Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, New York 10065.
the Departments of Pharmacology and Toxicology, Ruhr-University Bochum, 44780 Bochum, Germany.
J Biol Chem. 2011 Sep 2;286(35):30423-30432. doi: 10.1074/jbc.M111.266379. Epub 2011 Jul 1.
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.
线粒体是细胞能量代谢、细胞凋亡和衰老过程中的核心细胞器。最近的研究表明，一个调节这些功能的信号网络包括可溶性腺苷酸环化酶，作为线粒体基质中第二信使 cAMP 的局部来源。然而，对于这种 cAMP 信号的关闭所必需的线粒体 cAMP 降解磷酸二酯酶（PDE）尚未被鉴定。在这里，我们描述了从啮齿动物肝脏和大脑线粒体中鉴定和表征 PDE2A 同工型的过程。我们发现，线粒体 PDE2A 位于基质中，并且 PDE2A 同工型 2 的独特 N 末端特异性导致该同工型的线粒体定位。功能测定表明，线粒体 PDE2A 在基质中与可溶性腺苷酸环化酶形成局部信号系统，调节呼吸链的活性。我们的发现完成了线粒体中的 cAMP 信号级联，对于理解线粒体过程的调节及其药理学调节具有重要意义。
