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)

The compound 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes selective destruction of nigrostriatal dopaminergic neurons in primates, giving rise to a condition resembling Parkinson's disease. The toxicity of MPTP is believed to be due to its metabolite 1-methyl-4-phenylpyridinium (MPP+). MPP+ is an inhibitor of mitochondrial respiration at the NADH-ubiquinone oxidoreductase site and this, together with its selective transport into dopaminergic nerve terminals, accounts for its neurotoxicity. In this paper an electrode selective for MPP+ was developed and used to measure the rate of uptake and the steady-state accumulation of MPP+ in rat liver mitochondria. The initial rates of MPP+ uptake were not saturable, confirming previous work that the transport of MPP+ is not carrier-mediated. The membrane potential of mitochondria respiring on succinate was decreased by MPP+ and the steady-state accumulation ratio of MPP+ did not come to equilibrium with the mitochondrial transmembrane potential gradient (delta psi). The effect of the cation exchanger tetraphenylboron (5 microM) was to increase the initial rate of MPP+ uptake by about 20-fold and the steady-state accumulation by about 2-fold. This suggests that there may be a mechanism of efflux of MPP+ from mitochondria which allows MPP+ to cycle across the membrane and thus decrease delta psi. These data indicate that MPP+ interacts with mitochondria independently of its inhibition of NADH-ubiquinone oxidoreductase, and these alternative interactions may be of relevance for its mechanism of neurotoxicity.
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PMID:Uptake and accumulation of 1-methyl-4-phenylpyridinium by rat liver mitochondria measured using an ion-selective electrode. 146 48

There is increasing evidence that defective function of the mitochondrial enzyme NADH CoQ reductase (complex I) is involved not only in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity, but also in idiopathic Parkinson's disease (PD). Complex I deficiency has been identified in PD substantia nigra and appears to be disease-specific and selective for the substantia nigra within the central nervous system. We describe a method for preparation of an enriched mitochondrial fraction from 60 mL blood. Using this technique, we analyzed respiratory chain function in 25 patients with PD and 15 matched control subjects. We confirm a previous report of a specific complex I deficiency in PD platelet mitochondria. Although there was a statistically significant decrease in complex I activity in the PD group compared with the control group (p = 0.005), the defect was mild (16%); it was not possible to distinguish PD from control values on an individual basis. This deficiency is not detectable in platelet whole-cell homogenates, presumably reflecting the relative insensitivity of this preparation and the limited decrease in complex I activity in PD. The presence of a mild complex I defect in platelets together with a more severe defect in substantia nigra suggests either that the pharmacological characteristics shared by these two tissues render them susceptible to a particular toxin or toxins, or that the defect is widely distributed and other biochemical events enhance the deficiency in substantia nigra.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Platelet mitochondrial function in Parkinson's disease. The Royal Kings and Queens Parkinson Disease Research Group. 147 69

The recent discovery of mitochondrial complex I deficiency in the substantia nigra of patients with idiopathic Parkinson's disease has provided new understanding into the possible mechanisms that may underlie this neurodegenerative disorder. The biochemical defect is identical to that induced in humans, primates and mice exposed to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. We have studied mitochondrial respiratory chain function in various brain regions, in skeletal muscle and in blood platelets from patients with idiopathic Parkinson's disease and from matched controls. We provide evidence suggesting that the complex I deficiency in Parkinson's disease is limited to the brain and that this defect is specific for the substantia nigra. The tissue specificity of the complex I deficiency in Parkinson's disease and its localization to the substantia nigra support the proposition that complex I deficiency may be directly involved in the cause of dopaminergic cell death in Parkinson's disease. An understanding of the molecular basis of this biochemical defect will provide valuable insight into the cause of Parkinson's disease. Our findings of normal mitochondrial function in platelet homogenates suggests that this tissue cannot be used to develop a 'diagnostic test' for Parkinson's disease.
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PMID:Brain, skeletal muscle and platelet homogenate mitochondrial function in Parkinson's disease. 160 72

