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PubMed1989

alpha-Glycerophosphate shuttle in a clonal beta-cell line.

It has been proposed that the alpha-glycerophosphate (alpha-GOP) shuttle plays a crucial role in regulation of glycolysis in beta-cells by linking reoxidation of cytosolic NADH to formation of ATP in the electron transport chain (J. Biol. Chem. 265: 8287, 1981). Direct evidence for this suggestion is still lacking, however. In this work the operation of the alpha-GOP shuttle was investigated in the insulin-secreting cell line HIT-T15. The constituent enzymes of the pathway were found to be present in HIT cells. Flavin-linked alpha-GOP dehydrogenase was associated with the mitochondrial fraction, whereas NAD+-dependent alpha-GOP dehydrogenase was localized in the cytosol. In the presence of amobarbital (used to preserve the function of the alpha-GOP shuttle under conditions where oxidation of NADH by the respiratory chain was blocked), glucose increased insulin secretion, O2 consumption, and the cell [ATP]/[ADP] when compared with amobarbital alone. These results indicate that the alpha-GOP shuttle contributes to ATP generation in HIT cells and that its activation may be necessary for the initiation of insulin secretion by glucose.

Adenosine Diphosphate↗
PubMed2002

Inhibition of glutamate release via recovery of ATP levels accounts for a neuroprotective effect of aspirin in rat cortical neurons exposed to oxygen-glucose deprivation.

BACKGROUND AND PURPOSE: Aspirin is preventive against stroke not only because of its antithrombotic properties but also by other direct effects. The aim of this study was to elucidate its direct neuroprotective effects. METHODS: Viability parameters, glutamate release and uptake, and ATP levels were measured in cultured cortical neurons exposed to oxygen-glucose deprivation (OGD). In addition, ATP levels and oxygen consumption were studied in isolated brain mitochondria or submitochondrial particles. RESULTS: Aspirin inhibited OGD-induced neuronal damage at concentrations lower (0.3 mmol/L) than those reported to act via inhibition of the transcription factor nuclear factor-kappaB (which are >1 mmol/L), an effect that correlated with the inhibition caused by aspirin on glutamate release. This effect was shared by sodium salicylate but not by indomethacin, thus excluding the involvement of cyclooxygenase. A pharmacological dissection of the components involved indicated that aspirin selectively inhibits the increase in extracellular glutamate concentration that results from reversal of the glutamate transporter, a component of release that is due to ATP depletion. Moreover, aspirin-afforded neuroprotection occurred in parallel with a lesser decrease in ATP levels after OGD. Aspirin elevated ATP levels not only in intact cortical neurons but also in isolated brain mitochondria, an effect concomitant with an increase in NADH-dependent respiration by brain submitochondrial particles. CONCLUSIONS: Taken together, our present findings show a novel mechanism for the neuroprotective effects of aspirin, which takes place at concentrations in the antithrombotic-analgesic range, useful in the management of patients with high risk of ischemic events.

Adenosine Triphosphate↗
PubMed2001

[Effect of serum and osmotically active substances on metabolism in 262 tissue cultures of pig's corneas--improved preservation of donor tissue for keratoplasty].

