Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.6.3.14 (ATP synthase)
 7,042 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the present study we examined factors affecting the reversal of the ischemia-induced protonic inhibition of the mitochondrial ATPase described earlier (Rouslin, W. (1983) J. Biol. Chem. 258, 9657-9661). It was found that ATPase reactivation and accompanying inhibitor protein release during the re-energization of intact mitochondria isolated from 20-min ischemic canine heart muscle could be blocked completely by either carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP) or nigericin but was unaffected by valinomycin at 35 mM K+. At higher K+ concentrations, valinomycin also blocked ATPase reactivation but not quite as completely as did nigericin. These observations suggest that ATPase reactivation and inhibitor protein release are particularly dependent upon either the trans-inner membrane pH gradient (delta pH) or possibly upon matrix pH per se and slightly less dependent upon membrane potential (delta psi) in intact cardiac muscle mitochondria. The addition of FCCP at the end of the re-energization incubations limited partially the extent of both ATPase reactivation and inhibitor protein release. This latter effect appears to have been mediated by a partial reassociation of the inhibitor protein with the enzyme, and it was accentuated (when FCCP was added at the end of the incubations) or mimicked (when FCCP was absent) by lowering the pH of the re-energization medium. A close examination of the first 10 min of the time course of enzyme activation and of inhibitor protein release revealed that while the former process was essentially finished in 1 min or less, the latter required approximately 10 min for completion. This observation led to the proposal of a two-site model of enzyme-inhibitor interaction which is discussed.
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PMID:Factors affecting the reactivation of the oligomycin-sensitive adenosine 5'-triphosphatase and the release of ATPase inhibitor protein during the re-energization of intact mitochondria from ischemic cardiac muscle. 295 98

A survey of 12 species has revealed that reversible ischemia-induced protonic inhibition of the cardiac muscle mitochondrial adenosine 5'-triphosphatase (ATPase) described by this author earlier (Rouslin, W. J. Biol. Chem. 258: 9657-9661, 1983) occurs only in animals with heart rates lower than approximately 200 beats/min. It was thus fully demonstrable in rabbit, dog, sheep, human, pig, and beef heart mitochondria. In contrast, the in situ ATPase inhibition was completely absent in six smaller species capable of heart rates of approximately 300 or more beats/min. These were chicken, pigeon, guinea pig, rat, hamster, and mouse. Analyses of the cardiac muscle mitochondria of 9 of the 12 species studied showed them to contain normal levels of mitochondrial ATPase inhibitor; the three smallest species, rat, hamster, and mouse contained only very low levels of inhibitor. Thus, although chicken, pigeon, and guinea pig heart mitochondria contained normal levels of ATPase inhibitor, they (like the rat, hamster, and mouse) showed no in situ ischemia-induced ATPase inhibition. This and other observations suggest that the lack of in situ ATPase inhibition in hearts capable of 300 or more beats/min may be due to the presence of either an in situ nonfunctional ATPase inhibitor protein or to an in situ uninhibitable form of the mitochondrial ATPase in the faster-paced hearts. Alternatively, the mitochondria of the fast-paced hearts may be insulated somehow against the cytosolic acidosis which develops during ischemia and which triggers the ATPase inhibition in the slow heart-rate hearts. In the faster paced hearts, ATP hydrolysis does not appear to be regulated by inhibitor binding to the ATPase under nonenergizing conditions.
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PMID:The mitochondrial adenosine 5'-triphosphatase in slow and fast heart rate hearts. 295 Jul 75

Twenty minutes of ischemia in canine cardiac muscle produced a 50% to 60% inhibition of the mitochondrial ATPase. The inhibition has been shown to be triggered by a drop in cell pH under the non-energizing conditions which prevail in ischemic cells (Rouslin, W J Biol Chem 258, 9657-9661 (1983). In the present study we showed that the ATPase inhibition produced in situ in ischemic cardiac muscle was preserved in submitochondrial particles (SMP) prepared from mitochondria isolated from the ischemic tissue. The ischemic SMP ATPase was 45 +/- 3% as active as that of control particles. Measurements of the amounts of ATPase inhibitor protein of Pullman and Monroy present in extracts of control and ischemic SMP by two independent methods, titration of rat heart SMP ATPase and radioimmunoassay, revealed that control SMP contained 62 +/- 4% as much inhibitor as ischemic SMP as estimated by the titration procedure and 66 +/- 3% as much as estimated by the RIA. The results suggest that about one-third of the inhibitor was displaced from the control SMP. Finally, submitochondrial particles prepared from 20 min ischemic heart muscle showed a 2.5-fold increase in ATPase specific activity and a concomitant release of 35% of their inhibitor as a result of subsequent reenergization in vitro. Carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP) prevented both ATPase reactivation and inhibitor release. These findings support the hypothesis that the observed in situ ATPase inhibition is inhibitor protein mediated. Moreover, they suggest a pathophysiological function for the inhibitor protein in cardiac muscle.
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PMID:Protonic inhibition of the mitochondrial adenosine 5'-triphosphatase in ischemic cardiac muscle. Reversible binding of the ATPase inhibitor protein to the mitochondrial ATPase during ischemia. 296 Aug 23

