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PubMed1984

Mitochondria from the hepatopancreas of the marine clam Mercenaria mercenaria: substrate preferences and salt and pH effects on the oxidation of palmitoyl-L-carnitine and succinate.

A method is presented for the isolation of mitochondria with good respiratory control from the hepatopancreas of the marine clam Mercenaria mercenaria. Palmitoyl-L-carnitine is the preferred substrate of the mitochondria of the hepatopancreas based on state 3 rates of oxidation (in the presence of ADP). Rates of oxidation of pyruvate and glutamate were about one-half that of the lipid substrate in state 3. alpha-Glycerophosphate was oxidized at a rate about one-third that of palmitoyl-L-carnitine. All Krebs cycle intermediates were oxidized to some extent. Proline was not oxidized at detectable levels. The optimal range of KCl concentrations for the oxidation of palmitoyl-L-carnitine is between 250 and 500 mM whereas the optimal range of KCl concentration for the oxidation of succinate is between 200 and 350 mM. The optimal range of pH for the oxidation of succinate and for the oxidation of palmitoyl-L-carnitine lies between pH 6.5 and 7.5 based on the respiratory control ratio.

Animals↗
PubMed1999

Liver mitochondria, confirmed as intact by complete suppression of succinate uptake and oxidation, possess a carnitine palmitoyltransferase I that is totally inhibited by malonyl CoA.

Succinate dehydrogenase activity in mitochondria, which were isolated by centrifuging partially purified mitochondria through 1. 315 M sucrose, was completely suppressed when [14C]succinate uptake was abolished by prior incubation of the mitochondria with carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP) and valinomycin. The conclusion that these mitochondria were intact was confirmed by the fact that, when these mitochondria were broken by a freeze-thaw cycle followed by sonication, such inhibition was totally abolished. The yield of mitochondria, microsomes, and peroxisomes from the initial homogenate was 17.8, <0.1, and 0%, respectively, indicating that the mitochondria were not only intact but also essentially free of contamination from microsomes and peroxisomes. The overt form of carnitine palmitoyltransferase (CPT I) in these intact and pure mitochondria was totally inhibited by malonyl CoA, indicating that previous reports of incomplete inhibition in mitochondrial preparations resulted from interference from CPT activity in the inner mitochondrial membrane (CPT II), microsomes, or peroxisomes.

Animals↗
PubMed1975

Correlation of the effects of citric acid cycle metabolites on succinate oxidation by rat liver mitochondria and submitochondrial particles.

1. Succinate dehydrogenase is inhibited by citrate and beta-hydroxy-butyrate in a complex manner, both in mitochondria and submitochondrial particles. Kinetics of inhibition in the particles points to a competitive component in the mechanism involved. 2. Pyruvate, alpha-ketoglutarate, malate, and glutamate stimulate oxidation of succinate by mitochondria. 3. Stimulation by alpha-ketoglutarate and glutamate is not influenced by the presence of rotenone. 4. Stimulation by pyruvate is higher in the absence of rotenone and increases significantly in the presence of K+ and valinomycin. Pyruvate supplies in mitochondria reducing equivalents for malate dehydrogenase operating in the reverse direction-reduction of oxaloacetate to malate. 5. Stimulation by malate is higher in the presence of rotenone.

Animals↗
PubMed1985

Voltage dependence and ion selectivity of the mitochondrial channel, VDAC, are modified by succinic anhydride.

The mitochondrial protein VDAC forms voltage-dependent anion-selective channels in planar phospholipid membranes. When succinic anhydride was added to these membranes, it virtually eliminated VDAC's voltage-dependence and changed its selectivity from anion to cation. These results were obtained without large changes in open-channel conductance or in energy difference between the open and closed states in the absence of a field. Since succinic anhydride converts amino groups into carboxyl groups, we propose that amino groups are responsible for VDAC's voltage-dependence and anion selectivity. Perhaps the same charges are responsible for both functions.

Animals↗
PubMed2005

Succinate dehydrogenase deficiency in human.

Mitochondrial succinate dehydrogenase (SDH) consists merely of four nuclearly encoded subunits. It participates in the electron transfer in the respiratory chain and in succinate catabolism in the Krebs cycle. Mutations in the four genes, SDHA, B, C and D, have been reported, resulting in strikingly diverse clinical presentations. So far, SDHA mutations have been reported to cause an encephalomyopathy in childhood, while mutations in the genes encoding the other three subunits have been associated only with tumour formation. Following a brief description of SDH genes and subunits, we examine the properties and roles of SDH in the mitochondria. This allows further discussion of the several hypotheses proposed to account for the different clinical presentations resulting from impaired activity of the enzyme. Finally we stress the importance of SDH as a target and/or marker in a number of diseases and the need to better delineate the consequences of SDH deficiency in humans.

