UMLS:C0344329 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Target Concepts:

Query: UMLS:C0344329 (collapse)
28,634 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

2-Ethylhexanol (70 microM), a non-genotoxic carcinogen and peroxisome proliferator, stimulated oxygen uptake in the perfused rat liver by about 10% during the first 10 min of infusion. Perfusion with a higher, hepatotoxic dose of ethylhexanol (3 mM) led to a transient increase in oxygen uptake followed by a rapid inhibition of respiration of over 50% in 10 min. Lactate dehydrogenase (LDH) release, indicative of irreversible cell death, was detected in the effluent perfusate after 20 min. After 10 min of perfusion with ethylhexanol, livers were freeze-clamped, acid extracts were prepared and adenine nucleotides were measured by high-pressure liquid chromatography. Ethylhexanol decreased the ATP/ADP ratio from 2.5 to 0.9. Thus, marked decreases in hepatic energy state due to inhibition of respiration preceded cell death. To attempt to understand this phenomenon, the effect of ethylhexanol on isolated mitochondria was studied. Similar to classical uncoupling agents, ethylhexanol stimulated state-4 rates of respiration, diminished coupled rates of respiration, and decreased the P/O ratio in a dose-dependent manner in isolated mitochondria. Ethylhexanol also decreased uptake of radiolabeled 45CaCl2 by isolated mitochondria 4- to 5-fold. Therefore, we hypothesize that ethylhexanol initially uncouples oxidative phosphorylation leading to diminished ATP synthesis and collapse of ion gradients across the mitochondrial membrane.
...
PMID:2-Ethylhexanol uncouples oxidative phosphorylation in rat liver mitochondria. 204 57

We show that a synthetic peptide corresponding to the N-terminal 22 residues of the cytochrome c oxidase subunit IV presequence blocked import of pre-subunit IV into yeast mitochondria. The 22-residue peptide pL4-(1-22) did not alter the electrical potential across the mitochondrial inner membrane (the delta psi). Inhibition of import was reversible and could be overcome by the addition of increased amounts of precursor. Two other peptides, pL4-(1-16) and pL4-(1-23), which correspond to, respectively, the N-terminal 16 and 23 residues of the same presequence, also blocked import of pre-subunit IV. However, pL4-(1-16) was a much weaker inhibitor of import, while the inhibitory effect of pL4-(1-23) was due to its ability to completely collapse the delta psi. pL4-(1-22) seems to be a general inhibitor of mitochondrial import, in that it also blocked uptake of several other proteins. These included the precursors of the yeast proteins cytochrome c oxidase subunit Va, the F1-ATPase beta subunit, mitochondrial malate dehydrogenase, and the ATP/ADP carrier. In addition, uptake of two non-yeast precursor proteins (human ornithine transcarbamylase and a cytochrome oxidase subunit IV-dihydrofolate reductase fusion), was also blocked by the peptide. Subsequent studies revealed that pL4-(1-22) did not block the initial recognition or binding of proteins to mitochondria. Rather, our results suggest that the peptide acts at a subsequent translocation step which is common to the import pathways of many different precursor proteins.
...
PMID:A synthetic presequence reversibly inhibits protein import into yeast mitochondria. 216 Apr 69

