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)

H(+)/site, charge/site, and ATP/site ratios have been determined at coupling sites I, II, and III. Three e(-) donors have been used for coupling site III: ferrocyanide, ascorbate + tetramethyl-p-phenylenediamine (TMPD), and succinate + TMPD. The H(+)/site ratios are 4.0 with ferrocyanide and 6.0 with succinate + TMPD (at pH <7.0); the charge/site ratios are 6.0 with ferrocyanide and with succinate + TMPD (at pH <7.0) and 4.0 with ascorbate + TMPD; the ATP/site ratio is 1.34 with ascorbate + ferrocyanide. These ratios have been obtained in the presence of amounts of antimycin A that provide full inhibition of site II. For coupling sites I and II, ferricyanide has been used as e(-) acceptor and succinate or NAD-linked substrates as e(-) donors. The H(+)/site ratios are 4.0 at sites I and II; the charge/site ratios are 4.0 at site I and 2.0 at site II; the ATP/site ratios are 1.0 at site I and 0.5 at site II. Two major factors affect the stoichiometries: (i) dimension of [unk](H) and (ii) supply of H(+) from the matrix. There is a correlation between collapse of [unk](H) and increase of H(+)/site and charge/site ratios. This indicates that approximation of the phenomenologic stoichiometry of the H(+) pump is obtained when flow ratios are measured at level flow. That charge/site and ATP/site ratios increase when ferrocyanide is e(-) donor and decrease when ferricyanide is e(-) acceptor is attributed to the localization of the redox couple. This leads to separation of 1 charge/e(-) when ferrocyanide is e(-) donor and to consumption of 1 charge/e(-) when ferricyanide is e(-) acceptor. To account for an extrusion of H(+) in excess of that predicted by the loop model, it is proposed that each coupling site contains a channel acting as a H(+) pump.
 ...
PMID:H+/site, charge/site, and ATP/site ratios in mitochondrial electron transport. 3 12

The effect of the alcohol-deterrent drug, disulfiram, on mitochondrial Ca2+ content was studied. Addition of this drug (20 microM) to mitochondria induces a complete loss of accumulated Ca2+. The calcium release is accompanied by a collapse of the transmembrane potential, mitochondrial swelling, and a diminution of the NAD(P)H/NAD(P) radio. These effects of disulfiram depend on Ca2+ accumulation; thus, ruthenium red reestablished the membrane delta psi and prevents the oxidation of pyridine nucleotides. The binding of disulfiram to the membrane sulfhydryls appeared to depend on the metabolic state of mitochondria, as well as on the mitochondrial configuration. In addition, it is shown that modification of 9 nmol -SH groups per mg protein suffices to induce the release of accumulated Ca2+.
 ...
PMID:Extensive Ca2+ release from energized mitochondria induced by disulfiram. 254 69

Addition of Pb2+ to rat kidney mitochondria is followed by induction of several reactions: inhibition of Ca2+ uptake, collapse of the transmembrane potential, oxidation of pyridine nucleotides, and a fast release of accumulated Ca2+. When the incubation media are supplemented with ruthenium red, the effect of Pb2+ on NAD(P)H oxidation, membrane delta psi, and Ca2+ release are not prevented if malate-glutamate are the oxidizing substrates; however, the latter two lead-induced reactions are prevented by ruthenium red if succinate is the electron donor. It is proposed that in mitochondria oxidizing NAD-dependent substrates, Pb2+ induces Ca2+ release by promoting NAD(P)H oxidation and a parallel drop in delta psi due to its binding to thiol groups, located in the cytosol side of the inner membrane. In addition, it is proposed that with succinate as substrate, the Ca2+ -releasing effect of lead is due to the collapse of the transmembrane potential as a consequence of the uptake of Pb2+ through the calcium uniporter, since such effect is ruthenium red sensitive.
 ...
PMID:The mechanism of lead-induced mitochondrial Ca2+ efflux. 288 57

