Coenzyme Q₁redox metabolism during passage through the rat pulmonary circulation and the effect of hyperoxia

Abstract

The objective was to evaluate the pulmonary disposition of the ubiquinone homolog coenzyme Q(1) (CoQ(1)) on passage through lungs of normoxic (exposed to room air) and hyperoxic (exposed to 85% O(2) for 48 h) rats. CoQ(1) or its hydroquinone (CoQ(1)H(2)) was infused into the arterial inflow of isolated, perfused lungs, and the venous efflux rates of CoQ(1)H(2) and CoQ(1) were measured. CoQ(1)H(2) appeared in the venous effluent when CoQ(1) was infused, and CoQ(1) appeared when CoQ(1)H(2) was infused. In normoxic lungs, CoQ(1)H(2) efflux rates when CoQ(1) was infused decreased by 58 and 33% in the presence of rotenone (mitochondrial complex I inhibitor) and dicumarol [NAD(P)H-quinone oxidoreductase 1 (NQO1) inhibitor], respectively. Inhibitor studies also revealed that lung CoQ(1)H(2) oxidation was via mitochondrial complex III. In hyperoxic lungs, CoQ(1)H(2) efflux rates when CoQ(1) was infused decreased by 23% compared with normoxic lungs. Based on inhibitor effects and a kinetic model, the effect of hyperoxia could be attributed predominantly to 47% decrease in the capacity of complex I-mediated CoQ(1) reduction, with no change in the other redox processes. Complex I activity in lung homogenates was also lower for hyperoxic than for normoxic lungs. These studies reveal that lung complexes I and III and NQO1 play a dominant role in determining the vascular concentration and redox status of CoQ(1) during passage through the pulmonary circulation, and that exposure to hyperoxia decreases the overall capacity of the lung to reduce CoQ(1) to CoQ(1)H(2) due to a depression in complex I activity.

Quantifying mitochondrial and plasma membrane potentials in intact pulmonary arterial endothelial cells based on extracellular disposition of rhodamine dyes

“…It should be emphasized that the effect of hyperoxic exposure on pulmonary endothelial mitochondria would not have been revealed by measuring only the resting ⌬ m or using only a single commonly used CCCP concentration (5 M) to depolarize the mitochondria. Various indications of mitochondrial dysfunction have been reported by us and others in hyperoxiaexposed rat lung, pulmonary endothelial cells in culture, and other cell types (2,3,5,7,8,36,37,51,57). In this context, the present observations are consistent with a hyperoxia-induced mitochondrial deficiency.…”

Genetic evidence for NAD(P)H:quinone oxidoreductase 1-catalyzed quinone reduction on passage through the mouse pulmonary circulation

“…This is in contrast to the rat lung, in which CoQ 1 reduction is attributable to both NQO1 and complex I on the basis of inhibitor studies with dicumarol and rotenone (6). It is conceivable that the mouse lung is, instead, analogous to the bovine pulmonary artery endothelial cells, in which CoQ 1 appears to act as a selective probe for complex I activity (28).…”

“…As a basis for comparison with DQ, we also evaluated the impact of mouse lung NQO1 on the redox status of another amphipathic quinone, coenzyme Q 1 (CoQ 1 ). CoQ 1 has been shown to act as an electron acceptor for NADH dehydrogenase (complex I of the mitochondrial electron transport chain) and NQO1 in the perfused rat lung (6).…”

Coenzyme Q1as a probe for mitochondrial complex I activity in the intact perfused hyperoxia-exposed wild-type andNqo1-null mouse lung

“…As a step toward developing nondestructive probes for lung redox function, we have relied on the observation that the pulmonary endothelium and lung tissue participate in alteration of the redox status and disposition of redox-active compounds as they pass through the pulmonary circulation (2)(3)(4)(5)(6)36). Such compounds include certain amphipathic quinones, which are reduced to their two-electron reduction products, or hydroquinones, on passage through the lung.…”

“…Such compounds include certain amphipathic quinones, which are reduced to their two-electron reduction products, or hydroquinones, on passage through the lung. Furthermore, quinones with different physical and chemical properties have different propensities to be reduced via specific target quinone reductases within the lung tissue (2,4,6,36). Identification of the quinone reductases involved in this metabolism was initially based on the use of quinone reductase inhibitors.…”