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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.

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apoptosis, cAMP/PKA, cell biology, compartmentalisation, human, mitochondria, mouse, phosphodiesterases, rat, signalling, Animals, Apoptosis, Cell Line, Cyclic AMP, Cyclic AMP-Dependent Protein Kinases, Cyclic Nucleotide Phosphodiesterases, Type 2, Dynamins, Humans, Mice, Mitochondria, Phosphorylation, Protein Processing, Post-Translational, Rats