PXD025032

PXD025032 is an original dataset announced via ProteomeXchange.

Title	Characterization of a mitochondria associated phosphocreatine phosphatase in thermogenic adipocytes
Description	Adaptive thermogenesis has attracted much attention because of its ability to raise systemic energy expenditure and counter obesity and diabetes. Recent data have indicated that thermogenic fat cells utilize creatine to stimulate futile substrate cycling, dissipating chemical energy as heat. This model was based on the super-stoichiometric relationship between creatine added to mitochondria and O2 consumed, and this project aims at providing direct evidence for the molecular basis of this futile creatine cycling activity. In this project, we found that thermogenic fat cells contain robust phosphocreatine hydrolase (PCr’ase) activity, attributable to tissue-nonspecific alkaline phosphatase (TNAP), which was identified by the quantitative mass spectrometric analysis of a purified mitochondrial protein fraction containing the PCr’ase activity. TNAP hydrolyzes phosphocreatine to initiate a futile cycle of creatine dephosphorylation and phosphorylation; it is localized to mitochondria of thermogenic fat cells, where the futile creatine cycling occurs. Furthermore, we demonstrated in this project the essential role of TNAP in activating the futile creatine cycling and increasing whole body energy expenditure using genetic and pharmacological approaches. We also found that the genetic depletion of TNAP in murine adipose tissue causes rapid-onset obesity, with no change in movement or feeding behavior of the animals. Using quantitative mass spectrometry, we showed that genetic depletion of TNAP causes an upregulation of UCP1, as well as other proteins involved in oxidative metabolism, to compensate for a dampened thermogenesis. In summary, the data we acquired in this project illustrate the critical role of TNAP as a phosphocreatine phosphatase in the futile creatine cycling and adipose thermogenesis.
HostingRepository	PRIDE
AnnounceDate	2022-02-17
AnnouncementXML	Submission_2022-02-17_00:08:23.984.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	mark Jedrychowski
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	monohydroxylated residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2021-03-26 09:42:35	ID requested
⏵ 1	2022-02-17 00:08:24	announced

Sun Y, Rahbani JF, Jedrychowski MP, Riley CL, Vidoni S, Bogoslavski D, Hu B, Dumesic PA, Zeng X, Wang AB, Knudsen NH, Kim CR, Marasciullo A, Mill, á, n JL, Chouchani ET, Kazak L, Spiegelman BM, Mitochondrial TNAP controls thermogenesis by hydrolysis of phosphocreatine. Nature, 593(7860):580-585(2021) [pubmed]

submitter keyword: phosphocreatine, TNAP, adipocyte, thermogenesis, obesity

Bruce Spiegelman
contact affiliation	Dana Farber Cancer Institute
contact email	bruce_spiegelman@dfci.harvard.edu
lab head
mark Jedrychowski
contact affiliation	Harvard Medical School
contact email	mark_jedrychowski@hms.harvard.edu
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2022/02/PXD025032

PRIDE project URI

• PRIDE
  1. PXD025032
     1. Label: PRIDE project
     2. Name: Characterization of a mitochondria associated phosphocreatine phosphatase in thermogenic adipocytes