Glucose protection from MPP+-induced apoptosis depends on mitochondrial membrane potential and ATP synthase

MPP+ inhibits mitochondrial complex I and alpha-ketoglutarate dehydrogenase causing necrosis or apoptosis of catecholaminergic neurons. Low glucose levels or glycolytic blockade has been shown to potentiate MPP+ toxicity. We found that MPP+ caused concentration-dependent apoptosis of neuronally differentiated PC12 cells and that glucose, but not pyruvate, supplementation reduced apoptosis, Oligomycin concentrations sufficient to inhibit ATP synthase blocked the decreased apoptosis afforded by glucose supplementation. Laser-scanning confocal microscope imaging of chloromethyl-tetramethylrosamine methyl ester fluorescence to estimate Delta Psi(M) showed that MPP+ and atractyloside reduced Delta Psi(M), while cyclosporin A (CSA) and glucose supplementation reversed decreases in Delta Psi(M) caused by MPP+. Oligomycin blocked the effect of glucose supplementation on Delta Psi(M). These findings show that (i) MPP+-induced and atractyloside-induced apoptosis are associated with reduced Delta Psi(M); (ii) CSA maintains Delta Psi(M) and reduces MPP+-induced apoptosis; and (iii) glucose supplementation maintains Delta Psi(M), likely by glycolytic ATP-dependent proton pumping at ATP synthase and reduces MPP+-induced apoptosis. (C) 1999 Academic Press.