The PINK1/Parkin-mediated mitophagy is compromised by PD-associated mutations.
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.
Geisler
Sven
S
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.
Holmström
Kira M
KM
Treis
Angela
A
Skujat
Diana
D
Weber
Stephanie S
SS
Fiesel
Fabienne C
FC
Kahle
Philipp J
PJ
Springer
Wolfdieter
W
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
D011494:Protein Kinases; D034741:RNA, Small Interfering; D044767:Ubiquitin-Protein Ligases; D000099202:PTEN-Induced Putative Kinase; C111567:parkin protein