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Mitochondrial TNAP Controls Thermogenesis by Hydrolysis of Phosphocreatine

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Mitochondrial TNAP Controls Thermogenesis by Hydrolysis of Phosphocreatine Article Mitochondrial TNAP controls thermogenesis by hydrolysis of phosphocreatine https://doi.org/10.1038/s41586-021-03533-z Yizhi Sun1,2, Janane F. Rahbani3,4, Mark P. Jedrychowski1,2, Christopher L. Riley1,2, Sara Vidoni1,2, Dina Bogoslavski1, Bo Hu1,2, Phillip A. Dumesic1,2, Xing Zeng1,2, Alex B. Wang1,2, Received: 31 August 2020 Nelson H. Knudsen1,2, Caroline R. Kim1, Anthony Marasciullo1, José L. Millán5, Accepted: 11 April 2021 Edward T. Chouchani1,2, Lawrence Kazak3,4 & Bruce M. Spiegelman1,2 ✉ Published online: xx xx xxxx Check for updates 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-nonspecifc 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. Adipose tissues have gained considerable interest because of the New pathways of thermogenesis in adipose tissues have been dis- tight linkage between obesity and metabolic disorders such as type covered in the past few years14,15. Previously, a pathway was described 2 diabetes, cardiovascular diseases and many cancers1. Two particu- in which creatine (Cr) and phosphocreatine (PCr) are in a futile cycle, lar types of fat cell, brown and beige adipocytes, are notable for their which dissipates the high energy charge of PCr without performing exceptional ability to oxidize biological fuels and to support adaptive any mechanical or chemical work5. This was named the futile creatine thermogenesis2,3. These two types of thermogenic fat cell utilize futile cycle (FCC). Biochemical, pharmacological and genetic evidence indi- cycles to dissipate chemical energy in the form of heat without perform- cates that this pathway is an important component of adipose tissue ing mechanical or chemical work4. Accordingly, they both serve as a thermogenesis5,16–18. Proteomic and transcriptomic data also suggest physiological defence against hypothermia, obesity and obesity-linked that this pathway is important for thermogenesis in human fat19,20, and metabolic disorders. Notably, the presence of functional thermogenic cultured human brown or beige fat cells show a marked suppression adipocytes in adult humans is now well established6–8. of thermogenic respiration when creatine metabolism is inhibited5. Despite the important metabolic functions of adaptive thermogen- Despite the apparent physiological importance of the FCC, ques- esis, its molecular mechanisms are not fully understood. Although tions concerning its mechanism remain to be answered. PCr is iso- uncoupling protein 1 (UCP1) is the most-recognized thermogenic energetic with ATP and serves both as a reservoir and a shuttle of the effector9,10, it is required for defence of body temperature only on a high-energy phosphate21. In theory, the FCC could involve a direct pure genetic background in mice11,12. Ucp1-knockout mice on a mixed enzymatic hydrolysis of PCr, but such an enzymatic activity has never genetic background can tolerate cold exposure with no loss of core been described in the biomedical literature from cellular sources. In body temperature. Moreover, recent work has demonstrated that even this study, we identify TNAP (encoded by Alpl) as a robust PCr phos- within inbred strains of mice, cold exposure results in severe damage phatase in thermogenic fat. We find that TNAP in thermogenic fat cells to the entire electron transport chain in the mitochondria of brown localizes within mitochondria—a highly atypical subcellular location. fat without UCP113. These findings suggest that at least some part of Chemical and genetic ablation of adipose TNAP activity demonstrates the loss of defence against hypothermia due to the genetic absence that this enzyme has a critical role in supporting the FCC and adaptive of UCP1 must now be reconsidered mechanistically. thermogenesis. 1Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA. 2Department of Cell Biology, Harvard Medical School, Boston, MA, USA. 3Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada. 4Department of Biochemistry, McGill University, Montreal, Quebec, Canada. 