The (uninhibited) mitochondrial ATPase comprises approximately 90% of the total ATP hydrolyzing activity present in quiescent, ischemic canine heart muscle and its inhibition by its natural inhibitor protein plays a pivotal role in the slowing of tissue ATP depletion during ischemia. While dog heart mitochondria contain a full complement of mitochondrial ATPase inhibitor capable of fully down-regulating the enzyme activity present in this species, rat heart mitochondria contain a much lower level of inhibitor, sufficient to inhibit the enzyme activity present in this species by only approximately 20%. Moreover, this fractional complement of inhibitor remains largely inoperative in the ischemic rat heart. As shown in the present study, one apparent result of the lack of a functional complement of mitochondrial ATPase inhibitor in the rat heart is a more rapid rate of cell ATP depletion during zero-flow ischemia. This in turn results in a more rapidly developed and initially more severe cell acidosis in the ischemic rat heart because ATP hydrolysis produces protons. Finally, and consistent with earlier studies by us, the more rapid ATP depletion together with the more severe acidosis appears to result in a marked increase in the rate of loss of mitochondrial respiratory function in the ischemic rat heart compared to the ischemic dog heart. Our findings suggest that slow heart-rate hearts which contain in situ functional mitochondrial ATPase inhibitor, possess an effective mechanism for sparing cell ATP stores during early ischemia, whereas fast heart-rate hearts which lack in situ mitochondrial ATPase inhibitor function, possess a less effective ATP sparing mechanism.
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PMID:Factors affecting the loss of mitochondrial function during zero-flow ischemia (autolysis) in slow and fast heart-rate hearts. 297 46

We examined whether ultrastructural changes in renal mitochondria associated with Cyclosporine A treatment might reflect underlying alterations in mitochondrial molecular structure. A nonrejected renal transplant removed from a patient treated with Cyclosporine A showed a decreased level of beta subunit antigen of mitochondrial F1-ATPase compared to controls. This decrease was more marked in the medulla than in the cortex (56% vs. 70% of pooled controls). Spontaneously hypertensive rats treated with a high dose of Cyclosporine A showed a similar decrease of beta-subunit antigen in the renal medulla and decreased levels of two subunit antigens of cytochrome c oxidase, but had increased medullary levels of the alpha subunit antigen of the F1-ATPase. Such changes were not detected in a normotensive strain of rats. Our data indicate that Cyclosporine A administration is associated with structural alterations in renal mitochondria at the molecular level, predominantly in the medulla, and that additional renal damage due to ischemia or hypertension may predispose to this cyclosporine effect.
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PMID:Alterations in molecular structure of renal mitochondria associated with cyclosporine A treatment. 301 38

The molecular consequences of acute myocardial ischemia induced in rabbit hearts by ligation of the left circumflex branch of the coronary artery were assessed in terms of the biochemical properties of subcellular organelles. Mitochondrial alteration, as reflected in progressive decrease in the activity of azide-sensitive ATPase, was apparent as early as 5 min postligation, but the activity of another mitochondrial enzyme, cytochrome c oxidase, was unchanged, even following 60 min of coronary ligation. Sarcolemmal Na+K+-ATPase exhibited a time course of inactivation similar to that of the mitochondrial ATPase, but differed from the latter in that the impairment was not reversed on reperfusion. Cellular levels of ATP, which decreased in parallel with the loss of ATPase activities, also remained depressed following reperfusion. Decreases in lysosomal enzyme latency were noted, but these occurred somewhat later than the sarcolemmal and mitochondrial alterations. Attempts to demonstrate the production of a population of labile lysosomal structures during ischemia were unsuccessful. Similarly, no alterations in the gel electrophoretic profiles of proteins or in the P phosphatidylcholine/P phosphatidylethanolamine ratio of isolated mitochondrial or sarcolemmal membranes from hearts subjected to ischemia and (or) subsequent reperfusion could be found. It is suggested that sarcolemmal Na+,K+-ATPase may serve as a sensitive and readily quantifiable index of irreversible cellular necrosis and, therefore, be of value in assessing the possible beneficial effects of pharmacological interventions.
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PMID:Membrane alterations in acute myocardial ischemia. 625 43

