CALMOS

Type 2 diabetes (T2D) is an independent risk factor for the development of heart failure and arrhythmia. Epidemiological and clinical studies strongly support the existence of obesity and diabetic-related cardiomyopathies irrespective of coronary artery disease, hypertension or other co-morbidities. In addition, dysregulation of the energy conversion process is a hallmark of the diabetic heart in patient. In human diabetic myocardium samples, we recently demonstrated that pre-operative mitochondrial dysfunction of the atrial myocardium is associated with atrial fibrillation occurrence after cardiac surgery in patients with metabolic syndrome, identifying for the first time the mitochondrion as a potential key player in clinically relevant arrhythmia. Thus mitochondrial dysfunction has emerged as a major arrhythmogenic substrate in patients with metabolic syndrome. In the heart, mitochondria are thought to take up part of the Ca2+ release by the type 2 ryanodine (RyR2) of the sarcoplasmic reticulum through the mitochondrial Ca2+ uniporter (MCU). The MCU macromolecular complex structure controls its Ca2+ sensitivity. Once in the mitochondrial matrix, Ca2+ modulate the metabolic flux and the ATP production by regulating key enzyme involve in the carbohydrates oxydation. By modulating the respiratory chain activity, mitochondrial Ca2+ synergistically regulates the production of reactive oxygen species (ROS). There is, therefore, a close relationship between mitochondrial Ca2+, ATP and ROS. In the diabetic cardiomyopathy where the fatty acids -oxydation increases, the decrease in mitochondrial Ca2+ uptake is accompanied by an increase in mitochondrial ROS as well as an impaired respiratory chain activity and ATP production. Whereas such modulation of mitochondrial function may alter electrical activities and myocardial conduction properties, two mitochondrial Ca2+ uptake enhancer, efsevin (VDAC2 agonist) and kaempferol (MCU activator) was recently demonstrated to abolish Ca2+ dependent arrhythmia, in both murine model and in human iPSC-derived cardiomyocytes harbouring mutation of the RyR2. Most interestingly, several pre-clinical studies demonstrate the beneficial effects of kaempferol on the mitochondrial metabolism and metabolic syndrome development. Regulating mitochondrial Ca2+ uptake thus appear as a potent target to prevent cardiomyopathy and arrhythmia associated with T2D. Therefore, the goal of this project will be to investigate, in human atrial samples and in mice model presenting a metabolic syndrome, the molecular regulation of the dynamic mitochondrial Ca2+ signaling underlying the development of arrhythmia phenomenon. Our consortium aims at investigating from bench to bed side, how the regulation of dynamic mitochondrial Ca2+ signalling underlies the development of cardiac dysfunction and in particular arrhythmia. The final goal of this project is to develop novel approach translatable to the clinic that will allow the optimization of therapeutics strategies for the treatment diabetic cardiomyopathy.