The quantitative importance of glycolysis in cardiomyocyte reenergization and contractile recovery was examined in postischemic, preload-controlled, isolated working guinea pig hearts. A 25-min global but low-flow ischemia with concurrent norepinephrine infusion to exhaust cellular glycogen stores was followed by a 15-min reperfusion. With 5 mM pyruvate as sole reperfusion substrate, severe contractile failure developed despite normal sarcolemmal pyruvate transport rate and high intracellular pyruvate concentrations near 2 mM. Reperfusion dysfunction was characterized by a low cytosolic phosphorylation potential [( ATP]/[( ADP][Pi]) due to accumulations of inorganic phosphate (Pi) and lactate. In contrast, with 5 mM glucose plus pyruvate as substrates, but not with glucose as sole substrate, reperfusion phosphorylation potential and function recovered to near normal. During the critical ischemia-reperfusion transition at 30 s reperfusion the cytosolic creatine kinase appeared displaced from equilibrium, regardless of the substrate supply. When under these conditions glucose and pyruvate were coinfused, glycolytic flux was near maximum, the glyceraldehyde-3-phosphate dehydrogenase/3-phosphoglycerate kinase reaction was enhanced, accumulation of Pi was attenuated, ATP content was slightly increased, and adenosine release was low. Thus, glucose prevented deterioration of the phosphorylation potential to levels incompatible with reperfusion recovery. Immediate energetic support due to maximum glycolytic ATP production and enhancement of the glyceraldehyde-3-phosphate dehydrogenase/3-phosphoglycerate kinase reaction appeared to act in concert to prevent detrimental collapse of [ATP]/[( ADP][Pi]) during creatine kinase dysfunction in the ischemia-reperfusion transition. Dichloroacetate (2 mM) plus glucose stimulated glycolysis but failed fully to reenergize the reperfused heart; conversely, 10 mM 2-deoxyglucose plus pyruvate inhibited glycolysis and produced virtually instantaneous de-energization during reperfusion. The following conclusions were reached. (1) A functional glycolysis is required to prevent energetic and contractile collapse of the low-flow ischemic or reperfused heart (2). Glucose stabilization of energetics in pyruvate-perfused hearts is due in part to intensification of glyceraldehyde-3-phosphate dehydrogenase/3-phosphoglycerate kinase activity. (3) 2-Deoxyglucose depletes the glyceraldehyde-3-phosphate pool and effects intracellular phosphate fixation in the form of 2-deoxyglucose 6-phosphate, but the cytosolic phosphorylation potential is not increased and reperfusion failure occurs instantly. (4) Consistent correlations exist between cytosolic ATP phosphorylation potential and reperfusion contractile function. The findings depict glycolysis as a highly adaptive emergency mechanism which can prevent deleterious myocyte deenergization during forced ischemia-reperfusion transitions in presence of excess oxidative substrate.
...
PMID:Glucose requirement for postischemic recovery of perfused working heart. 231 14

The effects of procaine, lidocaine, tetracaine and dibucaine (10(-5) - 10(-2) M) were tested on isolated rat liver mitochondria by measurements of the respiratory rates and of the membrane potential and by electron microscopy. A general concentration-dependent stimulation of the basal state (respiration before ADP addition) was observed for all local anesthetics studied. Up to the concentration of 10(-3) M, the order of stimulation was: procaine less than lidocaine less than dibucaine less than tetracaine. However, with the exception of dibucaine, which inhibited state-3 respiration (ADP present) in a strictly concentration-dependent manner, the other drugs had a biphasic effect: slight stimulation of state 3 at low and moderate concentrations (less than or equal to 10(-3) M) and inhibition at higher concentrations. Nevertheless, due to a stronger stimulation of the basal state, the acceptor control ratio decreases progressively (uncoupling effect) as the concentration of the drugs increases. The only exception to this observation is procaine in the range of 10(-5) - 10(-4) M, where the stimulation of the two respiration states (although small) is approximately equal and thus the uncoupling effect is absent or negligible. Membrane potential recordings suggested that membrane integrity and phosphorylation capacity were negatively affected at high drug concentrations (greater than 10(-3) M), especially in the case of tetracaine and dibucaine, when 5 x 10(-3) M even produced the collapse of the membrane potential and complete loss of the phosphorylation ability. Electron microscopy confirmed these effects, showing an abundance of either swollen or supercondensed mitochondria, with many membrane ruptures. The action mechanisms of the tertiary amines studied are discussed in terms of interaction of drug with the lipid bilayer and with the membrane proteins. It is concluded that both the inhibitory and the uncoupling effects are dependent, in the first place, on the degree of hydrophobicity of each local anesthetic.
...
PMID:A comparative study of the effects of procaine, lidocaine, tetracaine and dibucaine on the functions and ultrastructure of isolated rat liver mitochondria. 239 19

Free fatty acids (FFA) are known to uncouple oxidative phosphorylation in mitochondria. However, their mechanism of action has not been elucidated as yet. In this study we have investigated in detail the patterns of uncoupling by the FFA oleate and palmitate in rat liver mitochondria and submitochondrial particles. The patterns of uncoupling by FFA were compared to uncoupling induced by the ionophores valinomycin (in the presence of K+) and gramicidin (in the presence of Na+) and the proton translocator carbonyl cyanide m-chlorophenylhydrazone (CCCP). The most striking difference in the pattern of uncoupling relates to the effect on the proton electrochemical potential gradient, delta mu H. Uncoupling by ionophores, particularly valinomycin, is associated with and most likely caused by a major reduction of delta mu H. In contrast, uncoupling by FFA is not associated with a significant reduction of delta mu H, indicating another mechanism of uncoupling. We suggest the use of the term decouplers for uncoupling agents such as FFA and general anesthetics that do not collapse the delta mu H [Rottenberg, H. (1983) Proc. Natl. Acad. Sci. U.S.A. 80, 3313-3317]. The protonophore CCCP and to some extent the ionophore gramicidin indicate a mixed mode of uncoupling since their effect on delta mu H is moderate when compared to that of valinomycin. Another distinguishing feature of uncouplers that collapse the delta mu H is their ability to stimulate ADP-stimulated respiration (state 3) further. Decouplers such as FFA and general anesthetics do not stimulate state 3 respiration.(ABSTRACT TRUNCATED AT 250 WORDS)
...
PMID:Fatty acid uncoupling of oxidative phosphorylation in rat liver mitochondria. 242 15

