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 shown here that the apoptosis inducer staurosporine causes an early decrease in the endogenous respiration rate in intact 143B.TK(-) cells. On the other hand, the activity of cytochrome c oxidase is unchanged for the first 8 h after staurosporine treatment, as determined by oxygen consumption measurements in intact cells. The decrease in the endogenous respiration rate precedes the release of cytochrome c from mitochondria. Moreover, we have ruled out caspases, permeability transition, and protein kinase C inhibition as being responsible for the decrease in respiration rate. Furthermore, overexpression of the gene for Bcl-2 does not prevent the decrease in respiration rate. The last finding suggests that Bcl-2 acts downstream of the perturbation in respiration. The evidence of normal enzymatic activities of complex I and complex III in staurosporine-treated 143B.TK(-) osteosarcoma cells indicates that the cause of the respiration decrease is probably an alteration in the permeability of the outer mitochondrial membrane. Presumably, the voltage-dependent anion channel closes, thereby preventing ADP and oxidizable substrates from being taken up into mitochondria. This interpretation was confirmed by another surprising finding, namely that, in staurosporine-treated 143B.TK(-) cells permeabilized with digitonin at a concentration not affecting the mitochondrial membranes in naive cells, the outer mitochondrial membrane loses its integrity; this leads to a reversal of its impermeability to exogenous substrates. The loss of outer membrane integrity leads also to a massive premature release of cytochrome c from mitochondria. Most significantly, Bcl-2 overexpression prevents the staurosporine-induced hypersensitivity of the outer membrane to digitonin. Our experiments have thus revealed early changes in the outer mitochondrial membrane, which take place long before cytochrome c is released from mitochondria in intact cells.
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PMID:Mitochondrial outer membrane permeability change and hypersensitivity to digitonin early in staurosporine-induced apoptosis. 1240 74

Several reactions in biological systems contribute to maintain the steady-state concentrations of superoxide anion (O(2)*-) and hydrogen peroxide (H(2)O(2)). The electron transfer chain of mitochondria is a well documented source of H(2)O(2); however, the release of O(2)*- from mitochondria into cytosol has not been unequivocally established. This study was aimed at validating mitochondria as sources of cytosolic O(2)*-, elucidating the mechanisms underlying the release of O(2)*- from mitochondria into cytosol, and assessing the role of outer membrane voltage-dependent anion channels (VDACs) in this process. Isolated rat heart mitochondria supplemented with complex I or II substrates generate an EPR signal ascribed to O(2)*-. Inhibition of the signal in a concentration-dependent manner by both manganese-superoxide dismutase and cytochrome c proteins that cannot cross the mitochondrial membrane supports the extramitochondrial location of the spin adduct. Basal rates of O(2)*- release from mitochondria were estimated at approximately 0.04 nmol/min/mg protein, a value increased approximately 8-fold by the complex III inhibitor, antimycin A. These estimates, obtained by quantitative spin-trapping EPR, were confirmed by fluorescence techniques, mainly hydroethidine oxidation and horseradish peroxidase-based p-hydroxyphylacetate dimerization. Inhibitors of VDAC, 4'-diisothiocyano-2,2'-disulfonic acid stilbene (DIDS), and dextran sulfate (in a voltage-dependent manner) inhibited O(2)*- production from mitochondria by approximately 55%, thus suggesting that a large portion of O(2)*- exited mitochondria via these channels. These findings are discussed in terms of competitive decay pathways for O(2)*- in the intermembrane space and cytosol as well as the implications of these processes for modulating cell signaling pathways in these compartments.
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PMID:Voltage-dependent anion channels control the release of the superoxide anion from mitochondria to cytosol. 1248 55

