Lung mitochondrial function following oxygen exposure and diethyl maleate-induced depletion of glutathione

Abstract Diethyl maleate (DEM) pretreatment has previously been shown to result in a transient depletion of lung glutathione and an associated decrease of the time to the onset of rat mortality resulting from exposures to 100% oxygen in vivo . The effects of oxygen exposure on mitochondrial energy metabolism were assessed by measurements of ADP-stimulated rates of O 2 utilization by lung homogenates prepared from untreated and DEM-treated rats following 4 and 24 hr of exposure to either air or 100% oxygen. Twenty-four hours of oxygen exposure of untreated rats resulted in significant decreases in lung homogenate ADP-stimulated rates of respiration supported by the substrates, pyruvate, isocitrate, and α-ketoglutarate. No changes were observed in succinate-supported respiration, indicating that oxygen exposure appears to adversely affect NAD-linked rather than FAD-linked pathways of mitochondrial energy metabolism. The decreased lung mitochondrial glutathione, observed 4 hr following DEM treatment, returned to normal levels following 24 hr of air and oxygen exposure. No effects of glutathione depletion were observed on ADP-stimulated rates of respiratory activity 4 hr following DEM treatment. The DEM-induced transient depletion of glutathione also did not result in any additional detrimental effects on mitochondrial respiratory activity following 24 hr of oxygen exposure in vivo . These results suggested that transient mitochondrial depletion of glutathione does not accelerate the oxygen-induced impairment of mitochondrial energy metabolism. The onset of mortality associated with DEM-pretreatment might therefore result from a failure of glutathione-dependent cytosolic protective mechanisms, rather than from an increased rate of oxygen-induced mitochondrial damage.