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PubMed1976

Effect of inhibitors on the substrate-dependent quenching of 9-aminoacridine fluorescence in inside-out membrane vesicles of Escherichia coli.

The effect of various inhibitors on the substrate-dependent quenching of the fluorescence of 9-aminoacridine was measured in inside-out membrane vesicles of Escherichia coli. The rate of fluorescence quenching in the presence of inhibitors was dependent on the rate of electron transfer through the respiratory chain with NADH, succinate, D-lactate or DL-glycerol 3-phosphate as substrates. Several patterns of response were given by the inhibitors. Inhibitors competitive with substrate, or those acting only on the dehydrogenases, gave a direct relationship between the extent of inhibition of oxidase activity and the rate of quenching. A biphasic relationship was given by 2-heptyl-4-hydroxyquinoline N-oxide and piericidin A which was due to these compounds acting both as inhibitors of the respiratory chain and, at higher concentrations, as uncoupling agents. Uncouplers inhibited fluorescence quenching with minimal inhibition of oxidase activity. The transmembrane pH difference was calculated from the extent of fluorescence quenching and the intravesicular volume. The maximum pH difference of 3.3--3.7 units was generated by each of the substrates tested.

Acridines↗
PubMed1972

Role of metabolic energy in the transport of -galactosides by Streptococcus lactis.

Streptococcus lactis (ATCC 7962) accumulated thiomethyl-beta-galactoside (TMG) and other galactosides against concentration gradients when the cells were supplied with a metabolizable substrate, such as glucose. The accumulated TMG was free and not phosphorylated. In the absence of glucose, TMG rapidly entered the cell to a concentration equal to that of the medium. Agents that uncouple oxidative phosphorylation abolished active transport but not the carrier-facilitated entry of TMG. Evidence that the transport carriers were functional in the absence of glucose or in the presence of uncoupling agents included the demonstration of counterflow, which depends on competitive inhibition for the carrier for exit.

Arginine↗
PubMed1975

The activation of non-phosphorylating electron transport by adenine nucleotides in Jerusalem-artichoke (Helianthus tuberosus) mitochondria.

In isolated plant mitochondria the oxidation of both succinate and exogenous NADH responded in the expected manner to the addition of ADP or uncoupling agents, and the uncoupled rate of respiration was often in excess of the rate obtained in the presence of ADP. However, the oxidation of NAD+-linked substrates responded in a much more complex manner to the addition of ADP or uncoupling agents such as carbonyl cyanide p-trifluoromethoxyphenylhydrazone to mitochondria oxidizing pyruvate plus malate failed to result in a reliable stimulation; this uncoupled rate could be stimulated by adding AMP or ADP in the presence of oligomycin or bongkrekic acid. Spectrophometric measurements showed that the addition of AMP or ADP resulted in the simultaneous oxidation of endogenous nicotinamide nucleotide and the reduction of cytochrome b. ADP was only effective in bringing about these changes in redox state in the presence of Mg2+ whereas AMP did not require Mg2+. It was concluded that AMP activated the flow of electrons from endogenous nicotinamide nucleotide to cytochrome b, possible at the level of the internal NADH dehydrogenase.

Adenosine Diphosphate↗
PubMed1976

The control of the adenosine triphosphatase of Rhodospirillum rubrum chromatophores by divalent cations and the membrane high energy state.

1. The rate of ATP hydrolysis, catalysed by Rhodospirilum rubrum chromatophores is accelerated by low concentrations and inhibited by high concentrations of uncoupling agent. 2. The inhibition at high concentrations of uncoupling agent is potentiated by the presence of free magnesium ions. At low uncoupler concentrations magnesium has no effect on the rate of ATP hydrolysis. 3. Inhibition of ATP hydrolysis by high concentrations of uncoupling agent and free magnesium ions is reversed by illumination. Illumination has less effect at low magnesium concentrations. 4. Free calcium ions inhibit ATP hydrolysis independently of the coupled state of the membrane. 5. Under coupled conditions, magnesium ions can overcome the inhibition induced by calcium. The two ions complete for the same site on the enzyme. 6. Inhibition by free magnesium in highly uncoupled chromatophores and inhibition by free calcium are both non-competitive with respect to the divalent cation-ATP substrate. 7. These data are consistent with a model in which divalent cations can bind to a site on the enzyme which is distinct from the substrate site. The regulation of the enzyme activity by the high energy state of the membrane is dependent on the occupant of this site.

