2. Academic Validation
  3. Phosphodiesterase 2A2 regulates mitochondria clearance through Parkin-dependent mitophagy

Phosphodiesterase 2A2 regulates mitochondria clearance through Parkin-dependent mitophagy

  • Commun Biol. 2020 Oct 21;3(1):596. doi: 10.1038/s42003-020-01311-7.
Miguel J Lobo 1,  Laia Reverte-Salisa 2,  Ying-Chi Chao 1,  Andreas Koschinski 1,  Frank Gesellchen 3,  Gunasekaran Subramaniam 1,  He Jiang 3,  Samuel Pace 1,  Natasha Larcom 1,  Ester Paolocci 1,  Alexander Pfeifer 2,  Sara Zanivan 4 5,  Manuela Zaccolo 6
Affiliations

Affiliations

  • 1 Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
  • 2 Institute of Pharmacology and Toxicology University of Bonn, Bonn, Germany.
  • 3 Institute of Neuroscience and Psychology, University of Glasgow, Glasgow, UK.
  • 4 Cancer Research UK Beatson Institute, University of Glasgow, Glasgow, UK.
  • 5 Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
  • 6 Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK. [email protected].
PMID: 33087821 DOI: 10.1038/s42003-020-01311-7
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.

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