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

  • Elife. 2017 May 2;6:e21374. doi: 10.7554/eLife.21374.
Stefania Monterisi  1  2 ,  Miguel J Lobo  1  2 ,  Craig Livie  3 ,  John C Castle  1  2 ,  Michael Weinberger  1  2 ,  George Baillie  4 ,  Nicoletta C Surdo  1  2 ,  Nshunge Musheshe  5 ,  Alessandra Stangherlin  3 ,  Eyal Gottlieb  6 ,  Rory Maizels  1  2 ,  Mario Bortolozzi  7  8 ,  Massimo Micaroni  9 ,  Manuela Zaccolo  1  2
Affiliations
  • 1. Department of Physiology Anatomy and Genetics, University of Oxford, Oxford, United Kingdom.
  • 2. BHF Centre of Research Excellence, University of Oxford, Oxford, United Kingdom.
  • 3. Institute of Neuroscioence and Psychology, University of Glasgow, Glasgow, United Kingdom.
  • 4. Institute of Cardiovascular and Medical Science, University of Glasgow, Glasgow, United Kingdom.
  • 5. Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands.
  • 6. Beatson Institute, University of Glasgow, Glasgow, United Kingdom.
  • 7. Department of Physics and Astronomy "G. Galilei", University of Padova, Padova, Italy.
  • 8. Venetian Institute of Molecular Medicine, University of Padova, Padova, Italy.
  • 9. Swedish National Centre for Cellular Imaging, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
PMID: 28463107 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.

Keywords
apoptosis; cAMP/PKA; cell biology; compartmentalisation; human; mitochondria; mouse; phosphodiesterases; rat; signalling.