Protection of Cytochrome c Oxidase against Cyanide Inhibition by Pyruvate and α-Ketoglutarate: Effect of Aeration in Vitro

Delhumeau, Graciela; Cruz-Mendoza, A M; Lojero, C.G.

doi:10.1006/taap.1994.1125

Cited by 27 publications

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“…Inhibition of Complex IV (CIV) by cyanide or azide cannot be used in our protocols because cyanide inhibition is reversed by keto acids pyruvate and α-ketoglutarate, added in our experiments and produced in the TCA cycle, respectively. In addition, the reversibility of this inhibition is particularly effective at the high oxygen levels required in experiments with permeabilized fibres [27], [44].…”

Section: Methodsmentioning

confidence: 99%

Physical Fitness and Mitochondrial Respiratory Capacity in Horse Skeletal Muscle

et al. 2012

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BackgroundWithin the animal kingdom, horses are among the most powerful aerobic athletic mammals. Determination of muscle respiratory capacity and control improves our knowledge of mitochondrial physiology in horses and high aerobic performance in general.Methodology/Principal FindingsWe applied high-resolution respirometry and multiple substrate-uncoupler-inhibitor titration protocols to study mitochondrial physiology in small (1.0–2.5 mg) permeabilized muscle fibres sampled from triceps brachii of healthy horses.Oxidative phosphorylation (OXPHOS) capacity (pmol O2•s−1•mg−1 wet weight) with combined Complex I and II (CI+II) substrate supply (malate+glutamate+succinate) increased from 77±18 in overweight horses to 103±18, 122±15, and 129±12 in untrained, trained and competitive horses (N = 3, 8, 16, and 5, respectively). Similar to human muscle mitochondria, equine OXPHOS capacity was limited by the phosphorylation system to 0.85±0.10 (N = 32) of electron transfer capacity, independent of fitness level. In 15 trained horses, OXPHOS capacity increased from 119±12 to 134±37 when pyruvate was included in the CI+II substrate cocktail. Relative to this maximum OXPHOS capacity, Complex I (CI)-linked OXPHOS capacities were only 50% with glutamate+malate, 64% with pyruvate+malate, and 68% with pyruvate+malate+glutamate, and ∼78% with CII-linked succinate+rotenone. OXPHOS capacity with glutamate+malate increased with fitness relative to CI+II-supported ETS capacity from a flux control ratio of 0.38 to 0.40, 0.41 and 0.46 in overweight to competitive horses, whereas the CII/CI+II substrate control ratio remained constant at 0.70. Therefore, the apparent deficit of the CI- over CII-linked pathway capacity was reduced with physical fitness.Conclusions/SignificanceThe scope of mitochondrial density-dependent OXPHOS capacity and the density-independent (qualitative) increase of CI-linked respiratory capacity with increased fitness open up new perspectives of integrative and comparative mitochondrial respiratory physiology.

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Section: Methodsmentioning

confidence: 99%

Physical Fitness and Mitochondrial Respiratory Capacity in Horse Skeletal Muscle

et al. 2012

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“…Defects in the electron transport chain (transport system that generates the major amount of energy through oxidative phosphorylation) are usually detrimental to the host demonstrating the importance of mitochondria. One such example is cyanide poisoning that inhibits the ability of mitochondria to use oxygen to generate ATP [3]. Thus it was not surprising when in the late 1990s scientists discovered a role for mitochondria in promoting cell death (Figure 1B).…”

Section: Historical Perspective On the Origin And Importance Of Mitocmentioning

confidence: 99%

Mitochondria: diversity in the regulation of the NLRP3 inflammasome

Gurung

Lukens

Kanneganti

2015

Trends in Molecular Medicine

331

227

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Recent studies have identified new roles for mitochondria in the regulation of autoinflammatory processes. Emerging data suggests that the release of danger signals from mitochondria in response to stress and infection promotes the formation of the inflammatory signaling platform known as inflammasomes. Activation of inflammasomes by damaged mitochondria results in caspase-1-dependent secretion of the inflammatory cytokines IL-1β and IL-18, and an inflammatory form of cell death referred to as pyroptosis. Here, we review recently described mechanisms that have been proposed to be involved in mitochondria-mediated regulation of inflammasome activation and inflammation. In addition, we highlight how aberrant regulation of mitochondria-induced inflammasome activation centrally contributes to the inflammatory process that are responsible for obesity and associated metabolic diseases.

