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The Journal of Neuroscience, January 1, 1999, 19(1):147-158
Nitric Oxide Acutely Inhibits Neuronal Energy Production
James R.
Brorson1,
Paul
T.
Schumacker2, and
He
Zhang3
1 Department of Neurology and the Committees on
Neurobiology and Cell Physiology, 2 Department of Medicine
and the Committee on Comparative Medicine and Pathology, and
3 Section of Neurosurgery, Department of Surgery, The
University of Chicago, Chicago, Illinois 60637
Disruption of mitochondrial respiration has been proposed as an
action of nitric oxide (NO) responsible for its toxicity, but the
effects of NO on the energetics of intact central neurons have not been
reported. We examined the effects of NO on mitochondrial function and
energy metabolism in cultured hippocampal neurons. The application of
NO from NO donors or from dissolved gas produced a rapid, reversible
depolarization of mitochondrial membrane potential, as detected by
rhodamine-123 fluorescence. NO also produced a progressive
concentration-dependent depletion of cellular ATP over 20 min
exposures. The energy depletion produced by higher levels of NO (2 µM or more) was profound and irreversible and proceeded
to subsequent neuronal death.
In contrast to the effects of NO, mitochondrial protonophores produced
complete depolarizations of mitochondrial membrane potential but
depleted the neuronal ATP stores only partially. Inhibitors of
mitochondrial oxidative phosphorylation (rotenone or 3-nitropropionic
acid) or of glycolysis (iodoacetate plus pyruvate) also produced only
partial ATP depletion, suggesting that either process alone could
partially maintain ATP stores. Only by combining the inhibition of
glycolytic energy production with the inhibition of mitochondria could
the effects of NO in depleting energy and inducing delayed toxicity be duplicated.
These results show that NO has rapid inhibitory actions on
mitochondrial metabolism in living neurons. However, the severe ATP-depleting effects of high concentrations of NO are not fully explained by the direct effects on mitochondrial activity alone but
must involve the inhibition of glycolysis as well. These inhibitory effects on energy production may contribute to the delayed toxicity of
NO in vitro and in ischemic stroke.
Key words:
nitric oxide; ischemia; peroxynitrite; poly-(ADP ribose)
polymerase; mitochondria; glycolysis
Copyright © 1999 Society for Neuroscience 0270-6474/99/191147-12$05.00/0
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