Pink1/parkin-mediated mitophagy is dependent on vdac1 and p62/sqstm1

ABSTRACT Parkinson's disease is the most common neurodegenerative movement disorder. Mutations in PINK1 and PARKIN are the most frequent causes of recessive Parkinson's disease.

However, their molecular contribution to pathogenesis remains unclear. Here, we reveal important mechanistic steps of a PINK1/Parkin-directed pathway linking mitochondrial damage,

ubiquitylation and autophagy in non-neuronal and neuronal cells. PINK1 kinase activity and its mitochondrial localization sequence are prerequisites to induce translocation of the E3 ligase

Parkin to depolarized mitochondria. Subsequently, Parkin mediates the formation of two distinct poly-ubiquitin chains, linked through Lys 63 and Lys 27. In addition, the autophagic adaptor

p62/SQSTM1 is recruited to mitochondrial clusters and is essential for the clearance of mitochondria. Strikingly, we identified VDAC1 (voltage-dependent anion channel 1) as a target for

Parkin-mediated Lys 27 poly-ubiquitylation and mitophagy. Moreover, pathogenic Parkin mutations interfere with distinct steps of mitochondrial translocation, ubiquitylation and/or final

clearance through mitophagy. Thus, our data provide functional links between PINK1, Parkin and the selective autophagy of mitochondria, which is implicated in the pathogenesis of

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our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS THE ROLE OF PINK1–PARKIN IN MITOCHONDRIAL QUALITY CONTROL Article 02 October 2024 DIFFERENTIAL MITOCHONDRIAL ROLES

FOR Α-SYNUCLEIN IN DRP1-DEPENDENT FISSION AND PINK1/PARKIN-MEDIATED OXIDATION Article Open access 17 August 2021 NOVEL PROTEIN COMPLEXES CONTAINING AUTOPHAGY AND UPS COMPONENTS REGULATE

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R. Baer for providing Parkin and ubiquitin mutants, and to R. de Silva for providing the pDsRed2-Mito construct. We thank Thomas Gasser for support. This work was supported by grants from

the _f_ortüne-program of the Medical Faculty of the University of Tübingen to W.S. (1667-0-0 and 1842-0-0), by the German National Genome Research Network (NGFNplus, 01GS08134) to P.J.K.,

and by the Hertie Foundation. K.M.H. is a NEUROTRAIN Early Stage Research Training fellow funded through the European Union research program FP6. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS

* Laboratory of Functional Neurogenetics, Otfried-Müller-Strasse 27, 72076, Tübingen, Germany Sven Geisler, Kira M. Holmström, Diana Skujat, Fabienne C. Fiesel, Philipp J. Kahle & 

Wolfdieter Springer * Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Otfried-Müller-Strasse 27, 72076, Tübingen, Germany

Sven Geisler, Kira M. Holmström, Diana Skujat, Fabienne C. Fiesel, Oliver C. Rothfuss, Philipp J. Kahle & Wolfdieter Springer Authors * Sven Geisler View author publications You can also

search for this author inPubMed Google Scholar * Kira M. Holmström View author publications You can also search for this author inPubMed Google Scholar * Diana Skujat View author

publications You can also search for this author inPubMed Google Scholar * Fabienne C. Fiesel View author publications You can also search for this author inPubMed Google Scholar * Oliver C.

Rothfuss View author publications You can also search for this author inPubMed Google Scholar * Philipp J. Kahle View author publications You can also search for this author inPubMed Google

Scholar * Wolfdieter Springer View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS S.G., K.M.H., and W.S. were responsible for the experimental

work. D.S. provided technical assistance. O.C.R. provided materials. S.G., F.C.F. and W.S. analysed data. F.C.F. and P.J.K. provided intellectual and/or financial support. W.S. planned the

project, designed experiments and wrote the manuscript. All authors discussed the data and commented on the manuscript. CORRESPONDING AUTHORS Correspondence to Philipp J. Kahle or Wolfdieter

Springer. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing financial interests. SUPPLEMENTARY INFORMATION SUPPLEMENTARY INFORMATION Supplementary Information (PDF

4557 kb) RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Geisler, S., Holmström, K., Skujat, D. _et al._ PINK1/Parkin-mediated mitophagy is dependent on

VDAC1 and p62/SQSTM1. _Nat Cell Biol_ 12, 119–131 (2010). https://doi.org/10.1038/ncb2012 Download citation * Received: 09 September 2009 * Accepted: 09 December 2009 * Published: 24 January

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