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)

We measured the activities of five respiratory chain enzymes in brain macrophages/microglial cells from Lewis rats with experimental autoimmune encephalomyelitis (EAE) and found a significant reduction of the activity of nicotinamide adenine dinucleotide-dehydrogenase (NADH-DH), succinate cytochrome c reductase (SCCR) and succinate dehydrogenase (SDH) when compared with age-matched healthy control animals. The inhibition of NADH-DH (complex I) was specific for EAE, while we also found a reduction of SCCR and SDH activities (complex II) in newborn rats and adjuvant-immunised rats. Activities of NADH cytochrome c reductase (NCCR) and cytochrome c oxidase (COX) were not significantly changed. These observations demonstrate an impairment of brain macrophage/microglial respiratory chain function in central nervous system inflammation.
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PMID:Inhibition of brain macrophage/microglial respiratory chain enzyme activity in experimental autoimmune encephalomyelitis of the Lewis rat. 772 46

Huntington's disease (HD) is a prototypical neurodegenerative disease characterized by selective loss of neurons in the basal ganglia. Although the gene defect has recently been identified, the mechanism by which it leads to neuronal degeneration remains unknown. We have hypothesized that a defect in oxidative phosphorylation may lead to slow, excitotoxic neuronal degeneration in this illness. Evidence for such a defect is reviewed here, including our recent studies using magnetic resonance imaging spectroscopy that show elevated lactate levels in the basal ganglia and cerebral cortex of patients with HD. If a defect in energy metabolism is responsible for neuronal degeneration in HD, it should be possible to mimic the neurodegenerative process with mitochondrial toxins. Our recent studies with 3-nitropropionic acid, an irreversible inhibitor of succinate dehydrogenase, show that it can produce striking similarities to the neuropathologic and neurochemical features of HD in both rodents and primates. If such a mechanism is indeed relevant to the pathogenesis of HD, then agents that can improve oxidative phosphorylation might prove to be efficacious. We found that both coenzyme Q10 and nicotinamide can ameliorate striatal lesions produced by mitochondrial toxins in vivo. Furthermore, they reduced elevated lactate concentrations when administered to patients with HD. This finding raises the possibility that such an approach might prove useful in trying to slow the neurodegenerative process.
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PMID:Neurochemistry and toxin models in Huntington's disease. 786 87

Ischemia/reperfusion mechanisms contribute to lung injury after transplantation, pulmonary embolism, and resolution of atelectasis. Alveolar tissue becomes hypoxic and deprived of substrate only when both ventilation and perfusion are interrupted, a situation modeled in vivo by complete, unilateral lung collapse. Because previously hypoxic mitochondria may be an important intracellular source of superoxide and hydrogen peroxide (H2O2) during reperfusion and re-oxygenation, the authors, in this study, investigated whether mitochondrial H2O2 release changed as a result of lung hypoxia/hypoperfusion resulting from collapse. Mitochondria were isolated from hypoxic (previously collapsed) right or contralateral left rabbits' lungs and from control rabbits' lungs. Mitochondrial H2O2 release, a marker of superoxide production, was measured fluorometrically after incubation with or without 1 mmol/L cyanide and 0.1 mmol/L nicotinamide adenine dinucleotide. Mitochondrial recovery was determined by assaying succinate dehydrogenase activity in mitochondrial preparations and lung homogenates. Lung succinate dehydrogenase activity and mitochondrial recovery were comparable among groups. Calculated lung mitochondrial content did not change (control subjects: left 7.9 +/- 0.5, right 13.8 +/- 1.7; hypoxic: left 10.3 +/- 1.3, right 10.5 +/- 2.4, all mg mitochondrial protein/lung). Mitochondria released hydrogen peroxide at approximately 5.6 nmol/h/mg pro in buffer alone and 14.8 nmol/h/mg pro in buffer with cyanide and nicotinamide adenine dinucleotide. However, lung collapse and resulting hypoxia caused no change in mitochondrial number or capacity to release H2O2 in vitro. Based on these findings, it is suggested that other sources of reactive oxygen metabolites, including xanthine oxidase and activated neutrophils, contribute to the oxidant injury observed in this model.
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PMID:Hydrogen peroxide release by mitochondria from normal and hypoxic lungs. 794 83

