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PubMed1983

Functional changes of rat brain mitochondrial enzymes induced by monomeric cholesterol.

The binding of [14C]cholesterol into rat brain mitochondrial membranes follows an exponential path described by the general formula y = a X ebx. [14C]cholesterol glucoside binding has a sigmoidal character where the "best-fit" curve of this type of binding is the one described by the Hill equation with Hill coefficient h = 2.06. These findings suggest a positive cooperativity in the binding of both compounds into rat brain mitochondrial membranes. The specific activity of the outer mitochondrial membrane enzyme monoamine oxidase was linearly decreased at different concentration of cholesterol or its glucoside. The specific activity of the inner mitochondrial membrane enzyme succinate-cytochrome c reductase was linearly decreased, while that of Rotenone-sensitive NADH-cytochrome c reductase was exponentially increased, at different concentrations of cholesterol. These results are discussed in terms of specific interactions of cholesterol with constituent mitochondrial membrane lipids and their implications for deviations from normal neuronal function.

Animals↗

PubMed1992

Regulating effect of mitochondrial lactate dehydrogenase on oxidation of cytoplasmic NADH via an "external" pathway in skeletal muscle mitochondria.

1. The specific activity of lactate dehydrogenase of skeletal muscle mitochondria was found to be 2.5 times lower than specific activity of total NADH-cytochrome c reductase. 2. The specific activity of mitochondrial LDH in skeletal muscle mitochondria was almost equal to the activity of rotenone-insensitive NADH-cytochrome c reductase. 3. Mitochondrial LDH acting as an oxidase of lactate to pyruvate may feed an "external" pathway, but the activity of the mitochondrial enzyme is a limiting factor in oxidation of lactate-derived NADH. 4. Mitochondrial LDH acting as a reductase of pyruvate to lactate successfully competes with an "external" pathway for cytoplasmic NADH. 5. Exogenous NADH oxidation via an "external" pathway was inhibited by pyruvic acid. This inhibition was overcome by addition of oxamic acid or hydrazine.

Animals↗

PubMed1993

Control of oxidative phosphorylation in AS-30D hepatoma mitochondria.

1. The distribution of control of the rate of state 3 respiration of AS-30D hepatoma mitochondria was determined. 2. The ATP/ADP carrier (flux control coefficient, Ci = 0.70) and the ATP synthase (Ci = 0.19-0.32) were the only steps that exerted significant control on the phosphorylating flux supported by either glutamate+malate, pyruvate+malate, or succinate+rotenone. This is in contrast to liver mitochondria where the control is distributed between several steps. 3. It is suggested that this pattern of control of phosphorylation in hepatoma mitochondria is a consequence of a lower content of adenine nucleotides or a higher content of Mg2+.

Adenine Nucleotides↗

PubMed1995

The effect of electron transport (ET) inhibitors and thiabendazole on the fumarate reductase (FR) and succinate dehydrogenase (SDH) of Strongyloides ratti infective (L3) larvae.

The fumarate reductase (FR) and succinate dehydrogenase (SDH) activities of isolated submitochondrial particles (SMPs) prepared from axenised L3 larvae of S. ratti were characterised with respect to their response to a selected range of inhibitors. Rotenone (a specific inhibitor of electron transport Complex I) inhibited the S. ratti FR (EC50 = 3.0 x 10(-7) M) but not SDH. This strongly suggests that the S. ratti FR is functionally linked with the S. ratti ET-Complex I. 2-Thenoyltrifluoroacetone (TTFA, an inhibitor of ET-Complex II) inhibited FR (EC50 = 2.6 x 10(-5) M) and SDH (EC50 = 2.8 x 10(-5) M) with similar effectiveness. Sodium malonate (substrate analogue of succinate) had a greater affinity for SDH (EC50 = 6.8 x 10(-4) M), than FR (EC50 = 1.9 x 10(-2) M). Sodium fumarate was ca. 8-fold more effective in inhibiting the S. ratti FR (EC50 = 6.0 x 10(-4) M) than SDH (EC50 = 4.8 x 10(-3) M). The S. ratti FR was more sensitive to inhibition by thiabendazole (TBZ; EC50 = 4.6 x 10(-4) M) than SDH (EC50 > 1.0 x 10(-3) M), suggesting that one of the sites-of-action of TBZ to be the FR of S. ratti mitochondria. More potent inhibitors of S. ratti FR, if developed, may prove to be effective chemotherapeutic agents in the management of human strongloidiasis.