Adenosine Triphosphatases↗
PubMed1984

Gap junction structure and cell-to-cell coupling regulation: is there a calmodulin involvement?

In most tissues neighboring cells communicate directly with each other by exchanging ions and small metabolites via cell-to-cell channels located at the intermembrane particles of gap junctions. Evidence indicates that the channels close when the [Ca2+]i or [H+]i increases. The channel occlusion (cell-to-cell uncoupling) is mainly a safety device by which cells can isolate themselves from damaged neighboring cells ("healing-over" process). Despite our knowledge of uncoupling agents, the uncoupling mechanism is still poorly understood. Uncoupling treatments have been shown to cause structural changes in gap junctions, characterized by an increase in tightness and regularity (crystallization) of particle packing and a decrease in particle size. Recently these changes have been shown to be induced by Ca2+ or H+ in isolated lens junctions and by Ca2+ in liver junctions, which suggests a close relationship between structural changes and uncoupling, but preliminary studies indicate that the junctional changes may not be synchronous with uncoupling but may lag behind it. However, recent X-ray diffraction data show that the channels of crystalline gap junctions (typical of uncoupled cells) are indeed closed, because they are inaccessible to sucrose (a gap junction permeant). Thus it seems that crystalline junctions are indeed in a non-permeable state, but the occlusion of the channels may precede the crystallization process. In the lens, junction crystallization is inhibited by a calmodulin (CaM) inhibitor, trifluoperazine (TFP). Is CaM involved in the uncoupling mechanism? To test this hypothesis, TFP and calmidazolium (CDZ), the most specific CaM inhibitor, were used on amphibian embryonic cells electrically uncoupled by CO2. Both TFP and CDZ effectively protect the cells from uncoupling, which suggests that CaM participates in the process. As a hypothesis, we propose that channel occlusion follows a CaM-mediated conformational change in the junctional protein. Particle crystallization may follow the conformational changes and result from a modification in electrostatic repulsion among the particles.

Animals↗
PubMed1980

Proton-linked D-xylose transport in Escherichia coli.

The addition of xylose to energy-depleted cells of Escherichia coli elicited an alkaline pH change which failed to appear in the presence of uncoupling agents. Accumulation of [14C]xylose by energy-replete cells was also inhibited by uncoupling agents, but not by fluoride or arsenate. Subcellular vesicles of E. coli accumulated [14C]xylose provided that ascorbate plus phenazine methosulfate were present for respiration, and this accumulation was inhibited by uncoupling agents or valinomycin. Therefore, the transport of xylose into E. coli appears to be energized by a proton-motive force, rather than by a phosphotransferase or directly energized mechanism. Its specificity for xylose as inducer and substrate and the genetic location of a xylose-H+ transport-negative mutation near mtl showed that the xylose-H+ system is distinct from other proton-linked sugar transport systems of E. coli.

Arsenates↗
PubMed1989

Effect of reducing agents and uncouplers on the electrical potential generated by mitochondrial ATPase activity.

Beef heart submitochondrial particles bound to phospholipids impregnated filters generated an electrical potential upon the addition of ATP. The magnitude of the electrical potential reached depended on the phospholipid mixture composition used for filter impregnation, phosphatidylethanolamine being the active component for the electrical potential generation. Uncoupler FCCP (p-trifluoromethoxy carbonyl cyanide phenylhydrazone) inhibited the transmembrane electrical potential generation by diminishing the electrical resistance of the system as a result of its protonophoric action. However, uncouplers 2, 4-dinitrophenol and dicoumarol did not provoke large modifications of the electrical resistance under the conditions of pH and concentration used, and their action varied with the time elapsed after the submitochondrial particles purification, favouring the idea of the uncoupler interaction with a specific site on the membrane. Addition of sodium dithionite resulted in a higher plateau value for the electrical potential consistent with the promoted increase in ATPase activity. The effect of this agent was reversed by the 2,6-dichlorophenol-indophenol added at equivalent concentrations.

Animals↗
PubMed1999

Further evidence for the selective disruption of intercellular communication by heptanol.

