The primary oxygen sensor of the cat carotid body is cytochrome <i>a</i><sub>3</sub> of the mitochondrial respiratory chain

Wilson, David F.; Mokashi, A.; Chugh, Deepak K.; Vinogradov, Sergei A.; Osanai, Shinobu; Lahiri, S.

doi:10.1016/0014-5793(94)00887-6

Cited by 119 publications

(75 citation statements)

References 24 publications

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“…The mechanism underlying sensing of acute variations in oxygen concentration has not been fully elucidated. Cumulative evidence indicates that a haem protein is involved (29), and cytochrome c oxidase has been proposed as a candidate (30,31). However, the K m (or p50) for oxygen observed in the isolated enzyme and mitochondrial preparations is 5-10ϫ lower than that measured in whole cells and tissues (32)(33)(34)(35)(36).…”

Section: Discussionmentioning

confidence: 99%

On the mechanism by which vascular endothelial cells regulate their oxygen consumption

Clementi

Brown

Foxwell

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

275

200

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Two enzymes, soluble guanylyl cyclase and cytochrome c oxidase, have been shown to be exquisitely sensitive to nitric oxide (NO) at low physiological concentrations. Activation of the soluble guanylyl cyclase by endogenous NO and the consequent increase in the second messenger cyclic GMP are now known to control a variety of biological functions. Cytochrome c oxidase, the terminal enzyme of the mitochondrial respiratory chain, is inhibited by NO. However, it is not clear whether NO produced by the constitutive NO synthase interacts with cytochrome c oxidase, nor is it known what the biological consequences of such an interaction might be. We now show that NO generated by vascular endothelial cells under basal and stimulated conditions modulates the respiration of these cells in response to acute changes in oxygen concentration. This action occurs at the cytochrome c oxidase and depends on inf lux of calcium. Thus, NO plays a physiological role in adjusting the capacity of this enzyme to use oxygen, allowing endothelial cells to adapt to acute changes in their environment.Evidence in favor of a role of endogenous nitric oxide (NO) as a modulator of cell respiration has been derived from experiments in cells activated with cytokines and bacterial products in which NO is generated continuously in large quantities by the inducible NO synthase (NOS). In these conditions, NOinduced inhibition of cell respiration is persistent and attributable to nonselective inhibition of various mitochondrial enzymes, including complexes I-IV in the respiratory chain. Such inhibition contributes to the pathological actions of NO (1). On the other hand, experiments in animals have suggested that inhibition of endogenous generation of NO increases whole body oxygen consumption (2, 3), and bradykinin (Bk) and carbachol have been shown to reduce oxygen consumption in skeletal and cardiac muscle in a manner that could be prevented by an inhibitor of NOS (3-5).Exogenous administration of low concentrations of NO inhibits cytochrome c oxidase (complex IV in the mitochondrial respiratory chain) in a variety of cells and isolated mitochondria. Such inhibition is competitive with oxygen and is fully reversible (6-9) even after several hours (10). These findings suggest that endogenous NO may regulate cell respiration. To test this hypothesis, we have analyzed the effect of endogenous NO, generated under basal conditions and after stimulation with Bk and ATP, on respiration in porcine aortic endothelial cells. Our results show that endogenously released NO, by acting on cytochrome c oxidase, is responsible for the physiological regulation of respiration in these cells. MATERIALS AND METHODSMaterials. Culture media and fetal calf serum were from GIBCO. Fura-2 acetoxymethylester was from Calbiochem. Other reagents were from Sigma.Cell Culture and Preparation. Endothelial cells were prepared from fresh porcine thoracic aortae obtained from the abattoir, were cultured overnight in DMEM 20% fetal calf serum, and then were grown to confluence...

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Section: Discussionmentioning

confidence: 99%

On the mechanism by which vascular endothelial cells regulate their oxygen consumption

Clementi

Brown

Foxwell

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

275

200

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“…As mentioned above, patch clamp experiments indicate that the oxygen sensor in carotid body type I cells resides in the plasma membrane (Ganfornina and López-Barneo, 1991). Nevertheless, several reports have suggested that mitochondria may play a critical role in oxygen sensing by the carotid body (Mulligan et al, 1981;Obeso et al, 1985;Duchen and Biscoe, 1992;Wilson et al, 1994;Lahiri et al, 1995). In view of the extraordinarily rich vascularity and high oxygen consumption of the carotid body, there may be a unique functional role for a mitochondrial oxygen sensor.…”

