Modulation of energy substrate transport by cAMP-hydrolysing phosphodiesterases in cardiac myocytes

Thesis

cAMP is a key second messenger responsible for mediating a myriad of cellular processes. cAMP signalling is compartmentalised, as different levels of this second messenger are achieved at different subcellular nanodomains within the cell. The tight spatial and temporal organisation of cAMP signals is what allows the specificity of cAMP signalling, avoiding spillage of information amongst different branches of this pathway which occur independently but concurrently to the β-adrenergic regulation of cardiac myocyte contraction and relaxation. It is the distribution and activity of different phosphodiesterases that ultimately defines the topography of active subcellular cAMP nanodomains, by locally degrading cAMP at specific sites. Even though this is now an established concept, only a very limited number of nanodomains have been characterised. The aim of this project is to further validate and characterise novel PDEdependent cAMP nanodomains in charge of the transport of metabolites for energy production in the cardiac myocyte. The results from this work validate the interaction of PDE2A2 and PDE3A1 with several elements involved in the transport of energy substrates. PDE2A2 is also shown to form a macromolecular complex with transporters of fatty acids, glucose, and pyruvate, suggesting a novel mechanism by which this enzyme may coordinate substrate uptake and mitochondrial import. Functional analyses demonstrate that PDE2A2 modulates fatty acid uptake and oxidation, likely through regulation of AMPK-dependent phosphorylation of acetyl-CoA carboxylase and subsequent modulation of CPT1 activity. These findings support a model in which PDE2A2 contributes to the modulation of a cAMP nanodomain at the mitochondrial outer membrane, positioning it as a critical regulator of cardiac metabolic flexibility and a potential therapeutic target in heart failure.

Authors: Zerio, A

• DOI: 10.5287/ora-gpyjar5ym
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English