BACKGROUND: The storage time of corneal organ cultures in limited in the closed system mainly used in European eye banks. In addition, swelling during storage reduces the quality of the donor material for keratoplasty. Therefore, dextrane was added in concentrations of 2.5%, 5%, 7.5% and 10% to the culture medium, and the energy producing metabolism was investigated. MATERIALS AND METHODS: The experiments were carried out with 262 pig corneas. MEM with some supplements was used at 31 degrees C. No serum was added, because glucose consumption, lactate production and ATP levels proved to be the same or better than with serum supplement. After 6 and 12 days, the corneas from organ cultures were extracted with perchloric acid. The levels of glucose and lactate in the stroma and of ATP and ADP in the epithelium were analysed with enzymatic-optical tests. RESULTS: Dextrane inhibited glycolysis and the production of ATP in corneal organ cultures during twelve days. With 7.5% and 10% dextrane in the medium, lactate levels in the cornea decreased from 6.09 to 4.5 and 4.6 microM/g H2O instead of increasing. At the same time, glucose increased paradoxical from 1.3 to 3.4 and 2.2 microM/g H2O, respectively. With 5% dextrane, glycolysis operated sufficiently producing an increase of lactate levels from 6.0 to 8.8 microM/g H2O and consuming glucose from levels of 1.27 down to 0.57 microM/g H2O. After 12 days with 7.5% and 10.0% dextrane, ATP levels were reduced, from 4.54 to 0.98 and 0.49 microM/g dry weight, and ATP/ADP ratios from 1.9 to 1.1 and 0.7 respectively. With 2.5% dextrane, the ATP was diminished from 4.5 to 2.2 microM/g dry weight. When 5% dextrane were added to the culture medium, the hydration was at optimum by 4.1, and ATP levels were reduced only from 4.5 to 2.6 microM/g dry weight. Moreover, the ATP/ADP ratios were at 2.1 as good as without dextrane. CONCLUSIONS: From the results it was concluded, that serum free medium may be used, and that permanent dewelling proved to be beneficial for the energy producing metabolism of the cornea in organ culture. Such conditions may improve morphological and metabolic quality of donor material. From previous publications, it was recommended, to use instead of toxic dextran the well tolerated HES (hydroxyethyl starch) and to apply a storage temperature of 21 degrees C, which slowed down glucose consumption without impairing the energy producing metabolism.

Adenosine Diphosphate↗
PubMed1989

Mechanism of toxicity of an experimental bidentate phosphine gold complexed antineoplastic agent in isolated rat hepatocytes.

SK&F 104524 (bis-[1,2 bis(diphenylphosphino)-ethane]gold(l) lactate) [( Au(dppe)2]+) is an experimental antineoplastic agent that is hepatotoxic in vivo in the dog as well as highly cytotoxic to isolated canine hepatocytes in vitro. Preliminary studies in isolated dog hepatocytes have indicated that [Au(dppe)2]+ causes an increase in hepatocyte respiration and a decrease in cellular ATP. The purpose of the present investigation was to characterize [Au(dppe)2]+-induced cytotoxicity and biochemical lesions in the intact cell and to correlate these changes with mitochondrial function. The uptake of [14C][Au(dppe)2]+ by rat hepatocytes was rapid, reaching a maximum by 30 min. [Au(dppe)2]+ was distributed throughout the hepatocyte and associated rapidly with mitochondria, nuclei, cytosol and cellular membranes. [Au(dppe)2]+ caused cell lethality in a concentration-dependent fashion; although 5 microM did not cause any changes in lactic dehydrogenase leakage, 20 microM produced 100% cell death by 120 min. [Au(dppe)2]+ also caused concentration-dependent bleb formation of the hepatocyte plasma membrane, increased oxygen consumption and loss of ATP within 30 min. ATP loss was associated with transient increases in AMP and ADP and a profound drop in the ATP/ADP ratio and energy charge. Total nucleotides (adenine and xanthine nucleotides) remained constant. The pattern of glutathione depletion coincided with that of lactic dehydrogenase leakage. Electron microscopy of hepatocytes exposed to [Au(dppe)2]+ for 30 min revealed depletion of glycogen granules and marked swelling of mitochondria. In isolated rat liver mitochondria, [Au(dppe)2]+ caused a stimulation of state 4 respiration and loss of the respiratory control ratio. [Au(dppe)2]+ also relieved the oligomycin-induced inhibition of state 3 (ADP-stimulated) respiration.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Effects of calcium on mitochondrial NAD(P)H in paced rat ventricular myocytes.

The response of the steady-state level of mitochondrial NAD(P)H of individual cardiac myocytes to substrate and to pharmacological alteration of intracellular calcium was investigated using a defined pacing protocol. Rapid pacing (5 Hz) reversibly decreased the NAD(P)H level and increased oxygen consumption whereas phosphocreatine and ATP levels did not change significantly. Verapamil plus NiCl2 blockade of calcium channels abolished contractions. Ryanodine, which prevents calcium-induced calcium release, also stopped cell contraction. NAD(P)H levels do not change in the absence of contraction. Blockade of sarcolemmal K+ channels did not stop contraction, and NAD(P)H levels reversibly decreased during rapid pacing. Thus rapid contractions are associated with a reversible decrease in NAD(P)H levels. Ruthenium red blockade of Ca2+ entry into mitochondria did not block contraction but significantly decreased NAD(P)H levels in both slowly paced (0.5 Hz) and rapidly paced cells. The simplest explanation of these data is that the steady-state reduction of NAD(P)H is strongly dependent on the rate of ATP utilization and not on sarcoplasmic Ca2+ levels when the oxygen and substrate supplies are not limiting and the intracellular calcium regulation is maintained. An effect of intracellular Ca2+ on NAD(P)H is observed only when Ca2+ entry into mitochondria is blocked with ruthenium red.

Adenosine Triphosphate↗
PubMed1967

Metabolism of propionate by sheep-liver mitochondria. Effects of alpha-oxoglutarate, adenosine triphosphate, sodium chloride and potassium chloride.

1. A study has been made of the effects of ATP and alpha-oxoglutarate on the rate of metabolism of propionate by whole mitochondria from sheep liver, and by mitochondria disrupted with ultrasonic energy or by freezing and thawing. Whole mitochondria metabolized propionate aerobically; the rate was increased and stabilized by 0.5mm-ATP, and increased at least a further 50% by 1.67mm-alpha-oxoglutarate. 2. Anaerobically, externally added ATP at high concentrations permitted slow consumption of propionate. 3. In the presence of 1.3mm-ATP, but in the absence of alpha-oxoglutarate, there was no significant lag phase in the removal of propionate by whole mitochondria, and the rate declined at concentrations below 2mm. In the additional presence of 1.67mm-alpha-oxoglutarate or -glutamate, propionate was removed at linear rates until the residual propionate concentration was about 0.1mm. 4. Maximum rates of metabolism of propionate by whole mitochondria with 1.3mm-ATP occurred with alkali-metal chloride concentrations of 65-95mm and with K(+)/Na(+) ratios 5-10, both in the presence and absence of alpha-oxoglutarate. 5. With disrupted mitochondria stimulatory effects of alpha-oxoglutarate were obtained only aerobically, only with propionate and not propionyl-CoA as substrate, and only when sufficient mitochondrial structure remained to permit unsupplemented metabolism of propionate to occur. 6. In the presence of ATP and CoA, disrupted mitochondria fixed [2-(14)C]propionate at a rate adequate to explain the rate with whole mitochondria stimulated with ATP and alpha-oxoglutarate. 7. With both whole and partially disrupted mitochondria in the absence of ATP, the rate of metabolism of propionate was inhibited by about 80% by 3.3mm-AMP. The inhibition was partly overcome by alpha-oxoglutarate plus CoA. 8. It is concluded that the ultimate effect of alpha-oxoglutarate was to increase the rate of supply of ATP within the mitochondria. Reasons are given why it is premature to conclude that the extra ATP arose entirely from the oxidation of alpha-oxoglutarate itself.

Adenosine Triphosphate↗
PubMed2000

Rotavirus alters paracellular permeability and energy metabolism in Caco-2 cells.

Rotaviruses infect epithelial cells of the small intestine, but the pathophysiology of the resulting severe diarrhea is incompletely understood. Histological damage to intestinal epithelium is not a consistent feature, and in vitro studies showed that intestinal cells did not undergo rapid death and lysis during viral replication. We show that rotavirus infection of Caco-2 cells caused disruption of tight junctions and loss of transepithelial resistance (TER) in the absence of cell death. TER declined from 300 to 22 Omega. cm(2) between 8 and 24 h after infection and was accompanied by increased transepithelial permeability to macromolecules of 478 and 4,000 Da. Distribution of tight junction proteins claudin-1, occludin, and ZO-1 was significantly altered during infection. Claudin-1 redistribution was notably apparent at the onset of the decline in TER. Infection was associated with increased production of lactate, decreased mitochondrial oxygen consumption, and reduced cellular ATP (60% of control at 24 h after infection), conditions known to reduce the integrity of epithelial tight junctions. In conclusion, these data show that rotavirus infection of Caco-2 intestinal cells altered tight junction structure and function, which may be a response to metabolic dysfunction.

Animals↗
PubMed1993

Hypoxic preconditioning attenuates stunning caused by repeated coronary artery occlusions in dog heart.

