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)

We have previously shown that in Nicotiana sylvestris cytoplasmic male-sterile (CMS) mutants where the mtDNA lacks the nad7 gene coding for a subunit of respiratory Complex I (NADH:ubiquinone oxidoreductase, EC 1.6.5.3), glycine (Gly) oxidation was lower than in the wild type and insensitive to rotenone, suggesting Complex I dysfunction. In contrast, the oxidation rate of exogenous NADH and the capacity of the cyanide-resistant respiration (AOX) were enhanced. Here we report that, in contrast to Gly, the rate of malate oxidation was not affected, but proceeded totally in a rotenone-insensitive pathway, strongly suggesting that survival of CMS plants depends on the activation of internal and external alternative NAD(P) H dehydrogenases and that Gly decarboxylase activity depends on Complex I functioning. A similar defect in Complex I activity and Gly oxidation was found in the NMS1 nuclear mutant, defective in the processing of the nad4 transcript, but alternative NAD(P) H dehydrogenases were less activated. In CMS and NMS1, the fraction of the AOX pathway was increased, as compared to wild type, associated with higher amounts of aox transcripts, AOX protein, and plant resistance to cyanide. Non-phosphorylating respiratory enzymes maintained normal in vivo respiration levels in both mutants, but photosynthesis was decreased, in correlation with lower leaf conductance, emphasizing mitochondrial control on photosynthesis.
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PMID:Complex I impairment, respiratory compensations, and photosynthetic decrease in nuclear and mitochondrial male sterile mutants of Nicotiana sylvestris. 1108 Mar

Increased neuronal cell death in neurodegenerative diseases has been suggested to result from an increased mitochondrial generation of radical oxygen species (ROS). To test this hypothesis, we investigated superoxide formation in cultured hippocampal neurons from diploid and trisomy 16 mice (Ts16), a model of Down's syndrome. Microflurometric techniques were used to measure superoxide-induced oxidation rate of hydroethidine (HEt) to ethidium and reduced nicotinamide adenine dinucleotide (NADH) and reduced nicotinamide adenine dinucleotide phosphate (NADPH) autofluorescence signal to monitor changes in neuronal energy metabolism. We found an increase in superoxide formation by more than 50% in Ts16 neurons in comparison with diploid control neurons. In the presence of the mitochondrial respiratory chain complex I inhibitor rotenone superoxide production was blocked in diploid neurons, but the increased superoxide generation in Ts16 neurons remained. Uncoupling of mitochondrial oxidative phosphorylation using carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP) caused irreversible deficiency in the energy metabolism, monitored by NAD(P)H autofluorescence in Ts16 neurons, but not in diploid control neurons. These results suggest an increased basal generation of superoxide in Ts16 neurons, probably caused by a deficient complex I of mitochondrial electron transport chain, which leads to an impaired mitochondrial energy metabolism and finally neuronal cell death.
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PMID:Increased mitochondrial superoxide generation in neurons from trisomy 16 mice: a model of Down's syndrome. 1128 Dec 91

The membrane fraction of Bacillus subtilis catalyzes the reduction of fumarate to succinate by NADH. The activity is inhibited by low concentrations of 2-(heptyl)-4-hydroxyquinoline-N-oxide (HOQNO), an inhibitor of succinate: quinone reductase. In sdh or aro mutant strains, which lack succinate dehydrogenase or menaquinone, respectively, the activity of fumarate reduction by NADH was missing. In resting cells fumarate reduction required glycerol or glucose as the electron donor, which presumably supply NADH for fumarate reduction. Thus in the bacteria, fumarate reduction by NADH is catalyzed by an electron transport chain consisting of NADH dehydrogenase (NADH:menaquinone reductase), menaquinone, and succinate dehydrogenase operating in the reverse direction (menaquinol:fumarate reductase). Poor anaerobic growth of B. subtilis was observed when fumarate was present. The fumarate reduction catalyzed by the bacteria in the presence of glycerol or glucose was not inhibited by the protonophore carbonyl cyanide m-chlorophenyl hydrazone (CCCP) or by membrane disruption, in contrast to succinate oxidation by O2. Fumarate reduction caused the uptake by the bacteria of the tetraphenyphosphonium cation (TPP+) which was released after fumarate had been consumed. TPP+ uptake was prevented by the presence of CCCP or HOQNO, but not by N,N'-dicyclohexylcarbodiimide, an inhibitor of ATP synthase. From the TPP+ uptake the electrochemical potential generated by fumarate reduction was calculated (Deltapsi = -132 mV) which was comparable to that generated by glucose oxidation with O2 (Deltapsi = -120 mV). The Deltapsi generated by fumarate reduction is suggested to stem from menaquinol:fumarate reductase functioning in a redox half-loop.
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PMID:Generation of a proton potential by succinate dehydrogenase of Bacillus subtilis functioning as a fumarate reductase. 1135 26

