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PubMed1989

Decreased vacuolar acidification capacity in drug-resistant rat liver preneoplastic nodules.

Rat liver nodules produced by intermittent 2-acetylaminofluorene feeding exhibit alterations in cell surface receptors reminiscent of impairment of vacuolar acidification. In this report, vacuolar acidification activity, measured as the ATP-dependent quenching of acridine orange, was characterized in liver and nodular membrane fractions using various ion-transport inhibitors and with respect to nucleotide specificity and divalent cation dependence. Based on these criteria and on the comparison of vacuolar acidification activity with mitochondrial, lysosomal, and plasma membrane marker enzymes in different subcellular fractions, it was concluded that the assay measures the proton pump associated with exocytic and/or endocytic vacuolar compartments. When the vacuolar acidification activity was compared in liver and nodular subcellular membrane fractions, it was found that the vacuolar acidification was most strongly reduced in nodular low-density membrane fractions enriched in Golgi-derived membranes and endocytic vesicles. The data indicate that vacuolar, i.e., exocytic and/or endocytic, prelysosomal intracellular compartments in rat liver nodules are markedly deficient in acidification capacity, possibly providing an explanation to various metabolic aberrations, such as diminished iron accumulation and reduced protein degradation, observed in rat liver nodular cells.

2-Acetylaminofluorene↗

PubMed1976

Bicarbonate re-absorption in renal stone patients with acidification defects.

A pathological renal response to ammonium chloride loading was found to be common in renal stone formers. In order to elicit further information about the impaired acidification capacity eight patients were investigated by bicarbonate loading. One patient with a mild acidification defect had normal tubular re-absorption of bicarbonate. Five of these eight patients with suspected proximal acidification defect and two patients with impaired distal acidification were found to have a low bicarbonate threshold and an increased, fractionated, bicarbonate excretion at a normal plasma bicarbonate level. Four of the patients with suspected, proximal, acidification defect reached a maximal re-absorption of bicarbonate (Tm) that was low, while three patients did not reach a Tm. These three factors indicate increased bicarbonate wastage from the kidneys. A constantly alkaline urine, such as exists in patients with proximal acidification defect may give rise to an increased risk of the precipitation of renal stones - primarily calcium-phosphate stones.

Acidosis, Renal Tubular↗

PubMed1987

Phagosomal acidification in Paramecium: effects on lysosomal fusion.

Phagosomes of paramecia and amoeba and endosomes of fibroblasts and other mammalian cells are acidified prior to lysosomal fusion. The question, whether the phagosomal acidification process in paramecia is required for phagosome-lysosome fusion, was studied using ionophores, weak bases, and cytochalasin B (CB) in combination with monoclonal antibodies, acid phosphatase (AcPase) cytochemistry, and lysosome morphometry. Digestive vacuoles (DVs) of known ages were treated and examined. In untreated cells, lysosome binding to the membrane of the acidified DV increased linearly with age and reached a maximum before lysosome-DV fusion. When the fusion of the acidosomes with the very young DVs was prevented by CB, causing a block in the normal vacuole-pH drop, lysosome binding to the DVs as well as the rate and extent of lysosome-DV fusion were all greatly reduced. These effects of CB were reversible. When present prior to acidification, three ionophores and two weak bases did not inhibit the acidosome-DV fusion but raised the phagosomal pH and reduced both the rates of DV acidification and of lysosome-DV fusion. However, when added after acidification but prior to lysosome-DV fusion, five of the six perturbants studied did not inhibit this fusion but prolonged the period when DVs remained AcPase positive. Lastly, lysosome-DV fusion rates were found to be related to acidification rates. We conclude that an inhibition in acidosome-DV fusion or a reduction in both the acidification rate and vacuolar-pH drop would inhibit lysosome-DV fusion.

Acid Phosphatase↗

PubMed1994

Relationship between phagosome acidification, phagosome-lysosome fusion, and mechanism of particle ingestion.

The fate of pathogens ingested by macrophages is dependent on phagosome acidification and fusion with different intracellular vesicles. Whereas the mode of particle recognition by the phagocyte seems the main determinant of phagosome-lysosome fusion, the influence of membrane reorganization, fusion events, and cell activation in phagosome acidification is not well known. We looked for a relationship between the nature of receptors involved in phagocytosis, phagosome acidification, and phagosome-lysosome fusion. Murine macrophage-like P388D1 cells were made to ingest sheep erythrocytes coated with immunoglobulin G (EIgG) or IgM and complement (EIgMC) or treated with glutaraldehyde and periodate (EGP). The following results were obtained: (1) As expected, the adhesion of the three particle types was differentially inhibited by monoclonal antibodies specific for Fc gamma RII and CD11b/CD18. (2) The phagosomes containing all three particle types displayed similar acidification kinetics with a pH decrease to 6 within the first 10 min after ingestion. (3) Only phagosomes containing EIgG or EIgMC were fused with peroxidase-loaded secondary lysosomes. (4) Coating EGP with IgG only partially restored fusion, even when the surface density of IgG was markedly higher than found on EIgG. It is concluded that phagosome acidification and fusion are regulated by different mechanisms. Also, the lack of fusion observed with EGP is not entirely accounted for by the absence of stimulation of suitable receptors on the phagocyte membrane, because it cannot be restored by providing such a stimulus.

Animals↗

PubMed1993

Chronic ethanol administration impairs ATP-dependent acidification of endosomes in rat liver.

Ethanol administration has been shown to alter various protein trafficking pathways in the liver, including protein secretion, plasma membrane assembly and receptor-mediated endocytosis. Molecules such as proteins are transported into and within the cells via endosomal vesicles, and acidification of these endosomes appears to be critical for efficient sorting and trafficking of proteins. In the present study we examined whether ethanol administration impaired the ATP-dependent acidification of endosomes. Liver endosomes were prepared from rats after intravenous labeling with fluorescently labeled ligands and the initial pH and extent of ATP-dependent acidification was determined. Our results showed that the intrinsic pH was significantly higher and that the ATP-dependent acidification of the interior of the endosomes was inhibited in ethanol-fed versus control animals. This impairment of endosomal acidification may play a role in the impaired protein trafficking which occurs as a result of ethanol administration.

Adenosine Triphosphate↗

PubMed1996

Acidification of the cytosol inhibits the uptake of tetanus toxin in NG108-15 and NBr-10A neurohybridoma cells.

The influence of cytosol acidification on the uptake of two-chain tetanus toxin (TeTX)1 by neurohybridoma cells NG 108-15 and NBr-10A was investigated with two established techniques, the NH4Cl pulse method and the pH-clamp method. With the former, the extracellular pH is maintained at its physiological value, but is set to different values with the latter. Acidification of the cytoplasm with an NH4Cl pulse retarded the uptake of TeTX by both NG 108-15 and NBr-10A cells. This result provides further evidence for a vesicular endocytotic uptake of TeTX. In contrast, acidification of both the external medium and the cytoplasm (pH-clamp method) resulted in a net increase of toxin uptake. This result is explained as follows: Acidification of the extracellular environment has been shown to facilitate the uptake of tetanus toxin, and under pH clamp conditions, this effect is stronger than the simultaneous retardation of the toxin uptake by acidification also of the cytosol.

Ammonium Chloride↗

PubMed1982

Effect of temperature on proximal tubular acidification.

The effect of temperature on proximal tubular acidification was studied in isolated rat kidney, perfused with 20 mM phosphate Ringer's containing 7.5 g/100 ml bovine albumin, equilibrated with air. Tubular pH was measured with Sb microelectrodes during stopped-flow microperfusion. The temperature of the kidney was varied between 10 and 46 degrees C. At 10 degrees C the proximal tubule was still able to maintain pH gradients of about 0.7 pH units. However, half-times (t/2) of both acidification and alkalinization were markedly increased, from 6-7 s at 37 degrees C to 27-30 s at 10 degrees C. In consequence, net H+-ion flux into the tubule was reduced to 26% of that at 37 degrees C. In this system, in the absence of exogenous HCO-3 and CO2, t/2 of acidification and alkalinization were very similar at 37 degrees C and below. Above 37 degrees C alkalinization t/2 fell markedly to 1.43 +/- 0.09 (11) s at 46 degrees C, while acidification t/2 stayed at about 7 s. H+-ion back-fluxes increased progressively from 10-46 degrees C, while secretory JH reached a maximal value at 37 degrees C and fell at higher temperatures. Apparent activation energies calculated from rate coefficients were 8.48 kcal . mol-1 for acidification, and 9.30 for alkalinization, and those calculated from JH were 6.30 and 9.55 respectively. These data indicate that both H-ion secretion and back-flux are carrier-mediated, probably flowing through the Na/H exchanger in the luminal membrane, since their activation energies are of the same order of magnitude and markedly higher than those for protons in solution.

