An integrated model of cardiac mitochondrial energy metabolism and calcium dynamics
An integrated model of cardiac mitochondrial energy metabolism and calcium dynamics
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DOI：
10.1016/s0006-3495(03)75079-6
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发表时间：
2003-04-01
影响因子：
3.4
通讯作者：
O'Rourke, B
中科院分区：
文献类型：
--
作者：
Cortassa, S;Aon, MA;O'Rourke, B
我们提出了一个描述心脏线粒体生物能控制的综合热动力学模型。该模型描述了三羧酸 (TCA) 循环、氧化磷酸化和线粒体 Ca2+ 处理。该模型的动力学组件包括调节 NADH 和 FADH(2) 产生的 TCA 循环酶效应子，电子传递链又利用这些效应子建立质子动力 (Deltamu(H))，驱动 F1F0-ATP 酶。此外，线粒体基质 Ca2+（由 Ca2+ 单向转运蛋白和 Na+/Ca2+ 交换器活性决定）调节 TCA 循环酶异柠檬酸脱氢酶和 α-酮戊二酸氢解酶的活性。该模型由 12 个常微分方程描述线粒体膜电位的时间变化率 (Deltapsi(m)) 以及 Ca2+、NADH、ADP 和 TCA 循环中间体的基质浓度。该模型用于预测线粒体对底物递送、代谢抑制、腺嘌呤核苷酸交换速率和 Ca2+ 变化的反应。该模型能够定性和半定量地重现有关线粒体生物能学、Ca2+ 动力学和呼吸控制的实验数据。当 Ca2+ 敏感脱氢酶是呼吸通量的主要速率控制步骤时，响应于细胞质 Ca2+ 的增加，耗氧量 (V-O2)、质子外流、NADH 和 ATP 合成显着增加。当控制转移到下游（例如呼吸链或腺嘌呤核苷酸易位子）时，这些反应就会减弱。在模拟工作量增加的条件下，该模型的时间依赖性行为密切再现了实验观察到的心脏小梁中受起搏频率变化的线粒体 NADH 动态。该模型的稳态和时间依赖性行为支持这样的假设：线粒体基质 Ca2+ 在匹配心肌细胞的能量供应与需求方面发挥着重要作用。
We present an integrated thermokinetic model describing control of cardiac mitochondrial bioenergetics. The model describes the tricarboxylic acid (TCA) cycle, oxidative phosphorylation, and mitochondrial Ca2+ handling. The kinetic component of the model includes effectors of the TCA cycle enzymes regulating production of NADH and FADH(2), which in turn are used by the electron transport chain to establish a proton motive force (Deltamu(H)), driving the F1F0-ATPase. In addition, mitochondrial matrix Ca2+, determined by Ca2+ uniporter and Na+/Ca2+ exchanger activities, regulates activity of the TCA cycle enzymes isocitrate dehydrogenase and alpha-ketoglutarate clehydrogenase. The model is described by twelve ordinary differential equations for the time rate of change of mitochondrial membrane potential (Deltapsi(m)), and matrix concentrations of Ca2+, NADH, ADP, and TCA cycle intermediates. The model is used to predict the response of mitochondria to changes in substrate delivery, metabolic inhibition, the rate of adenine nucleotide exchange, and Ca2+. The model is able to reproduce, qualitatively and semiquantitatively, experimental data concerning mitochondrial bioenergetics, Ca2+ dynamics, and respiratory control. Significant increases in oxygen consumption (V-O2), proton efflux, NADH, and ATP synthesis, in response to an increase in cytoplasmic Ca2+, are obtained when the Ca2+-sensitive dehydrogenases are the main rate-controlling steps of respiratory flux. These responses diminished when control is shifted downstream (e.g., the respiratory chain or adenine nucleotide translocator). The time-dependent behavior of the model, under conditions simulating an increase in workload, closely reproduces experimentally observed mitochondrial NADH dynamics in heart trabeculae subjected to changes in pacing frequency. The steady-state and time-dependent behavior of the model support the hypothesis that mitochondrial matrix Ca2+ plays an important role in matching energy supply with demand in cardiac myocytes.