BIFI TALKS: Sylvie Callegari, del Eliza Hall Institute of Medical Research, Australia

Title: Activating PINK1 to treat Parkinson’s disease

Abstract

PINK1, a protein linked to Parkinson’s disease, is a ubiquitin kinase that accumulates on the outer membrane of damaged mitochondria. Upon accumulation, PINK1 becomes activated and phosphorylates ubiquitin, generating a unique phospho-ubiquitin signal that triggers mitophagy to remove damaged mitochondria. Enhancing PINK1 activation is a promising strategy for boosting mitochondrial turnover in Parkinson’s patients. Using Cryo-EM, we recently elucidated the activation mechanism of PINK1 and used our structural platform to study PINK1 activator compounds, overturning previous assumptions about their mechanism of action. Another therapeutic approach to target PINK1 is to enhance it’s stabilisation on the outer mitochondrial membrane, but despite decades of research into PINK1 function, the mechanism of PINK1 stabilisation has remained elusive. Using single particle cryo-EM, we determine the structure of stabilised human PINK1 on the Translocase of the Outer Membrane (TOM) to a resolution of 2.8 Å. This uncovers an unusual arrangement of the TOM complex and challenges previous models on the mode of ubiquitin phosphorylation by PINK1. Understanding the mechanisms of PINK1 stabilisation and activation opens up new therapeutic possibilities for using PINK1 to promote the turnover of damaged mitochondria in Parkinson’s disease patients.

Thursday, 26th September 2024, 12:30 h
Edificio I+D (Conference room)