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PubMed1985

Effects of membrane channel-forming polypeptides on mitochondrial oxidative phosphorylation. A comparison of alamethicin, gramicidin A, melittin and tetraacetyl melittin.

Transmembrane channel-forming polypeptides can function as uncouplers of mitochondrial oxidative phosphorylation. The observed effects are dependent on the phosphate ion (Pi) concentration in the medium. At low Pi (2.5 mM) the order of uncoupling efficiencies is gramicidin A much greater than alamethicin greater than tetraacetyl melittin greater than melittin. The remarkably high activity of gramicidin A suggests insertion of preformed channel dimers into the membrane. It is also suggested that lipid phase association of peptides is necessary in the other cases. At Pi = 100 mM inhibitory effects are observed for alamethicin and tetraacetyl melittin. Less pronounced inhibition is seen for melittin, while no such effect is noted for gramicidin A. The site of inhibition is shown to be complex IV, and the differences in the behavior of the peptides are rationalized in terms of channel structures.

Alamethicin↗
PubMed1992

Subacute necrotizing encephalopathy: oxidative phosphorylation defects and the ATPase 6 point mutation.

Subacute necrotizing encephalopathy (SNE) or Leigh's disease is associated with various defects in oxidative phosphorylation (OXPHOS). However, the relationships between these OXPHOS defects and nuclear DNA or mitochondrial DNA (mtDNA) mutations is still unclear. We evaluated three SNE pedigrees (two singleton cases and a pedigree) biochemically for OXPHOS abnormalities and genetically for four mtDNA point mutations. There was a complex I defect in all three pedigrees that was associated with a complex III defect in two individuals. An mtDNA mutation in the ATPase, subunit 6 gene (np 8993) was present in one SNE pedigree. This mutation was maternally inherited, heteroplasmic, produced marked clinical and biochemical heterogeneity between pedigree members, and varied along the maternal lineage at levels ranging from 0% to > 95% of the total mtDNAs. These mtDNA mutations were not present in the other two pedigrees. These observations emphasize the importance of screening for OXPHOS defects and mtDNA mutations in SNE cases.

Adenosine Triphosphatases↗
PubMed1979

A fifth gene (uncE) in the operon concerned with oxidative phosphorylation in Escherichia coli.

Three mutant unc alleles (unc-408, unc-410, and unc-429) affecting the coupling of electron transport to oxidative phosphorylation in Escherichia coli K-12 have been characterized. Genetic complementation analyses using previously defined mutant unc alleles indicated that the new mutant unc alleles affect a previously undescribed gene designated uncE. The phenotype of strains carrying the uncE408 or uncE429 allele is similar in that Mg(2+)-adenosine triphosphatase activity is only found in the cytoplasmic fraction, and membranes do not bind the F(1) portion of adenosine triphosphatase purified from a normal strain. In contrast, adenosine triphosphatase activity is present both in the cytoplasm and on the membranes from a strain carrying the unc-410 allele, and normal F(1) binds to F(1)-depleted membranes from this strain. The adenosine triphosphatase solubilized from membranes of a strain carrying the unc-410 allele reconstituted ATP-dependent membrane energization in F(1)-depleted membranes from a normal strain. Genetic complementation tests using various Mu-induced unc alleles in partial diploid strains show that the uncE gene is in the unc operon and that the order of genes is uncB E A D C. The unc-410 allele differs from the uncE408 and uncE429 alleles in that complementation tests with the Mu-induced unc alleles indicate that more than one gene is affected. It is concluded that this is due to a deletion which includes part of the uncE gene and another gene, or genes, between the uncE and uncA genes.

Adenosine Triphosphatases↗
PubMed2005

Role of 5'-AMP-activated protein kinase in stimulation of glucose transport in response to inhibition of oxidative phosphorylation.

Glucose transport is stimulated in a variety of cells and tissues in response to inhibition of oxidative phosphorylation. However, the underlying mechanisms and mediating steps remain largely unknown. In the present study we first tested whether a decrease in the redox state of the cell per se and the resultant increase in generation of reactive oxygen species (ROS) lead to stimulation of glucose transport. Clone 9 cells (expressing the Glut1 isoform of facilitative glucose transporters) were exposed to azide, lactate, and ethanol for 1 h. Although all three agents stimulated glucose transport and increased cell NADH-to-NAD(+) ratio and phospho-ERK1/2, signifying increased ROS generation, the response to the stimuli was not blocked by N-acetyl-l-cysteine (an agent that counteracts ROS); moreover, the response to azide was not blocked by diamide (an intracellular sulfhydryl oxidizing agent). We then found that cell AMP-to-ATP and ADP-to-ATP ratios were increased and 5'-AMP-activated protein kinase (AMPK) was stimulated by all three agents, as evidenced by increased phosphorylation of AMPK and acetyl-CoA carboxylase. We conclude that although azide, lactate, and ethanol increase NADH-to-NAD(+) ratios and ROS production, their stimulatory effect on glucose transport is not mediated by increased ROS generation. However, all three agents increased cell AMP-to-ATP ratio and stimulated AMPK, making it likely that the latter pathway plays an important role in the glucose transport response.

