Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.6.5.3 (complex I)
8,901 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Defects in complex I and alpha-ketoglutarate dehydrogenase (alpha-KGDH) occur in the substantia nigra in Parkinson's disease (PD). Isoquinoline derivatives structurally related to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 1-methyl-4-phenylpyridinium (MPP+) are implicated in the cause of PD as endogenous toxins and are inhibitors of complex I. However, their effects on alpha-KGDH and other mitochondrial non-respiratory chain enzymes are unknown. We have examined the effects of six isoquinoline derivatives (isoquinoline, N-methylisoquinolinium, N-n-propylisoquinolinium, 1,2,3,4-tetrahydroisoquinoline, N-methyl-1,2,3,4-tetrahydroisoquinoline and salsolinol) and MPP+ on the activities of alpha-KGDH, citrate synthase (CS) and glutamate dehydrogenase (GDH) in mitochondrial fragments from rat forebrain. None of the compounds examined had any effect on CS or GDH activity. In contrast, all isoquinoline derivatives investigated and MPP+ inhibited alpha-KGDH activity in a concentration-dependent manner with IC50s ranging from 2.0 to 18.9 mM. MPP+ was previously shown to inhibit alpha-KGDH, but this is the first report of inhibition of alpha-KGDH by isoquinoline derivatives. These findings may represent an additional mechanism contributing to mitochondrial dysfunction and cell death in Parkinson's disease.
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PMID:Inhibition of alpha-ketoglutarate dehydrogenase by isoquinoline derivatives structurally related to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). 766 87

We report an immunohistochemical study of the mitochondrial alpha-ketoglutarate dehydrogenase complex (KGDHC) in the substantia nigra in Parkinson's disease. The KGDHC, the three enzyme complex catalyzing the oxidation of alpha-ketoglutarate to succinate through succinic semialdehyde, is the rate-regulating enzyme of the TCA cycle. The mitochondrial toxin, MPP+, inhibits not only complex I but also the KGDHC. Therefore, we investigated this enzyme complex in Parkinson's disease. In the control patients (n = 6), the immunostaining of the melanized nigral neurons was generally uniform; most of the melanized neurons showed good immunostaining with some neurons showing somewhat reduced staining. In Parkinson's disease (n = 9), many melanized neurons showed reduced immunostaining for the KGDHC, and those neurons were more frequently seen in the lateral one-third of substantia nigra. The decrease in the immunostaining for the KGDHC correlated roughly with the severity of degeneration. The KGDHC is more vulnerable to degeneration than complex II, III, and IV as noted in our previous immunohistochemical study. Even if secondary, the loss may play a role in the progression of the disease.
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PMID:An immunohistochemical study on alpha-ketoglutarate dehydrogenase complex in Parkinson's disease. 810