Humans↗
PubMed1990

Assay for 2-oxoglutarate decarboxylating enzymes based on the determination of [1-14C]succinate: application to prolyl 4-hydroxylase.

A method for the assay of 2-oxoglutarate decarboxylating enzymes based on determination of the reaction product [1-14C]succinate after precipitation of remaining 2-oxo[5-14C]glutarate with 2,4-dinitrophenyl hydrazine is reported. It is particularly useful for the study of the 2-oxoglutarate-coupled dioxygenase prolyl 4-hydroxylase (EC 1.14.11.2); it is superior to previously described assay methods of this enzyme with respect to simplicity of the procedure, speed, cost, and radiochemical safety. The results are highly reproducible, the standard deviation of repeated measurements being about 2% of the mean. The commercially available 2-oxo[5-14C]glutarate used in this study contained approximately 3% of radioactivity coeluting with succinate in HPLC and 1.5% of an unidentified radioactive compound as impurities, which contributed to the background.

Animals↗
PubMed1992

Inhibition of mitochondrial succinate oxidation--similarities and differences between N-methylated beta-carbolines and MPP+.

N-Methylated beta-carbolinium compounds (N-Me-BCs), including 2-N-methyl and 2,9-N,N-dimethyl analogs, structural analogs of 1-methyl-4-phenylpyridinium (MPP+), may be endogenously bioactivated, MPP(+)-like toxins, capable of inducing parkinsonism. Both MPP+ and selected N-Me-BCs inhibit NADH-linked mitochondrial respiration (Complex I). We now show that both also inhibit succinate-supported (Complex II) respiration, the greatest inhibition (80%) being seen for 2,9-dimethylharmanium. Complex I inhibition occurs at MPP+ concentrations (IC50 = 0.17 mM) about one order of magnitude lower than Complex II inhibition (greater than 1.2 mM). In contrast, Complex I and Complex II inhibition by the N-Me-BCs tested occurred at similar concentrations (I, 0.1 mM; II, 0.25 mM) and concentrations similar to Complex I inhibition by MPP+. 2,9-N,N-Dimethyl-BCs, which are the permanently charged BC analogs of MPP+, show inhibitory characteristics similar to MPP+: slow onset of inhibition, potentiation by TPB, and reversal by DNP. The fact that succinate oxidation cannot bypass the Complex II inhibition by N-Me-BCs could enhance any chronic neurotoxicity of N-Me-BCs.

1-Methyl-4-phenylpyridinium↗
PubMed1980

Modulation of the flavin redox potential as mode of regulation of succinate dehydrogenase activity.

The redox properties of flavin in active and non-active (oxaloacetate reacted) soluble succinate dehydrogenase were studied. Quantitative analysis of reductive activation titrations of redox titrations of active and non-active enzyme reveal that the redox potential of the histidyl-flavin in the active enzyme (-3 +/- 15 mV) is high enough to allow reduction by succinate, whereas in the non active enzyme it is -196 +/- 19 mV, far to low to be reduced by substrate. The flavin radical in the active enzyme attains 60% of total flavin at a poised redox potential of about +60 mV, upon addition of oxaloacetate the magnitude of the signal is diminished and the potential where it reaches maximal concentration is shifted by about -200 mV. A mechanism is proposed which ascribes the fundamental difference between active and non-active enzyme to the inability of the latter to be reduced by substrate.

Animals↗
PubMed1984

Succinate and phenylsuccinate as modifiers of sulfhydryl groups of inner mitochondrial membrane protein. Study by EPR.

Paramagnetic labels specific for sulfhydryl (SH) groups have been used to study the conformational changes of the inner mitochondrial membrane. The EPR spectra of the SH-groups spin-labeled with maleimide or iodoacetamide show the existence of two populations of sulfhydryl groups, differing in their mobility (one weakly, the other strongly immobilized). The incubation with succinate or phenylsuccinate decreased the binding of these labels of the weakly immobilized sites while the number of total SH groups was the same before and after the incubation. These results suggest that succinate or phenylsuccinate induce a reversible change in protein conformation or in protein arrangement within the inner mitochondrial membrane. This change is concomitant to the protein movement between inner membrane and perimembranal space induced by either of these two molecules.

