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 le vels or glycolytic blockade has been shown to potentiate MPP+ toxicity. We found that MPP+ caused concentration-dependent apoptosis of neuronally diff erentiated PC12 cells and that glucose, but not pyruvate, supplementation r educed apoptosis, Oligomycin concentrations sufficient to inhibit ATP synth ase blocked the decreased apoptosis afforded by glucose supplementation. La ser-scanning confocal microscope imaging of chloromethyl-tetramethylrosamin e methyl ester fluorescence to estimate Delta Psi(M) showed that MPP+ and a tractyloside reduced Delta Psi(M), while cyclosporin A (CSA) and glucose su pplementation reversed decreases in Delta Psi(M) caused by MPP+. Oligomycin blocked the effect of glucose supplementation on Delta Psi(M). These findi ngs show that (i) MPP+-induced and atractyloside-induced apoptosis are asso ciated with reduced Delta Psi(M); (ii) CSA maintains Delta Psi(M) and reduc es MPP+-induced apoptosis; and (iii) glucose supplementation maintains Delt a Psi(M), likely by glycolytic ATP-dependent proton pumping at ATP synthase and reduces MPP+-induced apoptosis. (C) 1999 Academic Press.