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The respiration of rat liver mitochondria was stimulated by three different ways of energy drain: (a) partial uncoupling (equivalent to direct collapse of the proton-motive force), (b) intramitochondrial utilization of ATP for citrulline synthesis, and (c) extramitochondrial utilization of ATP for glucose phosphorylation. At identical rates of respiration, the intramitochondrial ATP : ADP ratios were the same in all three systems. Furthermore, the proton-motive force was the same in partially uncoupled mitochondria and in the presence of hexokinase plus glucose up to a respiration rate amounting to about 60% of that of the fully active state. However, external ATP : ADP ratios were considerably different in various systems at comparable rates of oxygen uptake, being the lowest under conditions when ATP was being utilized externally. On this basis, it is concluded that the respiratory rate is controlled directly by the proton-motive force and the mitochondrial ATP-synthesizing system operates under near-equilibrium conditions with respect to the membrane energy state parameters. However, a disequilibrium exists at the step of the transport of ATP from mitochondria to the external (cytoplasmic) compartment.
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PMID:Influence of different energy drains on the interrelationship between the rate of respiration, proton-motive force and adenine nucleotide patterns in isolated mitochondria. 728 43

A method is described, based on the differential accumulation of Rb+ and methyltriphenylphosphonium, for the simultaneous estimation of the membrane potentials across the plasma membrane of isolated nerve endings (synaptosomes), and across the inner membrane of mitochondria within the synaptosomal cytoplasm. These determinations, together with measurements of respiratory rates, and ATP and phosphocreatine concentrations, are used to define the bioenergetic behaviour of isolated synaptosomes under a variety of conditions. Under control conditions, in the presence of glucose, the plasma and mitochondrial membrane potentials are respectively 45 and 148mV. Addition of a proton translocator induces a 5-fold increase in respiration, and abolishes the mitochondrial membrane potential. The addition of rotenone to inhibit respiration does not affect the plasma membrane potential, and only lowers the mitochondrial membrane potential to 128mV. Evidence is presented that ATP synthesis by anaerobic glycolysis is sufficient under these conditions to maintain ATP-dependent processes, including the reversal of the mitochondrial ATP synthetase. Addition of oligomycin under non-respiring conditions leads to a complete collapse of the mitochondrial potential. Even under control conditions the plasma membrane (Na+ + K+)-dependent ATPase is responsible for a significant proportion of the synaptosomal ATP turnover. Veratridine greatly increases respiration, and depolarizes the plasma membrane, but only slightly lowers the mitochondrial membrane potential. High K+ and ouabain also lower the plasma membrane potential without decreasing the mitochondrial membrane potential. In non-respiring synaptosomes, anaerobic glycolysis is incapable of maintaining cytosolic ATP during the increased turnover induced by veratridine, and the mitochondrial membrane potential collapses. It is concluded that the internal mitochondria must be considered in any study of synaptosomal transport.
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PMID:Energy transduction in intact synaptosomes. Influence of plasma-membrane depolarization on the respiration and membrane potential of internal mitochondria determined in situ. 737 8

Ca2+ efflux from rat liver mitochondria can occur when endogenous nicotinamide nucleotides are oxidized. It is suggested that nicotinamide nucleotide induced by acetoacetate sensitizes the mitochondria to damaage resulting from the accumulation of Ca2+ in the presence of Pi. Thus, acetoacetate-induced Ca2+ efflux is associated with a loss of respiratory control. Both the effluxes induced by acetoacetate and by high Ca2+ accumulation are prevented by ATP plus oligomycin, although these agents do not prevent the endoagenous nicotinamide nucleotides from becoming oxidized on addition of acetoacetate. Acetoacetate addition only results in Ca2+ release if the Ca2+ and Pi concentration are above a critical value. The acetoacetate-induced Ca2+ effflux is exactly paralled by the virtually complete collapse of the membrane potential. The presence of acetoacetate decreases the concentration of total Ca2+ necessary to induced mitochondrial damage by about 130 nmol of Ca2+/mg of protein. It is concluded that acetoacetate-induced efflux occurs by reversal of the Ca2+ uniporter after the collapse of the membrane potential.
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PMID:The nature of the calcium ion efflux induced in rat liver mitochondria by the oxidation of endogenous nicotinamide nucleotides. 740 74