Mitochondrial electron transport inhibitors induced two distinct pathways for acute cell death: lipid peroxidation-dependent and -independent in isolated rat hepatocytes. The toxic effects of mitochondrial complex I and II inhibitors, rotenone (ROT) and thenoyltrifluoroacetone (TTFA), respectively, were dependent on oxidative stress and lipid peroxidation, while cell death induced by inhibitors of complexes III and IV, antimycin A (AA) and cyanide (CN), respectively, was caused by MMP collapse and loss of cellular ATP. Accordingly, cellular and mitochondrial antioxidant depletion or supplementation, in general, resulted in a dramatic potentiation or prevention, respectively, of toxic injury induced by complex I and II inhibitors, with little or no effect on complex III and IV inhibitor-induced toxicity. ROT-induced oxidative stress was prevented by the addition of d-alpha-tocopheryl succinate (TS) but surprisingly TS did not afford hepatocytes protection against TTFA-induced oxidative damage. TS treatment prevented ROT-induced mitochondrial lipid hydroperoxide formation but had no effect on the loss of mitochondrial GSH or cellular ATP, suggesting a mitochondrial lipid peroxidation-mediated mechanism for ROT-induced acute cell death. In contrast, only fructose treatment provided excellent cytoprotection against AA- and CN-induced toxicity. Our findings indicate that complex III and IV inhibitors cause a rapid and severe depletion of cellular ATP content resulting in acute cell death that is dependent on cellular energy impairment but not lipid peroxidation. In contrast, inhibitors of mitochondrial complex I or II moderately deplete cellular ATP levels and thus cause acute cell death via a lipid peroxidation pathway.
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PMID:Mitochondrial electron transport inhibitors cause lipid peroxidation-dependent and -independent cell death: protective role of antioxidants. 1151 65

1. The mechanisms responsible for sensing hypoxia and initiating hypoxic pulmonary vasoconstriction (HPV) are unclear. We therefore examined the roles of the mitochondrial electron transport chain (ETC) and glycolysis in HPV of rat small intrapulmonary arteries (IPAs). 2. HPV demonstrated a transient constriction (phase 1) superimposed on a sustained constriction (phase 2). Inhibition of complex I of the ETC with rotenone (100 nM) or complex III with myxothiazol (100 nM) did not cause vasoconstriction in normoxia, but abolished both phases of HPV. Rotenone inhibited the hypoxia-induced rise in intracellular Ca(2+) ([Ca(2+)](i)). Succinate (5 mM), a substrate for complex II, reversed the effects of rotenone but not myxothiazol on HPV, but did not affect the rise in NAD(P)H fluorescence induced by hypoxia or rotenone. Inhibition of cytochrome oxidase with cyanide (100 microM) potentiated phase 2 constriction. 3. Phase 2 of HPV, but not phase 1, was highly correlated with glucose concentration, being potentiated by 15 mM but abolished in its absence, or following inhibition of glycolysis by iodoacetate or 2-deoxyglucose. Glucose concentration did not affect the rise in [Ca(2+)](i) during HPV. 4. Depolarisation-induced constriction was unaffected by hypoxia except in the absence of glucose, when it was depressed by approximately 50 %. Depolarisation-induced constriction was depressed by rotenone during hypoxia by 23 +/- 4 %; cyanide was without effect. 5. Hypoxia increased 2-deoxy-[(3)H]glucose uptake in endothelium-denuded IPAs by 235 +/- 32 %, and in mesenteric arteries by 218 +/- 38 %. 6. We conclude that complex III of the mitochondrial ETC acts as the hypoxic sensor in HPV, and initiates the rise in smooth muscle [Ca(2+)](i) by a mechanism unrelated to changes in cytosolic redox state per se, but more probably by increased production of superoxide. Additionally, glucose and glycolysis are essential for development of the sustained phase 2 of HPV, and support an endothelium-dependent Ca(2+)-sensitisation pathway rather than the rise in [Ca(2+)](i).
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PMID:Divergent roles of glycolysis and the mitochondrial electron transport chain in hypoxic pulmonary vasoconstriction of the rat: identity of the hypoxic sensor. 1157 52

