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PINK1-Dependent Mitophagy Inhibits Elevated Ubiquitin Phosphorylation Caused by Mitochondrial Damage

Lookup NU author(s): Shane Bell, Dr Oliver Russell


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© 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.

Publication metadata

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

ISSN (print): 0022-2623

ISSN (electronic): 1520-4804

Publisher: American Chemical Society


DOI: 10.1021/acs.jmedchem.3c00555

PubMed id: 37248632


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