AMP-Activated Protein Kinases↗
PubMed1994

Quantitative determination of the regulation of oxidative phosphorylation by cadmium in potato tuber mitochondria.

The effects of cadmium on respiration rate, phosphorylation rate, proton leak rate, the protonmotive force and the effective P/O ratio were determined over a range of respiratory conditions and cadmium concentrations by applying top-down regulation analysis. To quantify the effects of cadmium, we determined the overall response coefficients of these variables of oxidative phosphorylation to cadmium in different respiratory states between state 4 and state 3 and at different cadmium concentrations. The overall response coefficients to cadmium showed quantitatively how cadmium stimulated substrate oxidation rate at high cadmium concentrations near state 4 but inhibited it to different extents under all other conditions, how cadmium inhibited the rate of proton leak rate at low cadmium concentrations near state 4 but stimulated it under all other conditions, and how cadmium inhibited the rate of phosphorylation and depressed the protonmotive force and the effective P/O ratio to different extents under all conditions. Cadmium is known to stimulate the proton leak and to inhibit the substrate oxidation reactions; we calculated the elasticities of these subsystems to cadmium to quantify its effects. To describe fully how the cadmium effects on different subsystems produce the overall responses of the system to cadmium, we then calculated the partial response coefficients of the system variables to cadmium acting through each subsystem. The partial response coefficients quantify the contribution of each block to the overall effect of cadmium on each variable in any condition, and sum to the overall response coefficient in each condition. Together with the elasticity analysis and the control analysis and internal regulation analysis presented in the preceding papers [Kesseler, A. & Brand, M. D. (1994) Eur. J. Biochem. 225, pp. 897-906; Kesseler, A. & Brand, M. D. (1994) Eur. J. Biochem. 225, pp. 907-922] they completely describe how cadmium exerts its effects on oxidative phosphorylation at the system level.

Cadmium↗
PubMed1998

Maintained coupling of oxidative phosphorylation to creatine kinase activity in sarcomeric mitochondrial creatine kinase-deficient mice.

The importance of mitochondrial creatine kinase (mi-CK) in oxidative muscle was tested by studying the functional properties of in situ mitochondria in saponin-skinned muscle fibres from sarcomeric mi-CK-deficient (mutant) mice. Biochemical analyses showed that the lack of mi-CK in mutant muscle was associated with a decrease in specific activity of MM-CK in mutant ventricle, and increase in mutant soleus (oxidative) muscle. Lactate dehydrogenase activity and isoenzyme analysis showed an increased glycolytic metabolism in mutant soleus. No change was observed in ventricular muscle. In control animals, the apparent K(m) of mitochondrial respiration for ADP in ventricle and soleus (232 +/- 36 and 381 +/- 63 microM, respectively) was significantly reduced in the presence of creatine (52 +/- 8 and 45 +/- 12 microM, respectively). There was no change in the K(m) in oxidative fibres from mutant mice (258 +/- 27 and 399 +/- 66 microM, respectively) compared with control, though surprisingly, it was also significantly decreased in the presence of creatine (144 +/- 8 and 150 +/- 27 microM, respectively) despite the absence of mi-CK. It is proposed that in mutant (and perhaps normal) oxidative tissue, cytosolic MM-CK can relocate to the outer mitochondrial membrane, where it is coupled to oxidative phosphorylation by close proximity to porin, and the adenine nucleotide translocase. Such an effect can preserve the functioning of the CK shuttle and the energetic properties of mi-CK deficient tissue.

Animals↗
PubMed1988

Chronic administration of the oral hypoglycaemic agent diphenyleneiodonium to rats. An animal model of impaired oxidative phosphorylation (mitochondrial myopathy).

Daily subcutaneous administration of the oral hypoglycaemic agent, diphenyleneiodonium at a low dose (1.5 mg/kg body weight) over a 4-5 week period resulted in a normoglycaemic stable animal model of impaired oxidative phosphorylation in the rat. Diphenyleneiodonium specifically inhibits NAD-linked mitochondrial oxidation [Bloxham, Biochem. Soc. Trans. 7, 103 (1979)], and in isolated mitochondrial preparations from heart, soleus and gastrocnemius muscle and liver from treated animals NAD-linked respiration was reduced by 40% or more of mean control values. Brain and kidney mitochondria isolated from the treated group had similar rates of NAD-linked respiration to their respective control values. The activity of NADH-ferricyanide reductase was significantly reduced in all tissues tested, even in the isolated brain and kidney mitochondria where the activity in these tissues was 60-75% of control values. This suggests that at least 40% of Complex I activity must be inhibited before there is a decline in NAD-linked mitochondrial respiration. This paper discusses the use of diphenyleneiodonium as a means of establishing an animal model of the human disease state, termed mitochondrial myopathy.