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

4-Phenyl-N-methylpyridinium (MPP+), the oxidation product of the neurotoxic amine MPTP, is considerably more inhibitory to the oxidation of NAD+-linked substrates in intact mitochondria in State 3 than is 4-phenylpyridine. On adding uncouplers, the inhibition by MPP+ progressively diminishes, while the effect of 4-phenylpyridine remains. This is in accord with the fact that MPP+ is rapidly concentrated in the mitochondria by an energy-dependent process, while 4-phenylpyridine seems to enter passively with the concentration gradient. Collapse of the electrical gradient after addition of uncouplers thus leaves the inhibition by 4-phenylpyridine unaffected but causes efflux of MPP+ from the mitochondria and a reversal of its inhibitory action. In isolated inner membranes the inhibition of NADH oxidation via the respiratory chain by 4-phenylpyridine is much greater than by MPP+. MPTP and 4-phenyl-N-methylpyridinone also inhibit more than MPP+, whereas N-methylpyridinium has relatively little effect. The block is not at the point of entry of electrons into the flavoprotein since the NADH-ferricyanide activity is not inhibited by MPP+ at Vmax.
 ...
PMID:Inhibition of mitochondrial NADH dehydrogenase by pyridine derivatives and its possible relation to experimental and idiopathic parkinsonism. 348 28

The oxidation of NAD+-linked substrates by rat brain mitochondria is completely inhibited by pre-incubation with 0.5 mM N-methyl-4-phenylpyridine (MPP+). The effect is dependent on the integrity of the mitochondria because far higher concentrations of MPP+ are required to inhibit NADH oxidation in inverted mitochondria or isolated inner membrane preparations. The reason for this difference in behavior has been traced to a novel system for the uptake of MPP+ into mitochondria against a concentration gradient. The uptake system is energized by the transmembrane potential, as shown by the fact that valinomycin plus K+, which collapses this gradient, abolishes MPP+ uptake, while agents which collapse the proton gradient have no effect on the process. If an uncoupler is added to mitochondria preloaded with MPP+, efflux of the latter occurs with the concentration gradient. The uptake system has been studied in liver, whole brain, cortex, and midbrain preparations from rats. It may be readily distinguished from the synaptic dopamine reuptake system, since the former is blocked by uncouplers and respiratory inhibitors, but not by dopamine or mazindol, whereas the synaptic system is blocked by mazindol and competitively inhibited by dopamine but is not affected by respiratory inhibitors or uncouplers. Energy-driven uptake of MPP+ by brain mitochondria may be a crucial step in the complex sequence of events leading to the neurotoxic actions of its precursor, MPTP.
 ...
PMID:Energy-driven uptake of N-methyl-4-phenylpyridine by brain mitochondria mediates the neurotoxicity of MPTP. 348 84

Ca2+ release from liver mitochondria induced by N-ethylmaleimide, diamide, inorganic phosphate, palmitoyl-coenzyme A, and oxaloacetate occurs by a common mechanism. With all agents, a collapse of membrane potential, uptake of hydrogen ion, progressive acceleration of respiration, and large amplitude swelling accompanies Ca2+ release. These findings indicate that the agents promote an increase in the permeability of the inner membrane and that Ca2+ release can be explained under these conditions without invoking the action of a Ca2+ release carrier. The increase in permeability produced by the Ca2+-releasing agents requires the accumulation of exogenouse Ca2+. Sr2+ and Mn2+ cannot substitute for Ca2+ and the permeability increase is prevented by nupercaine. Free fatty acid accumulation in the mitochondria accompanies the increase in permeability. Polyunsaturated fatty acids accumulate more rapidly than saturated plus monounsaturated fatty acids, which indicates the accumulation of 1-acyllysophospholipid. Any inhibitor or condition which prevents the permeability change also prevents the accumulation of lysophospholipid, suggesting that these compounds cause the permeability increase. As Ca2+ release and swelling proceed, there is an accompanying oxidation of pyridine nucleotides. This oxidation occurs both with releasing agents which can oxidize the nucleotides through the action of mitochondrial enzymes as well as with agents which cannot. Any inhibitor or condition which prevents the increase in permeability also largely prevents the oxidation of pyridine nucleotides. The increase in the NAD(P)+/NAD(P)H ratio produced by the releasing agents can be explained as an effect secondary to the increase in permeability and collapse of the mitochondrial pH gradient rather than a primary cause of Ca2+ release.
 ...
PMID:The relationship between mitochondrial membrane permeability, membrane potential, and the retention of Ca2+ by mitochondria. 741 Mar 87

