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PDE2A2 regulates mitochondria morphology and apoptotic cell death via local modulation of cAMP/PKA signalling

  1. Stefania Monterisi
  2. Miguel J Lobo
  3. Craig Livie
  4. John C Castle
  5. Michael Weinberger
  6. George S Baillie
  7. Nicoletta C Surdo
  8. Nshunge Musheshe
  9. Alessandra Stangherlin
  10. Eyal Gottlieb
  11. Rory J Maizels
  12. Mario Bortolozzi
  13. Massimo Micaroni
  14. Manuela Zaccolo  Is a corresponding author
  1. University of Oxford, United Kingdom
  2. University of Glasgow, United Kingdom
  3. University of Groningen, Netherlands
  4. University of Padova, Italy
  5. University of Gothenburg, Sweden
Research Article
  • Cited 30
  • Views 1,709
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Cite this article as: eLife 2017;6:e21374 doi: 10.7554/eLife.21374

Abstract

cAMP/PKA signalling is compartmentalised with tight spatial and temporal control of signal propagation underpinning specificity of response. The cAMP-degrading enzymes, phosphodiesterases (PDEs), localise to specific subcellular domains within which they control local cAMP levels and are key regulators of signal compartmentalisation. Several components of the cAMP/PKA cascade are located to different mitochondrial sub-compartments, suggesting the presence of multiple cAMP/PKA signalling domains within the organelle. The function and regulation of these domains remain largely unknown. Here, we describe a novel cAMP/PKA signalling domain localised at mitochondrial membranes and regulated by PDE2A2. Using pharmacological and genetic approaches combined with real-time FRET imaging and high resolution microscopy we demonstrate that in rat cardiac myocytes and other cell types mitochondrial PDE2A2 regulates local cAMP levels and PKA-dependent phosphorylation of Drp1. We further demonstrate that inhibition of PDE2A, by enhancing the hormone-dependent cAMP response locally, affects mitochondria dynamics and protects from apoptotic cell death.

Article and author information

Author details

  1. Stefania Monterisi

    Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  2. Miguel J Lobo

    Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Craig Livie

    Institute of Cardiovascular and Medical Science, University of Glasgow, Glasgow, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. John C Castle

    Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6017-7794
  5. Michael Weinberger

    Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. George S Baillie

    Institute of Cardiovascular and Medical Science, University of Glasgow, Glasgow, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Nicoletta C Surdo

    Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. Nshunge Musheshe

    Department of Molecular Pharmacology, University of Groningen, Groningen, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  9. Alessandra Stangherlin

    Institute of Neuroscience and Psychology, University of Glasgow, Glasgow, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7296-1183
  10. Eyal Gottlieb

    Beatson Institute, University of Glasgow, Glasgow, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  11. Rory J Maizels

    Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  12. Mario Bortolozzi

    Venetian Institute of Molecular Medicine, University of Padova, Padova, Italy
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7198-9838
  13. Massimo Micaroni

    Swedish National Centre for Cellular Imaging, University of Gothenburg, Gothenburg, Sweden
    Competing interests
    The authors declare that no competing interests exist.
  14. Manuela Zaccolo

    Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom
    For correspondence
    manuela.zaccolo@dpag.ox.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0934-3662

Funding

British Heart Foundation (PG/10/75/28537)

  • Manuela Zaccolo

BHF Centre of Research Excellence, Oxford (RE/08/004)

  • Manuela Zaccolo

British Heart Foundation (RG/12/3/29423)

  • Manuela Zaccolo

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All procedures were carried out in compliance with the standards for the care and use of animal subjects as stated by the requirements of the UK Home Office (ASPA1986 Amendments Regulations 2012) incorporating the EU directive 2010/63/EU.

Reviewing Editor

  1. Tony Hunter, Salk Institute for Biological Studies, United States

Publication history

  1. Received: September 9, 2016
  2. Accepted: April 29, 2017
  3. Accepted Manuscript published: May 2, 2017 (version 1)
  4. Version of Record published: May 9, 2017 (version 2)

Copyright

© 2017, Monterisi et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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