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)

Mitochondria are the main site of ATP synthesis in aerobic cells, using the free energy of the oxidation of metabolic fuels by oxygen. They have a matrix space containing the enzymes of the citrate cycle and beta-oxidation, enclosed by an inner membrane containing the 4 complexes of the electron transport chain, ATP synthase and specific carriers for metabolites. Mitochondria also have a relatively permeable outer membrane and an intermembrane space. ATP synthesis (oxidative phosphorylation) is critically dependent on the structural integrity of the mitochondrion. Electrons from substrate oxidations feed into the electron transport chain at complex I or complex II, and then successively flow to complex III, complex IV and finally to oxygen. Complexes I, III and IV are redox pumps and electron transport causes extrusion of protons from the matrix generating an electrochemical proton gradient (proton motive force) across the inner membrane. Protons return to the matrix 'through' ATP synthase driving the synthesis of ATP. The stoichiometry of proton extrusion and the yield of ATP are still uncertain. Mitochondria have genetic continuity and are inherited maternally. They possess a small amount of DNA which codes for some, but not all, of the subunits of complexes I, III, IV of ATP synthase. mtDNA also codes for mitochondrial ribosomal and messenger RNAs involved in the synthesis of mitochondrially coded subunits. All other mitochondrial peptides are synthesised on cytosolic ribosomes and are imported and targeted to their specific intramitochondrial locations, often after proteolytic removal of leader sequences.
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PMID:Mitochondria: structure and function. 196 47

The effects of amiodarone on the respiration of isolated mouse liver mitochondria have been determined. Amiodarone (200 microM) had a biphasic effect on state 4 respiration supported by either glutamate plus malate or succinate. Initially, the respiratory rate was increased. This stimulatory effect was not prevented by oligomycin (an inhibitor of ATP synthase). It was associated with marked accumulation of amiodarone in the mitochondria, and with collapse of the mitochondrial membrane potential. This initial uncoupling effect was followed by a progressive decrease in the state 4 respiration rate, leading eventually to marked inhibition. Preincubation for 5 min with amiodarone (200 microM) also decreased markedly ADP-stimulated (state 3) respiration, ATP production and dinitrophenol-stimulated (uncoupled) respiration supported by glutamate plus malate (which donate electrons to complex I), and respiration supported by succinate (which donate electrons to complex II), but did not affect respiration supported by duroquinol (donating electrons to complex III) or by ascorbate plus N,N,N',N'-tetramethyl-p-phenylenediamine (donating electrons to cytochrome c). Preincubation with amiodarone (150-200 microM) decreased markedly respiration mediated by fatty acids of various chain length and respiration mediated by citrate, a tricarboxylic acid cycle substrate. We conclude that amiodarone has a dual effect on mitochondrial respiration. The initial uncoupling effect is probably due to the entry of protonated amiodarone, releasing a proton in the matrix. Accumulation of amiodarone soon leads to inhibition of the respiratory chain at the levels of complex I and complex II and to decreased ATP formation.
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PMID:Dual effect of amiodarone on mitochondrial respiration. Initial protonophoric uncoupling effect followed by inhibition of the respiratory chain at the levels of complex I and complex II. 197 17

In this paper we have examined the effect of cold exposure on hepatic mitochondrial state 3 respiration and ATP synthesis, using succinate as the substrate, in euthyroid, hypothyroid and hyperthyroid rats. The results show that cold exposure does not elicit any variation in the above parameters in euthyroid and hyperthyroid rats, whereas when hypothyroid rats are exposed to cold, a significant increase (about +45%) occurs in state 3 respiration and ATP synthesis. We have also measured succinic dehydrogenase specific activity and uncoupled respiration during cold exposure in various thyroid states. The finding that cold exposure elicits no variation in the above parameters indicates that there is some control on ATP synthase and/or adenine nucleotide translocator. The above findings, as a whole, suggest that cold exposure acts on oxidative phosphorylation only if triiodothyronine is lacking, by controlling ATP synthase and/or adenine nucleotide translocator.
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PMID:The effect of thyroid state and cold exposure on rat liver oxidative phosphorylation. 205 Feb 63

Oxidative phosphorylation can be treated as two groups of reactions; those that generate protonmotive force (dicarboxylate carrier, succinate dehydrogenase and the respiratory chain) and those that consume protonmotive force (adenine nucleotide and phosphate carriers. ATP synthase and proton leak). Mitochondria from hypothyroid rats have lower rates of respiration in the presence of ADP (state 3) than euthyroid controls. We show that the kinetics of the protonmotive-force generators are unchanged in mitochondria from hypothyroid animals, but the kinetics of the protonmotive-force consumers are altered, supporting proposals that the important effects of thyroid hormone on state 3 are on the ATP synthase or the adenine nucleotide translocator.
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PMID:Thyroid-hormone control of state-3 respiration in isolated rat liver mitochondria. 230 10

