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PubMed1980

Interactions of cytochrome c with mitochondrial membranes. Binding to succinate-cytochrome c reductase.

Methyl-4-azidobenzoimidate was reacted with horse heart cytochrome c to give a photoaffinity-labeled derivative of this heme protein. The modified cytochrome c bound to cytochrome c-depleted mitochondria with the same Kd as native cytochrome c and restored oxygen uptake to the same extent. Irradiation of cytochrome c-depleted mitochondrial membranes with 3- to 4-fold excess of photoaffinity-labeled cytochrome c over cytochrome c oxidase resulted in covalent binding of the derivative to the membranes. Fractionation of the irradiated mitochondria in the presence of detergents and salts followed by chromatography on an agarose Bio-Gel-A-5m showed that the labeled cytochrome c was bound covalently to succinate-cytochrome c reductase. The covalently bound cytochrome c was active in mediating electron transfer between its reductase and oxidase. Sodium dodecyl sulfate polyacrylamide gel electrophoresis of the succinate-cytochrome c reductase containing photoaffinity-labeled 125I-cytochrome c showed that the reductase contained a protein binding site for cytochrome c. It is suggested that cytochrome c1 is the most likely site for the cytochrome c binding in mitochondria in situ.

Affinity Labels↗
PubMed1984

[Effect of phenformin and succinic acid on the transplacental carcinogenic effect of N-nitroso-N-ethylurea in rats].

The study was concerned with the influence of a long-term postnatal treatment with an antidiabetic biguanide-phenformin and a biologic stimulating agent-succinic acid upon the realization of transplacental carcinogenic effect of N-ethyl-N-nitrosourea (ENU) in rats. Phenformin treatment inhibited the development of induced tumors in the nervous system and kidneys, significantly decreased the total incidence and multiplicity of these tumors, the incidence of brain and spinal cord tumors and multiplicity of brain tumors. Succinic acid did not influence the transplacental carcinogenic effect of ENU.

Animals↗
PubMed1982

[Response of adenine nucleotide metabolism in the aged rat liver to fasting and succinate injections].

The total adenine nucleotide content in the livers from 24-month-old rats was shown to be by 30% lower than that of 3--4-month-old rat livers. A 24-hr fasting resulted in a decrease of the hepatic ATP levels, ATP/ADP ratios, phosphorylation potentials, adenylate energy charges and action mass ratios of adenylate kinase, crude at the same extents in adult and aged rats as well as in the equal increase of ADP, AMp and Pi levels. Injections of 0.9% NaCl or ammonium succinate to the aged rats (daily for 6 days prior to the experiment) did not affect the hepatic energy metabolism. The effects of potassium succinate was essentially the same as that of the fasting. Any treatment of the aged rats did not increase the total content of adenine nucleotides in the livers. Possible mechanisms of disturbances in adenine nucleotide metabolism upon ageing are discussed.

Adenosine Diphosphate↗
PubMedDate not supplied

[An experimental study of the anti-ulcer effect of administering sodium succinate and a solution of whey in immobilization stress].

The experiments carried out on the model of immobilization stress permit establishing the antiulcer effect of preventive introduction of sodium succinate solution, milk serum solution and solution of milk serum with sodium succinate. A decrease in the degree and number of ulcers and in the integrative indices characterizing the ulcer process after introduction of the studied drugs was accompanied by a fall of the intensity of lipid peroxidation processes.

Animals↗
PubMedDate not supplied

[The effect of 2,4-dinitrophenol and glucose on the utilization of succinate, lactate, pyruvate and formate by Escherichia coli K12].

The effect of protonophore 2,4-dinitrophenol (5-25 microM) in lithium chloride acidic medium (pH 4.5) on utilization of acidic energetic substrates was studied in the presence and absence of glucose. The rate of succinate, lactate and pyruvate utilization by AB 1157 strains was two times lower, than by the KS 400 strain. Isomolar glucose concentration (0.5 mM) decreased the utilization rate of succinate by 60% pyruvate by 30% the AB 1157 strain being much more sensitive than the KS 400 strain both to the action of glucose and to the reaction to glucose and 2,4-dinitrophenol. Acidification of the medium by bacteria has been observed, which shows changes in energy metabolism (glycolysis takes place instead of oxidation of substrates) under conditions of intensive aeration. The results obtain permit assuming that the AB 1157 strain has a certain defect of the membrane which causes increased proton conduction.

2,4-Dinitrophenol↗
PubMed2000

Effects of the dimethyl ester on succinic acid on the hormonal and metabolic response to exercise in hereditarily diabetic starved rats.