OBJECTIVE: The aim was to test whether a brief period of non-ischaemic hypoxia can attenuate cardiac contractile dysfunction, ie, "stunning", due to repeated coronary artery occlusions. METHODS: 20 anaesthetised dogs underwent six 5 min occlusions of the left anterior descending coronary artery with intervening 10 min reperfusions, prior to 90 min reperfusion. In the treated group (n = 9), hearts were preconditioned by 5 min extracorporeal left anterior perfusion with severely hypoxic blood [O2 content 14(SEM 3) ml.litre-1] followed by 10 min reperfusion, prior to the repeated coronary occlusions. Controls (n = 9) were sham preconditioned by 5 min extracorporeal perfusion with normoxic blood [O2 content 179(7) ml.litre-1]. Regional contractile function was assessed by systolic segmental shortening measured by microsonometry. Regional myocardial oxygen consumption, an index of ATP utilisation, was measured in these protocols to evaluate the hypothesis that reduction of myocardial energy demand could be a mechanism of hypoxic preconditioning. RESULTS: Hypoxic preconditioning slightly decreased systolic segmental shortening [64.1(9.5)% of baseline at 10 min reoxygenation v 85.5(6.5)% for control, p < 0.05]. In contrast, 5 min coronary occlusion in controls produced more marked cardiodepression [segmental shortening 33.5(10.1)% of baseline at 10 min reperfusion; p < 0.05 v 10 min reoxygenation in the hypoxic-preconditioned group]. Systolic shortening was preserved in hypoxic-preconditioned hearts as compared to controls during each 10 min reperfusion period. Furthermore, functional recovery at 90 min reperfusion after the last occlusion in hypoxic preconditioned hearts was more complete than in control hearts, at 40.8(13.1)% v -16.1(14.4)%; p < 0.05. However, myocardial oxygen consumption was not suppressed by hypoxic preconditioning. CONCLUSIONS: Five minutes of hypoxic preconditioning attenuated contractile dysfunction due to repeated brief ischaemia/reperfusion stress. This protective effect was not due to the suppression of myocardial energy demand.

Adenosine Triphosphate↗
PubMed1988

Energy metabolism in glutamatergic neurons, GABAergic neurons and astrocytes in primary cultures.

Several aspects of energy metabolism (glucose utilization, lactate production, 14CO2 production from labeled glucose, glutamate or pyruvate, oxygen consumption and contents of ATP and phosphocreatine) were measured in cerebellar granule cells (glutamatergic) in primary cultures and compared with corresponding data for cerebral cortical neurons (mainly GABA-ergic) and astrocytes. Cerebellar granule cells and astrocytes were metabolically more active than cerebral cortical neurons. Glutamate which is utilized as a major metabolic fuel as astrocytes and, to a lesser extent, in cerebral cortical neurons, was virtually not oxidized in cerebellar granule cells.

Animals↗
PubMed2005

Acrolein-induced cell death in PC12 cells: role of mitochondria-mediated oxidative stress.

Oxidative stress has been implicated in acrolein cytotoxicity in various cell types, including mammalian spinal cord tissue. In this study we report that acrolein also decreases PC12 cell viability in a reactive oxygen species (ROS)-dependent manner. Specifically, acrolein-induced cell death, mainly necrosis, is accompanied by the accumulation of cellular ROS. Elevating ROS scavengers can alleviate acrolein-induced cell death. Furthermore, we show that exposure to acrolein leads to mitochondrial dysfunction, denoted by the loss of mitochondrial transmembrane potential, reduction of cellular oxygen consumption, and decrease of ATP level. This raises the possibility that the cellular accumulation of ROS could result from the increased production of ROS in the mitochondria of PC12 cells as a result of exposure to acrolein. The acrolein-induced significant decrease of ATP production in mitochondria may also explain why necrosis, not apoptosis, is the dominant type of cell death. In conclusion, our data suggest that one possible mechanism of acrolein-induced cell death could be through mitochondria as its initial target. The subsequent increase of ROS then inflicts cell death and further worsens mitochondria function. Such mechanism may play an important role in CNS trauma and neurodegenerative diseases.

