Cytosolic cleaved PINK1 represses Parkin translocation to mitochondria and mitophagy

• Published in: EMBO reports Vol. 15; no. 1; pp. 86 - 93
• Main Authors: Fedorowicz, Maja A., de Vries-Schneider, Rosa L. A., Rüb, Cornelia, Becker, Dorothea, Huang, Yong, Zhou, Chun, Alessi Wolken, Dana M., Voos, Wolfgang, Liu, Yuhui, Przedborski, Serge
• Format: Journal Article
• Language: English
• Published: London Blackwell Publishing Ltd 01.01.2014; Nature Publishing Group UK; Springer Nature B.V; BlackWell Publishing Ltd
• Subjects: Cytosol - enzymology; EMBO07; EMBO20; HEK293 Cells; HeLa Cells; Humans; Kinases; Leupeptins - pharmacology; Mitochondria; Mitochondria - metabolism; Mitochondrial Degradation; Mitochondrial Membranes - enzymology; mitophagy; Parkin; Parkinson Disease - enzymology; Parkinson's disease; Pathogenesis; PINK1; Proteasome Inhibitors - pharmacology; Protein Binding; Protein Interaction Domains and Motifs; Protein Kinases - physiology; Protein Transport; Proteolysis; Scientific Report; Scientific Reports; Translocation; Ubiquitin-Protein Ligases - metabolism; Valinomycin - pharmacology; mitophagy; PINK1; Parkinson's disease; mitochondria; Parkin
• ISSN: 1469-221X; 1469-3178; 1469-3178
• DOI: 10.1002/embr.201337294

PINK1 is a mitochondrial kinase proposed to have a role in the pathogenesis of Parkinson's disease through the regulation of mitophagy. Here, we show that the PINK1 main cleavage product, PINK1 52, after being generated inside mitochondria, can exit these organelles and localize to the cytosol, where it is not only destined for degradation by the proteasome but binds to Parkin. The interaction of cytosolic PINK1 with Parkin represses Parkin translocation to the mitochondria and subsequent mitophagy. Our work therefore highlights the existence of two cellular pools of PINK1 that have different effects on Parkin translocation and mitophagy. Synopsis The kinase PINK1, mutants of which are associated with Parkinson disease development, is thought to function in mitochondria. Here, PINK1 is shown to participate in maintaining a healthy pool of mitochondria also by functioning in the cytosol, where it interacts with Parkin. Cleaved PINK152 is retrotranslocated from mitochondria into the cytosol. PINK152 directly interacts with Parkin in the cytosol and prevents Parkin mitochondrial translocation. Cytosolic PINK152 attenuates valinomycin‐induced mitophagy. Graphical Abstract PINK1, mutants of which are associated with Parkinson, is thought to function in mitochondria. Here, PINK1 is shown to be exported into the cytosol after cleavage, where it binds Parkin, inhibiting its mitochondrial recruitment and preventing mitophagy.