The effect of atp-dependent potassium uptake on mitochondrial functions under acute hypoxia

Акопова, О. В.; Nosar, V. I.; Gavenauskas, Bronislav; Bratus, L.V.; Kolchinskaya, L. I.; Mankovskaya, I. N.; Сагач, В. Ф.

doi:10.1007/s10863-015-9642-8

Cited by 9 publications

(20 citation statements)

References 39 publications

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“…Worth mention, that main limitation of our study was the use of indirect methods to assess mK ATP -channel activity and inability of molecular identification of ATPsensitive K + transport sensitive to diazoxide in the absence of MgATP. However, an estimate of native mK ATP -channel activity (~40 nmol K + ·min − 1 ·mg − 1 ) using respiration and proton transport assays well agreed with the assessment of mK ATP -channel activity with K + -selective electrode (45.0 ± 5.0 nmol K + ·min − 1 ·mg − 1 ) by monitoring ATP-sensitive potassium efflux from deenergized mitochondria [26]. Also, sequential blockage of K + transport by Mg 2+ and ATP proved the activation of native mK ATP -channel by diazoxide.…”

Section: Discussionsupporting

confidence: 58%

Diazoxide affects mitochondrial bioenergetics by the opening of mKATP channel on submicromolar scale

Акопова

Kolchinskaya

Nosar

et al. 2020

BMC Mol and Cell Biol

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Background: Cytoprotection afforded by mitochondrial ATP-sensitive K + -channel (mK ATP -channel) opener diazoxide (DZ) largely depends on the activation of potassium cycle with eventual modulation of mitochondrial functions and ROS production. However, generally these effects were studied in the presence of Mg•ATP known to block K + transport. Thus, the purpose of our work was the estimation of DZ effects on K + transport, K + cycle and ROS production in rat liver mitochondria in the absence of Mg•ATP. Results: Without Mg·ATP, full activation of native mK ATP -channel, accompanied by the increase in ATP-insensitive K + uptake, activation of K + -cycle and respiratory uncoupling, was reached at ≤0.5 μM of DZ,. Higher diazoxide concentrations augmented ATP-insensitive K + uptake, but not mK ATP -channel activity. mK ATP -channel was blocked by Mg·ATP, reactivated by DZ, and repeatedly blocked by mK ATP -channel blockers glibenclamide and 5hydroxydecanoate, whereas ATP-insensitive potassium transport was blocked by Mg 2+ and was not restored by DZ. High sensitivity of potassium transport to DZ in native mitochondria resulted in suppression of mitochondrial ROS production caused by the activation of K + -cycle on sub-micromolar scale. Based on the oxygen consumption study, the share of mK ATP -channel in respiratory uncoupling by DZ was found. Conclusions:The study of mK ATP -channel activation by diazoxide in the absence of MgATP discloses novel, not described earlier, aspects of mK ATP -channel interaction with this drug. High sensitivity of mK ATP -channel to DZ results in the modulation of mitochondrial functions and ROS production by DZ on sub-micromolar concentration scale. Our experiments led us to the hypothesis that under the conditions marked by ATP deficiency affinity of mK ATP -channel to DZ can increase, which might contribute to the high effectiveness of this drug in cardio-and neuroprotection. BackgroundCytoprotective effects afforded by the mitochondrial K ATP -channel (mK ATP -channel) opening generally are supposed to result from the modulation of mitochondrial functions and protective redox signaling triggered by ATP-sensitive K + transport, which helped tissues recovery from the impairments caused by ischemic, hypoxic [1-5] and metabolic stress conditions [6][7][8][9]. Numerous pathophysiological conditions primarily affect mitochondrial bioenergetic. Prevention of Ca 2+ overload [8], restoration of ATP synthesis, prevention of mitochondrial depolarization [3] and the regulation of mitochondrial ROS production resulting from mK ATP -channels opening in different cell types were shown to block apoptotic and necrotic pathways triggered by multiple pathophysiological states [1-9].

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Section: Discussionsupporting

confidence: 58%

Diazoxide affects mitochondrial bioenergetics by the opening of mKATP channel on submicromolar scale

Акопова

Kolchinskaya

Nosar

et al. 2020

BMC Mol and Cell Biol

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“…The inhibition of the pore activity following mKATP channels opening was shown to prevent the development of cellular apoptosis and necrosis under pathophysiological conditions [1,2,11]. Meanwhile, several published data, including the results of our work have shown that oxidative phosphorylation system is another important target of the pharmacological modulators of mKATP channels [12]. However, physiological meaning of the impact of mKATP channels opening on mitochondrial ATP synthesis is not quite well understood.…”

Section: Introductionmentioning

confidence: 73%

“…In our previous work we also tried to assess physiological relevance of the effect of mKATP channels opening on the oxidative phosphorylation by studying the impact of short-term acute hypoxia on the physical endurance of the animals subject to compulsory swimming with a load. By our observations, increase of mKATP channel activity after the short-term acute hypobaric hypoxia resulted in the improvement of the rats' endurance to physical stress, which prompted further extension of our research [12]. So, the aim of this work was to find the role of mKATP channel in the regulation of energy metabolism in vivo by examining the correlation between animals' endurance to exercise training and the endogenous mKATP channel activity.…”

