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Lookup NU author(s): Dr Shane Bell, Dr Oliver RussellORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2023 The Authors. Published by American Chemical Society.Ubiquitin phosphorylation by the mitochondrial protein kinase PTEN-induced kinase 1 (PINK1), upon mitochondrial depolarization, is an important intermediate step in the recycling of damaged mitochondria via mitophagy. As mutations in PINK1 can cause early-onset Parkinson’s disease (PD), there has been a growing interest in small-molecule activators of PINK1-mediated mitophagy as potential PD treatments. Herein, we show that N6-substituted adenosines, such as N6-(2-furanylmethyl)adenosine (known as kinetin riboside) and N6-benzyladenosine, activate PINK1 in HeLa cells and induce PINK1-dependent mitophagy in primary mouse fibroblasts. Interestingly, pre-treatment of HeLa cells and astrocytes with these compounds inhibited elevated ubiquitin phosphorylation that is induced by established mitochondrial depolarizing agents, carbonyl cyanide m-chlorophenyl-hydrazine and niclosamide. Together, this highlights N6-substituted adenosines as progenitor PINK1 activators that could potentially be developed, in the future, as treatments for aged and sporadic PD patients who have elevated phosphorylated ubiquitin levels in the brain.
Author(s): Lambourne OA, Bell S, Wilhelm LP, Yarbrough EB, Holly GG, Russell OM, Alghamdi AM, Fdel AM, Varricchio C, Lane EL, Ganley IG, Jones AT, Goldberg MS, Mehellou Y
Publication type: Article
Publication status: Published
Journal: Journal of Medicinal Chemistry
Year: 2023
Volume: 66
Issue: 11
Pages: 7645-7656
Print publication date: 08/06/2023
Online publication date: 30/05/2023
Acceptance date: 02/04/2021
Date deposited: 03/09/2025
ISSN (print): 0022-2623
ISSN (electronic): 1520-4804
Publisher: American Chemical Society
URL: https://doi.org/10.1021/acs.jmedchem.3c00555
DOI: 10.1021/acs.jmedchem.3c00555
Data Access Statement: The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jmedchem.3c00555.
PubMed id: 37248632
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