The role of Ca2+ in coupling cardiac metabolism with regulation of contraction: in silico modeling.

The heart adapts the rate of mitochondrial ATP production to energy demand without noticeable changes in the concentration of ATP, ADP and Pi, even for large transitions between different workloads. We suggest that the changes in demand modulate the cytosolic Ca2+ concentration that changes mitochondrial Ca2+ to regulate ATP production. Thus, the rate of ATP production by the mitochondria is coupled to the rate of ATP consumption by the sarcomere cross-bridges (XBs). An integrated model was developed to couple cardiac metabolism and mitochondrial ATP production with the regulation of Ca2+ transient and ATP consumption by the sarcomere. The model includes two interrelated systems that run simultaneously utilizing two different integration steps: (1) The faster system describes the control of excitation contraction coupling with fast cytosolic Ca2+ transients, twitch mechanical contractions, and associated fluctuations in the mitochondrial Ca2+. (2) A slower system simulates the metabolic system, which consists of three different compartments: blood, cytosol, and mitochondria. The basic elements of the model are dynamic mass balances in the different compartments. Cytosolic Ca2+ handling is determined by four organelles: sarcolemmal Ca2+ influx and efflux; sarcoplasmic reticulum (SR) Ca2+ release and sequestration (SR); binding and dissociation from sarcomeric regulatory troponin complexes; and mitochondrial Ca2+ flows. Mitochondrial Ca2+ flows are determined by the Ca2+ uniporter and the mitochondrial Na+Ca2+ exchanger. The cytosolic Ca2+ determines the rate of ATP consumption by the sarcomere. Ca2+ binding to troponin regulates the rate of XBs recruitment and force development. The mitochondrial Ca2+ concentration determines the pyruvate dehydrogenase activity and the rate of ATP production by the F(1)-F(0) ATPase. The workload modulates the cytosolic Ca2+ concentration through feedback loops. The preload and afterload affect the number of strong XBs. The number of strong XBs determines the affinity of troponin for Ca2+, which alters the cytosolic Ca2+ transient. Model simulations quantify the role of Ca2+ in simultaneously controlling the power of contraction and the rate of ATP production. It explains the established empirical observation that significant changes in the metabolic fluxes can occur without significant changes in the key nucleotide (ATP and ADP) concentrations. Quantitative investigations of the mechanisms underlying the cardiac control of biochemical to mechanical energy conversion may lead to novel therapeutic modalities for the ischemic and failing myocardium.