We recently showed that melatonin counteracted mitochondrial oxidative stress and increased the activity of the mitochondrial oxidative phosphorylation (OXPHOS) enzymes both in vivo and in vitro. To further clarify these effects, we studied here the activity of OXPHOS enzymes and the synthesis of ATP in rat liver and brain mitochondria in vitro. In sub-mitochondrial particles, melatonin increases the activity of the complexes I and IV dose-dependently, the effect being significant between 1 and 10nM. Blue native-PAGE followed by histochemical analysis of the OXPHOS enzymes further showed the melatonin-induced increase of complex I activity. Titration studies show that melatonin counteracts the partial inhibition of complex IV induced by 5 microM potassium cyanide. However, melatonin (up to 5mM) was unable to recover the activity of complex IV when it was completely blocked by 100 microM cyanide. These data suggest that the indoleamine could stimulate the activity of the non-inhibited part of the complex IV. Melatonin also increases the production of ATP in control mitochondria and counteracts the cyanide-induced inhibition of ATP synthesis. These results provide new hormonal mechanism regulating mitochondrial homeostasis and may explain, at least in part, the anti-aging and neuroprotective properties of melatonin.
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PMID:Melatonin increases the activity of the oxidative phosphorylation enzymes and the production of ATP in rat brain and liver mitochondria. 1185 34

Cytokine-mediated regulation of hypoxia-inducible factor-1 alpha (HIF-1 alpha) non-hypoxic stabilization, translocation and activation is not well characterized. Furthermore, evidence that reactive oxygen species (ROS) signaling mediates interleukin (IL)-1 beta-dependent regulation of HIF-1 alpha has yet to be ascertained in alveolar epithelial cells. Recombinant human IL-1 beta induced, in a time-dependent manner, the nuclear translocation of HIF-1 alpha, an effect associated with up-regulating the activity of this transcription factor under normoxic conditions. In addition, analysis of the mode of action of IL-1 beta revealed a novel induction of intracellular ROS, including hydrogen peroxide (H(2)O(2)), the superoxide anion (O(2)(-*)) and the hydroxyl radical (*OH). The antioxidants, dimethyl sulfoxide (DMSO) and 1,3-dimethyl-2-thiourea (DMTU), purported to be prototypical scavengers of H2O2 and *OH, attenuated, in a dose-dependent manner, IL-1 beta-induced HIF-1 alpha nuclear translocation and activation. The NADPH-oxidase inhibitor, 4'-hydroxy-3'-methoxy-acetophenone (HMAP), which may affect mitochondrial ROS production, attenuated IL-1 beta-mediated nuclear translocation and activation of HIF-1 alpha. Inhibition of the mitochondrion complex I nicotinamide adenine dinucleotide phosphate-dependent oxidase by diphenylene iodonium (DPI), which blocks the conversion of ubiquinone --> ubiquinol, abrogated IL-1 beta-dependent nuclear translocation and activation of HIF-1 alpha. Similarly, interrupting the respiratory chain with potassium cyanide reversed the excitatory effect of IL-1 beta on HIF-1 alpha nuclear translocation and activation. These results indicate that a non-hypoxic pathway mediates cytokine-dependent regulation of HIF-1 alpha translocation and activation in a ROS-sensitive mechanism.
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PMID:Recombinant human interleukin (IL)-1 beta-mediated regulation of hypoxia-inducible factor-1 alpha (HIF-1 alpha) stabilization, nuclear translocation and activation requires an antioxidant/reactive oxygen species (ROS)-sensitive mechanism. 1210 Oct 82

