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J. Biol. Chem. 286 (35): 30423-30432

© 2011 by The American Society for Biochemistry and Molecular Biology, Inc.

A Phosphodiesterase 2A Isoform Localized to Mitochondria Regulates Respiration*

Rebeca Acin-Perez{ddagger}1, Michael Russwurm§1, Kathrin Günnewig, Melanie Gertz{ddagger}{ddagger}, Georg Zoidl||, Lavoisier Ramos**, Jochen Buck**, Lonny R. Levin**, Joachim Rassow, Giovanni Manfredi{ddagger}, , and Clemens Steegborn{ddagger}{ddagger}2

From the {ddagger}Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, New York 10065,
the Departments of §Pharmacology and Toxicology,
Physiological Chemistry, and
the ||Department of Neuroanatomy and Molecular Brain Research, Ruhr-University Bochum, 44780 Bochum, Germany,
{ddagger}{ddagger}Department of Biochemistry, University of Bayreuth, 95447 Bayreuth, Germany, and
the **Department of Pharmacology, Weill Medical College of Cornell University, New York, New York 10021

ABSTRACT Back to Top

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.

Key Words: Adenylate Cyclase (Adenylyl Cyclase) • Cyclic AMP (cAMP) • Cyclic GMP (cGMP) • Mitochondria • Mitochondrial Metabolism • Phosphodiesterases

Received for publication May 30, 2011. Revision received June 21, 2011.


1 Both authors contributed equally to this work.

2 To whom correspondence should be addressed: Dept. of Biochemistry, University of Bayreuth, Universitätsstr. 30, 95447 Bayreuth, Germany. Tel.: 49-921-552420; Fax: 49-921-552432; E-mail: Clemens.Steegborn{at}

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