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 respiration, succinate dehydrogenase coenzyme Q reductase, and myosin B were investigated in ischemic myocardium from experimental myocardial infarction in dogs. Respiratory control ratio of mitochondria was impaired by ischemia at 60 min after coronary ligation, and oxygen consumption was inhibited 120 min later. Enzyme activity of succinate dehydrogenase coenzyme Q reductase was decreased at 6 hr after coronary ligation. Calcium ion sensitivity of myosin B declined 12 hr after coronary ligation. However, adenosine triphosphatase activity of myosin A from infarcted myocardium was not different from that of the intact one. These results suggest that interaction in the sequence of enzyme complexes was first impaired in ischemic myocardium and that deterioration of enzyme activity was then manifested.
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PMID:Relationship between energy liberation and utilization in ischemic cardiac muscle. 103 51

The loss of NADH-ubiquinone oxidoreductase activity, the activity of mitochondrial electron transfer complex I, underlies the loss of mitochondrial phosphorylating respiration with NAD-linked substrates observed during myocardial ischemia. In the present study the loss of complex I activity was found to be considerably more rapid during zero-flow ischemia in rat heart, a fast heart-rate heart, than in dog heart, a slow heart-rate heart. Moreover, the greater rapidity of the loss of complex I activity in the ischemic rat heart appeared to reflect the more rapid and more severe decreases in tissue pH and in tissue ATP characteristic of the zero-flow ischemic rat heart compared to zero-flow ischemic dog heart. In vitro enzyme inactivation studies on dog heart electron transfer complex I showed that the enzyme was approximately 40% inactivated after 1 minute by incubation at pH 6.0 in the absence of added ATP. The effect of low pH upon enzyme activity was mitigated considerably by the presence of one to two mM MgATP in the incubation mixtures. Moreover, a portion of the activity-sparing effect of MgATP was still observed in the presence of the uncoupler, FCCP. This latter observation suggests that part of the function-stabilizing effect of ATP was attributable to inner membrane energization and part appeared to have been due to a direct protective effect of ATP upon the complex.
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PMID:Effects of acidosis and ATP depletion on cardiac muscle electron transfer complex I. 174 4

Modeling of ischemic phenomena in vitro has been hindered by the inability to create specific alterations in the variables of interest over a defined time-frame. In particular, changes in the adenine nucleotide pool have been quite difficult to mimic because of the putative low metabolic rate in culture and the long times necessary to achieve even partial chemical energy depletion. Here we present evidence for a rapid method of producing a profound chemical energy depletion with the combination of a NADH dehydrogenase inhibitor (amytal) and a mitochondrial proton ionophore (CCCP). Treatment with our protocol in enriched spinal cultures results in a 40% decrease in ATP within 2 min and a fall to one-third of control values by 15 min. The overall pool size of the total adenine nucleotides is decreased 46% by 15 min and does not completely recover after 5 min of reenergization. The ATP/ADP ratio declines to one-third of control values during deenergization and returns to control values after 5 min in control buffer. Such a loss of the total adenylate pool closely mimics that seen in vivo during ischemia and provides an in vitro model system in which the effects of the combination of this means of cellular injury with others (e.g., excitotoxins) may be examined.
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PMID:Energy depletion in culture. Adenine nucleotides are altered as in vivo. 177 32

A case of mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes, in which a pituitary growth hormone (GH) secretion deficiency of hypothalamic origin was revealed through neuro-endocrinological examinations, was described. The case was a 10-year-old girl, who had been suffering from generalized tonic seizures since age 5, four episodes of alternating hemiplegia since age 6, stunted growth since age 7, and simple partial motor seizures as well as gelastic seizures since age 8. Marked elevation of lactate and pyruvate in both serum and CSF, abundant ragged red fibers in biopsied muscle, and low density areas in the left occipital lobe and bilateral globus pallidus in addition to diffuse brain atrophy on CT scan and MRI of the head were demonstrated, although the activities of muscle enzymes complex I-IV were within normal ranges. Pituitary GH secretion was deficient under the loadings with insulin, L-DOPA, sleep, and a single growth hormone releasing factor (GRF) administration, but normal GH response was registered under the repetitive stimulation with GRF. Activities of other hormonal axes were normal. It is likely that short stature commonly observed in MELAS patients is due to hypothalamic dysfunction, which might be brought out by chronic ischemia and energy deficiency of the diencephalon based upon mitochondrial abnormality of that region. It is likely that gelastic seizure in this case is due to hypothalamic dysfunction.
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PMID:[Hypothalamic GH Deficiency and gelastic seizures in a 10-year-old girl with MELAS]. 187 57

