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:1.3.5.1 (succinate dehydrogenase)
8,177 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

3-Hydroxyglutaric acid (3HGA) accumulates in the inherited neurometabolic disorder known as glutaryl-CoA dehydrogenase deficiency. The disease is clinically characterized by severe neurological symptoms, frontotemporal atrophy and striatum degeneration. Because of the pathophysiology of the brain damage in glutaryl-CoA dehydrogenase deficiency is not completed clear, we investigated the in vitro effect of 3HGA (0.01-5.0mM) on critical enzyme activities of energy metabolism, including the respiratory chain complexes I-V, creatine kinase isoforms and Na(+),K(+)-ATPase in cerebral cortex and striatum from 30-day-old rats. Complex II activity was also studied in rat C6-glioma cells exposed to 3HGA. The effect of 3HGA was further investigated on the rate of oxygen consumption in mitochondria from rat cerebrum. We observed that 1.0mM 3HGA significantly inhibited complex II in cerebral cortex and C6 cells but not the other activities of the respiratory chain complexes. Creatine kinase isoforms and Na(+),K(+)-ATPase were also not affected by the acid. Furthermore, no inhibition of complex II activity occurred when mitochondrial preparations from cerebral cortex or striatum homogenates were used. In addition, 3HGA significantly lowered the respiratory control ratio in the presence of glutamate/malate and succinate under stressful conditions or when mitochondria were permeabilized with digitonin. Since 3HGA stimulated oxygen consumption in state IV and compromised ATP formation, it can be presumed that this organic acid might act as an endogenous uncoupler of mitochondria respiration. Finally, we observed that 3HGA changed C6 cell morphology from a round flat to a spindle-differentiated shape, but did not alter cell viability neither induced apoptosis. The data provide evidence that 3HGA provokes a moderate impairment of brain energy metabolism and do not support the view that 3HGA-induced energy failure would solely explain the characteristic brain degeneration observed in glutaryl-CoA dehydrogenase deficiency patients.
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PMID:3-Hydroxyglutaric acid moderately impairs energy metabolism in brain of young rats. 1611 21

Glutaric acidemia type I is an inherited metabolic disorder biochemically characterized by tissue accumulation of predominantly glutaric acid (GA). Affected patients present frontotemporal hypotrophy, as well as caudate and putamen injury following acute encephalopathic crises. Considering that the underlying mechanisms of basal ganglia damage in this disorder are poorly known, in the present study we tested the effects of glutaric acid (0.2-5mM) on critical enzyme activities of energy metabolism, namely the respiratory chain complexes I-IV, succinate dehydrogenase and creatine kinase in midbrain of developing rats. Glutaric acid significantly inhibited creatine kinase activity (up to 26%) even at the lowest dose used in the assays (0.2mM). We also observed that CK inhibition was prevented by pre-incubation of the homogenates with reduced glutathione, suggesting that the inhibitory effect of GA was possibly mediated by oxidation of essential thiol groups of the enzyme. In addition, the activities of the respiratory chain complex I-III and of succinate dehydrogenase were also significantly inhibited by 20 and 30%, respectively, at the highest glutaric acid concentration tested (5mM). In contrast, complexes II-III and IV activities of the electron transport chain were not affected by the acid. The effect of glutaric acid on the rate of oxygen consumption in intact mitochondria from the rat cerebrum was also investigated. Glutaric acid (1mM) significantly lowered the respiratory control ratio (state III/state IV) up to 40% in the presence of the respiratory substrates glutamate/malate or succinate. Moreover, state IV respiration linked to NAD and FAD substrates was significantly increased in GA-treated mitochondria while state III was significantly diminished. The results indicate that the major metabolite accumulating in glutaric acidemia type I moderately compromises brain energy metabolism in vitro.
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PMID:Glutaric acid moderately compromises energy metabolism in rat brain. 1629 44