The mitochondrion is the only extranuclear organelle containing DNA (mtDNA). As such, genetically determined mitochondrial diseases may result from a molecular defect involving the mitochondrial or the nuclear genome. The first is characterized by maternal inheritance and the second by Mendelian inheritance. Ragged-red fibers (RRF) are commonly seen with primary lesions of mtDNA, but this association is not invariant. Conversely, RRF are seldom associated with primary lesions of nuclear DNA. Large-scale rearrangements (deletions and insertions) and point mutations of mtDNA are commonly associated with RRF and lactic acidosis, e.g. Kearns-Sayre syndrome (KSS) (major large-scale rearrangements), Pearson syndrome (large-scale rearrangements), myoclonus epilepsy with RRF (MERRF) (point mutation affecting tRNA(lys) gene), mitochondrial myopathy, lactic acidosis, and stroke-like episodes (MELAS) (two point mutations affecting tRNA(leu)(UUR) gene) and a maternally-inherited myopathy with cardiac involvement (MIMyCa) (point mutation affecting tRNA(leu)(UUR) gene). However, RRF and lactic acidosis are absent in Leber hereditary optic neuropathy (LHON) (one point mutation affecting ND4 gene, two point mutations affecting ND1 gene, and one point mutation affecting the apocytochrome b subunit of complex III), and the condition associated with maternally inherited sensory neuropathy (N), ataxia (A), retinitis pigmentosa (RP), developmental delay, dementia, seizures, and limb weakness (NARP) (point mutation affecting ATPase subunit 6 gene). The point mutations in MELAS, MIMyCa, and MERRF, and the large-scale mtDNA rearrangements in KSS and Pearson syndrome have a broader biochemical impact since these molecular defects involve the translational sequence of mitochondrial protein synthesis. The nuclear defects involving mitochondrial function generally are not associated with RRF. The biochemical classification of mitochondrial diseases principally catalogues these nuclear defects. This classification divides mitochondrial diseases into five categories. Primary and secondary deficiencies of carnitine are examples of a substrate transport defect. A lipid storage myopathy is often present. Disturbances of pyruvate or fatty acid metabolism are examples of substrate utilization defects. Only four defects of the Krebs cycle are known: fumarase deficiency, dihydrolipoyl dehydrogenase deficiency, alpha-ketoglutarate dehydrogenase deficiency, and combined defects of muscle succinate dehydrogenase and aconitase. Luft disease is the singular example of a defect in oxidation-phosphorylation coupling. Defects of respiratory chain function are manifold. Two clinical syndromes predominate, one involving limb weakness, and the other primarily affecting brain function. Leigh syndrome may result from different enzyme defects, most notably pyruvate dehydrogenase complex deficiency, cytochrome c oxidase deficiency, complex I deficiency, and complex V deficiency associated with the recently described NARP point mutation. A new group of mitochondrial diseases has emerged.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The expanding clinical spectrum of mitochondrial diseases. 833 7

Isoquinoline derivatives exert 1-methyl-4-phenylpyridinium (MPP+)-like activity as inhibitors of complex I and alpha-ketoglutarate dehydrogenase activity in rat brain mitochondrial fragments. We now examine the ability of 19 isoquinoline derivatives and MPP+ to accumulate and inhibit respiration in intact rat liver mitochondria, assessed using polarographic techniques. None of the compounds examined inhibited respiration supported by either succinate + rotenone or tetramethylparaphenylenediamine (TMPD) + ascorbate. However, with glutamate + malate as substrates, 15 isoquinoline derivatives and MPP+ inhibited state 3 and, to a lesser extent, state 4 respiration in a time-dependent manner. None of the isoquinoline derivatives were more potent than MPP+. 6,7-Dimethoxy-1-styryl-3,4-dihydroisoquinoline uncoupled mitochondrial respiration. Qualitative structure-activity relationship studies revealed that isoquinolinium cations were more active than isoquinolines in inhibiting mitochondrial respiration; these, in turn, were more active than dihydroisoquinolines and 1,2,3,4-tetrahydroisoquinolines. Three-dimensional quantitative structure-activity relationship studies using Comparative Molecular Field Analysis showed that the inhibitory potency of isoquinoline derivatives was determined by steric, rather than electrostatic, properties of the compounds. A hypothetical binding site was identified that may be related to a rate-limiting transport process, rather than to enzyme inhibition. In conclusion, isoquinoline derivatives are less potent in inhibiting respiration in intact mitochondria than impairing complex I activity in mitochondrial fragments. This suggests that isoquinoline derivatives are not accumulated by mitochondria as avidly as MPP+. The activity of charged and neutral isoquinoline derivatives implicates both active and passive processes by which these compounds enter mitochondria, although the quaternary nitrogen moiety of the isoquinolinium cations favours mitochondrial accumulation and inhibition of respiration. These findings suggest that isoquinoline derivatives may exert mitochondrial toxicity in vivo similar to that of MPTP/MPP+.
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PMID:Effects of isoquinoline derivatives structurally related to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on mitochondrial respiration. 863 91

