Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.6.5.3 (complex I)
8,901 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mitochondrial disorder is characteristic of many myocardial injuries such as endotoxemia, shock, acidosis, ischemia/reperfusion, and others. The goal of possible therapy is to increase ATP production. Derivatives of vitamins K may be a potent electron carrier between various mitochondrial electron-donating and electron-accepting enzyme complexes. We aimed to test the possibility that menadione or its water-soluble derivative AK-135, the newly synthesized analogues of vitamin K1--N-derivatives of 2-methyl-3-aminomethyl 1.4-naphthoquinone, would reduce cardiomyocyte damage after hypoxia or mitochondrial respiratory chain inhibition in culture. Menadione, and more effectively, AK-135, restored the electron flow in defective respiratory chain (hypoxia or rotenone) systems. As was shown in this study, 3 microM of AK-135 restored ATP production after blockade of electron flow through mitochondrial complex I with 5 microM rotenone up to 13.18+/-1.56 vs. 3.21+/-1.12 nmol/mg protein in cells treated with rotenone only. In cultures pretreated with 4 microM dicumarol (DT-diaphorase inhibitor), the protective effect of AK-135 and menadione was abolished completely (1.67+/-1.43 and 2.97+/-0.57 nmol/mg protein, respectively). Inhibition of mitochondrial oxidative phosphorylation caused an increase in intracellular Ca(2+) levels. Here we have demonstrated restoration of calcium oscillations and cardiomyocyte contractility by menadione and its derivative after blockade of NADH: ubiquinone oxidoreductase with rotenone, and decrease of Ca(2+) overloading during hypoxia.
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PMID:Effects of menadione and its derivative on cultured cardiomyocytes with mitochondrial disorders. 1589 62

Course treatment with mexidol in a dose of 25 mg/kg for 3 days decreased activities of aspartate transaminase and creatine phosphokinase in the plasma on day 3 after the incidence of skin ischemia (by 1.3 and 1.66 times, respectively). Under these conditions the index of cytolysis decreased by 1.3 times. Therefore, mexidol prevented progression of necrotic processes in the skin. Mexidol therapy of animals with skin ischemia restored the reserve capacity of systems for energy supply and antioxidant defense. The systems of NADH-ubiquinone reductase and succinate-ubiquinone reductase served as the targets for the action of mexidol. Mexidol significantly decreased the damaging effect of reactive oxygen species. Dermatoprotective properties of mexidol were associated with its influence on the energy supply system (regulation of enzyme activity in the electron transport chain, ubiquinone metabolism) and antioxidant defense.
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PMID:Antihypoxic and antinecrotic effect of mexidol in skin ischemia. 1602 7

Long-chain N-acylethanolamines (NAEs) have been found to uncouple oxidative phosphorylation and to inhibit uncoupled respiration of rat heart mitochondria [Wasilewski, M., Wieckowski, M.R., Dymkowska, D. and Wojtczak, L. (2004) Biochim. Biophys. Acta 1657, 151-163]. The aim of the present work was to investigate in more detail the mechanism of the inhibitory effects of NAEs on the respiratory chain. In connection with this, we also investigated a possible action of NAEs on the generation of reactive oxygen species (ROS) by respiring rat heart mitochondria. It was found that unsaturated NAEs, N-oleoylethanolamine (N-Ole) and, to a greater extent, N-arachidonoylethanolamine (N-Ara), inhibited predominantly complex I of the respiratory chain, with a much weaker effect on complexes II and III, and no effect on complex IV. Saturated N-palmitoylethanolamine had a much smaller effect compared to unsaturated NAEs. N-Ara and N-Ole were found to decrease ROS formation, apparently due to their uncoupling action. However, under specific conditions, N-Ara slightly but significantly stimulated ROS generation in uncoupled conditions, probably due to its inhibitory effect on complex I. These results may contribute to our better understanding of physiological roles of NAEs in protection against ischemia and in induction of programmed cell death.
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PMID:Effects of N-acylethanolamines on the respiratory chain and production of reactive oxygen species in heart mitochondria. 1609 57

