A simulation study on the role of mitochondria-sarcoplasmic reticulum Ca²⁺ interaction in cardiomyocyte energetics...

Previous studies demonstrated that the mitochondrial Ca²⁺ uniporter MCU and the Na⁺-Ca²⁺ exchanger NCLX exist in proximity to the sarcoplasmic reticulum (SR) ryanodine receptor RyR and the Ca²⁺ pump SERCA, respectively, creating a mitochondria-SR Ca²⁺ interaction. However, the physiological relevance of the mitochondria-SR Ca²⁺ interaction has remained unsolved. Furthermore, although mitochondrial Ca²⁺ has been proposed to be an important factor regulating mitochondrial energy metabolism, by activating NADH-producing dehydrogenases, the contribution of the Ca²⁺-dependent regulatory mechanisms to cellular functions under physiological conditions has been controversial. In this study, we constructed a new integrated model of human ventricular myocyte with excitation-contraction-energetics coupling and investigated systematically the contribution of mitochondria-SR Ca²⁺ interaction, especially focusing on cardiac energetics during dynamic workload transitions in exercise. Simulation analyses revealed that the spatial coupling of mitochondria and SR, particularly via mitochondrial Ca²⁺ uniport activity-RyR, was the primary determinant of mitochondrial Ca²⁺ concentration, and that the Ca²⁺-dependent regulatory mechanism facilitated mitochondrial NADH recovery during exercise and contributed to the stability of NADH in the workload transition by about 40%, while oxygen consumption rate and cytoplasmic ATP level were not influenced. We concluded that the mitochondria-SR Ca²⁺ interaction, created via the uneven distribution of Ca²⁺ handling proteins, optimizes the contribution of the mitochondrial Ca²⁺-dependent regulatory mechanism to stabilizing NADH during exercise. KEY POINTS: The mitochondrial Ca²⁺ uniporter protein MCU and the Na⁺-Ca²⁺ exchanger protein NCLX are reported to exist in proximity to the sarcoplasmic reticulum (SR) ryanodine receptor RyR and the Ca²⁺ pump SERCA, respectively, creating a mitochondria-SR Ca²⁺ interaction in cardiomyocytes. Mitochondrial Ca²⁺ (Ca²⁺ _mit) has been proposed to be an important factor regulating mitochondrial energy metabolism, by activating NADH-producing dehydrogenases. Here we constructed an integrated model of a human ventricular myocyte with excitation-contraction-energetics coupling and investigated the role of the mitochondria-SR Ca²⁺ interaction in cardiac energetics during exercise. Simulation analyses revealed that the spatial coupling particularly via mitochondrial Ca²⁺ uniport activity-RyR is the primary determinant of Ca²⁺ _mit concentration, and that the activation of NADH-producing dehydrogenases by Ca²⁺ _mit contributes to NADH stability during exercise. The mitochondria-SR Ca²⁺ interaction optimizes the contribution of Ca²⁺ _mit to the activation of NADH-producing dehydrogenases.