Nigral cell death in Parkinson's disease is associated with decreased reduced glutathione (GSH) levels, impaired complex I activity and inhibition of alpha-ketoglutarate dehydrogenase (alpha-KGDH) in substantia nigra. Thioctic acid exerts antioxidant activity through a thiol-disulphide redox couple and is an essential cofactor for alpha-KGDH. However, it is not known whether or not thioctic acid enters basal ganglia or exerts beneficial effects in Parkinson's disease. As a global measure of altered cerebral function, the effect of R- and S-thioctic acid on 14C-2-deoxyglucose (14C-2DG) incorporation was investigated in rats. Rats were treated with either R- or S-thioctic acid (50 mg/kg IP) or 0.9% saline acutely or for 5 days and 14C-2DG incorporation in basal ganglia was assessed. Following acute administration, R- but not S-thioctic acid caused an overall increase in 14C-2DG incorporation that was significant in both substantia nigra zona compacta and zona reticulata. R-thioctic acid also increased the incorporation of 14C-2DG in the medial forebrain bundle, thalamus, and red nucleus. S-thioctic acid decreased 14C-2DG incorporation in the subthalamic nucleus, but increased it in the red nucleus. Following repeated administration, R-thioctic acid no longer increased 14C-2DG incorporation in either zona compacta or zona reticulata of substantia nigra. However, both R- and S-thioctic acid now decreased 14C-2DG incorporation in the subthalamic nucleus. The data suggest that thioctic acid does enter the brain can alter neuronal activity in areas of the basal ganglia intimately associated with the motor deficits exhibited in Parkinson's disease.
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PMID:The isomers of thioctic acid alter C-deoxyglucose incorporation in rat basal ganglia. 865 49

We review the recent progress in the research of the etiology, pathogenesis and treatment of Parkinson's disease. It has been postulated that mitochondrial respiratory failure and oxidative stress are two major contributors to nigral cell death in Parkinson's disease. Loss of mitochondrial complex I and the alpha-ketoglutarate dehydrogenase complex in the substantia nigra has been reported. Evidence to indicate oxidative stress includes a high dopamine content, increase in superoxide dismutase activities, increase in iron, and decrease in glutathione in the substantia nigra. The question posed is which one occurs first. We believe mitochondrial respiratory failure occurs first, because slowing down of the electron transport induces an increase in the formation of activated oxygen species. The primary cause of Parkinson's disease is still unknown, but we believe the interaction of environmental toxins and genetic predispositions is important. In this respect, molecular genetic studies on familial Parkinson's disease are very important.
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PMID:Parkinson's disease: from etiology to treatment. 877 62

Studies on the effect of various Cd2+ concentrations on substrate oxidation by whole cells of cadmium-sensitive Staphylococcus aureus 17810S showed that oxidation of glutamate or pyruvate was highly sensitive to low Cd2+ concentrations (5 microM), whereas L-lactate oxidation was insensitive even to high Cd2+ concentrations (100 microM). Location of the cadmium-sensitive targets in the enzyme systems involved in oxidation of these substrates was studied in subcellular fractions prepared from cells pretreated with 5 or 100 microM Cd2+. Activities of the cytoplasmic 2-oxoglutarate dehydrogenase complex (ODHC)') and pyruvate dehydrogenase complex (PDHC) were strongly inhibited with 5 microM Cd2+, while with 100 microM Cd2+ the inhibition was almost complete. In contrast, activities of the cytoplasmic NAD-dependent glutamate dehydrogenase (NAD-GDH), the membrane-bound NADH dehydrogenase (NDH) and HQNO-sensitive NADH oxidase were not sensitive to 100 microM Cd2+. These data indicate that the accessible, cadmium-sensitive targets are located only in the cytoplasmic ODHC and PDHC. It is postulated that two vicinal dithiols present in ODHC and PDHC may be regarded as the primary cadmium-sensitive targets in the systems oxidizing glutamate or pyruvate. Since activities of the membrane-bound NAD-independent L-lactate dehydrogenase (iLDH) and HQNO-sensitive L-lactate oxidase were not affected by 100 microM Cd2+, this indicates that the L-lactate oxidizing system lacks the accessible, cadmium-sensitive targets. The mechanism of Cd2+ toxicity to energy conservation with glutamate, pyruvate or L-lactate in S. aureus is discussed.
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PMID:Cadmium-sensitive targets in the aerobic respiratory metabolism of Staphylococcus aureus. 895 92

