Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.3.3.1 (citrate synthase)
 4,488 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

High concentrations of thapsigargin (TG) have been used to study the process of necrotic cell death, which involves mitochondria in the cell rapidly undergoing the mitochondrial permeability transition (MPT). We therefore investigated the effects of TG on MPT in isolated liver and heart mitochondria. Using a matrix swelling assay in combination with a novel enzymatic method based on inner membrane permeability to citrate synthase substrates, TG induced MPT in a concentration-dependent manner, independent of extramitochondrial [Ca2+] and inhibitable by cyclosporin A. Evidence from alamethicin-permeabilized mitochondria suggests that TG induces MPT by causing Ca2+ release from mitochondrial matrix Ca2+-binding sites. These findings suggest that the MPT-inducing effect of TG may contribute to its pro-necrotic and pro-apoptotic effects in various cell types.
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PMID:Thapsigargin directly induces the mitochondrial permeability transition. 1049 Nov 83

1. The adult fast character and a Ca2+-inducible reversible transition from a fast to a slow type of rabbit myotube in a primary culture were demonstrated at the mRNA level by Northern blot analysis with probes specific for different myosin heavy chain (MyHC) isoforms and enzymes of energy metabolism. 2. No non-adult MyHC isoform mRNA was detected after 22 days of culture. After 4 weeks of culture the fast MyHCIId mRNA was strongly expressed while MyHCI mRNA was virtually absent, indicating the fast adult character of the myotubes in the primary skeletal muscle culture. 3. The data show that a fast-to-slow transition occurred in the myotubes at the level of MyHC isoform gene expression after treatment with the Ca2+ ionophore A23187. The effects of ionophore treatment were decreased levels of fast MyHCII mRNA and an augmented expression of the slow MyHCI gene. Changes in gene expression started very rapidly 1 day after the onset of ionophore treatment. 4. Levels of citrate synthase mRNA increased and levels of glyceraldehyde 3-phosphate dehydrogenase mRNA decreased during ionophore treatment. This points to a shift from anaerobic to oxidative energy metabolism in the primary skeletal muscle culture cells at the level of gene expression. 5. Withdrawal of the Ca2+ ionophore led to a return to increased levels of MyHCII mRNA and decreased levels of MyHCI mRNA, indicating a slow-to-fast transition in the myotubes and the reversibility of the effect of ionophore on MyHC isoform gene expression.
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PMID:Reversible Ca2+-induced fast-to-slow transition in primary skeletal muscle culture cells at the mRNA level. 1067 42

With a training schedule (8 weeks' treadmill running at 30 m/min up a 10% incline 5 d/wk for 90 min/day), we investigated whether exercise modifies aortic wall dimensions, composition (calcium and elastin content), or stiffness in normotensive 6-month-old male Wistar WAG/Rij rats. Maximal oxygen uptake was measured in half of the rats (n=10 per group). Wall stiffness was evaluated in the other half (9 trained and 10 untrained) on the basis of changes in thoracoabdominal pressure pulse wave velocity and differences in amplitude between the peripheral and central aortic pressure signals. Experiments were performed in nonanesthetized, unrestrained rats and then after pithing. The impact of exercise on the oxidative capacity of the plantaris muscles was evaluated with the measurement of citrate synthase activity. Training increased maximal oxygen uptake by 34% and citrate synthase activity by 40%. Mean peripheral aortic pressure increased by 6% and 19% in trained rats, under awake and pithed conditions, whereas mean central aortic pressure increased by 16%, after pithing only. All indexes of aortic stiffness were similar in trained and control rats, as were aortic wall dimensions, composition, cardiac mass, and heart rate. In conclusion, physical exercise in young rats appears to have no effect on aortic stiffness.
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PMID:Physical exercise, aortic blood pressure, and aortic wall elasticity and composition in rats. 1077 62

Activation of the transcription factor nuclear factor of activated T cells by the calcium-sensitive serine/threonine phosphatase calcineurin has been proposed as one of the molecular mechanisms by which motor nerve activity establishes the slow muscle phenotype. To investigate whether the calcineurin pathway can regulate the large spectrum of slow muscle characteristics in vivo, we treated rats for three weeks with cyclosporin A (an inhibitor of calcineurin). In soleus (slow muscle), but not in plantaris (fast muscle), the proportion of slow myosin heavy chain (MHC-1) and slow sarcoplasmic reticulum ATPase (SERCA2a) was decreased, whereas that of fast MHC (MHC-2A) and fast SERCA1 increased, indicating a slow to fast contractile phenotype transition. Cytosolic isoforms of creatine kinase and lactate dehydrogenase (most abundant in fast fibers), as well as mitochondrial creatine kinase and citrate synthase activities (elevated in fast/oxidative fibers) were dose dependently increased by cyclosporin A treatment in soleus muscle, with no change in plantaris. Calcineurin catalytic subunit was more abundant in soleus muscle fibers compared with plantaris. Taken together these results suggest that the calcineurin pathway co-regulates a set of multigenic protein families involved in the transition between slow oxidative (type I) to fast oxidative (type IIa) phenotype in soleus muscle.
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PMID:Calcineurin Co-regulates contractile and metabolic components of slow muscle phenotype. 1077 82

