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*
Division of Critical Care, Children’s Hospital Medical Center, Cincinnati, OH 45229; and
Department of Pathophysiology, University Medical School of Debrecen, Debrecen, Hungary
Reactive oxidant species are important mediators of tissue injury
in shock, inflammation, and reperfusion injury. The actions of a number
of these oxidants (e.g., hydroxyl radical and peroxynitrite, a reactive
oxidant produced by the reaction of nitric oxide and superoxide) are
mediated in part by the activation of the nuclear nick sensor enzyme,
poly(ADP)-ribose synthetase (PARS), with consequent cellular energy
depletion. Here we investigated whether PARS activation contributes to
the mitochondrial alterations in cells exposed to oxidants. Authentic
peroxynitrite (20 µM), the peroxynitrite-generating compound
3-morpholinosidnonimine, the combination of pyrogallol and
S-nitroso-N-acetyl-D,L-penicillamine,
as well as hydrogen peroxide induced a time- and dose-dependent
decrease in mitochondrial transmembrane potential (
m)
in thymocytes, as determined by flow cytometry using the mitochondrial
potential sensitive dyes DiOC6(3) and JC-1. A time- and dose-dependent
increase in secondary reactive oxygen intermediate production and loss
of cardiolipin, an indicator of mitochondrial membrane damage, were
also observed, as measured by flow cytometry using the fluorescent dyes
dihydroethidine and nonyl-acridine orange, respectively. Inhibition of
PARS by 3-aminobenzamide or 5-iodo-6-amino-1,2-benzopyrone attenuated
peroxynitrite-induced m reduction, secondary reactive
oxygen intermediate generation, cardiolipin degradation, and
intracellular calcium mobilization. Furthermore, thymocytes from
PARS-deficient animals were protected against the peroxynitrite- and
hydrogen peroxide-induced functional and ultrastructural mitochondrial
alterations. In conclusion, mitochondrial perturbations during
oxidant-mediated cytotoxicity are, to a significant degree, related to
PARS activation rather than to direct effects of the oxidants on the
mitochondria.
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