An 11-year-old girl with exercise intolerance, fatiguability from early childhood, had high blood lactate levels. Histochemistry showed increased activity of succinate dehydrogenase at the periphery of the muscle fibres, whereas aggregates of mitochondria were seen by electron microscopy. Biochemical investigation of isolated mitochondria and homogenate from muscle showed evidence of a severe complex I deficiency. In contrast, succinate dehydrogenase, complex II+III and complex IV were increased in activity. Therapy with biotin, riboflavin, nicotinamide, carnitine and amino acids resulted in an improvement of her endurance. 31P NMR spectroscopy of her forearm muscle showed a decreased ratio of phosphocreatine (PCr) over ATP. After exercise the PCr recovery rate was 26% of the average rate in 20 healthy untrained controls. When the therapy was suspended the PCr/ATP ratio at rest decreased from 2.60 to 2.34, and the PCr recovery rate after exercise decreased to 21% of the average control rate. The therapy was reinstituted but only riboflavin and carnitine were given. The PCr/ATP ratio increased to 2.60 and the PCr recovery rate increased to 32% of the control rate. Improvement of the energy metabolism in patients with defects in the oxidative phosphorylation may add to the quality of life; 31P NMR spectroscopy can measure these improvements.
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PMID:Vitamin-responsive complex I deficiency in a myopathic patient with increased activity of the terminal respiratory chain and lactic acidosis. 796 74

A potential mechanism of neuronal injury in neurodegenerative diseases is a defect in energy metabolism that may lead to slow excitotoxic neuronal death. Consistent with this possibility, we showed that specific inhibitors of the electron transport chain produce excitotoxic lesions in vivo. In the present study we examined whether agents that improve energy metabolism can block lesions produced by the mitochondrial toxin malonate. Striatal lesions produced by the complex II inhibitor malonate were blocked in a dose-dependent manner by oral pretreatment with coenzyme Q10. Administration of nicotinamide by Alzet pump for 1 week attenuated malonate-induced lesions, but riboflavin had no effect. Administration of nicotinamide intraperitoneally just prior to and following induction of the lesions produced dose-dependent neuroprotection. A combination of coenzyme Q10 with nicotinamide was more effective than either compound alone, as shown by both lesion size and magnetic resonance imaging in vivo. Both coenzyme Q10 and nicotinamide blocked adenosine triphosphate depletions and lactate increases. These results confirm that mitochondrial toxins produce striatal excitotoxic lesions by a mechanism involving energy depletion in vivo. Furthermore, they suggest novel neuroprotective strategies that may be useful in the treatment of both mitochondrial encephalopathies and neurodegenerative diseases.
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PMID:Coenzyme Q10 and nicotinamide block striatal lesions produced by the mitochondrial toxin malonate. 799 75

