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- W2083609969 abstract "Pressure-volume work of the heart increases with increases in rate, stroke volume and afterload. The cardiac [Ca2+]i transient is a key cellular signal that activates contraction and links electrical activity to the mechanical response of the heart. It also influences the mitochondrial calcium ([Ca2+]m ) that is thought to be a major regulator of mitochondrial ATP production by stimulating the three calcium-dependent dehydrogenases of tricarboxylic acid cycle and the F1F0 ATPase. Here we examine this Ca2+ hypothesis of mitochondrial ATP production using a mathematical model of mitochondrial function. However, the magnitude of [Ca2+]mfluctuations resulting from cytosolic Ca2+variations is actively investigated by many groups and remains controversial. Our starting position was ourearlier model that examined mitochondrial energy production and ionic homeostasis(Nguyen et al, 2007).We reduced the assumed Ca2+ fluxes into and out of the mitochondria so that they were consistent with recent publications from our group (Boyman et al 2014). This revised model thus produced smaller variations of [Ca2+]m during a beat and was thus consistent with our recent analysis of calcium uniporter fluxes from diverse investigations (Williams et al 2013). Our simulations showed that although the new formulation results in a smaller fractional rise in ATP production during pacing, it showed a 10-fold higher efficiency of ATP production (when normalized tosubstrate entry). The model suggests that this improved efficiency is due to a reduction in mitochondrial membrane potential depolarization due to the Ca2+ influx and a reduction in the dissipation of the mitochondrial proton gradient across the inner membrane. This analysis suggests that there is profound energy benefit to the myocardium when mitochondrial ATP production is regulated by small calcium transients in the mitochondria ([Ca2+]m ) with each heartbeat." @default.
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- W2083609969 date "2015-01-01" @default.
- W2083609969 modified "2023-10-18" @default.
- W2083609969 title "Analysis of ATP Production Efficiency of Beat-To-Beat Calcium Fluctuations in Cardiac Mitochondria" @default.
- W2083609969 doi "https://doi.org/10.1016/j.bpj.2014.11.617" @default.
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