In this study we have examined (1) the integrated function of the mitochondrial respiratory chain by polarographic measurements and (2) the activities of the respiratory chain complexes I, II-III, and IV as well as the ATP synthase (complex V) in free mitochondria and synaptosomes isolated from gerbil brain, after a 30-min period of graded cerebral ischaemia. These data have been correlated with cerebral blood flow (CBF) values as measured by the hydrogen clearance technique. Integrated functioning of the mitochondrial respiratory chain, using both NAD-linked and FAD-linked substrates, was initially affected at CBF values of approximately 35 ml 100 g-1 min-1, and declined further as the CBF was reduced. The individual mitochondrial respiratory chain complexes, however, showed differences in sensitivity to graded cerebral ischaemia. Complex I activities decreased sharply at blood flows below approximately 30 ml 100 g-1 min-1 (mitochondria and synaptosomes) and complex II-III activities decreased at blood flows below 20 ml 100 g-1 min-1 (mitochondria) and 35-30 ml 100 g-1 min-1 (synaptosomes). Activities declined further as CBF was reduced below these levels. Complex V activity was significantly affected only when the blood flow was reduced below 15-10 ml 100 g-1 min-1 (mitochondria and synaptosomes). In contrast, complex IV activity was unaffected by graded cerebral ischaemia, even at very low CBF levels.
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PMID:Changes of respiratory chain activity in mitochondrial and synaptosomal fractions isolated from the gerbil brain after graded ischaemia. 772 7

Cytosolic Ca2+ overload may play a key role in the process of lead-induced retinal injury and degeneration. We report that retinal calcium content was elevated following developmental and in vitro lead exposure. To determine the concentration-dependent effects of Ca2+ (5-1000 nM) on retinal mitochondrial bioenergetics an isolation procedure was developed. Isolated mitochondria were efficiently coupled; had good respiratory control ratios with the NAD-linked substrates, glutamate or pyruvate plus malate (G/M or P/M), and the FAD-linked substrate, succinate plus rotenone (S/R); and possessed a Na+/Ca2+ exchanger. The major finding was that at equimolar [Ca2+] > or = 35 nM, mitochondria were more sensitive to and exhibited a greater degree of inhibition of coupled and uncoupled respiration with NAD-linked substrates compared to S/R. At all [Ca2+], decreases in State 3 and uncoupled respiration were similar, thereby eliminating the ATP synthase and ADP/ATP translocase as sites of inhibition and suggesting that opening the mitochondrial permeability transition pore (MTP) did not contribute to the inhibition. The effects of toxicological [Ca2+] were: (1) blocked by ruthenium red, (2) blocked by dibucaine only in the presence of NAD-linked substrates, and (3) partially reversed by NAD+ with G/M after opening the MTP. Results with G/M suggest that Ca2+ acts on the inner membrane phospholipase A2 to decrease NADH CoQ reductase activity and/or produce a NAD+ leak, whereas with S/R, Ca2+ may inhibit succinate dehydrogenase. In conclusion, Ca2+ inhibits retinal mitochondrial ATP production, which may contribute to the retinal cell injury and death observed in developmentally lead-exposed rats.
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PMID:Substrate-dependent effects of calcium on rat retinal mitochondrial respiration: physiological and toxicological studies. 817 38

Primary aliphatic alcohols from hexanol to pentadecanol were tested for their effects on the succinate-supported respiration of intact mitochondria isolated from rat liver. Alkanols were found to inhibit State 3 and uncoupled respiration. The ADP/oxygen ratios, a measure of the efficiency of oxidative phosphorylation, also were lowered, but to a lesser degree when compared on the basis of percentage of controls. Given each alkanol's nearly identical effect on State 3 and uncoupled respiration, action is not directly on ATP synthase, but earlier in the respiratory process. In agreement with many other studies of the homologous series of alkanols, potency increased with number of carbons in the chain until reaching a peak, in this case at undecanol, then tapered off to tridecanol before reaching a cutoff, at tetradecanol. If tetradecanol or longer homologs have activity, it is only after a lag phase of >15-min preincubation. All alkanols up to tridecanol also acted as uncouplers. At higher doses, hexanol inhibited State 4 rates, whereas longer chain alkanols did not, even at doses that completely eliminated respiratory control. Hexanol and decanol also were assayed against freeze-thawed (broken) mitochondria to distinguish effects on the mitochondrial substrate carrier from those on the electron transport chain. Both compounds were only weak inhibitors of respiration in broken mitochondria, suggesting that inhibition originates from interference with the dicarboxylate carrier, which must transport succinate across the mitochondrial membranes before it can be fed into complex II, rather than affecting the electron transport chain itself.
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PMID:Alkanols inhibit respiration of intact mitochondria and display cutoff similar to that measured in vivo. 1086 81