Reductions in copper due to dietary restriction or transporter deficiency in brindled mice or humans with Menkes disease lead to reduced cuproenzyme activities, mitochondrial abnormalities, neurodegeneration and early mortality. The mechanisms for observed neuropathology remain unknown. Some researchers studying mutant mice suggest brain apoptosis as a possible factor based on changes in transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining and increased cytosolic cytochrome c and decreased Bcl-2 levels. Perinatal copper deficiency was induced in Holtzman rats during late gestation and lactation to investigate the role of apoptosis in the developing brain. Analysis of 13- and 24-d-old (P13 and P24) brains from male copper-deficient and copper-adequate rats revealed no difference in cytosolic cytochrome c or total Bcl-2 levels. Cerebellar TUNEL staining and caspase-3 activity were higher in the P12 copper-deficient than in the copper-adequate pups. However, TUNEL staining decreased and caspase-3 activity was not detected at P24 even though pups were more copper deficient based on cortex copper, Cu, Zn-superoxide dismutase and cytochrome c oxidase activities. This suggests that neuronal apoptosis is not enhanced by dietary copper deficiency in the brain. Lower Bcl-2 levels were detected in the copper-deficient rat hearts, consistent with apoptotic processes in mice reported by others. A robust enhancement of cytochrome c was observed in the total brain extracts and purified brain mitochondria of copper-deficient pups. Higher cytochrome c appeared to be correlated with the degree of copper deficiency and seemed to be associated with increased mitochondrial mass, because higher levels of voltage-dependent anion channel and mitochondrial complex I were also detected. The biochemical mechanisms for elevated cytochrome c are not known nor are the physiological consequences.
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PMID:Increased rat brain cytochrome c correlates with degree of perinatal copper deficiency rather than apoptosis. 1460 45

Apoptosis may be initiated in neurons via mitochondrial release of the respiratory protein, cytochrome c. The mechanism of cytochrome c release has been studied extensively, but little is known about its dynamics. It has been claimed that release is all-or-none, however, this is not consistent with accumulating evidence of cytosolic mechanisms for 'buffering' cytochrome c. This study has attempted to model an underlying disease pathology, rather than inducing apoptosis directly. The model adopted was diminished activity of the mitochondrial respiratory chain complex I, a recognized feature of Parkinson's disease. Titration of rat brain mitochondrial respiratory function, with the specific complex I inhibitor rotenone, caused proportional release of cytochrome c from isolated synaptic and non-synaptic mitochondria. The mechanism of release was mediated, at least in part, by the mitochondrial outer membrane component Bak and voltage-dependent anion channel rather than non-specific membrane rupture. Furthermore, preliminary data were obtained demonstrating that in primary cortical neurons, titration with rotenone induced cytochrome c release that was subthreshold for the induction of apoptosis. Implications for the therapy of neurodegenerative diseases are discussed.
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PMID:Cytochrome c release from rat brain mitochondria is proportional to the mitochondrial functional deficit: implications for apoptosis and neurodegenerative disease. 1568 86

We used proteomics to detect regional differences in protein expression levels from mitochondrial fractions of control, ischemia-reperfusion (IR), and ischemic preconditioned (IPC) rabbit hearts. Using 2-DE, we identified 25 mitochondrial proteins that were differentially expressed in the IR heart compared with the control and IPC hearts. For three of the spots, the expression patterns were confirmed by Western blotting analysis. These proteins included 3-hydroxybutyrate dehydrogenase, prohibitin, 2-oxoglutarate dehydrogenase, adenosine triphosphate synthases, the reduced form of nicotinamide adenine dinucleotide (NADH) oxidoreductase, translation elongation factor, actin alpha, malate dehydrogenase, NADH dehydrogenase, pyruvate dehydrogenase and the voltage-dependent anion channel. Interestingly, most of these proteins are associated with the mitochondrial respiratory chain and energy metabolism. The successful use of multiple techniques, including 2-DE, MALDI-TOF-MS and Western blotting analysis demonstrates that proteomic analysis provides appropriate means for identifying cardiac markers for detection of ischemia-induced cardiac injury.
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PMID:Potential biomarkers for ischemic heart damage identified in mitochondrial proteins by comparative proteomics. 1640 59

