Monterisi, S. et al. (2017) PDE2A2 regulates mitochondria morphology and apoptotic cell death via local modulation of cAMP/PKA signalling. eLife, 6, e21374. (doi: 10.7554/eLife.21374) (PMID:28463107) (PMCID:PMC5423767)
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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.
| Item Type: | Articles |
|---|---|
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Baillie, Professor George and Gottlieb, Professor Eyal and Zaccolo, Professor Manuela and Stangherlin, Dr Alessandra |
| Authors: | Monterisi, S., Lobo, M. J., Livie, C., Castle, J. C., Weinberger, M., Baillie, G., Surdo, N. C., Musheshe, N., Stangherlin, A., Gottlieb, E., Maizels, R., Bortolozzi, M., Micaroni, M., and Zaccolo, M. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Cancer Sciences College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health College of Medical Veterinary and Life Sciences > School of Psychology & Neuroscience |
| Journal Name: | eLife |
| Publisher: | eLife Sciences Publications |
| ISSN: | 2050-084X |
| ISSN (Online): | 2050-084X |
| Copyright Holders: | Copyright © 2017 Monterisi et al |
| First Published: | First published in eLife 6:e21374 |
| Publisher Policy: | Reproduced under a Creative Commons License |
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