Correlations were made among ATP synthesis, transmembrane K+ gradients, and leakage of three amino acid neurotransmitters, gamma-aminobutyric acid (GABA), aspartate, and glutamate, in rat brain synaptosomes incubated under normoxic and respiration-limited conditions. Even under normoxic conditions, a substantial proportion of total ATP synthesis (8%) was provided by glycolysis. Limitation of respiration by approximately 30% through addition of amobarbital (Amytal) caused a twofold decrease in the creatine phosphate/creatine ([CrP]/[Cr]) ratio, and consequently the [ATP]/[ADP] ratio, and a threefold increase in lactate production. There was a detectable decrease in intracellular [K+] and small rises in external GABA, aspartate, and glutamate concentrations. More severe limitations in ATP synthesis caused larger declines in the [CrP]/[Cr] ratio and progressive leakage of K+ and neurotransmitter amino acids. A comparison of delta GATP and delta GNa, K showed the former to be larger by 6 kcal, which indicates that the plasma membrane Na+/K+ pump operates at far from equilibrium. Under respiration-limited conditions, even when total ATP synthesis decreased by approximately 80% and [ATP] declined to less than 0.4 mM, delta GATP was still larger than delta GNa,K. It is suggested that during hypoxia and ischemia, the activity of the plasma membrane Na+/K+ pump in brain becomes limited by [ATP], which falls below the Km value for the low-affinity regulatory site on the enzyme. This failure of the pump and consequent collapse of the ion gradients may contribute to the leakage of neurotransmitter amino acids that occurs in these pathological states.
...
PMID:Relationships among ATP synthesis, K+ gradients, and neurotransmitter amino acid levels in isolated rat brain synaptosomes. 244 8

Isolated rat hepatocytes were incubated with ATP to induce high intracellular free Ca2+ concentrations as determined with the Quin-2 method. Immediately after addition of ATP, the intracellular concentration of Ca2+ rose from 200 nM to more than 2.5 microM. It stayed at this value during the first 1/2 h; the rise was absolutely dependent on extracellular Ca2+. After the first 1/2 h the Ca2+ concentration decreased to 1-2 microM (5-10 times the control value). These high intracellular free Ca2+ concentrations did not lead to an immediate loss of cell viability. Only after 2 h of incubation a substantial number of cells lost viability. This was preceded by a decrease in cellular NADH (greater than 40%) and accompanied by a sharp increase in the intracellular Ca2+ concentration. Under these conditions the NADPH concentration was not affected. Cellular GSH was decreased to 30% of the initial value, but no lipid peroxidation or protein-thiol depletion was observed. Intracellular ATP, ADP and AMP were increased in the presence of extracellular ATP. Ca2+-dependent proteases seemed not to be involved in cell death. These observations are consistent with a collapse of mitochondrial functions as a final trigger of cell death.
...
PMID:Prolonged high intracellular free calcium concentrations induced by ATP are not immediately cytotoxic in isolated rat hepatocytes. Changes in biochemical parameters implicated in cell toxicity. 259 7

