In the heart, contraction is initiated by the propagation of an action potential on the cell surface, which corresponds to a rapid and transient membrane depolarization of the myocytes. During an action potential, Ca2+ ions enter into the cells and open a channel called the ryanodine receptor (RyR) located on the sarco-endoplasmic reticulum (ER/SR) surface. The ER/SR is a cellular organelle where large amounts of Ca2+ are stored during the relaxation. Following RyR opening, Ca2+ is massively released from the ER/SR and bound to the contractile apparatus to trigger the cellular contraction. Relaxation occurs when the Ca2+ is pumped back into the ER/SR by the sarco-endoplasmic recticulum Ca2+ ATPase (or SERCA).
The energy requires during a contraction-relaxation cycle is dynamically produced by the powerhouse called the mitochondria. Mitochondria represent almost 40% of the total volume of a cardiomyocyte and consume the breathing oxygen to transform nutriments, such as fatty acids and carbohydrates, to produce ATP
This a high-energy molecule is then used by the myocytes during the contractile process as well as to maintain ionic homeostasis or control dynamic protein synthesis. Mitochondrial respiration rate and of ATP synthesis are dynamically regulated by mitochondrial Ca2+ movements. Mitochondria and the ER/SR are spatially and functionally organized as a network with specific contact points.
The physical association between the two organelles, referred to as mitochondrial-associated membranes (MAM), plays a pivotal role in Ca2+ signaling and energy metabolism. Within the MAM, the voltage-dependent anion channel (VDAC) of the outer mitochondrial membrane and the inositol-1,4,5- triphosphate receptor (IP3R), another ER/SR Ca2+ channel, interact to allow an efficient Ca2+ transfert between the two organelles. Although, at the cardiac level, a physical coupling between ER/SR membrane and mitochondria supports local Ca2+ exchange involving IP3R, it is worth noting that RyR are twenty times more expressed than IP3R and also affect mitochondrial Ca2+ movements.
Figure 1 : Simultaneous dynamics measurements of mitochondria-ER/SR Ca2+ movements during a cardiac action potential. A. Cardiomyocytes are loaded with fluorescent dyes to measure mitochondrial Ca2+ (left panel) and ER/SR Ca2+ content (right panel) and simultaneously patch clamped in the whole configuration (middle panel) to measure electrical activity such as the action potential. B. During an action potential mitochondria take up Ca2+ whereas ER/SR Ca2+ content decreases. The right panel represents the normalized fluorescence in each organelles.
Mitochondrial Ca2+ uptake is essential for the regulation of both mitochondrial metabolism and ER/SR homeostasis, and alteration of this ER/SR-mitochondria crosstalk may result in a disruption of Ca2+ transfer between the two organelles. Using original technics (see Figure 1), we aimed to understand the dynamics control of ER/SR-mitochondrial Ca2+ movements in the context of pathophysiological conditions such as ischemia/reperfusion, Duchene muscular dystrophy, metabolic disorder or arrhythmias.
- Cécile Delettre INM,
- Michel Ovize, INSERM UMR-1060, Laboratoire CarMeN, Université Lyon 1,
- Håkan Westerblad, Karolinska Institut et Muscle Physiology group,
- Andrew R. Marks , Columbia University College of Physicians & Surgeons, New York,
Financial support :
- PHC dàlen (franco-suédois)
Major Publications :
- Roussel J, Thireau J, Brenner C, Saint N, Scheuermann V, Lacampagne A, Le Guennec JY,Fauconnier J. “Palmitoyl-carnitine increases RyR2 oxidation and sarcoplasmic reticulum Ca(2+) leak in cardiomyocytes: Role of adenine nucleotide translocase.. “ Biochim Biophys Acta. 2015 May;1852(5):749-58.
- Roberge S, Roussel J, Andersson DC, Meli AC, Vidal B, Blandel F, Lanner JT, Le Guennec JY, Katz A, Westerblad H, Lacampagne A, Fauconnier J. “TNF-α-mediated caspase-8 activation induces ROS production and TRPM2 activation in adult ventricular myocytes. “ Cardiovasc Res. 2014 Jul 1;103(1):90-9.
- Fauconnier J, Roberge S, Saint N, Lacampagne A. “Type 2 ryanodine receptor: a novel therapeutic target in myocardial ischemia/reperfusion. “ Pharmacol Ther. 2013 Jun; 138(3):323-32. Review.Fauconnier J, Meli AC, Thireau J, Roberge S, Shan J, Sassi Y, Reiken SR, Rauzier JM, Marchand A, Chauvier D, Cassan C, Crozier C, Bideaux P, Lompré AM, Jacotot E, Marks AR, Lacampagne A. “Ryanodine receptor leak mediated by caspase-8 activation leads to left ventricular injury after myocardial ischemia-reperfusion. “ Proc Natl Acad Sci U S A. 2011 Aug 9;108(32):13258-63.
- Fauconnier J, Thireau J, Reiken S, Cassan C, Richard S, Matecki S, Marks AR, Lacampagne A. “Leaky RyR2 trigger ventricular arrhythmias in Duchenne muscular dystrophy. “. Proc Natl Acad Sci U S A. 2010 Jan 26;107(4):1559-64.
- Fauconnier J, Andersson DC, Zhang SJ, Lanner JT, Wibom R, Katz A, Bruton JD, Westerblad H. “Effects of palmitate on Ca(2+) handling in adult control and ob/ob cardiomyocytes: impact of mitochondrial reactive oxygen species. “ Diabetes. 2007 Apr;56(4):1136-42.