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Chemical Blockage of the Mitochondrial Rhomboid Protease PARL by Novel Ketoamide Inhibitors Reveals Its Role in PINK1/Parkin-Dependent Mitophagy
- 1.0566618 - ÚOCHB 2024 RIV US eng J - Journal Article
Poláchová, Edita - Bach, Kathrin - Heuten, E. - Stanchev, Stancho - Tichá, Anežka - Lampe, P. - Majer, Pavel - Langer, T. - Lemberg, M. K. - Stříšovský, Kvido
Chemical Blockage of the Mitochondrial Rhomboid Protease PARL by Novel Ketoamide Inhibitors Reveals Its Role in PINK1/Parkin-Dependent Mitophagy.
Journal of Medicinal Chemistry. Roč. 66, č. 1 (2023), s. 251-265. ISSN 0022-2623. E-ISSN 1520-4804
R&D Projects: GA MŠMT LO1302; GA MŠMT(CZ) EF16_019/0000729
Institutional support: RVO:61388963
Keywords : lipid bilayer nanodiscs * membrane proteins * PINK1
OECD category: Biochemistry and molecular biology
Impact factor: 7.3, year: 2022
Method of publishing: Open access
https://doi.org/10.1021/acs.jmedchem.2c01092
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.
Permanent Link: https://hdl.handle.net/11104/0338165
Number of the records: 1