The import pathways of the alternative oxidase and the F(A)d subunit of the ATP synthase from soybean were characterised. The F(A)d precursor does not require extramitochondrial ATP for import and this was shown to be a characteristic of the mature protein. The alternative oxidase and F(A)d precursors were shown to differ in their requirement for a membrane potential. The membrane potential was modified using malonate, a competitive inhibitor to complex II. The alternative oxidase could be imported at higher malonate concentrations compared to the F(A)d. This difference could not be ascribed to the number of positive charges in each presequence as would be predicted from similar studies in fungi.
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PMID:Protein import into plant mitochondria: precursor proteins differ in ATP and membrane potential requirements. 1129 77

In 32D cl 3 hematopoietic progenitor cells, the overexpression of manganese superoxide dismutase (MnSOD, SOD2), the enzyme normally found in mitochondria, protects against the damaging effects of ionizing radiation. In the presence of a nitric oxide donor, which exacerbates the damage, inhibition of mitochondrial function can be demonstrated to be associated with respiratory complexes I (NADH dehydrogenase) and III (cytochrome c reductase), but not II (succinate dehydrogenase), IV (cytochrome c oxidase), or V (ATP synthase). The same pattern of inhibition is observed in the case of isolated bovine heart mitochondria exposed to ionizing radiation and the nitric oxide donor. The addition of authentic peroxynitrite (ONO2(-)) to isolated mitochondria also results in damage to complexes I and III (but not II, IV, and V), as shown by assays of electron-transfer activities and electron paramagnetic resonance (EPR) spectroscopic measurements, suggesting ONO2(-) to be responsible for most of the observed radiation damage in both the cultured cell lines and isolated mitochondria. It is argued that, in general, production of ONO2(-) is an important contributor to radiation damage in biological systems and the implications of these findings in relation to possible mechanisms of oxidant-linked apoptosis are briefly considered.
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PMID:Identification of respiratory complexes I and III as mitochondrial sites of damage following exposure to ionizing radiation and nitric oxide. 1129 62

Parkinson's disease is the second most common neurodegenerative disorder after Alzheimer's disease affecting approximately1% of the population older than 50 years. There is a worldwide increase in disease prevalence due to the increasing age of human populations. A definitive neuropathological diagnosis of Parkinson's disease requires loss of dopaminergic neurons in the substantia nigra and related brain stem nuclei, and the presence of Lewy bodies in remaining nerve cells. The contribution of genetic factors to the pathogenesis of Parkinson's disease is increasingly being recognized. A point mutation which is sufficient to cause a rare autosomal dominant form of the disorder has been recently identified in the alpha-synuclein gene on chromosome 4 in the much more common sporadic, or 'idiopathic' form of Parkinson's disease, and a defect of complex I of the mitochondrial respiratory chain was confirmed at the biochemical level. Disease specificity of this defect has been demonstrated for the parkinsonian substantia nigra. These findings and the observation that the neurotoxin 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP), which causes a Parkinson-like syndrome in humans, acts via inhibition of complex I have triggered research interest in the mitochondrial genetics of Parkinson's disease. Oxidative phosphorylation consists of five protein-lipid enzyme complexes located in the mitochondrial inner membrane that contain flavins (FMN, FAD), quinoid compounds (coenzyme Q10, CoQ10) and transition metal compounds (iron-sulfur clusters, hemes, protein-bound copper). These enzymes are designated complex I (NADH:ubiquinone oxidoreductase, EC 1.6. 5.3), complex II (succinate:ubiquinone oxidoreductase, EC 1.3.5.1), complex III (ubiquinol:ferrocytochrome c oxidoreductase, EC 1.10.2.2), complex IV (ferrocytochrome c:oxygen oxidoreductase or cytochrome c oxidase, EC 1.9.3.1), and complex V (ATP synthase, EC 3.6.1.34). A defect in mitochondrial oxidative phosphorylation, in terms of a reduction in the activity of NADH CoQ reductase (complex I) has been reported in the striatum of patients with Parkinson's disease. The reduction in the activity of complex I is found in the substantia nigra, but not in other areas of the brain, such as globus pallidus or cerebral cortex. Therefore, the specificity of mitochondrial impairment may play a role in the degeneration of nigrostriatal dopaminergic neurons. This view is supported by the fact that MPTP generating 1-methyl-4-phenylpyridine (MPP(+)) destroys dopaminergic neurons in the substantia nigra. Although the serum levels of CoQ10 is normal in patients with Parkinson's disease, CoQ10 is able to attenuate the MPTP-induced loss of striatal dopaminergic neurons.
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PMID:Ubiquinone (coenzyme q10) and mitochondria in oxidative stress of parkinson's disease. 1135 Nov 30


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