This study was designed to assess the effect of the dimethyl ester of succinic acid (SAD) upon the hormonal and metabolic response to a 60-min exercise in overnight-starved Goto-Kakizaki rats. Twenty Goto-Kakizaki rats were starved overnight and then either maintained at rest or obliged to swim for 60 min. Half of the rats were injected intraperitoneally with the dimethyl ester of succinic acid (SAD, 5.0 micromol g(-1) body wt) immediately before exercise (or 60 min of rest). In the hereditarily diabetic rats, overnight starvation lowered the plasma D- glucose, insulin and lactate concentrations, while increasing that of free fatty acids and beta-hydroxybutyrate. In resting rats, the injection of SAD increased the glycogen content of liver, heart and muscle and the plasma concentration of D-glucose, insulin, glycerol and free fatty acids. In control animals, not injected with SAD, exercise increased the plasma concentration of D- glucose, lactate and glycerol, whilst lowering both that of insulin and the glycogen content of liver, heart and muscle. The injection of SAD before exercise failed to prevent and, on occasion, even accentuated the changes in both the glycogen content of liver, heart and muscle and the plasma concentration of D-glucose, insulin, glycerol and free fatty acids, whilst minimizing the increase in lactate concentration otherwise caused by exercise. Nevertheless, the comparison between resting and exercising rats, both injected with SAD, suggested that the ester abolished the exercise-induced rise in D-glucose, glycerol and fatty acid concentrations. By comparison with comparable experiments conducted in overnight-starved normal rats, these findings emphasize both the difference between normal and diabetic rats in their metabolic response to exercise, especially in terms of changes in glycemia, and the usefulness of SAD to compensate for the increased consumption of endogenous nutrients during exercise.

3-Hydroxybutyric Acid↗
PubMed2003

Vigabatrin and newer interventions in succinic semialdehyde dehydrogenase deficiency.

Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare disorder characterized by an inborn error of the catabolism of the inhibitory neurotransmitter GABA. Because of the deficiency of SSADH, the final enzyme of the GABA degradation pathway, the substrate, succinic semialdehyde, is shunted towards production of 4-hydroxybutyric acid (gamma-hydroxybutyric acid). Elevations of gamma-hydroxybutyric acid can be detected in the physiologic fluids of patients with SSADH deficiency, and forms the mainstay of diagnosis. The clinical features of SSADH deficiency include nonspecific neurologic manifestations such as mental retardation/developmental delay, absent speech, hypotonia, nonprogressive ataxia, features of autism or pervasive developmental delay, developmental language delay (dyspraxia, receptive, and expressive delays), and occasionally, seizures. Although the metabolic pathway has been established, it is not known whether insufficient GABA and/or excess gamma-hydroxybutyric acid contribute to the disease phenotype. Pharmacological therapy in patients with this disorder has been limited to vigabatrin, an anticonvulsant that blocks GABA transaminase. This review will discuss therapeutic options in SSADH deficiency, on the basis of patient experience, and preliminary work using a murine model. Finally, a discussion of adjunctive therapies will be included.

Aldehyde Oxidoreductases↗
PubMed2003

Succinic semialdehyde dehydrogenase deficiency in children and adults.

Succinic semialdehyde dehydrogenase deficiency is a rare disorder of the degradation pathway of gamma-aminobutyric acid. The disorder is detected when 4-hydroxybutyric aciduria is present on urine organic acid analysis, and is subsequently confirmed by enzyme measurement on leucocytes. The disorder has been identified in approximately 350 individuals worldwide. We review the clinical features in 60 patients. The most common characteristics are developmental delay maximally involving expressive language, hypotonia, mental retardation, ataxia, and behavioral problems. Seizures occur in approximately half of patients, and include tonic-clonic, absence, and myoclonic seizures, including status epilepticus. Electroencephalographic findings are background slowing and generalized and focal epileptiform discharges. Magnetic resonance imaging typically reveals increased T2-weighted signal of the globus pallidus bilaterally, with variable involvement of white matter and the cerebellar dentate nucleus. Preliminary human cerebrospinal fluid measurements are consistent with neurometabolic aberrations documented in the murine animal model, with elevations in gamma-aminobutyric acid, gamma-hydroxybutyrate, and homocarnosine, and low glutamine. Succinic semialdehyde dehydrogenase deficiency may be an underrecognized neurometabolic disorder with a nonspecific and wide phenotypic spectrum, and carries implications for a comprehensive fundamental understanding of interrelations between multiple neurotransmitter systems.

