Acin-Perez et al. have identified a phosphodiesterase (PDE) associated with the mitochondrial matrix, thereby completing a mitochondrial cAMP (cyclic adenosine monophosphate) signaling cascade. A soluble adenylyl cyclase (sAC) and cAMP effectors such as protein kinase A (PKA) have been identified in mitochondria, which suggests the existence of a local cAMP signaling network. However, a complete cAMP-signaling system requires a mechanism for terminating the cAMP signal. Acin-Perez et al. showed that a membrane-permeant form of cAMP increased ATP production and cytochrome c oxidase activity in mitochondria isolated from mouse brain, whereas a PKA inhibitor decreased them. Thus, as with liver mitochondria, signaling mediated by cAMP (which does not cross the inner mitochondrial membrane) stimulates the electron transport chain in brain mitochondria. Pharmacological analysis indicated that brain and liver mitochondria contained PDE activity consistent with PDE2A. Western analysis revealed PDE2A in purified mitochondria, and mitochondrial fractionation, combined with proteinase K treatment, indicated that it was localized to the mitochondrial matrix. Many matrix proteins contain an N-terminal sorting signal, and analyses of PDE2A isoforms led to the prediction that the N-terminal 19 residues of the PDE2A2 isoform targeted this isoform to the matrix. Indeed, the PDE2A N terminus [PDE2A2(1-120)] bound to isolated mitochondria, whereas a truncated form [PDE2A2(18-120)] did not, and the N-terminal 17 residues of PDE2A2 targeted a fusion protein to mitochondria. Moreover, confocal analysis revealed that a protein in which PDE2A2 residues 1 to 216 were fused to green fluorescent protein colocalized with mitochondria in HEK (human embryonic kidney) cells. Pharmacological analysis of isolated mitochondria indicated that PDE2A acted on the same pool of cAMP as sAC to regulate mitochondrial cAMP abundance, ATP synthesis, and oxygen consumption. Thus, the authors conclude that PDE2A2 acts in concert with sAC to create a cAMP signaling domain in the mitochondrial matrix that regulates activity of the respiratory chain.
R. Acin-Perez, M. Russwurm, K. Günnewig, M. Gertz, G. Zoidl, L. Ramos, J. Buck, L. R. Levin, J. Rassow, G. Manfredi, C. Steegborn, A phosphodiesterase 2A isoform localized to mitochondria regulates respiration. J. Biol. Chem. 286, 30423–30432 (2011). [Abstract] [Full Text]