Section: Introductionmentioning

confidence: 89%

“…Swimming time (ST) as the measure of physical endurance was registered. Using approach developed previously, the rats exhibiting high and low resistance to physical loading based on their ST (HR and LR groups) were separated from those showing intermediate results, and mKATP channels activity was assessed ex vivo on isolated liver mitochondria with K + -selective electrode as we described earlier [12,13].…”

Section: The Animalsmentioning

confidence: 99%

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The Impact of Mitochondrial KATP Channel Opening on Energy Metabolism under Physical Stress

Акопова¹

2018

IJBP

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The modulation of mKATP channel activity is known to have a great impact on energy metabolism in a living organism. The aim of this work was to study the impact of mKATP channels opening on the physical endurance in the rats subject to compulsory swimming with a load. Our purpose was to find a mechanistic basis to explain the modulation of the energy metabolism under exercise training by studying the direct effect of mKATP channel opening on mitochondrial functions. Male Wistar rats exhibiting high and low resistance to physical stress were separated in two groups, and subjected to compulsory swimming with a load. Swimming time (ST) was monitored from the start till the time when the rats began to drawn. ST was reliably higher in high resistance group, which coincided with higher endogenous mKATP channels activity. mKATP channels blockers, glibenclamide and 5-hydroxydecanoate shown to completely block mKATP channel in vivo, dramatically reduced ST in both groups, which indicated its dependence on mKATP channel activity. To find a mechanistic basis for the observed dependence, we studied the effect of mKATP channels opening on mitochondrial functions in vitro. mKATP channels opener diazoxide stimulated state 4 respiration and decreased RCR, but increased P/O ratio. On the contrary, mKATP channels blockers, dramatically reduced P/O. Based on the experiments, we came to the conclusion of the correlation between the physical endurance and P/O ratio, both dependent on mKATP channels activity. Thus, mKATP channels opening inhibited phosphorylation, but increased its efficiency. In vivo this resulted in the improvement of the endurance in the animals with elevated mKATP channel activity. Physiological relevance of the observed phenomena is discussed.

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“…Here and in [15] have found that the increase of conductivity of mitochondrial potassium channels of the rat liver and ATP-dependent K + inflow in acute hypoxia is an important chain of regulation of energy metabolism. Flocalin (activator of K ATP channels) modulates oxidative phosphorylation system of mitochondria (disrupted by 2,4-dinitrophenol) toward the side of ATP synthesis.…”

Section: T a B L E 1 The Changes Of Fibrinolytic Activity Of Plasma mentioning

confidence: 89%

The experimental investigation of fibrinolytic system under the influence of flocalin in conditions of acute hypoxic kidney injury

Гоженко¹,

Gubsky²,

Filipets³

et al. 2017

Ukr.Biochem.J.

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in the experiments on rats subjected to acute hypoxic histochemical nephropathy, caused by sodium nitrite and 2,4-dinitrophenol, fibrinolytic activities of blood plasma, urine, renal cortex, medulla, and T he essential biochemical characteristic of plasma membranes ATP-sensitive potassium (K ATP ) channels, which are gated by intracellular nucleotides ATP and ADP, is their sensitivity to disturbances in cellular metabolism. Subsequently, rapid activation and opening of K ATP channels in response to the decrease of ATP level, in particular under conditions of ischemia and hypoxia, results in plasma membrane hyperpolarization and the decrease of voltage dependent inflow of Ca 2+ ions. The latter event is accompanied by drastic disturbance of energy metabolism compliance with the functional needs of the cell and initiates the pathological cascades leading to the profound cellular pathology.The regulatory role of K ATP channels in conditions of cellular oxygenation restriction was first studied on cardiomyocytes and smooth muscle cells of blood vessels [1], that resulted in the use of pharmacological activators of these channel types for treatment of cardiovascular diseases. In recent years the convincing evidence of cardioprotective and vasodilatory effects of the original K ATP channels fluoride-containing activator Flocalin -N-(-4-difluoromethoxyphenyl)-N′-1,2,2-trimethylpropyl-N′′-cyanoguanidine [2] were obtained. Owing to the presence of fluoride, flocalin is more selective to K ATP channels and less toxic compared to other representatives of potassium channels modulators that makes it perspective and promising pharmacological substance as physiological regulator and protector of metabolic processes disturbed under hypoxic and ischemic conditions.

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The effect of atp-dependent potassium uptake on mitochondrial functions under acute hypoxia

Cited by 9 publications

References 39 publications

Diazoxide affects mitochondrial bioenergetics by the opening of mKATP channel on submicromolar scale

Diazoxide affects mitochondrial bioenergetics by the opening of mKATP channel on submicromolar scale

The Impact of Mitochondrial KATP Channel Opening on Energy Metabolism under Physical Stress

The experimental investigation of fibrinolytic system under the influence of flocalin in conditions of acute hypoxic kidney injury

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