Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.3.5.1 (succinate dehydrogenase)
 8,177 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Incubation of aldehyde dehydrogenase-free mitochondrial preparations with biogenic amines serotonin, tyramine, 2-phenylethylamine and 5-methoxytryptamine resulted in inhibition of enzymes activity of both outer (rotenone-insensitive NADH-cytochrome c reductase) and inner (succinate dehydrogenase, succinate cytochrome c reductase) mitochondrial membranes. Solubilization of mitochondria after the incubation did not influence the amine-induced alteration of succinate dehydrogenase activity. Pretreatment of the organelles with a mixture containing chlorgyline and deprenyl completely inhibited monoamine oxidase (MAO) activity and prevented the effects of all the amines studied on mitochondrial enzymes. MAO-dependent effects of 5-methoxytryptamine were fully reproduced by 5-methoxyindolyl-3-acetaldehyde (one of probable products of 5-methoxytryptamine deamination). The effect of the aldehyde was not prevented by chlorgyline and deprenyl. After selective inhibition of MAO-A by chlorgyline the order of MAO-B-dependent effects of biogenic amines on mitochondrial enzymes studied was as follows: tyramine greater than or equal to 2-phenylethylamine much greater than serotonin. In deprenyl pretreated mitochondria the potency of MAO-A-dependent effects of these amines was: serotonin greater than tyramine much greater than much greater than 2-phenylethylamine. The data obtained suggest that the product(s) of oxidative deamination of biogenic amines (probably the aldehydes) catalyzed by both types of MAO (MAO-A and MAO-B) are able to regulate the energy functions of mitochondria.
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PMID:[The role of monoamine oxidase in the regulation of mitochondrial energy functions]. 175 90

The effect of age upon monoamine oxidase -A and -B (MAO-A and -B) in 23 different, regions of human brain was determined. There was a significant positive correlation with age in 19 out of 23 regions for MAO-B, but no positive correlation with age was found for MAO-A. The increased MAO-B activity was found, in 5 out of 5 regions tested, to be due entirely to an increased enzyme concentration, rather than due to an increased molecular turnover number of the enzyme. The responses of the mitochondrial marker enzymes succinate dehydrogenase (SDH) and malate dehydrogenase (MDH) were studied in 5 brain regions, and no consistent change in activity found with age. The lysosomal enzyme acid phosphatase was found to tend towards an increased activity with age. No difference in either the specific activities or molecular characteristics of MAO were found between men and women. Cross-correlation studies of the data, after compensation for the effects of age, indicated that the activities of the two enzyme forms are under some form of organized control across the whole brain. Such a finding is consistent with a genetic regulation of the enzyme forms.
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PMID:The effect of age on the activity and molecular properties of human brain monoamine oxidase. 744 Dec 34

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), has been demonstrated to cause selective neurotoxicity by inhibiting complex I in mitochondria, through its toxic metabolite 1-methyl-4-phenylpyridine (MPP+) which is formed during the bioactivation of MPTP by monoamine oxidase B. In this report, we have evaluated the effect of MPP+ on the 4 mitochondrial respiratory chain complexes by incubating brain mitochondria of mice at 3 different age groups with MPP+ (200 microM) and monitoring enzyme activities of complexes I, II, III, and IV at 5, 10, 15, 30, 60, and 120 min. Complexes I, III, and IV showed significant inhibition within 15 min in all the age groups studied, followed by some recovery in enzyme activities upon further incubation for complexes I and IV. However, complex II was not affected by MPP+ at any age. Our data suggest that inhibition of complexes I, III, and IV by MPP+ efficiently restrict the transport of electrons down the respiratory chain which ultimately leads to decreased ATP production. This could further aggravate oxidative stress as ATP is required for the synthesis of glutathione (GSH), one of the important scavengers of free radicals. In this study, inhibition was more severe in mitochondrial preparations from older rather than younger mice. Additionally, young animals showed faster recovery following inhibition than old animals for complex I. Impaired respiratory chain function in older animals compared to younger ones supports the hypothesis of accumulation of age-related mitochondrial DNA mutations which partly encode for subunits of complexes I, III, and IV. From this study, it seems that inhibition of complexes I, III, and IV may be the underlying cause of neurotoxicity due to MPP+ which could be intensified by age-associated dysfunction of electron transport.
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PMID:MPP(+)-induced neurotoxicity in mouse is age-dependent: evidenced by the selective inhibition of complexes of electron transport. 873 16