The lack of selective gap junctional uncoupling agents has hampered evaluation of the contribution of intercellular communication to pharmacomechanical coupling and vascular contractility. Thus we further explored the utility and selectivity of heptanol as a gap junctional uncoupling agent in isolated rat aortic rings. Fifty-two aortic rings were obtained from 15 rats and were precontracted to approximately 75% of maximum with phenylephrine (PE). When contraction achieved steady state (approximately 5 min), a single concentration of heptanol (200 microM) was added to each aortic ring at 1- to 3-min intervals for up to 42 min post-PE addition. At early time points (5-10 min after PE), heptanol elicited an approximately 50% loss of tension (i.e., relaxation). At subsequent time points post-PE, a gradual and time-dependent decrease in the magnitude of the heptanol-induced relaxation was observed until, after approximately 40 min, addition of heptanol was associated with little, if any, detectable relaxation. Linear regression analysis of the magnitude of the heptanol-induced relaxation vs. the square root of the elapsed time interval (from addition of PE) revealed a highly significant negative correlation (P < 0.001, R = 0.81). Studies conducted on KCl-precontracted aortic rings revealed no detectable heptanol-induced relaxation after development of the steady-state KCl-induced contraction. These data extend our previous observations to further document the potential utility of heptanol as a "relatively selective" uncoupling agent.

Animals↗
PubMed1987

Altered mitochondrial respiration in selectively vulnerable brain subregions following transient forebrain ischemia in the rat.

Mitochondrial respiratory function, assessed from the rate of oxygen uptake by homogenates of rat brain subregions, was examined after 30 min of forebrain ischemia and at recirculation periods of up to 48 h. Ischemia-sensitive regions which develop extensive neuronal loss during the recirculation period (dorsal-lateral striatum, CA1 hippocampus) were compared with ischemia-resistant areas (paramedian neocortex, CA3 plus CA4 hippocampus). All areas showed reductions (to 53-69% of control) during ischemia for oxygen uptake rates determined in the presence of ADP or an uncoupling agent, which then recovered within 1 h of cerebral recirculation. In the ischemia-resistant regions, oxygen uptake rates remained similar to control values for at least 48 h of recirculation. After 3 h of recirculation, a significant decrease in respiratory activity (measured in the presence of ADP or uncoupling agent) was observed in the dorsal-lateral striatum which progressed to reductions of greater than 65% of the initial activity by 24 h. In the CA1 hippocampus, oxygen uptake rates were unchanged for 24 h, but were significantly reduced (by 30% in the presence of uncoupling agent) at 48 h. These alterations parallel the development of histological evidence of ischemic cell change determined previously and apparently precede the appearance of differential changes between sensitive and resistant regions in the content of high-energy phosphate compounds. These results suggest that alterations of mitochondrial activity are a relatively early change in the development of ischemic cell death and provide a sensitive biochemical marker for this process.

Adenosine Diphosphate↗
PubMed1965

CALCIUM ION ACCUMULATION AND VOLUME CHANGES OF ISOLATED LIVER MITOCHONDRIA. REVERSAL OF CALCIUM ION-INDUCED SWELLING.

1. The excessive accumulation of Ca(2+) by mitochondria suspended in an iso-osmotic buffered potassium chloride medium containing oxidizable substrate and phosphate led to extensive swelling and release of accumulated Ca(2+) from the mitochondria. When the Ca(2+) was removed from the medium by chelation with ethylene glycol bis(aminoethyl)tetra-acetate, the swelling was reversed in a respiration-dependent contraction. The contracted mitochondria were shown to have regained some degree of respiratory control. 2. The respiration-dependent contraction could be supported by electron transport through a restricted portion of the respiratory chain, and by substrates donating electrons at different levels in the respiratory chain. 3. Respiratory inhibitors appropriate to the substrate present completely inhibited the contraction. Uncoupling agents, and the inhibitors oligomycin and atractyloside, were without effect. 4. When the reversal of swelling had been prevented by respiratory inhibitors, the addition of ATP induced a contraction of the mitochondria. In the absence of added chelating agent the contraction was very slow. The ATP-induced contraction was completely inhibited by oligomycin and atractyloside, was incomplete in the presence of uncoupling agents and was unaffected by respiratory inhibitors. 5. The relationship between the energy requirements of respiration-dependent contraction and the requirements of ion transport and other contractile systems are discussed.

Adenosine Triphosphate↗
PubMed1965

CALCIUM ION ACCUMULATION AND VOLUME CHANGES OF ISOLATED LIVER MITOCHONDRIA. CALCIUM ION-INDUCED SWELLING.

