Mitochondrial energetics, pH regulation, and ion dynamics: a computational-experimental approach.
Mitochondrial energetics, pH regulation, and ion dynamics: a computational-experimental approach.
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DOI：
10.1016/j.bpj.2011.05.027
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发表时间：
2011-06
影响因子：
3.4
通讯作者：
An-Chi Wei;M. Aon;B. O’Rourke;R. Winslow;S. Cortassa
中科院分区：
文献类型：
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作者：
An-Chi Wei;M. Aon;B. O’Rourke;R. Winslow;S. Cortassa
我们开发了一个线粒体能量学的计算模型，包括Ca2+，质子，Na+和磷酸盐动力学。该模型考虑了配合物I和配合物II底物的不同呼吸通量，pH对平衡常数和酶动力学的影响，以及能量中间体的酸碱平衡分布。我们通过实验测定了从断电到通电、从2/4状态到3状态呼吸、或进入缺氧和解偶联状态时豚鼠线粒体的NADH和ΔΨmin，并将结果与模型模拟结果进行了比较。该模型定量地再现了实验观察到的ΔΨm的大小、NADH水平的范围、呼吸通量和呼吸控制率在连续添加底物和ADP引起的转变时的范围。模拟结果也能够模拟ΔΨmupon向状态4线粒体添加磷酸盐，导致基质酸化和ΔΨmpolarization的变化。综合线粒体模型的稳态行为定性地模拟了呼吸对质子动力的依赖，以及呼吸和ATP合成通量与氧化还原和磷酸化电位之间存在的预期通量-力关系。这种升级的线粒体模型为模拟线粒体在功能失调状态下的生理行为提供了新的机会，包括pH和离子动力学的变化。
We developed a computational model of mitochondrial energetics that includes Ca2+, proton, Na+, and phosphate dynamics. The model accounts for distinct respiratory fluxes from substrates of complex I and complex II, pH effects on equilibrium constants and enzyme kinetics, and the acid-base equilibrium distributions of energy intermediaries. We experimentally determined NADH and ΔΨmin guinea pig mitochondria during transitions from de-energized to energized, or during state 2/4 to state 3 respiration, or into hypoxia and uncoupling, and compared the results with those obtained in model simulations. The model quantitatively reproduces the experimentally observed magnitude of ΔΨm, the range of NADH levels, respiratory fluxes, and respiratory control ratio upon transitions elicited by sequential additions of substrate and ADP. Simulation results are also able to mimic the change in ΔΨmupon addition of phosphate to state 4 mitochondria, leading to matrix acidification and ΔΨmpolarization. The steady-state behavior of the integrated mitochondrial model qualitatively simulates the dependence of respiration on the proton motive force, and the expected flux-force relationships existing between respiratory and ATP synthesis fluxes versus redox and phosphorylation potentials. This upgraded mitochondrial model provides what we believe are new opportunities for simulating mitochondrial physiological behavior during dysfunctional states involving changes in pH and ion dynamics.