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 DeltaPsiM showed that MPP+ and atractyloside reduced DeltaPsiM, while cyclosporin A (CSA) and glucose supplementation reversed decreases in DeltaPsiM caused by MPP+. Oligomycin blocked the effect of glucose supplementation on DeltaPsiM. These findings show that (i) MPP+-induced and atractyloside-induced apoptosis are associated with reduced DeltaPsiM; (ii) CSA maintains DeltaPsiM and reduces MPP+-induced apoptosis; and (iii) glucose supplementation maintains DeltaPsiM, likely by glycolytic ATP-dependent proton pumping at ATP synthase and reduces MPP+-induced apoptosis.
Chalmers-Redman
R M
RM
Department of Neurology, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, New York, 10029-6574, USA.
Fraser
A D
AD
Carlile
G W
GW
Pong
A
A
Tatton
W G
WG
D015655:1-Methyl-4-phenylpyridinium / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001278:Atractyloside / Q000494:pharmacology; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology; D053938:DNA Fragmentation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D006019:Glycolysis / Q000187:drug effects; D008564:Membrane Potentials / Q000187:drug effects*; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D009414:Nerve Growth Factors / Q000494:pharmacology; D009840:Oligomycins / Q000494:pharmacology; D016716:PC12 Cells; D006180:Proton-Translocating ATPases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019289:Pyruvic Acid / Q000494:pharmacology; D051381:Rats; D013997:Time Factors
D009414:Nerve Growth Factors; D009840:Oligomycins; D001278:Atractyloside; D016572:Cyclosporine; D019289:Pyruvic Acid; D006180:Proton-Translocating ATPases; D005947:Glucose; D015655:1-Methyl-4-phenylpyridinium