PINK1-Dependent Mitophagy Inhibits Elevated Ubiquitin Phosphorylation Caused by Mitochondrial Damage
Olivia A. Lambourne, Shane Bell, Léa P. Wilhelm, Erika B. Yarbrough, Gabriel G. Holly, Oliver M. Russell, Arwa M. Alghamdi, Azeza M. Fdel, Carmine Varricchio, Emma L. Lane, Ian G. Ganley, Arwyn T. Jones, Matthew S. Goldberg, Youcef Mehellou
Abstract
High Resolution Image Download MS PowerPoint Slide 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 N 6 -substituted adenosines, such as N 6 -(2-furanylmethyl)adenosine (known as kinetin riboside) and N 6 -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 N 6 -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.