Parkinson's disease is one of the commonest neurodegenerative disorders in Western society. Although the neuropathological changes have been well documented, the underlying biochemical defect is unknown. Toxins may play a part in the aetiology of this disorder. It has been shown that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces a Parkinson-like syndrome in both man and primates and 1-methyl-4-phenylpyridine (MPP+), a metabolite of MPTP, inhibits NADH-ubiquinone oxidoreductase (complex I) of the mitochondrial respiratory chain. We studied mitochondrial respiratory chain function in skeletal muscle from patients with Parkinson's disease because, like brain, it has a high dependence on oxidative metabolism. Our results show low activity in all complexes studied (I, II and IV). The implications of these findings are discussed in relation to the aetiology of Parkinson's disease.
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PMID:Respiratory chain abnormalities in skeletal muscle from patients with Parkinson's disease. 165 41

Insights into the etiology and pathophysiology of Parkinson's disease may derive from elucidation of the neurotoxic mechanisms of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its active metabolite, 1-methyl-4-phenylpyridinium (MPP+). In previous studies, MPP+ provoked oxidation of cytochrome b and K+ leakage into the extracellular space of rat striatal slices. Magnitudes of these time-dependent responses were far greater than expected had the MPP+ effects been limited to dopaminergic terminals. To determine whether cytochromes become oxidized from K(+)-induced increases in ion transport activity or from electron transport inhibition at complex I, oxygen consumption was measured because this should be increased by the former and decreased by the latter mechanism. Low MPP+ concentrations (1 microM) decreased O2 consumption (approximately 40% in 3 h) in striatal slices. This decrease was diminished by mazindol and did not occur in hippocampal slices. High toxin concentrations (100 microM) inhibited oxygen consumption to a greater extent (approximately 60%) in striatal slices; this inhibition was still greater in hippocampal slices. These results support the hypothesis that acute effects of low ("selective") MPP+ concentrations require the presence of dopaminergic terminals to trigger a sequence of destructive metabolic events but that the metabolic consequences of MPP+ spread to neighboring cells. In contrast, high MPP+ concentrations nonselectively inhibit metabolic and ion transport activity without requiring the presence of dopaminergic terminals. These results also suggest that physiological effects of "selective" MPP+ concentrations extend to nondopaminergic cells.
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PMID:Selective and nonselective effects of 1-methyl-4-phenylpyridinium on oxygen consumption in rat striatal and hippocampal slices. 189 8

Two major lines of evidence support the hypothesis that an impairment of mitochondrial function may underlie neuronal death in Parkinson's disease. First, the neurotoxicity of the parkinsonism-inducing compound 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is due to the generation of its 1-methyl-4-phenylpyridinium (MPP+) metabolite in the central nervous system; the toxicity of MPP+ is likely to result from its ability to block mitochondrial electron flow at the level of complex I. Second, recent studies have revealed a deficiency of mitochondrial complex I activity in the brain as well as other tissues of parkinsonian patients. This enzyme activity reduction might be explained by a defect in one or more of the genes coding for the subunits of complex I. Since seven of these genes are localized in the mitochondrial genome, it is conceivable that abnormal mitochondrial DNA (mtDNA) might play a role in the pathogenesis of Parkinson's disease. The entire sequence of the human mitochondrial genome is known, and human mtDNA can be isolated and rapidly analyzed using techniques such as the polymerase chain reaction. Therefore, identification of an easily detectable mtDNA alteration might ultimately be used as a marker for the diagnosis and screening of Parkinson's disease.
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PMID:Mitochondrial DNA and Parkinson's disease. 190 41