Animals↗

PubMed1985

Release of AMP and adenosine from rat heart mitochondria.

Release of AMP and adenosine from rat heart mitochondria was studied. The rate of appearance of extramitochondrial adenosine was independent of the extramitochondrial phosphate concentration between 5 and 20 mM. In the absence of exogenous, respiratory substrates or in the presence of glutamate/malate plus rotenone, the rate of appearance of adenosine was relatively low when phosphate was not added. The appearance of extramitochondrial AMP + adenosine was found to be directly proportional to the extra-mitochondrial phosphate concentration. Zn2+ (10 mM) decreased the rate of adenosine appearance by 90% and increased the rate of AMP appearance 6-fold. The mitochondrial preparations dephosphorylated exogenous AMP; this activity was inhibited by 10 mM Zn2+. We conclude that the adenosine appearing in the extramitochondrial space was not due to a direct release from the matrix, but instead was due to adenine nucleotide release with subsequent conversion to adenosine in the extramitochondrial space.

5'-Nucleotidase↗

PubMed1987

Kinetic alterations of cytochrome c oxidase in carbon tetrachloride induced cirrhotic rat liver.

In a study of the chronic effects of CCl4 on the respiratory activities of rat liver mitochondria, the content of cytochrome c oxidase increased from 0.077 +/- 0.010 (nmol/mg protein) for normal rats to 0.101 +/- 0.009, and its specific activity increased from Vmax = 345 +/- 24 (e-/s/cytochrome aa3) to 431 +/- 19 in mitochondria of CCl4 treated rats. There was a slight increase in Km for cytochrome c from 5.63 +/- 0.08 microM to 7.79 +/- 0.80. These results would strongly suggest that an appreciable decrease in the steady state concentration of ATP in hepatic cells of CCl4 treated rats brought about a compensatory increase in the overall activity of cytochrome c oxidase. However, when the rate of oxygen uptake by mitochondria was measured in the presence of rotenone and tetramethyl-p-phenylene-diamine with NADH as substrate, the specific activity in CCl4 treated rats was lower than that of normal rats (Vmax = 345 +/- 31 (e-/s/cytochrome aa3), as compared to Vmax = 408 +/- 21) in spite of the increased activity of cytochrome c oxidase. This phenomenon was ascribed to a decrease in the activity of NADH cytochrome b5 reductase in the mitochondrial outer membrane due to CCl4 treatment.

Adenosine Triphosphate↗

PubMed1985

The contribution of hepatic metabolism to diet-induced thermogenesis.

In order to examine the possible contribution of the liver to diet-induced thermogenesis, we examined the metabolism of hepatocytes from rats that had been fed a varied choice of highly palatable human food items ("cafeteria feeding"). Liver cells derived from cafeteria-fed rats that had been fasted for 20 hours showed marked increases in rates of respiration and gluconeogenesis in the presence of glycerol or sorbitol. These cells were also much less sensitive to the inhibitory effects of rotenone than were hepatocytes of control animals. hepatocytes from fasted cafeteria-fed rats also demonstrated a substantially enhanced rate of fatty acid oxidation and ketogenesis, which did not appear to be correlated with cellular demands for adenosine triphosphate (ATP). This apparent fall in metabolic efficiency was confirmed by calorimetric studies, which indicated augmented cellular heat production. These changes in hepatic metabolism, associated with cafeteria-feeding, suggest that the liver may have a significant role in diet-induced thermogenesis.

Animals↗

PubMed1987

Increased free intrasynaptosomal Ca2+ by neurotoxic organometals: distinctive mechanisms.

