Effect of exogenous and endogenous nitric oxide on mitochondrial respiration of rat hepatocytes

Abstract

Although nitric oxide (.N = O) biosynthesis is inducible in rat hepatocytes (HC), the physiological significance of .N = O production by these cells is unknown. Short exposure of HC to authentic .N = O led to a concentration-dependent inhibition of mitochondrial aconitase, NADH-ubiquinone oxidoreductase, and succinate-ubiquinone oxidoreductase (complexes I and II of the mitochondrial electron transport chain). Most susceptible to .N = O inhibition was mitochondrial aconitase, in which a reduction in enzyme activity to 20.2 +/- 1.6% of control was observed. In contrast to mitochondrial aconitase, cytosolic aconitase activity was not inhibited by .N = O. After exposure to a maximal inhibitory concentration of .N = O, mitochondrial aconitase activity recovered completely within 6 h. Complex I did not fully recover within this incubation period. Endogenous .N = O biosynthesis was induced in HC by a specific combination of cytokines and lipopolysaccharide. After 18 h of incubation with these stimuli, a significant inhibition of mitochondrial aconitase activity to 70.8 +/- 2.4% of controls was detected. However, this was due only in part to the action of .N = O. A non- .N = O-dependent inhibition of mitochondrial function appeared to be mediated by tumor necrosis factor.

Mitochondrial biogenesis by NO yields functionally active mitochondria in mammals

“…Furthermore, binding of NO to COX-IV leads to a switch to glycolysis in competent cells, redistribution of O 2 , and regulation of the levels of the hypoxia-inducible factor 1 ␣, thus contributing to long-term adaptation to hypoxic conditions (10,11). By contrast, high concentrations of NO persistently inhibit complexes I and II of the respiratory chain, as well as enzymes of the glycolytic pathway and Krebs cycle, thus leading to metabolic imbalance and cell damage (12)(13)(14)(15).…”

Nitrogen oxide‐induced autoprotection in isolated rat hepatocytes

“…Two critical intracellular targets for the toxic effects of nitric oxide formation are the iron-containing enzymatic activities aconitase and mitochondrial electron transfer (most especially complexes I and II) [16], including the isolated rat hepatocyte [17]. Fig.…”

“…It is worth noting in this regard that Kuo and Slivka have shown that endogenously produced 'NO is capable of modulation of intracellular glutathione levels in hepatocytes suggesting the possibility that the changes in the intensity of the DNIC signal may reflect changes in thiol levels [40]. The lesser amount of mitochondrial activity loss by low-SNAP pretreatment could be due to several factors, including increased scavenging of • NO (perhaps reflected by the increased DNIC signal) and/or increased recovery/repair of activity [17,41].…”

Modulation of endothelin and nitric oxide: A rational approach to improve canine hepatic microcirculation

“…It appears that multiple factors, such as NO-superoxide radical ratios, 36 hepatic store of reduced glutathione, 37 and length of ischemia, all determine whether NO will act as a cytoprotective or cytotoxic agent. Another possible explanation for the cytotoxicity of NO in group II animals might be the depressed mitochondrial respiration described by Stadler et al 38 Also, the mean arterial blood pressure was significantly lower in group II animals following reperfusion as a result of the direct vasodilatory effect of NO, which might explain some of the adverse effects of NO in these animals. Moreover, it is important to note that we frequently observed oozing from the wounds in animals in groups II and VI that might result from defective hepatocyte protein synthesis including coagulation factors at higher NO doses.…”