Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mitochondrial complexes I, II, and III were studied in isolated brain mitochondrial preparations with the goal of determining their relative abilities to reduce O2 to hydrogen peroxide (H2O2) or to reduce the alternative electron acceptors nitroblue tetrazolium (NBT) and diphenyliodonium (DPI). Complex I and II stimulation caused H2O2 formation and reduced NBT and DPI as indicated by dichlorodihydrofluorescein oxidation, nitroformazan precipitation, and DPI-mediated enzyme inactivation. The O2 consumption rate was more rapid under complex II (succinate) stimulation than under complex I (NADH) stimulation. In contrast, H2O2 generation and NBT and DPI reduction kinetics were favored by NADH addition but were virtually unobservable during succinate-linked respiration. NADH oxidation was strongly suppressed by rotenone, but NADH-coupled H2O2 flux was accelerated by rotenone. Alpha-phenyl-N-tert-butyl nitrone (PBN), a compound documented to inhibit oxidative stress in models of stroke, sepsis, and parkinsonism, partially inhibited complex I-stimulated H2O2 flux and NBT reduction and also protected complex I from DPI-mediated inactivation while trapping the phenyl radical product of DPI reduction. The results suggest that complex I may be the principal source of brain mitochondrial H2O2 synthesis, possessing an "electron leak" site upstream from the rotenone binding site (i.e., on the NADH side of the enzyme). The inhibition of H2O2 production by PBN suggests a novel explanation for the broad-spectrum antioxidant and antiinflammatory activity of this nitrone spin trap.
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PMID:Interaction of alpha-phenyl-N-tert-butyl nitrone and alternative electron acceptors with complex I indicates a substrate reduction site upstream from the rotenone binding site. 983 55

Contraction-induced respiratory muscle fatigue and sepsis-related reductions in respiratory muscle force-generating capacity are mediated, at least in part, by reactive oxygen species (ROS). The subcellular sources and mechanisms of generation of ROS in these conditions are incompletely understood. We postulated that the physiological changes associated with muscle contraction (i.e., increases in calcium and ADP concentration) stimulate mitochondrial generation of ROS by a phospholipase A(2) (PLA(2))-modulated process and that sepsis enhances muscle generation of ROS by upregulating PLA(2) activity. To test these hypotheses, we examined H(2)O(2) generation by diaphragm mitochondria isolated from saline-treated control and endotoxin-treated septic animals in the presence and absence of calcium and ADP; we also assessed the effect of PLA(2) inhibitors on H(2)O(2) formation. We found that 1) calcium and ADP stimulated H(2)O(2) formation by diaphragm mitochondria from both control and septic animals; 2) mitochondria from septic animals demonstrated substantially higher H(2)O(2) formation than mitochondria from control animals under basal, calcium-stimulated, and ADP-stimulated conditions; and 3) inhibitors of 14-kDa PLA(2) blocked the enhanced H(2)O(2) generation in all conditions. We also found that administration of arachidonic acid (the principal metabolic product of PLA(2) activation) increased mitochondrial H(2)O(2) formation by interacting with complex I of the electron transport chain. These data suggest that diaphragm mitochondrial ROS formation during contraction and sepsis may be critically dependent on PLA(2) activation.
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PMID:PLA(2) dependence of diaphragm mitochondrial formation of reactive oxygen species. 1090 37

The involvement of mitochondrial dysfunction in septic disturbances of tissues is controversial. The aim of this study was to investigate the effects of endotoxin-induced sepsis on the function of heart and skeletal muscle mitochondria. Rabbits were made septic by subcutaneous injection of endotoxin (lipopolysaccharide, LPS) from Escherichia coli at concentrations of 100 or 150 microg LPS.kg(-1) 24 h prior to the experiments. Mitochondrial respiration was measured in saponin-skinned muscle fibers and compared with photometrically detected activities of respiratory chain enzymes as well as with function of perfused hearts. In heart fibers a dosage of 100 microg LPS.kg(-1) caused a significant decrease of state 3-respiration for the substrates pyruvate (-38%), octanoyl-carnitine (-38%) and succinate (-30%) with correspondingly decreased respiratory control indexes (RCI). In addition, endotoxin caused a decreased temporal stability of the rate of state 3-respiration. At least in part these changes can be attributed to a reduced activity of complex I + III (-50%) of the respiratory chain. State 4-respiration rates were not significantly altered. The lowered state 3-respiration in heart mitochondria seems to contribute to the impairment of heart muscle function as detected by an increase of coronary vascular resistance (CVR) in endotoxin-treated hearts. Functional properties of mitochondria from M. Vastus lasteralis were not affected by 100 microg LPS.kg(-1) but a higher dosage of 150 microg LPS.kg(-1) caused decreased RCI for the substrates pyruvate (-29%) and octanoyl-carnitine (-32%). Also the activity of complex I + III was not significantly affected at lower dose of endotoxin but decreased (-42%) after treatment with 150 microg LPS.kg(-1). Results demonstrate the involvement of impaired mitochondria in the pathophysiology of septic organ failure and a tissue specificity of endotoxaemia.
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PMID:Different sensitivity of rabbit heart and skeletal muscle to endotoxin-induced impairment of mitochondrial function. 1123 Dec 95

