Mr Jonathan Bernardini - Cell Signalling and Cell Death division

Mr Jonathan Bernardini - Cell Signalling and Cell Death division

Location: 
Davis Auditorium
Start Time: 
Wed, 14/11/2018 - 1:00pm
End Time: 
Wed, 14/11/2018 - 2:00pm

1 Hour Parkin: Mitophagy at the Crossroads of Cell Death

​Wednesday seminar  (this is a PhD completion seminar)

Mitophagy is the selective autophagic clearance of damaged mitochondria and is critical for the maintenance of a healthy mitochondrial network. PINK1 and Parkin are the essential effectors of damage-induced mitophagy and their loss is associated with early onset Parkinson’s disease and also cancer, with recent studies highlighting a potential role for inflammation. PINK1 is stabilised on damaged mitochondria provoking recruitment and activation of the E3 ubiquitin ligase Parkin. Following recruitment, Parkin ubiquitinates a number of mitochondrial substrates, including members of the BCL-2 family of apoptotic regulators. However, how these interactions co-ordinate a cell’s response to mitochondrial damage and ultimately cell fate is unclear.
This study identifies distinct mechanisms by which Parkin modulates apoptosis through the critical apoptosis effectors BAK and BAX. Using a combination of cell biology and biochemical approaches, BAK was characterised as a novel Parkin substrate. The non-degradative ubiquitination of BAK was shown to be an important and reversible step to limit apoptosis and allow effective clearance of damaged mitochondria. Furthermore, this study provides new evidence that mitochondrial damage during apoptosis activates Parkin and so highlights a potential new mechanism to limit inflammatory signalling.
Together, this study provides new insight into the mechanisms by which mutations in Parkin drive the pathogenesis of Parkinson’s disease and cancer.