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

eLife

Alessandra Stangherlin¹  Mario Bortolozzi¹  Nicoletta C Surdo¹  John C Castle¹  Miguel J Lobo¹  Massimo Micaroni²  Rory Maizels³  George Baillie³  Stefania Monterisi³  Craig Livie³  Nshunge Musheshe³  Eyal Gottlieb⁴  Manuela Zaccolo⁵  Michael Weinberger⁵ 

[1] BHF Centre of Research Excellence, University of Oxford, Oxford, United Kingdom;Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands;Department of Physiology Anatomy and Genetics, University of Oxford, Oxford, United Kingdom;Institute of Cardiovascular and Medical Science, University of Glasgow, Glasgow, United Kingdom;Institute of Neuroscioence and Psychology, University of Glasgow, Glasgow, United Kingdom;

关键词: signalling;    cAMP/PKA;    compartmentalisation;    mitochondria;    apoptosis;    phosphodiesterases;   

DOI  :  10.7554/eLife.21374

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown