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PubMed1994

ATP/ADP antiporter is involved in uncoupling of plant mitochondria induced by low concentrations of palmitate.

Carboxyatractyloside partially restored the transmembrane electrical potential difference (delta psi) dissipated by low concentrations of palmitate in pea stem mitochondria. This effect was more marked when mitochondria from sunflower were assayed. It is suggested that the ATP/ADP translocator is involved in the free fatty acid-induced uncoupling of oxidative phosphorylation in plant mitochondria, only when its level is sufficiently high and the concentration of the fatty acid is low to collapse only partially the delta psi.

Atractyloside↗
PubMed2002

Increase in cytosolic Ca2+ levels through the activation of non-selective cation channels induced by oxidative stress causes mitochondrial depolarization leading to apoptosis-like death in Leishmania donovani promastigotes.

Reactive oxygen species are important regulators of protozoal infection. Promastigotes of Leishmania donovani, the causative agent of Kala-azar, undergo an apoptosis-like death upon exposure to H2O2. The present study shows that upon activation of death response by H2O2, a dose- and time-dependent loss of mitochondrial membrane potential occurs. This loss is accompanied by a depletion of cellular glutathione, but cardiolipin content or thiol oxidation status remains unchanged. ATP levels are reduced within the first 60 min of exposure as a result of mitochondrial membrane potential loss. A tight link exists between changes in cytosolic Ca2+ homeostasis and collapse of the mitochondrial membrane potential, but the dissipation of the potential is independent of elevation of cytosolic Na+ and mitochondrial Ca2+. Partial inhibition of cytosolic Ca2+ increase achieved by chelating extracellular or intracellular Ca2+ by the use of appropriate agents resulted in significant rescue of the fall of the mitochondrial membrane potential and apoptosis-like death. It is further demonstrated that the increase in cytosolic Ca2+ is an additive result of release of Ca2+ from intracellular stores as well as by influx of extracellular Ca2+ through flufenamic acid-sensitive non-selective cation channels; contribution of the latter was larger. Mitochondrial changes do not involve opening of the mitochondrial transition pore as cyclosporin A is unable to prevent mitochondrial membrane potential loss. An antioxidant like N-acetylcysteine is able to inhibit the fall of the mitochondrial membrane potential and prevent apoptosis-like death. Together, these findings show the importance of non-selective cation channels in regulating the response of L. donovani promastigotes to oxidative stress that triggers downstream signaling cascades leading to apoptosis-like death.

Acetylcysteine↗
PubMed1983

Alteration of membrane permeability in Bacillus subtilis by clofoctol.

When Bacillus subtilis was treated with a bacteriostatic concentration of clofoctol [2-(2,4-dichlorobenzyl)-4-(tetramethyl-1,1,3,3-butyl)phenol], UV-absorbing material was released. Electron micrographs showed evidence of physical alteration of the bacterial envelope. The uptake of [14C]glutamate was strongly inhibited by clofoctol, and preloaded glutamate was found to leak from the bacteria. Clofoctol caused an immediate and dramatic decrease in the amount of intracellular ATP. This was neither the consequence of the stimulation of an ATPase, nor of the inhibition of bacterial respiration. Both the proton gradient and the potential gradient across the cytoplasmic membrane collapsed and this inhibition of energy metabolism was sufficient to account for the inhibition of growth by clofoctol. At the same bacteriostatic concentration complete permeabilization of the bacteria occurred.

Adenosine Triphosphate↗
PubMed1999

Release of Ca2+ from the sarcoplasmic reticulum increases mitochondrial [Ca2+] in rat pulmonary artery smooth muscle cells.

1. The Ca2+-sensitive fluorescent indicator rhod-2 was used to measure mitochondrial [Ca2+] ([Ca2+]m) in single smooth muscle cells from the rat pulmonary artery, while simultaneously monitoring cytosolic [Ca2+] ([Ca2+]i) with fura-2. 2. Application of caffeine produced an increase in [Ca2+]i and also increased [Ca2+]m. The increase in [Ca2+]m occurred after the increase in [Ca2+]i, and remained elevated for a considerable time after [Ca2+]i had returned to resting values. 3. The protonophore carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone (FCCP), which causes the mitochondrial membrane potential to collapse, markedly attenuated the increase in [Ca2+]m following caffeine application and also increased the half-time for recovery of [Ca2+]i to resting values. 4. Activation of purinoceptors with ATP also produced increases in both [Ca2+]i and [Ca2+]m in these smooth muscle cells. In some cells, oscillations in [Ca2+]i were observed during ATP application, which produced corresponding oscillations in [Ca2+]m and membrane currents. 5. This study provides direct evidence that Ca2+ release from the sarcoplasmic reticulum, either through ryanodine or inositol 1,4, 5-trisphosphate (InsP3) receptors, increases both cytosolic and mitochondrial [Ca2+] in smooth muscle cells. These results have potential implications both for the role of mitochondria in Ca2+ regulation in smooth muscle, and for understanding how cellular metabolism is regulated.

Adenosine Triphosphate↗
PubMed1986

The protective action of allopurinol in an experimental model of haemorrhagic shock and reperfusion.

Haemorrhagic shock was induced in anaesthetized, open-chest dogs by controlled arterial bleeding, sufficient to reduce and maintain mean arterial blood pressure at 40 mmHg for 30 min. The blood volume was then restored to the pre-shock level by rapid, intravenous reinfusion of the blood shed during the shock period. Haemorrhagic shock produced significant haemodynamic changes, characterized by a marked depression of myocardial function. Cardiac output (1226 +/- 57 ml min-1), peak aortic blood flow (6030 +/- 383 ml min-1) and maximum rate of rise of left ventricular pressure (2708 +/- 264 mmHg s-1) were all reduced by more than 50%. The haemodynamic profile was markedly improved by reinfusion of shed blood but this improvement was not sustained. There was a gradual decline such that 50% of the untreated animals suffered complete circulatory collapse and death between 60 and 120 min following reinfusion. Neither haemorrhagic shock, nor reinfusion of shed blood produced any consistent or significant changes in the myocardial adenine nucleotide pool. The ATP, ADP and AMP levels were, respectively, 25.9 +/- 4.2; 15.6 +/- 1.0; 4.3 +/- 1.9 nmol g-1 protein, before haemorrhagic shock; 21.6 +/- 3.4; 21.5 +/- 2.5; 10.2 +/- 2.7 nmol g-1 protein, after 30 min haemorrhagic shock; and 29.9 +/- 3.9; 16.5 +/- 1.2; 4.2 +/- 1.1 nmol g-1 protein, 60 min following reinfusion of shed blood. Pretreatment with allopurinol (50.0 mg kg-1 i.v.), 60 min before inducing haemorrhagic shock, had no significant effect upon the haemodynamic response to shock, but did prevent the gradual decline seen following reinfusion in the untreated animals. All of the allopurinol-treated animals displayed significantly better haemodynamic profiles than the untreated animals, furthermore, there was a 100% survival rate in this group. 5 Allopurinol had no significant effect upon the myocardial adenine nucleotide pool either during haemorrhagic shock or following reinfusion of shed blood.

Adenine Nucleotides↗
PubMed2001

Drug transport by reconstituted P-glycoprotein in proteoliposomes. Effect of substrates and modulators, and dependence on bilayer phase state.

The P-glycoprotein multidrug transporter (Pgp) is an active efflux pump for chemotherapeutic drugs, natural products and hydrophobic peptides. Pgp is envisaged as a 'hydrophobic vacuum cleaner', and drugs are believed to gain access to the substrate binding sites from within the membrane, rather than from the aqueous phase. The intimate association of both Pgp and its substrates with the membrane suggests that its function may be regulated by the biophysical properties of the lipid bilayer. Using the high affinity fluorescent substrate tetramethylrosamine (TMR), we have monitored, in real time, transport in proteoliposomes containing reconstituted Pgp. The TMR concentration gradient generated by Pgp was collapsed by the addition of either the ATPase inhibitor, vanadate, or Pgp modulators. TMR transport by Pgp obeyed Michaelis--Menten kinetics with respect to both of its substrates. The Km for ATP was 0.48 mM, close to the K(m) for ATP hydrolysis, and the K(m) for TMR was 0.3 microM. TMR transport was inhibited in a concentration-dependent fashion by verapamil and cyclosporin A, and activated (probably by a positive allosteric effect) by the transport substrate colchicine. TMR transport by Pgp reconstituted into proteoliposomes composed of two synthetic phosphatidylcholines showed a highly unusual biphasic temperature dependence. The rate of TMR transport was relatively high in the rigid gel phase, reached a maximum at the melting temperature of the bilayer, and then decreased in the fluid liquid crystalline phase. This pattern of temperature dependence suggests that the rate of drug transport by Pgp may be dominated by partitioning of drug into the bilayer.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1990

Phagosomal acidification is mediated by a vacuolar-type H(+)-ATPase in murine macrophages.

The mechanism underlying phagosomal acidification was studied in thioglycolate-elicited murine macrophages. The pH of the phagosomal compartment (pHp) was measured fluorimetrically in macrophage suspensions following ingestion of fluorescein isothiocyanate-labeled Staphylococcus aureus. At 37 degrees C, pHp decreased rapidly, reaching a steady state value of 5.8-6.1, while the cytoplasmic pH remained near neutrality, pH 7.1. The phagosome to cytosol pH gradient could be collapsed by addition of nigericin, monensin, or weak bases. The substrate dependence and inhibitor sensitivity profile of phagosomal acidification were investigated in intact and permeabilized cells. Phagosomal acidification was inhibited when ATP was depleted using metabolic inhibitors or permeabilizing the plasma membrane by electroporation. In permeabilized cells, acidification could be initiated by readdition of both Mg2+ and ATP. Neither adenosine 5'-(beta,gamma-imido)triphosphate nor adenosine 5'-(gamma-thio)triphosphate supported phagosomal acidification. Inhibitors of F1F0-type H(+)-ATPase such as oligomycin and azide, and the E1E2-type H(+)-ATPase inhibitor vanadate had no effect on phagosomal acidification. In contrast, the rate of phagosomal acidification was reduced by micromolar concentrations of N-ethylmaleimide and N,N'-dicyclohexylcarbodiimide. In permeabilized cells, nitrate inhibited the acidification with an apparent Ki of 25 mM. Phagosomal acidification was also effectively blocked by the macrolide antibiotic bafilomycin A1, with an apparent Ki of approximately 3 mM in both intact and electroporated cells. In this concentration range, bafilomycin A1 selectively inhibits vacuolar H(+)-ATPases. The substrate requirement and inhibitor susceptibility profile of phagosomal acidification strongly suggest that proton translocation across the phagosomal membrane is mediated by a vacuolar-type H(+)-ATPase.

Animals↗
PubMed1985

A model of lambda DNA arrangement in the viral particle.

The icosahedral shape of the lambda head suggests a 12-subunit structure of the collapsed DNA inside. The internal space of an icosahedron can optimally be filled by 12 geometrical figures each of which is a combination of a cone and more than half of a sphere. Such a pear-like geometrical figure is, in fact, formed spontaneously by DNA collapsed under certain conditions in vitro (Eickbush & Moudrianakis, 1978). It is proposed that a pear-like structure formed by about 4000 bp is the fundamental structural subunit of packaged lambda DNA. A possible arrangement of the 12 subunits inside the phage head relative to the tail is discussed. We hypothesize that lambda DNA is packaged into proheads in its condensed form. A driving force promoting the DNA translocation could be an ATP-dependent activity of a DNA topoisomerase (gpA/gpNu1), which would induce further reduction in the linking number of the already strongly negatively supercoiled DNA by rotation of one DNA strand around the other. The additional strain accumulated at the end of DNA molecule bound by the topoisomerase beyond a critical value would lead to regional collapse of the viral genome into a pear-like structure.

Animals↗
PubMed2003

A nuclear restorer-of-fertility mutation disrupts accumulation of mitochondrial ATP synthase subunit alpha in developing pollen of S male-sterile maize.

Mitochondrial biogenesis and function depend upon the interaction of mitochondrial and nuclear genomes. Forward genetic analysis of mitochondrial function presents a challenge in organisms that are obligated to respire. In the S-cytoplasmic male sterility (CMS-S) system of maize, expression of mitochondrial open reading frames (orf355-orf77) conditions collapse of developing haploid pollen. Nuclear restorer-of-fertility mutations that circumvent pollen collapse are often homozygous lethal. These spontaneous mutations potentially result from disruption of nuclear genes required for mitochondrial gene expression, in contrast to homozygous-viable restorer-of-fertility alleles that function to block or compensate for the expression of mitochondrial CMS genes. Consistent with this hypothesis, the homozygous-lethal restoring allele historically designated RfIII was shown to be recessive in diploid pollen produced by tetraploid CMS-S plants. Accordingly, the symbol for this allele has been changed to restorer-of-fertility lethal 1 (rfl1). In haploid rfl1 pollen, orf355-orf77 transcripts and mitochondrial transcripts encoding the alpha-subunit of the ATP synthase (ATPA) were decreased in abundance. Haploid rfl1 pollen failed to accumulate wild-type levels of ATPA protein, indicating that functional requirements for mitochondrial protein accumulation are relaxed in maize pollen. The CMS-S system and rfl mutations therefore allow for the selection of nuclear mutations disrupting mitochondrial biogenesis in a multicellular eukaryote.

Alleles↗
PubMed2000

BiP and PDI cooperate in the oxidative folding of antibodies in vitro.

Immunoglobulin heavy chain binding protein (BiP), a member of the Hsp70 chaperone family, and the oxidoreductase protein-disulfide isomerase (PDI) play an important role in the folding and oxidation of proteins in the endoplasmic reticulum. However, it was not clear whether both cooperate in this process. We show here that BiP and PDI act synergistically in the in vitro folding of the denatured and reduced Fab fragment. Several ATP-dependent cycles of binding, release, and rebinding of the unfolded antibody chains by BiP are required for efficient reactivation. Our data suggest that in the absence of BiP unfolded antibody chains collapse rapidly upon refolding, rendering cysteine side chains inaccessible for PDI. BiP binds the unfolded polypeptide chains and keeps them in a conformation in which the cysteine residues are accessible for PDI. These findings support the idea of a network of folding helper proteins in the endoplasmic reticulum, which makes this organelle a dedicated protein-processing compartment.

Carrier Proteins↗
PubMed2005

Nitrate uptake in the halotolerant cyanobacterium Aphanothece halophytica is energy-dependent driven by DeltapH.

The energetics of nitrate uptake by intact cells of the halotolerant cyanobacterium Aphanothece halophytica were investigated. Nitrate uptake was inhibited by various protonophores suggesting the coupling of nitrate uptake to the proton motive force. An artificially-generated pH gradient across the membrane (DeltapH) caused an increase of nitrate uptake. In contrast, the suppression of DeltapH resulted in a decrease of nitrate uptake. The increase of external pH also resulted in an enhancement of nitrate uptake. The generation of the electrical potential across the membrane (Deltapsi) resulted in no elevation of the rate of nitrate uptake. On the other hand, the valinomycin-mediated dissipation of Deltapsi caused no depression of the rate of nitrate uptake. Thus, it is unlikely that Deltapsi participated in the energization of the uptake of nitrate. However, Na(+)-gradient across the membrane was suggested to play a role in nitrate uptake since monensin which collapses Na(+)-gradient strongly inhibited nitrate uptake. Exogenously added glucose and lactate stimulated nitrate uptake in the starved cells. N, N'-dicyclohexylcarbodiimide, an inhibitor of ATPase, could alsoinhibit nitrate uptake suggesting that ATP hydrolysis was required for nitrate uptake. All these results indicate that nitrate uptake in A. halophytica is ATP-dependent, driven by DeltapH and Na(+)-gradient.

Adenosine Triphosphatases↗
PubMed1984

Measurement of delta pH and membrane potential in secretory vesicles isolated from bovine pituitary intermediate lobe.

Pro-opiomelanocortin (ACTH/endorphin prohormone) is processed within the secretory vesicles of pituitary intermediate lobe cells to alpha-melanotropin and beta-endorphin. In order to learn more about the microenvironment in which processing occurs, a method was developed to purify large quantities of bovine intermediate lobe secretory vesicles (ILSV) using isoosmolar metrizamide-sucrose gradients. Analysis of alpha-melanotropin and marker enzymes revealed that the gradients provided a 94-fold purification of secretory vesicles with respect to lysosomes and a 15-fold purification with respect to mitochondria. Pro-opiomelanocortin-converting enzyme activity in the ILSVs was assayed and found to be maximally active around pH 5. From measuring the delta pH across the intact ILSV membrane using 9-aminoacridine fluorescence quenching, the internal pH of ILSVs was determined to be less than 5.6, consistent with the operating pH range of the converting enzyme activity. The pH gradient of the ILSVs collapsed in the presence of ammonium sulfate or by using a combination of nigericin and K+, when the external medium pH was 7. Using the voltage-sensitive dye, oxanol VI, Mg2+ ATP was shown to cause a marked change in the ILSV membrane potential with the inside being positive which was reversed by the proton ionophore carbonyl cyanide p-trifluoromethoxyphenylhydrazone. Thus, the ILSVs appear to have a Mg2+ ATP-dependent electrogenic proton-translocating system.

Adrenocorticotropic Hormone↗
PubMed1987

Metabolite transport in mitochondria as a function of osmolarity.

The effect of increasing sucrose concentrations on some mitochondrial functions was studied. The results showed that high osmolarity inhibits oxidative phosphorylation as well as ATPase activity and ATP-dependent delta phi formation as a consequence of adenine nucleotide translocase inhibition. It is also shown that high osmolarity does not affect delta phi formation and energy-dependent Ca2+ uptake as driven by succinate oxidation. Sodium dodecyl sulphate-polyacrylamide gel electrophoresis of membrane proteins showed a different reactivity to o-phenantroline/Cu2+ as function of osmolarity. It is proposed that high sucrose concentrations induce a collapse of the matrix compartment that results in a restricted diffusion of some metabolites.

Adenine Nucleotides↗
PubMed1988

Na+-independent release of Ca2+ from rat heart mitochondria. Induction by adriamycin aglycone.

The effect of adriamycin aglycones on Ca2+ retention by isolated, preloaded rat heart mitochondria was assessed. After an initial lag, which decreased with increasing drug concentration, the 7-hydroxy-aglycone (5-20 microM) triggered Ca2+ release. Aglycone-induced Ca2+ release was correlated with Ca2+-dependent mitochondrial swelling, Ca2+-dependent collapse of the mitochondrial membrane potential, Ca2+-dependent oxidation of mitochondrial pyridine nucleotides, and a transition from the condensed to the orthodox configuration. Aglycone-induced Ca2+ release was inhibited by dibucaine, dithiothreitol, ATP, and bovine serum albumin. It can be concluded, therefore, that aglycone-induced Ca2+ release reflects the Ca2+-dependent increase in the permeability of the inner mitochondrial membrane to solutes of molecular weight less than 1000 which has been observed with other triggering agents [R. A. Haworth and D. R. Hunter, Archs Biochem. Biophys. 195, 460 (1979); I. Al-Nasser and M. Crompton, Biochem. J. 239, 19 (1986)]. In particular, the 7-hydroxy-aglycone decreased the amount of Ca2+ required to trigger the permeability increase. No effect of the aglycone on Ca2+ uptake could be discerned. 7-Deoxy-adriamycin aglycone, the more prominent biological metabolite of adriamycin, was similarly effective in inducing Ca2+ release, and both aglycones were substantially more effective than the parent drug. Adriamycin and related anthracyclines are potent antineoplastic agents, the clinical use of which is limited by severe cardiotoxicity. These results suggest that aglycone formation and the resultant disruption of both cellular Ca2+ homeostasis and metabolite compartmentation may mediate anthracycline cardiotoxicity.

Animals↗
PubMed2001

RecA protein promotes the regression of stalled replication forks in vitro.

Replication forks are halted by many types of DNA damage. At the site of a leading-strand DNA lesion, forks may stall and leave the lesion in a single-strand gap. Fork regression is the first step in several proposed pathways that permit repair without generating a double-strand break. Using model DNA substrates designed to mimic one of the known structures of a fork stalled at a leading-strand lesion, we show here that RecA protein of Escherichia coli will promote a fork regression reaction in vitro. The regression process exhibits an absolute requirement for ATP hydrolysis and is enhanced when dATP replaces ATP. The reaction is not affected by the inclusion of the RecO and R proteins. We present this reaction as one of several potential RecA protein roles in the repair of stalled and/or collapsed replication forks in bacteria.

DNA Replication↗
PubMed1981

Measurement of delta pH and membrane potential in isolated neurosecretory vesicles from bovine neurohypophyses.

The steady state concentration ratios of [3H]methylamine and [14C]SCN- were measured to determine the pH gradient and electrical potential, respectively, across the membrane of purified, intact, neurosecretory vesicles from bovine posterior pituitary. The intravesicular pH was 5.8 when the medium pH was 7. Varying the external pH had only a small effect on the intravesicular pH and resulted in a change in the pH gradient. Extrapolation to zero pH gradient yielded a value of 5.5 for the intravesicular pH. When the medium pH was 7, the pH gradient collapsed in the presence of ammonium sulfate or the combination of nigericin and K+. Measurement of the thiocyanate distribution across the vesicle membrane suggested the existence of an inside negative membrane potential. Mg2+ ATP caused a marked shift in the potential to +50 mV (inside positive) without altering the intravesicular pH. This shift was inhibited by carbonyl cyanide p-trifluoromethoxyphenylhydrazone. The possible roles of the large pH gradient and membrane potential in the storage of peptide hormones and their secretion is discussed.

Adenosine Triphosphate↗
PubMed2004

The K(ATP)+ channel is involved in a low-amplitude permeability transition in plant mitochondria.

Pea (Pisum sativum) stem mitochondria, energized by NADH, succinate or malate plus glutamate, underwent a spontaneous low-amplitude permeability transition (PT), which could be monitored by dissipation of the electrical potential (deltapsi) or swelling. The occurrence of the latter effects was dependent on O2 availability, because O2 shortage anticipated the manifestation of both deltapsi dissipation and swelling. Spontaneous deltapsi collapse was also monitored in sucrose-resuspended mitochondria and again O2 deprivation caused an anticipation of the phenomenon. However, in this case deltapsi dissipation was not accompanied by a parallel mitochondrial swelling. The latter effect was, indeed, evident only if mitochondria were resuspended in KCl (as osmoticum), or other cations with a molecular mass up to 100 Da (choline+). PT was also induced by protonophores (carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP) or free fatty acids) or valinomycin (only in KCl). The FCCP-induced dissipation of deltapsi and swelling were inhibited by ATP and stimulated (anticipated) by cyclosporin A or O2 shortage. The FCCP-induced PT was accompanied by the release of pyridine nucleotides from the matrix and of cytochrome c from the intermembrane space of KCl-resuspended mitochondria. The spontaneous and FCCP-induced low-amplitude PT of plant mitochondria are interpreted as due to the activity of a recently identified K(ATP)+ channel whose open/closed state is dependent on polarization of the inner membrane and on the oxidoreductive state of some sulfhydryl groups.

Journal Article↗
PubMed2001

Cyclosporin A induces the opening of a potassium-selective channel in higher plant mitochondria.

The immunosuppressive drug, cyclosporin A (CsA), induces the generation of a transmembrane electrical potential difference (deltapsi) in deenergized plant mitochondria incubated in sucrose-based media. Build up of deltapsi is prevented by external monovalent cations in the order K+ > Rb+ = Li+ > Na+, or by the protonophore carbonyl cyanide p-trifluoromethoxyphenylhydrazone, which also collapses the deltapsi generated by CsA. Entry of K+ into mitochondria can be monitored as swelling by incubating the organelles in a medium containing KCl to maintain constant osmolarity. This swelling is inhibited by ATP and stimulated by CsA or valinomycin. In addition, in mitochondria energized by succinate, KCl causes a dissipation of deltapsi, with sigmoidal kinetics, which is favored by CsA. Therefore, plant mitochondria appear to possess a K+ selective, voltage-dependent channel, which is opened by CsA, regulated by the redox state, and inhibited by nucleotides. The hypothetical roles of this new K+ATP channel are discussed in relation to its potential involvement in mitochondrial volume regulation, thermogenesis, apoptosis, and/or prevention of reactive oxygen species formation in plants.

Cyclosporine↗