Yaniv Yael, Stanley William C, Saidel Gerald M, Cabrera Marco E, Landesberg Amir
Faculty of Biomedical Engineering, Technion, Isreal Institute of Technology, Haifa 32000 Israel.
Ann N Y Acad Sci. 2008 Mar;1123:69-78. doi: 10.1196/annals.1420.009.
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.
心脏可使线粒体ATP生成速率适应能量需求，即便在不同工作负荷之间发生大幅转变时，ATP、ADP和磷酸（Pi）的浓度也不会有明显变化。我们认为，需求变化会调节胞质Ca2+浓度，进而改变线粒体Ca2+浓度以调节ATP生成。因此，线粒体的ATP生成速率与肌节横桥（XB）的ATP消耗速率相耦合。我们构建了一个综合模型，将心脏代谢和线粒体ATP生成与肌节Ca2+瞬变调节及ATP消耗联系起来。该模型包括两个相互关联的系统，它们同时运行并采用两个不同的整合步骤：（1）较快的系统描述了兴奋收缩偶联的控制过程，包括快速的胞质Ca2+瞬变、抽搐性机械收缩以及线粒体Ca2+的相关波动。（2）较慢的系统模拟代谢系统，该系统由三个不同的区室组成：血液、胞质溶胶和线粒体。模型的基本要素是不同区室中的动态质量平衡。胞质Ca2+的处理由四种细胞器决定：肌膜Ca2+的流入和流出；肌浆网（SR）Ca2+的释放和螯合（SR）；与肌节调节肌钙蛋白复合物的结合和解离；以及线粒体Ca2+流动。线粒体Ca2+流动由Ca2+单向转运体和线粒体Na+Ca2+交换体决定。胞质Ca2+决定肌节的ATP消耗速率。Ca2+与肌钙蛋白的结合调节XB募集速率和力量发展。线粒体Ca2+浓度决定丙酮酸脱氢酶活性以及F(1)-F(0)ATP酶的ATP生成速率。工作负荷通过反馈回路调节胞质Ca2+浓度。前负荷和后负荷影响强力XB的数量。强力XB的数量决定肌钙蛋白对Ca2+的亲和力，从而改变胞质Ca2+瞬变。模型模拟量化了Ca2+在同时控制收缩力和ATP生成速率方面的作用。它解释了已有的经验观察结果，即代谢通量可发生显著变化，而关键核苷酸（ATP和ADP）浓度却无显著变化。对心脏生化能向机械能转化控制机制的定量研究可能会为缺血性和衰竭心肌带来新的治疗方法。
