TY - JOUR
T1 - Mitochondrial TNAP controls thermogenesis by hydrolysis of phosphocreatine
AU - Sun, Yizhi
AU - Rahbani, Janane F.
AU - Jedrychowski, Mark P.
AU - Riley, Christopher L.
AU - Vidoni, Sara
AU - Bogoslavski, Dina
AU - Hu, Bo
AU - Dumesic, Phillip A.
AU - Zeng, Xing
AU - Wang, Alex B.
AU - Knudsen, Nelson H.
AU - Kim, Caroline R.
AU - Marasciullo, Anthony
AU - Millán, José L.
AU - Chouchani, Edward T.
AU - Kazak, Lawrence
AU - Spiegelman, Bruce M.
N1 - Funding Information:
Acknowledgements We thank C. J. Rosen for sharing the Alplfl/flmouse strain with permission of J.L.M.; R. Garrity for help with CLAMS studies; the NMR Core jointly operated by Harvard Medical School and Dana-Farber Cancer Institute for help with NMR data acquisition; Nikon Imaging Center at Harvard Medical School for help with fluorescence imaging studies; the EM Core at Harvard Medical School for APEX2/EM imaging studies; and the Mass Spectrometry Facility at Beth Israel Deaconess Medical Center for targeted metabolomics studies. Y.S. and C.L.R. are supported by the American Heart Association postdoctoral fellowship. J.F.R. is supported by the Charlotte and Leo Karassik Fellowship. B.H. was a Cancer Research Institute/ Leonard Kahn Foundation Fellow. P.A.D. is supported by a Damon Runyon Cancer Research Foundation Fellowship. This study was supported by NIDCR grant DE12889 to J.L.M., NIH grant DK 123095 to E.T.C., Canadian Institutes of Health Research (CIHR) grant PJT-159529 to L.K. and JPB Foundation 6293803 and NIH grant DK123228 to B.M.S.
Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2021/5/27
Y1 - 2021/5/27
N2 - Adaptive thermogenesis has attracted much attention because of its ability to increase systemic energy expenditure and to counter obesity and diabetes1–3. 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.
AB - Adaptive thermogenesis has attracted much attention because of its ability to increase systemic energy expenditure and to counter obesity and diabetes1–3. 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.
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U2 - 10.1038/s41586-021-03533-z
DO - 10.1038/s41586-021-03533-z
M3 - Article
C2 - 33981039
AN - SCOPUS:85105776241
SN - 0028-0836
VL - 593
SP - 580
EP - 585
JO - Nature
JF - Nature
IS - 7860
ER -