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)

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

Duodenal mitochondria were isolated from broiler breeder males with high (0.79+/-0.01, n = 9) and low (0.63+/-0.02, n = 9) feed efficiency (FE) to assess relationships of FE with duodenal mitochondrial function and site-specific defects in electron transport. Sequential additions of adenosine diphosphate (ADP) resulted in 1) higher respiratory control ratio (RCR; an index of respiratory chain coupling) in high FE mitochondria provided succinate, and 2) higher ADP to oxygen ratio (ADP:O; an index of oxidative phosphorylation) in low FE mitochondria provided NADH-linked substrates (malate, pyruvate, or both). Basal electron leak, measured as H2O2 production, was greater in low FE mitochondria provided succinate (P = 0.08) or NADH-linked substrates. As H2O2 levels were elevated in low FE compared with high FE mitochondria by complex I (P+/-0.07) and complex II inhibition, the higher basal electron leak in low FE mitochondria was apparently due to site-specific defects in electron transport at complexes I and II. Elevations in H2O2 above basal levels indicated that high FE mitochondria may also exhibit electron transport defects at complexes I and III. Despite an ability to produce adenosine triphosphate (ATP) that was equal or superior to that demonstrated in high FE duodenal mitochondria, low FE mitochondria exhibited a greater inherent degree of electron leak. The results provide insight into the role that duodenal mitochondria play in the phenotypic expression of FE in broilers.
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PMID:Determination of mitochondrial function and site-specific defects in electron transport in duodenal mitochondria in broilers with low and high feed efficiency. 1533 16

3-nitropropionic acid (3-NPA), a complex II inhibitor of the electron transport chain, causes Huntington disease-like symptoms after administration into animals. However, primary mechanisms of cell death are not clearly understood. This study tested the hypothesis that 3-NPA leads to the generation of reactive oxygen species (ROS), mitochondrial DNA damage, and loss of mitochondrial function. Amplex red and horseradish peroxidase were used to accurately measure the amount of H2O2, and showed that PC12 cells treated with 3-NPA (4 mM) lead to the production of hydrogen peroxide (1 nmol/10(6) cells/h). This amount of 3-NPA also leads to a rapid decline of ATP levels. There was time- and dose-dependent mitochondrial DNA damage following 3-NPA treatment. Overexpression of the proto-oncogene bcl-2 protects cells from apoptosis induced by various stimuli. Overexpression of Bcl-2 leads to almost threefold higher levels of ATP and also decreased the 3-NPA-mediated induction of hydrogen peroxide by over 50%. Bcl-2-overexpressing PC12 cells were also protected from mitochondrial DNA damage. These data show that ROS production followed by mitochondrial DNA damage is the primary event in 3-NPA toxicity, and Bcl-2 protects PC12 cells from 3-NPA toxicity by preventing mitochondrial DNA damage.
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PMID:3-nitropropionic acid-induced hydrogen peroxide, mitochondrial DNA damage, and cell death are attenuated by Bcl-2 overexpression in PC12 cells. 1571 Feb 38

Age-related changes in mitochondrial H2O2 release (MHR) could be responsible for an increase in oxidative stress in skeletal muscle and participate in the development of sarcopenia. We compared MHR in vastus lateralis biopsies obtained from young (23.5+/-2.0 year, n=6) and elderly (67.3+/-1.5 year, n=6) healthy sedentary men. Isolated mitochondria were incubated in the presence of glutamate/malate/succinate, with or without rotenone. Muscle fat oxidative capacity, citrate synthase, complex II, complex III, and cytochrome c oxidase activities were also measured. In parallel, we analyzed in gastrocnemius of young male Wistar rats (n=6), the impact of lidocaine (local anesthetic used in humans) on mitochondrial respiration and MHR. In humans, muscle oxidative capacity was preserved with age but muscle MHR was markedly enhanced in elderly subjects compared to young adults (+175%, P<0.05). Rotenone abolished this increase, demonstrating that it was due to a free radical release during reverse electron transfer from complex II towards complex I. Lidocaine can interfere with MHR measurements (intra-muscular injection in rats) but it can be avoided by minimizing contact with muscle (small multiple subcutaneous injections in humans). Physiologic consequences of the observed increase in muscle MHR with aging remain to be determined.
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PMID:Due to reverse electron transfer, mitochondrial H2O2 release increases with age in human vastus lateralis muscle although oxidative capacity is preserved. 1572 9

