The progressive loss of midbrain dopaminergic neurons is the hallmark of Parkinson's disease (PD). Defects in mitochondrial electron transport and mitochondrial DNA replication predispose to the onset of PD. The protein products of several PD genes, including Parkin, Pink1 and DJ1 are known to localize to mitochondria; pathological mutations in these genes may disrupt mitochondrial function. In a previous study we found that the anti-apoptotic protein Bcl-xL enhances the efficiency of neuronal energy metabolism by increasing total cellular ATP levels while decreasing cellular oxygen use. Bcl-xL produces this effect in part through a direct interaction with the beta subunit of the F1Fo ATP synthase. The interaction causes a decrease in leak of H+ ions across the mitochondrial inner membrane, correlated with an increase in coupling of oxidative phosphorylation. We now show that the Parkinson's disease gene-encoded protein, DJ1 (PARK7), is also associated with the ATP synthase complex and has a similar regulatory effect on enzymatic activity of the synthase and on the coupling of oxidation to phosphorylation. Pathological mutations of DJ1 may disrupt mitochondrial efficiency leading to neurodegeneration of mesencephalic dopaminergic neurons. The exact site of the leak inhibited by Bcl-xL and DJ1 is now being determined, but likely resides in or adjacent to the c-subunit ring of the ATP synthase Fo. Improved mitochondrial metabolic efficiency that accompanies decreases in H+ leak may result in long lasting changes in synaptic efficacy and survival in both healthy and at-risk neurons, suggesting a role for leak regulation in future therapeutic interventions.