Ethylmalonic aciduria is a common finding in patients affected by short-chain acyl-CoA dehydrogenase (SCAD) deficiency and other diseases characterized by encephalopathy, muscular symptomatology, and lactic acidemia. Considering that the pathophysiological mechanisms of these disorders are practically unknown and that lactic acidosis suggest an impairment of energy production, the objective of the present work was to investigate the in vitro effect of ethylmalonic acid (EMA), at concentrations varying from 0.25 to 5.0 mM, on important parameters of energy metabolism in human skeletal muscle, such as the activities of the respiratory chain complexes and of creatine kinase, which are responsible for most of the ATP produced and transferred inside the cell. We verified that EMA significantly inhibited the activity of complex I-III at concentrations as low as 0.25 mM, complex II-III at 1 mM and higher concentrations, and complex II at the concentration of 5 mM. In contrast, complex IV was not inhibited by the acid. Finally, we observed that the activity of creatine kinase was significantly inhibited by EMA at the concentrations of 1 and 5 mM. These results suggest that EMA compromises energy metabolism in human skeletal muscle. In case the in vitro effects detected in the present study also occur in vivo, it is tempting to speculate that they may contribute, at least in part, to explain the hypotonia/myopathy, as well as the increased concentrations of lactic acid present in the patients affected by illnesses in which EMA accumulates.
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PMID:Inhibition of the electron transport chain and creatine kinase activity by ethylmalonic acid in human skeletal muscle. 1677 66

Central core disease is a nonprogressive or slowly progressive congenital myopathy with a variable degree of hypotonia and axial and proximal muscle weakness that is histologically characterized by areas devoid of oxidative enzyme activity, resulting from an absence or low numbers of mitochondria in these regions (central core). A 10-month-old, male, pony foal was examined because of stiff gait, marked contractures of the distal portion of the limbs, flexion deformities of the hooves, and moderate hypotonia that had been present from birth. The foal had increased creatine kinase (282 U/liter; reference interval 10-135 U/liter), lactate dehydrogenase (1,188 U/liter; reference interval 150-450 U/liter), and aspartate transaminase (377 U/liter; reference interval <290 U/liter) activities, suggesting muscle disease. Muscle biopsy was performed. In cytochrome oxidase-, succinate dehydrogenase-, and reduced nicotinamide adenine dinucleotide tetrazolium reductase-reacted sections, the dominant morphologic feature was the absence of oxidative enzyme activity in the cores. By use of immunohistochemical technique with a monoclonal antibody against desmin, the cores were clearly delineated and a desmin network was present within the cores. Ultrastructurally, the core areas were characterized by preserved sarcomeres with irregular Z-lines, with some streaming or zigzag appearance and abnormal sarcoplasmic reticulum profiles and T-tubules. Lack of mitochrondria within central cores was observed. Diagnosis of myopathy with central cores was made.
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PMID:Myopathy with central cores in a foal. 1684 6

Creatine kinase is a crucial enzyme for brain, heart and skeletal muscle energy homeostasis, and a decrease of its activity has been associated with cell death. Many biological properties have been attributed to ruthenium complexes. In this context, this work was performed in order to evaluate creatine kinase activity from rat brain, heart and skeletal muscle (quadriceps) after administration of ruthenium complexes, trans-[RuCl(2)(nic)(4)] (nic=3-pyridinecarboxylic acid) 180.7 micromol/kg (complex I), trans-[RuCl(2)(i-nic)(4)] (i-nic=4-pyridinecarboxylic acid) 13.6 micromol/kg (complex II), trans-[RuCl(2)(dinic)(4)] (dinic=3,5-pyridinedicarboxylic acid) 180.7 micromol/kg (complex III) and trans-[RuCl(2)(i-dinic)(4)] (i-dinic=3,4-pyridinedicarboxylic acid) 180.7 micromol/kg (complex IV). Our results showed that complex I caused inhibition of creatine kinase activity in hippocampus, striatum, cerebral cortex, heart and skeletal muscle. Besides, complex II did not affect the enzyme activity. complexes III and IV increased creatine kinase activity in hippocampus, striatum, cerebral cortex and heart, but not in skeletal muscle. Besides, none of the complexes in vitro altered creatine kinase activity, suggesting that enzymatic activity is indirectly affected by complexes I, III and IV. It is believed that diminution of creatine kinase in brain of rats caused by complex I may be related to results from other study reporting memory impairment caused by the same complex. Further research is necessary in order to elucidate the effects of ruthenium complexes in other important metabolic enzymes.
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PMID:Modulation of creatine kinase activity by ruthenium complexes. 1710 65

