Nitric oxide regulation of mitochondrial oxygen consumption II: molecular mechanism and tissue physiology

2007 ◽  
Vol 292 (6) ◽  
pp. C1993-C2003 ◽  
Author(s):  
Chris E. Cooper ◽  
Cecilia Giulivi
Keyword(s):  
Nitric Oxide ◽  
Oxygen Consumption ◽  
Cytochrome C ◽  
Cytochrome Oxidase ◽  
Molecular Mechanism ◽  
Guanylate Cyclase ◽  
Redox State ◽  
Physiological Role ◽  
Metabolic Effects ◽  
Whole Body

Nitric oxide (NO) is an intercellular signaling molecule; among its many and varied roles are the control of blood flow and blood pressure via activation of the heme enzyme, soluble guanylate cyclase. A growing body of evidence suggests that an additional target for NO is the mitochondrial oxygen-consuming heme/copper enzyme, cytochrome c oxidase. This review describes the molecular mechanism of this interaction and the consequences for its likely physiological role. The oxygen reactive site in cytochrome oxidase contains both heme iron ( a3) and copper (CuB) centers. NO inhibits cytochrome oxidase in both an oxygen-competitive (at heme a3) and oxygen-independent (at CuB) manner. Before inhibition of oxygen consumption, changes can be observed in enzyme and substrate (cytochrome c) redox state. Physiological consequences can be mediated either by direct “metabolic” effects on oxygen consumption or via indirect “signaling” effects via mitochondrial redox state changes and free radical production. The detailed kinetics suggest, but do not prove, that cytochrome oxidase can be a target for NO even under circumstances when guanylate cyclase, its primary high affinity target, is not fully activated. In vivo organ and whole body measures of NO synthase inhibition suggest a possible role for NO inhibition of cytochrome oxidase. However, a detailed mapping of NO and oxygen levels, combined with direct measures of cytochrome oxidase/NO binding, in physiology is still awaited.

Acute effect of insulin on nitric oxide synthesis in humans: a precursor-product isotopic study

2007 ◽  
Vol 293 (3) ◽  
pp. E776-E782 ◽  
Author(s):  
Paolo Tessari ◽  
Anna Coracina ◽  
Lucia Puricelli ◽  
Monica Vettore ◽  
Alessandra Cosma ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Acute Effect ◽  
Oxidation Products ◽  
No Oxidation ◽  
Metabolic Effects ◽  
Whole Body ◽  
Fasting State ◽  
Isotopic Study ◽  
Euglycemic Hyperinsulinemic Clamp

Nitric oxide (NO) is a key regulatory molecule with wide vascular, cellular, and metabolic effects. Insulin affects NO synthesis in vitro. No data exist on the acute effect of insulin on NO kinetics in vivo. By employing a precursor-product tracer method in humans, we have directly estimated the acute effect of insulin on intravascular NOx (i.e., the NO oxidation products) fractional (FSR) and absolute (ASR) synthesis rates in vivo. Nine healthy male volunteers were infused iv with l-[15N2-guanidino]arginine ([15N2]arginine) for 6 h. Timed measurements of 15NOx and [15N2]arginine enrichments in whole blood were performed in the first 3 h in the fasting state and then following a 3-h euglycemic-hyperinsulinemic clamp (with plasma insulin raised to ≈1,000 pmol/l). In the last 60 min of each experimental period, at ≈steady-state arginine enrichment, a linear increase of 15NOx enrichment (mean r = 0.9) was detected in both experimental periods. In the fasting state, NOx FSR was 27.4 ± 4.3%/day, whereas ASR was 0.97 ± 0.36 mmol/day, accounting for 0.69 ± 0.27% of arginine flux. Following hyperinsulinemia, both FSR and ASR of NOx increased (FSR by ≈50%, to 42.4 ± 6.7%/day, P < 0.005; ASR by ≈25%, to 1.22 ± 0.41 mmol/day, P = 0.002), despite a ≈20–30% decrease of arginine flux and concentration. The fraction of arginine flux used for NOx synthesis was doubled, to 1.13 ± 0.35% ( P < 0.003). In conclusion, whole body NOx synthesis can be directly measured over a short observation time with stable isotope methods in humans. Insulin acutely stimulates NOx synthesis from arginine.

scholarly journals Roles of nitric oxide synthase and cyclooxygenase in leg vasodilation and oxygen consumption during prolonged low-intensity exercise in untrained humans

