PINK1-Dependent mitophagy inhibits elevated ubiquitin phosphorylation caused by mitochondrial damage

Lambourne, Olivia A., Bell, Shane, Wilhelm, Léa P., Yarbrough, Erika B., Holly, Gabriel G., Russell, Oliver M., Alghamdi, Arwa M., Fdel, Azeza M., Varricchio, Carmine ORCID: https://orcid.org/0000-0002-1673-4768, Lane, Emma L. ORCID: https://orcid.org/0000-0001-8800-3764, Ganley, Ian G., Jones, Arwyn T. ORCID: https://orcid.org/0000-0003-2781-8905, Goldberg, Matthew S. and Mehellou, Youcef ORCID: https://orcid.org/0000-0001-5720-8513 2023. PINK1-Dependent mitophagy inhibits elevated ubiquitin phosphorylation caused by mitochondrial damage. Journal of Medicinal Chemistry 66 (11) , pp. 7645-7656. 10.1021/acs.jmedchem.3c00555

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Abstract

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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Pharmacy
Publisher:	American Chemical Society
ISSN:	0022-2623
Funders:	MRC, Wellcome Trust
Date of First Compliant Deposit:	31 May 2023
Date of Acceptance:	16 May 2023
Last Modified:	06 Jan 2024 02:31
URI:	https://orca.cardiff.ac.uk/id/eprint/160075

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