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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. Objectives To investigate whether Opa1 (protein involved in mitochondrial inner-membrane fusion) deficiency affects I/R injuries. Methods and Results We examined mice exhibiting Opa1(delTTAG) 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 SER-CA2a, 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. Conclusion Opa1 deficiency was associated with increased sensitivity to I/R, imbalance in dynamic mitochondrial Ca2+ uptake, and subsequent increase in NCX activity.
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