PDE2A2 regulates Parkin dependent mitophagy
Miguel J Lobo, Manuela Zaccolo
Department of Physiology, Anatomy and Genetics, University of Oxford, UK
Disrupted mitochondrial quality control is a hallmark of PD. Activation of Parkin and its translocation to damaged mitochondria promotes mitophagy and maintenance of mitochondrial homeostasis. Thus, augmenting mitophagy by activating the PINK1/Parkin pathway is an attractive target for therapeutic intervention (Mukherjee et al., 2015). The cAMP/PKA signalling pathway is involved in a wide variety of subcellular processes, including PINK1 protein levels at the OMM and consequently regulation of Parkin translocation to depolarized mitochondria (Akabane et al., 2016). Phosphodiesterases (PDEs), by degrading cAMP locally play a key role in the spatial regulation of cAMP propagation and modulate cAMP levels within individual subcellular compartments. In this way, PDEs dictate which PKA subsets are activated and therefore the downstream targets that are phosphorylated, determining the specificity of the resulting cellular response (Surdo et al., 2017). PDE2A2 (isoform 2 of PDE2A) is part of a distinct cAMP/PKA signaling domain located at the mitochondria (Monterisi et al., 2017). Here, we demonstrate that PDE2A2 interacts with components of the MINOS complex, such as Mitofilin and ChChD3, and that PDE2A inhibition promotes Mitofilin PKA-mediated phosphorylation. We also show that PDE2A ablation does not affect mitochondria cristae morphology and total protein levels of Parkin, PINK1 or Mitofilin, suggesting selective effect on Mitofilin phosphorylation status. Moreover, PDE2A inhibition results in reduced recruitment of Parkin to the mitochondria and reduced mitophagy. Conversely, PDE2A2 overexpression promotes Parkin translocation to damaged mitochondria and enhances mitophagy. PDE2A2 is a potentially 'druggable' enzyme and, unlike the highly promiscuous PKA, it specifically localizes to the mitochondria where it interacts with the MINOS complex to regulate a local pool of cAMP (Monterisi et al., 2017). Our findings suggest the novel and exciting possibility that modulation of PDE2A activity may provide a new avenue to control Parkin-dependent mitophagy.
Medical Research Council and St John's College (MJL) and British Heart Foundation (MZ)