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PubMed2002

Diagnostic value of succinate ubiquinone reductase activity in the identification of patients with mitochondrial DNA depletion.

Mitochondrial DNA (mtDNA) depletion syndrome (McKusick 251880) is characterized by a progressive quantitative loss of mtDNA resulting in severe mitochondrial dysfunction. A diagnosis of mtDNA depletion can only be confirmed after Southern blot analysis of affected tissue. Only a limited number of centres have the facilities to offer this service, and this is frequently on an irregular basis. There is therefore a need for a test that can refine sample selection as well as complementing the molecular analysis. In this study we compared the activities of the nuclear-encoded succinate ubiquinone reductase (complex II) to the activities of the combined mitochondrial and nuclear-encoded mitochondrial electron transport chain (ETC) complexes; NADH:ubiquinone reductase (complex I), ubiquinol-cytochrome-c reductase (complex III), and cytochrome-c oxidase (complex IV), in skeletal muscle biopsies from 7 patients with confirmed mtDNA depletion. In one patient there was no evidence of an ETC defect. However, the remaining 6 patients exhibited reduced complex I and IV activities. Five of these patients also displayed reduced complex II-III (succinate:cytochrome-c reductase) activity. Individual measurement of complex II and complex III activities demonstrated normal levels of complex II activity compared to complex III, which was reduced in the 5 biopsies assayed. These findings suggest a possible diagnostic value for the detection of normal levels of complex II activity in conjunction with reduced complex I, III and IV activity in the identification of likely candidates for mtDNA depletion syndrome

DNA, Mitochondrial↗
PubMed2002

Modification of radiation-induced changes in the reproductive system of male rats with sodium succinate.

We studied the effects of sodium succinate on the reproductive system and blood leukocyte count in rats 30 and 60 days after fractionated irradiation in a dose of 1 Gy. Sodium succinate in concentrations of 0.2 and 0.5% was given ad libitum with water before (1 week) and during irradiation (5 days). The preparation promoted morphofunctional recovery of the testes and epididymides and restored the count of peripheral blood leukocytes.

Animals↗
PubMed2002

In vitro response of mitochondrial succinate oxidase system to epinephrine in human blood lymphocytes from health individuals and patients with neurocirculatory dystonia.

Activities of succinate dehydrogenase (SDH) and alpha-glycerophosphate dehydrogenase (hyaloplasmic and mitochondrial: alpha-GPDHH and alpha-GPDHM) in peripheral blood lymphocytes, and the response of SDH activity to exogenous epinephrine in vitro (the epinephrine test) were studied in 20 healthy subjects and 46 patients with hypertensive neurocirculatory dystonia. Activities of SDH, alpha-GPDHH, and alpha-GPDHM in blood lymphocytes and SDH adrenoreactivity in epinephrine test were higher in patients than in healthy controls. Treatment with hypotensive agents (isradipin and pyrroxan) moderated adrenoreactivity. Phytotherapy normalized the baseline activities of succinate oxidase system and alpha-glycerophosphate pathway in blood lymphocytes.

Adult↗
PubMed2004

Effect of melatonin, ascorbic acid, and succinic acid on the cumulative toxic effect of repeated treatment with gammafos (amifostine).

Daily treatment of outbred albino mice with gammafos in radioprotective doses of 300 and 500 mg/kg for 4 days produced a cumulative toxic effect. This effect was not observed after decreasing the dose of gammafos to 100 mg/kg. Repeated peroral administration of melatonin and ascorbic acid in a dose of 200 mg/kg 30 min before treatment with gammafos reduced its cumulative toxic effect. Succinic acid in a dose of 100 mg/kg was ineffective under these conditions. The cumulative death time for 50% animals receiving gammafos alone or in combination with melatonin, ascorbic acid, and succinic acid was 3.08, 4.29, 4.06, and 2.97 days, respectively.

Amifostine↗
PubMed1998

A mutation in succinate dehydrogenase cytochrome b causes oxidative stress and ageing in nematodes.

