title: A phosphodiesterase 2A isoform localized to mitochondria regulates respiration.
abstract: Mitochondria are central organelles in cellular energy metabolism, apoptosis, and aging processes. A signaling network regulating these functions was recently shown to include soluble adenylyl cyclase as a local source of the second messenger cAMP in the mitochondrial matrix. However, a mitochondrial cAMP-degrading phosphodiesterase (PDE) necessary for switching off this cAMP signal has not yet been identified. Here, we describe the identification and characterization of a PDE2A isoform in mitochondria from rodent liver and brain. We find that mitochondrial PDE2A is located in the matrix and that the unique N terminus of PDE2A isoform 2 specifically leads to mitochondrial localization of this isoform. Functional assays show that mitochondrial PDE2A forms a local signaling system with soluble adenylyl cyclase in the matrix, which regulates the activity of the respiratory chain. Our findings complete a cAMP signaling cascade in mitochondria and have implications for understanding the regulation of mitochondrial processes and for their pharmacological modulation.
authors: Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, New York 10065.
authors: Rebeca
authors: R
authors: Acin-Perez
authors: the Departments of Pharmacology and Toxicology, Ruhr-University Bochum, 44780 Bochum, Germany.
authors: Michael
authors: M
authors: Russwurm
authors: Physiological Chemistry, Ruhr-University Bochum, 44780 Bochum, Germany.
authors: Kathrin
authors: K
authors: Günnewig
authors: Physiological Chemistry, Ruhr-University Bochum, 44780 Bochum, Germany; Department of Biochemistry, University of Bayreuth, 95447 Bayreuth, Germany.
authors: Melanie
authors: M
authors: Gertz
authors: Department of Neuroanatomy and Molecular Brain Research, Ruhr-University Bochum, 44780 Bochum, Germany.
authors: Georg
authors: G
authors: Zoidl
authors: Department of Pharmacology, Weill Medical College of Cornell University, New York, New York 10021.
authors: Lavoisier
authors: L
authors: Ramos
authors: Department of Pharmacology, Weill Medical College of Cornell University, New York, New York 10021.
authors: Jochen
authors: J
authors: Buck
authors: Department of Pharmacology, Weill Medical College of Cornell University, New York, New York 10021.
authors: Lonny R
authors: LR
authors: Levin
authors: Physiological Chemistry, Ruhr-University Bochum, 44780 Bochum, Germany.
authors: Joachim
authors: J
authors: Rassow
authors: Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, New York 10065.
authors: Giovanni
authors: G
authors: Manfredi
authors: Physiological Chemistry, Ruhr-University Bochum, 44780 Bochum, Germany; Department of Biochemistry, University of Bayreuth, 95447 Bayreuth, Germany. Electronic address: Clemens.Steegborn@uni-bayreuth.de.
authors: Clemens
authors: C
authors: Steegborn
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000737:chemistry; D000818:Animals; D001921:Brain / Q000378:metabolism; D019069:Cell Respiration; D006152:Cyclic GMP / Q000378:metabolism; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2 / Q000096:biosynthesis / Q000502:physiology*; D019286:Endopeptidase K / Q000737:chemistry; D049452:Green Fluorescent Proteins / Q000737:chemistry; D006801:Humans; D008099:Liver / Q000378:metabolism; D018613:Microscopy, Confocal / Q000379:methods; D008928:Mitochondria / Q000378:metabolism*; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D051381:Rats; D015398:Signal Transduction
chemical_list: D020033:Protein Isoforms; D049452:Green Fluorescent Proteins; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2; C517275:PDE2A protein, human; C517278:Pde2a protein, rat; D019286:Endopeptidase K; D006152:Cyclic GMP