The binding site for oxaloacetate on succinate dehydrogenase

Vinogradov, Andrei D.; Winter, Daryl B.; King, Tsoo E.

doi:10.1016/0006-291x(72)90430-5

Cited by 39 publications

(14 citation statements)

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“…The degree of inhibition was shown to increase progressively. Our results are consistent with published data that mitochondrial deenergization is followed by a 10-fold increase in affi nity of SDH to oxaloacetate [14]. When the basic incubation medium contained glutamate (Fig.…”

Section: Resultssupporting

confidence: 95%

Effect of Bovine Serum Albumin on Mitochondrial Respiration in the Brain and Liver of Mice and Rats

et al. 2010

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We studied the effect of BSA (in the isolation medium) on the oxidation rate of succinate, glutamate, pyruvate, and α-ketoglutarate by mitochondria of the brain and liver from C57Bl/6g mice and Taconic Sprague Dawley rats. BSA had no effect on liver mitochondrial respiration, but increased oxidation of substrates (particularly of succinate) in brain mitochondria. Therefore, the major effect of BSA on brain mitochondria is manifested in activation of SDH. The improvement of mitochondrial properties in the brain after treatment with BSA is associated with antioxidant activity of this agent. Our results confirm the hypothesis that inhibition of SDH in brain mitochondria is not the artifact. This process serves as a mechanism protecting neurons from free oxygen radicals during succinate oxidation.

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Section: Resultssupporting

confidence: 95%

Effect of Bovine Serum Albumin on Mitochondrial Respiration in the Brain and Liver of Mice and Rats

et al. 2010

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“…The affinity of SDH for OAA changes with the reduction of the enzyme's sulfhydryl group depending on mitochondrial energization (51). Upon de-energization of mitochondria, the affinity of SDH to OAA increases 10-fold (51). Another important property of SDH is that, besides succinate, the enzyme can also oxidize malate with similar affinity (52).…”

Section: Discussionmentioning

confidence: 99%

The Neuromediator Glutamate, through Specific Substrate Interactions, Enhances Mitochondrial ATP Production and Reactive Oxygen Species Generation in Nonsynaptic Brain Mitochondria

Panov

Schönfeld

Dikalov

et al. 2009

Journal of Biological Chemistry

107

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The finding that upon neuronal activation glutamate is transported postsynaptically from synaptic clefts and increased lactate availability for neurons suggest that brain mitochondria (BM) utilize a mixture of substrates, namely pyruvate, glutamate, and the tricarboxylic acid cycle metabolites. We studied how glutamate affected oxidative phosphorylation and reactive oxygen species (ROS) production in rat BM oxidizing pyruvate ؉ malate or succinate. Simultaneous oxidation of glutamate ؉ pyruvate ؉ malate increased state 3 and uncoupled respiration by 52 and 71%, respectively. The state 4 ROS generation increased 100% over BM oxidizing pyruvate ؉ malate and 900% over that of BM oxidizing glutamate ؉ malate. Up to 70% of ROS generation was associated with reverse electron transport. These effects of pyruvate ؉ glutamate ؉ malate were observed only with BM and not with liver or heart mitochondria. The effects of glutamate ؉ pyruvate on succinate-supported respiration and ROS generation were not organ-specific and depended only on whether mitochondria were isolated with or without bovine serum albumin. With the non-bovine serum albumin brain and heart mitochondria oxidizing succinate, the addition of pyruvate and glutamate abrogated inhibition of Complex II by oxaloacetate. We conclude that (i) during neuronal activation, simultaneous oxidation of glutamate ؉ pyruvate temporarily enhances neuronal mitochondrial ATP production, and (ii) intrinsic inhibition of Complex II by oxaloacetate is an inherent mechanism that protects against ROS generation during reverse electron transport.Recently, it has emerged that mitochondrial dysfunctions play an important role in the pathogenesis of degenerative diseases of the central nervous system (1-3). The processes underlying neuronal degeneration are complex, and some authors suggest that several genetic alterations are involved (4). However, another level of complexity may be derived from the fact that virtually all cellular activities depend upon energy metabolism in the cell (5). Alterations in energy metabolism processes within cells may also contribute to pathogenic mechanisms underlying neurodegenerative disease.A large body of evidence suggests that increased oxidative stress is an important pathogenic mechanism that promotes neurodegeneration (6). Because neurons have a long life span, and most neurodegenerative diseases have a clear association with age (7), it is important to understand mechanisms underlying reactive oxygen species (ROS) 2 production in neurons. Recently, Kudin et al. (8) analyzed the contribution of mitochondria to the total ROS production in brain tissue. They concluded that mitochondria are the major source of ROS and that at least 50% of ROS generated by brain mitochondria was associated with succinate-supported reverse electron transport (RET). Under conditions of normoxia, about 1% of the respiratory chain electron flow was redirected to form superoxide (8).Recently, we suggested that the organization of the respiratory chain complexes into supe...