Disturbances in energy metabolism during sepsis are not clearly understood. The aim of the study was to globally assess the energy drive in septic rat myocytes, studying both glycolysis rates and mitochondrial maximal activities together, using recent in vitro techniques. Measurements were assessed before (H0) and 4 h after sepsis induction (H4). Hyperlactatemia was observed in all septic animals ([lactate] = 1.2 +/- 0.3 mmol/L at H0 versus 3.3 +/- 0.6 mmol/L at H4; p < 0.001). An enhanced glycolysis rate was observed in both aerobic ( J(A) = 7.2 +/- 0.9 at H0 versus 18.2 +/- 4.1 nmol glucose/min/g at H4; p < 0.05) and anaerobic ( J(B) = 7.5 +/- 1.2 at H0 versus 15.4 +/- 3.4 micromol glucose/min/g at H4; p < 0.05) fluxes, associated with a selective significant pyruvate-malate-dependent oxygen consumption rate decrease (V O(2)-PM = 0.144 +/- 0.008 at H0 versus 0.113 +/- 0.007 micromol O(2)/h/mg at H4; p < 0.05). This oxygen consumption decrease can be interpreted either as a complex I and/or a complex I-ubiquinone relation alteration. Our results are consistent with the hypothesis that an altered mitochondrial function during sepsis is responsible, at least in part, for hyperlactatemia, which is thus a consequence of an increased glycolysis rate.
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PMID:A global approach to energy metabolism in an experimental model of sepsis. 1170 93

In LPS-mediated states of sepsis, inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) production inhibit cellular respiration and mitochondrial electron transport. NO has been demonstrated to inhibit mitochondrial respiration by nitrosylation of the iron-sulfur centers of aconitase, complex I (NADH-ubiquinone oxidoreductase), complex II (succinate-ubiquinone oxidoreductase), and complex IV (cytochrome c oxidase). However, little is known of the effect of NO on expression of critical proteins in the electron transport chain. In ANA-1 murine macrophages, LPS-mediated NO synthesis decreases Cyt b protein expression and steady-state mRNA levels. Mitochondrial run-on analysis demonstrates unaltered Cyt b mitochondrial gene transcription. In this study utilizing LPS-stimulated ANA-1 murine macrophages, we demonstrate that expression of the mitochondrial protein, Cyt b, is significantly decreased as the result of a unique and previously unknown, NO-dependent posttranscriptional regulatory mechanism. (c)2001 Elsevier Science.
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PMID:Nitric oxide inhibits expression of cytochrome B in endotoxin-stimulated murine macrophages. 1174 Dec 89

Mitochondria, that provide most of the ATP needed for cell work, and that play numerous specific functions in biosyntheses and degradations, as well as contributing to Ca2+ signaling, also play a key role in the pathway to cell death. Impairment of mitochondrial functions caused by mutations of mt-genome, and by acute processes, are responsible for numerous diseases. The involvement of impaired mitochondria in the pathogenesis of sepsis is discussed. By means of the skinned fiber technique and high resolution respirometry, we have detected significantly reduced rates of mitochondrial respiration in heart and skeletal muscle of endotoxaemic rabbits. Mitochondria from heart were more affected than those from skeletal muscle. Decreased respiration rates were accompanied by reduced activities of complex I + III of the respiratory chain. Endotoxin-caused impairment was also detectable at the level of the Langendorff perfused heart, where the coronary vascular resistance was significantly increased. For an investigation of the influence of bacteraemia on the mitochondrial respiratory chain, baboons were made septic by infusion of high and low amounts of E. coli. For complex I + III and II + III, a clear dose-dependent decrease was detectable and in animals which died in septic shock, a further decrease of enzyme activities in comparison to the controls were found. These results are discussed in the light of current knowledge on the role of mitochondria in cell pathology in respect to sepsis. In conclusion, we present evidence that mitochondrial function is disturbed during sepsis. Besides ischaemic and poison-induced disturbances of mitochondrial function, sepsis is a further example of an acute disease where impaired mitochondria have to be taken into account.
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PMID:Mitochondrial dysfunction in sepsis: evidence from bacteraemic baboons and endotoxaemic rabbits. 1241 53

Sepsis is an increasingly common problem, particularly among critically ill patients. Mechanisms by which sepsis induces organ dysfunction have not been elucidated. The coexisting findings (unique to sepsis) of metabolic acidosis yet increased tissue oxygen tensions suggest cellular availability but decreased use of oxygen (tissue dysoxia). Because mitochondria use more than 90% of total body oxygen consumption for adenosine triphosphate (ATP) generation, a bioenergetic abnormality is implied. Cell and animal data have shown that nitric oxide (and its metabolites), produced in considerable excess in patients with sepsis, can affect oxidative phosphorylation by inhibiting several of its component respiratory enzymes. Human data are scarce. However, in skeletal muscle biopsies taken from patients with sepsis, we have recently demonstrated a relationship between increased nitric oxide production, antioxidant depletion, reduced respiratory chain complex I activity, and low ATP levels. These findings correlated with severity of disease and outcome and support the notion that mitochondrial dysfunction resulting in bioenergetic failure may be an important factor in the pathophysiology of sepsis-associated multiorgan failure. However, a reasonable argument can be made that the reduction in energy supply could represent a last-ditch adaptive response to ongoing inflammation, resulting in a cellular shutdown analogous to hibernation that allows eventual restoration of organ function and long-term survival in patients fit enough to survive the acute phase.
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PMID:Mitochondrial Dysfunction in Sepsis. 1367 65

