Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.6.5.3 (complex I)
 8,901 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Progression of Parkinson's disease has been associated with several biochemical changes in the substantia nigra including increased oxidative challenge, catechol oxidation, and inhibition of mitochondrial complex I activity. Cysteinylcatechols, formed by nucleophilic addition of cysteine to oxidized catechols, have been identified as markers of catechol oxidation in brain tissue. We have examined the neurotoxicity of a series of cysteinylcatechols. Of the compounds examined, only 5-S-cysteinyl-3,4-dihydroxyphenylacetate (cysdopac) was specifically cytotoxic to differentiated P19 neuroglial cultures. Cysdopac also was neurotoxic to pyramidal neurons in organotypic cultures of hippocampus, and this effect was ablated by selective N-methyl-D-aspartate (NMDA) receptor antagonists. In vitro, cysdopac was a potent inhibitor of mitochondrial complex I activity. However, electrophysiologic experiments failed to demonstrate NMDA receptor agonist activity for cysdopac, nor did cysdopac inhibit glutamate uptake. These results showed that cysdopac was the most potent neurotoxin of this series of cysteinylcatechols and suggest that cysdopac may function as an indirect excitotoxin, potentially via inhibition of mitochondrial respiration.
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PMID:Neurotoxicity of endogenous cysteinylcatechols. 939 47

Metabolic hypofunction is a common finding in a number of neurodegenerative diseases, including Alzheimer's disease (AD). The strong linkage between the amyloid precursor protein (APP) and AD led us to examine whether over-expression of this protein in CNS-type cells had an effect on mitochondria. We found abnormal morphology in mitochondria of the neuroectodermal progeny of P19 cells stably transfected with human APP751. In addition, the mitochondria of APP-transfected clones had a decreased mitochondrial membrane potential. These changes were independent of Abeta toxicity and distinct from complex I inhibition. Our results have important implications for the earliest events in the pathophysiology of AD and, by extrapolation, for intervention therapies.
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PMID:Mitochondrial abnormalities in neuroectodermal cells stably expressing human amyloid precursor protein (hAPP751). 1009 30

Considerable evidence implicates the involvement of mitochondrial dysfunction in neurodegenerative diseases. 6OHDA is a mitochondrial complex I inhibitor which is frequently used to model Parkinson's disease-like cell loss. We investigated the cell death pathways triggered by 6OHDA in PC12 and P19 cells with a view to shedding light on the molecular basis of Parkinson's disease. We found that 6OHDA triggered mostly necrosis and less than 5% apoptosis in PC12 cells, whereas 6OHDA-induced death in P19 cells was apoptotic. While desipramine, a dopamine uptake blocker, attenuated 6OHDA-induced apoptosis in PC12 cells, this compound had no effect on the large scale necrotic death. Furthermore, desipramine failed to reduce apoptosis in 6OHDA-treated P19 cells, suggesting that the mechanism of 6OHDA toxicity does not require uptake via the dopamine transporter. As cell death triggered by 6OHDA was not blocked by free radical scavengers or NMDA receptor antagonists, a non-specific extracellular mechanism may be involved.
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PMID:The toxicity of 6-hydroxydopamine on PC12 and P19 cells. 1035 Jun 40

The significance of metabolic networks in guiding the fate of the stem cell differentiation is only beginning to emerge. Oxidative metabolism has been suggested to play a major role during this process. Therefore, it is critical to understand the underlying mechanisms of metabolic alterations occurring in stem cells to manipulate the ultimate outcome of these pluripotent cells. Here, using P19 murine embryonal carcinoma cells as a model system, the role of mitochondrial biogenesis and the modulation of metabolic networks during dimethyl sulfoxide (DMSO)-induced differentiation are revealed. Blue native polyacrylamide gel electrophoresis (BN-PAGE) technology aided in profiling key enzymes, such as hexokinase (HK) [EC 2.7.1.1], glucose-6-phosphate isomerase (GPI) [EC 5.3.1.9], pyruvate kinase (PK) [EC 2.7.1.40], Complex I [EC 1.6.5.3], and Complex IV [EC 1.9.3.1], that are involved in the energy budget of the differentiated cells. Mitochondrial adenosine triphosphate (ATP) production was shown to be increased in DMSO-treated cells upon exposure to the tricarboxylic acid (TCA) cycle substrates, such as succinate and malate. The increased mitochondrial activity and biogenesis were further confirmed by immunofluorescence microscopy. Collectively, the results indicate that oxidative energy metabolism and mitochondrial biogenesis were sharply upregulated in DMSO-differentiated P19 cells. This functional metabolic and proteomic study provides further evidence that modulation of mitochondrial energy metabolism is a pivotal component of the cellular differentiation process and may dictate the final destiny of stem cells.
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PMID:Mitochondrial biogenesis and energy production in differentiating murine stem cells: a functional metabolic study. 2435 Aug 92