Rats may develop sustained tolerance against lethal cerebral ischemia after exposure to a sublethal ischemic insult (ischemic preconditioning (IPC)). Two windows for the induction of tolerance by IPC have been proposed, one that occurs within 1h following IPC, and the other one that occurs 1-3 days after IPC. An important difference between these two windows is that in contrast to the second window, neuroprotection against lethal ischemia is transient in the first window. We tested the hypothesis that rapid IPC would reduce or prevent ischemia-induced changes in mitochondrial function. IPC and ischemia were produced by bilateral carotid occlusions and systemic hypotension (50 mmHg) for 2 and 10 min, respectively. The non-synaptosomal mitochondria were harvested 30 min following the 10 min 'test' ischemia. Mitochondrial rate of respiration decreased by 10% when the substrates were pyruvate and malate, and 29% when the substrates were ascorbic acid and N,N,N',N'-tetramethyl-p-phenylenediamine ( P< 0.01). The activities of complex I-III decreased in ischemic group by 16, 23 (P < 0.05) and 24%, respectively. IPC was unable to prevent decreases in the rate of respiration and activities of different complexes. These data suggest that rapidly induced IPC is unable to protect the integrity of mitochondrial oxidative phosphorylation following cerebral ischemia, perhaps explaining why IPC only provides transitory protection in the 'first window'.
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PMID:Effect of the first window of ischemic preconditioning on mitochondrial dysfunction following global cerebral ischemia. 1612 Mar 19

Hypoxic inhibition of K+ channels provides a link between low O2 and cell function, and in glossopharyngeal neurons hypoxic inhibition of a TWIK-related halothane-inhibitable K+ channel-1 (THIK-1)-like background K+ channel regulates neuronal function. In the present study, we examined directly the O2 sensitivity of recombinant THIK-1 channels, expressed in human embryonic kidney (HE293) cells. THIK-1 expression conferred a moderately outwardly rectifying halothane-inhibited and arachidonic acid-potentiated K+ current and invoked a strongly hyperpolarized resting membrane potential. Endogenous K+ currents in untransfected cells were unaffected by either agent. Hypoxia (P(O2), 20 mmHg) reversibly inhibited THIK-1 currents and caused membrane depolarization, effects that were occluded by halothane. Neither the mitochondrial complex I inhibitors rotenone, myxothiazol and sodium cyanide, nor the NADPH oxidase inhibitors diphenylene iodonium and phenylarsine oxide, were effective in inhibiting the O2-sensitivity of THIK-1. Thus, hypoxic inhibition of THIK-1 occurs by a mechanism dissimilar to that which regulates the activity of other members of the background K+ channel family. Given the O2 sensitivity of THIK-1 channels and their abundant expression in the CNS, we raise for the first time the possibility of a physiological and/or pathological role for these channels during brain ischemia.
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PMID:O2 sensing by recombinant TWIK-related halothane-inhibitable K+ channel-1 background K+ channels heterologously expressed in human embryonic kidney cells. 1615 84

Cardiac ischemia damages the mitochondrial electron transport chain. Irreversible blockade of electron transport at complex I by rotenone decreases ischemic damage to cardiac mitochondria by decreasing the loss of cytochrome c and preserving respiration through cytochrome oxidase. Therapeutic intervention to protect myocardium during ischemia and reperfusion requires the use of a reversible inhibitor that allows resumption of oxidative metabolism during reperfusion. Amobarbital is a reversible inhibitor at the rotenone site of complex I. We asked whether amobarbital administered immediately before ischemia protected respiratory function. Isolated rat hearts were perfused for 15 min followed by 25-min global ischemia at 37 degrees C. Amobarbital-treated hearts received drug for 1 min before ischemia. Subsarcolemmal (SSM) and interfibrillar (IFM) populations of mitochondria were isolated after ischemia, and oxidative phosphorylation was measured. Amobarbital protected oxidative phosphorylation, including through cytochrome oxidase, in both SSM and IFM in a dose-dependent manner, with an optimal dose of 2 to 2.5 mM. Amobarbital also preserved cytochrome c content in both SSM and IFM. Thus, reversible blockade of the electron transport chain during ischemia protects mitochondrial respiration.
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PMID:Blockade of electron transport before cardiac ischemia with the reversible inhibitor amobarbital protects rat heart mitochondria. 1617 99

A key pathologic event in cardiac ischemia reperfusion (I-R) injury is mitochondrial energetic dysfunction, and several studies have attributed this to complex I (CxI) inhibition. In isolated perfused rat hearts, following I-R, we found that CxI-linked respiration was inhibited, but isolated CxI enzymatic activity was not. Using the mitochondrial thiol probe iodobutyl-triphenylphosphonium in conjunction with proteomic tools, thiol modifications were identified in several subunits of the matrix-facing 1alpha sub-complex of CxI. These thiol modifications were accompanied by enhanced ROS generation from CxI, but not complex III. Implications for the pathology of cardiac I-R injury are discussed.
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PMID:Mitochondrial dysfunction in cardiac ischemia-reperfusion injury: ROS from complex I, without inhibition. 1627 76

