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:3.6.3.14 (ATP synthase)
7,042 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Preconditioning and stunning are the chief adaptive changes induced in myocardium by a brief episode of reversible ischemia followed by arterial reperfusion. In the dog heart, both coexist for a period of at least 20 minutes of reperfusion, but after 120 minutes of reflow, preconditioning is much diminished, while stunning remains fully developed. Preconditioned, stunned, myocardium differs from control "virgin" myocardium in that adenine nucleotide content is reduced to about 50-70% of control, whereas creatine phosphate (CP) greatly exceeds normal--the so-called CP overshoot. When preconditioned myocardium is subjected to sustained ischemia, ATP utilization and anaerobic glycolysis occur at much slower rates than those observed in virgin myocardium. As a result of the early difference in metabolic rate, a longer period of ischemia is required for the ATP and lactate of the preconditioned tissue to reach the levels associated with irreversible injury. Associated with this change is a delay in myocyte death. The molecular events responsible for slower ischemic metabolism and associated tolerance of preconditioned, stunned tissue to a new ischemic episode are not known. Among the reactions that could cause a reduction in energy metabolism is reduced approximately P expenditure by stunned myocardium attempting to contract during the initial phase of ischemia. However, results from in vivo and in vitro experiments suggest that although stunning may be necessary for preconditioning to develop, it alone is not sufficient to cause preconditioning. Alternatively, metabolic changes may be explained by depressed activity of the mitochondrial ATPase during the episode of sustained ischemia. However, no direct experimental evidence supporting this hypothesis is available up to the present time.
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PMID:Preconditioning myocardium with ischemia. 175 40

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.
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PMID:Effect of inhibition of the mitochondrial ATPase on net myocardial ATP in total ischemia. 183 1

The metabolic changes associated with the sudden onset of ischemia caused by occlusion of a major coronary artery include (a) cessation of aerobic metabolism, (b) depletion of creatine phosphate (CP), (c) onset of anaerobic glycolysis, and (d) accumulation of glycolytic products, such as lactate and alpha glycerol phosphate (alpha GP), and catabolites of the nucleotide pools in the tissue. These changes are associated with contractile failure and electrocardiographic alterations. Since the demand of the myocardium for high-energy phosphate (approximately P) exceeds the available supply, the net amount of ATP in tissue decreases. Eighty percent of the supply of approximately P utilized by severely ischemic tissue comes from anaerobic glycolysis using glycogen as the principal substrate. Early in ischemia, contractile activity utilizes ATP, but much of the continuing utilization of ATP by the ischemic tissue is energy wasted via the mitochondrial ATPase. A lesser quantity of ATP is used by ion transport ATPases. Metabolic changes slow as the duration of ischemia increases. Irreversibly injured myocytes exhibit (a) very low levels of ATP (less than 10% of control); (b) cessation of anaerobic glycolysis; (c) high levels of H+, AMP, INO, lactate, and alpha GP; (d) a greatly increased osmolar load; (e) mitochondrial swelling and formation of amorphous matrix densities; and (f) disruption of the sarcolemma. The latter event is generally recognized as lethal, but its pathogenesis remains to be established. Most severely ischemic myocytes are dead in regional ischemia in the anesthetized open-chest dog heart after only 60 minutes of ischemia. Less severely ischemic myocytes in the mid- and subepicardial myocardium survive for as long as six hours. Virtually all myocytes destined to die in a zone of ischemia are irreversibly injured after six hours of ischemia have passed. Certain changes exhibited by myocytes injured by severe ischemia and reperfused late in the reversible phase of injury do not return to the control conditions for a period of days, while others rebound in only seconds to minutes. The adenine nucleotide pool still is not fully restored after four days of reperfusion. Stunning disappears after one to two days of reflow. The preconditioning effect is partially lost after two hours of reperfusion. The timing of its disappearance has not been fully established. Aerobic metabolism is restored after only a few minutes of reperfusion. Thus, reperfusion salvages injured myocardium and restores its structure and function to the control state at a variable rate.
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PMID:The cell biology of acute myocardial ischemia. 203 69

