Increased sarco-endoplasmic reticulum – mitochondria interaction and mitochondrial dysfunction in dystrophin-deficient mdx heart - 26/03/18
, M. Lacote, A. Lacampagne, J. FauconnierRésumé |
Sarco-endoplasmic reticulum (SR/ER) calcium leak due to post-transcriptional type-2 ryanodine receptor (RyR2) modifications and mitochondrial dysfunction are two main defects observed in the heart of mdx mice, the murine model of Duchenne muscular dystrophy. However, whether SR/ER-mitochondria interaction is involved in the development of the pathology remain unknown in heart.
Aim |
The aim of the present study was to determine the potential link between calcium leak and the mitochondrial metabolism dysfunction in mdx mice.
Methods and results |
In ventricular cardiomyocytes isolated from mdx mice, we characterized, by Western blot, the post-transcriptional RyR2 modifications at 1 month of age and we observed an increase of S-nitrosylation and carboxylation of the RyR2. Using Proximity Ligand Assay experiment, we showed an increase of contact points between the SR/ER and mitochondria, which induces higher mitochondrial calcium, content in 3 month-old mdx mice. Using oxygraphy experiments, we observed a severe decrease of the maximal respiration driven by β-oxidation pathway at the same age. This metabolism dysfunction is associated with an increase in the production of radical oxygen species (ROS) attested by a higher Mitosox fluorescence.
Conclusions |
Our data demonstrate for the first time that at the early stage of the pathology the excessive SR/ER-mitochondria coupling is associated with an increase of calcium uptake by mitochondria. Higher calcium content is in turn involved in a mitochondrial dysfunction which induces ROS production.
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Vol 10 - N° 2
P. 230 - avril 2018 Retour au numéro
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