Reactive oxygen species (ROS) are considered an important factor in ischemia/reperfusion injury to cardiac myocites. Mitochondrial respiration is an important source of ROS generation and hence a potential contributor to cardiac reperfusion injury. Appropriate treatment strategy could be particularly useful to limit this ROS generation and associated mitochondrial dysfunction. In the present study, we examined the effect of lowering the oxygen tension, at the onset of the reperfusion, on various parameters of mitochondrial bioenergetics in rat heart tissue. After isolation of mitochondria from control, ischemic, normoxic and hypoxic reperfused rat heart, various bioenergetic parameters were evaluated such as rates of mitochondrial oxygen consumption, complex I and complex III activity, H2O2 production and in addition, the degree of lipid peroxidation, cardiolipin content and cardiolipin oxidation. We found that normoxic reperfusion significantly altered all these mitochondrial parameters, while hypoxic reperfusion had a protective effect attenuating these alterations. This effect appears to be due, at least in part, to a reduction of mitochondrial ROS generation with subsequent preservation of cardiolipin integrity, protection of mitochondrial function and improvement of post-ischemic hemodynamic function of the heart.
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PMID:Mitochondrial dysfunction associated with cardiac ischemia/reperfusion can be attenuated by oxygen tension control. Role of oxygen-free radicals and cardiolipin. 1632 47

We used proteomics to detect regional differences in protein expression levels from mitochondrial fractions of control, ischemia-reperfusion (IR), and ischemic preconditioned (IPC) rabbit hearts. Using 2-DE, we identified 25 mitochondrial proteins that were differentially expressed in the IR heart compared with the control and IPC hearts. For three of the spots, the expression patterns were confirmed by Western blotting analysis. These proteins included 3-hydroxybutyrate dehydrogenase, prohibitin, 2-oxoglutarate dehydrogenase, adenosine triphosphate synthases, the reduced form of nicotinamide adenine dinucleotide (NADH) oxidoreductase, translation elongation factor, actin alpha, malate dehydrogenase, NADH dehydrogenase, pyruvate dehydrogenase and the voltage-dependent anion channel. Interestingly, most of these proteins are associated with the mitochondrial respiratory chain and energy metabolism. The successful use of multiple techniques, including 2-DE, MALDI-TOF-MS and Western blotting analysis demonstrates that proteomic analysis provides appropriate means for identifying cardiac markers for detection of ischemia-induced cardiac injury.
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PMID:Potential biomarkers for ischemic heart damage identified in mitochondrial proteins by comparative proteomics. 1640 59

Reactive oxygen species (ROS) are considered an important factor in ischemia/reperfusion injury to cardiac myocytes. Mitochondrial respiration, mainly at the level of complex I and III, is an important source of ROS generation and hence a potential contributor of cardiac reperfusion injury. Appropriate antioxidant strategies could be particularly useful to limit this ROS generation and associated mitochondrial dysfunction. Melatonin has been shown to effectively protect against ischemic-reperfusion myocardial damage. The mechanism by which melatonin exerts this cardioprotective effect is not well established. In the present study we examined the effects of melatonin on various parameters of mitochondrial bioenergetics in a Langerdoff isolated perfused rat heart model. After isolation of mitochondria from control, ischemic-reperfused and melatonin-treated ischemic-reperfused rat heart, various bioenergetic parameters were evaluated such as rates of mitochondrial oxygen consumption, complex I and complex III activity, H2O2 production as well as the degree of lipid peroxidation, cardiolipin content, and cardiolipin oxidation. We found that reperfusion significantly altered all these mitochondrial parameters, while melatonin treatment had strong protective effect attenuating these alterations. This effect appears to be due, at least in part, to the preservation, by ROS attack, of the content and integrity of cardiolipin molecules which play a pivotal role in mitochondrial bioenergetics. Protection of mitochondrial dysfunction was associated with an improvement of post-ischemic hemodynamic function of the heart. Melatonin had also strong protective effect against oxidative alterations to complex I and III as well as to cardiolipin in isolated mitochondria.
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PMID:Protective effect of melatonin against mitochondrial dysfunction associated with cardiac ischemia- reperfusion: role of cardiolipin. 1644 99


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