Administration, Oral↗
PubMed1990

Neoplastic transformation is associated with coordinate induction of nuclear and cytoplasmic oxidative phosphorylation genes.

Neoplastic transformation was found to have a marked effect on the expression of nuclear DNA (nDNA)- and mitochondrial DNA (mtDNA)-encoded oxidative phosphorylation (OXPHOS) genes. Examining three pairs of human diploid fibroblasts and their SV 40-transformed counterparts revealed that mRNAs for the nuclear-encoded ATP synthase beta and the adenine nucleotide translocator (ANT) isoform 1 and 2 genes were markedly induced, whereas the mRNA for the ANT isoform 3 gene remained unchanged. The mRNA levels for the mtDNA-encoded 12 S rRNA, ND2, ATPase6+8, COIII, ND5+6, and Cytb genes were also increased, whereas the mtDNA number declined. Similar analysis of a cervical carcinoma (HeLa), fibrosarcoma (HT1080), and an Epstein-Barr virus (EBV)-transformed lymphoblastoid line (EBV-L) revealed that all three ANT isoforms were also expressed in these cells. Hence, changes in the expression of OXPHOS genes may be a common feature of transformed cells.

Base Sequence↗
PubMed1988

Effect of the plasticizer di-(2-ethylhexyl)phthalate on oxidative phosphorylation in rat liver mitochondria: modification of the function of the adenine nucleotide translocator.

The effect of di-(2-ethylhexyl)phthalate (DEHP) on oxidative phosphorylation of isolated rat liver mitochondria was investigated. DEHP at concentrations of 20-1000 microM had no effect on state 4 respiration, but at 40 microM, DEHP decreased the rate of state 3 respiration by about 20%. Although DEHP had no effect on electron transport through the respiratory chain, it decreased the rate of adenosine triphosphate (ATP) synthesis. Its inhibition of ATP synthesis showed a similar concentration dependence to that of state 3 respiration. Furthermore, DEHP at 40 microM inhibited the uptake of [3H]adenosine diphosphate into mitochondria. DEHP also retarded the action of cationic uncoupling agents, which are known to modify the 29000-dalton protein involved in adenine nucleotide exchange. These results suggest that DEHP affects the activity of adenine nucleotide exchange and consequently partially decreases the rate of state 3 respiration. The action of DEHP on the 29000-dalton protein involves a protective effect against mitochondrial damage induced by hydrophobic cations or heavy metal cations.

Adenosine Diphosphate↗
PubMed1995

[Participation of SH-groups in regulating oxidative phosphorylation by malate and palmitate-uncoupled respiration in liver mitochondria].

The effect of malate on respiration in liver mitochondria has been studied during oxidation of succinate in the presence of rotenone both in state 3 and after palmitate addition. Malate was shown to stimulate the rate of mitochondrial respiration in the both respiratory states, its effect being increased in the presence of the NAD-dependent substrates of oxidation-glutamate and pyruvate or thiols (cysteine and thiourea) Preincubation of mitochondria for 5 min in the absence of respiratory substrates eliminated the stimulating effect of malate. However, this effect was manifested in the conditions when the NAD-dependent respiratory substrates or thiols were added after preincubation of mitochondria. p-Chloromercuribenzoate eliminated the stimulating effect of malate. Carboxyatractyloside and ATP inhibited mitochondrial respiration in the presence of palmitate. Malate did not influence the action of the first effector but eliminated that of the second effector. It is concluded that malate can regulate oxidative phosphorylation and palmitate-uncoupled respiration by affecting the adenine nucleotide transported. The SH-groups localized outside the mitochondria in the hydrophilic region play an important role in the realization of malate effects.

Adenosine Triphosphate↗
PubMedDate not supplied

Gliomas are driven by glycolysis: putative roles of hexokinase, oxidative phosphorylation and mitochondrial ultrastructure.