In substantia nigra from patients with Parkinson's disease, there are decreased levels of reduced glutathione (GSH) and diminished activities of mitochondrial complex I and alpha-ketoglutarate dehydrogenase (alpha-KGDH), along with increased activity of superoxide dismutase (SOD). However, the interrelationship among these events is uncertain. We now report the effect of decreased brain GSH levels on SOD and mitochondrial respiratory enzyme activity in rat brain. In addition, we have investigated the ability of thioctic acid, an endogenous antioxidant, to alter these parameters. Unilateral or bilateral intracerebroventricular (ICV) administration of buthionine sulphoximine (BSO; 1 x 3.2 mg or 2 x 1.6 mg) over a 48-hr period reduced cortical GSH by 55-70%. There was no change in the activity of complex I, II/III, or IV or of citrate synthase in cortex. Similarly, there was no alteration of mitochondrial or cytosolic SOD activity. Thioctic acid (50 or 100 mg/kg IP) alone had no effect on cortical GSH levels in control animals and did not reverse the decrease in GSH levels produced by unilateral or bilateral ICV BSO administration. Thioctic acid (50 or 100 mg/kg IP) had no overall effect on complex I, II/III, or IV or on citrate synthase activity in control animals. Thioctic acid also did not alter cortical mitochondrial respiratory enzyme activity in BSO-treated rats. At the lower dose, thioctic acid tended to increase mitochondrial and cytosolic SOD activity in control animals and in BSO-treated rats. However, at the higher dose, thioctic acid tended to decrease mitochondrial SOD activity. Overall, there was no consistent effect of thioctic acid (50 or 100 mg/kg IP) on SOD activity in control or BSO-treated animals. This study shows that BSO-induced glutathione deficiency does not lead to alterations in mitochondrial respiratory enzyme activity or to changes in SOD activity. GSH depletion in Parkinson's disease therefore may not account for the alterations occurring in complex I and mitochondrial SOD in substantia nigra. Thioctic acid did not alter brain GSH levels or mitochondrial function. Interestingly, however, it did produce some alterations in SOD activity, which may reflect either its antioxidant activity or its ability to act as a thiol-disulphide redox couple.
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PMID:Mitochondrial respiratory enzyme function and superoxide dismutase activity following brain glutathione depletion in the rat. 898 27

During the progression of certain degenerative conditions, including myocardial ischemia-reperfusion injury, mitochondria are a source of increased free-radical generation and exhibit declines in respiratory function(s). It has therefore been suggested that oxidative damage to mitochondrial components plays a critical role in the pathology of these processes. Polyunsaturated fatty acids of membrane lipids are prime molecular targets of free-radical damage. A major product of lipid peroxidation, 4-hydroxy-2-nonenal (HNE), is highly cytotoxic and can readily react with and damage protein. In this study, the effects of HNE on intact cardiac mitochondria were investigated to gain insight into potential mechanisms by which free radicals mediate mitochondrial dysfunction. Exposure of mitochondria to micromolar concentrations of HNE caused rapid declines in NADH-linked but not succinate-linked state 3 and uncoupled respiration. The activity of complex I was unaffected by HNE under the conditions of our experiments. Loss of respiratory activity reflected the inability of HNE-treated mitochondria to meet NADH demand during maximum rates of O2 consumption. HNE exerted its effects on intact mitochondria by inactivating alpha-ketoglutarate dehydrogenase. These results therefore identify a potentially important mechanism by which free radicals bring about declines in mitochondrial respiration.
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PMID:Inhibition of NADH-linked mitochondrial respiration by 4-hydroxy-2-nonenal. 942 76

The effect of alpha-tocopherol pretreatment (6 mg/100 g body wt/day, orally for a period of 90 days) on mitochondrial electron transport in myocardial infarction induced by isoproterenol (20 mg/100 g body wt, subcutaneously for two days) was studied in rats. A significant decrease was observed in the activities of isocitrate dehydrogenase, alpha-ketoglutarate dehydrogenase, succinate dehydrogenase, malate dehydrogenase, NADH dehydrogenase and cytochrome oxidase in heart mitochondria of isoproterenol administered rats. The cytochrome content and the oxidation of succinate in state 3 and state 4 decreased significantly in the cardiac mitochondria treatment. In alpha-tocopherol pretreated rats, the activities of TCA cycle enzymes, concentration of cytochromes and the oxidation of succinate in state 3 and state 4 were retained at near normal values, following isoproterenol administration.
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PMID:Effect of alpha-tocopherol on mitochondrial electron transport in experimental myocardial infarction in rats. 975 71


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