Animals↗
PubMed1992

Two reactions are simultaneously catalyzed by a single enzyme: the arginine-dependent simultaneous formation of two products, ethylene and succinate, from 2-oxoglutarate by an enzyme from Pseudomonas syringae.

A single enzyme isolated from Pseudomonas syringae pv. phaseolicola PK2 simultaneously catalyzed two reactions, namely, the formation of ethylene and succinate from 2-oxoglutarate, at a molar ratio of 2:1. In the main reaction, 2-oxoglutarate was dioxygenated to produce one molecule of ethylene and three molecules of carbon dioxide. In the sub-reaction, both 2-oxoglutarate and L-arginine were mono-oxygenated to yield succinate plus carbon dioxide and L-hydroxyarginine, respectively, the latter being further transformed to guanidine and L-delta 1-pyrroline-5-carboxylate. We propose a dual-circuit mechanism for the entire reaction, in which the binding of L-arginine and 2-oxoglutarate in a Schiff-base structure generates a common intermediate for two reactions.

Arginine↗
PubMed1987

Different effects of 2,4-dinitrophenol on rat liver mitochondrial oxidation of various substrates: succinate and glutamate vs 3-hydroxybutyrate and glycerol 3-phosphate.

In homogenate and isolated mitochondria from the liver of male and female rats of Wistar and August strains, a higher uncoupled vs State 3 oxidation of succinate and glutamate and lower that of 3-hydroxybutyrate and glycerol 3-phosphate were observed. The optimal concentration of 2,4-dinitrophenol (DNP) was in the range 7-12 microM for 3-hydroxybutyrate oxidation and 50-100 microM for succinate or glutamate oxidation.

2,4-Dinitrophenol↗
PubMed1991

Na(+)-dependent succinate uptake in Corynebacterium glutamicum.

Succinate is effectively taken up by washed cells of Corynebacterium glutamicum. The apparent Km value of uptake is about 150 microM and the Vmax 4-7 nmol (mg dry weight)-1 min-1 and uptake can be competetively inhibited by fumarate and oxaloacetate. The activation energy was determined to be 50 kJ/mol. The transport activity is clearly dependent on the presence of Na+ ions in the incubation medium and on the membrane potential and has a pH optimum around 8.5. It is concluded that succinate is taken up in C. glutamicum via a specific carrier by a secondary active, Na+ coupled mechanism.

Binding, Competitive↗
PubMed2006

An assay for Fe(II)/2-oxoglutarate-dependent dioxygenases by enzyme-coupled detection of succinate formation.

The Fe(II)/2-oxoglutarate-dependent dioxygenases are a catalytically diverse family of nonheme iron enzymes that oxidize their primary substrates while decomposing the 2-oxoglutarate cosubstrate to form succinate and CO(2). We report a generic assay for these enzymes that uses succinyl-coenzyme A synthetase, pyruvate kinase, and lactate dehydrogenase to couple the formation of the product succinate to the conversion of reduced nicotinamide adenine dinucleotide to nicotinamide adenine dinucleotide. We demonstrate the utility of this new method by measuring the kinetic parameters of two bacterial Fe(II)/2-oxoglutarate-dependent dioxygenases. Significantly, this method can be used to investigate both the productive turnover reactions and the nonproductive "uncoupled" decarboxylation reactions of this enzyme family, as demonstrated by using wild-type and variant forms of 2-oxoglutarate-dependent taurine dioxygenase. This assay is amenable to miniaturization and easily adapted to a format suitable for high-throughput screening; thus, it will be a valuable tool to study Fe(II)/2-oxoglutarate-dependent dioxygenases.

Dioxygenases↗
PubMed2005

Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase.

Several mitochondrial proteins are tumor suppressors. These include succinate dehydrogenase (SDH) and fumarate hydratase, both enzymes of the tricarboxylic acid (TCA) cycle. However, to date, the mechanisms by which defects in the TCA cycle contribute to tumor formation have not been elucidated. Here we describe a mitochondrion-to-cytosol signaling pathway that links mitochondrial dysfunction to oncogenic events: succinate, which accumulates as a result of SDH inhibition, inhibits HIF-alpha prolyl hydroxylases in the cytosol, leading to stabilization and activation of HIF-1alpha. These results suggest a mechanistic link between SDH mutations and HIF-1alpha induction, providing an explanation for the highly vascular tumors that develop in the absence of VHL mutations.

Animals↗
PubMed2002

Archaeal complex II: 'classical' and 'non-classical' succinate:quinone reductases with unusual features.