Adult↗
PubMed1982

Gas-liquid chromatographic analysis of synovial fluid. Succinic acid and lactic acid as markers for septic arthritis.

Nonvolatile short-chain fatty acids from 80 synovial fluids were quantified by gas-liquid chromatography. Succinic acid was detectable in all 23 septic synovial fluids infected with either gram-positive or gram-negative organisms and in only 5 of 57 nonseptic synovial fluids. Lactic acid was present in all of the effusions but was correlated with septic arthritis only when present in concentrations greater than 250 mg%. Neither short-chain fatty acid was more sensitive than high white blood cell counts (greater than 50,000 mm3) or depressed glucose concentration (less than 40 mg/dl) in diagnosing septic arthritis before antibiotic therapy; however, the detection of succinic acid was helpful in identifying patients with septic arthritis who had been given antibiotic treatment before arthrocentesis. Thus, gas-liquid chromatography, a rapid and sensitive method for the detection of short-chain fatty acids, may complement the currently available methods used to diagnose septic arthritis.

Arthritis, Infectious↗
PubMed2003

The convergent synthesis of poly(glycerol-succinic acid) dendritic macromolecules.

The high-yield convergent synthesis of dendrons, dendrimers, and dendritic-linear hybrid macromolecules composed of succinic acid, glycerol, and poly(ethylene glycol) (PEG) is described. This convergent synthesis relies on two orthogonal protecting groups; namely, the benzylidene acetal (bzld) for the protection of the 1,3-hydroxyls of glycerol and the tert-butyldiphenylsilyl (TBDPS) ester for protection of the carboxylic acid of succinic acid. These novel polyester dendritic macromolecules are composed entirely of building blocks known to be biocompatible or degradable in vivo to give natural metabolites. Derivatization of the dendritic periphery with a methacrylate affords a polymer that can be subsequently photo-cross-linked. The three-dimensional cross-linked gels formed by ultraviolet irradiation are optically transparent, with mechanical properties dependent on the initial cross-linkable dendritic macromolecule.

Biocompatible Materials↗
PubMed1992

cDNA sequence of three cysteine-rich clusters in the iron-sulfur subunit of complex II (succinate-ubiquinone oxidoreductase) from Caenorhabditis elegans determined by automated DNA sequencer.

Homology probing by using mixed primers for polymerase chain reaction (PCR) and a subsequent sequence analysis by automated DNA sequencer were applied to determine a partial cDNA sequence of the iron-sulfur subunit of complex II (succinate-ubiquinone oxidoreductase). Complex II is a membrane-bound flavoenzyme, which catalyzes the oxidation of succinate to fumarate in the tricarboxylic acid cycle, and it is a component of the mitochondrial and bacterial respiratory chains. In this study, the partial amino acid sequence of iron-sulfur subunits in Caenorhabditis elegans mitochondria was deduced from the DNA sequence obtained from cDNA-PCR. Mixed oligonucleotide primers corresponding to two conserved regions which appear to be the binding site for the prosthetic group were used. The product of PCR was cloned into plasmid vector pUC 119 and the sequence was determined from double strand plasmid DNA by the dideoxy method using of one-dye, four-lane type the automated DNA sequencer (DSQ-1, Shimadzu). The PCR product contained 483 nucleotides and its deduced amino acid sequence was highly homologous with that in human liver (68.9%) and that of Escherichia coli sdh B product (50.3%). As expected, striking sequence conservation was found around the three cysteine-rich clusters which have been thought to comprise the iron-sulfur centers of the enzyme.

Amino Acid Sequence↗
PubMed1986

The effects of cadmium on succinate and NADH-linked substrate oxidations in rat hepatic mitochondria.

Low concentrations of cadmium (3.3-40 microM) inhibited State 3 NADH-linked respiration in rat hepatic mitochondria, but failed to release oligomycin (1 microgram) inhibited State 3 respiration, or to significantly change the State 4 rate. In the presence of succinate, 40 microM cadmium inhibited State 3 respiration by 89%, while concentrations between 3.3 and 13.3 microM stimulated State 4 respiration. Higher concentrations caused marked inhibition. In the presence of succinate, cadmium released oligomycin inhibited State 3 respiration. Cadmium (0.001-1.0 mM) did not stimulate mitochondrial ATPase activity or inhibit ferricyanide reduction, but stimulated NAD+ linked mitochondrial dehydrogenase activities and NADH oxidation. These results indicate that cadmium interacts with either the NADH dehydrogenase complex or other NADH-dependent enzymes and not solely by an uncoupling action.