Intrastriatal administration of the succinate dehydrogenase (SDH) inhibitor malonate produces neuronal injury by a "secondary excitotoxic" mechanism involving the generation of reactive oxygen species (ROS). Recent evidence indicates dopamine may contribute to malonate-induced striatal neurodegeneration; infusion of malonate causes a pronounced increase in extracellular dopamine and dopamine deafferentation attenuates malonate toxicity. Inhibition of the catabolic enzyme monoamine oxidase (MAO) also attenuates striatal lesions induced by malonate. In addition to forming 3,4-dihydroxyphenylacetic acid, metabolism of dopamine by MAO generates H2O2, suggesting that dopamine metabolism may be a source of ROS in malonate toxicity. There are two isoforms of MAO, MAO-A and MAO-B. In this study, we have investigated the role of each isozyme in malonate-induced striatal injury using both pharmacological and genetic approaches. In rats treated with either of the specific MAO-A or -B inhibitors, clorgyline or deprenyl, respectively, malonate lesion volumes were reduced by 30% compared to controls. In knock-out mice lacking the MAO-A isoform, malonate-induced lesions were reduced by 50% and protein carbonyls, an index ROS formation, were reduced by 11%, compared to wild-type animals. In contrast, mice deficient in MAO-B showed highly variable susceptibility to malonate toxicity precluding us from determining the precise role of MAO-B in this form of brain damage. These findings indicate that normal levels of MAO-A participate in expression of malonate toxicity by a mechanism involving oxidative stress.
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PMID:Striatal damage and oxidative stress induced by the mitochondrial toxin malonate are reduced in clorgyline-treated rats and MAO-A deficient mice. 1509 36

The aim of the study was the estimation of structural and metabolic changes in histaminergic neurons of rat hypothalamic E2 nucleus induced by total external bile drainage. The investigation was carried out on male Wistar rats (n=45). The control group comprised the sham-operated animals, in which the physiological bile drainage was preserved during the whole experimental period. Quantitative histological and histochemical methods were used. In serial frontal cryostat sections of posterior hypothalamus, the activity of the following enzymes was demonstrated histochemically: monoamine oxidase B, succinate dehydrogenase, NADH- dehydrogenase, NADPH-dehydrogenase, glucose-6-phosphate dehydrogenase, lactate dehydrogenase and acid phosphatase. Morphometric study of histaminergic neurons was performed in thionin-stained sections. It was found that total external bile drainage resulted in a temporary reduction of the sizes and rounding of neuronal perikarya. Metabolic changes were detected already after 1 day of bile loss, and they were found to progress henceforth. All the pathways of energy metabolism were suppressed, while the acid phosphatase activity was increased, on day 5.
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PMID:[Structural and metabolic changes in the rat hypothalamic histaminergic neurons induced by the bile loss]. 1841 18

The aim of the present work was to assess metabolic changes in histaminergic neurons in the rat brain during subhepatic cholestasis. Studies were performed on male Wistar rats using quantitative histochemical methods. The results showed that in cholestasis, histaminergic neurons in the rat hypothalamus developed significant changes in succinate dehydrogenase, lactate dehydrogenase, and glucose-6-phosphate dehydrogenase activity, in NADH and NADPH, and in acid phosphatase and monoamine oxidase B. These changes depended on the duration of cholestasis and had a dynamic, wave-like nature. The changes were apparent after five days of cholestasis, reached a maximum at 10-20 days, decreased at 45 days, and completely disappeared at 90 days.
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PMID:Metabolic changes in rat brain histaminergic neurons during subhepatic cholestasis. 1880 67