Mitochondrial respiratory chain enzyme Complexes are present in placenta at proportion similar to other tissues with exception of glycerophosphate dehydrogenase (mGPDH) which is expressed at a very high rate. As shown by Western blot quantification and respiratory chain enzyme activity measurements, the specific content of mGPDH is similar to that of succinate dehydrogenase or NADH dehydrogenase. Using fluorometric probe dichlorodihydrofluorescein diacetate we found that placental mitochondria display high rate of glycerophosphate-dependent hydrogen peroxide production. This was confirmed by oxygraphic detection of glycerophosphate-induced, KCN- or antimycin A-insensitive oxygen uptake. Hydrogen peroxide production by mGPDH was highly activated by one-electron acceptor, potassium ferricyanide and it was depressed by inhibitors of mGPDH and by cytochrome c. Our results indicate that mGPDH should be considered as an additional source of reactive oxygen species participating in induction of oxidative stress in placenta.
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PMID:Specific properties of heavy fraction of mitochondria from human-term placenta - glycerophosphate-dependent hydrogen peroxide production. 1594 44

Variations in broiler growth and efficiency have been explained in part by differences in mitochondrial function and biochemistry in broilers. To further our knowledge in this regard, 2 experiments were carried out to determine the relationships of a) mitochondrial function and activities of various electron transport chain (ETC) complexes; b) production of H2O2, a reactive oxygen species (ROS), and its association with protein oxidation; and c) mitochondrial protein expression in liver of a single line male broilers with low or high feed efficiency (FE, n = 5 to 8 per group). Mitochondrial function and complex activities were measured polarographically and spectrophotometrically, respectively. H2O2 was measured fluorimetrically, whereas oxidized protein (carbonyls) and specific mitochondrial proteins were analyzed using Western blots. Mitochondrial function (ETC coupling) and activities of ETC complexes (I, II, III, and IV) were higher in high FE compared with low FE broilers. H2O2 and protein carbonyls were higher in the livers of low FE broilers than in high FE broilers. Whereas the expression of 4 immunoreactive proteins [NAD3 (complex I), subunit VII (complex III), cytochrome c oxidase subunits (COX) II, and COX IVb (complex IV)] were higher in low FE liver mitochondria and 2 proteins [subunit 70 (complex II) and a-ATP synthase (complex V)] were higher in high FE birds, there were no differences between groups in the expression of 18 other mitochondrial proteins. In conclusion, increases in oxidative stress in low FE broilers were caused by or may contribute to differences in mitochondrial function (ETC coupling and complex activities) or the differential expression of steady-state levels of some mitochondrial proteins in the liver. Understanding the role of oxidative stress in Low FE broilers will provide clues in understanding the cellular basis of feed efficiency.
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PMID:Compromised liver mitochondrial function and complex activity in low feed efficient broilers are associated with higher oxidative stress and differential protein expression. 1597 33

Phosphorylation of the light-harvesting chlorophyll a/b complex II (LHC II) proteins is induced in light via activation of the LHC II kinase by reduction of cytochrome b(6)f complex in thylakoid membranes. We have recently shown that, besides this activation, the LHC II kinase can be regulated in vitro by a thioredoxin-like component, and H2O2 that inserts an inhibitory loop in the regulation of LHC II protein phosphorylation in the chloroplast. In order to disclose the complex network for LHC II protein phosphorylation in vivo, we studied phosphorylation of LHC II proteins in the leaves of npq1-2 and npq4-1 mutants of Arabidopis thaliana. In comparison to wild-type, these mutants showed reduced non-photochemical quenching and increased excitation pressure of Photosystem II (PS II) under physiological light intensities. Peculiar regulation of LHC II protein phosphorylation was observed in mutant leaves under illumination. The npq4-1 mutant was able to maintain a high amount of phosphorylated LHC II proteins in thylakoid membranes at light intensities that induced inhibition of phosphorylation in wild-type leaves. Light intensity-dependent changes in the level of LHC II protein phosphorylation were smaller in the npq1-2 mutant compared to the wild-type. No significant differences in leaf thickness, dry weight, chlorophyll content, or the amount of LHC II proteins were observed between the two mutant and wild-type lines. We propose that the reduced capacity of the mutant lines to dissipate excess excitation energy induces changes in the production of reactive oxygen species in chloroplasts, which consequently affects the regulation of LHC II protein phosphorylation.
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PMID:LHC II protein phosphorylation in leaves of Arabidopsis thaliana mutants deficient in non-photochemical quenching. 1604 77

