小柯机器人

美国丹娜-法伯癌症研究所Bruce M. Spiegelman研究组的研究发现线粒体TNAP通过磷酸肌酸水解来调控产热。该研究于2021年5月12日在线发表于国际学术期刊《自然》杂志。

研究人员提供了小鼠进行无效肌酸循环活性的直接分子证据。产热脂肪细胞具有很强的磷酸肌酸磷酸酶活性，这归因于组织非特异性碱性磷酸酶（TNAP）。TNAP通过水解磷酸肌酸开启无效的肌酸去磷酸化和磷酸化循环。与其他细胞不同，产热脂肪细胞中的TNAP定位于线粒体，而线粒体是无效肌酸循环的发生地。当小鼠暴露于寒冷环境时，会有效诱导TNAP的表达，其在孤立线粒体中的抑制作用导致无效肌酸循环的丧失。此外，敲除脂肪细胞中 的TNAP基因可减少全身能量消耗，并导致小鼠产生肥胖，但不影响运动或摄食行为。这些数据揭示了TNAP在无效肌酸循环中作为磷酸肌酸磷酸酶的关键作用。

据悉，适应性热产因其具有增加全身能量消耗以及抵抗肥胖和糖尿病的能力而备受关注。最近的研究表明，产热脂肪细胞利用肌酸刺激无用的底物循环，将化学能转化为热能。该模型是基于进入到线粒体的肌酸与消耗氧气量之间的化学计量关系得到。

附：英文原文

Title: Mitochondrial TNAP controls thermogenesis by hydrolysis of phosphocreatine

Author: Yizhi Sun, Janane F. Rahbani, Mark P. Jedrychowski, Christopher L. Riley, Sara Vidoni, Dina Bogoslavski, Bo Hu, Phillip A. Dumesic, Xing Zeng, Alex B. Wang, Nelson H. Knudsen, Caroline R. Kim, Anthony Marasciullo, Jos L. Milln, Edward T. Chouchani, Lawrence Kazak, Bruce M. Spiegelman

Issue&Volume: 2021-05-12

Abstract: Adaptive thermogenesis has attracted much attention because of its ability to increase systemic energy expenditure and to counter obesity and diabetes1,2,3. Recent data have indicated that thermogenic fat cells use creatine to stimulate futile substrate cycling, dissipating chemical energy as heat4,5. This model was based on the super-stoichiometric relationship between the amount of creatine added to mitochondria and the quantity of oxygen consumed. Here we provide direct evidence for the molecular basis of this futile creatine cycling activity in mice. Thermogenic fat cells have robust phosphocreatine phosphatase activity, which is attributed to tissue-nonspecific alkaline phosphatase (TNAP). TNAP hydrolyses phosphocreatine to initiate a futile cycle of creatine dephosphorylation and phosphorylation. Unlike in other cells, TNAP in thermogenic fat cells is localized to the mitochondria, where futile creatine cycling occurs. TNAP expression is powerfully induced when mice are exposed to cold conditions, and its inhibition in isolated mitochondria leads to a loss of futile creatine cycling. In addition, genetic ablation of TNAP in adipocytes reduces whole-body energy expenditure and leads to rapid-onset obesity in mice, with no change in movement or feeding behaviour. These data illustrate the critical role of TNAP as a phosphocreatine phosphatase in the futile creatine cycle.

DOI: 10.1038/s41586-021-03533-z

Source: https://www.nature.com/articles/s41586-021-03533-z

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