RT Journal Article SR Electronic T1 Electron Transport-Mediated Wasteful Consumption of NADH Promotes the Lethal Response of U937 Cells to Tert-Butylhydroperoxide JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 1112 OP 1121 VO 284 IS 3 A1 Brambilla, Liliana A1 Sestili, Piero A1 Guidarelli, Andrea A1 Palomba, Letizia A1 Cantoni, Orazio YR 1998 UL http://jpet.aspetjournals.org/content/284/3/1112.abstract AB The toxicity of a short-term exposure totert-butylhydroperoxide in U937 cells was markedly reduced by chemically or experimentally induced respiratory deficiency. Rotenone mitigated the lethal effects of the hydroperoxide over the same concentration-range in which the complex I inhibitor inhibited oxygen utilization. U937 cells that were made respiration deficient by growing them in the presence of either chloramphenicol or ethidium bromide, were in both circumstances highly resistant totert-butylhydroperoxide. The improved survival was not a direct consequence of the absence of electron transport, but rather was attributable to the large amounts of NADH which accumulate in the mitochondria of chemically hypoxic or respiration-deficient cells. Indeed, the toxicity elicited by tert-butylhydroperoxide was also abolished by supplementation with either of two different NADH-linked substrates, namely pyruvate or β-hydroxybutyrate. Accumulation of intramitochondrial NADH, and the resulting cytoprotective effects, was associated with prevention of the loss of nonprotein sulphydryls and mitochondrial membrane potential. Neither rotenone nor pyruvate reduced the toxicity oftert-butylhydroperoxide in thiol-depleted cells. Taken together, these results indicate that depletion of mitochondrial NADH is a critical event in the cytotoxic response totert-butylhydroperoxide since this pyridine nucleotide prevents mitochondrial dysfunction and cell death caused by the hydroperoxide. As a consequence, in hydroperoxide-treated cells electron transport is highly detrimental since it consumes mitochondrial NADH. The American Society for Pharmacology and Experimental Therapeutics