Quinolinic acid (QA) is found at increased concentrations in brain of patients affected by various common neurodegenerative disorders, including Huntington's and Alzheimer's diseases. Considering that the neuropathology of these disorders has been recently attributed at least in part to energy deficit, in the present study we investigated the in vitro effect of QA (0.1-100 microM) on various parameters of energy metabolism, such as glucose uptake, (14)CO(2) production and lactate production, as well as on the activities of the respiratory chain complexes I-V, the citric acid cycle (CAC) enzymes, creatine kinase (CK), lactate dehydrogenase (LDH) and Na(+),K(+)-ATPase and finally the rate of oxygen consumption in brain of 30-day-old rats. We initially observed that QA significantly increased glucose uptake (55%), whereas (14)CO(2) generation from glucose, acetate and citrate was inhibited (up to 60%). Furthermore, QA-induced increase of brain glucose uptake was prevented by the NMDA receptor antagonist MK-801. Complex II activity was also inhibited (up to 35%) by QA, whereas the other activities of the respiratory chain complexes, CAC enzymes, CK and Na(+),K(+)-ATPase were not affected by the acid. Furthermore, inhibition of complex II activity was fully prevented by pre-incubating cortical homogenates with catalase plus superoxide dismutase, indicating that this effect was probably mediated by reactive oxygen species. In addition, lactate production was also not altered by QA, in contrast to the conversion of pyruvate to lactate catalyzed by LDH, which was significantly decreased (17%) by this neurotoxin. We also observed that QA did not change state III, state IV and the respiratory control ratio in the presence of glutamate/malate or succinate, suggesting that its effect on cellular respiration was rather weak. The data provide evidence that QA provokes a mild impairment of brain energy metabolism in vitro and does not support the view that the brain energy deficiency associated to certain neurodegenerative disorders could be solely endorsed to QA accumulation.
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PMID:In vitro effect of quinolinic acid on energy metabolism in brain of young rats. 1712 38

In the present study we investigated the effect of intrastriatal administration of 150 nmol quinolinic acid to young rats on critical enzyme activities of energy production and transfer, as well as on 14CO2 production from [1-14C]acetate at distinct periods after quinolinic acid injection. We observed that quinolinic acid injection significantly inhibited complexes II (50%), III (46%) and II-III (35%), as well as creatine kinase (27%), but not the activities of complexes I and IV and citrate synthase in striatum prepared 12 h after treatment. In contrast, no alterations of these enzyme activities were observed 3 or 6 h after quinolinic acid administration. 14CO2 production from [1-14C]acetate was also significantly inhibited (27%) by quinolinic acid in rat striatum prepared 12 h after injection. However, no alterations of these activities were observed in striatum homogenates incubated in the presence of 100 microm quinolinic acid . Pretreatment with the NMDA receptor antagonist MK-801 and with creatine totally prevented all inhibitory effects elicited by quinolinic acid administration. In addition, alpha-tocopherol plus ascorbate and the nitric oxide synthase inhibitor l-NAME completely abolished the inhibitions provoked by quinolinic acid on creatine kinase and complex III. Furthermore, pyruvate pretreatment totally blocked the inhibitory effects of quinolinic acid injection on complex II activity and partially prevented quinolinic acid-induced creatine kinase inhibition. These observations strongly indicate that oxidative phosphorylation, the citric acid cycle and cellular energy transfer are compromised by high concentrations of quinolinic acid in the striatum of young rats and that these inhibitory effects were probably mediated by NMDA stimulation.
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PMID:Evidence that quinolinic acid severely impairs energy metabolism through activation of NMDA receptors in striatum from developing rats. 1723 Jun 42