The aim of the present work was to evaluate structural and metabolic changes in histaminergic neurons in hypothalamic nucleus E2 in rats in conditions of complete external drainage of bile. Studies were performed on male Wistar rats (n = 45). Controls consisted of animals subjected to sham surgery with preservation of physiological bile flow throughout the experiment. Quantitative histological and histochemical methods were used. Serial frontal cryostat sections cut from the posterior hypothalamus were used for detection of the activity of the following enzymes: monoamine oxidase B, succinate dehydrogenase, NADH dehydrogenase, NADPH dehydrogenase, glucose-6-phosphate dehydrogenase, lactate dehydrogenase, and acid phosphatase. Morphological studies of histaminergic neurons were performed on preparations stained with thionine. These studies showed that complete external drainage of bile led to transient size reductions and rounding of cell perikarya. Metabolic changes were seen within a day of bile loss and subsequently progressed. All energy metabolic pathways were suppressed and acid phosphatase activity was increased on day 5.
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PMID:Structural-metabolic changes in histaminergic neurons of the rat hypothalamus in conditions of loss of bile. 1897 11

We previously demonstrated that spare respiratory capacity of the TCA cycle enzyme alpha-ketoglutarate dehydrogenase (KGDH) was completely abolished upon increasing levels of MAO-B activity in a dopaminergic cell model system (Kumar et al., J Biol Chem 278:46432-46439, 2003). MAO-B mediated increases in H(2)O(2) also appeared to result in direct oxidative inhibition of both mitochondrial complex I and aconitase. In order to elucidate the contribution that each of these components exerts over metabolic respiratory control as well as the impact of MAO-B elevation on their spare respiratory capacities, we performed metabolic respiratory control analysis. In addition to KGDH, we assessed the activities and substrate-mediated respiration of complex I, pyruvate dehydrogenase (PDH), succinate dehydrogenase (SDH), and mitochondrial aconitase in the absence and presence of complex-specific inhibitors in specific and mixed substrate conditions in mitochondria from our MAO-B elevated cells versus controls. Data from this study indicates that Complex I and KGDH are the most sensitive to inhibition by MAO-B mediated H(2)O(2) generation, and could be instrumental in determining the fate of mitochondrial metabolism in this cellular PD model system.
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PMID:Metabolic control analysis in a cellular model of elevated MAO-B: relevance to Parkinson's disease. 1952 85

The trends of novel AD therapeutics are focused on multitarget-directed ligands (MTDLs), which combine cholinesterase inhibition with additional biological properties such as antioxidant properties to positively affect neuronal energy metabolism as well as mitochondrial function. We examined the in vitro effects of 10 novel MTDLs on the activities of mitochondrial enzymes (electron transport chain complexes and citrate synthase), mitochondrial respiration, and monoamine oxidase isoform (MAO-A and MAO-B) activity. The drug-induced effects of 7-MEOTA-adamantylamine heterodimers (K1011, K1013, K1018, K1020, and K1022) and tacrine/7-MEOTA/6-chlorotacrine-trolox heterodimers (K1046, K1053, K1056, K1060, and K1065) were measured in pig brain mitochondria. Most of the substances inhibited complex I- and complex II-linked respiration at high concentrations; K1046, K1053, K1056, and K1060 resulted in the least inhibition of mitochondrial respiration. Citrate synthase activity was not significantly inhibited by the tested substances; the least inhibition of complex I was observed for compounds K1060 and K1053, while both complex II/III and complex IV activity were markedly inhibited by K1011 and K1018. MAO-A was fully inhibited by K1018 and K1065, and MAO-B was fully inhibited by K1053 and K1065; the other tested drugs were partial inhibitors of both MAO-A and MAO-B. The tacrine/7-MEOTA/6-chlorotacrine-trolox heterodimers K1046, K1053, and K1060 seem to be the most suitable molecules for subsequent in vivo studies. These compounds had balanced inhibitory effects on mitochondrial respiration, with low complex I and complex II/III inhibition and full or partial inhibition of MAO-B activity.
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PMID:Effects of Novel Tacrine Derivatives on Mitochondrial Energy Metabolism and Monoamine Oxidase Activity-In Vitro Study. 3308 24