Animals↗

PubMed1994

Chemiosmotic coupling of ion transport in the yeast vacuole: its role in acidification inside organelles.

Acidification inside the vacuo-lysosome systems is ubiquitous in eukaryotic organisms and essential for organelle functions. The acidification of these organelles is accomplished by proton-translocating ATPase belonging to the V-type H(+)-ATPase superfamily. However, in terms of chemiosmotic energy transduction, electrogenic proton pumping alone is not sufficient to establish and maintain those compartments inside acidic. Current studies have shown that the in situ acidification depends upon the activity of V-ATPase and vacuolar anion conductance; the latter is required for shunting a membrane potential (interior positive) generated by the positively charged proton translocation. Yeast vacuoles possess two distinct Cl- transport systems both participating in the acidification inside the vacuole, a large acidic compartment with digestive and storage functions. These two transport systems have distinct characteristics for their kinetics of Cl- uptake or sensitivity to a stilbene derivative. One shows linear dependence on a Cl- concentration and is inhibited by 4,4'-diisothiocyano-2,2'-stilbenedisulfonic acid (DIDS). The other shows saturable kinetics with an apparent Km for Cl- of approximately 20 mM. Molecular mechanisms of the chemiosmotic coupling in the vacuolar ion transport and acidification inside are discussed in detail.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗

PubMed1990

Effect of cytoplasmic acidification on the membrane potential of T-lymphocytes: role of trace metals.

The effect of lowering intracellular pH on the membrane potential (Em) of rat thymic lymphocytes was studied using the potential-sensitive dye bis-oxonol. Cells were acid loaded by addition of the electroneutral K+/H+ exchanging ionophore nigericin. Acidification to pH 6.3 in Na(+)-free solution resulted in a biphasic change in Em: an early transient hyperpolarization followed by a sustained depolarization. These changes were associated with a rise in cytosolic free Ca2+ ([Ca2+]i). The hyperpolarization was eliminated when the change in [Ca2+]i was prevented using BAPTA, an intracellular Ca2+ chelator. Moreover, a similar hyperpolarization was elicited by elevation of [Ca2+]i at physiological pHi using ionomycin, suggesting involvement of Ca2(+)-activated K+ channels. In contrast, the depolarization phase could not be mimicked by raising [Ca2+]i with ionomycin. However, intracellular BAPTA effectively inhibited the acidification-induced depolarization. Inhibition was also obtained by extracellular addition of EGTA or dithiothreitol, even when the external free Ca2+ concentration remained unaltered. These observations suggested a possible role of contaminating trace metals. Cytosolic acidification is envisaged to induce intracellular accumulation of one or more trace metals, which induces the observed changes in Em. Accordingly, similar changes in Em can be induced without acidification by the addition of small amounts of Cu2+ to the medium. The ionic basis of the Em changes induced by acidification and the significance of these observations are discussed.

Animals↗

PubMed1990

Increase in gap junction resistance with acidification in crayfish septate axons is closely related to changes in intracellular calcium but not hydrogen ion concentration.

