Mechanism of futile creatine cycling in thermogenesis.
Mechanism of futile creatine cycling in thermogenesis.
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生热作用中无效肌酸循环的机制。
DOI：
10.1152/ajpendo.00444.2020
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Spiegelman,BruceM
中科院分区：
文献类型：
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作者：
Kazak,Lawrence;Spiegelman,BruceM
在大多数细胞中，磷酸肌酸-肌酸的正向和反向磷酸转移反应与ATP/ADP偶对严格按1:1的化学计量进行(9)。然而，产热脂肪细胞中的线粒体相对于添加的肌酸释放出大量过量的ADP（2,10）。基于生物能量学原理和P/O比率（消耗每个氧原子合成的ATP分子）的既定化学计量学（23），我们提出了两种模型，其中肌酸可能支持ADP的超化学计量再生，以驱动脂肪中的产热呼吸（10,12,18）。第一个也是最简单的模型是，线粒体肌酸激酶将使用线粒体ATP将肌酸磷酸化为磷酸肌酸（PCr），随后在细胞器内局部释放ADP将是一个强大的呼吸刺激。下一步，聚合酶链反应将是磷酸酶的直接底物，它将补充线粒体肌酸池。由PCr直接水解产生的再生肌酸将作为另一轮无效肌酸循环的底物。由于我们在分离的线粒体中发现了肌酸引起的呼吸作用（2,10），但由于粗线粒体制剂不是100%纯的，因此PCr水解酶活性可能存在于线粒体本身或与其共同纯化的细胞器上。因此，要么聚合酶链反应和肌酸在膜间空间（IMS）内循环，要么聚合酶链反应被引导出膜间空间，进入线粒体外部的聚合酶链反应磷酸酶活性。实验数据与两种情况一致（2,10）。我们还提出了第二种模型，即在PCr下游的磷代谢物水解磷酸盐之前可能会发生多个磷转移反应（10,12）。这些无效肌酸循环的变化最近得到了广泛的回顾（12,18）。基于非脂肪细胞工作的理论观点，Wallimann及其同事（22）假设产热脂肪细胞利用PCr/肌酸激酶回路(3)来促进产热。在这个回路中，线粒体肌酸激酶产生PCr，它可以扩散到整个细胞，以维持ATP消耗位点附近的高ATP/ADP比率。在他们的假设模型中，Wallimann等人提出了肌酸驱动的钙循环，其中PCr/肌酸激酶回路将通过在sarco/内质网Ca2+ ATP酶（SERCA）泵中维持高ATP/ADP比率来支持钙循环（20）。脂肪细胞中PCr/肌酸激酶回路的操作与线粒体中产热无效肌酸循环并不相互排斥。然而，实验证据来自
The forward and reverse phosphotransfer reactions of phosphocreatine–creatine in most cells occur in a strict 1: 1 stoichiometry with the ATP/ADP couple (9). However, mitochondria in thermogenic adipocytes liberate a large molar excess of ADP with respect to added creatine (2, 10). Based on bioenergetics principles and the established stoichiometry of the P/O ratio (ATP molecules synthesized per oxygen atom consumed)(23), we proposed two models wherein creatine might support this super-stoichiometric regeneration of ADP to drive thermogenic respiration in fat (10, 12, 18).The first and simplest model is that a mitochondrial creatine kinase will use mitochondrial ATP to phosphorylate creatine to phosphocreatine (PCr), and the ensuing liberation of ADP locally within the organelle would be a powerful respiratory stimulus. Next, PCr would be the direct substrate of a phosphatase, which would replenish the mitochondrial creatine pool. The regenerated creatine from direct hydrolysis of PCr would act as a substrate for another round of this futile creatine cycle. Since we identified creatine-elicited respiration in isolated mitochondria (2, 10), but because crude mitochondrial preparations are not 100% pure, PCr hydrolase activity could be present within mitochondria themselves or on organelles that co-purify with them. Thus, either a pool of PCr and creatine circulate within the intermembrane space (IMS) or PCr is channeled out of the IMS toward PCr phosphatase activity that is external from mitochondria. The experimental data are consistent with either scenario (2, 10). We also proposed a second model where multiple phosphotransfer reactions might occur before phosphate hydrolysis from a phosphometabolite that lies downstream of PCr (10, 12). These variations on the futile creatine cycle have recently been extensively reviewed (12, 18). Based on theoretical points founded in non-adipocyte work, Wallimann and colleagues (22) hypothesize that thermogenic adipocytes utilize the PCr/creatine kinase circuit (3) to fuel thermogenesis. In this circuit, mitochondrial creatine kinase generates PCr, which can diffuse throughout the cell to maintain high ATP/ADP ratios locally near sites of ATP consumption. In their hypothetical model, Wallimann et al. propose a creatine-driven calcium cycle wherein the PCr/creatine kinase circuit would support calcium cycling by sustaining a high ATP/ADP ratio at the sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) pump (20). Operation of a PCr/creatine kinase circuit in adipocytes is not mutually exclusive with thermogenic futile creatine cycling in mitochondria. Nevertheless, the experimental evidence from