To elucidate the reasons for glycolytic deviation commonly found in brain tumors, hexokinase (HK) activity, mitochondria-HK binding, oxidative phosphorylation and mitochondrial ultrastructure were studied in 4 human xenografted gliomas. Lactate/pyruvate ratios were increased 3-4 fold and HK activity was of 2-4 fold lower than that of normal rat brain tissue, used as the control. The mitochondria-bound HK (mHK) fraction varied considerably and represented 9 to 69% of the total HK of that normal rat brain. The respiratory activity of glioma mitochondria, assessed by polarography and spectrophotometry, was within the normal range. However, the mitochondrial content of gliomas was lower than in the rat brain tissue, as revealed by the markedly decreased, activities of two unrelated mitochondrial enzymes, cytochrome c oxidase and citrate synthase in glioma homogenates. Electron microscopical studies confirmed the reduced number of mitochondria in 3 out of the 4 gliomas. Profound alterations of mitochondrial ultrastructure, namely of cristae and matrix densities, were observed in the 4 gliomas. The intercrista space was wider in all gliomas and the crista area was larger in 3 out of the 4 gliomas than in normal rat brain. Finally, the outer membrane of glioma mitochondria interacted intimately and extensively with the rough endoplasmic reticulum (RER) and/or nuclear membrane. These results suggest that, because of the very low content of normally functioning mitochondria, gliomas shift their energy metabolism towards a high-level glycolysis to generate their cellular ATP supply, probably through RER-mitochondria interactions and transformation-dependent redistribution of particulate HK from non-mitochondrial to mitochondrial receptors.

Animals↗
PubMed2000

Activities of mitochondrial oxidative phosphorylation enzymes in cultured amniocytes.

Amniocytes represent a population of foetal cells that can be used for prenatal diagnosis in families with suspected mitochondrial oxidative phosphorylation (OXPHOS) defects. In this paper, we present a complex protocol for evaluation of the function of mitochondrial OXPHOS enzymes in cultured amniocytes using three independent and complementary methods: (a) spectrophotometry as a tool for determination of the capacities of mitochondrial respiratory-chain enzymes (NADH ubiquinone oxidoreductase, succinate- and glycerophosphate cytochrome c reductase, cytochrome c oxidase and citrate synthase); (b) polarography as a tool for the evaluation of mitochondrial OXPHOS enzyme functions in situ using digitonin-permeabilised amniocytes (rotenone-sensitive oxidation of pyruvate+malate, antimycin A-sensitive oxidation of succinate, KCN-sensitive oxidation of cytochrome c, ADP-activated substrate oxidation) and (c) cytofluorometric determination of tetramethyl rhodamine methyl ester (TMRM) fluorescence in digitonin-permeabilised amniocytes as a sensitive way to determine the mitochondrial membrane potential under steady-state conditions (state 4 with succinate). These protocols are presented together with reference control values using 9-22 independent cultures of amniocytes.

Adenosine Diphosphate↗
PubMed1980

Ultrastructural and biochemical studies of the brain and other organs in rat after chronic ethanol administration. III. Influence of ethanol intoxication on oxidative phosphorylation of the rat brain mitochondria with ultrastructural and morphometric evaluation of mitochondrial fraction).

The effect of chronic ethanol intoxication on oxidative phosphorylation in the rat brain mitochondrial fraction was examined. Moreover, electron microscopy was used to verify the quantitative composition of the fraction and for examination of ultrastructural changes in the mitochondria. The experiments were carried out with 60 rats receiving, beside the normal diet, ethyl alcohol according to a modified RATCLIFFE model. In isolated rat brain mitochondria the NAD-dependent oxidation of substrates (glutamate + malate) was decreased. The phosphorylation index ADP/0 and the respiratory control ratio (RCR) in rat brain mitochondria from ethanol-treated rats were unchanged in the presence of both succinate and glutamate + malate. Chronic ethanol feeding did not induce any changes of succinate dehydrogenase and cytochrome oxidase activities in solubilised mitochondria fractions of rat brain. Electron microscopy studies revealed that mitochondria from control animals retained their outer and inner membranes, whereas those from rats given ethanol were almost always swollen and some were disrupted. In mitochondrial fractions isolated from ethanol-intoxicated rats an increase was observed of contaminating elements i.e. axons and synaptosomes of various sizes. It should be stressed that the mitochondria located inside synaptosomes and axons were unchanged. The composition of the fractions was quantitatively evaluated and confirmed the diminution of "free" mitochondria in the experimental fractions in favour of "bound" mitochondria which mainly occurred in the synaptosomes with preserved metabolic activity. On the basis of electron microscopy studies it could be suggested that ethanol intoxication causes the damage of some mitochondria, which become more sensitive to mechanical destruction during isolation procedure, and they do not sediment together with the fraction of normal ones. The absence of "free" mitochondria in pellets explains the spurious lack of disturbances in the energy metabolism of brain mitochondria after chronic ethanol intoxication.

Adenosine Diphosphate↗
PubMed1967

Oxidative phosphorylation in experimental bilirubin encephalopathy.

Mitochondria from the whole brain or cerebellum of newborn guinea pigs with experimental bilirubin encephalopathy failed to exhibit uncoupling of oxidative phosphorylation. The pigment concentrations required to initiate uncoupling in vitro are much higher than those found in the brain of neurotoxic animals.

Animals↗