Ischemia and reperfusion causes severe mitochondrial damage, including swelling and deposits of hydroxyapatite crystals in the mitochondrial matrix. These crystals are indicative of a massive influx of Ca2+ into the mitochondrial matrix occurring during reoxygenation. We have observed that mitochondria isolated from rat hearts after 90 minutes of anoxia followed by reoxygenation, show a specific inhibition in the electron transport chain between NADH dehydrogenase and ubiquinone in addition to becoming uncoupled (unable to generate ATP). This inhibition is associated with an increased H2O2 formation at the NADH dehydrogenase level in the presence of NADH dependent substrates. Control rat mitochondria exposed for 15 minutes to high Ca2+ (200 nmol/mg protein) also become uncoupled and electron transport inhibited between NADH dehydrogenase and ubiquinone, a lesion similar to that observed in post-ischemic mitochondria. This Ca(2+)-dependent effect is time dependent and may be partially prevented by albumin, suggesting that it may be due to phospholipase A2 activation, releasing fatty acids, leading to both inhibition of electron transport and uncoupling. Addition of arachidonic or linoleic acids to control rat heart mitochondria, inhibits electron transport between Complex I and III. These results are consistent with the following hypothesis: during ischemia, the intracellular energy content drops severely, affecting the cytoplasic concentration of ions such as Na+ and Ca2+. Upon reoxygenation, the mitochondrion is the only organelle capable of eliminating the excess cytoplasmic Ca2+ through an electrogenic process requiring oxygen (the low ATP concentration makes other ATP-dependent Ca2+ transport systems non-operational).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mitochondrial generation of oxygen radicals during reoxygenation of ischemic tissues. 206 Aug 40

The in vivo action of cyclosporine A (CS) on rat renal cortical mitochondria was investigated. CS (30 mg.kg-1.day-1) given orally to rats for 30 days caused an augmentation of renal mitochondrial oxidative phosphorylation. The ADP-stimulated respiratory rate was increased by 37.0% with glutamate plus malate as respiratory substrates (P less than 0.025) but not with succinate-supported respiration, indicating enhancement of mitochondrial complex I activity. This reaction may be a response to the 32.5% reduction of renal blood (P less than 0.005) in the CS-treated group, possibly serving to maximize ATP synthesis during ischemia. Ligation-induced decreases in renal blood flow also resulted in enhancement of mitochondrial complex I activity.
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PMID:Cyclosporine augments renal mitochondrial function in vivo and reduces renal blood flow. 258 85

Impairment of mitochondrial respiration in early myocardial ischemia was studied with special reference to myocellular irreversible injury. The technique used was total ligation of the left anterior descending coronary artery, followed by reconstruction of coronary blood flow, in the dog. State 3 respiratory activity reduced significantly to 76% of that of the non-ischemic myocardium in subendocardial muscle (Endo) as early as 30 min after occlusion, and at 60 min to 84% in the subepicardium (Epi). The activity was not recovered by reperfusion. The activity of complex I of sonicated submitochondrial particles decreased at 30 min to 67% in Endo and at 60 min to 71% in Epi, and was not recovered by reperfusion. Complex II and IV activities were kept in the control level until 60 min of ischemia. DNP-stimulated ATPase activity reduced to 79% in Endo at 15 min and to 70% in Epi at 30 min, but recovered significantly by reperfusion until 30 min of ischemia. Mitochondrial respiratory activity was impaired irreversibly in ischemia for 30 min in Endo and this spread to Epi later. Degradation of complex I is considered to be one of the causes of myocardial irreversibility in early ischemia.
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PMID:Impairment of mitochondrial respiratory activity in the early ischemic myocardium--with special reference to electron transport system. 284 64

