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 thatN6-substituted adenosines, such
asN6-(2-furanylmethyl)adenosine (known
as kinetin riboside) andN6-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 cyanidem-chlorophenyl-hydrazine
and niclosamide. Together, this highlightsN6-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.