In the present study we examined the regulation of the cardiac muscle mitochondrial ATPase both in situ and in vitro in intact and sonicated mitochondria from rabbit, pigeon, and rat. We chose to study these three species because each is representative of one of the three classes into which all species thus far studied may be placed with respect to the in situ activity of their cardiac muscle mitochondrial ATPase inhibitor and with respect to the amount of ATPase inhibitor present in their cardiac muscle mitochondria (1). Class A species (rabbit) contain a full complement of ATPase inhibitor and show a marked ATPase inhibition during ischemia. Class B species (pigeon) also contain a full complement of inhibitor but exhibit only a low level of ATPase inhibition in situ. Class C species (rat) contain only low levels of inhibitor and, like class B species, don't appear to utilize the inhibitor they possess during ischemia in situ. We found that, while hearts from all three species developed a marked cytosolic acidosis during ischemia, only rabbit exhibited a marked ATPase inhibition in situ. In in vitro experiments in which matrix pH values close to 6.2 and delta psi values close to zero were measured in intact mitochondria from all three species, matrix pH appeared to be an important factor regulating ATPase inhibition in rabbit, but it had little effect upon ATPase--inhibitor interaction in pigeon and rat despite the lack of membrane potential. However, a pH-dependent further release of ATPase inhibitor was observed in sonicated pigeon heart mitochondria only. This latter observation suggests that, while slow heart-rate heart mitochondria appear to be designed for ATPase down regulation during ischemia by inhibitor binding to the ATPase, fast heart-rate heart mitochondria appear to be designed primarily for ATPase up regulation by a further release of inhibitor from the enzyme.
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PMID:Regulation of the mitochondrial adenosine 5'-triphosphatase in situ during ischemia and in vitro in intact and sonicated mitochondria from slow and fast heart-rate hearts. 214 Dec 43

In the present study, isolated dog and rat hearts were perfused in the Langendorff mode with Krebs bicarbonate buffer in the absence and presence of 10(-5) M oligomycin. The perfusion protocols employed allowed tissue pH to drop during subsequent ischemic incubations essentially as it would in blood-perfused hearts. Tissue pH, ATP, lactate, and mitochondrial respiratory function were measured during the course of subsequent zero-flow ischemic incubations. The adenosinetriphosphatase (ATPase) activities attributable to both mitochondrial and nonmitochondrial ATPases in sonicated heart homogenates and the actomyosin ATPase in isolated cardiac myofibrils were measured in both species. Consistent with earlier results with a different model in which tissue pH was buffered during the ischemic incubations [W. Rouslin, J. L. Erickson, and R. J. Solaro. Am. J. Physiol. 250 (Heart Circ. Physiol. 19): H503-H508, 1986], the inhibition of the mitochondrial ATPase in situ by oligomycin markedly slowed both tissue ATP depletion and the loss of mitochondrial function during ischemia in the dog. However, oligomycin had only a very small and transient effect on ATP depletion and mitochondrial function in the rat. This was apparently so because of the fivefold higher rate of glycolytic ATP production as well as the nearly threefold higher total nonmitochondrial ATPase activity of ischemic rat compared with ischemic dog heart. These results suggest that although the inhibition of the mitochondrial ATPase makes a major contribution to ATP conservation in ischemic dog heart, it makes only a very small contribution in rat.
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PMID:ATP depletion and mitochondrial functional loss during ischemia in slow and fast heart-rate hearts. 214 59

