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 evolutionarily conserved cAMP and/or cGMP hydrolyzing 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...
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| Language: | English |
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MDPI AG
2022-08-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/15/8587 |
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| author | Silvia Cardarelli Adriana Erica Miele Federica Campolo Mara Massimi Patrizia Mancini Stefano Biagioni Fabio Naro Mauro Giorgi Michele Saliola |
| author_facet | Silvia Cardarelli Adriana Erica Miele Federica Campolo Mara Massimi Patrizia Mancini Stefano Biagioni Fabio Naro Mauro Giorgi Michele Saliola |
| author_sort | Silvia Cardarelli |
| collection | DOAJ |
| description | 3′-5′ cyclic nucleotide phosphodiesterases (PDEs) are a family of evolutionarily conserved cAMP and/or cGMP hydrolyzing 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 <i>Kluyveromyces lactis</i> 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 the MmPDE5A2 is responsible for its mitochondrial localization. Overexpression of the three isoforms alters at different levels the cAMP/cGMP equilibrium as well as the NAD(P)<sup>+</sup>/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. |
| first_indexed | 2024-03-09T12:30:22Z |
| format | Article |
| id | doaj.art-1f5e292048e340a3bbdf91a514e3f0b2 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T12:30:22Z |
| publishDate | 2022-08-01 |
| publisher | MDPI AG |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-1f5e292048e340a3bbdf91a514e3f0b22023-11-30T22:29:31ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-08-012315858710.3390/ijms23158587Cellular Redox Metabolism Is Modulated by the Distinct Localization of Cyclic Nucleotide Phosphodiesterase 5A IsoformsSilvia Cardarelli0Adriana Erica Miele1Federica Campolo2Mara Massimi3Patrizia Mancini4Stefano Biagioni5Fabio Naro6Mauro Giorgi7Michele Saliola8Department of Biology and Biotechnology “C. Darwin”, Sapienza University of Rome, Piazzale A. Moro 5, 00185 Rome, ItalyDepartment of Biochemical Sciences, Sapienza University of Rome, Piazzale A. Moro 5, 00185 Rome, ItalyDepartment of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, ItalyDepartment of Life, Health and Environmental Sciences, University of L’Aquila, Via Vetoio, 67100 L’Aquila, ItalyDepartment of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, ItalyDepartment of Biology and Biotechnology “C. Darwin”, Sapienza University of Rome, Piazzale A. Moro 5, 00185 Rome, ItalyDepartment of Anatomical, Histological, Forensic, and Orthopaedic Sciences, Sapienza University of Rome, Via A. Borelli 50, 00161 Rome, ItalyDepartment of Biology and Biotechnology “C. Darwin”, Sapienza University of Rome, Piazzale A. Moro 5, 00185 Rome, ItalyDepartment of Biology and Biotechnology “C. Darwin”, Sapienza University of Rome, Piazzale A. Moro 5, 00185 Rome, Italy3′-5′ cyclic nucleotide phosphodiesterases (PDEs) are a family of evolutionarily conserved cAMP and/or cGMP hydrolyzing 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 <i>Kluyveromyces lactis</i> 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 the MmPDE5A2 is responsible for its mitochondrial localization. Overexpression of the three isoforms alters at different levels the cAMP/cGMP equilibrium as well as the NAD(P)<sup>+</sup>/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.https://www.mdpi.com/1422-0067/23/15/8587cGMP-specific phosphodiesteraseglycolytic/respiratory flux<i>Kluyveromyces lactis</i>redox balancerag phenotype |
| spellingShingle | Silvia Cardarelli Adriana Erica Miele Federica Campolo Mara Massimi Patrizia Mancini Stefano Biagioni Fabio Naro Mauro Giorgi Michele Saliola Cellular Redox Metabolism Is Modulated by the Distinct Localization of Cyclic Nucleotide Phosphodiesterase 5A Isoforms International Journal of Molecular Sciences cGMP-specific phosphodiesterase glycolytic/respiratory flux <i>Kluyveromyces lactis</i> redox balance rag phenotype |
| title | Cellular Redox Metabolism Is Modulated by the Distinct Localization of Cyclic Nucleotide Phosphodiesterase 5A Isoforms |
| title_full | Cellular Redox Metabolism Is Modulated by the Distinct Localization of Cyclic Nucleotide Phosphodiesterase 5A Isoforms |
| title_fullStr | Cellular Redox Metabolism Is Modulated by the Distinct Localization of Cyclic Nucleotide Phosphodiesterase 5A Isoforms |
| title_full_unstemmed | Cellular Redox Metabolism Is Modulated by the Distinct Localization of Cyclic Nucleotide Phosphodiesterase 5A Isoforms |
| title_short | Cellular Redox Metabolism Is Modulated by the Distinct Localization of Cyclic Nucleotide Phosphodiesterase 5A Isoforms |
| title_sort | cellular redox metabolism is modulated by the distinct localization of cyclic nucleotide phosphodiesterase 5a isoforms |
| topic | cGMP-specific phosphodiesterase glycolytic/respiratory flux <i>Kluyveromyces lactis</i> redox balance rag phenotype |
| url | https://www.mdpi.com/1422-0067/23/15/8587 |
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