Parkinson’s disease (PD) is characterised by compromised mitophagy, a highly specialised quality control process that removes dysfunctional mitochondria through a macroautophagy pathway. The proteins Parkin and PINK1 are key players in the mitophagic process. In healthy mitochondria with normal membrane potential, Parkin is located mainly in the cytosol, where its ubiquitin ligase activity is inhibited while PINK1 is imported into the mitochondria and becomes degraded by proteolysis. Following cellular stress, the depolarization of the mitochondrial membrane potential allows the stabilisation of PINK1 at the outer mitochondrial membrane (OMM), where it phosphorylates ubiquitin. This induces activation of Parkin and its translocation to damaged mitochondria, followed by mitophagy. Recent advances revealed that Parkin recruitment to depolarized mitochondria is severely inhibited by treatment with cAMP raising agents. cAMP-dependent activation of PKA has been shown to reduce PINK1 protein levels at the OMM through phosphorylation of MICOS (mitochondrial contact site and cristae organising system). Here we show that phosphodiesterase 2A2 (PDE2A2), a cAMP-degrading enzyme, interacts with components of the MICOS complex and regulates cAMP levels selectively at the mitochondria. Furthermore, our preliminary data show that in mouse embryonic fibroblasts deleted of PDE2A2 (MEF)PDE2A-/- the amount of Parkin recruited to the mitochondria is reduced compared to MEFWT under basal conditions. In agreement with these results, treatment with BAY 60–7550, a selective PDE2A inhibitor, promotes PKA-dependent phosphorylation of Mitofilin. In conclusion, we propose that PDE2A2 regulates a local cAMP pool at the mitochondria that leads to PKA-dependent phosphorylation of MICOS and Parkin recruitment to damaged mitochondria.
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