PDE2A2 regulates mitochondria morphology and apoptotic cell death via local modulation of cAMP/PKA signalling
- University of Oxford, United Kingdom
- University of Glasgow, United Kingdom
- University of Groningen, Netherlands
- University of Padova, Italy
- University of Gothenburg, Sweden
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.
Article and author information
Author details
Alessandra Stangherlin
Funding
British Heart Foundation (PG/10/75/28537)
- Manuela Zaccolo
BHF Centre of Research Excellence, Oxford (RE/08/004)
- Manuela Zaccolo
British Heart Foundation (RG/12/3/29423)
- Manuela Zaccolo
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All procedures were carried out in compliance with the standards for the care and use of animal subjects as stated by the requirements of the UK Home Office (ASPA1986 Amendments Regulations 2012) incorporating the EU directive 2010/63/EU.
Copyright
© 2017, Monterisi et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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PDE2A2 regulates mitochondria morphology and apoptotic cell death via local modulation of cAMP/PKA signalling
eLife 6:e21374.
https://doi.org/10.7554/eLife.21374
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