2010 ◽  
Vol 109 (3) ◽  
pp. 768-777 ◽  
Author(s):  
William G. Schrage ◽  
Brad W. Wilkins ◽  
Christopher P. Johnson ◽  
John H. Eisenach ◽  
Jacqueline K. Limberg ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Young Adults ◽  
Oxygen Consumption ◽  
Steady State ◽  
Nitric Oxide Synthase ◽  
Muscle Blood Flow ◽  
Blood Gases ◽  
Whole Body ◽  
Oxide Synthase

The vasodilator signals regulating muscle blood flow during exercise are unclear. We tested the hypothesis that in young adults leg muscle vasodilation during steady-state exercise would be reduced independently by sequential pharmacological inhibition of nitric oxide synthase (NOS) and cyclooxygenase (COX) with NG-nitro-l-arginine methyl ester (l-NAME) and ketorolac, respectively. We tested a second hypothesis that NOS and COX inhibition would increase leg oxygen consumption (V̇o2) based on the reported inhibition of mitochondrial respiration by nitric oxide. In 13 young adults, we measured heart rate (ECG), blood pressure (femoral venous and arterial catheters), blood gases, and venous oxygen saturation (indwelling femoral venous oximeter) during prolonged (25 min) steady-state dynamic knee extension exercise (60 kick/min, 19 W). Leg blood flow (LBF) was determined by Doppler ultrasound of the femoral artery. Whole body V̇o2 was measured, and leg V̇o2 was calculated from blood gases and LBF. Resting intra-arterial infusions of acetylcholine (ACh) and nitroprusside (NTP) tested inhibitor efficacy. Leg vascular conductance (LVC) to ACh was reduced up to 53 ± 4% by l-NAME + ketorolac infusion, and the LVC responses to NTP were unaltered. Exercise increased LVC from 4 ± 1 to 33.1 ± 2 ml·min−1·mmHg−1 and tended to decrease after l-NAME infusion (31 ± 2 ml·min−1·mmHg−1, P = 0.09). With subsequent administration of ketorolac LVC decreased to 29.6 ± 2 ml·min−1·mmHg−1 ( P = 0.02; n = 9). While exercise continued, LVC returned to control values (33 ± 2 ml·min−1·mmHg−1) within 3 min, suggesting involvement of additional vasodilator mechanisms. In four additional subjects, LVC tended to decrease with l-NAME infusion alone ( P = 0.08) but did not demonstrate the transient recovery. Whole body and leg V̇o2 increased with exercise but were not altered by l-NAME or l-NAME + ketorolac. These data indicate a modest role for NOS- and COX-mediated vasodilation in the leg of exercising humans during prolonged steady-state exercise, which can be restored acutely. Furthermore, NOS and COX do not appear to influence muscle V̇o2 in untrained healthy young adults.

Control of proteoliposomal cytochrome c oxidase: the partial reactions

1990 ◽  
Vol 68 (9) ◽  
pp. 1135-1141 ◽  
Author(s):  
Peter Nicholls
Keyword(s):  
Electron Transfer ◽  
Steady State ◽  
Membrane Potential ◽  
Cytochrome C ◽  
Cytochrome Oxidase ◽  
Cytochrome C Oxidase ◽  
Redox State ◽  
Ph Gradient ◽  
Transfer Model ◽  
State Reduction

The steady-state spectroscopic behaviour and the turnover of cytochrome c oxidase incorporated into proteoliposomes have been investigated as functions of membrane potential and pH gradient. The respiration rate is almost linearly dependent on [cytochrome c2+] at high flux, but while the cytochrome a redox state is always dependent on the [cytochrome c2+] steady state, it reaches a maximum reduction level less than 100% in each case. The maximal aerobic steady-state reduction level of cytochrome a is highest in the presence of valinomycin and lowest in the presence of nigericin. The proportion of [cytochrome c2+] required to achieve 50% of maximal reduction of cytochrome a varies with the added ionophores; the apparent redox potential of cytochrome a is most positive in the fully decontrolled system (plus valinomycin and nigericin). At low levels of cytochrome a reduction, the rate of respiration is no longer a linear function of [cytochrome c2+], but is dependent upon the redox state of both cytochromes a and c. That is, proteoliposomal oxidase does not follow Smith–Conrad kinetics at low cytochrome c reduction levels, especially in the controlled states. The control of cytochrome oxidase turnover by ΔpH and by ΔΨ can be explained either by an allosteric model or by a model with reversed electron transfer between the binuclear centre and cytochrome a. Other evidence suggests that the reversed electron transfer model may be the correct one.Key words: proteoliposomes, cytochrome c, cytochrome oxidase, membrane potential, pH gradient, cytochrome a, electron transfer.

