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Title: Determining the role of PDE2 within the mitochondria
Author: Livie, Craig
ISNI:       0000 0004 5365 1624
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 2015
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3’,5’-cyclic adenosine monophosphate (cAMP) is a near ubiquitous second messenger responsible for the regulation of a myriad of physiological processes. It is produced by the adenylyl cyclases (AC) and degraded by phosphodiesterases (PDEs). The primary effector of cAMP is protein kinase A (PKA). In order to overcome cross-contamination of separate cAMP-mediated processes within the same cell strict spatiotemporal control is required. Compartmentalisation sculpts cAMP gradients allowing targeted cAMP/PKA action with the cell. This is achieved by the tethering of unique isoforms of AC, PKA and PDEs to distinct subcellular locations. This subcellular targeting is often carried out by A kinase anchoring proteins (AKAPs) which act as docking sites for the components of the cAMP signalling machinery. A number of AKAPs have been identified as tethering components of the cAMP signalling cascade to organelles facilitating the cultivation of a discrete localised pool of cAMP. This allows for the highly specific PKA-mediated phosphorylation of target proteins. There are reports of two AKAPs localised at the mitochondria: optic atrophy 1 (OPA1) and sphingosine kinase anchoring protein (SKIP). However, despite the acknowledged presence of these two key components of the cAMP signalling cascade being present at the mitochondria little is known about the functional relevance of cAMP signalling within the mitochondria. In this study, I established PDE2 as located within the mitochondria of both primary cardiac cells and a cardiac cell line. Furthermore, the PDE2 isoform present was identified as PDE 2A2. It was then demonstrated that PDE 2A2 was part of a previously identified protein complex located within the mitochondria known as the mitochondrial inner membrane organising system (MINOS) complex. Furthermore, the potential for direct protein-protein interactions between PDE2 and MINOS constituents was examined. It was then demonstrated that when PDE2 activity/expression was reduced mitochondrial length would significantly increase and when PDE2 was overexpressed mitochondrial length would significantly decrease. Furthermore, manipulation of PDE2 expression/activity also led to significant changes in mitochondrial membrane potential (MMP). In summary, the data presented here indicate that PDE 2A2 is part of a multiprotein complex located within the mitochondria. Furthermore, disruption of PDE 2A2 within this complex leads to alterations in mitochondrial physiology.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Q Science (General) ; R Medicine (General)