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)

Oxidative stress occurs in diverse life forms during programmed cell death and appears to be a significant mediator since a wide range of manipulations that enhance cellular antioxidant systems are protective. Using a recently developed flow cytometry technique to assess respiratory chain function, we have investigated the mechanism of reactive oxygen generation in OCI/AML-2 leukemic blasts following treatment with cytosine arabinoside, etoposide, and gamma-irradiation. Increases in mitochondrially generated reactive oxygen were seen using all three agents, in association with hyperpolarization of the mitochondrial inner membrane. Increased reactive oxygen occurred when mitochondria were energized using substrates for either complex I or complex II, indicating that the likely source is complex III (cytochrome c reductase). These findings are consistent with impaired adenine nucleotide exchange across the mitochondrial membrane, recently proposed to be an important event during the early stages of apoptosis induction (M. G. Vander Heiden et al., 1999, Mol. Cell 3, 159-167). Elevations of the antioxidants glutathione and thioredoxin occurred in association with this oxidative stress, likely the result of feedback mechanisms based on redox-sensitive transcription factors. Since glutathione and thioredoxin can protect from drug-induced apoptosis, their upregulation in response to respiratory chain-generated reactive oxygen might represent a cellular adaptation to DNA damage that promotes cell survival.
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PMID:Respiratory chain-generated oxidative stress following treatment of leukemic blasts with DNA-damaging agents. 1126 91

The selenoprotein thioredoxin reductase (TrxR1) is an essential antioxidant enzyme known to reduce many compounds in addition to thioredoxin, its principle protein substrate. Here we found that TrxR1 reduced ubiquinone-10 and thereby regenerated the antioxidant ubiquinol-10 (Q10), which is important for protection against lipid and protein peroxidation. The reduction was time- and dose-dependent, with an apparent K(m) of 22 microm and a maximal rate of about 12 nmol of reduced Q10 per milligram of TrxR1 per minute. TrxR1 reduced ubiquinone maximally at a physiological pH of 7.5 at similar rates using either NADPH or NADH as cofactors. The reduction of Q10 by mammalian TrxR1 was selenium dependent as revealed by comparison with Escherichia coli TrxR or selenium-deprived mutant and truncated mammalian TrxR forms. In addition, the rate of reduction of ubiquinone was significantly higher in homogenates from human embryo kidney 293 cells stably overexpressing thioredoxin reductase and was induced along with increasing cytosolic TrxR activity after the addition of selenite to the culture medium. These data demonstrate that the selenoenzyme thioredoxin reductase is an important selenium-dependent ubiquinone reductase and can explain how selenium and ubiquinone, by a combined action, may protect the cell from oxidative damage.
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PMID:The mammalian cytosolic selenoenzyme thioredoxin reductase reduces ubiquinone. A novel mechanism for defense against oxidative stress. 1243 34

Subunit B8 from ubiquinone oxidoreductase (complex I) (CI-B8) is one of several nuclear-encoded supernumerary subunits that are not present in bacterial complex I. Its solution structure shows a thioredoxin fold with highest similarities to the human thioredoxin mutant C73S and thioredoxin 2 from Anabeana sp. Interestingly, these proteins contain active sites in the same area, where the disulfide bond of oxidized CI-B8 is located. The redox potential of this disulfide bond is -251.6 mV, comparing well to that of disulfides in other thioredoxin-like proteins. Analysis of the structure reveals a surface area that is exclusively composed of highly conserved residues and thus most likely a subunit interaction site within complex I.
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PMID:The oxidized subunit B8 from human complex I adopts a thioredoxin fold. 1534 29

Paraquat, N-methyl-4-phenyl-1,2,3,6 tetrahydropyridine, and rotenone have been shown to reproduce several features of Parkinson's disease in animal and cell culture models. Although these chemicals are known to perturb dopamine homeostasis and induce dopaminergic cell death, their molecular mechanisms of action are not well defined. We have previously shown that paraquat does not require functional dopamine transporter and does not inhibit mitochondrial complex I in order to mediate its toxic action (Richardson et al., 2005). In this study, we show that paraquat specifically oxidized the cytosolic form of thioredoxin and activated Jun N-terminal kinase (JNK), followed by caspase-3 activation. Conversely, 1-methyl-4-phenylpyridinium (MPP(+)) and rotenone oxidized the mitochondrial form of thioredoxin but did not activate JNK-mitogen-activated protein kinase and caspase-3. Loading cells with exogenous dopamine did not exacerbate the toxicity of any of these compounds. These data suggest that oxidative modification of cytosolic proteins is critical to paraquat toxicity, while oxidation of mitochondrial proteins is important for MPP(+) and rotenone toxicity. In addition, intracellular dopamine does not seem to exacerbate the toxicity of these dopaminergic neurotoxicants in this model.
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PMID:Divergent mechanisms of paraquat, MPP+, and rotenone toxicity: oxidation of thioredoxin and caspase-3 activation. 1701 46