Effects of several alkylmetals on free intrasynaptosomal Ca2+ concentration, [Ca2+]i, were studied in vitro using the fluorescent Ca2+ indicator fura-2. Neurotoxic alkylmetals methylmercury (Met-Hg), triethyllead (TEL), triethyltin (TET), and trimethyltin (TMT) (at 2.5-30 microM) increased [Ca2+]i to different degrees. Met-Hg was the most potent, elevating [Ca2+]i 100-800 nM, dose dependently and significantly more than high K+ (150 nM) or veratridine (350 nM). The effect of Met-Hg could not be inhibited with a Ca2+ channel blocker, verapamil, nor with a Na+ channel blocker, tetrodotoxin. Inhibition of the mitochondrial Ca2+ uptake in situ with rotenone + oligomycin decreased the potency of Met-Hg to elevate [Ca2+]i but did not change the resting [Ca2+]i. Met-Hg also slightly decreased synaptosomal ATP. TEL and TET elevated [Ca2+]i by 100-200 nM. The effect of TEL, but not that of TET, could be blocked with verapamil (36%) and veratridine (67%). TEL was less efficient in the presence of ouabain. Neither TEL nor TET had significant mitochondrial effects in situ contributing to [Ca2+]i. TMT increased [Ca2+]i less than TET while dimethyltin and methyltin were inactive. These results indicate that neurotoxic derivatives of alkylmetals studied increase [Ca2+]i. This occurs mainly either by nonspecific increase (Met-Hg, TET) of Ca2+ leakage through the plasma membrane and/or specific interference with the mechanisms regulating Ca2+ fluxes through the plasma membrane (TEL).

Adenosine Triphosphate↗

PubMed1991

Mitochondrial development in Trypanosoma brucei brucei transitional bloodstream forms.

Intermediate and short stumpy bloodstream forms of Trypanosoma brucei brucei are transitional stages in the differentiation of mammal-infective long slender bloodstream forms into the procyclic forms found in the midgut of the tsetse vector. Although the mitochondria of the proliferative long slender forms do not accumulate rhodamine 123, the mitochondria of the transitional forms attain this ability thus revealing the development of an electromotive force (EMF) across the inner mitochondrial membrane. The EMF is inhibited by 2,4-dinitrophenol, rotenone and salicylhydroxamic acid but not by antimycin A or cyanide. Consequently, NADH dehydrogenase, site I of oxidative phosphorylation, is the source of the EMF and the plant-like trypanosome alternative oxidase (TAO) supports the electron flow serving as the terminal oxidase of the chain. Although the TAO is present in the long slender forms as well, it serves only as the terminal oxidase for electrons from glycerol-3-phosphate dehydrogenase. The data presented here, combined with older data, lead to the conclusion that the mitochondria of transitional intermediate and short stumpy forms likely produce ATP. This putative production is either by F1F0 ATPase driven by the complex I proton pump or by mitochondrial substrate level phosphorylation, or most likely by both. These conclusions contrast with the previously held dogma that all bloodstream form mitochondria are incapable of ATP production.

2,4-Dinitrophenol↗

PubMed1995

Characterization of the respiratory chain of Leishmania donovani promastigotes.

Inhibition analysis of respiration of Leishmania donovani promastigotes in resting, starved and permeabilized cells in the presence of classical electron transfer complex inhibitors such as rotenone, thenoyltrifluoroacetone and antimycin demonstrated the absence of complex I component of the respiratory chain in this organism. Cyanide failed to completely block the oxygen uptake (residual 25-30%) even at high concentrations. The alternative oxidase inhibitor for Trypanosoma brucei, salicylhydroxamic acid (SHAM) had no effect on respiration while the cytochrome o inhibitor orthohydroxydiphenyl (OHD) could block cyanide-insensitive respiration at low concentrations. Succinate-dependent O2 uptake in permeabilized cells follows the classical pathway. Oxidation of NADH by a membrane-rich fraction produced H2O2 as the end product and was insensitive to respiratory chain inhibitors. The presence of NADH-fumarate reductase was demonstrated in membrane-rich fraction and fumarate could reduce H2O2 production from NADH indicating fumarate to be an endogenous substrate for accepting electrons from NADH. A differential route for NADH oxidation was further confirmed by NADH cytochrome c reductase insensitivity to antimycin. A tentative scheme for electron transfer pathway in this organism is proposed in which a reversal of Krebs cycle enzymes occur producing succinate that can be excreted or oxidized depending upon the energy demands of the cell. Inhibition studies also suggest bifurcations of the respiratory chain that can be of minor importance for the organism.

Animals↗

PubMedDate not supplied

Localisation of a particulate luliberin hydrolysing activity in microsomal membranes of guinea pig brain.