The present studies investigated whether the effect of high glucose levels on angiotensinogen (ANG) gene expression in kidney proximal tubular cells is mediated via reactive oxygen species (ROS) generation and p38 MAPK activation. Rat immortalized renal proximal tubular cells (IRPTCs) were cultured in monolayer. Cellular ROS generation and p38 MAPK phosphorylation were assessed by lucigenin assay and Western blot analysis, respectively. The levels of immunoreactive rat ANG secreted into the media and cellular ANG mRNA were determined by a specific RIA and RT-PCR, respectively. High glucose (25 mM) evoked ROS generation and p38 MAPK phosphorylation as well as stimulated immunoreactive rat ANG secretion and ANG mRNA expression in IRPTCs. These effects of high glucose were blocked by antioxidants (taurine and tiron), inhibitors of mitochondrial electron transport chain complex I (rotenone) and II (thenoyltrifluoroacetone), an inhibitor of glycolysis-derived pyruvate transport into mitochondria (alpha-cyano-4-hydroxycinnamic acid), an uncoupler of oxidative phosphorylation (carbonyl cyanide m-chlorophenylhydrazone), a manganese superoxide dismutase mimetic, catalase, and a specific inhibitor of p38 MAPK (SB 203580), but were not affected by an inhibitor of the malate-aspartate shuttle (aminooxyacetate acid). Hydrogen peroxide (>/=10(-5) M) also stimulated p38 MAPK phosphorylation, ANG secretion, and ANG mRNA gene expression, but its stimulatory effect was blocked by catalase and SB 203580. These studies demonstrate that the stimulatory action of high glucose on ANG gene expression in IRPTCs is mediated at least in part via ROS generation and subsequent p38 MAPK activation.
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PMID:High glucose stimulates angiotensinogen gene expression via reactive oxygen species generation in rat kidney proximal tubular cells. 1213 May 63

When petunia (Petunia hybrida Vilm, cv Rosy Morn) cells are cultured in the presence of 2 [mu]M antimycin A (AA), respiration proceeds mainly via the cyanide-resistant pathway. Cyanide-resistant respiratory rates were higher in mitochondria from AA cells than in control mitochondria. Compared with control cells, an increase in alternative oxidase protein was observed in AA cells, as well as an increase in ubiquinone (UQ) content. A change in the kinetics of succinate dehydrogenase was observed: there was a much higher activity at high UQ reduction in mitochondria from AA cells compared with control mitochondria. No changes were found for external NADH dehydrogenase kinetics. In AA cells in vivo, UQ reduction was only slightly higher than in control cells, indicating that increased electron transport via the alternative pathway can prevent high UQ reduction levels. Moreover, O2 consumption continues at a similar rate as in control cells, preventing O2 danger. These adaptations to stress conditions, in which the cytochrome pathway is restricted, apparently require, in addition to an increase in alternative oxidase protein, a new setup of the relative amounts and/or kinetic parameters of all of the separate components of the respiratory network.
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PMID:Changes in Mitochondrial Respiratory Chain Components of Petunia Cells during Culture in the Presence of Antimycin A. 1222 30

When germinating Zea mays L. seeds are rapidly desiccated, free radical-mediated lipid peroxidation and phospholipid de-esterification is accompanied by a desiccation-induced buildup of a stable free radical associated with rapid loss of desiccation tolerance. Comparison of the electron paramagnetic resonance and electron nuclear double resonance properties of this radical with those of the radical in dried, desiccation-intolerant moss showed that the two were identical. At the subcellular level, the radical was associated with the hydrophilic fraction resulting from lipid extraction. Isolated mitochondria subjected to drying were also found to accumulate an identical radical in vitro. When increasing concentrations of cyanide were used, a significant positive correlation was shown between rates of respiration and the accumulation of the radical in desiccation-intolerant tissues. Another positive correlation was found when rates of O2 uptake by radicles at different stages of germination were plotted against free radical content following desiccation. This indicates that free radical production is closely linked to respiration in a process likely to involve the desiccation-induced impairment of the mitochondrial electron transport chain to form thermodynamically favorable conditions to induce accumulation of a stable free radical and peroxidized lipids. Modulation of respiration using a range of inhibitors resulted in broadly similar modulation of the buildup of the stable free radical. One site of radical generation was likely to be the NADH dehydrogenase of complex I and probably as a direct consequence of desiccation-impaired electron flow at or close to the ubiquinone pool.
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PMID:The Involvement of Respiration in Free Radical Processes during Loss of Desiccation Tolerance in Germinating Zea mays L. (An Electron Paramagnetic Resonance Study). 1223 72


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