Author:

Abstract:

Mutations in the gene for Parkin are a major cause of recessive Parkinson disease. Recent work has shown that Parkin may protect neurons by translocating from the cytosol to depolarized mitochondria and inducing their autophagic removal [1]. The molecular mechanisms underlying Parkin-mediated mitophagy are poorly understood. Here, we have used tandem affinity purification (TAP) and mass-spectrometric analysis (MS) to assess whether Parkin interacts with autophagy-regulating proteins. We have identified Ambra1 (activating molecule in Beclin1-regulated autophagy) as a Parkin interactor. Ambra1 promotes autophagy in the CNS by activating the class III phosphatidylinositol 3-kinase (PI3K) that is essential for new phagophore formation [2]. We show that the Parkin-Ambra1 interaction strongly increases upon prolonged mitochondrial depolarization and that Ambra1 is critically important for mitochondrial clearance. Ambra1 is recruited in a Parkin-dependent fashion to perinuclear clusters of depolarized mitochondria and activates class III PI3K in their immediate vicinity.