Adenosine Triphosphate↗
PubMedDate not supplied

Cardioteratogenic dose of ethanol reduces both lactic dehydrogenase and succinic dehydrogenase activity in the bulbar ridges of the embryonic chick heart.

It has been established previously that the chick embryo is an appropriate model for studying the pathogenesis of ethanol-induced ventricular septal defect and that the growth and fusion of the proximal bulbar ridges are critical to ventricular septation within the embryonic heart. To determine whether enzyme activity was altered significantly in bulbar ridges in response to a cardioteratogenic dose of ethanol, we injected 0.32 ml of 50% ethanol in chick Ringer's saline (CRS) into the air cells of 3-day-old chick embryos (72-84 h incubation, Hamburger-Hamilton stages 18-19, Dekalb Delta strain). Embryos were harvested 48-60 h after treatment (stages 26-27). Hearts were removed, frozen and sectioned, and the tissues were processed for enzyme histochemical demonstrations of lactic and succinic dehydrogenase. Twelve ethanol-treated embryos and 12 CRS-treated controls were compared for lactic dehydrogenase (LDH) levels. Fourteen ethanol-treated embryos and 14 controls were compared for succinic dehydrogenase (SDH) levels. Formazan deposits were quantified by means of computer-assisted microdensitometry. Our results showed that ethanol decreased the mean LDH activity level by 36.3% (P = 0.005) and the mean SDH level by 40.8% (P < 0.02). Furthermore, ethanol significantly reduced LDH activity in 41.7% of the matched embryo pairs and significantly reduced SDH activity in 57.1% of the matched embryo pairs. Although some investigators have proposed that a disturbance in neural crest cell migration plays a major role in the pathogenesis of ethanol-induced cardiac malformations, this study provides evidence that the bulbar ridges of the embryonic heart are also potential target tissues for ethanol.

Animals↗
PubMed2006

Aluminum toxicity elicits a dysfunctional TCA cycle and succinate accumulation in hepatocytes.

Aluminum (Al), a known environmental toxicant, has been linked to a variety of pathological conditions such as dialysis dementia, osteomalacia, Alzheimer's disease, and Parkinson's disease. However, its precise role in the pathogenesis of these disorders is not fully understood. Using hepatocytes as a model system, we have probed the impact of this trivalent metal on the aerobic energy-generating machinery. Here we show that Al-exposed hepatocytes were characterized by lipid and protein oxidation and a dysfunctional tricarboxylic acid (TCA) cycle. BN-PAGE, SDS-PAGE, and Western blot analyses revealed a marked decrease in activity and expression of succinate dehydrogenase (SDH), alpha-ketoglutarate dehydrogenase (KGDH), isocitrate dehydrogenase-NAD+ (IDH), fumarase (FUM), aconitase (ACN), and cytochrome c oxidase (Cyt C Ox). 13C-NMR and HPLC studies further confirmed the disparate metabolism operative in control and Al-stressed cells and provided evidence for the accumulation of succinate in the latter cultures. In conclusion, these results suggest that Al toxicity promotes a dysfunctional TCA cycle and impedes ATP production, events that may contribute to various Al-induced abnormalities.

Aluminum↗
PubMed1976

Pharmaceutical applications of solid dispersion systems: dissolution of griseofulvin-succinic acid eutectic mixture.

The dissolution profile of the griseofulvin-succinic acid eutectic mixture system was evaluated using the powder and constant-surface are tablet methods. Factors contributing to the enhancement of griseofulvin dissolution from the dispersion in succinic acid are discussed. Contrary to the original proposal of Sekiguchi and coworkers, dissolution rates of driseofulvin from solid dispersions were found to be markedly affected by the particle size of solid dispersions.

Anhydrides↗
PubMed1993

Estimates of glycolysis, pyruvate (de)carboxylation, pentose phosphate pathway, and methyl succinate metabolism in incapacitated pancreatic islets.