Reversible succinate dehydrogenase (SDH) activities have been ubiquitously detected in organisms from the three domains of life. They represent constituents either of respiratory complexes II in aerobes, or of fumarate dehydrogenase complexes in anaerobes. The present review gives a survey on archaeal succinate:quinone oxidoreductases (SQRs) analyzed so far. Though some of these could be studied in detail enzymologically and spectroscopically, the existence of others has been deduced only from published genome sequences. Interestingly, two groups of enzyme complexes can be distinguished in Archaea. One group resembles the properties of SDHs known from bacteria and mitochondria. The other represents a novel class with an unusual iron-sulfur cluster in subunit B and atypical sequence motifs in subunit C which may influence electron transport mechanisms and pathways. This novel class of SQRs is discussed in comparison to the so-called 'classical' complexes. A phylogenetic analysis is presented suggesting a co-evolution of the flavoprotein-binding subunit A and subunit B containing the three iron-sulfur clusters.

Amino Acid Sequence↗
PubMed2000

Purification and characterization of Plasmodium falciparum succinate dehydrogenase.

Succinate dehydrogenase (SDH), a Krebs cycle enzyme and complex II of the mitochondrial electron transport system was purified to near homogeneity from the human malarial parasite Plasmodium falciparum cultivated in vitro by FPLC on Mono Q, Mono S and Superose 6 gel filtration columns. The malarial SDH activity was found to be extremely labile. Based on Superose 6 FPLC, sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and nondenaturing-PAGE analyses, it was demonstrated that the malarial enzyme had an apparent native molecular mass of 90 +/- 8 kDa and contained two major subunits with molecular masses of 55 +/- 6 and 35 +/- 4 kDa (n = 8). The enzymatic reaction required both succinate and coenzyme Q (CoQ) for its maximal catalysis with Km values of 3 and 0.2 microM, and k(cat) values of 0.11 and 0.06 min(-1), respectively. Catalytic efficiency of the malarial SDH for both substrates were found to be relatively low (approximately 600-5000 M(-1) s(-1)). Fumarate, malonate and oxaloacetate were found to inhibit the malarial enzyme with Ki values of 81, 13 and 12 microM, respectively. The malarial enzyme activity was also inhibited by substrate analog of CoQ, 5-hydroxy-2-methyl-1,4-naphthoquinone, with a 50% inhibitory concentration of 5 microM. The quinone had antimalarial activity against the in vitro growth of P. falciparum with a 50% inhibitory concentration of 0.27 microM and was found to completely inhibit oxygen uptake of the parasite at a concentration of 0.88 microM. A known inhibitor of mammalian mitochondrial SDH, 2-thenoyltrifluoroacetone. had no inhibitory effect on both the malarial SDH activity and the oxygen uptake of the parasite at a concentration of 50 microM. Many properties observed in the malarial SDH were found to be different from the host mammalian enzyme.

Animals↗
PubMed2005

A mitochondrial NADH-dependent fumarate reductase involved in the production of succinate excreted by procyclic Trypanosoma brucei.

Trypanosoma brucei is a parasitic protist responsible for sleeping sickness in humans. The procyclic stage of T. brucei expresses a soluble NADH-dependent fumarate reductase (FRDg) in the peroxisome-like organelles called glycosomes. This enzyme is responsible for the production of about 70% of the excreted succinate, the major end product of glucose metabolism in this form of the parasite. Here we functionally characterize a new gene encoding FRD (FRDm1) expressed in the procyclic stage. FRDm1 is a mitochondrial protein, as evidenced by immunolocalization, fractionation of digitonin-permeabilized cells, and expression of EGFP-tagged FRDm1 in the parasite. RNA interference was used to deplete FRDm1, FRDg, or both together. The analysis of the resulting mutant cell lines showed that FRDm1 is responsible for 30% of the cellular NADH-FRD activity, which solves a long standing debate regarding the existence of a mitochondrial FRD in trypanosomatids. FRDg and FRDm1 together account for the total NADH-FRD activity in procyclics, because no activity was measured in the double mutant lacking expression of both proteins. Analysis of the end products of 13C-enriched glucose excreted by these mutant cell lines showed that FRDm1 contributes to the production of between 14 and 44% of the succinate excreted by the wild type cells. In addition, depletion of one or both FRD enzymes results in up to 2-fold reduction of the rate of glucose consumption. We propose that FRDm1 is involved in the maintenance of the redox balance in the mitochondrion, as proposed for the ancestral soluble FRD presumably present in primitive anaerobic cells.

Amino Acid Sequence↗