THE RESPIRATION OF ASCARIS LUMBRICOIDES EGGS

1955 ◽  
Vol 33 (6) ◽  
pp. 1033-1046 ◽  
Author(s):  
Richard F. Passey ◽  
Donald Fairbairn
Keyword(s):  
Carbon Monoxide ◽  
Oxygen Consumption ◽  
Cytochrome C ◽  
Cytochrome Oxidase ◽  
Ascaris Lumbricoides ◽  
Enzyme System ◽  
High Sensitivity ◽  
Partial Pressures ◽  
Rate Of Oxygen Consumption ◽  
Low Sensitivity

The rate of oxygen consumption of developing ascaris eggs decreased rapidly to a minimum after 1.5 days, and thereafter increased to a maximum at 10 days, when the embryos were vermiform. During the 10–20 day period, when the embryo matures and molts once in the egg, the respiration decreased steadily, and continued to decrease more slowly until at 140 days the rate was scarcely measurable. Nevertheless, the eggs remained viable and hatched readily in the mouse gut. Cytochrome c and cytochrome oxidase could not be detected by direct assay or isolation. However, the high sensitivity of the respiration to carbon monoxide (in the dark), to cyanide, and to azide, and the low sensitivity to carbon monoxide (in the light) and to decreasing partial pressures of oxygen, indicated that oxidases such as the flavoproteins, phenolases, and peroxidases were unlikely respiratory catalysts, and that cytochrome oxidase, or a similar and hitherto undescribed enzyme, was the major component of the terminal respiratory enzyme system.

Nitric oxide, cytochrome c and mitochondria

1999 ◽  
Vol 66 ◽  
pp. 17-25 ◽  
Author(s):  
Guy C. Brown ◽  
Vilmante Borutaite
Keyword(s):  
Nitric Oxide ◽  
Hydrogen Peroxide ◽  
Cytochrome C ◽  
Cytochrome Oxidase ◽  
Protease Activity ◽  
Complex I ◽  
Glutamate Release ◽  
Nerve Terminals ◽  
No Inhibition ◽  
Brain Nerve Terminals

Nitric oxide (NO) and its derivative, peroxynitrite (ONOO-), inhibit mitochondrial respiration, and this inhibition may contribute to both the physiological and cytotoxic actions of NO. Nanomolar concentrations of NO rapidly and reversibly inhibited cytochrome oxidase in competition with oxygen, as shown with isolated cytochrome oxidase, mitochondria, brain nerve terminals and cells. Cultured astrocytes and macrophages activated (by cytokines and endotoxin) to express the inducible form of NO synthase produced up to 1 μM NO, and inhibited their own respiration and that of co-incubated cells via reversible NO inhibition of cytochrome oxidase. NO-induced inhibition of respiration in brain nerve terminals resulted in rapid glutamate release, which might contribute to the neurotoxicity of NO. NO inhibition of cytochrome oxidase is reversible; however, incubation of cells with NO donors for 4 hours resulted in an inhibition of complex I, which was reversible by light and thiol reagents and may be due to nitrosylation of thiols in complex I. NO also caused the acute inhibition of catalase, stimulation of hydrogen peroxide production by mitochondria, and reaction with hydrogen peroxide on superoxide dismutase to produce peroxynitrite. Peroxynitrite inhibited complexes I, II and V (the ATP synthase), aconitase, creatine kinase, and increases the proton leak in isolated mitochondria. Peroxynitrite also caused opening of the permeability transition pore, resulting in the release of cytochrome c, which might then trigger apoptosis. Hypoxia/ischaemia also resulted in an acute reversible inhibition of cytochrome oxidase. Heart ischaemia caused the release of cytochrome c from mitochondria into the cytosol, and at the same time caspase-3-like-protease activity was activated in the cytoplasm. Addition of cytochrome c to non-ischaemic cytosol also caused activation of this protease activity, suggesting that caspase activation and consequent apoptosis is at least partly a result of this cytochrome c release.

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