A general overview is presented of the changes in the genetic expression along a time curve through the first 20 min after acidification to pH 4.5 of exponentially growing cultures of the food pathogenic strain Staphylococcus aureus 50583. A newly developed method for statistical significance testing was used to detect significant gene expression responses. Most responses showed an increase or decrease from time zero to 10 min after acidification, and then generally a stabilization in expression level from 10 to 20 min. Increased urease activity appeared to be an important factor in the acid defence, along with proton excretion by NADH dehydrogenase and macromolecule repair mechanisms. Oxidative-stress responses, such as increased expression of thioredoxin genes and upregulation of pentose phosphate pathway genes to generate more reducing power, were also induced. A general reduction in the expression of genes encoding ribosomal proteins and genes involved in nucleotide synthesis, as well as fatty acid and lipoprotein metabolism, reflected the lowered growth rate after acidification. The pH shock did not appear to trigger major virulence responses or biofilm formation. Metal ion regulation and transport were affected by the acid shock, and production of several cofactors such as molybdopterin was increased. Many of the presented observations could be explained, while some represent still-unknown mechanisms. The patterns of regulation were confirmed by quantitative reverse transcriptase PCR (QRT-PCR). Together, these results showed the main responses of S. aureus and will be a good starting point for future, more specific, in-depth studies of specific gene responses that occur in conjunction with the acid-stress defence of S. aureus.
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PMID:Acid-shock responses in Staphylococcus aureus investigated by global gene expression analysis. 1760 73

Light regulates photosynthesis, growth and reproduction, yield and properties of phycocolloids, and starch contents in seaweeds. Despite its importance as an environmental cue that regulates many developmental, physiological, and biochemical processes, the network of genes involved during light deprivation are obscure. In this study, we profiled the transcriptome of Gracilaria changii at two different irradiance levels using a cDNA microarray containing more than 3,000 cDNA probes. Microarray analysis revealed that 93 and 105 genes were up- and down-regulated more than 3-fold under light deprivation, respectively. However, only 50% of the transcripts have significant matches to the nonredundant peptide sequences in the database. The transcripts that accumulated under light deprivation include vanadium chloroperoxidase, thioredoxin, ferredoxin component, and reduced nicotinamide adenine dinucleotide dehydrogenase. Among the genes that were down-regulated under light deprivation were genes encoding light harvesting protein, light harvesting complex I, phycobilisome 7.8 kDa linker polypeptide, low molecular weight early light-inducible protein, and vanadium bromoperoxidase. Our findings also provided important clues to the functions of many unknown sequences that could not be annotated using sequence comparison.
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PMID:Profiling the transcriptome of Gracilaria changii (Rhodophyta) in response to light deprivation. 1904 58

Incidence of Parkinson's disease (PD) is lower in women compared to men (1:1.46), which is reflected in animal models. However, precise mechanisms are unclear. Administration of MPTP (1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine) to female mice does not lead to mitochondrial complex I inhibition as seen in males and the progressive dopaminergic cell loss in substantia nigra (SNpc) is significantly attenuated. Redox driven apoptotic signaling pathways regulated by thiol disulfide oxidoreductase(s) have been implicated in the neurodegeneration seen in PD. Oxidation of thioredoxin leads to activation of apoptosis signal regulating kinase 1 (ASK1; MAPKKK) initiating cell death cascade through MAP kinase(s). Higher constitutive expression of enzymes involved in cellular redox maintenance, such as glutathione reductase, thioredoxin, and thioredoxin reductase is observed in female brain. Exposure to MPTP activates ASK1 in male but not in female mice. Higher expression of Trx in females potentially prevents ASK1 activation. Downstream of ASK1, phosphorylation of p38 MAP kinase is seen in male but not female mice. Expression of DJ-1, the redox sensing protein is higher in females and the loss of nuclear DJ-1, followed by translocation of Daxx (death associated protein) from the nucleus to the cytosol, which promotes ASK1 mediated death cascade is not seen in females. The enzymes involved in redox maintenance potentially could play a crucial role in preventing the activation of redox driven death signaling cascade and offer neuroprotection. Theraupeutic strategies that help maintain redox homeostasis may help prevent the progressive neurodegeneration seen in PD.
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PMID:Redox activated MAP kinase death signaling cascade initiated by ASK1 is not activated in female mice following MPTP: novel mechanism of neuroprotection. 1952 88