Hypoglycaemia and anoxia both cause massive release of glutamate from the brain in vivo, and the nature of this release was investigated using guinea-pig cerebral-cortical synaptosomes and iodoacetate and rotenone to simulate the energetic consequences of these conditions. Glutamate release (by continuous fluorimetry), cytoplasmic free Ca2+ (by fura-2), membrane potentials, ATP, ADP and creatine phosphate were determined in parallel, following the addition of iodoacetate or rotenone, alone or in combination. Ca2+-dependent glutamate release had a high energy requirement which could only be satisfied by aerobic glycolysis. Respiration using endogenous substrates, or anaerobic glycolysis following rotenone, caused a progressive inhibition of Ca2+-dependent release, correlating with a decline in the total ATP/ADP ratio and creatine phosphate. With rotenone, an increase in Ca2+-independent glutamate release was observed, correlating with a decline in plasma membrane potential. Only a slight increase in free Ca2+ was seen. Rotenone plus iodoacetate caused an almost immediate collapse of ATP/ADP ratio and a parallel loss of Ca2+-dependent glutamate release before free Ca2+ had risen to a level sufficient for exocytosis. In contrast, Ca2+-independent glutamate release increased. The Ca2+-dependent release of L-glutamate had the characteristics of an exocytotic transmitter release mechanism, being energy-dependent and triggered by elevated cytoplasmic free Ca2+ concentration. A distinct Ca2+-independent release of cytoplasmic glutamate occurred by reversal of the Na+-coupled uptake carrier, which was accelerated by a decline in the Na+ gradient. It is concluded that the Ca2+-independent release of cytoplasmic glutamate may make the major contribution to the excitotoxic release of glutamate in hypoglycaemic and anoxic conditions.
...
PMID:Ca2+-dependent and Ca2+-independent glutamate release, energy status and cytosolic free Ca2+ concentration in isolated nerve terminals following metabolic inhibition: possible relevance to hypoglycaemia and anoxia. 290 64

Incubation of rat liver mitochondria with benzoquinone derivatives in the presence of succinate plus rotenone has been shown to cause NAD(P)H oxidation followed by Ca2+ release. Further investigation revealed: (1)p-Benzoquinone-induced Ca2+ release was not initiated by a collapse of the mitochondrial membrane potential. However, Ca2+ release and subsequent Ca2+ cycling caused limited increased membrane permeability. (2) p-Benzoquinone-induced NAD(P)H oxidation and Ca2+ release were prevented by isocitrate, 3-hydroxybutyrate, and glutamate but not by pyruvate or 2-oxoglutarate. (3) Inhibition of pyruvate and 2-oxoglutarate dehydrogenases by p-benzoquinone was attributed to arylation of the SH groups of the cofactors, CoA and lipoic acid. Isocitrate dehydrogenase was also inhibited by p-benzoquinone, but the cofactors NAD(P)H and Mn2+ protected the enzyme. Glutamate dehydrogenase was not inhibited by p-benzoquinone. (4) Arylation of mitochondrial protein thiols by p-benzoquinone was associated with an inhibition of state 3 respiration, which was attributed to the inactivation of the phosphate translocase. In contrast, state 4 respiration, and the F1.F0-ATPase and ATP/ADP translocase activities were not inhibited. It was concluded that inhibition of mitochondrial NAD(P)H dehydrogenases by arylation of critical thiol groups will decrease the NAD(P)+-reducing capacity, and possibly lower the NAD(P)H/NAD(P)+ redox status in favor of Ca2+ release.
...
PMID:Role of sulfhydryl groups in benzoquinone-induced Ca2+ release by rat liver mitochondria. 321 68

Crossbridges in quick-frozen deep-etched blowfly flight muscles (from Sarcophaga bullata) were compared with those observed in the traditional waterbug preparation (Lethocerus) and found to be indistinguishable. Hence, blowfly was chosen as a fresher more accessible tissue for determining the effect of various fixatives and nucleotides on crossbridge structure. In rigor control, crossbridges were most regular in muscles that were stabilized before freezing by prefixation in glutaraldehyde followed by 'hardening' with neutralized tannic acid, so all nucleotide treatments were terminated by such fixation. MgATP (5 mM) converted the rigor pattern of crossbridges into a random array of disconnected thick filament projections. Lower levels of ATP (0.1 mM) caused a variable but generally lesser degree of crossbridge disconnection, as did 5 mM ADP (probably because it slowly converted to ATP inside the muscle fibres). Vanadate (1-2 mM) potentiated muscle relaxation in the latter two nucleotide treatments (i.e. produced a greater degree of crossbridge disconnection). Thus, differences in overall crossbridge abundance were readily apparent in chemically fixed muscles. Structural details within individual crossbridges were less well preserved, however. Chemical prefixation tended to collapse the muscle lattice, add a surface film to the filaments and thus obscure crossbridge details. Rigorous control of fixative pH largely prevented these problems and permitted recognition of the fact that in Sarcophaga flight muscle, as in Lethocerus muscle in rigor, the S1 'heads' of crossbridges attach to the thin filaments in the expected 'arrowhead' configuration.
...
PMID:Crossbridges in insect flight muscles of the blowfly (Sarcophaga bullata). 365 57

<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>