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.

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.

MeSH terms

  • Animals
  • Apoptosis*
  • Cell Line
  • Cyclic AMP / metabolism*
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • Cyclic Nucleotide Phosphodiesterases, Type 2 / metabolism*
  • Dynamins / metabolism*
  • Humans
  • Mice
  • Mitochondria / metabolism*
  • Mitochondria / ultrastructure*
  • Phosphorylation
  • Protein Processing, Post-Translational
  • Rats

Substances

  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • Cyclic Nucleotide Phosphodiesterases, Type 2
  • Pde2a protein, rat
  • Dnm1l protein, rat
  • Dynamins