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“…1C). Such an interaction has been suggested to be responsible for the inhibition of succinate dehydrogenase by oxaloacetate (37), which, like pyruvate, is an ␣-keto acid. Oxaloacetate associates with a sulfhydryl located within the active site of the enzyme, preventing the binding of succinate, the inhibitor malonate, or NEM (38,39).…”

Section: ␣-Keto Acid Activation Of the Cyanide-resistant Oxidasementioning

confidence: 99%

The Reaction of the Soybean Cotyledon Mitochondrial Cyanide-resistant Oxidase with Sulfhydryl Reagents Suggests That α-Keto Acid Activation Involves the Formation of a Thiohemiacetal

Umbach

Siedow

1996

Journal of Biological Chemistry

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The cyanide-resistant alternative oxidase of plant mitochondria is known to be activated by ␣-keto acids, such as pyruvate, and by the reduction of a disulfide bond that bridges the two subunits of the enzyme homodimer. When the regulatory cysteines are oxidized, the inactivated enzyme is much less responsive to pyruvate than when these groups are reduced. When soybean cotyledon mitochondria were isolated in the presence of iodoacetate or N-ethylmaleimide, the intermolecular disulfide bond did not form and the alternative oxidase was present only as a noncovalently associated dimer. N-Ethylmaleimide inhibited alternative oxidase activity, but iodoacetate was found to stimulate activity much like pyruvate, including enhancing the enzyme's apparent affinity for reduced ubiquinone. The presence of pyruvate or iodoacetate blocked inhibition of the enzyme by N-ethylmaleimide, indicating that all three compounds acted at the same sulfhydryl group on the alternative oxidase protein. The site of pyruvate and iodoacetate action was shown to be a different sulfhydryl than that involved in the redox-active regulatory disulfide bond, because iodoacetate bound to the alternative oxidase at the activating site even when the redox-active regulatory sulfhydryls were oxidized. Given the nature of the covalent adduct formed by the reaction of iodoacetate with sulfhydryls, the activation of the alternative oxidase by ␣-keto acids appears to involve the formation of a thiohemiacetal.Plant mitochondria possess a terminal cyanide-resistant alternative oxidase in the electron transport system of the inner membrane (1, 2). This oxidase reduces oxygen to water with electrons derived directly from the ubiquinone pool. Because no protonmotive force is generated during this reaction, the alternative pathway appears to be energetically wasteful (1, 2). cDNA sequences have now been reported for the nuclear-encoded alternative oxidase from several plants, two fungi, and a protozoan (2-7).1 The mature protein contains 280 -290 amino acids and migrates as a 32-35-kDa protein on SDS-PAGE gels as revealed by immunoblotting. Hydropathy analysis has led to a model in which the alternative oxidase protein is anchored to the mitochondrial inner membrane by two membrane-spanning ␣-helices, with large hydrophilic domains approximately 100 amino acids in length flanking each membrane-spanning region and extending into the mitochondrial matrix (9). In the carboxyl-terminal hydrophilic domain, just beyond the second membrane-spanning region, is a set of conserved amino acid motifs found in the family of coupled binuclear iron proteins to which methane monooxygenase belongs (9, 10). Cross-linking studies have indicated that the plant alternative oxidase exists in the membrane as a homodimer (11).As a result of a search for the role of the alternative oxidase in plant metabolism, several regulators of its activity have been identified. The amounts of alternative oxidase protein in the membrane (e.g. Refs. 12-14) and the extent of ubiquinone pool reduction (...

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The binding site for oxaloacetate on succinate dehydrogenase

Cited by 39 publications

References 6 publications

Effect of Bovine Serum Albumin on Mitochondrial Respiration in the Brain and Liver of Mice and Rats

Effect of Bovine Serum Albumin on Mitochondrial Respiration in the Brain and Liver of Mice and Rats

The Neuromediator Glutamate, through Specific Substrate Interactions, Enhances Mitochondrial ATP Production and Reactive Oxygen Species Generation in Nonsynaptic Brain Mitochondria

The Reaction of the Soybean Cotyledon Mitochondrial Cyanide-resistant Oxidase with Sulfhydryl Reagents Suggests That α-Keto Acid Activation Involves the Formation of a Thiohemiacetal

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