It has long been known that pyruvate is essential for survival of prenatal neurons in culture. To understand the role of exogenous pyruvate in neuronal calcium homeostasis, we have investigated the effects of pyruvate (plus malate) addition to dissociated adult rat hippocampal and cerebral cortex cells and cultured CNS neurons having an unrestricted glucose supply. We found that pyruvate (plus malate) increased the respiration rate while ATP levels were unchanged. At the same time, cytosolic free calcium concentrations, [Ca2+]i, decreased while total 45Ca2+ and 40Ca2+ accumulation increased. The extra Ca2+ accumulated by the cells is attributable to an increase in the size of the intracellular calcium pools. Two such pools were identified on the basis of their sensitivity to specific drugs. The first pool was mobilized by thapsigargin plus tert-butyl hydroquinone and caffeine while the second pool was discharged by the mitochondrial uncoupler carbonyl cyanide p-trifluoromethoxphenylhydrazone (FCCP) (plus oligomycin). The two pools represented about 15-20% and 15-30%, respectively, of the rapidly exchangeable 45Ca2+ pools in cerebral cortex cells. In cultured hippocampal neurons, the collapse of the mitochondrial membrane potential (as induced by uncouplers (FCCP) or respiratory chain inhibitors (antimycin) caused a large increase in [Ca2+]i which varied in size and shape among cells and was reduced by external Ca2+ chelation. The latter condition also resulted in a partial discharge of FCCP-releasable 45Ca2+. The effects of FCCP did not result simply from ATP depletion since incubation in glucose-free medium and sequential additions of 2 mM deoxyglucose and 10 microM oligomycin, conditions that led to a dramatic reduction in cellular ATP levels, did not abolish the FCCP-induced [Ca2+]i rise. Taken together, the results indicate that mitochondria harbor a significant proportion of cellular Ca2+. The sensitivity of the mitochondrial pool size to pyruvate (plus malate) questions previous hypotheses concerning a kinetic limitation for Ca2+ accumulation in mitochondria in resting neurons.
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PMID:The role of pyruvate in neuronal calcium homeostasis. Effects on intracellular calcium pools. 750 25

Middle cerebral artery occlusion was performed in rats while the animals were inside the nuclear magnetic resonance (NMR) tomograph. Successful occlusion was confirmed by the collapse of amplitude on an electrocorticogram. The ultrafast NMR imaging technique UFLARE was used to measure the apparent diffusion coefficient (ADC) immediately after the induction of cerebral ischemia. ADC values of normal cortex and caudate-putamen were 726 +/- 22 x 10(-6) mm2/s and 659 +/- 17 x 10(-6) mm2/s, respectively. Within minutes of occlusion, a large territory with reduced ADC became visible in the ipsilateral hemisphere. Over the 2 h observation period, this area grew continuously. Quantitative analysis of the ADC reduction in this region showed a gradual ADC decrease from the periphery to the core, the lowest ADC value amounting to about 60% of control. Two hours after the onset of occlusion, the regional distribution of ATP and tissue pH were determined with bioluminescence and fluorescence techniques, respectively. There was a depletion of ATP in the core of the ischemic territory (32 +/- 20% of the hemisphere) and an area of tissue acidosis (57 +/- 19% of the hemisphere) spreading beyond that of ATP depletion. Regional CBF (rCBF) was measured autoradiographically with the iodo[14C]antipyrine method. CBF gradually decreased from the periphery to the ischemic core, where it declined to values as low as 5 ml 100 g-1. When reductions in CBF and in ADC were matched to the corresponding areas of energy breakdown and of tissue acidosis, the region of energy depletion corresponded to a threshold in rCBF of 18 +/- 14 ml 100 g-1 min-1 and to an ADC reduction to 77 +/- 3% of control. Tissue acidosis corresponded to a flow value below 31 +/- 11 ml 100 g-1 min-1 and to an ADC value below 90 +/- 4% of control. Thus, the quantification of ADC in the ischemic territory allows the distinction between a core region with total breakdown of energy metabolism and a corona with normal energy balance but severe tissue acidosis.
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PMID:Evolution of regional changes in apparent diffusion coefficient during focal ischemia of rat brain: the relationship of quantitative diffusion NMR imaging to reduction in cerebral blood flow and metabolic disturbances. 759 32