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

In the present study we examined three factors affecting the reversal of the ischemia-induced inhibition of the mitochondrial ATPase described by us earlier (W. Rouslin (1983) J. Biol. Chem. 258, 9657-9661). These factors were the pH, the MgATP concentration, and the pCa of the medium in which mitochondria were sonicated following their reenergization in vitro. It was found that the extent of ATPase reactivation, on the one hand, and the extent of inhibitor protein release, on the other, following the reenergization in vitro and subsequent sonication of intact mitochondria isolated from 20-min-ischemic canine cardiac muscle were affected differently by each of the three factors studied. While raising the pH of the medium in which the mitochondria were sonicated subsequent to reenergization from approximately 7.0 to approximately 8.2 resulted in marked parallel increases in both ATPase reactivation and inhibitor protein release, lowering the pH of the medium to approximately 6.4 resulted in a marked decrease in ATPase reactivation but also in the apparent irreversible binding and/or denaturation of a portion of the ATPase inhibitor. Increasing the MgATP concentration of the sonication medium from zero to 2.0 mM resulted in approximately a one-third decrease in ATPase reactivation. The effect upon inhibitor release was more dramatic. MgATP at 2 mM decreased inhibitor release by approximately two-thirds. The pCa of the sonication medium was varied between 9.0 and 3.5 using Ca-ethylenebis(oxyethylenenitrilo)-tetraacetic acid (EGTA) buffers. Decreasing the pCa of the medium from 9.0 to 3.5 had a paradoxical effect. It resulted in increases both in ATPase reactivation and in the amount of inhibitor bound to the particles. Such a paradoxical effect may be explained if one assumes the existence of two kinds of inhibitor-enzyme interaction sites, namely, regulatory and nonregulatory binding sites. Thus, decreasing the pCa may decrease interaction at regulatory sites while enhancing interaction at nonregulatory inhibitor binding sites.
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PMID:Factors affecting the reactivation of the mitochondrial adenosine 5'-triphosphatase and the release of ATPase inhibitor protein during and following the reenergization of mitochondria from ischemic cardiac muscle. 253 91

With a variety of forms of ischemic and toxic tissue injury, cellular accumulation of Ca2+ and generation of oxygen free radicals may have adverse effects upon cellular and, in particular, mitochondrial membranes. Damage to mitochondria, resulting in impaired ATP synthesis and diminished activity of cellular energy-dependent processes, could contribute to cell death. In order to model, in vitro, conditions present post-ischemia or during toxin exposure, the interactions between Ca2+ and oxygen free radicals on isolated renal mitochondria were characterized. The oxygen free radicals were generated by hypoxanthine and xanthine oxidase to simulate in vitro one of the sources of oxygen free radicals in the early post-ischemic period in vivo. With site I substrates, pyruvate and malate, Ca2+ pretreatment, followed by exposure to oxygen free radicals, resulted in an inhibition of electron transport chain function and complete uncoupling of oxidative phosphorylation. These effects were partially mitigated by dibucaine, a phospholipase A2 inhibitor. With the site II substrate, succinate, the electron transport chain defect was not manifest and respiration remained partially coupled. The electron transport chain defect produced by Ca2+ and oxygen free radicals was localized to NADH CoQ reductase. Calcium and oxygen free radicals reduced mitochondrial ATPase activity by 55% and adenine nucleotide translocase activity by 65%. By contrast oxygen free radicals alone reduced ATPase activity by 32% and had no deleterious effects on translocase activity. Dibucaine partially prevented the Ca2+-dependent reduction in ATPase activity and totally prevented the Ca2+-dependent translocase damage observed in the presence of oxygen free radicals. These findings indicate that calcium potentiates oxygen free radical injury to mitochondria. The Ca2+-induced potentiation of oxygen free radical injury likely is due in part to activation of phospholipase A2. This detrimental interaction associated with Ca2+ uptake by mitochondria and exposure of the mitochondria to oxygen free radicals may explain the enhanced cellular injury observed during post-ischemic reperfusion.
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PMID:Mechanism of calcium potentiation of oxygen free radical injury to renal mitochondria. A model for post-ischemic and toxic mitochondrial damage. 287 85

Reversal of mitochondrial dysfunction caused by uncouplers of oxidative phosphorylation, diamide, ageing and ischemia was studied using 2-mercaptopropionylglycine (MPG) in reduced and oxidized (ox-MPG) forms and other SH compounds. Rat heart mitochondria and mitochondrial ATPase, OS-ATPase from beef heart and the isolated working rat heart preparation were examined. MPG and ox-MPG partly prevented and reversed mitochondrial uncoupling and improved deteriorated heart function. ATPase activities were decreased by MPG and ox-MPG in both types of preparation. Three mechanisms are probably involved in thiol action. These comprise alternatively and/or additively: a) SH/S-S interchange reactions; b) free radical scavenger function; c) polar-polar (apolar) interactions. This may contribute to improve oxidative phosphorylation which is considered as a result of recoupling damaged mitochondria by MPG.
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PMID:2-Mercaptopropionylglycine and related compounds in treatment of mitochondrial dysfunction and postischemic myocardial damage. 293 61

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.
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PMID:Subcellular myocardial abnormalities in experimental diabetes: role of long-chain acylcarnitines. 294 27


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