A simulation study on the role of mitochondria-sarcoplasmic reticulum Ca 2+ interaction in cardiomyocyte energetics during exercise.

Autor: Takeuchi A; Department of Integrative and Systems Physiology, Faculty of Medical Sciences and Life Science Innovation Center, University of Fukui, Fukui, Japan., Matsuoka S; Department of Integrative and Systems Physiology, Faculty of Medical Sciences and Life Science Innovation Center, University of Fukui, Fukui, Japan.
Jazyk: angličtina
Zdroj: The Journal of physiology [J Physiol] 2024 Oct 10. Date of Electronic Publication: 2024 Oct 10.
DOI: 10.1113/JP286054
Abstrakt: Previous studies demonstrated that the mitochondrial Ca 2+ uniporter MCU and the Na + -Ca 2+ exchanger NCLX exist in proximity to the sarcoplasmic reticulum (SR) ryanodine receptor RyR and the Ca 2+ pump SERCA, respectively, creating a mitochondria-SR Ca 2+ interaction. However, the physiological relevance of the mitochondria-SR Ca 2+ interaction has remained unsolved. Furthermore, although mitochondrial Ca 2+ has been proposed to be an important factor regulating mitochondrial energy metabolism, by activating NADH-producing dehydrogenases, the contribution of the Ca 2+ -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 Ca 2+ 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 Ca 2+ uniport activity-RyR, was the primary determinant of mitochondrial Ca 2+ concentration, and that the Ca 2+ -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 Ca 2+ interaction, created via the uneven distribution of Ca 2+ handling proteins, optimizes the contribution of the mitochondrial Ca 2+ -dependent regulatory mechanism to stabilizing NADH during exercise. KEY POINTS: The mitochondrial Ca 2+ uniporter protein MCU and the Na + -Ca 2+ exchanger protein NCLX are reported to exist in proximity to the sarcoplasmic reticulum (SR) ryanodine receptor RyR and the Ca 2+ pump SERCA, respectively, creating a mitochondria-SR Ca 2+ interaction in cardiomyocytes. Mitochondrial Ca 2+ (Ca 2+ 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 Ca 2+ interaction in cardiac energetics during exercise. Simulation analyses revealed that the spatial coupling particularly via mitochondrial Ca 2+ uniport activity-RyR is the primary determinant of Ca 2+ mit concentration, and that the activation of NADH-producing dehydrogenases by Ca 2+ mit contributes to NADH stability during exercise. The mitochondria-SR Ca 2+ interaction optimizes the contribution of Ca 2+ mit to the activation of NADH-producing dehydrogenases.
(© 2024 The Author(s). The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)
Databáze: MEDLINE
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