It is well established that several iron complexes can induce oxidative damage in hepatic mitochondrial membranes by catalyzing the formation of OH radicals and/or by promoting lipid peroxidation. This is a relevant process for the molecular basis of iron overload diseases. The present work demonstrates that Fe(II)ATP complexes (5-50 microM) promote an oxygen consumption burst in a suspension of isolated rat liver mitochondria (either in the absence or presence of Antimycin A), caused mainly by lipid peroxidation. Fe(II)ATP alone induced small levels of oxygen uptake but no burst. The time course of Fe(II)ATP oxidation to Fe(II)ATP in the extramitochondrial media also reveals a simultaneous 'burst phase'. The iron chelator Desferal (DFO) or the chain-break antioxidant butylated hydroxytoluene (BHT) fully prevented both lipid peroxidation (quantified as oxygen uptake burst) and mitochondrial swelling. DFO and BHT were capable of stopping the ongoing process of peroxidation at any point of their addition to the mitochondrial suspension. Conversely, DFO and BHT only halted the Fe(II)ATP-induced mitochondrial swelling at the onset of the process. Fe(II)ATP could also cause the collapse of mitochondrial potential, which was protected by BHT if added at the onset of the damaging process. These results, as well as correlation studies between peroxidation and mitochondrial swelling, suggest that a two phase process is occurring during Fe(II)ATP-induced mitochondrial damage: one dependent and another independent of lipid peroxidation. The involvement of lipid peroxidation in the overall process of mitochondrial membrane injury is discussed.
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PMID:Characteristics of Fe(II)ATP complex-induced damage to the rat liver mitochondrial membrane. 765 78

We have recently reported that ATP induces an uncoupling pathway in Saccharomyces cerevisiae mitochondria [Prieto, Bouillaud, Ricquier and Rial (1992) Eur. J. Biochem. 208, 487-491]. The presence of this pathway would explain the reported low efficiency of oxidative phosphorylation in S. cerevisiae, and may represent one of the postulated energy-dissipating mechanisms present in these yeasts. In this paper we demonstrate that ATP exerts its action in two steps: first, at low ATP/Pi ratios, it increases the respiratory-chain activity, probably by altering the kinetic properties of cytochrome c oxidase. Second, at higher ATP/Pi ratios, an increase in membrane permeability leads to a collapse in membrane potential. The ATP effect on cytochrome c oxidase corroborates a recent report showing that ATP interacts specifically with yeast cytochrome oxidase, stimulating its activity [Taanman and Capaldi (1993) J. Biol. Chem. 268, 18754-18761].
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PMID:The mechanism for the ATP-induced uncoupling of respiration in mitochondria of the yeast Saccharomyces cerevisiae. 774 93

In the presence of KCl and only at low phosphate concentrations, ATP stimulated state 4 of the respiration of isolated yeast mitochondria. This effect could be related to a partial collapse of the transmembrane potential which was created by the respiratory chain or the F0F1-ATPase. Sodium and lithium could not replace potassium ion. Atractyloside prevented the opening of this K+ pathway, suggesting that only matricial ATP operated. All these effects were inhibited by increasing phosphate concentration, or by adding propranolol, quinine, Zn2+ or Mg2+.
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PMID:ATP opens an electrophoretic potassium transport pathway in respiring yeast mitochondria. 775 May 62

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

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 delta psi.
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PMID:ATP/ADP antiporter is involved in uncoupling of plant mitochondria induced by low concentrations of palmitate. 798 63


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