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1 Department of Medicine, Birmingham DVAMC, Birmingham, AL, USA; Department of Medicine/Pulmonary Division, UAB, Birmingham, AL, USA
* To whom correspondence should be addressed. E-mail: rjackson{at}uab.edu.
Both NADH dehydrogenase (Complex I) and aconitase are inactivated partially in vitro by superoxide (O2-)and other oxidants that cause loss of iron from enzyme cubane (4Fe-4S) centers. We tested whether hypoxia-reoxygenation (H-R) by itself would decrease lung epithelial cell NADH dehydrogenase, aconitase and succinate dehydrogenase (SDH) activities, and if transfection with adenoviral vectors expressing MnSOD (Ad.MnSOD) would inhibit oxidative enzyme inactivation and thus confirm a mechanism involving O2-. Human lung carcinoma cells with alveolar epithelial cell characteristics (A549 cells) were exposed to <1% O2/5% CO2 (hypoxia) for 24 hours followed by air/5% CO2 for 24 hours (reoxygenation). NADH dehydrogenase activity was assayed in submitochondrial particles; aconitase and SDH activities were measured in cell lysates. H-R significantly decreased NADH dehydrogenase, aconitase and SDH activities. Ad.MnSOD increased mitochondrial MnSOD substantially and prevented the inhibitory effects of H-R on enzyme activities. Addition of 
-ketoglutarate+aspartate, but not succinate, to medium prevented cytotoxicity due to 2, 3-dimethoxy-1, 4-naphthoquinone (DMNQ). After hypoxia, cells displayed significantly increased DHR fluorescence indicating increased mitochondrial oxidant production. Inhibition of NADH dehydrogenase, aconitase and SDH activities during reoxygenation are due to excess O2- produced in mitochondria, because enzyme inactivation can be prevented by over expression of MnSOD.
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