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Mitochondrial ROS regulate thermogenic energy expenditure and sulfenylation of UCP1

Nature volume 532, pages 112116 (07 April 2016) | Download Citation

  • A Corrigendum to this article was published on 18 May 2016

Abstract

Brown and beige adipose tissues can dissipate chemical energy as heat through thermogenic respiration, which requires uncoupling protein 1 (UCP1)1,2. Thermogenesis from these adipocytes can combat obesity and diabetes3, encouraging investigation of factors that control UCP1-dependent respiration in vivo. Here we show that acutely activated thermogenesis in brown adipose tissue is defined by a substantial increase in levels of mitochondrial reactive oxygen species (ROS). Remarkably, this process supports in vivo thermogenesis, as pharmacological depletion of mitochondrial ROS results in hypothermia upon cold exposure, and inhibits UCP1-dependent increases in whole-body energy expenditure. We further establish that thermogenic ROS alter the redox status of cysteine thiols in brown adipose tissue to drive increased respiration, and that Cys253 of UCP1 is a key target. UCP1 Cys253 is sulfenylated during thermogenesis, while mutation of this site desensitizes the purine-nucleotide-inhibited state of the carrier to adrenergic activation and uncoupling. These studies identify mitochondrial ROS induction in brown adipose tissue as a mechanism that supports UCP1-dependent thermogenesis and whole-body energy expenditure, which opens the way to improved therapeutic strategies for combating metabolic disorders.

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Acknowledgements

Supported by the JPB Foundation and National Institutes of Health (DK031405) to B.M.S. and by grants from Human Frontiers Science Program (to E.T.C.) and the Canadian Institutes for Health Research (to L.K.). We acknowledge M. Murphy, Y. Kirichok, and A. Bertholet for many discussions. We also thank M. Murphy for providing MitoQ.

Author information

Author notes

    • Edward T. Chouchani
    •  & Lawrence Kazak

    These authors contributed equally to this work.

Affiliations

  1. Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Edward T. Chouchani
    • , Lawrence Kazak
    • , Gina Z. Lu
    • , Dina Laznik-Bogoslavski
    •  & Bruce M. Spiegelman
  2. Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Edward T. Chouchani
    • , Lawrence Kazak
    • , Mark P. Jedrychowski
    • , Gina Z. Lu
    • , Brian K. Erickson
    • , John Szpyt
    • , Steve P. Gygi
    •  & Bruce M. Spiegelman
  3. Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA

    • Kerry A. Pierce
    •  & Clary B. Clish
  4. Department of Neurology, Harvard Medical School, Boston, Massachusetts 02215, USA

    • Ramalingam Vetrivelan
  5. MRC Mitochondrial Biology Unit, Hills Road, Cambridge CB2 0XY, UK

    • Alan J. Robinson

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Contributions

E.T.C. designed research, performed biochemical, cellular, and in vivo experiments, analysed data, and co-wrote the paper. L.K. designed and performed cellular and mutagenesis experiments. M.P.J. and K.A.P. performed and analysed data from mass spectrometric experiments. G.Z.L. performed cellular experiments. C.B.C. and S.P.G. oversaw mass spectrometric experiments. A.J.R. designed and performed structural modelling. E.T.C. and B.M.S. directed the research and co-wrote the paper, with assistance from all other authors.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Bruce M. Spiegelman.

Extended data

Supplementary information

PDF files

  1. 1.

    Supplementary Figures

    This file contains Supplementary Figures 1-3, which contain the uncropped scans with size markers indications for Figures 1-3 and Extended Data Figure 3 (1); Extended Data Figure 4 (2) and Extended Data Figure 6 (3).

  2. 2.

    Supplementary Data

    This file contains the MS2 spectra of all UCP1 cysteine, containing peptides identified in the dimedone-MS experiments in either their unmodified (NEM alkylated form) or dimedone alkylated form.

Excel files

  1. 1.

    Supplementary Table 1

    Iodo-TMT data file including summary of all identified proteins and peptides, those identified as substantially redox sensitive during thermogenesis, and pathway analysis.

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DOI

https://doi.org/10.1038/nature17399

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