Neutral-carrier pH- and Ca-sensitive microelectrodes were used to investigate the relationship between junctional electrical resistance and either pHi or [Ca2+]i in crayfish septate axons uncoupled by acidification. For measuring [Ca2+]i a new neutral carrier sensor sensitive to picomolar [Ca2+] and virtually insensitive to other ions was used. Uncoupling was induced by superfusing the axons with Na-acetate solutions (pH 6.3). With acetate, the time course of changes in junctional resistance differed markedly from that of pHi or [H+]i, and [H+]i peaked 40-90 sec before junctional resistance. The difference in shape and peak time between pHi and junctional resistance curves caused significant hysteresis in the pHi versus junctional resistance relationship. In addition, junctional resistance maxima reached with slow acidification rates were 3-4 times greater than those with fast acidification of similar magnitude. With acetate, [Ca2+]i increased by approximately one order of magnitude from basal values of 0.1-0.3 microM. The curves describing the time course of changes in [Ca2+]i and junctional resistance matched well with each other in shape, peak time and magnitude. Both junctional resistance and [Ca2+]i recovered following a single exponential decay with a time constant of approximately 2 min. Different rates of acidification caused increases in [Ca2+]i and junctional resistance comparable in magnitude. The data indicate that the increase in junctional resistance induced by acidification is more closely related to [Ca2+]i than to [H+]i.

Animals↗

PubMed2005

Modest intracellular acidification suppresses death signaling in ouabain-treated cells.

The signaling cascade resulting in the death of several types of cells treated with ouabain or other cardiotonic steroids (CTS) remains poorly understood. Recently, we observed that ouabain kills epithelial and endothelial cells via its interaction with Na(+), K(+) -ATPase, but independently of inhibition of Na(+), K(+) -ATPase-mediated ion fluxes and inversion of the [Na(+)](i)/[K(+)](i) ratio. Here, we report that the death of ouabain-treated epithelial cells from the Madin-Darby canine kidney (C7-MDCK) and endothelial cells from porcine aortae is suppressed by acidification of medium from pH 7.4 to 7.0, i.e. under conditions when pH(i) was decreased from approximately 7.2 to 6.9. The rescue of ouabain-treated C7-MDCK cells was also detected under selective intracellular acidification caused by inhibition of Na(+)/H(+) exchanger. In these cells, neither Na(+), K(+) pump activity nor [(3)H]-ouabain binding was significantly affected by modest acidification. The death of ouabain-treated cells was independent of inhibition of RNA and protein synthesis with actinomycin D and cycloheximide. In contrast, both compounds sharply attenuated the protective action of acidified medium. Thus, our results show that very modest intracellular acidification is sufficient to inhibit the Na(+) (i)/K(+) (i)-independent death signal triggered in epithelial and endothelial cells by CTS. They also suggest that the protective action of acidification is mediated by de novo expression of genes involved in inhibition of the cell death machinery.

Animals↗

PubMed1998

The membrane potential of Arabidopsis thaliana guard cells; depolarizations induced by apoplastic acidification.

The apoplastic pH of guard cells probably acidifies in response to light, since light induces proton extrusion by both guard cells and epidermal leaf cells. From the data presented here, it is concluded that these apoplastic pH changes will affect K+ fluxes in guard cells of Arabidopsis thaliana (L.) Heynh. Guard cells of this species were impaled with double-barrelled micro-electrodes, to measure the membrane potential (Em) and the plasma-membrane conductance. Guard cells were found to exhibit two states with respect to their Em, a depolarized and a hyperpolarized state. Apoplastic acidification depolarized Em in both states, though the origin of the depolarization differed for each state. In the depolarized state, the change in Em was the result of a combined pH effect on instantaneously activating conductances and on the slow outward rectifying K+ channel (s-ORC). At a more acidic apoplastic pH, the current through instantaneously activated conductances became more inwardly directed, while the maximum conductance of s-ORC decreased. The effect on s-ORC was accompanied by an acceleration of activation and deactivation of the channel. Experiments with acid loading of guard cells indicated that the effect on s-ORC was due to a lowered intracellular pH, caused by apoplastic acidification. In the hyperpolarized state, the pH-induced depolarization was due to a direct effect of the apoplastic pH on the inward rectifying K+ channel. Acidification shifted the threshold potential of the channel to more positive values. This effect was accompanied by a decrease in activation times and an increase of deactivation times, of the channel. From the changes in Em and membrane conductance, the expected effect of acidification on K+ fluxes was calculated. It was concluded that apoplastic acidification will increase the K(+)-efflux in the depolarized state and reduce the K(+)-influx in the hyperpolarized state.

