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

Ubiquitin phosphorylation by the mitochondrial proteinkinase PTEN-inducedkinase 1 (PINK1), upon mitochondrial depolarization, is an importantintermediate 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 activatorsof PINK1-mediated mitophagy as potential PD treatments. Herein, weshow that N (6)-substituted adenosines, suchas N (6)-(2-furanylmethyl)-adenosine (knownas kinetin riboside) and N (6)-benzyladenosine,activate PINK1 in HeLa cells and induce PINK1-dependent mitophagyin primary mouse fibroblasts. Interestingly, pre-treatment of HeLacells and astrocytes with these compounds inhibited elevated ubiquitinphosphorylation that is induced by established mitochondrial depolarizingagents, carbonyl cyanide m-chlorophenyl-hydrazineand niclosamide. Together, this highlights N (6)-substituted adenosines as progenitor PINK1 activators thatcould potentially be developed, in the future, as treatments for agedand sporadic PD patients who have elevated phosphorylated ubiquitinlevels in the brain.

Automated summary

Ubiquitin phosphorylation by PINK1 is crucial for mitophagy and potential PD treatments. N (6)-substituted adenosines, like kinetin riboside and N (6)-benzyladenosine, activate PINK1 and induce mitophagy in cells. Moreover, these adenosines can inhibit elevated ubiquitin phosphorylation induced by mitochondrial depolarizing agents.