It is known that nitric oxide (NO) is produced in response to a septic insult such as bacterial invasion and that overproduction of NO can have serious debilitating consequences. The mechanism by which NO causes damage at the cellular level is less clear. We have therefore studied the response to a septic insult in an anaesthetised spontaneously breathing Sprague-Dawley rat model. Six rats were given either an intravenous infusion of bacterial cell wall lipopolysaccharide (LPS, 5 mg/kg) or saline control over 1 hour. For electron paramagnetic resonance (EPR) studies, blood samples were collected every hour for a further two hours and liver tissue samples were collected postmortem. Measurement was also made of PaO2, blood pressure, base deficit, aortic and renal blood flow and hepatic microvascular pO2 (using porphyrin phosphoresence). Tissue samples were also collected for mitochondrial complex activity analysis. After the administration of LPS blood pressure, blood flow and microvascular PO2 were diminished and the base deficit increased. In addition a clear difference was observed by EPR between control and insulted blood and tissue samples. A large heam-nitrosyl signal is observed as well as an increase in the signal at g = 1.94, corresponding to the iron-sulphur centres of complex I becoming more reduced. However, no significant difference was observed for any of the mitochondrial complex activities. The effect of the NO produced was to depress the circulatory variables and increase base deficit, combined with a reduced oxygen consumption this implies an impairment of normal aerobic respiration. This was supported by increased iron-sulphur signals observed by EPR indicating a blockage in the mitochondrial redox chain with the subsequent accumulation of electrons. As no effect was observed in the mitochondrial complex activities this indicates that this inhibition is reversible in early stage sepsis. We conclude that nitric oxide produced in response to a septic insult can inhibit mitochondria causing an impairment of oxygen utilisation by aerobic respiration.
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PMID:Inhibition of mitochondrial respiration during early stage sepsis. 1456 71

Although sepsis is the major cause of mortality and morbidity in the critically ill, precise mechanism(s) causing multiorgan dysfunction remain unclear. Findings of impaired oxygen utilization in septic patients and animals implicate nitric oxide-mediated inhibition of the mitochondrial respiratory chain. We recently reported a relationship between skeletal muscle mitochondrial dysfunction, clinical severity, and poor outcome in patients with septic shock. We thus developed a long-term, fluid-resuscitated, fecal peritonitis model utilizing male Wistar rats that closely replicates human physiological, biochemical, and histological findings with a 40% mortality. As with humans, the severity of organ dysfunction and eventual poor outcome were associated with nitric oxide overproduction and increasing mitochondrial dysfunction (complex I inhibition and ATP depletion). This was seen in both vital (liver) and nonvital (skeletal muscle) organs. Likewise, histological evidence of cell death was lacking, suggesting the possibility of an adaptive programmed shutdown of cellular function. This study thus supports the hypothesis that multiorgan dysfunction induced by severe sepsis has a bioenergetic etiology. Despite the well-recognized limitations of laboratory models, we found clear parallels between this long-term model and human disease characteristics that will facilitate future translational research.
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PMID:Mitochondrial dysfunction in a long-term rodent model of sepsis and organ failure. 1460 43

Our results show that melatonin and N-acetyl-5-methoxykynurenamine (aMK) physiologically regulate both the electron transport chain (ETC) and OXPHOS, increasing the electron transport and ATP synthesis by normal mitochondria. Melatonin also counteracts mitochondrial oxidative damage induced by t-butyl hydroperoxide, recovering glutathione levels and ATP production. However, the effects of melatonin not only depend of its antioxidant properties, since the indoleamine specifically interacts with complex I and IV of the ETC increasing their activity. Experiments in vivo showed that melatonin administration prevents sepsis-induced ETC damage decreasing the activity and expression of INOS and mtNOS, thus reducing intramitochondrial nitric oxide (NO) and peroxynitrite (ONOO-) levels. Consequently, mitochondrial ETC ad ATP production recovered to normal conditions. The presence of specific binding of melatonin in mitochondrial matrix led us to explore the genomic role of the indoleamine in these organelles. In vivo and in vitro experiments showed that administration of melatonin increased mtONA transcriptional activity of the subunits 1-3 of the complex IV. These effects correlated well with the effects of melatonin on complex IV activity. The data suggest a new rate for melatonin to regulate mitochondrial homeostasis. Due to the relationships between mitochondrial damage, aging and neurodegenerative diseases, the effects of melatonin here described further support its antiaging and neuroprotective properties.
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PMID:Mitochondrial regulation by melatonin and its metabolites. 1520 73


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