In order to detect and identify ubiquitous lipid raft marker proteins, we isolated lipid rafts from different mouse organs, including the liver, lung, large brain, and kidney, and analyzed their proteins via 2-DE. Many protein spots were determined to be ubiquitous in all of the lipid rafts, and were annotated via LC and MS/MS. Twelve proteins were identified as ubiquitous raft proteins, and most of these were determined to be mitochondrial proteins, including mortalin, prohibitin, voltage-dependent anion channel, ATP synthase, NADH dehydrogenase, and ubiquinol-cytochrome c reductase. Via immunoblotting, these proteins were shown to exist in detergent-resistant lipid rafts prepared using different organ tissues. Since these oxidation-reduction respiratory chains and ATP synthase complex were detected in detergent-resistant lipid raft fractions which had been isolated from the plasma membrane but not from the mitochondria, and found in the cell surface when determined by immunofluoresence and immunohistochemistry, we conclude that plasma membrane lipid rafts might contain oxidation-reduction respiratory chains and ATP synthase complex.
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PMID:Oxidation-reduction respiratory chains and ATP synthase complex are localized in detergent-resistant lipid rafts. 1652 83

Experimental traumatic brain injury (TBI) results in a significant loss of cortical tissue at the site of injury, and in the ensuing hours and days a secondary injury exacerbates this primary injury, resulting in significant neurological dysfunction. The mechanism of the secondary injury is not well understood, but evidence implicates a critical role for mitochondria in this cascade. This mitochondrial dysfunction is believed to involve excitotoxicity, disruption of Ca(2+) homeostasis, production of reactive oxygen species (ROS), ATP depletion, oxidative damage of mitochondrial proteins, and an overall breakdown of mitochondrial bioenergetics. Although oxidative damage occurs following TBI, the identities of proteins undergoing oxidative modification after TBI have not been investigated. In the present study, we utilized the 3-h post-injury controlled cortical impact model of experimental TBI in 20 young adult male Sprague-Dawley rats, coupled with proteomics to identify specific mitochondrial fraction proteins from the cortex and hippocampus that were oxidatively modified after TBI. We identified, from the cortex, pyruvate dehydrogenase, voltage-dependent anion channel, fumarate hydratase 1, ATP synthase, and prohibitin. From the hippocampus, we identified cytochrome C oxidase Va, isovaleryl coenzyme A dehydrogenase, enolase-1, and glyceraldehyde-3-phosphate dehydrogenase as proteins that had undergone oxidative modification following TBI. In addition, we have also shown that, following TBI, there is a reduction in the activities of pyruvate dehydrogenase (PDH), complex I, and complex IV. These findings demonstrate that, following TBI, several proteins involved in mitochondrial bioenergetics are highly oxidatively modified, which may possibly underlie the massive breakdown of mitochondrial energetics and eventual cell death known to occur in this model. The identification of these proteins provides new insights into the mechanisms that take place following TBI and may provide avenues for possible therapeutic interventions after TBI.
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PMID:Proteomic identification of oxidized mitochondrial proteins following experimental traumatic brain injury. 1751 33

Parkinson's disease (PD) is a progressive neurodegenerative disorder with a prevalence of 1-2% in people over the age of 50. Mitochondrial dysfunction occurred in PD patients showing a 15-30% loss of activity in complex I. Asiatic acid (AA), a triterpenoid, is an antioxidant and used for depression treatment, but the effect of AA against PD-like damage has never been reported. In the present study, we investigated the protective effects of AA against H(2)O(2) or rotenone-induced cellular injury and mitochondrial dysfunction in SH-SY5Y cells. Mitochondrial membrane potential (MMP) and the expression of voltage-dependent anion channel (VDAC) were detected with or without AA pretreatment following cellular injury to address the possible mechanisms of AA neuroprotection. The results showed that pre-treatment of AA (0.01-100 nM) protected cells against the toxicity induced by rotenone or H(2)O(2). In addition, MMP dissipation occurred following the exposure of rotenone, which could be prevented by AA treatment. More interestingly, pre-administration of AA inhibited the elevation of VDAC mRNA and protein levels induced by rotenone(100 nM) or H(2)O(2) (300 microM).These data indicate that AA could protect neuronal cells against mitochondrial dysfunctional injury and suggest that AA might be developed as an agent for PD prevention or therapy.
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PMID:Protective effects of asiatic acid on rotenone- or H2O2-induced injury in SH-SY5Y cells. 1880 51