5Sanford Children’s Health Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA. ✉e-mail: [email protected] Nature | www.nature.com | 1 Article a PCr Hydrolase Pi 1+ ² 2 1+ 2 ² P ² H O 2 2– 2 + 2 + 1 1 + HPO4 ² 1 1 2 + 2 2 b c d PCr Sonication 400 Cold BAT Room-temperature BAT ) –1 Heart Buffer Ultracentrifugation 300 control 200 Pi Detergent 100 PCr phosphatase Mitochondrial SEC, IEX activity (nM min extract 0 4 2 0 –2 –4 –5 Mass spectrometry 078 910111213 31P (ppm) SEC elution volume (ml) e PCr phosphatase Protein ID Gene symbol Description Peptides Enrichment f 1,500 sp|Q9CZ13|QCR1_MOUSE Uqcrc1 Cytochrome b-c1 complex subunit 1, mitochondrial 17 17.82 Cold sp|Q62465|VAT1_MOUSE Vat1 Synaptic vesicle membrane protein VAT-1 homologue 6 11.67 Warm sp|Q3UWW6|GA2L3_MOUSE Gas2I3 GAS2-like protein 3 1 11.50 1,000 sp|O35114|SCRB2_MOUSE Scarb2 Lysosome membrane protein 2 24 8.72 sp|O08749|DLDH_MOUSE Dld Dihydrolipoyl dehydrogenase, mitochondrial 25 7.43 sp|P09242|PPBT_MOUSE Alpl Alkaline phosphatase, tissue-nonspecic isozyme 23 7.19 500 sp|P51912|AAAT_MOUSE Neutral amino acid transporter B 1 5.56 Slc1a5 mRNA expression sp|P06909|CFAH_MOUSE Cfh Complement factor H 47 5.45 (normalized counts) sp|P11438|LAMP1_MOUSE Lamp1 Lysosome-associated membrane glycoprotein 1 29 5.25 Alpl 0 sp|P38647|GRP75_MOUSE Hspa9 Stress-70 protein, mitochondrial 81 4.72 Brown Beige Fig. 1 | Isolation and identification of TNAP as a cold-inducible PCr errors of nonlinear regression that fits a straight-line model to the initial linear phosphatase from mitochondria of thermogenic fat. a, Chemical equation phase of PCr hydrolysis kinetics measured by 31P NMR over four time points for the hydrolysis of phosphocreatine, with the phosphorus-containing (shown in Source Data). e, The top 10 proteins enriched in the active fraction chemical species indicated at the top. b, Stacked one-dimensional 31P NMR compared with a nearby, less-active fraction from ion-exchange chromatography. spectra showing the hydrolysis of phosphocreatine 6 h after the addition of TNAP (encoded by Alpl) is highlighted in grey. f, UCP1 TRAP (translating mitochondrial protein extract (1.0 mg ml−1) from BAT of cold-acclimated mice. ribosome affinity purification) data showing the cold-sensitivity of Alpl c, Scheme showing the isolation and identification of PCr phosphatase(s) from expression in brown and beige adipocytes. Data were adapted from ref. 23 and the sucrose-gradient-purified mitochondrial preparations obtained from normalized with DESeq241, and are presented as mean ± s.e.m.; n = 5 for cold and mouse tissues. IEX, ion-exchange chromatography. d, The PCr phosphatase warm brown adipocytes, 4 for cold beige adipocytes, and 3 for warm beige activities of different fractions from SEC. Error bars represent the standard adipocytes (all are biologically independent samples). spectrometry was performed on an active fraction (fraction a) and a PCr phosphatase activity in thermogenic fat nearby, much less active fraction (fraction b). The gene alkaline phos- To determine whether thermogenic fat displays PCr phosphatase activ- phatase, liver form (Alpl), which encodes TNAP, was sevenfold enriched ity, we incubated PCr with mitochondrial protein extracts prepared in the active fraction compared with the less active fraction (Fig. 1e), in from the interscapular brown adipose tissue (BAT) of mice that were agreement with the detected hydrolytic activities. The enrichment of chronically exposed to cold (4 °C for 2 weeks). 31P nuclear magnetic TNAP in the active fractions was validated by western blotting, using resonance (NMR) was used to simultaneously monitor the consump- an antibody that detects endogenous TNAP (Extended Data Fig. 1c). tion of PCr and the production of inorganic phosphate (Pi) (Fig. 1a, b). In addition, the PCr phosphatase activity detected in the total mito- Using this approach, we found that mitochondrial protein extracts chondrial protein extract derived from BAT was diminished by treat- of interscapular BAT and inguinal white adipose tissue (iWAT) (con- ment with SBI-425, a highly specific inhibitor of TNAP22 (Extended Data taining beige adipocytes) exhibited a robust PCr phosphatase activity Fig.
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