Much attention has focused on the aetiology of oxidative damage in cellular and organismal ageing. Especially toxic are the reactive oxygen byproducts of respiration and other biological processes. A mev-1(kn1) mutant of Caenorhabditis elegans has been found to be hypersensitive to raised oxygen concentrations. Unlike the wild type, its lifespan decreases dramatically as oxygen concentrations are increased from 1 to 60%. Strains bearing this mutation accumulate markers of ageing (such as fluorescent materials and protein carbonyls) faster than the wild type. We show here that mev-1 encodes a subunit of the enzyme succinate dehydrogenase cytochrome b, which is a component of complex II of the mitochondrial electron transport chain. We found that the ability of complex II to catalyse electron transport from succinate to ubiquinone is compromised in mev-1 animals. This may cause an indirect increase in superoxide levels, which in turn leads to oxygen hypersensitivity and premature ageing. Our results indicate that mev-1 governs the rate of ageing by modulating the cellular response to oxidative stress.

Aging↗
PubMed1969

Reversible activation of succinate dehydrogenase.

1. Treatment of particulate respiratory chain preparations in ways expected to raise or lower the concentration of endogenous soluble low-molecular-weight compounds respectively increased and diminished the capacity of succinate dehydrogenase to become activated reversibly and ;spontaneously' when preparations were diluted in tris acetate buffer and incubated at 37 degrees . 2. Addition of critically low concentrations of recognized activators to preparations that failed to undergo reversible ;spontaneous' activation when incubated at 1mg. of protein/ml. conferred on them the capacity to do so. 3. Preparations with a diminished tendency to undergo reversible ;spontaneous' activation had an increased tendency to become irreversibly inactivated on prolonged incubation at 1mg. of protein/ml. in tris acetate. 4. Extraction procedures designed to demonstrate the presence of possible endogenous activators in enzyme preparations failed to reveal a single substance to which such a role could be conclusively attributed. A mixture of compounds was found, however, including certain amino acids that have been shown to act as activators. It is questionable whether these compounds would be present at sufficiently high concentrations to act as activators when enzyme preparations are diluted to 1mg. of protein/ml. 5. Despite the failure to demonstrate conclusively the presence of endogenous activators, the balance of evidence appears to favour the hypothesis that reversible ;spontaneous' activation of these preparations can best be explained by the presence of such substances, and a scheme describing the mechanism of activation and deactivation of succinate dehydrogenase is discussed in relation to these and other observations.

Amino Acids↗
PubMed1980

Studies on the stabilized ubisemiquinone species in the succinate-cytochrome c reductase segment of the intact mitochondrial membrane system.

1. Evidence is presented for the presence of a stable ubisemiquinone pair in the vicinity of iron-sulphur centre S-3, based on its thermodynamic and spin relaxation properties. 2. These semiquinones are coupled by dipolar interaction; quantitative analysis of the signals of the spin-coupled semiquinones (at pH 7.4) gives midpoint redox potentials E1 (oxidized to semiquinone state) and E2 (semiquinone to fully reduced state) of 140 and 80mV, respectively, for individual ubiquinones. 3. Values of pKS (pK of the semiquinone form) below 6.5 and pKR (pK of the fully reduced ubiquinone) of about 8.0 or above were estimated from the pH-dependence of the midpoint potentials of the spin coupled signals. Thus the ubisemiquinone associated with succinate dehydrogenase (designated as SQS) functions mostly in the anionic form of the physiological pH range. 4. Theonyltrifluoroacetone, a specific inhibitor of the succinate-ubiquinone reductase segment of the respiratory chain, destabilized the intermediate redox state; thus it quenches both the g = 2.00 signal and ubisemiquinone (SQS) and split signals from the spin coupled pair. This inhibitor has no significant effect on another bound ubisemiquinone species present in the cytochrome bc1 region (designated as SQC). 5. The possible function and location of these stabilized ubisemiquinone species were discussed in connection with Site-II energy transduction.