A particulate luliberin hydrolysing enzyme has been described for guinea pig brain. Examination of subcellular fractions generated under different conditions indicated that particulate luliberin hydrolysing activity was most closely associated with the microsomal marker, rotenone-insensitive NADH cytochrome C reductase. The results obtained indicate that luliberin hydrolysing activity is not associated with synaptosomal membrane preparations and that such luliberin hydrolysing activity as is observed in synaptosomal membranes is probably the result of contamination by microsomes. The enzyme could be released from microsomes by Triton X-100 treatment and the solubilised enzyme was found to be inhibited by puromycin and sulphydryl reagents but to be unaffected by phosphoramidon, captopril, phenylmethyl sulphonyl fluoride and by chelating agents except 1,10-phenanthroline.

Acid Phosphatase↗

PubMed1993

L-pipecolic acid oxidation in rat: subcellular localization and developmental study.

By using a sensitive radioactive assay method, we present here evidence that L-pipecolic acid oxidase is localized in both mitochondria and peroxisomes of rat liver. Brain white matter contained a more than 2-fold higher activity of L-pipecolic acid oxidation than the brain cortex. Suborganellar fractionation studies indicate that while the enzyme is a matrix protein in mitochondria, it is membrane-associated in peroxisomes. Both rotenone and antimycin A completely inhibited the enzyme activity in mitochondria but not in peroxisomes. The enzyme was shown to be inducible in mitochondria and peroxisomes of rat liver and brain tissues by glucagon and di-(2-ethylhexyl)phthalate, respectively. We report here for the first time the developmental aspects of L-pipecolic acid oxidation activity in rat liver and brain tissues. L-Pipecolic acid oxidase activity was detectable in whole rat embryo at 10 days of gestation, suggesting active L-pipecolic acid metabolism early during development. In both liver and brain tissues L-pipecolic acid oxidation activity was highest at 15 days of gestation and decreased with age in prenatal and postnatal conditions.

Aging↗

PubMed1992

Paraquat damage of rat liver mitochondria by superoxide production depends on extramitochondrial NADH.

Pure rat liver heavy mitochondrial fractions, in which the absence of significant microsomal contamination was confirmed by electron microscopy and by the lack of glucose-6-phosphatase activity, were used to demonstrate the effect of paraquat on mitochondrial ultrastructure in the presence of external NADH. Starved mitochondria (orthodox conformation) did not show O2 uptake or structural injury from either paraquat alone or NADH alone. Marked O2 uptake and structural breakage occurred only when paraquat and NADH were added in combination. These alterations were resistant to rotenone and malate plus glutamate or NADPH could not substitute for NADH. Paraquat was reduced anaerobically by the mitochondria in the presence of NADH, but not of NADPH. The addition of superoxide dismutase, ferricytochrome c or p-benzoquinone protected against the breakage of mitochondria caused by paraquat plus NADH. These results demonstrate that mitochondria may produce paraquat radicals in the presence of extramitochondrial NADH and thus generate superoxide anion radicals, resulting in structural injury to the mitochondria, by mechanisms that may involve the mitochondrial outer membrane rather than the electron transfer chain. These mitochondrial mechanisms in paraquat toxicity seemed to be more probable in vivo than are microsomal mechanisms; the latter are postulated to function in detoxication because phenobarbital diminished paraquat toxicity and SKF 525-A or cobaltous ions enhanced the toxicity.

Animals↗

PubMed1994

Aminooxyacetic acid striatal lesions attenuated by 1,3-butanediol and coenzyme Q10.

We previously showed that intrastriatal administration of aminooxyacetic acid (AOAA) produces striatal lesions by a secondary excitotoxic mechanism associated with impairment of oxidative phosphorylation. In the present study, we show that and the specific complex I inhibitor rotenone produces a similar neurochemical profile in the striatum, consistent with an effect of AOAA on energy metabolism. Lesions produced by AOAA were dose-dependently blocked by MK-801, with complete protection against GABA and substance P depletions at a dose of 3 mg/kg. AOAA lesions were significantly attenuated by pretreatment with either 1,3-butanediol or coenzyme Q10, two compounds which are thought to improve energy metabolism. These results provide further evidence that AOAA produces striatal excitotoxic lesions as a consequence of energy depletion and they suggest therapeutic strategies which may be useful in neurodegenerative diseases.

