title: The PINK1/Parkin-mediated mitophagy is compromised by PD-associated mutations.
abstract: Mitochondrial dysfunction is an early sign of many neurodegenerative diseases. Very recently, two Parkinson disease (PD) associated genes, PINK1 and Parkin, were shown to mediate the degradation of damaged mitochondria via selective autophagy (mitophagy). PINK1 kinase activity is needed for prompt and efficient Parkin recruitment to impaired mitochondria. PD-associated Parkin mutations interfere with the process of mitophagy at distinct steps. Here we show that whole mitochondria are turned over via macroautophagy. Moreover, disease-associated PINK1 mutations also compromise the selective degradation of depolarized mitochondria. This may be due to the decreased physical binding activity of PD-linked PINK1 mutations to Parkin. Thus, PINK1 mutations abrogate autophagy of impaired mitochondria upstream of Parkin. In addition to compromised PINK1 kinase activity, reduced binding of PINK1 to Parkin leads to failure in Parkin mitochondrial translocation, resulting in the accumulation of damaged mitochondria, which may contribute to disease pathogenesis.
authors.affiliation: Laboratory of Functional Neurogenetics, Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, and German Centre for Neurodegenerative Diseases, Tübingen, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Geisler
authors.forename: Kira M
authors.initials: KM
authors.lastname: Holmström
authors.forename: Angela
authors.initials: A
authors.lastname: Treis
authors.forename: Diana
authors.initials: D
authors.lastname: Skujat
authors.forename: Stephanie S
authors.initials: SS
authors.lastname: Weber
authors.forename: Fabienne C
authors.initials: FC
authors.lastname: Fiesel
authors.forename: Philipp J
authors.initials: PJ
authors.lastname: Kahle
authors.forename: Wolfdieter
authors.initials: W
authors.lastname: Springer
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008928:Mitochondria / Q000473:pathology / Q000502:physiology; D009154:Mutation; D010300:Parkinson Disease / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D011494:Protein Kinases / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism; D000099202:PTEN-Induced Putative Kinase
chemical_list: D011494:Protein Kinases; D034741:RNA, Small Interfering; D044767:Ubiquitin-Protein Ligases; D000099202:PTEN-Induced Putative Kinase; C111567:parkin protein