CARDIAC ENERGETICS · Cardiac energetics in silico: micro-compartmentation of adenine nucleotides and the cross talk between organelles

Final Activity Report Summary - CARDIAC ENERGETICS (Cardiac energetics in silico: micro-compartmentation of adenine nucleotides and the cross talk between organelles)

Ischemic cardiomyopathy and heart failure represent a leading cause of degradation of quality of life, recurrent hospitalisations, adverse cardiovascular events and death in European countries. Although major advances have been made in the treatment of coronary artery disease and heart failure, the mechanism of these myocardial disorders remains poorly understood. Alternations of intracellular energetics, compartment-ation of important metabolites and changes in cellular energy transfer networks may play a pivotal role here. In this project we combined the knowledge of compartmentalized energy transfer obtained from the studies on cardiac cells to interpret the data gathered from the beating heart. Using a multidisciplinary approach by combining experimental measurements with the mathematical modelling, we are trying to understand how the high order of organization of intracellular energy transfer influences the heart energetics. The Marie Curie Reintegration Grant was used to finance the first year of the project. Our main results were as follows. First, we developed a mathematical model of interaction between two important proteins in the energy transfer pathway of the cardiac cell (creatine kinase and adenine nucleotide translocase). The main difference between the earlier models and the developed one is computational efficiency of the model while preserving accurate description of interaction between proteins. The new model can be incorporated into larger scale models and allows us to analyse influence of interaction between proteins on energetics of the cell. Our approach can be applied to many interacting proteins in the cell. Second, we were able to demonstrate the changes in energy transfer pathway at extreme work in isolated hearts. Namely, when the work reached loads which were maximal in our preparation, the concentration of key metabolites (ATP and phosphocreatine) reduced, and, energy transfer pathway shifted from coordinated transfer through specialised creatine kinase shuttle system to simple diffusion of ATP between ATP-consuming and ATP-producing organelles. Similar shift has been reported for cyanide-inhibited hearts earlier. Third, we developed a novel method to quantitatively analyse mitochondrial positioning in three dimensions. The developed method can be used to describe intracellular organisation, and may also be used for analysis of time-dependent organisational changes. We used the new method to quantify distribution of mitochondria in ventricular myocytes of rat and trout. The analysis revealed a high order of organization of intermyofibrillar mitochondria in rat cells. The mitochondria are arranged in parallel strands. These strands are separated by approx. 1.8µm and can be found in any transversal direction relative to each other. In contrast to rat, trout ventricular myocytes exhibit a relatively chaotic mitochondrial pattern. The obtained quantitative description of mitochondrial organisation is a requisite for accurate mathematical analysis of mitochondrial systems biology. The influence of mitochondrial arrangement on intracellular energy transfer as well as interaction between different intracellular organelles will be analysed by a new three-dimensional model of energy transfer. The development of such model started as a part of this project.

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