The effect of aglycaemic hypoxia (AH) on the activity of the mitochondrial respiratory chain complexes was measured in superfused neonatal cortical brain slices. After 30 min AH, there were no significant changes in the activities of complex I, II-III and IV or citrate synthase compared to controls. Following 30 min AH and a 30-min reperfusion period (with oxygen and glucose), the activities of complex II-III and complex IV were significantly reduced (by 25 and 17%, respectively). These reductions in enzyme activity were not abrogated by removing external calcium prior to and throughout AH, but could be reversed by the presence of the nitric oxide (NO) synthase inhibitor N omega-nitro-L-arginine during these periods. These data suggest that NO or an NO-derived species is involved in the decreases in mitochondrial enzyme activities observed after AH
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PMID:Nitric-oxide-induced inhibition of mitochondrial complexes following aglycaemic hypoxia in neonatal cortical rat brain slices. 1111 Nov 51

The addition of cyclosporin A (500 ng ml(-1)) - an inhibitor of the Ca2+-calmodulin-regulated serine/threonine phosphatase calcineurin - to primary cultures of rabbit skeletal muscle cells had no influence on the expression of fast myosin heavy chain (MHC) isoforms MHCIIa and MHCIId at the level of protein and mRNA, but reduced the expression of slow MHCI mRNA. In addition, no influence of cyclosporin A on the expression of citrate synthase (CS) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA was found. The level of enzyme activity of CS was also not affected. When the Ca2+ ionophore A23187 (4 x 10(-7) M) was added to the medium, a partial fast-to-slow transformation occurred. The level of MHCI mRNA increased, and the level of MHCIId mRNA decreased. Cotreatment with cyclosporin A was able to prevent the upregulation of MHCI at the level of mRNA as well as protein, but did not reverse the decrease in MHCIId expression. The expression of MHCIIa was also not influenced by cyclosporin A. Cyclosporin A was not able to prevent the upregulation of CS mRNA under Ca2+ ionophore treatment and failed to reduce the increased enzyme activity of CS. The expression of GAPDH mRNA was reduced under Ca2+ ionophore treatment and was not altered under cotreatment with cyclosporin A. When the myotubes in the primary muscle culture were electrostimulated at 1 Hz for 15 min periods followed by pauses of 30 min, a partial fast-to-slow transformation was induced. Again, cotreatment with cyclosporin A prevented the upregulation of MHCI at the level of mRNA and protein without affecting MHCIId expression. The nuclear translocation of the calcineurin-regulated transcription factor nuclear factor of activated thymocytes (NFATc1) during treatment with Ca2+ ionophore, and the prevention of the translocation in the presence of cyclosporin A, were demonstrated immunocytochemically in the myotubes of the primary culture. The effects of cyclosporin A demonstrate the involvement of calcineurin-dependent signalling pathways in controlling the expression of MHCI, but not of MHCIIa, MHCIId, CS and GAPDH, during Ca2+ ionophore- and electrostimulation-induced fast-to-slow transformations. The data indicate a differential regulation of MHCI, of MHCII and of metabolism. Calcineurin alone is not sufficient to mediate the complete transformation.
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PMID:Calcineurin regulates slow myosin, but not fast myosin or metabolic enzymes, during fast-to-slow transformation in rabbit skeletal muscle cell culture. 1135 Oct 29

Six young men performed five 1-min bicycle exercise bouts to exhaustion. Muscle lactate increased to congruent with 114 mmol x kg(-1) dwt and pH decreased to congruent with 6.6. Mitochondria were prepared from a needle biopsy sample taken from m. vastus lateralis immediately after the last exercise bout. No significant effect of exhaustion on the proton permeability and amount of cytochromes c and aa3 in isolated mitochondria was detected. The activities of the following enzymes and systems were not altered either: citrate synthase, succinate dehydrogenase, cytochrome oxidase, succinate + glutamate respiration, malate + glutamate respiration, the respiratory chain, and the reactions involved in ATP synthesis. Thus, the mitochondria did not appear globally altered upon exhaustion. However, the following NAD-linked activities were significantly lowered: pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase, glutamate dehydrogenase and fatty acid beta-oxidation. The activities of alpha-glycerophosphate dehydrogenase and exo-NADH oxidase, enzymes that might catalyze the oxidation of sarcoplasmic NADH, were increased. These changes may be due to the action of reactive oxygen species, protons and Ca2+. Transient opening of the permeability transition pore may also be involved. Some effects may have been reversed during isolation of the mitochondria and the changes in mitochondrial function in situ upon exhaustion may have been more extensive than observed.
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PMID:The effect of high-intensity exhaustive exercise studied in isolated mitochondria from human skeletal muscle. 1171 42