Aminooxyacetic Acid↗

PubMed1990

Mitochondrial NADH oxidase activity of Setaria cervi.

The bovine filarial parasite, Setaria cervi, has been found to contain NAD(P)H oxidase activity. The system was predominantly located in the mitochondrial membranes, with very little activity available in the soluble fraction of the organelle. The membrane preparation also exhibited the presence of a reduced pyridine nucleotide transhydrogenase which converted NADPH into NADH by transferring a hydride ion. The oxidase activity was inhibited by all the respiratory inhibitors examined, with the greatest sensitivity to rotenone, a site I-specific inhibitor. The system was also found to be susceptible to exposure to anthelmintics, amongst which levamisole proved the most effective.

Aerobiosis↗

PubMed1978

The effect of ammonium chloride and glucagon on the metabolism of glutamine in isolated liver cells from starved rats.

1. Glucagon stimulated gluconeogenesis from glutamine in isolated liver cells to a far greater extent than that from any other amino-acid precursor. 2. Low concentrations of ammonium chloride (less than 1 mM) stimulated glucose production from glutamine. Glucagon further stimulated this glucose production, even in the presence of saturating concentrations of ammonium chloride. 3. In agreement with previous reports, glutamine hydrolysis by isolated mitochondria was found to be stimulated by ammonium chloride. It was found that ammonium chloride activated mitochondrial glutamine hydrolysis at the same concentrations at whict it stimulated glucose production from glutamine in liver cells. The effective activation of glutamine hydrolysis by ammonimum chloride in intact mitochondria was partially inhibited by rotenone and was abolished by uncoupling agents. 4. The addition of glucagon to hepatocytes metabolising glutamine led to a decrease in the intracellular concentration of glutamine and an increase in the intracellular concentration of glutamate. 5. It is likely that glucagon stimulates gluconeogenesis from glutamine by mechanisms which are additional to those that may operate in the stimulation of gluconeogenesis from other amino-acid precursors. It is suggested that both ammonium chloride and glucagon exert their effects on glutamine metabolism by increasing the effective activity of mitochondrial glutaminase (EC 3.5.1.2.).

Amino Acids↗

PubMed1980

Effect of succinate on aminopyrine N-demethylase activity.

Succinate stimulated the aminopyrine N-demethylase activity in the presence of rate-limiting concentrations of NADPH in the crude mitochondrial preparation, as well as in a reconstituted system containing microsomes and microsome-free mitochondria. The increase in enzyme activity was accompanied by a decrease of the apparent Km of NADPH. The stimulating effect of succinate was counteracted by malonate, rotenone and pentachlorophenol. No significant formaldehyde oxidation was exhibited by the crude mitochondrial preparation under the conditions of N-demethylase assay. Enhancement of the N-demethylase activity by succinate is supposed to be due to a mitochondrial-microsomal interaction which may play a role in the regulation of drug metabolism.

Aminopyrine N-Demethylase↗

PubMed1991

Effect of metabolic inhibitors on uptake of non-transferrin-bound iron by reticulocytes.

The relationship between transferrin-free iron uptake and cellular metabolism was investigated using rabbit reticulocytes in which energy metabolism was altered by incubation with metabolic inhibitors (antimycin A, 2,4-dinitrophenol, NaCN, NaN3 and rotenone) or substrates. Measurements were made of cellular ATP concentration and the rate of uptake of Fe(II) from a sucrose solution buffered at pH 6.5. There was a highly significant correlation between the rate of iron uptake into cytosolic and stromal fractions of the cells and ATP levels. Iron transport into the cytosol showed saturation kinetics. The metabolic inhibitors all reduced the Vmax but had no effect on the Km values for this process. It is concluded that the uptake of transferrin-free iron by reticulocytes is dependent on the cellular concentration of ATP and that it crosses the cell membrane by an active, carrier-mediated transport process. Additional studies were performed using transferrin-bound iron. The metabolic inhibitors also reduced the uptake of this form of iron but the inhibition could be accounted for entirely by reduction in the rate of transferrin endocytosis.

2,4-Dinitrophenol↗