PLoS ONE (Jan 2016)

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

  • Sophie Le Page,
  • Marjorie Niro,
  • Jérémy Fauconnier,
  • Laura Cellier,
  • Sophie Tamareille,
  • Abdallah Gharib,
  • Arnaud Chevrollier,
  • Laurent Loufrani,
  • Céline Grenier,
  • Rima Kamel,
  • Emmanuelle Sarzi,
  • Alain Lacampagne,
  • Michel Ovize,
  • Daniel Henrion,
  • Pascal Reynier,
  • Guy Lenaers,
  • Delphine Mirebeau-Prunier,
  • Fabrice Prunier

DOI
https://doi.org/10.1371/journal.pone.0164066
Journal volume & issue
Vol. 11, no. 10
p. e0164066

Abstract

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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 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.Opa1 deficiency was associated with increased sensitivity to I/R, imbalance in dynamic mitochondrial Ca2+ uptake, and subsequent increase in NCX activity.