Calcineurin regulates Parkin-translocation to mitochondria and mitophagy

The selective removal of dysfunctional mitochondria, named mitophagy, is crucial for the maintenance of cellular homeostasis. This event is initiated by the translocation of the E3 ubiquitin ligase Parkin to intoxicated mitochondria and it requires the kinase PINK1. In a remarkable set of studies it was found that PINK1 operates upstream Parkin in a linear pathway that culminates in the phosphorylation of Parkin, Ubiquitin and Parkin mitochondrial substrates, leading to the ubiquitination of outer mitochondrial membrane proteins. Ubiquitin decorated mitochondria are selectively recruiting autophagy receptors which are required to terminate the organelle via autophagy. In this study we show a previously uncharacterized molecular pathway that correlates the activation of the Ca2+-dependent phosphatase Calcineurin (CaN) to PINK1/Parkin-dependent mitophagy. CaN downregulation or genetic inhibition prevents Parkin translocation to intoxicated mitochondria, and impairs stress-induced mitophagy. Moreover, CaN constitutive activation can trigger Parkin translocation under basal conditions also in the absence of PINK1, but requires PINK1 expression to promote mitophagy. In summary, we identified CaN as a novel key player in the regulation of Parkin translocation and PINK1/Parkin dependent mitophagy.