Little is known about the alterations of metabolic organization of the human liver tissue in chronic liver diseases. We therefore compared the distribution of the following zonal metabolic markers in 10 samples of normal liver tissue, 10 samples of fibrotic tissue, and 22 samples of cirrhotic tissue: (a) the enzymatic activities of glucose-6-phosphatase (G6P), lactate dehydrogenase (LDH), succinate dehydrogenase (SDH), nicotinamide-adenine-dinucleotide-phosphate [NAPH] dehydrogenase (ND), beta-hydroxybutyrate dehydrogenase (HBDH), and glutamate dehydrogenase (GDH); (b) the protein glutamine synthetase (GLS); and (c) albumin messenger RNA (mRNA). The normal human hepatic lobule was characterized by the periportal predominance of G6P and SDH enzymatic activities and albumin mRNAs, the perivenous predominance of ND and GDH, the restriction of GLS to a small perivenous compartment, and the predominanc of beta-HBDH at the contact of both portal tracts and centrilobular veins. In fibrosis, the overall metabolic organization of the normal liver tissue was retained. The expression of periportal markers predominated around enlarged portal tracts and that of perivenous markers around residual centrilobular veins. GLS was constantly detected at the contact of centrilobular veins. In cirrhotic nodules, no zonation was observed for most enzymatic activities or for albumin. Only G6P usually predominated at the periphery of the nodules. GLS was constantly undetectable. No difference accordingly to the etiology of the underlying disease was observed. In conclusion, the normal human hepatic lobule presents a marked metabolic zonation, preserved in fibrotic lesions, but lost in cirrhotic nodules. The alterations of the metabolic organization observed in cirrhosis might contribute to the pathogenesis of some of the metabolic disorders associated with advanced liver disease.
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PMID:The metabolic organization of the adult human liver: a comparative study of normal, fibrotic, and cirrhotic liver tissue. 870 47

A 13 year-old girl with scoliosis and central core disease is reported. She was noted to have mild psychomotor developmental delay since early infancy. Scoliosis with minimal muscle weakness was noted at about five years old. The neurological examination disclosed absent knee jerk. The spine MRI showed no significant finding. The serum CK revealed 518 U/L. The muscle biopsy obtained from the quadriceps femoris muscle showed Type 1 fiber atrophy and predominance, as is commonly seen in congenital myopathies. Under nicotinamide adenine dinucleotide dehydrogenase (NADH) and succinate dehydrogenase (SDH) stains, core structures were identified and the diagnosis of central core disease (CCD) was made. Since kyphoscoliosis usually becomes prominent as muscle weakness progresses to loss of ambulation in other myopathies, the disproportionate spinal involvement in central core disease appears to be a striking feature. We suggest that all patients with idiopathic scoliosis deserve a thorough neurological evaluation if congenital myopathies are suspected. Muscle biopsy should also be recommended for a confirmatory diagnosis even if only minimal muscle weakness present. Besides, early detection of CCD helps us to identify the population who are at a higher risk for malignant hyperthermia.
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PMID:Central core disease associated with scoliosis: report of one case. 929 32

Our previous studies in iron-loaded rat heart cells showed that in vitro iron loading results in peroxidative injury, manifested in a marked decrease in rate and amplitude of heart cell contractility and rhythmicity, which is correctable by treatment with deferoxamine (DF). In the present studies we explored the role of mitochondrial damage in myocardial iron toxicity. Iron loading by 24-hour incubation with 0.36 mmol/L ferric ammonium citrate resulted in a decrease in the activity of nicotinamide adenine dinucleotide (NADH)-cytochrome c oxidoreductase (complex I+III) to 35.3%+/-11.2% of the value in untreated controls; of succinate-cytochrome c oxidoreductase (complex II+III) to 57.4%+/-3.1%; and of succinate dehydrogenase to 63.5%+/-12.6% (p < 0.001 in all cases). The decrease in activity of other mitochondrial enzymes, including NADH-ferricyanide reductase, succinate ubiquinone oxidoreductase (complex II), cytochrome c oxidase (complex IV), and ubiquinol cytochrome c oxidoreductase (complex III), was less impressive and ranged from 71.5%+/-15.8% to 91.5%+/-14.6% of controls. That the observed loss of respiratory enzyme activity was a specific effect of iron toxicity was clearly demonstrated by the complete restoration of enzyme activities by in vitro iron chelation therapy. Sequential treatment with iron and doxorubicin caused a loss of complex I+III and complex II+III activity that was greater than that seen with either agent alone but was only partially correctable by DF treatment. Alterations in cellular adenosine triphosphate measurements paralleled very closely the changes observed in respiratory complex activity. These findings demonstrate for the first time the impairment of cardiac mitochondrial respiratory enzyme activity caused by iron loading at conditions formerly shown to produce severe abnormalities in contractility and rhythmicity.
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PMID:Mitochondrial respiratory enzymes are a major target of iron toxicity in rat heart cells. 960 12