The mechanism by which 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces lesions in the nigrostriatal dopamine system has been extensively studied. MPTP, a lipophilic molecule, enters the brain rapidly where it is converted to the pyridinium metabolite 1-methyl-4-phenylpyridinium (MPP+), by a two-step reaction that requires the enzyme monoamine oxidase. Following this conversion, which occurs primarily in astrocytes, MPP+ is sequestered within monoaminergic neurons by the energy-requiring monoaminergic transporters. Inside the neuron, MPP+ is thought to act as a mitochondrial toxin, slowly sapping the neuron of its energy-producing potential by blocking the action of NADH dehydrogenase. Much attention has been focused on cell death after MPTP administration, but little attention has been paid to the effects of small subtoxic doses of MPTP (i.e., doses that do not produce overt neuropathologic changes), which might occur during environmental exposure to a nigrostriatal toxin. Low doses of MPTP (as little as 1/25th of a toxic dose) produce long-term (greater than 6 weeks) but reversible changes in catecholamine metabolism. These changes are characterized by a decrease in the products of enzymatic oxidative deamination without a concomitant decrease in the amine concentrations (apparent MAO inhibition). Striatal concentrations of MPP+, which is retained in catecholaminergic terminals for similarly long periods, parallel the metabolic changes. Thus, the long-term storage of the MPTP metabolite, MPP+, correlates with altered catecholamine metabolism. The data on the effects of MPTP have been combined into a working model of how MPP+ exerts its effects following subtoxic or toxic doses. The site of this long-term neuronal storage of MPP+ after exposure to subtoxic doses of MPTP is as yet undetermined, but several studies suggest that monoaminergic vesicles may be the primary site, with mitochondria contributing some storage capacity. This vesicular site could represent a potential brain site for the accumulation of toxins during continual or repeated exposure to low levels of MPTP. Induced release from this site might accelerate the toxic interactions with cellular components such as mitochondria.
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PMID:A model of chronic neurotoxicity: long-term retention of the neurotoxin 1-methyl-4-phenylpyridinium (MPP+) within catecholaminergic neurons. 195 87

The reduced form of nicotinamide adenine dinucleotide coenzyme Q reductase (complex I) activity has recently been shown to be deficient in the substantia nigra of patients dying with Parkinson's disease. This biochemical defect is identical to that produced by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which also produces parkinsonism in humans. Complex I comprises 25 polypeptides, seven of which are encoded by mitochondrial DNA. Restriction fragment analysis of substantia nigra DNA from six patients with Parkinson's disease did not show any major deletion. In two cases, there were different novel polymorphisms that were not observed in control brain (n = 6) or blood (n = 34) samples.
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PMID:Mitochondrial DNA analysis in Parkinson's disease. 197 56

1-Methyl-4-phenylpyridinium (MPP+), the neurotoxic bioactivation product of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), interrupts mitochondrial electron transfer at the NADH dehydrogenase-ubiquinone junction, as do the respiratory chain inhibitors rotenone, piericidin A and barbiturates. Proof that these classical respiratory chain inhibitors and MPP+ react at the same site in the complex NADH dehydrogenase molecule has been difficult to obtain because none of these compounds bind covalently to the target. The 4'-alkyl derivatives of MPP+ inhibit NADH oxidation in submitochondrial particles at much lower concentrations than does MPP+ itself, but still dissociate on washing the membrane preparations, with consequent re-activation of the enzyme. The MPP+ analogues with short alkyl chains prevent the binding of 14C-labelled piericidin A to the membrane and thus must act at the same site, but analogues with alkyl chains longer than heptyl do not prevent binding of [14C]piericidin.
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PMID:Evidence that the inhibition sites of the neurotoxic amine 1-methyl-4-phenylpyridinium (MPP+) and of the respiratory chain inhibitor piericidin A are the same. 199 Oct 43

Nigrostriatal cell death in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease results from the inhibition of mitochondrial respiration by 1-methyl-4-phenylpyridinium (MPP+). MPP+ blocks electron flow from NADH dehydrogenase to coenzyme Q at or near the same site as do rotenone and piericidin and protects against binding of and loss of activity due to these inhibitors. The 4'-analogs of MPP+ showed increasing affinity for the site with increasing length of alkyl chain, with the lowest Ki, for 4'-heptyl-MPP+, being 6 microM. The 4'-analogs compete with rotenone for the binding site in a concentration-dependent manner. They protect the activity of the enzyme from inhibition by piericidin in parallel to preventing its binding, indicating that the analogs and piericidin bind at the same inhibitory site(s). The optimum protection, however, was afforded by 4'-propyl-MPP+. The lesser protection by the more lipophilic MPP+ analogs with longer alkyl chains may involve a different orientation in the hydrophobic cleft, allowing rotenone and piericidin to still bind even when the pyridinium cation is in a position to interrupt electron flow from NADH to coenzyme Q.
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PMID:Interaction of 1-methyl-4-phenylpyridinium ion (MPP+) and its analogs with the rotenone/piericidin binding site of NADH dehydrogenase. 200 36


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