Pancreatic islets were cultured for 24 h in the presence of 1 mM glucose, which renders islets incapable of responding to glucose with insulin release. These islets were compared to islets maintained at 20 mM glucose for 24 h. Detritiation of [2-3H]glucose and [5-3H]glucose in 1 mM glucose islets was normal, suggesting that glucose transport and phosphorylation and all enzymes of glycolysis were not down-regulated in the incapacitated islets. 14CO2 formation from [U-14C]glucose and [6-14C]glucose was inhibited up to 80% and 14CO2 from methyl succinate was inhibited up to 60%, indicating that down-regulation at (a) mitochondrial site(s) might explain the incapacitated insulin release. 14CO2 formation from [3,4-14C]glucose (which becomes [1-14C]pyruvate) was decreased, indicating that the reaction catalyzed by pyruvate dehydrogenase was down-regulated. This decrease, however, was not as large as the decreases in 14CO2 formation from [U-14C]glucose, [2-14C]glucose (which becomes [2-14C]pyruvate), or [6-14C]glucose (which becomes [3-14C]pyruvate), indicating that other reactions were also down-regulated. 14CO2 formation from [1-14C]glucose was inhibited less than that from [6-14C]glucose in the incapacitated islets (34 vs 54%) and these rates indicated that flux of glucose through the pentose phosphate pathway was increased in the incapacitated islet, such that 29% (0.4 nmol of 1.4 glucose/100 islets/90 min) was metabolized via this pathway in the incapacitated islet but only 3.4% (0.1 of 2.9 nmol glucose/100 islets/90 min) was metabolized via the pentose pathway in the 20 mM glucose islets. With rates of 14CO2 evolved from glucose labeled at C2 and C6 and from methyl succinate labeled at C1 + C4 and C2 + C3 the 14CO2 ratio formula was used to calculate the ratios of carboxylated and decarboxylated pyruvate. Roughly equal amounts of pyruvate entered the citric acid cycle by each route in islets maintained for 24 h at 1, 5, or 20 mM glucose. The results indicate that decarboxylation and carboxylation of pyruvate were about equally suppressed in incapacitated islets and that direct inhibition of reactions of the cycle was unlikely. This is consistent with evidence which indicates that down-regulation of both pyruvate carboxylase and pyruvate dehydrogenase occurs in incapacitated islets, i.e., under long-term conditions that modify amounts of enzymes (MacDonald et al., 1991, J. Biol. Chem. 266, 22392-22397).(ABSTRACT TRUNCATED AT 400 WORDS)

Acetates↗
PubMed1999

Comparison of the tetrazolium salt assay for succinate dehydrogenase with the cytosensor microphysiometer in the assessment of compound toxicities.

The cytosensor microphysiometer (a biosensing instrument for detecting cellular metabolism) was compared to the established tetrazolium salt assay as a chemosensitivity test. Two coumarin compounds, 7-hydroxycoumarin and esculetin, were examined to determine their effect on the cellular metabolism of A431 cells over a 24-h exposure period. In the tetrazolium salt assay, 7-hydroxycoumarin caused suppression of the succinate dehydrogenase activity at concentrations greater than 10 microg/ml. Esculetin exerted a more serious effect on succinate dehydrogenase, with decreases in activity observed at greater than 1 microg/ml. The observed effect was dose-dependent for both compounds examined. The metabolic activities of cells exposed to 100 microg/ml of drug were 90.37 +/- 2.8 and 71.62 +/- 2.96 (n = 3), of control values, for 7-hydroxycoumarin and esculetin, respectively. Using the cytosensor microphysiometer to assess metabolic activities, a similar pattern of inhibition was observed, with esculetin more detrimental to cellular metabolism than 7-hydroxycoumarin. The effect was dose- and time-dependent for both compounds. 7-Hydroxycoumarin (100 microg/ml) caused the cellular metabolic rate to drop to 44.21 +/- 5.34% (n = 4) of the control metabolic rate, while 100 microg/ml esculetin caused the metabolic rate to fall to 21.5 +/- 4.54% (n = 4) of the control rate. The cytosensor method proved to be superior to the tetrazolium salt assay for a number of reasons, which are discussed in this paper.

Antioxidants↗
PubMed2000

Poliovirus induces an early impairment of mitochondrial function by inhibiting succinate dehydrogenase activity.

Poliovirus infection of COS-1 and T47D cells caused a rapid decrease in total cell respiration, and this was attributed to an inhibition of mitochondrial respiration. The stimulation of mitochondrial respiration by pyruvate plus malate or succinate was impaired in saponin-permeabilised cells. However, this inhibition could be overcome by the addition of N,N,N',N'-tetramethyl-1, 4-phenylenediamine and ascorbate. The activity of succinate dehydrogenase was impaired in parallel with the inhibition of mitochondrial respiration during poliovirus infection. This shows that mitochondrial function is profoundly altered during poliovirus infection and that this occurs primarily through inhibition of electron flow at complex II of the mitochondrial respiratory chain.

Animals↗