Acrolein↗
PubMed2002

Mitochondria, Ca2+ and neurodegenerative disease.

Mitochondria play a central role in cell biology not only as producers of ATP, but also in the sequestration of Ca(2+) and the generation of free radicals. They are also repositories of several proteins which regulate apoptosis. Perturbations in the normal functions of mitochondria will inevitably disturb cell function, may sensitise cells to neurotoxic insults and may initiate cell death. Neuronal Ca(2+) overload, such as follows excessive stimulation of Ca(2+) permeant excitatory amino acid receptors, can cause cell death. Recent evidence suggests that the accumulation of Ca(2+) into mitochondria during episodes of cellular Ca(2+) overload initiates a cascade of events that culminate in cell death. Cell death appears to require not only mitochondrial Ca(2+) overload, but rather a combination of raised intramitochondrial Ca(2+) concentration with increased production of nitric oxide and possibly other oxyradical species. Cell death may proceed through either necrotic or apoptotic mechanisms, depending on the rate of consumption and depletion of ATP. Evidence is also accumulating to suggest that more subtle alterations in mitochondrial function may serve as predisposing factors in the pathogenesis of a number of neurodegenerative disorders.

Animals↗
PubMed1985

Disparate mechanisms for hypoxic cell injury in different nephron segments. Studies in the isolated perfused rat kidney.

Hypoxic injury was evaluated morphologically in the proximal tubule and in the medullary thick ascending limb of isolated rat kidneys perfused for 90 min without O2 or with various metabolic inhibitors. Inhibition of mitochondrial respiration (with rotenone, antimycin, oligomycin) or of intermediary metabolism (with monofluoroacetate, malonate, 2-deoxyglucose) caused reduction in renal oxygen consumption, renal function, and ATP content comparable with those elicited by oxygen deprivation. Metabolic inhibition produced hypoxiclike injury in the first portions of the proximal tubule, S1 and S2 ("clubbing" of microvilli, mitochondrial swelling), and the extent of damage was correlated with the degree of ATP depletion. In the third portion of the proximal tubule, S3, hypoxiclike damage (cytoplasmic edema or fragmentation) occurred most consistently when both aerobic and anaerobic metabolism were inhibited simultaneously. In the medullary thick ascending limb, none of the metabolic or mitochondrial inhibitors used could reproduce the injury of oxygen deprivation. Thus, the proximal tubule and the thick ascending limb have markedly different responses to cellular energy depletion, suggesting disparate mechanisms for hypoxic injury along the nephron.

Adenosine Triphosphate↗
PubMed2000

Proliferative activity and tumorigenic conversion: impact on cellular metabolism in 3-D culture.

Oxygen consumption, glucose, lactate, and ATP concentrations, as well as glucose and lactate turnover rates, have been studied in a three-dimensional carcinogenesis model of differently transformed rat embryo fibroblasts (spontaneously immortalized Rat1 and myc-transfected M1, and the ras-transfected, tumorigenic descendants Rat1-T1 and MR1) to determine metabolic alterations that accompany tumorigenic conversion. Various bioluminescence techniques, thymidine labeling, measurement of PO(2) distributions with microelectrodes, and determination of cellular oxygen uptake rates (Qc(O(2))) have been applied. In the ras-transfected, tumorigenic spheroid types, the size dependencies of some of the measured parameters exhibited sharp breaks at diameters of approximately 830 microm for Rat1-T1 and approximately 970 microm for MR1 spheroids, respectively, suggesting that some fundamental change in cell metabolism occurred at these characteristic diameters (denoted as "metabolic switch"). Qc(O(2)) decreased and lactate concentration increased as functions of size below the characteristic diameters. Concomitantly, glucose and lactate turnover rates decreased in MR1 spheroids and increased in Rat1-T1. Spheroids larger than the characteristic diameters (exhibiting cell quiescence and lactate accumulation) showed an enhancement of Qc(O(2)) with size. Systematic variations in the ATP and glucose levels in the viable cell rim were observed for Rat1-T1 spheroids only. Proliferative activity, Qc(O(2)), and ATP levels in small, nontumorigenic Rat1 and M1 aggregates did not differ systematically from those recorded in the largest spheroids of the corresponding ras transfectants. Unexpectedly, respiratory activity was present not only in viable but also in the morphologically disintegrated core regions of M1 aggregates. Our data suggest that myc but not ras transfection exerts major impacts on cell metabolism. Moreover, some kind of switch has been detected that triggers profound readjustment of tumor cell metabolism when proliferative activity begins to stagnate, and that is likely to initiate some other, yet unidentified energy-consuming process.