Animals↗
PubMed1984

Nucleotide sequence encoding the flavoprotein and hydrophobic subunits of the succinate dehydrogenase of Escherichia coli.

The nucleotide sequence of a 3614 base-pair segment of DNA containing the sdhA gene, encoding the flavoprotein subunit of succinate dehydrogenase of Escherichia coli, and two genes sdhC and sdhD, encoding small hydrophobic subunits, has been determined. Together with the iron-sulphur protein gene (sdhB) these genes form an operon (sdhCDAB) situated between the citrate synthase gene (gltA) and the 2-oxoglutarate dehydrogenase complex genes (sucAB): gltA-sdhCDAB-sucAB. Transcription of the gltA and sdhCDAB gene appears to diverge from a single intergenic region that contains two pairs of potential promoter sequences and two putative CRP (cyclic AMP receptor protein)-binding sites. The sdhA structural gene comprises 1761 base-pairs (587 codons, excluding the initiation codon, AUG) and it encodes a polypeptide of Mr 64268 that is strikingly homologous with the flavoprotein subunit of fumarate reductase (frdA gene product). The FAD-binding region, including the histidine residue at the FAD-attachment site, has been identified by its homology with other flavoproteins and with the flavopeptide of the bovine heart mitochondrial succinate dehydrogenase. Potential active-site cysteine and histidine residues have also been indicated by the comparisons. The sdhC (384 base-pairs) and sdhD (342 base-pairs) structural genes encode two strongly hydrophobic proteins of Mr 14167 and 12792 respectively. These proteins resemble in size and composition, but not sequence, the membrane anchor proteins of fumarate reductase (the frdC and frdD gene products).

Amino Acid Sequence↗
PubMed1984

Nucleotide sequence encoding the iron-sulphur protein subunit of the succinate dehydrogenase of Escherichia coli.

The nucleotide sequence of a 961 base-pair segment of DNA containing the sdhB gene, which encodes the iron-sulphur protein subunit of the E. coli succinate dehydrogenase, has been determined. The sdhB structural gene comprises 711 base pairs (237 codons, excluding the translational initiator and terminator). It is separated by a 15 base-pair intergenic region from the preceding flavoprotein gene (sdhA) and is the distal gene of an operon that also includes genes (sdhC and D) encoding two hydrophobic subunits, sdhCDAB. The distal end of the sdh operon is linked to the 2-oxoglutarate dehydrogenase gene (sucA) by a complex region of dyad symmetry that is homologous with several potential intercistronic regulatory elements or transcriptional attenuators. The sdhB structural gene encodes a polypeptide of Mr26637 that is strikingly homologous with the iron-sulphur protein subunit of fumarate reductase (38% identity, increasing to 58% when conservative changes are included). Both subunits contain 11 cysteine residues, 10 being conserved in three clusters resembling those found in ferredoxins. This work completes the sequence of a 9897 base-pair segment of DNA containing seven tricarboxylic acid cycle genes encoding three enzymes or enzyme complexes, citrate synthase (gltA), succinate dehydrogenase (sdh), and the 2-oxoglutarate dehydrogenase complex (suc), that are organized thus: gltA-sdhCDAB-sucAB.

Amino Acids↗
PubMed1991

Topography of succinate dehydrogenase in the mitochondrial inner membrane. A study using limited proteolysis and immunoblotting.

