Department of Physiology Anatomy and Genetics, University of Oxford, Oxford, United Kingdom; BHF Centre of Research Excellence, University of Oxford, Oxford, United Kingdom
Miguel J Lobo
Department of Physiology Anatomy and Genetics, University of Oxford, Oxford, United Kingdom; BHF Centre of Research Excellence, University of Oxford, Oxford, United Kingdom
Craig Livie
Institute of Neuroscioence and Psychology, University of Glasgow, Glasgow, United Kingdom
Department of Physiology Anatomy and Genetics, University of Oxford, Oxford, United Kingdom; BHF Centre of Research Excellence, University of Oxford, Oxford, United Kingdom
Michael Weinberger
Department of Physiology Anatomy and Genetics, University of Oxford, Oxford, United Kingdom; BHF Centre of Research Excellence, University of Oxford, Oxford, United Kingdom
George Baillie
Institute of Cardiovascular and Medical Science, University of Glasgow, Glasgow, United Kingdom
Nicoletta C Surdo
Department of Physiology Anatomy and Genetics, University of Oxford, Oxford, United Kingdom; BHF Centre of Research Excellence, University of Oxford, Oxford, United Kingdom
Nshunge Musheshe
Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands
Institute of Neuroscioence and Psychology, University of Glasgow, Glasgow, United Kingdom
Eyal Gottlieb
Beatson Institute, University of Glasgow, Glasgow, United Kingdom
Rory Maizels
Department of Physiology Anatomy and Genetics, University of Oxford, Oxford, United Kingdom; BHF Centre of Research Excellence, University of Oxford, Oxford, United Kingdom
Department of Physics and Astronomy “G. Galilei”, University of Padova, Padova, Italy; Venetian Institute of Molecular Medicine, University of Padova, Padova, Italy
Massimo Micaroni
Swedish National Centre for Cellular Imaging, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
Department of Physiology Anatomy and Genetics, University of Oxford, Oxford, United Kingdom; BHF Centre of Research Excellence, University of Oxford, Oxford, United Kingdom
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.
