TY  - JOUR
AU  - Geisler, Sven
AU  - Holmström, Kira M
AU  - Treis, Angela
AU  - Skujat, Diana
AU  - Weber, Stephanie S
AU  - Fiesel, Fabienne C
AU  - Kahle, Philipp
AU  - Springer, Wolfdieter
TI  - The PINK1/Parkin-mediated mitophagy is compromised by PD-associated mutations.
JO  - Autophagy
VL  - 6
IS  - 7
SN  - 1554-8627
CY  - Abingdon, Oxon
PB  - Taylor & Francis
M1  - DZNE-2020-02441
SP  - 871-878
PY  - 2010
AB  - 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.
KW  - Animals
KW  - Autophagy: genetics
KW  - HEK293 Cells
KW  - HeLa Cells
KW  - Humans
KW  - Mitochondria: pathology
KW  - Mitochondria: physiology
KW  - Mutation
KW  - Parkinson Disease: genetics
KW  - Parkinson Disease: pathology
KW  - Parkinson Disease: physiopathology
KW  - Protein Kinases: genetics
KW  - Protein Kinases: metabolism
KW  - RNA, Small Interfering: genetics
KW  - RNA, Small Interfering: metabolism
KW  - Ubiquitin-Protein Ligases: genetics
KW  - Ubiquitin-Protein Ligases: metabolism
KW  - RNA, Small Interfering (NLM Chemicals)
KW  - Ubiquitin-Protein Ligases (NLM Chemicals)
KW  - parkin protein (NLM Chemicals)
KW  - Protein Kinases (NLM Chemicals)
KW  - PTEN-induced putative kinase (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:20798600
DO  - DOI:10.4161/auto.6.7.13286
UR  - https://pub.dzne.de/record/136119
ER  -