title: A dimeric PINK1-containing complex on depolarized mitochondria stimulates Parkin recruitment.
abstract: Parkinsonism typified by sporadic Parkinson disease is a prevalent neurodegenerative disease. Mutations in PINK1 (PTEN-induced putative kinase 1), a mitochondrial Ser/Thr protein kinase, or PARKIN, a ubiquitin-protein ligase, cause familial parkinsonism. The accumulation and autophosphorylation of PINK1 on damaged mitochondria results in the recruitment of Parkin, which ultimately triggers quarantine and/or degradation of the damaged mitochondria by the proteasome and autophagy. However, the molecular mechanism of PINK1 in dissipation of the mitochondrial membrane potential (ΔΨm) has not been fully elucidated. Here we show by fluorescence-based techniques that the PINK1 complex formed following a decrease in ΔΨm is composed of two PINK1 molecules and is correlated with intermolecular phosphorylation of PINK1. Disruption of complex formation by the PINK1 S402A mutation weakened Parkin recruitment onto depolarized mitochondria. The most disease-relevant mutations of PINK1 inhibit the complex formation. Taken together, these results suggest that formation of the complex containing dyadic PINK1 is an important step for Parkin recruitment onto damaged mitochondria.
authors.affiliation: From the Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku 156-8506, Tokyo.
authors.forename: Kei
authors.initials: K
authors.lastname: Okatsu
authors.forename: Midori
authors.initials: M
authors.lastname: Uno
authors.forename: Fumika
authors.initials: F
authors.lastname: Koyano
authors.forename: Etsu
authors.initials: E
authors.lastname: Go
authors.forename: Mayumi
authors.initials: M
authors.lastname: Kimura
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Oka
authors.forename: Keiji
authors.initials: K
authors.lastname: Tanaka
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Matsuda
mesh_terms: D006367:HeLa Cells; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000378:metabolism*; D009154:Mutation; D010766:Phosphorylation; D011485:Protein Binding; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D055503:Protein Multimerization; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D000099202:PTEN-Induced Putative Kinase
chemical_list: D011494:Protein Kinases; D044767:Ubiquitin-Protein Ligases; D000099202:PTEN-Induced Putative Kinase; C111567:parkin protein
keywords: Mitochondria; Parkin; Parkinson Disease; Phosphorylation; Pink1