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)

The effect of inhibition of the mitochondrial ATPase with oligomycin on the rate of ATP depletion and anaerobic glycolysis was studied in the totally ischemic dog heart. An oxygenated, buffered crystalloidal solution containing 10 microM oligomycin and 12 mM glucose was delivered at 100 mmHg pressure to the circumflex bed of the excised cooled heart. Buffered solution without oligomycin was delivered simultaneously to the anterior descending bed of the same heart. Little metabolic evidence of ischemia developed until the heart was made totally ischemic by incubating it in a sealed plastic bag at 37 degrees C. Successful inhibition of the mitochondrial ATPase was confirmed by the absence of both mitochondrial ATPase activity and the loss of respiratory control in mitochondria isolated from treated tissue. ATP, glycolytic intermediates and catabolites of the adenine nucleotide pool were measured in the control and treated beds at various intervals during 120 min of ischemia. Inhibition of the ATPase resulted in slowing of the rates of ATP depletion and anaerobic glycolysis (estimated by lactate accumulation). Also, degradation of the adenine nucleotide pool occurred more slowly in the inhibited group. These data establish that about 35% of the ATP utilization observed during the first 90 min of total ischemia in the canine heart is due to mitochondrial ATPase activity.
J Mol Cell Cardiol 1991 Dec
PMID:Effect of inhibition of the mitochondrial ATPase on net myocardial ATP in total ischemia. 183 1

During ischemia in so-called slow heart-rate hearts, there is a marked inhibition of the mitochondrial ATPase mediated by inhibitor protein binding to the enzyme (Rouslin, W., and Pullman, M. E. (1987) J. Mol. Cell. Cardiol. 19, 661-668). This ischemia-induced ATPase inhibition is triggered by a drop in mitochondrial matrix pH (Rouslin, W. (1987) J. Biol. Chem. 262, 3472-3476) which occurs as a result of the cell acidification which develops rapidly during the ischemic process. One effect of the ATPase inhibition is a marked slowing of the net rate of tissue ATP hydrolysis and, thus, a prolongation of cell viability during ischemia. In the present study, we demonstrate that matrix acidification in intact mitochondria from slow heart-rate hearts appears to be mediated by the Pi transporter. Pi/H+ symport appears to be the primary process which mediates matrix acidification and thus ATPase inhibition in intact slow heart-rate heart mitochondria made acidotic in vitro and, presumably, also in mitochondria in situ during the ischemic process. In contrast, intact mitochondria from a so-called fast heart-rate species, which exhibited only a low level of ischemia-induced ATPase inhibition in situ (Rouslin, W. (1987) Am. J. Physiol. 252, H622-H627), failed to exhibit a Pi- and pH-dependent mitochondrial ATPase inhibition mechanism in vitro. The Pi-dependent mitochondrial ATPase inhibition mechanism reported here for slow heart-rate hearts is consistent with a role for Pi as a coordinating signal promoting the conservation of cell ATP during myocardial ischemia.
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PMID:Regulation of mitochondrial matrix pH and adenosine 5'-triphosphatase activity during ischemia in slow heart-rate hearts. Role of Pi/H+ symport. 252 49

Long-chain acylcarnitines are membrane-active intermediates of fatty acid metabolism whose intracellular accumulation has been implicated in the myocardial injury associated with both streptozotocin-induced diabetes and acute ischemia. In the present study, rats treated with streptozotocin (50 mg/kg i.v.) exhibited increases in myocardial long-chain acylcarnitines comparable to those previously reported to occur in moderate to severe ischemic injury. With the exception of a reduction in the sedimentable (lysosome-associated) fraction of myocardial N-acetyl-beta-glucosaminidase and a decrease in sarcoplasmic reticulum K+, Ca++-stimulated ATPase activity, other characteristic indices of myocardial ischemic damage, notably inhibition of sarcolemmal and mitochondrial ATPase activities as well as alterations in the ionic composition of myocardial tissue, were not apparent in the hearts of the streptozotocin-diabetic animals. On the basis of in vitro studies using palmitylcarnitine, it does not seem that differential sensitivity to long-chain acylcarnitine inactivation can explain the preferential inhibition of the sarcoplasmic reticulum ATPase enzyme observed in vivo. Our data are consistent with the findings of others suggesting that long-chain acylcarnitines are unlikely to be the most important or sole mediators of myocardial ischemic injury. However, a modulatory role of these substances in myocardial ischemic injury or in determining the increased susceptibility of diabetics to the complications of ischemic heart disease cannot be excluded at present.
Can J Cardiol
PMID:Subcellular myocardial abnormalities in experimental diabetes: role of long-chain acylcarnitines. 294 27

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.
J Mol Cell Cardiol 1987 Jul
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.
J Mol Cell Cardiol 1988 Nov
PMID:Factors affecting the loss of mitochondrial function during zero-flow ischemia (autolysis) in slow and fast heart-rate hearts. 297 46

