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Despite improvements in the management of severely injured patients, development of multiple organ dysfunction syndrome (MODS) remains a morbid complication of traumatic shock. One of the key attributes of MODS is a profound bioenergetics crisis, for which the mediators and mechanisms are poorly understood. We hypothesized that metabolic uncoupling using an experimental phosphoinositol-3 kinase (PI3-K) inhibitor, LY294002 (LY), may prevent mitochondrial abnormalities that lead to the generation of mitochondrial DNA (mtDNA) damage and the release of mtDNA damage-associated molecular patterns (DAMPs).Sixteen swine were studied using LY, a nonselective PI3-K inhibitor. Animals were assigned to trauma only (TO, n = 3), LY drug only (LYO, n = 3), and experimental (n = 10), trauma + drug (LY + T) groups. Both trauma groups underwent laparotomy, 35% hemorrhage, severe ischemia-reperfusion injury, and protocolized resuscitation. A battery of hemodynamic, laboratory, histological, and bioenergetics parameters were monitored. Mitochondrial DNA damage was determined in lung, liver, and kidney using Southern blot analyses, whereas plasma mtDNA DAMP analysis used polymerase chain reaction amplification of a 200-bp sequence of the mtDNA D-loop region.Relative to control animals, H + I/R (hemorrhage and ischemia/reperfusion) produced severe, time-dependent decrements in hepatic, renal, cardiovascular, and pulmonary function accompanied by severe acidosis and lactate accumulation indicative of bioenergetics insufficiency. The H-I/R animals displayed prominent oxidative mtDNA damage in all organs studied, with the most prominent damage in the liver. Mitochondrial DNA damage was accompanied by accumulation of mtDNA DAMPs in plasma. Pretreatment of H + I/R animals with LY resulted in profound metabolic suppression, with approximately 50% decreases in O2 consumption and CO2 production. In addition, it prevented organ and bioenergetics dysfunction and was associated with a significant decrease in plasma mtDNA DAMPs to the levels of control animals.These findings show that H + I/R injury in anesthetized swine is accompanied by MODS and by significant mitochondrial bioenergetics dysfunction, including oxidative mtDNA damage and accumulation in plasma of mtDNA DAMPs. Suppression of these changes with the PI3-K inhibitor LY indicates that pharmacologically induced metabolic uncoupling may comprise a new pharmacologic strategy to prevent mtDNA damage and DAMP release and prevent or treat trauma-related MODS.Therapeutic study, level III.