The arrangement of the large (70,000-Mr) and small (30,000-Mr) subunits of succinate dehydrogenase in the mitochondrial inner membrane was investigated by immunoblot analysis of bovine heart mitochondria (right-side-out, outer membrane disrupted) or submitochondrial particles (inside-out) that had been subjected to surface-specific proteolysis. Both subunits were resistant to proteinase treatment provided that the integrity of the inner membrane was preserved, suggesting that neither subunit is exposed at the cytoplasmic surface of the membrane. The bulk of the small subunit appears to protrude into the matrix compartment, since the 30,000-Mr polypeptide is degraded extensively during limited proteolysis of submitochondrial particles without the appearance of an immunologically reactive membrane-associated fragment: moreover, a soluble 27,000-Mr peptide derived from this subunit is observed transiently on incubation with trypsin. Similar data obtained from the large subunit suggest that this polypeptide interacts with the matrix side of the inner membrane via two distinct domains; these are detected as stable membrane-associated fragments of 32,000 Mr and 27,000 Mr after treatment of submitochondrial particles with papain or proteinase K, although the 27,000-Mr fragment can be degraded further to low-Mr peptides with trypsin or alpha-chymotrypsin. A stable 32,000-34,000-Mr fragment is generated by a variety of specific and non-specific proteinases, indicating that it may be embedded largely within the lipid bilayer, or is inaccessible to proteolytic attack owing to its proximity to the surface of the intact membrane, possibly interacting with the hydrophobic membrane anchoring polypeptides of the succinate: ubiquinone reductase complex.

Animals↗
PubMed1995

Characterization of the excitotoxic potential of the reversible succinate dehydrogenase inhibitor malonate.

Although the mechanism of neuronal death in neurodegenerative diseases remains unknown, it has been hypothesized that relatively minor metabolic defects may predispose neurons to N-methyl-D-aspartate (NMDA) receptor-mediated excitotoxic damage in these disorders. To further investigate this possibility, we have characterized the excitotoxic potential of the reversible succinate dehydrogenase (SDH) inhibitor malonate. After its intrastriatal stereotaxic injection into male Sprague-Dawley rats, malonate produced a dose-dependent lesion when assessed 3 days after surgery using cytochrome oxidase histochemistry. This lesion was attenuated by coadministration of excess succinate, indicating that it was caused by specific inhibition of SDH. The lesion was also prevented by administration of the noncompetitive NMDA antagonist MK-801. MK-801 did not induce hypothermia, and hypothermia itself was not neuroprotective, suggesting that the neuroprotective effect of MK-801 was due to blockade of the NMDA receptor ion channel and not to any nonspecific effect. The competitive NMDA antagonist LY274614 and the glycine site antagonist 7-chlorokynurenate also profoundly attenuated malonate neurotoxicity, further indicating an NMDA receptor-mediated event. Finally, the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) antagonist NBQX (2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)-quinoxaline) was ineffective at preventing malonate toxicity at a dose that effectively reduced S-AMPA toxicity, indicating that non-NMDA receptors are involved minimally, if at all, in the production of the malonate lesion. We conclude that inhibition of SDH by malonate results in NMDA receptor-mediated excitotoxic neuronal death. If this mechanism of "secondary" or "weak" excitotoxicity plays a role in neurodegenerative disease, NMDA antagonists and other "antiexcitotoxic" strategies may have therapeutic potential for these diseases.

Animals↗
PubMed1995

Suppression of mitochondrial succinate dehydrogenase, a primary target of beta-amyloid, and its derivative racemized at Ser residue.

beta-Amyloid cores contain considerable amounts of D-Ser and D-Asp residues in Alzheimer's disease. We investigated the cytotoxic effects of various synthetic beta-amyloids, including D-Ser-substituted derivatives, on primary cultured neurons and nonneuronal HeLa cells. beta 25-35, its D-Ser26-substituted derivative, and beta 1-40 in 10-100 nM specifically suppressed mitochondrial succinate dehydrogenase activity [MTT [3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide] reduction] in HeLa cells, which are dependent on ATP production mainly from glycolysis, but did not exert detectable cytotoxicity, assessed by dye exclusion test, NADH levels, and uptake of [3H]Leu and [3H]Tdr. The beta-amyloids, on the other hand, did exert neurodegenerative effects on rat hippocampal cultured neurons in which ATP is mostly synthesized by the mitochondrion. The activities of beta 25-35 and [D-Ser26] beta 25-35 are dependent on their having beta-structures and not random forms. Although beta 25-35 was degraded rapidly by proteinase(s) in brain extract or leucine aminopeptidase, [D-Ser26] beta 25-35 is fairly resistant. These results indicate that one of the primary targets of beta-amyloids is suppression of mitochondrial succinate dehydrogenase, and the vulnerability of the brain of beta-amyloids can be explained by its large dependence on mitochondrial energy production. Moreover, racemization of serine residues of beta-amyloids may be involved in neurodegeneration and formation of senile plaques through escaping from the degradation process by brain proteinases.