Arabidopsis↗

PubMed2006

Cytosolic acidification and lysosomal alkalinization during TNF-alpha induced apoptosis in U937 cells.

Apoptosis is often associated with acidification of the cytosol and since loss of lysosomal proton gradient and release of lysosomal content are early events during apoptosis, we investigated if the lysosomal compartment could contribute to cytosolic acidification. After exposure of U937 cells to tumor necrosis factor-alpha, three populations; healthy, pre-apoptotic, and apoptotic cells, were identified by flow cytometry. These populations were investigated regarding intra-cellular pH and apoptosis-associated events. There was a drop in cytosolic pH from 7.2 +/- 0.1 in healthy cells to 6.8 +/- 0.1 in pre-apoptotic, caspase-negative cells. In apoptotic, caspase-positive cells, the pH was further decreased to 5.7 +/- 0.04. The cytosolic acidification was not affected by addition of specific inhibitors towards caspases or the mitochondrial F(0)F(1)-ATPase. In parallel to the cytosolic acidification, a rise in lysosomal pH from 4.3 +/- 0.3, in the healthy population, to 4.8 +/- 0.3 and 5.5 +/- 0.3 in the pre-apoptotic- and apoptotic populations, respectively, was detected. In addition, lysosomal membrane permeability increased as detected as release of cathepsin D from lysosomes to the cytosol in pre-apoptotic and apoptotic cells. We, thus, suggest that lysosomal proton release is the cause of the cytosolic acidification of U937 cells exposed to TNF-alpha.

Amides↗

PubMed1991

Depolarization produces an acidification of adrenal gland perfusates.

Stimulation of adrenal glands with a variety of agonists or high potassium produced an acidification of the perfusion medium. The magnitude of the transient pH decrease was similar to that found in other nervous structures, and depended on the buffering capacity of the perfusion medium. However, no alkaline transient could be detected in this tissue. This acidification required Ca2+ and occurred under conditions producing catecholamine release. Since firstly the acidification could not be directly correlated with the amount of catecholamine released and secondly the time-course of both phenomena was different, suggesting that the acidification did not only result from the exocytosis of the acidic content of the chromaffin vesicles. The extracellular acidification may in addition originate: (a) partly from the proton release from acidic proteins, (b) from an output of acid equivalents from the cytoplasmic medium, either by the Na+/H+ antiporter present in all animal cells [24], or another mechanism yet to be determined.

Acetylcholine↗

PubMed1991

The role of intracellular acidification in calcium mobilization in human neutrophils.

Propionic acid induces a calcium mobilization in human neutrophils which is prevented by pretreatment with phorbol ester or pertussis toxin. The effect is reminiscent of that of chemotactic factors and leukotriene B4 and was attributed to cytoplasmic acidification (Naccache, P.H. et al. (1988) J. Cell. Physiol. 136, 118-124). We show there that other weak acids also induced cytoplasmic alkalinization and calcium mobilization. However, addition of trimethylamine together with propionic acid prevented the cytoplasmic acidification without modifying the calcium mobilization. Propionic acid increased the production of inositol phosphates but this effect was largely prevented by the joint addition of trimethylamine. The ionophores nigericin and monensin can both be forced to produce either cytoplasmic acidification or alkalinization by manipulating the extracellular concentrations of Na+, K+ or H+. Both ionophores produced calcium mobilization in all the cases, irrespective of the direction of the cytoplasmic pH shift. The ionophores were documented to collapse existing pH gradients among the cytoplasm and intracellular compartments. We conclude that the calcium-mobilizing effect of propionic acid and other weak acids is not due to the acidification of the cytoplasm. Our results are consistent, however, with calcium mobilization induced by weak acids and ionophores arising from acidification of an alkaline intracellular compartment.

Calcium↗

PubMed1992

Ammonium chloride-induced acidification in renal TALH SVE.1 cells monitored by 31P-NMR.

