CE17 - Recherche translationnelle en santé

Mitochondrial calcium homeostasis in the control of arrhythmia associated with metabolic cardiomyopathy – CALMOS

Mitochondrial calcium homeostasis in the control of arrhythmia associated with metabolic cardiomyopathy

The mechanisms underlying arrhythmia in patients with metabolic disorders are poorly understood. Our consortium thus 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 arrhythmic phenomenon so called “metabolic arrhythmias”.

Targeting the mitochondrial calcium uniporter complex to limit arrhythmia associated with diabetes and metabolic disorder

The control and the regulation of the mitochondrial Ca2+ homeostasis is a primary sensor of the cardiac metabolic disorder. We here propose that (i) MCU expression, structure and function integrates cardiac metabolic flexibility, (ii) the MCU composition dynamically affect mitochondrial Ca2+ homeostasis and ATP production, (iii) change in the dynamic mitochondrial Ca2+ impaired the interaction between mitochondria and the SR, (iv) mitochondrial Ca2+ homeostasis is impaired in the myocardium of patients with metabolic syndrome and contributes to post-operative atrial fibrillation (POAF), (v) improvement of mitochondrial Ca2+ uptake reduces metabolic arrhythmias.

Mitochondrial Calcium Uniporter were purified from atria and ventricles from myocardium isolated from mice fed with an high fat sucrose (HFS) diet and normal diet during two weeks and 3 months. Once purified the MCU was incorporated in planar lipid bilayer electrophysiological set up and the biophysical properties of the single MCU channel complex was analyzed. The composition of the MCU proteins complexe was measured with classical biochemistry (Western Blot BN-Page).
In parallel, the susceptibility of these mice to trigger atrial arrhythmia, such as atrial fibrillation was assessed by an transoesophagial electrical stimulation.

Using these approaches we here demonstrate for the first time a remodeling of the MCU complex in atria and ventricules from pre-diabetes and diabetic mice (15days, and 3months of HFS diet respectively). Mainly the MICU1 regulatory protein of the MCU is significantly increased. The MCU single channel activity is consequently decreased for low Ca2+ concentration. This decrease in MCU activity is associated with a decrease in mitochondrial Ca2+ uptake in ventricles after 15days of HFS diet.
In parallel the susceptibility of Atrial fibrillation is increased in prediabetes and diabetes mice models. One week treatment with the MCU activator, kaempferol, prevents the triggering of Atrial fibrillation

These results are major for several aspects: 1- this is the first time that the MCU single channel activity was recorded from native tissues; 2- Micu1 expression is increased in diabetic cardiomyopathy and MCU complex activity is reduced for physiological Ca2+ concentration; 3- MCU activation in diabetic cardiomyopathy reduced atrial fibrillation susceptibility.
Perspectives: Measure MCU complex in human atria; Analyse the effects of kaempferol on the MCU function, Target the MICU1 expression to limit diabetic cardiomyopathy in arrhythmia

Part of this project has been postponed due to Covid pandemic. We are now finalizing last experiments for publication

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.

Project coordination

Jeremy Fauconnier (Physiologie et médecine expérimentale du coeur et des muscles)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.


PHYMEDEXP Physiologie et médecine expérimentale du coeur et des muscles

Help of the ANR 442,920 euros
Beginning and duration of the scientific project: - 36 Months

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