Adenosine Triphosphate↗
PubMed1989

Glycolytic and oxidative metabolism in primary renal proximal tubule cultures.

Cultured cells often exhibit alterations in energy metabolism (increased glycolytic activity and decreased oxidative metabolism) during adaptation to the culture environment. The role of hypoxia as a mediator of these effects was examined by comparison of metabolism in primary rabbit renal proximal tubule (RPT) cultures maintained in stationary culture dishes (DISH), shaking Erlenmeyer flasks (SHAKE), and DISH cultures transferred back to SHAKE conditions (RESHAKE). Both oxidative metabolism and transport capacity were fully preserved in SHAKE cultures over a 24-h period. In contrast, within 6 h, DISH cultures exhibited a continuous decline in transport-dependent and -independent oxygen consumption, respiratory capacity, and ATP and K+ contents. The loss of oxidative metabolism in DISH cultures was accompanied by stimulation of lactate production, detectable within 1 h after plating. Comparison of metabolic properties of DISH cultures to those of RPT exposed to graded levels of hypoxia suggested that medium oxygen tensions may be as low as 1-3% in DISH cultures. RESHAKE cultures exhibited metabolic properties comparable to those of SHAKE cultures, indicating reversibility of DISH culture metabolism on reoxygenation. We concluded that DISH cultures rapidly become hypoxic as a consequence of static culture conditions. Shaking suspension cultures may provide a more metabolically appropriate model for long-term in vitro studies.

Adenosine Triphosphate↗
PubMed1997

The effect of L-deprenyl, D-deprenyl and MDL72974 on mitochondrial respiration: a possible mechanism leading to an adaptive increase in superoxide dismutase activity.

L-Deprenyl is an irreversible monoamine oxidase-B inhibitor with a complex pharmacological profile. For instance, L-deprenyl administration to rat and mice increases cytosolic CuZn- and mitochondrial Mn-superoxide dismutase activities in the striatum. CuZn- and Mn-superoxide dismutase are enzymes involved in defense against superoxide (O2.) radicals. Hence, an increase in CuZn- and Mn-superoxide dismutase activities is suggestive of oxidative stress. The major intracellular site of O2. radicals formation is the mitochondrial respiratory chain. Several reports indicated that alterations in mitochondrial respiratory functions enhances O2. production. We observed that L-deprenyl induced a dose-dependent inhibition of oxygen (O2) consumption (state 3) during ATP synthesis in presence of complex I (pyruvate and malate) and complex II (succinate) substrates in fresh mitochondrial preparations. D-Deprenyl produced a similar inhibitory profile whereas MDL72974, a selective monoamine oxidase-B inhibitor, was less effective. Administration of D-deprenyl or MDL72974 to mice resulted in an increase in both striatal CuZn- and -Mn-superoxide dismutase activities. Accordingly, we propose that the impairment of mitochondrial respiratory functions which stimulates O2. formation could modulate CuZn- and Mn-superoxide dismutase activities, through a mechanism that appears to be independent of monoamine oxidase-B inhibition.

Allyl Compounds↗
PubMed2006

Oxygen sensing by mitochondria at complex III: the paradox of increased reactive oxygen species during hypoxia.