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“…The evidence for this in vivo and in vitro is incomplete. Indeed, isolated cytochrome C oxidase is only reactivated to 30% of control levels by 48 mM pyruvate (17). This lack of complete reactivation, compared to our complete and supra-basal reactivation, is indicative of striking differences in the ability of cyanide to bind to cytochrome C oxidase in vivo compared to in vitro.…”

Section: Discussionmentioning

confidence: 62%

“…It has been proposed that the ability of pyruvate to increase the LD 50 of cyanide is due to a reaction mechanism caused by the production of a non-toxic cyanohydrin (17). The evidence for this in vivo and in vitro is incomplete.…”

Section: Discussionmentioning

confidence: 99%

“…In vitro, under fully reduced conditions, oxygen may displace cyanide from cytochrome C oxidase (21), although evidence for this in vivo is lacking (22). Delhumeau et al, (17) proposed that oxygenation might effect cyanide binding in isolated mitochondria, but oxygenation in their experiments was performed by exposure to ambient air with the risk of altering the solution pCO (17) and not routinely used. It is interesting, however, to speculate that there may be some importance in the production of CO 2 within the mitochondrial matrix ascribed to the two α-keto acids in that this is the next step for both of these Krebs cycle intermediates.…”

Section: Discussionmentioning

confidence: 99%

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Intact smooth muscle metabolism its responses to cyanide poisoning and pyruvate stimulation

Matsumoto²,

Nakayama³

2000

Front Biosci

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Smooth muscle mitochondria are unique in their compartmentalization of metabolism with the contractile proteins and putative role in cell fate choice. In this study we examine the relative and quantitative differences that smooth muscle mitochondria have with regard to cyanide inhibition. The effect of cyanide poisoning in the mitochondria of smooth muscle was examined in the intact porcine carotid artery and intact guinea pig stomach. The respiratory responses of these tissues were monitored in the presence of cyanide and following the addition of various metabolites. In HEPES buffer with 10 mM glucose as the substrate, it was found that the EC 50 for cyanide inhibition was 0.11±0.02 and 0.14±0.02 mM in the pig carotid and guinea stomach respectively. We also found that the signaling metabolite, pyruvate could partially reverse this inhibition. With pyruvate (10 mM) as the substrate, the EC 50 increased significantly to 6.52±0.11 (carotid artery) and 1.95±0.30 (stomach) mM as well as being significantly different between the tissues. This apparent resistance to cyanide inhibition caused by pyruvate was lost when sodium bicarbonate buffer was used (EC 50 in the presence of pyruvate of 0.13±0.04 and 0.25±0.04 for carotid and stomach respectively). HEPES buffer permitted pyruvate's protection from cyanide poisoning whereas bicarbonate buffer did not. The rate of respiration caused by pyruvate re-stimulation was not significantly different than control in the stomach (2.63±0.77 and 2.69±0.3 µMol O 2 /min/g dw respectively) but was significantly greater in the carotid artery. Therefore, smooth muscle with 10 mM pyruvate and 1 mM cyanide had a rate or respiration significantly greater than with 10 mM glucose alone (0.90±0.2 and 0.59±0.06 µMol O 2 /min/g dw respectively). Using 31 P NMR spectroscopy, we observed a complete normalisation of high energy phosphates and pH in the guinea pig stomach smooth muscle caused by pyruvate after cyanide poisoning. These results suggest that cyanide's toxicity of smooth muscle oxidative metabolism is affected by the buffer (HEPES versus Bicarbonate) and metabolic signalling molecules or substrates (pyruvate versus glucose) in which the tissues are exposed to as well as tissue to tissue variations.

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Protection of Cytochrome c Oxidase against Cyanide Inhibition by Pyruvate and α-Ketoglutarate: Effect of Aeration in Vitro

Cited by 27 publications

References 0 publications

Physical Fitness and Mitochondrial Respiratory Capacity in Horse Skeletal Muscle

Physical Fitness and Mitochondrial Respiratory Capacity in Horse Skeletal Muscle

Mitochondria: diversity in the regulation of the NLRP3 inflammasome

Intact smooth muscle metabolism its responses to cyanide poisoning and pyruvate stimulation

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