Computer analysis of the crystallographic structure of the A subunit of Escherichia coli heat-labile toxin (LT) was used to predict residues involved in NAD binding, catalysis and toxicity. Following site-directed mutagenesis, the mutants obtained could be divided into three groups. The first group contained fully assembled, non-toxic new molecules containing mutations of single amino acids such as Val-53-->Glu or Asp, Ser-63-->Lys, Val-97-->Lys, Tyr-104-->Lys or Asp, and Ser-114-->Lys or Glu. This group also included mutations in amino acids such as Arg-7, Glu-110 and Glu-112 that were already known to be important for enzymatic activity. The second group was formed by mutations that caused the collapse or prevented the assembly of the A subunit: Leu-41-->Phe, Ala-45-->Tyr or Glu, Val-53-->Tyr, Val-60-->Gly, Ser-68-->Pro, His-70-->Pro, Val-97-->Tyr and Ser-114-->Tyr. The third group contained those molecules that maintained a wild-type level of toxicity in spite of the mutations introduced: Arg-54-->Lys or Ala, Tyr-59-->Met, Ser-68-->Lys, Ala-72-->Arg, His or Asp and Arg-192-->Asn. The results provide a further understanding of the structure-function of the active site and new, non-toxic mutants that may be useful for the development of vaccines against diarrhoeal diseases.
 ...
PMID:Probing the structure-activity relationship of Escherichia coli LT-A by site-directed mutagenesis. 783 May 60

Physiological increases in matrix calcium are known to stimulate three mitochondrial dehydrogenases. In mitochondria isolated from rat heart, calcium stimulates rates of State 3 respiration during oxidation of succinate and of several NAD-linked substrates. In this study, we investigated the effects of calcium on NADH dehydrogenase and succinate dehydrogenase activities since the mechanism of these effects is unresolved. The respiratory activities of intact mitochondria and submitochondrial particles (SMP) were compared during incubation in media containing either ethylene glycol bis(beta-aminoethyl ether)-N,N'-tetraacetic acid (EGTA) or a Ca2+/EGTA buffer (approximately 1 microM free Ca2+). In intact mitochondria oxidizing 20 mM glutamate plus 2 mM malate, the membrane potential (delta psi) and matrix NAD(P)H were maintained at higher levels, and the maximal rate of ADP-stimulated respiration (State 3) was increased twofold by the presence of calcium. With succinate as substrate, calcium stimulated State 3 respiration but it did not influence the pyridine nucleotides redox state or membrane potential. Stimulation of succinate-supported respiration by addition of 6-10 microM ADP in the presence of hexokinase caused a sudden decrease in NAD(P)H and collapse of delta psi. This effect was not caused by inhibition of succinate dehydrogenase or by opening of the nonspecific pore. Calcium did not influence the oxidation of succinate by SMP containing either activated or nonactivated succinate dehydrogenase. In addition, calcium did not alter the kinetics of succinate dehydrogenase activation. Calcium and magnesium, in the concentration range of 0.02 to 5 mM, did not influence the NADH dehydrogenase activity of SMP. Energization of SMP by oligomycin addition, however, dramatically influenced the kinetic properties of NADH dehydrogenase. It is proposed that in heart mitochondria, calcium does not affect directly the components of electron transport but it may influence the activity of NADH dehydrogenase indirectly by increasing delta psi.
 ...
PMID:Influence of calcium on NADH and succinate oxidation by rat heart submitochondrial particles. 786 38

Adriamycin and related anthracyclines are potent oncolytic agents, the clinical utility of which is limited by severe cardiotoxicity. Aglycone metabolites of Adriamycin (5-20 microM) induce a Ca(2+)-dependent increase in the permeability of the inner mitochondrial membrane of both heart and liver mitochondria to small (< 1,500 Da) solutes; this phenomenon is accompanied by release of mitochondrial Ca2+, mitochondrial swelling, collapse of the membrane potential, oxidation of mitochondrial pyridine nucleotides [NAD(P)H], uncoupling, and a transition from the condensed to the orthodox conformation and is inhibited by ATP, dithiothreitol, the immunosuppressant cyclosporin A, and the ubiquitous polyamine spermine. Aglycones also modify mitochondrial sulfhydryl groups and induce a Ca2+ independent oxidation of mitochondrial NAD(P)H which appears to reflect electron transport from NADH to oxygen, mediated by the aglycones and resulting in the production of superoxide (O2-). Selenium deficiency and butylated hydroxytoluene inhibit aglycone-induced Ca2+ release from liver, but not heart, mitochondria, suggesting that the interactions of the aglycones with mitochondria differ in these two tissues. It can be proposed that the effects of Adriamycin aglycones on heart mitochondria are responsible for the cardiotoxicity of the parent drug.
 ...
PMID:Interactions of adriamycin aglycones with mitochondria may mediate adriamycin cardiotoxicity. 789 Jan 13


1 2 3 4 5 Next >>