Phosphodiesterase 2A2 regulates mitochondria clearance through Parkin-dependent mitophagy

Lobo, M. J. et al. (2020) Phosphodiesterase 2A2 regulates mitochondria clearance through Parkin-dependent mitophagy. Communications Biology, 3, 596. (doi: 10.1038/s42003-020-01311-7) (PMID:33087821) (PMCID:PMC7578833)

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Abstract

Programmed degradation of mitochondria by mitophagy, an essential process to maintain mitochondrial homeostasis, is not completely understood. Here we uncover a regulatory process that controls mitophagy and involves the cAMP-degrading enzyme phosphodiesterase 2A2 (PDE2A2). We find that PDE2A2 is part of a mitochondrial signalosome at the mitochondrial inner membrane where it interacts with the mitochondrial contact site and organizing system (MICOS). As part of this compartmentalised signalling system PDE2A2 regulates PKA-mediated phosphorylation of the MICOS component MIC60, resulting in modulation of Parkin recruitment to the mitochondria and mitophagy. Inhibition of PDE2A2 is sufficient to regulate mitophagy in the absence of other triggers, highlighting the physiological relevance of PDE2A2 in this process. Pharmacological inhibition of PDE2 promotes a ‘fat-burning’ phenotype to retain thermogenic beige adipocytes, indicating that PDE2A2 may serve as a novel target with potential for developing therapies for metabolic disorders.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Zaccolo, Professor Manuela and Jiang, Mr He and Zanivan, Professor Sara and Gesellchen, Dr Frank
Authors: Lobo, M. J., Reverte-Salisa, L., Chao, Y.-C., Koschinski, A., Gesellchen, F., Subramaniam, G., Jiang, H., Pace, S., Larcom, N., Paolocci, E., Pfeifer, A., Zanivan, S., and Zaccolo, M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
College of Medical Veterinary and Life Sciences > Institute of Neuroscience and Psychology
College of Science and Engineering > School of Engineering > Biomedical Engineering
Journal Name:Communications Biology
Publisher:Nature Research
ISSN:2399-3642
ISSN (Online):2399-3642
Copyright Holders:Copyright © 2020 The Authors
First Published:First published in Communications Biology 3: 596
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
164599Quantitative analysis of cAMP dynamics in cardiac myocytes sub-compartments.Manuela ZaccoloBritish Heart Foundation (BHF)PG/10/75/28537Institute of Neuroscience & Psychology