During open heart surgery, needle biopsy material was obtained in four patients, and electron microscopic preparations of the mitochondrial ATPases (coupling factors 1) in human myocardial cells were performed. The pre-ischemic, normal structure of the mitochondrial ATPases and the changes which occur during the ischemic interval were described. An increase in the center-to-center space was shown in the post-ischemic phase. This result was discussed for the pathogenesis of subcellular injuries due to ischemia.
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PMID:Electron microscopic visible ischemic changes of the mitochondrial ATPases in human myocardial cells during extracorporal circulation. 645 81

Isolated intact quiescent myocytes from the adult rat were used as a model system for investigating the determinants of contracture induced by metabolic deprivation. The model simulated the pattern of contracture and ATP decline seen in the intact heart during ischemia. Three new insights into the contracture process were gained: (1) in the quiescent cell system, the rate of onset of contracture was independent of external Ca2+, supporting the view that the Ca2+ dependence of the rate of onset in the whole heart is related to beat-dependent substrate utilization; (2) the second phase of ATP decline was paralleled by a decline in the percentage of cells which had not undergone contracture, suggesting that-in any cell-contracture is immediately preceded by a total loss of ATP; and (3) oligomycin delayed the onset of contracture by 55 +/- 12%, suggesting that mitochondrial ATPase activity is a significant drain on energy resources in the quiescent ischemic heart.
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PMID:Contracture in isolated adult rat heart cells. Role of Ca2+, ATP, and compartmentation. 729 79

Ischemic preconditioning of the heart is referred as a manifest increase in tolerance of the myocardium to otherwise damaging ischemic insult, achieved by one or few consequent initial short exposures to ischemia, each followed by reperfusion of the ischemic area. Several mechanisms such as opening of collateral vessels, the action of catecholamines, inositol phosphates, G-proteins and/or adenosine; inhibition of mitochondrial ATPase, the effects of different endogenous protective substances like heat stress or shock proteins, etc., are believed to cooperate in the mechanism of induction of preconditioning or in maintaining its effect. The present study is an attempt to extend the present knowledge about preconditioning from two aspects: i.) the peculiarities of energy equilibrium in preconditioned myocardium including adaptation of cardiac sarcolemmal ATPases to ischemia and/or hypoxia, and ii) participation of a new endogenous cardioprotective substance in the mechanism of preconditioning. The energy equilibrium in preconditioning is characterized by adaptation of cardiac energy demands to the capacity of energy production and delivery decreased by anaerobiosis and is manifested by constant ratios between ATP, ADP, AMP and the sum of ADN. Principles are proposed that may enable a prediction and mathematical modelling of the balanced energetic state in the preconditioned myocardium. These principles are based on thermodynamics and involve besides others a more economic handling of ATP by sarcolemmal ATPases. The latter enzymes adapt themselves to lowered availability of ATP by decreasing besides their Vmax also their values of Km (increase in the affinity) for ATP and some of them even adjust their activation energy (the anaerobiosis-induced elevation of Ea.t. is missing).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Adaptation of the heart to ischemia by preconditioning: effects on energy equilibrium, properties of sarcolemmal ATPases and release of cardioprotective proteins. 749 41

Recent studies have suggested that modifications in mitochondrial F1-adenosinetriphosphatase (ATPase) activity may play an important role in the regulation of myocardial oxidative phosphorylation. The goal of the present study was to develop and characterize an assay of F1-ATPase activity that could be performed repeatedly on an intact heart under various physiological states. With the use of submitochondrial particles prepared from biopsy samples of canine myocardium, we found reproducible F1-ATPase activity when normalized to the activity of the intramitochondrial enzyme citrate synthase. The oligomycin-sensitive component of the ATPase activity was found to be mainly F1-ATPase. F1-ATPase activity of normal myocardium increased by incubation in high salt-pH buffer, suggesting baseline inhibition. Five minutes after global ischemia, F1-ATPase activity decreased to 60% of baseline. Hypoxia for 10 min resulted in no significant change in F1-ATPase activity. With phenylephrine infusion, myocardial oxygen consumption more than doubled, whereas F1-ATPase activity increased by approximately 30%. Both returned to baseline levels after discontinuation of the drug. With the use of an assay developed to measure F1-ATPase activity of intact myocardium, changes of the enzyme activity were found during both ischemia and at increased work loads. These data suggest that alterations of F1-ATPase activity may contribute to the regulation of myocardial oxidative phosphorylation.
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PMID:Mitochondrial F1-ATPase activity of canine myocardium: effects of hypoxia and stimulation. 802 1


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