The aim of this study was to investigate the effect of NH4+ on the intracellular pH in TALH SVE.1 cells derived from the medullary thick ascending limb of Henle's loop (TALH) of rabbit kidney. These cells are specialized to perform NH4+ transport in vivo. Intracellular pH was monitored by 31P-NMR. The steady state intracellular pH (pHi) under standard conditions was 7.24 +/- 0.04 (n = 46). Exposure to NH4Cl resulted in an initial intracellular acidification of the TALH SVE.1 cells, followed by a recovery to the initial steady-state pHi value. The NH4(+)-induced acidification followed saturation kinetics up to 20 mM NH4Cl (delta pHmax = 0.2 pHunits). Half-maximal acidification was observed at 0.6 mmol/l. The intracellular acidification due to NH4Cl exposure was completely inhibited by 0.1 mM of the diuretic bumetanide, an inhibitor of the Na+/K+/2Cl- cotransporter. The effect of bumetanide was dose-dependent and a Ki value of 8.10(-7) M was calculated. NH4+ influx via K+ channels or the (Na+ + K+)ATPase could not be detected. pHi recovery to the initial value was caused mainly by amiloride-sensitive Na+/H+ exchange and to a lesser extent by an amiloride-insensitive system, which was not studied in detail. In the presence of bumetanide, pulses of high concentrations of NH4Cl induced small intracellular alkalinizations. From these experiments, an intrinsic buffer capacity (beta i) in TALH SVE.1 cells of 26 +/- 3 mM x pH-1 (pHi = 7.65) was determined. It could also be shown that the TALH SVE.1 cells exhibit maximal 'functional buffer capability' between pHout 6.9 and 7.3. Within these limits the cells can maintain their intracellular pH at a constant level, even though the extracellular pH changes. These data strongly suggest that the Na+/K+/2Cl- cotransporter is the main site of NH4+ entry into rabbit thick ascending limb cells in culture. A high intracellular buffer capacity and potent acid extrusion mechanism cooperate in counteracting the intracellular acidification caused by NH4+ influx into the cell.

Amiloride↗

PubMed1989

Neutrophil dysfunction after thermal injury: alteration of phagolysosomal acidification in patients with large burns.

The neutrophil phagolysosomal acidification during phagocytosis of Staphylococcus aureus was examined in six patients with large burns, using a flow cytometric technique allowing the simultaneous measurement of phagocytosis and phagolysosomal pH. The kinetics of neutrophil phagolysosomal acidification were altered during the first 20 days following injury, as the initial alkalinization of the phagolysosomes documented in control neutrophils could not be demonstrated in patient cells. Only at discharge and follow-up were the kinetics of phagolysosomal acidification normal. In addition, measurements of neutrophil maximal phagolysosomal acidification showed a lower pH in patient phagolysosomes than in the controls during the first 5 days of hospitalization. The changes of phagolysosomal acidification did not correlate with the alterations of neutrophil maturity or phagocytic capacity. The results demonstrate alterations of an oxygen-independent microbicidal mechanism in neutrophils from patients with large burns, which may contribute to the reduced capacity of neutrophil intracellular killing following thermal injury.

Adolescent↗

PubMed2006

Acidification improves cryotolerance of Lactobacillus delbrueckii subsp. bulgaricus CFL1.

The effect of acidification of the fermented broth at the end of the culture was examined on the growth and the cryotolerance of Lactobacillus bulgaricus CFL1, as a new means to better preserve lactic acid bacteria. Cryotolerance was investigated by evaluating the loss of specific acidification activity during freezing and frozen storage. An experimental design made it possible to determine optimal acidification conditions that improved cryotolerance, such as pH 5.15 for 30min. These conditions were also conducive to high biomass productivity. By considering the type of acid used, H(2)SO(4) enabled us to obtain cells with better cryotolerance, as compared to HCl. It was also observed that increasing the pH after acidification slightly minimised the acid shock, thus improving cryotolerance. Moreover, it was concluded that this improvement was related to a physiological adaptation of L. bulgaricus CFL1 during the 30-min acidification at pH 5.15.

Acids↗