Glucose Protection from MPP+-Induced Apoptosis Depends on Mitochondrial Membrane Potential and ATP Synthase

MPP+inhibits mitochondrial complex I and α-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 ΔΨMshowed that MPP+and atractyloside reduced ΔΨM, while cyclosporin A (CSA) and glucose supplementation reversed decreases in ΔΨMcaused by MPP+. Oligomycin blocked the effect of glucose supplementation on ΔΨM. These findings show that (i) MPP+-induced and atractyloside-induced apoptosis are associated with reduced ΔΨM; (ii) CSA maintains ΔΨMand reduces MPP+-induced apoptosis; and (iii) glucose supplementation maintains ΔΨM,likely by glycolytic ATP-dependent proton pumping at ATP synthase and reduces MPP+-induced apoptosis.