Cellular Redox Metabolism Is Modulated by the Distinct Localization of Cyclic Nucleotide Phosphodiesterase 5A Isoforms

3’-5’ cyclic nucleotide phosphodiesterases (PDEs) are a family of evolutionary conserved cAMP and/or cGMP hydrolysing enzymes, components of transduction pathways regulating crucial aspects of cell life. Among them, cGMP-specific PDE5, being a regulator of vascular smooth muscle contraction, is the molecular target of several drugs used to treat erectile dysfunction and pulmonary hypertension.Production of full-length murine PDE5A isoforms in the milk-yeast Kluyveromyces lactis showed that the quaternary assembly of MmPDE5A1 is a mixture of dimers and tetramers, while MmPDE5A2 and MmPDE5A3 only assembled as dimers. We showed that the N-terminal peptide is responsible for the tetramer assembly of MmPDE5A1, while that of MmPDE5A2 for its mitochondrial localization.Overexpression of the three isoforms alters at different levels the cAMP/cGMP equilibrium as well as the NAD(P)+/NAD(P)H balance and induces a metabolic switch from oxidative to fermentative. In particular, the mitochondrial localization of MmPDE5A2 unveiled the existence of a cAMP-cGMP signaling cascade in this organelle, for which we propose a metabolic model that could explain the role of PDE5 in some cardiomyopathies and some of the side effects of its inhibitors.