Endothelial nitric oxide synthase-derived NO and its derivative, peroxynitrite (ONOO(-)), suppresses oxygen consumption by nitration of mitochondrial proteins after reperfusion. However, very few nitrated proteins are identified to date. In this paper, ischemia/reperfusion (I/R) injury was induced in mouse heart by ligation and release of the left anterior descending coronary artery. Western blotting showed that tyrosine nitration was higher in I/R hearts. Nitrated proteins were identified by capillary-liquid chromatography-nanospray tandem mass spectrometry. A total of 23 proteins were identified as being nitrated after I/R and 10 of them were from mitochondria. The nitrated mitochondrial proteins included 4 subunits from the oxidative phosphorylation system (the 24 and the 30 kDa subunits of complex I, the Rieske ISP of complex III, and the alpha subunit of ATP synthase), five enzymes in the matrix, and voltage-dependent anion channel. In purified complex I treated with ONOO(-), 3-NT was identified locating at the residue of Y247 of the 30 kDa subunit and the residues of Y47, Y53 of the 49 kDa subunit. In conclusion, I/R induced protein nitration and mitochondrial proteins were the major targets. Selective nitration of proteins from the oxidative phosphorylation system at the beginning of reperfusion may contribute to the suppression of oxygen consumption.
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PMID:Proteomic analysis of protein tyrosine nitration after ischemia reperfusion injury: mitochondria as the major target. 1915 Apr 19

The use of DOX (doxorubicin), an antibiotic used in oncological treatments, is limited by a dose-related cardiotoxicity against which acute exercise is protective. However, the mitochondrial-related mechanisms of this protection remain unknown. Therefore the present study aimed to determine the effects of an acute endurance exercise bout performed 24 h before DOX treatment on heart and liver mitochondrial function. A total of 20 adult male Wistar rats were divided into groups as follows: non-exercised with saline (NE + SAL), non-exercised DOX-treated (NE + DOX), exercised with saline (EX + SAL) and exercised DOX-treated (EX + DOX). The animals performed a 60 min exercise bout on a treadmill or remained sedentary 24 h before receiving either a DOX bolus (20 mg/kg of body weight) or saline. Heart and liver mitochondrial function [oxygen consumption, membrane potential (DeltaPsi) and cyclosporin-A-sensitive calcium-induced MPTP (mitochondrial permeability transition pore) opening] were evaluated. The activities of the respiratory complex, Mn-SOD (superoxide dismutase), caspases 3 and 9, as well as the levels of ANT (adenine nucleotide translocase), VDAC (voltage-dependent anion channel), CypD (cyclophilin D), Bax and Bcl-2, were measured. Acute exercise prevented the decreased cardiac mitochondrial function (state 3, phosphorylative lagphase; maximal DeltaPsi generated both with complex I- and II-linked substrates and calcium-induced MPTP opening) induced by DOX treatment. Exercise also prevented the DOX-induced decreased activity of cardiac mitochondrial chain complexes I and V, and increased caspase 3 and 9 activities. DOX administration and exercise caused increased cardiac mitochondrial SOD activity. Exercise ameliorated liver mitochondrial complex activities. No alterations were observed in the measured MPTP and apoptosis-related proteins in heart and liver mitochondria. The results demonstrate that acute exercise protects against cardiac mitochondrial dysfunction, preserving mitochondrial phosphorylation capacity and attenuating DOX-induced decreased tolerance to MPTP opening.
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PMID:Acute exercise protects against calcium-induced cardiac mitochondrial permeability transition pore opening in doxorubicin-treated rats. 2066 33


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