The hypothesis that mitochondria damaged during complete cerebral ischemia generate increased amounts of superoxide anion radical and hydrogen peroxide (H2O2) upon postischemic reoxygenation has been tested. In rat brain mitochondria, succinate supported H2O2 generation, whereas NADH-linked substrates, malate plus glutamate, did so only in the presence of respiratory chain inhibitors. Succinate-supported H2O2 generation was diminished by rotenone and the uncoupler carbonyl cyanide m-chlorphenylhydrazone and enhanced by antimycin A and increased oxygen tensions. When maximally reduced, the NADH dehydrogenase and the ubiquinone-cytochrome b regions of the electron transport chain are sources of H2O2. These studies suggest that a significant portion of H2O2 generation in brain mitochondria proceeds via the transfer of reducing equivalents from ubiquinone to the NADH dehydrogenase portion of the electron transport chain. Succinate-supported H2O2 generation by mitochondria isolated from rat brain exposed to 15 min of postdecapitative ischemia was 90% lower than that of control preparations. The effect of varying oxygen tensions on H2O2 generation by postischemic mitochondrial preparations was negligible compared with the increased H2O2 generation measured in control preparations. Comparison of the effects of respiratory chain inhibitors and oxygen tension on succinate-supported H2O2 generation suggests that the ability for reversed electron transfer is impaired during ischemia. These data do not support the hypothesis that mitochondrial free radical generation increases during postischemic reoxygenation.
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PMID:Generation of hydrogen peroxide by brain mitochondria: the effect of reoxygenation following postdecapitative ischemia. 291 86

Complex I (NADH-ubiquinone reductase) is a complex system located in the inner mitochondrial membrane and has the ability to catalyse several different enzymatic reactions concerned in electron transport. It is known to be one of the first components of the respiratory chain to be damaged by ischemia. Our results, using autolysis in the rat heart as experimental model, indicate that the NADH dehydrogenase system was impaired relatively early during ischemia while transhydrogenation and NADPH dehydrogenation appeared to be relatively resistant.
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PMID:Changes in NADH-ubiquinone reductase (complex I) with autolysis in the rat heart as experimental model. 309 11

Ischemic myocardium was produced by occluding the left circumflex coronary artery in anesthetized dogs. Autolyzed myocardium was produced by incubating transmural samples of canine left ventricle at 37 degrees C. Tissue pH was recorded continuously in each model using a microcombination pH electrode impaled into the midmyocardium. The activities of the five mitochondrial inner membrane enzyme complexes of electron transport and coupled oxidative phosphorylation were assayed as a function of time of ischemia or autolysis. While the activities of complex II (succinate-CoQ reductase) and IV (cytochrome c oxidase) were completely stable, that of complex I (NADH-CoQ reductase) decreased markedly, but largely only after 20 min of ischemia or autolysis. At 20 min and beyond, the decrease in the activity of complex I paralleled closely the decrease in whole mitochondrial oxygen uptake with NAD-linked substrates in both models. The activity of complex III (CoQH2-c reductase) decreased at a more gradual rate during ischemia or autolysis, and its rate of decrease paralleled that of succinate-supported oxygen uptake. The activity of complex V (oligomycin-sensitive ATPase) decreased most rapidly (by 40% in only 5 min of autolysis) but nearly leveled off beyond 20 min in the two models. A strikingly similar pattern of differential enzyme lability was observed in isolated control mitochondria incubated at lowered pH values. The results demonstrate 1) differential enzyme lability within the mitochondrial inner membrane, 2) a connection between severity of acidosis and the degree of enzyme activity loss, and 3) the usefulness of simple tissue autolysis as an analogue of in situ myocardial ischemia.
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PMID:Mitochondrial complexes I, II, III, IV, and V in myocardial ischemia and autolysis. 630 12


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