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.
Basic Res Cardiol
PMID:Electron microscopic visible ischemic changes of the mitochondrial ATPases in human myocardial cells during extracorporal circulation. 645 81

Our previous work indicated that energy transduction, as measured by myocyte respiration, was inhibited by hydrogen peroxide, but the mitochondrial membrane potential was relatively unaffected. Therefore, we determined in the present study the critical steps in mitochondrial energy transduction by measuring the sensitivity to hydrogen peroxide of NADH-CoQ reductase, ATP synthase, and adenine nucleotide translocase in situ in myocytes. Adult rat heart cells were isolated using collagenase and incubated in the presence of 0.1-10 mM hydrogen peroxide for 30 min. Activities of NADH-CoQ reductase and oligomycin-sensitive ATP synthase were assayed enzymatically with sonicated myocytes, and adenine nucleotide translocase activities were determined by atractyloside-inhibitable [14C]ADP uptake of myocytes, permeabilized by saponin. The NADH-CoQ reductase and ATP synthase activities were inhibited to 77% and 67% of control, respectively, following an exposure to 10 mM hydrogen peroxide for 30 min. The adenine nucleotide translocase activities were inhibited in a concentration- and time-dependent manner and by 10 mM hydrogen peroxide to 44% of control. The dose-response relationship indicated that the translocase was the most susceptible to hydrogen peroxide among the three enzymes studied. Combined treatment of myocytes with 3-amino-1,2,4-triazole, 1,3-bis(2-chloroethyl)-1-nitrosourea and diethyl maleate (to inactivate catalase, to inhibit glutathione reductase activity, and to deplete glutathione, respectively) enhanced the sensitivity of translocase to hydrogen peroxide, supporting the view that the cellular defense mechanism is a significant factor in determining the toxicity of hydrogen peroxide. The results indicate that hydrogen peroxide can cause dysfunction in mitochondrial energy transduction, principally as the result of inhibition of adenine nucleotide translocase.
Basic Res Cardiol
PMID:Effects of hydrogen peroxide on mitochondrial enzyme function studied in situ in rat heart myocytes. 821 72

The aim of this study was: (1) to elucidate in more detail the relationship between stress protein expression and brief periods of ischaemia and reperfusion, such as occur during early (classical) ischaemic preconditioning (PC) in the rabbit myocardium; (2) to determine whether stress protein expression is affected by adenosine receptor modulation, since adenosine is a mediator of the preconditioning response. We have studied the expression of the 60 kDa (hsp60); 70 kDa (hsp70-inducible and constitutive isoforms) and 27 kDa (hsp27) stress proteins and the mitochondrial ATP-synthase beta-subunit using Northern blotting. Hsp60, hsp70 and hsp27 expression were also determined at the protein level by Western blotting. Total RNA and proteins were prepared from frozen samples of ischaemic left ventricle and non-ischaemic right ventricle rabbit myocardium after the following treatments (1) sham-operated; (2) 15 min stabilization + 5 min coronary occlusion + 10 min reperfusion (PC); (3) PC + 30 min coronary occlusion (I); (4) PC + 30 min coronary occlusion + 2 h reperfusion (I/R) (5) the adenosine receptor antagonist 8-(p-sulpho-phenyl) theophyline (SPT) given 5 min prior to PC; (6) the adenosine receptor agonist 2-chlorocyclopentyl-N6-adenosine (CCPA) given in place of PC. A transient, approximately two-fold elevation in hsp60 mRNA occurred following 5 min coronary occlusion + 10 min reperfusion (PC) which was stable during a subsequent 30 min ischaemia (I), but returned to baseline during the second (2 h) reperfusion (I/R). An inducible hsp70 mRNA species appeared within 10 min of the second (30 min) coronary occlusion (I) which continued to increase to high levels during the second (2 h) reperfusion (I/R). Hsp27 mRNA expression was not altered following PC or subsequent ischaemia and reperfusion (I/R). ATP synthase beta-subunit mRNA did not change during PC or I but decreased during the subsequent 2 h reperfusion (I/R). Western blot analysis showed no change in left ventricle ischaemic zone hsp60, hsp70i/hsc70 or hsp27 protein during PC compared to an approximately two-fold elevation of hsp70i 24 h following whole body heat stress or 24 h following 4 x 5 min coronary occlusion (as reported by Marber et al., 1993). However, hsp70i, hsp60 and hsp27 showed significant decreases in immunodetectable protein following subsequent ischaemia and reperfusion (I/R). SPT inhibited the increase in hsp60 mRNA following PC (P < or = 0.05), but had no effect on hsp70, hsp27 or ATP-synthase mRNA levels. Therefore, differential expression of mRNAs for hsp60 and hsp70 occurred following ischaemia and reperfusion, with hsp70 mRNA expression involving a significant reperfusion-dependent component. CCPA had no effect on expression of mRNAs for hsp60, hsp70, hsp27 or ATP-synthase. We conclude that the early phase of adenosine receptor-dependent preconditioning in the rabbit heart is not mediated via stress protein expression. However, brief ischaemia and reperfusion resulted in differential changes in individual stress protein gene expression which may be due to different physiological and/or biochemical components of ischaemia and reperfusion in the heart. In addition, partial dependence of hsp60 expression on adenosine receptor modulation was observed.
J Mol Cell Cardiol 1995 Oct
PMID:Differential stress protein mRNA expression during early ischaemic preconditioning in the rabbit heart and its relationship to adenosine receptor function. 857 30

