Effect of exogenous and endogenous nitric oxide on mitochondrial respiration of rat hepatocytes.
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.
Stadler
J
J
Department of Surgery, University of Pittsburgh, Pennsylvania 15261.
Billiar
T R
TR
Curran
R D
RD
Stuehr
D J
DJ
Ochoa
J B
JB
Simmons
R L
RL
D000818:Animals; D002478:Cells, Cultured; D042963:Electron Transport Complex II; D007700:Kinetics; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism*; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors; D016660:NAD(P)H Dehydrogenase (Quinone); D009569:Nitric Oxide / Q000378:metabolism / Q000494:pharmacology*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors; D010101:Oxygen Consumption / Q000187:drug effects*; D014176:Protein Biosynthesis; D011808:Quinone Reductases / Q000037:antagonists & inhibitors; D051381:Rats; D011919:Rats, Inbred Strains; D013385:Succinate Dehydrogenase / Q000037:antagonists & inhibitors
D009097:Multienzyme Complexes; D009569:Nitric Oxide; D010088:Oxidoreductases; D042963:Electron Transport Complex II; D013385:Succinate Dehydrogenase; D016660:NAD(P)H Dehydrogenase (Quinone); D011808:Quinone Reductases