All eukaryotic cells utilize oxidative phosphorylation to maintain their high-energy phosphate stores. Mitochondrial oxygen consumption is required for ATP generation, and cell survival is threatened when cells are deprived of O(2). Consequently, all cells have the ability to sense O(2), and to activate adaptive processes that will enhance the likelihood of survival in anticipation that oxygen availability might become limiting. Mitochondria have long been considered a likely site of oxygen sensing, and we propose that the electron transport chain acts as an O(2) sensor by releasing reactive oxygen species (ROS) in response to hypoxia. The ROS released during hypoxia act as signalling agents that trigger diverse functional responses, including activation of gene expression through the stabilization of the transcription factor hypoxia-inducible factor (HIF)-alpha. The primary site of ROS production during hypoxia appears to be complex III. The paradoxical increase in ROS production during hypoxia may be explained by an effect of O(2) within the mitochondrial inner membrane on: (a) the lifetime of the ubisemiquinone radical in complex III; (b) the relative release of mitochondrial ROS towards the matrix compartment versus the intermembrane space; or (c) the ability of O(2) to access the ubisemiquinone radical in complex III. In summary, the process of oxygen sensing is of fundamental importance in biology. An ability to control the oxygen sensing mechanism in cells, potentially using small molecules that do not disrupt oxygen consumption, would open valuable therapeutic avenues that could have a profound impact on a diverse range of diseases.

Animals↗
PubMed1985

Phosphorus nuclear magnetic resonance of fast- and slow-twitch muscle.

Phosphorus nuclear magnetic resonance (NMR) spectra were obtained at 109.3 MHz from isolated, arterially perfused cat biceps brachi (greater than 75% fast-twitch, glycolytic fibers) and soleus (greater than 92% slow-twitch, oxidative) muscles at 30 degrees C. The perfused muscles were stable with respect to O2 consumption, twitch characteristics, and ATP and phosphocreatine (PC) levels for up to 10 h. NMR spectra showed a higher PC/Pi ratio in the biceps (11) than in the soleus (1.7). Relatively higher Pi levels were observed in extracts of clamp-frozen muscles than in the intact muscles. This difference could be accounted for by artifactual hydrolysis of PC during muscle freezing. Based on the NMR and chemical data, the free cytosolic ADP level, calculated from the creatine kinase equilibrium, was 14 microM in the soleus and less than 1 microM in the biceps. Intracellular Pi concentration was 10 mM in the soleus and 3 mM in the biceps. Intracellular pH, estimated from the chemical shift of phosphate or 2-deoxyglucose 6-phosphate, was 7.0 in both muscles (perfusate pH 7.2). Both extracellular space and pH measurements were obtained from NMR spectra of muscles perfused with 10 mM sodium phenylphosphonate added to the perfusate. These results document larger differences in the phosphate metabolites in the two types of mammalian muscles than previously reported.

Adenosine Diphosphate↗
PubMedDate not supplied

The interaction of new plant flavonoids with rat liver mitochondria: relation between the anti- and pro-oxydant effect and flavonoids concentration.

Flavonoids are polyphenols derivatives of plant origin that possesses a broad range of pharmacological properties, including protection of cells and tissues against the deleterious effects of reactive oxygen species. Their antioxidant activity results from scavenging of free radicals and other oxidizing intermediates, from the chelation of iron or copper ions and from inhibition of oxidases. But a number of studies have found both anti and prooxidant effects for many of these compounds. These reasons prompted us to investigate whether flavonoids compounds alone or combined flavonoids had antioxidant, free radical scavenger and antiapoptotic properties. The investigation was carried in vitro using rat hepatic mitochondria. Respiratory control ratio (RCR), oxygen consumption, adenosine tri phosphate (ATP) synthesis, scavenging action, enzymatic activities of involved complexes, superoxide anion and the release of cytochrome C were measured to assess the mechanisms of action of these drugs. Our data showed that the decrease of RCR induced by high concentrations (0.1 mM and 0.01 mM) of all flavonoids tested was due to a common inhibition of oxidative phosphorylation (State 4) and activation of state 3. At the opposite mitochondrial swelling was slightly induced only by low concentrations (10(-8) and 10(-9) M) of the flavonoids. They had no effects on the mitochondrial complexes (I to V) activity. Furthermore the mitochondrial membrane potential was not affected by any flavonoids. The effect of flavonoids on superoxide anion generation was variable. All the flavonoids studied acted between 10(-4) M and 10(-6) M with no effects at lower concentrations. These effects were similar on lipid peroxidation (malondialdehyde [MDA] levels). We remarked a concentration-dependent in the effect of flavonoids since they acted as antioxidant and also as uncoupler at high concentrations, which is a risk for the cells. We conclude that flavonoids extracted from algerian plants have some protecting effects against oxidative stress by protecting the mitochondria.

Animals↗