Earlier studies by Rouslin and coworkers showed that, during myocardial ischemia in slow heart-rate species which include rabbits and all larger mammals examined including humans, there is an IF1-mediated inhibition of the mitochondrial ATPase due to an increase in the amount of IF1 bound to the ATPase (Rouslin, W., and Pullman, M.E., J. Mol. Cell. Cardiol. 19,661-668, 1987). Earlier work by Guerrieri and colleagues demonstrated that IF1 binding to bovine heart ESMP was accompanied by parallel decreases in ATPase activity and in passive proton conduction (Guerrieri, F., et al., FEBS Lett. 213, 67-72, 1987). In the present study rabbit was used as the slow heart-rate species and rat as the fast heart-rate species. Rat is a fast heart-rate species that contains too little IF1 to down regulate the ATPase activity present. Mitochondria were prepared from control and ischemic hearts and ESMP were made from aliquots by sonication at pH 8.0 with 2 mM EDTA. Oligomycin-sensitive ATPase activity and IF1 content were measured in SMP prepared from the control and ischemic mitochondrial samples. After identical incubation procedures, oligomycin-sensitive ATPase activity, oligomycin-sensitive proton conductivity, and IF1 content were also measured in ESMP samples. The study was undertaken to corroborate further what appear to be fundamental differences in ATPase regulation between slow and fast heart-rate mammalian hearts evident during total myocardial ischemia. Thus, passive proton conductivity was used as an independent measure of these regulatory differences. The results show that, consistent with the low IF1 content of rat heart cardiac muscle mitochondria, control rat heart ESMP exhibit approximately twice as much passive proton conductivity as control rabbit heart ESMP regardless of the pH of the incubation and assay. Moreover, while total ischemia caused an increase in IF1 binding and a commensurate decrease in passive proton conductivity in rabbit heart ESMP regardless of pH, neither IF1 content nor proton conductivity changed significantly in rat heart ESMP as a result of ischemia.
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PMID:ATPase activity, IF1 content, and proton conductivity of ESMP from control and ischemic slow and fast heart-rate hearts. 859 81

The ability of ischemic preconditioning (IP) to protect the myocardium against prolonged ischemia may derive from improved energy balance. We therefore examined myocardial energy metabolism and mitochondrial oxidative phosphorylation in isolated perfused rat hearts which were either subjected (IP group), or not subjected (control group), to preconditioning prior to 30 min sustained ischemia and 30 min reperfusion. Preconditioning was achieved with two cycles of 5 min ischemia followed by 5 min reperfusion. Recovery of myocardial function was significantly greater, and creatine kinase release was significantly lower, in the IP group. Although ATP hydrolysis during the sustained ischemia remained unchanged in both groups, greater preservation of high energy phosphate (eg. ATP and CP) was observed in the IP group after reperfusion. CP content immediately after preconditioning greatly exceeded pre-ischemic values. Lactate production during the sustained ischemia was significantly lower in the IP group, suggesting a decrease in anaerobic glycolysis and a probable attenuation of intracellular acidosis. Oligomycin-sensitive mitochondrial ATPase activity in the control group was significantly decreased both after the sustained ischemia and the reperfusion, but in the IP group it did not change after the preconditioning, sustained ischemia, or reperfusion. Although atractyloside-inhibitable adenine nucleotide translocase activity was markedly decreased during sustained ischemia in both groups, its activity was significantly higher after reperfusion in the IP group. These data suggest that (1) mitochondrial ATPase contributes only slightly to ATP depletion during sustained ischemia, (2) both the CP overshoot phenomenon and the decrease in anaerobic glycolysis can be attributable to cardioprotection during the sustained ischemia, and (3) the preservation of ATPase and adenine nucleotide translocase activities may be a possible explanation for the restoration of high energy phosphates after sustained ischemia-reperfusion injury in the preconditioned hearts of rats.
J Mol Cell Cardiol 1996 Feb
PMID:Effect of ischemic preconditioning on mitochondrial oxidative phosphorylation and high energy phosphates in rat hearts. 872 72


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