Experimental and clinical studies support the view that the semisynthetic tetracycline minocycline exhibits neuroprotective roles in several models of neurodegenerative diseases, including ischemia, Huntington, Parkinson diseases, and amyotrophic lateral sclerosis. However, recent evidence indicates that minocycline does not always present beneficial actions. For instance, in an in vivo model of Huntington's disease, it fails to afford protection after malonate intrastriatal injection. Moreover, it reverses the neuroprotective effect of creatine in nigrostriatal dopaminergic neurons. This apparent contradiction prompted us to analyze the effect of this antibiotic on malonate-induced cell death. We show that, in rat cerebellar granular cells, the succinate dehydrogenase inhibitor malonate induces cell death in a concentration-dependent manner. By using DFCA, monochlorobimane and 10-N-nonyl-Acridin Orange to measure, respectively, H2O2-derived oxidant species and reduced forms of GSH and cardiolipin, we observed that malonate induced reactive oxygen species (ROS) production to an extent that surpasses the antioxidant defense capacity of the cells, resulting in GSH depletion and cardiolipin oxidation. The pre-treatment for 4 h with minocycline (10-100 microM) did not present cytoprotective actions. Moreover, minocycline failed to block ROS production and to abrogate malonate-induced oxidation of GSH and cardiolipin. Additional experiments revealed that minocycline was also unsuccessful to prevent the mitochondrial swelling induced by malonate. Furthermore, malonate did not induce the expression of the iNOS, caspase-3, -8, and -9 genes which have been shown to be up-regulated in several models where minocycline resulted cytoprotective. In addition, malonate-induced down-regulation of the antiapoptotic gene Bcl-2 was not prevented by minocycline, controversially the mechanism previously proposed to explain minocycline protective action. These results suggest that the minocycline protection observed in several neurodegenerative disease models is selective, since it is absent from cultured cerebellar granular cells challenged with malonate.
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PMID:Minocycline fails to protect cerebellar granular cell cultures against malonate-induced cell death. 1624 43

Mice that lack the mitochondrial form of superoxide dismutase (SOD2) incur severe pathologies and mitochondrial deficiencies, including major depletion of complex II, as a consequence of buildup of endogenous reactive oxygen species (Melov, S., Coskun, P., Patel, M., Tuinstra, R., Cottrell, B., Jun, A. S., Zastawny, T. H., Dizdaroglu, M., Goodman, S. I., Huang, T. T., Miziorko, H., Epstein, C. J., and Wallace, D. C. (1999) Proc. Natl. Acad. Sci. U. S. A. 96, 846-851 and Li, Y., Huang, T. T., Carlson, E. J., Melov, S., Ursell, P. C., Olson, J. L., Noble, L. J., Yoshimura, M. P., Berger, C., Chan, P. H., Wallace, D. C., and Epstein, C. J. (1995) Nat. Genet. 11, 376-381). These problems can be greatly attenuated or rescued by synthetic antioxidant treatment, such as with the catalytic antioxidant EUK189 (Hinerfeld, D., Traini, M. D., Weinberger, R. P., Cochran, B., Doctrow, S. R., Harry, J., and Melov, S. (2004) J. Neurochem. 88, 657-667). We have used heart mitochondria from sod2 null mice to better understand mitochondrial reactive oxygen species production both in the absence of SOD2 and following in vivo antioxidant treatment. Isolated heart mitochondria from 5-day-old sod2 null animals respiring on the complex II substrate succinate exhibited statistically significant higher levels of mitochondrial O2* (157%, p < 0.01) but significantly less H2O2 (33%, p < 0.001) than wild type littermates. Treatment of sod2 nullizygous mice with EUK189 proportionately increased the levels of complex II and H2O2. Increased production of O2* resulting from complex II normalization had no effect on steady state levels due to the rapid conversion to H2O2, a process presumably aided by the presence of the EUK189, an SOD mimetic.
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PMID:Mitochondrial reactive oxygen species in mice lacking superoxide dismutase 2: attenuation via antioxidant treatment. 1632 10

A deficiency in mitochondrial frataxin causes an increased generation of mitochondrial reactive oxygen species (ROS), which may contribute to the cell degenerative features of Friedreich's ataxia. In this work the authors demonstrate mitochondrial iron-sulfur cluster (ISC) defects and mitochondrial heme defects, and suggest how both may contribute to increased mitochondrial ROS in lymphoblasts from human patients. Mutant cells are deficient in the ISC-requiring mitochondrial enzymes aconitase and succinate dehydrogenase, but not in the non-ISC mitochondrial enzyme citrate synthase; also, the mitochondrial iron-sulfur scaffold protein IscU2 co-immunoprecipitates with frataxin in vivo. Presumably as a consequence of the iron-sulfur cluster defect, cytochrome c heme is deficient in mutants, as well as heme-dependent Complex IV. Mitochondrial superoxide is elevated in mutants, which may be a consequence of cytochrome c deficiency. Hydrogen peroxide, glutathione peroxidase activity, and oxidized glutathione (GSSG) are each elevated in mutants, consistent with activation of the glutathione peroxidase pathway. Mutant status blunted the effects of Complex III and IV inhibitors, but not a Complex I inhibitor, on superoxide production. This suggests that heme defects late in the electron transport chain of mutants are responsible for increased mutant superoxide. The impact of ISC and heme defects on ROS production with age are discussed.
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PMID:Frataxin, iron-sulfur clusters, heme, ROS, and aging. 1667 95


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