1. Liver mitochondria suspended in an iso-osmotic buffered potassium chloride medium containing an oxidizable substrate and phosphate accumulated added Ca(2+). During this process H(+) appeared in the medium and the mitochondrial suspension showed increased light-scattering. Respiration was markedly stimulated. 2. The addition of excess of Ca(2+), respiratory inhibitors or uncoupling agents caused extensive mitochondrial swelling associated with release of Ca(2+) into the suspending medium. When the suspension became anaerobic extensive swelling also occurred. Only under conditions when the addition of uncoupling agents would have produced high rates of electron transport, e.g. in the presence of succinate, was the structural integrity of the mitochondrion maintained after Ca(2+) accumulation. 3. Conditions that prevented respiration-dependent Ca(2+) accumulation also prevented Ca(2+)-induced swelling. Bovine plasma albumin was without effect, indicating that U-factor was not involved. Oligomycin together with ADP or ATP partially stabilized the mitochondria against Ca(2+)-induced swelling. 4. It is suggested that a ;high-energy' intermediate generated by coupled electron transport is required to prevent the mitochondrial swelling that results as a consequence of Ca(2+) accumulation.

Adenosine Triphosphate↗
PubMed1974

Biochemical and ultrastructural aspects of Ca2+ transport by mitochondria of the hepatopancreas of the blue crab Callinectes sapidus.

Mitochondria isolated from the hepatopancreas of the blue crab Callinectes sapidus show up to 12-fold stimulation of respiration on addition of Ca(2+), which is accompanied by Ca(2+) accumulation (Ca(2+):site = 1.9) and H(+) ejection (H(+):Ca(2+) = 0.85). Sr(2+) and Mn(2+) are also accumulated; Mg(2+) is not. A strongly hypertonic medium (383 mosM), Mg(2+), and phosphate are required for maximal Ca(2+) uptake. Ca(2+) uptake takes precedence over oxidative phosphorylation of ADP for respiratory energy. Once Ca(2+) is accumulated by the crab mitochondria, it is stable and only very slowly released, even by uncoupling agents. ATP hydrolysis also supports Ca(2+) uptake. Respiration-inhibited crab hepatopancreas mitochondria show both high-affinity and low-affinity Ca(2+)-binding sites, which are inactive in the presence of uncoupling agents. Crab hepatopancreas mitochondria have an enormous capacity for accumulation of Ca(2+), up to 5,500 ng-atoms Ca(2+) per mg protein, with an equivalent amount of phosphate. Freshly isolated mitochondria contain very large amounts of Ca(2+), Mg(2+), phosphate, K(+), and Na(+); their high Ca(2+) content is a reflection of the vary large amount of extra-mitochondrial Ca(2+) in the whole tissue. Electron microscopy of crab mitochondria loaded with Ca(2+) and phosphate showed large electron-dense deposits, presumably of precipitated calcium phosphate. They consisted of bundles of needle-like crystals, whereas Ca(2+)-loaded rat liver mitochondria show only amorphous deposits of calcium phosphate under similar conditions. The very pronounced capacity of crab hepatopancreas mitochondria for transport of Ca(2+) appears to be adapted to a role in the storage and release of Ca(2+) during the molting cycle of this crustacean.

Adenosine Diphosphate↗
PubMed1980

Inhibition, but not uncoupling, of respiratory energy coupling of three bacterial species by nitrite.

The effect of nitrite on respiratory energy coupling of three bacteria was studied in light of a recent report that nitrite acted as an uncoupling agent with Paracoccus denitrificans grown under denitrifying conditions. Our determinations of proton translocation stoichiometry of Pseudomonas putida (aerobically grown), Pseudomonas aeruginosa, and P. denitrificans (grown both aerobically and under denitrifying conditions) showed nitrite inhibition of proton-to-oxidant stoichiometry, but not uncoupling. Nitrite both reduced the H+/O ratio and decreased the rate of proton resorption. Increased proton resorption rates, characteristic of authentic uncoupling agents, were not observed. The lack of enhanced proton permeability due to nitrite was verified via passive proton permeability assays. The H+/O ratio of P. aeruginosa increased when growth conditions were changed from aerobic to denitrifying. This suggested the induction of an additional coupling site in the electron transport chain of denitrifying P. aeruginosa.

Carbonyl Cyanide m-Chlorophenyl Hydrazone↗