Amino Acid Sequence↗
PubMed2002

Focal neurometabolic alterations in mice deficient for succinate semialdehyde dehydrogenase.

Metabolite profiling in succinate semialdehyde dehydrogenase (SSADH; Aldh5a1-/-) deficient mice previously revealed elevated gamma-hydroxybutyrate (GHB) and total GABA in urine and total brain and liver extracts. In this study, we extend our metabolic characterization of these mutant mice by documenting elevated GHB and total GABA in homogenates of mutant kidney, pancreas and heart. We quantified beta-alanine (a GABA homolog and putative neurotransmitter) to address its potential role in pathophysiology. We found normal levels of beta-alanine in urine and total homogenates of mutant brain, heart and pancreas, but elevated concentrations in mutant kidney and liver extracts. Amino acid analysis in mutant total brain homogenates revealed no abnormalities except for significantly decreased glutamine, which was normal in mutant liver and kidney extracts. Regional amino acid analysis (frontal cortex, parietal cortex, hippocampus and cerebellum) in mutant mice confirmed glutamine results. Glutamine synthetase protein and mRNA levels in homogenates of mutant mouse brain were normal. We profiled organic acid patterns in mutant brain homogenates to assess brain oxidative metabolism and found normal concentrations of Kreb's cycle intermediates but increased 4,5-dihydroxyhexanoic acid (a postulated derivative of succinic semialdehyde) levels. We conclude that SSADH-deficient mice represent a valid metabolic model of human SSADH deficiency, manifesting focal neurometabolic abnormalities which could provide key insights into pathophysiologic mechanisms.

Aldehyde Oxidoreductases↗
PubMed2003

Oxidation of 4-hydroxy-2-nonenal by succinic semialdehyde dehydrogenase (ALDH5A).

Elevated levels of 4-hydroxy-trans-2-nonenal (HNE) are implicated in the pathogenesis of numerous neurodegenerative disorders. Although well-characterized in the periphery, the mechanisms of detoxification of HNE in the CNS are unclear. HNE is oxidized to a non-toxic metabolite in the rat cerebral cortex by mitochondrial aldehyde dehydrogenases (ALDHs). Two possible ALDH enzymes which might oxidize HNE in CNS mitochondria are ALDH2 and succinic semialdehyde dehydrogenase (SSADH/ALDH5A). It was previously established that hepatic ALDH2 can oxidize HNE. In this work, we tested the hypothesis that SSADH oxidizes HNE. SSADH is critical in the detoxification of the GABA metabolite, succinic semialdehyde (SSA). Recombinant rat SSADH oxidized HNE and other alpha,beta-unsaturated aldehydes. Inhibition and competition studies in rat brain mitochondria showed that SSADH was the predominant oxidizing enzyme for HNE but only contributed a portion of the total oxidizing activity in liver mitochondria. In vivo administration of diethyldithiocarbamate (DEDC) effectively inhibited (86%) ALDH2 activity but not HNE oxidation in liver mitochondria. The data suggest that a relationship between the detoxification of SSA and the neurotoxic aldehyde HNE exists in the CNS. Furthermore, these studies show that multiple hepatic aldehyde dehydrogenases are able to oxidize HNE.

Aldehyde Dehydrogenase↗
PubMed2002

Improvement of the bioavailability of colchicine in rats by co-administration of D-alpha-tocopherol polyethylene glycol 1000 succinate and a polyethoxylated derivative of 12-hydroxy-stearic acid.

