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Cardio-metabolic coupling

Inherited and acquired mitochondrial disorders contribute to cardiac function impairment, and can thus indirectly lead to arrhythmias, complicating myocardial remodeling in an unspecific manner. The direct involvement of mitochondria in cardiac electrical function has recently emerged from in vitro studies showing that modulation of mitochondrial respiration, reactive oxygen production and ion channels alter action potential and myocardial conduction properties. Morphological evidence show that a fraction of mitochondria is interacting with SR terminal cisternae where the ryanodine receptors / calcium release channels (RyR2) are localized. We and others demonstrated that the mitochondrial Ca²⁺ uptake shapes cytosolic Ca²⁺ signals on a beat-to-beat basis and that mitochondrial Ca²⁺ uptake is affected in several pathophysiological conditions (diabetes, heart failure, ischemia-reperfusion, mitochondrial myopathy). To enter in the mitochondria, Ca²⁺ passes the outer and the inner membrane of the mitochondria through specific mitochondrial channels (namely VDAC and MCU respectively). As the RyR2, the MCU is a macromolecular complex comprising several associated proteins and controlling mitochondrial Ca²⁺ uptake. Once in the mitochondrial matrix, Ca²⁺ ions modulate the oxidative metabolism through three dehydrogenases of the Krebs cycle, i.e. pyruvate deshydrogenase (PDH), isocitrate dehydrogenase (IDH) and 2-oxoglutarate dehydrogenase. In addition to its putative role in the control of excitation-metabolism coupling and mitochondrial respiration, dynamic mitochondrial Ca²⁺ may also impact reactive oxygen production and oxidative stress. Thus, dynamic mitochondrial Ca²⁺ homeostasis may serve as central hub to control the energy supply requires during the excitation-contraction coupling as well as the metabolic fluxes. To analyze the contribution of the dynamic mitochondrial Ca²⁺ signaling remodelling to myocardial metabolism and excitability in pathophysiological context, our objectives are: 1- Evaluating the mitochondrial function and contribution of the excitation-oxidative metabolism in the genesis of arrhythmic events associated with ion channels mutation and channelopathies (i.e. Atrial Fibrillation, CPVT, PVT, LQTs) and 2- determine the impact of the dynamic mitochondrial adaptation and metabolic fluxes on myocardial excitability and function and excitability under an acute change in energy supply  (i.e. obesity, Type 2 diabetes, acute ischemia, Ducehenne muscular Dystrophy). Several therapeutics and nutritional interventions are evaluated to develop novel approach translatable to the clinic and optimize of the strategies for the treatment of cardiac metabolic disorder.