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Papers In Press, published online ahead of print September 19, 2005
Buck Institute for Age Research, Novato, CA 94945
Corresponding Author: svesce{at}buckinstitute.org
Decreases in glutathione (GSH) pools detected during ischemia sensitize neurons to excitotoxic damage. Thermodynamic analysis predicts that partial GSH depletion will cause an oxidative shift in the thiol redox potential. To investigate the acute bioenergetic consequences, neurons were exposed to monochlorobimane (mBCl) which depletes GSH by forming a fluorescent conjugate. Neurons transfected with redox-sensitive green fluorescent protein showed a positive shift in thiol redox potential synchronous with the formation of the conjugate. Mitochondria within neurons treated with mBCl for 1 hr failed to hyperpolarize on addition of oligomycin to inhibit their ATP synthesis. A decreased ATP turnover was confirmed by monitoring neuronal oxygen consumption in parallel with mitochondrial membrane potential (Dym) and GSH-mBCl formation. mBCl progressively decreased cell respiration with no effect on mitochondrial proton leak or maximal respiratory capacity, suggesting adequate glycolysis and a functional electron transport chain. This approach to ‘state 4' could be mimicked by the adenine nucleotide translocator inhibitor bongkrekate, which did not further decrease respiration when administered after mBCl. The cell ATP/ADP ratio was decreased by mBCl and, consistent with a failure of mitochondrial ATP export, respiration could not respond to an increased cytoplasmic ATP demand by plasma membrane Na+ cycling; instead mitochondria depolarized. More prolonged mBCl exposure induced mitochondrial failure, with Dym collapse followed by cytoplasmic Ca2+ deregulation. The initial bioenergetic consequence of neuronal GSH depletion in this model is thus an inhibition of ATP export that precedes other forms of mitochondrial dysfunction.
J. Biol. Chem, 10.1074/jbc.M506575200
Submitted on June 16, 2005
Revised on August 16, 2005
Accepted on September 16, 2005
Acute glutathione depletion restricts mitochondrial ATPExport in cerebellar granule neurons
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