Cysteine plays a number of important roles in protecting the cell from oxidative damage through its thiol functional group. These defensive functions are generally considered to be carried out by the low molecular weight thiol glutathione and by cysteine residues in the active sites of proteins such as thioredoxin and peroxiredoxin. In addition, there are thiols exposed on protein surfaces that are not directly involved with protein function, although they can interact with the intracellular environment. In the present study, in subcellular fractions prepared from rat liver or heart, we show that the quantitatively dominant free thiols are those of cysteine residues exposed on protein surfaces and not those carried by glutathione. Within the mitochondrial matrix, the concentration of exposed protein thiols is 60-90 mm, which is approximately 26-fold higher than the glutathione concentration in that compartment. This suggests that exposed protein thiols are of greater importance than glutathione for nonenzyme catalysed reactions of thiols with reactive oxygen and nitrogen species and with electrophiles within the cell. One such antioxidant role for exposed protein thiols may be to prevent protein oxidative damage. In the present study, in mitochondrial membranes and in complex I, we show that exposed protein thiols protect against tyrosine nitration and protein dysfunction caused by peroxynitrite. Therefore, exposed protein thiols are the dominant free thiol within the cell and may play a critical role in intracellular antioxidant defences against oxidative damage.
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PMID:Cysteine residues exposed on protein surfaces are the dominant intramitochondrial thiol and may protect against oxidative damage. 2014 60

Hexavalent chromium (Cr(VI)) compounds (e.g., chromates) are strong oxidants that readily enter cells, where they are reduced to reactive Cr species that also facilitate reactive oxygen species generation. Recent studies demonstrated inhibition and oxidation of the thioredoxin system, with greater effects on mitochondrial thioredoxin (Trx2). This implies that Cr(VI)-induced oxidant stress may be especially directed at the mitochondria. Examination of other redox-sensitive mitochondrial functions showed that Cr(VI) treatments that cause Trx2 oxidation in human bronchial epithelial cells also result in pronounced and irreversible inhibition of aconitase, a TCA cycle enzyme that has an iron-sulfur (Fe-S) center that is labile with respect to certain oxidants. The activities of electron transport complexes I and II were also inhibited, whereas complex III was not. Electron paramagnetic resonance (EPR) studies of samples at liquid helium temperature (10K) showed a strong signal at g=1.94 that is consistent with the inhibition of electron flow through complex I and/or II. A signal at g=2.02 was also observed, which is consistent with oxidation of the Fe-S center of aconitase. The g=1.94 signal was particularly intense and remained after extracellular Cr(VI) was removed, whereas the g=2.02 signal declined in intensity after Cr(VI) was removed. A similar inhibition of these activities and analogous EPR findings were noted in bovine airways treated ex vivo with Cr(VI). Overall, the data support the hypothesis that Cr(VI) exposure has deleterious effects on a number of redox-sensitive core mitochondrial proteins. The g=1.94 signal could prove to be an important biomarker for oxidative damage resulting from Cr(VI) exposure. The EPR spectra simultaneously showed signals for Cr(V) and Cr(III), which verify Cr(VI) exposure and its intracellular reductive activation.
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PMID:The pro-oxidant chromium(VI) inhibits mitochondrial complex I, complex II, and aconitase in the bronchial epithelium: EPR markers for Fe-S proteins. 2088 76

Glutaredoxin belongs to the oxidoreductase family, with cytosolic glutaredoxin 1 (Grx1) and mitochondrial glutaredoxin 2 (Grx2) isoforms. Of the two isozymes, the function of Grx2 is not well understood. This paper describes the effects of Grx2 deletion on cellular function using primary lens epithelial cell cultures isolated from Grx2 gene knockout (KO) and wild-type (WT) mice. We found that both cell types showed similar growth patterns and morphology and comparable mitochondrial glutathione pool and complex I activity. Cells with deleted Grx2 did not show affected Grx1 or thioredoxin expression but exhibited high sensitivity to oxidative stress. Under treatment with H(2)O(2), the KO cells showed less viability, higher membrane leakage, enhanced ATP loss and complex I inactivation, and weakened ability to detoxify H(2)O(2) in comparison with the WT cells. The KO cells had higher glutathionylation in the mitochondrial proteins, particularly the 75-kDa subunit of complex I. Recombinant Grx2 deglutathionylated complex I and restored most of its activity. We conclude that Grx2 has a function that protects cells against H(2)O(2)-induced injury via its peroxidase and dethiolase activities; particularly, Grx2 prevents complex I inactivation and preserves mitochondrial function.
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PMID:Glutaredoxin 2 knockout increases sensitivity to oxidative stress in mouse lens epithelial cells. 2198 34


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