PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1.
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 Parkinson's disease.
Geisler
Sven
S
Laboratory of Functional Neurogenetics, Otfried-Müller-Strasse 27, 72076 Tübingen, Germany.
Holmström
Kira M
KM
Skujat
Diana
D
Fiesel
Fabienne C
FC
Rothfuss
Oliver C
OC
Kahle
Philipp J
PJ
Springer
Wolfdieter
W
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D001343:Autophagy / Q000235:genetics / Q000502:physiology*; D001692:Biological Transport / Q000235:genetics / Q000502:physiology; D045744:Cell Line, Tumor; D005455:Fluorescent Antibody Technique; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D008928:Mitochondria / Q000378:metabolism*; D009154:Mutation; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D000071456:Sequestosome-1 Protein; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D050995:Voltage-Dependent Anion Channel 1 / Q000235:genetics / Q000378:metabolism*; D000099202:PTEN-Induced Putative Kinase
D048868:Adaptor Proteins, Signal Transducing; D011494:Protein Kinases; D000071456:Sequestosome-1 Protein; D044767:Ubiquitin-Protein Ligases; D050995:Voltage-Dependent Anion Channel 1; D000099202:PTEN-Induced Putative Kinase; C099718:SQSTM1 protein, human; C494762:VDAC1 protein, human; C111567:parkin protein