Familial Parkinson’s disease (PD) protein DJ-1 mutations are linked to early onset PD. We have found that DJ-1 binds
directly to the F1FO ATP synthase β subunit. DJ-1’s interaction with the β subunit decreased mitochondrial uncoupling
and enhanced ATP production efficiency while in contrast mutations in DJ-1 or DJ-1 knockout increased mitochondrial
uncoupling, and depolarized neuronal mitochondria. In mesencephalic DJ-1 KO cultures, there was a progressive loss
of neuronal process extension. This was ameliorated by a pharmacological reagent, dexpramipexole, that binds to ATP
synthase, closing a mitochondrial inner membrane leak and enhancing ATP synthase efficiency. ATP synthase csubunit can form an uncoupling channel; we measured, therefore, ATP synthase F1 (β subunit) and c-subunit protein
levels. We found that ATP synthase β subunit protein level in the DJ-1 KO neurons was approximately half that found
in their wild-type counterparts, comprising a severe defect in ATP synthase stoichiometry and unmasking c-subunit.
We suggest that DJ-1 enhances dopaminergic cell metabolism and growth by its regulation of ATP synthase protein
components.