Section: Mitochondrial Complex IV Heme Proteinmentioning

confidence: 97%

Oxygen sensing and signaling: impact on the regulation of physiologically important genes

Zhu

Bunn

1999

Respiration Physiology

151

101

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A growing number of physiologically relevant genes are regulated in response to changes in intracellular oxygen tension. It is likely that cells from a wide variety of tissues share a common mechanism of oxygen sensing and signal transduction leading to the activation of the transcription factor hypoxia-inducible factor 1 (HIF-1). Besides hypoxia, transition metals (Co 2+ , Ni 2+ and Mn 2+ ) and iron chelation also promote activation of HIF-1. Induction of HIF-1 by hypoxia is blocked by the heme ligands carbon monoxide and nitric oxide. There is growing, albeit indirect, evidence that the oxygen sensor is a flavoheme protein and that the signal transduction pathway involves changes in the level of intracellular reactive oxygen intermediates. The activation of HIF-1 by hypoxia depends upon signaling-dependent rescue of its α-subunit from oxygendependent degradation in the proteasome, allowing it to form a heterodimer with HIF-1β (ARNT), which then translocates to the nucleus and impacts on the transcription of genes whose cis-acting elements contain cognate hypoxia response elements.

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“…The primary oxygen sensor of vascular PO 2 is the carotid body (41). The fact that carbon monoxide can mimic low O 2 in activating this pathway, and that the photoaction spectrum of this activation closely resembled that of CO dissociation from cytochrome c oxidase, suggested that the primary oxygen sensor could, in fact, be the cytochrome c oxidase itself (50,92). One concern with this mechanism is that the K m for oxygen for the enzyme might too low to be able to respond to the small changes from physiological PO 2 that the carotid body detects.…”

Section: Why Inhibit O2 Consumption In Physiology? the Metabolic Argumentioning

confidence: 99%

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

Cooper¹,

Giulivi

2007

American Journal of Physiology-Cell Physiology

147

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Cooper CE, Giulivi C. Nitric oxide regulation of mitochondrial oxygen consumption II: molecular mechanism and tissue physiology. Am J Physiol Cell Physiol 292: C1993-C2003, 2007. First published February 28, 2007 doi:10.1152/ajpcell.00310.2006 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. mitochondria; cytochrome oxidase NITRIC OXIDE (NO) is known as an intercellular messenger, synthesized in mammalian systems from arginine, NADPH, and oxygen by the NO synthase (NOS) class of enzymes (1). It has a wide range of physiological functions, most notably the control of blood pressure and blood flow (46, 63) mediated by the production of cGMP via its activation of the heme enzyme, soluble guanylate cyclase (45).Just over a decade ago, several groups demonstrated that the primary target for NO interactions with mammalian mitochondria is at the level of the oxygen-consuming enzyme, cytochrome c oxidase (15,20,73). These, and numerous subsequent studies, have demonstrated that in vitro cytochrome c oxidase is reversibly inhibited by nanomolar levels of NO. The possible cellular consequences of this effect are described in our previous paper (38). This review will instead focus on the importance of NO interactions with cytochrome oxidase at levels of organization above that of the individual cell.Two major questions arise when contemplating the possible consequences of this interaction at the tissue/organ level. First, does it occur in vivo? Second, if so, what are the physiological consequences? Whereas the detailed molecular mechanism of inhibition might appear to be of more interest to biochemists than physiologists, un...

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The primary oxygen sensor of the cat carotid body is cytochrome a₃ of the mitochondrial respiratory chain

Cited by 119 publications

References 24 publications

On the mechanism by which vascular endothelial cells regulate their oxygen consumption

On the mechanism by which vascular endothelial cells regulate their oxygen consumption

Oxygen sensing and signaling: impact on the regulation of physiologically important genes

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

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The primary oxygen sensor of the cat carotid body is cytochrome a3 of the mitochondrial respiratory chain

Cited by 119 publications

References 24 publications

On the mechanism by which vascular endothelial cells regulate their oxygen consumption

On the mechanism by which vascular endothelial cells regulate their oxygen consumption

Oxygen sensing and signaling: impact on the regulation of physiologically important genes

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

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The primary oxygen sensor of the cat carotid body is cytochrome a₃ of the mitochondrial respiratory chain