Chemical Blockage of the Mitochondrial Rhomboid Protease PARL by Novel Ketoamide Inhibitors Reveals Its Role in PINK1/Parkin-Dependent Mitophagy

The mitochondrial rhomboid protease PARL regulates mitophagy by
balancing intramembrane proteolysis of PINK1 and PGAM5. It has been
implicated in the pathogenesis of Parkinson’s disease, but
its investigation as a possible therapeutic target is challenging
in this context because genetic deficiency of PARL may result in compensatory
mechanisms. To address this problem, we undertook a hitherto unavailable
chemical biology strategy. We developed potent PARL-targeting ketoamide
inhibitors and investigated the effects of acute PARL suppression
on the processing status of PINK1 intermediates and on Parkin activation.
This approach revealed that PARL inhibition leads to a robust activation
of the PINK1/Parkin pathway without major secondary effects on mitochondrial
properties, which demonstrates that the pharmacological blockage of
PARL to boost PINK1/Parkin-dependent mitophagy is a feasible approach
to examine novel therapeutic strategies for Parkinson’s disease.
More generally, this study showcases the power of ketoamide inhibitors
for cell biological studies of rhomboid proteases.