1 In this study, we have used isolated brain mitochondria to investigate the effects of superoxide anions (O(2)(-)) on mitochondrial parameters related to apoptosis, such as swelling, potential, enzymatic activity, NAD(P)H, cytochrome c release, and caspase activity. 2 Addition of the reactive oxygen species (ROS) generator KO(2) produced brain mitochondrial swelling, which was blocked by cyclosporin A (CSA), and which was Ca(2+) independent. 3 Calcium induced mitochondrial swelling only at high concentrations and in the presence of succinate. This correlated with the increase in O(2)(-) production detected with hydroethidine in mitochondrial preparations exposed to Ca(2+) and the fact that ROS were required for Ca(2+)-induced mitochondrial swelling. 4 Superoxide anions, but not Ca(2+), decreased citrate synthase and dehydrogenase enzymatic activities and dropped total mitochondrial NAD(P)H levels. 5 Calcium, but not O(2)(-), triggered a rapid loss of mitochondrial potential. Calcium-induced Deltapsi(m) dissipation was inhibited by Ruthenium Red, but not by CSA. 6 Calcium- and superoxide-induced mitochondrial swelling released cytochrome c and increased caspase activity from isolated mitochondria in a CS A-sensitive manner. 7 In summary, superoxide potently triggers mitochondrial swelling and the release of proteins involved in activation of postmitochondrial apoptotic pathways in the absence of mitochondrial depolarization.
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PMID:Reactive oxygen species induce swelling and cytochrome c release but not transmembrane depolarization in isolated rat brain mitochondria. 1281 3

The purpose of this study was to test the hypothesis that calcineurin, a calcium-dependent protein phosphatase recently implicated in the signaling of skeletal muscle hypertrophy and fiber type conversion, is required to induce some mitochondrial enzyme adaptations to endurance exercise training in skeletal muscle. Three- to four-week-old male Sprague-Dawley rats with an initial body weight ranging from 45 to 55 g were used in this study. The rats were randomly assigned to groups injected with either a specific calcineurin inhibitor, cyclosporin A (CsA), (group CI) or vehicle (group VI). CsA was subcutaneously injected into the rats at a rate of 50 mg.kg(-1) body weight per day for 10 days. The CI and VI groups were further assigned to sedentary (SED) or exercise training (EX) groups. In the EX group, the rats were trained for 10 days (90 min.day(-1), approximately 14-20 m.min(-1), 10% grade). The citrate synthase (CS) activities in the soleus and plantaris muscles of the EX group rats were significantly higher than those of the SED group rats ( p<0.001). Furthermore, 3-beta-hydroxyacyl-CoA dehydrogenase (3-HAD) activities in the soleus and plantaris muscles were significantly higher in the EX group rats than in the SED group rats ( p<0.001). However, there were no significant differences in CS and 3-HAD activities between the VI and CI groups. The interactions between CsA injection and exercise training were not statistically significant in any of the parameters. These results may suggest that calcineurin is not involved in some mitochondrial enzyme adaptations to endurance exercise training.
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PMID:Calcineurin is not involved in some mitochondrial enzyme adaptations to endurance exercise training in rat skeletal muscle. 1285 86

Mitochondrial proteins such as uncoupling protein 3 (UCP3) and adenine nucleotide translocase (ANT) may mediate back-leakage of protons and serve as uncouplers of oxidative phosphorylation. We hypothesized that UCP3 and ANT increase after prolonged exercise and/or endurance training, resulting in increased uncoupled respiration (UCR). Subjects were investigated with muscle biopsies before and after acute exercise (75 min of cycling at 70% of .VO2peak) or 6 weeks endurance training. Mitochondria were isolated and respiration measured in the absence (UCR or state 4) and presence of ADP (coupled respiration or state 3). Protein expression of UCP3 and ANT was measured with Western blotting. After endurance training, .VO2peak, citrate synthase activity (CS), state 3 respiration and ANT increased by 24, 47, 40 and 95%, respectively (all P < 0.05), whereas UCP3 remained unchanged. When expressed per unit of CS (a marker of mitochondrial volume) UCP3 and UCR decreased by 54% and 18%(P < 0.05). CS increased by 43% after acute exercise and remained elevated after 3 h of recovery (P < 0.05), whereas the other muscle parameters remained unchanged. An intriguing finding was that acute exercise reversibly enhanced the capacity of mitochondria to accumulate Ca2+(P < 0.05) before opening of permeability transition pores. In conclusion, UCP3 protein and UCR decrease after endurance training when related to mitochondrial volume. These changes may prevent excessive basal thermogenesis. Acute exercise enhances mitochondrial resistance to Ca2+ overload but does not influence UCR or protein expression of UCP3 and ANT. The increased Ca2+ resistance may prevent mitochondrial degradation and the mechanism needs to be further explored.
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PMID:Effects of acute and chronic endurance exercise on mitochondrial uncoupling in human skeletal muscle. 1463 2


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