Two surface-active formulation ingredients, a water-soluble derivative of vitamin E (D-alpha-tocopherol polyethylene glycol 1000 succinate, vitamin E-TPGS) as well as a polyethoxylated derivative of 12-hydroxy-stearic acid (Solutol HS 15) were investigated in rats for their potential to increase the oral bioavailability of the p-glycoprotein (p-gp) and cytochrome P450 substrate colchicine. D-alpha-Tocopherol polyethylene glycol 1000 succinate and the polyethoxylated derivative of 12-hydroxy-stearic acid will be referred to as "surfactant 1" and "surfactant 2" in the following. Colchicine was administered to the animals at a dose level of 5 mg/kg in each 10% surfactant containing formulation. A solution of colchicine in isotonic saline was selected as a reference formulation. It was found that the administration of colchicine in the surfactant containing formulations resulted in significantly higher systemic exposures as compared to the aqueous reference vehicle (2-fold increase in AUC in the presence of surfactant 1 and 4-fold increase in AUC in the presence of surfactant 2). The aqueous solubility of colchicine was about 16.7 mg/ml, and the increase in solubility in the presence of 1% surfactant 1 or surfactant 2 to about 20.5 and 18.5 mg/ml was not considered to significantly affect the oral bioavailability. In summary, it was demonstrated that both surfactants are suitable formulation ingredients to improve the systemic exposure of colchicine in the rat. Due to the high aqueous solubility of colchicine the most likely reasons for these findings are inhibition of p-gp and/or metabolism as well as permeability enhancement by interactions of the surfactants with the intestinal membrane.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2003

Atpenins, potent and specific inhibitors of mitochondrial complex II (succinate-ubiquinone oxidoreductase).

Enzymes in the mitochondrial respiratory chain are involved in various physiological events in addition to their essential role in the production of ATP by oxidative phosphorylation. The use of specific and potent inhibitors of complex I (NADH-ubiquinone reductase) and complex III (ubiquinol-cytochrome c reductase), such as rotenone and antimycin, respectively, has allowed determination of the role of these enzymes in physiological processes. However, unlike complexes I, III, and IV (cytochrome c oxidase), there are few potent and specific inhibitors of complex II (succinate-ubiquinone reductase) that have been described. In this article, we report that atpenins potently and specifically inhibit the succinate-ubiquinone reductase activity of mitochondrial complex II. Therefore, atpenins may be useful tools for clarifying the biochemical and structural properties of complex II, as well as for determining its physiological roles in mammalian tissues.

Animals↗
PubMed1995

Molecular cloning of the mature NAD(+)-dependent succinic semialdehyde dehydrogenase from rat and human. cDNA isolation, evolutionary homology, and tissue expression.

Three rat brain cDNA clones approximately 3500, 1465, and 1135 base pairs in length encoding succinic semialdehyde dehydrogenase (SSADH; EC 1.2.1.24) were isolated from two cDNA libraries using a polymerase chain reaction derived probe. Restriction mapping and DNA sequencing revealed that the 3.5-kilobase clone contained an 84-base pair (28 amino acid) insert in the coding region. Composite clones encoding mature SSADH predicted proteins with 488 amino acids (M(r) = 52,188) when including the insert and 460 amino acids (M(r) = 48,854) without the insert. The cDNA clones were confirmed by expression of enzyme activity in bacteria and protein sequence data obtained from sequencing purified rat brain SSADH. Two human liver SSADH cDNA clones of 1091 and 899 base pairs were also isolated. Human and rat SSADH share 83 and 91% identity in nucleotide and protein sequence, respectively. Northern blot analysis revealed two differentially expressed SSADH transcripts of approximately 2.0 and 6.0 kilobases in both rat and human tissues. Human genomic Southern blots indicate that the two SSADH transcripts are encoded by a greater than 20-kilobase single copy gene. Mammalian SSADH contains significant homology to bacterial NADP(+)-succinic semialdehyde dehydrogenase (EC 1.2.1.16) and conserved regions of general aldehyde dehydrogenases (EC 1.2.1.3), suggesting it is a member of the aldehyde dehydrogenase superfamily of proteins.

Aldehyde Dehydrogenase↗