Role of the creatine/phosphocreatine system in the regulation of mitochondrial respiration
Role of the creatine/phosphocreatine system in the regulation of mitochondrial respiration
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DOI：
10.1046/j.1365-201x.2000.00715.x
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发表时间：
2000-04-01
期刊：
影响因子：
--
通讯作者：
Kay, L
中科院分区：
文献类型：
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作者：
Saks, VA;Kongas, O;Kay, L
在透性化的小鼠心脏纤维中实验研究了心肌细胞中线粒体呼吸的代谢调节机制，并通过计算机模拟进行了研究。实验表明，线粒体呼吸速率可由线粒体肌酸激酶在线粒体膜间隙局部产生ADP来控制。空间非均匀的反应扩散模型的划分的能量转移被用来分析细胞质中的代谢物水平可能是重要的呼吸调节。在低和中等工作负荷下，VO 2等于70 μ mol min（-1）g（-1）干重，呼吸反应的唯一因素是无机磷酸盐。在VO 2值高于70 μ mol min（-1）g（-1）干重时，呼吸速率主要对肌酸、磷酸肌酸和时间平均（在收缩周期内）胞质中ADP浓度的变化作出反应。这些结果表明，在中等工作负荷的条件下，在给定的生理肌酸和磷酸肌酸浓度下的肌酸激酶活性（在这些条件下可达到的表观最大活性）超过氧化磷酸化速率，氧化磷酸化速率由从后者的非常低的值开始的Pi浓度变化控制。在较高的工作负荷，应通过增加肌酸和降低磷酸肌酸浓度上调mi-CK，只有在非常高的工作负荷的ADP扩散通量应增加上调氧化磷酸化。因此，根据对磷酸肌酸/肌酸系统的区室化能量转移的计算机模拟研究，作者得出结论，存在多个平行的调节因素，根据工作量控制氧气消耗率。如果肌酸激酶被抑制（并且没有肌激酶活性），则呼吸需要ADP的高扩散通量返回线粒体，这是呼吸的唯一调节器。然而，这需要增加细胞质中的ADP浓度，从而抑制收缩。
The mechanism of metabolic regulation of mitochondrial respiration in cardiac muscle cells was studied experimentally in the permeabilized heart fibres of mice and by computer modelling in silico. The experiments showed that the rate of mitochondrial respiration could be controlled by local production of ADP by mitochondrial creatine kinase in the intermembrane space of mitochondria. The spatially inhomogenous reaction-diffusion model of compartmentalized energy transfer was used to analyse which metabolite level in cytoplasm may be important for regulation of respiration. At low and moderate workloads, up to VO2 equal to 70 mu mol min(-1) g(-1) dry weight, the only factor to which respiration responded was inorganic phosphate. At the values of VO2 higher than 70 mu mol min(-1) g(-1) dry weight, the respiration rate responded mostly to changes in creatine, phosphocreatine and then time-averaged (over the contractile cycle) ADP concentrations in the cytoplasm. These results are taken to show that under conditions of moderate workloads, creatine kinase activity at given physiological creatine and phosphocreatine concentrations (apparent maximal activity achievable under these conditions) is in excess to oxidative phosphorylation rate, which is controlled by P-i concentration changes starting from very low values of the latter. At higher workloads mi-CK should be upregulated by increasing creatine and decreasing phosphocreatine concentrations, and only at very high workloads the ADP diffusion flux should be increased to upregulate oxidative phosphorylation. Thus, on the basis of the study in silico of compartmentalized energy transfer by phophocreatine/creatine system, the authors conclude that there exist multiple parallel regulatory factors controlling the rate of oxygen consumption in dependence of the workload. If creatine kinase is inhibited (and there is no myokinase activity), respiration requires high diffusive flux of ADP back into mitochondria, which is the sole regulator of respiration. This needs, however, increased ADP concentrations in the cytoplasm, which in turn result in inhibition of contraction.