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10.03.2010 Hausseminar: Wolfdieter Springer, Uni Tuebingen


by Annette Leiderer — last modified 02.03.2010 01:38
What Lecture
When 10.03.2010
from 14:05 to 14:05
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Parkinson's Disease –

Linking Ubiquitin to Damaged Mitochondria for Selective Autophagy

 

 

Mitochondrial dysfunctions and impairments of protein homeostasis have both been connected to the pathogenesis of Parkinson's disease (PD). The discovery of a PINK1/Parkin-directed pathway for selective degradation of damaged mitochondria links these two PD-related genes and therefore both implicated cellular dysfunctions into a common mechanism that might confer susceptibility to neurodegeneration.

Thereby, PINK1 and Parkin physically interact and functionally cooperate to target damaged mitochondria for selective autophagy (mitophagy). Moreover, PD-associated PINK1 and Parkin mutations abrogate mitophagy at distinct steps of an apparently sequential process. The mitochondrial kinase PINK1 is a prerequisite for the translocation of the cytosolic E3 ubiquitin ligase Parkin to damaged mitochondria. Upon translocation of Parkin, mitochondria cluster at perinuclear regions. This involves Parkin-dependent ubiquitylation of itself as well as of the mitochondrial outer membrane channel VDAC1. Next, the ubiquitin-autophagic adapter protein p62 is recruited to clustered mitochondria and is essential for the subsequent clearance of ubiquitin-marked mitochondria via the autophagic pathway.

The identified PINK1/Parkin-directed mitophagy pathway provides mechanistic links between mitochondrial damage, specific protein ubiquitylation and selective autophagy of mitochondria implicated in the pathogenesis of PD.