Guanidinoacetate methyltransferase (GAMT) deficiency is an inherited neurometabolic disorder biochemically characterized by tissue accumulation of guanidinoacetate (GAA) and depletion of creatine. Affected patients present epilepsy and mental retardation whose etiopathogeny is unclear. In a previous study we showed that instrastriatal administration of GAA caused a reduction of Na(+),K(+)-ATPase and creatine kinase (CK) activities, as well as an increase in TBARS (an index of lipid peroxidation). In the present study we investigated the in vitro and in vivo effects of GAA on glucose uptake from [U-(14)C] acetate (citric acid cycle activity) and on the activities of complexes II, II-III, III and IV of the respiratory chain in striatum of rats. Results showed that 50 and 100 microM GAA (in vitro studies) and GAA administration (in vivo studies) significantly inhibited complexes II and II-III, respectively, but did not alter complexes III and IV, as well as CO(2) production. We also studied the influence of taurine or vitamins E and C on the inhibitory effects caused by intrastriatal administration of GAA on complexes II and II-III, Na(+),K(+)-ATPase and CK activities, and on TBARS in rat striatum. Pre-treatment with taurine and vitamins E and C revealed that taurine prevents the effects of intrastriatal administration of GAA on the inhibition of complex II, complex II-III, and Na(+),K(+)-ATPase activities. Vitamins E and C prevent the effects of intrastriatal administration of GAA on the inhibition of CK and Na(+),K(+)-ATPase activities, and on the increase of TBARS. The data suggest that GAA in vivo and in vitro treatment disturbs important parameters of striatum energy metabolism and that oxidative damage may be mediating these effects. It is presumed that defects in striatum bioenergetics might be involved in the pathophysiology of striatum damage characteristic of patients with GAMT-deficiency.
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PMID:Evidence that the inhibitory effects of guanidinoacetate on the activities of the respiratory chain, Na+,K+-ATPase and creatine kinase can be differentially prevented by taurine and vitamins E and C administration in rat striatum in vivo. 1740 7

This study investigated the effects of probenecid to inhibit the multi-drug resistance-associated protein-1 (MRP-1) in mediating the efflux and myotoxicity in rat skeletal muscles, with administration of rosuvastatin. Male Sprague-Dawley rats were administered daily, for 15 days, with either rosuvastatin (50, 100 or 200 mg/kg) or probenecid (100 mg/kg) alone, or with a combination of rosuvastatin (50, 100 or 200 mg/kg) and probenecid (100 mg/kg). Skeletal muscle toxicity was elevated with probenecid administered with 200 mg/kg/day of rosuvastatin, with the elevation of creatine kinase by 12-fold, alanine aminotrasferase by 10-fold and creatinine by 9-fold at day 15, with no adverse effects observed when probenecid was given alone. Mitochondria ultrastructural damage with enlargement, disruption, cristolysis and vaculation was seen in the soleus and plantaris of animals administered with probenecid and high dosages of statin. These muscles were also expressing more succinic dehydrogenase (SDH)-positive and cytochrome oxidase (CyOX)-positive fibers. Although generally well-tolerated, statins produce a variety of adverse skeletal muscle events. Hydrophilic statins, with reduced levels of non-specific passive diffusion rates into extra-hepatic tissues, are still seen to produce myopathy. This highlights the important roles of transport mechanisms in statin transport at the skeletal muscles. Excessive influx, reduced efflux or the combination of the two could result in elevated cellular levels of statins at the skeletal muscles, resulting in toxicity. This study provides preliminary evidence that the MRP-1 transporter and efflux at skeletal muscles possibly play significant roles in statin-induced myopathy.
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PMID:Role of multi-drug resistance-associated protein-1 transporter in statin-induced myopathy. 1850 83

The mechanisms responsible to the development of brain dysfunction during sepsis are not well understood. The objective of this study is to evaluate mitochondrial respiratory chain and creatine kinase activities in the brain after cecal ligation and perforation (CLP) in rats. We performed a prospective, controlled experiment in male Wistar rats. Rats were subjected to CLP (sepsis group) with saline resuscitation (at 50mL/kg immediately and 12h after cecal ligation and perforation) or sham operation (control group). Several times (0, 6, 12, 24, 48 and 96h) after CLP six rats were killed by decapitation, and brain structures (cerebellum, hippocampus, striatum and cortex) were isolated. Mitochondrial respiratory chain and creatine kinase activity were then measured. It was observed that animals submitted to CLP presented decreased mitochondrial respiratory chain activity in complex I, but not in complex II, III and IV, 24, 48 and 96h in all analyzed structures. Activity of succinate dehydrogenase was decreased in 48 and 96h in all analyzed structures. Creatine kinase activity increased after CLP in cerebellum, hippocampus and cortex (after 0h) and striatum (after 6h). Sepsis associated brain injury may include dysfunction in the mitochondrial respiratory chain activity.
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PMID:Mitochondrial respiratory chain and creatine kinase activities in rat brain after sepsis induced by cecal ligation and perforation. 1865 32


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