To better evaluate the role of a possible mitochondrial alteration in the pathogenesis of cleft lip, we obtained and examined 38 orbicularis oris muscle specimens taken from the cleft margin of both cleft and noncleft sides of 10 unilateral cleft lip infants at the time of primary closure. Part of each sample was frozen in liquid nitrogen/cooled isopentane, while the remainder was fixed in 2.5% glutaraldehyde, postfixed in osmium tetroxide, and embedded in Araldyte resin. Ten-micrometer-thick sections were obtained from the frozen samples and stained for histologic (Gomori trichrome) and histochemical (adenosine triphosphatase, nicotinamide adenine dinucleotide-tetrazolium reductase, cytochrome c-oxidase, succinate dehydrogenase) techniques. Ultra-thin sections (70 to 100 nm) of the resin-embedded specimens were stained with uranyl acetate and lead cytrate and were examined with a Zeiss 109 transmission electron microscope operating at 80 kV. Muscular fiber-type ratio was found to be 19.2 percent type 1 and 80.8 percent type 2 fibers on the cleft side and 26.3 percent type 1 and 73.7 percent type 2 fibers on the noncleft side. We detected aspecific structural alterations, such as variations in the fiber size without fiber group atrophy or fiber-type grouping with the ATPase reaction, in all biopsies. Although Gomori trichrome revealed a dark staining and red granularity of the fibers, suggesting an increase in mitochondria activity, no ragged-red fibers or cytochrome c-oxidase-negative/succinate dehydrogenase-positive fibers were found. At the ultrastructural level, the mitochondrial morphology was always preserved, without inclusions or variations in size and/or shape. On the other hand, we invariably noticed an increase of the number of mitochondria, associated with abnormal glycogen deposits, in some areas of every specimen. Both of these two latter findings were regularly localized at the periphery of the sarcolemma, resembling the so-called lobulated fibers, an aspecific sign of muscular flogosis. Our findings, although excluding an inherent metabolic myopathy of orbicularis oris muscle in unilateral cleft lip patients, evinced both an increased oxidative metabolism and a generic inflammatory condition of that muscle, the nature of which must still be defined.
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PMID:Mitochondrial activity of orbicularis oris muscle in unilateral cleft lip patients. 973 10

Because mitochondrial inner membrane respiratory complexes are important targets of iron toxicity, we used iron-loaded rat heart cells in culture to study the beneficial effect on mitochondrial enzymes of the iron chelators deferoxamine (DFO) and deferiprone (L1) and of antioxidants and reducing agents (ascorbate and alpha-tocopherol). Reduced nicotinamide adenine dinucleotide-cytochrome c oxidoreductase (complex I-III) and succinate dehydrogenase were the most-sensitive indicators of iron toxicity and cardioprotective effect. Although at concentrations below 0.3 mmol/L the iron-mobilizing effect of L1 was less than that of DFO, both were equally effective in protecting or restoring mitochondrial respiratory enzyme activity. At 1.0 mmol/L, L1 toxicity was manifested in respiratory enzyme inhibition, whereas DFO had no such effect. Ascorbate (0.057 to 5.7 mmol/L) had a mild cardioprotective effect at the highest concentration only, in association with decreased cellular iron uptake. By contrast, alpha-tocopherol (0.023 mmol/L) completely inhibited mitochondrial iron toxicity without affecting iron uptake or release, and irrespective of whether it was used before, during, or after in vitro iron loading. These observations illustrate the usefulness and limitations of iron chelators and other agents used for preventing iron toxicity to the heart and other vital organs, and they underline the need for exploring in more detail the effects of these agents in the clinical setting.
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PMID:Cardioprotective effect of alpha-tocopherol, ascorbate, deferoxamine, and deferiprone: mitochondrial function in cultured, iron-loaded heart cells. 998 70


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