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PubMed1980

[Effect of cobalt and copper o-phenanthroline complexes on electron transport and energy coupling activity in reaction centers and chromatophores of purple bacteria].

The effects of cobalt and copper o-phenanthroline complexes on electron transfer and energy coupling activity in the reaction center and chromatophore preparations of purple bacteria were studied. In terms of their effects on the systems under study these complexes fall into two groups, i.e. cobalt complexes with a high electron transfer activity, which stimulate membrane energization, and copper complexes which contribute to the chromatophore membrane deenergization. Among a variety of complexes studied the perchlorate tris-o-phenanthroline complex Co(II) and the chloride 4,7-diphenyl-o-phenanthroline complex Cu(II) were found to have the highest activity. Both cobalt and copper o-phenanthroline complexes may be a promising tool for regulating bioenergetic processes.

Bacterial Chromatophores↗
PubMed2000

Measuring the quantity and activity of mitochondrial electron transport chain complexes in tissues of central nervous system using blue native polyacrylamide gel electrophoresis.

Mitochondrial dysfunction and degeneration are associated with many neurodegenerative disorders. A dysfunctional mitochondrial electron transport chain (ETC) impairs ATP production and accelerates the generation of free radicals. To evaluate mitochondrial function, reliable methods are needed. Conventional spectrophotometric assays may not eliminate interference from nonspecific enzyme activities and do not measure quantities of specific ETC complexes. Blue native polyacrylamide gel electrophoresis (BN-PAGE) has been used to resolve mitochondrial ETC complexes. Combined with histochemical staining, it has also been applied to measure ETC enzyme activities in muscles. The current study is to determine (1) whether BN-PAGE can be used to detect ETC complexes from different regions of the central nervous system (CNS) and (2) the quantitative range of BN-PAGE in measuring the amounts and activities of different ETC complexes. By systematically varying the protein amount and the time of histochemical reactions, we have found linear ranges comparable to spectrophotometric assays for measuring enzyme activities of several ETC complexes. In addition, we found linear ranges for measuring protein quantities in several ETC complexes. These results demonstrate that BN-PAGE can be used to measure the amount and activity of the ETC enzymes from the nerve tissues and, thus, can be applied to evaluate the functional changes of mitochondria in neurodegenerative disorders.

Animals↗
PubMed1995

Postnatal development of the complexes of the electron transport chain in synaptic mitochondria from rat brain.

The postnatal development of the complexes of the electron transport chain in mitochondria isolated from rat brain synaptosomes was investigated. Synaptosomal brain mitochondria were isolated from rats aged 10-60 days, and the activities of mitochondrial complex I, complex II-III, complex IV and complex V were measured. There was a significant increase in the activity of II-III from day 10 to day 15 and complex IV from day 10 to day 21, thereafter the activities of complexes I-III and IV did not change significantly. The activity of complex I did not change significantly during the period 10-60 days post partum. In synaptic mitochondria, complex V activity was higher than in non-synaptic mitochondria, whereas the activity of complex I was lower than in non-synaptic mitochondria. These data show that the complexes of the respiratory chain within synaptic mitochondria have activities different from those of non-synaptic mitochondria and may have major implications for the relative susceptibility of mitochondria in different brain cell types to neurotoxins such as MPP+, hypoxic/ischaemic damage and oxidative stress.

Acetylcholinesterase↗
PubMedDate not supplied

Effect of starvation and insulin-induced hypoglycemia on oxidative stress scavenger system and electron transport chain complexes from rat brain, liver, and kidney.

Considerable evidence suggests that oxidative stress plays an important role in tissue damage associated with hypoglycemia and other metabolic disorders. The altered brain neurotransmitters metabolism, cerebral electrolyte contents, and impaired blood-brain barrier function may contribute to CNS dysfunction in hypoglycemia. The present study elucidates the effect of starvation and insulin-induced hypoglycemia on the free radical scavanger system--reduced glutathione (GSH) content, glutathione S-transferase (GST), glutathione peroxidase (GPx), glutathione reductase (GR), gamma-glutamyl transpeptidase (gamma-GTP), gamma-glutamyl cystein synthetase (gamma-GCS), catalase and superoxide dismutase (SOD), and mitochondrial electron transport chain (ETC) complexes I-IV from three different regions of rat brain, namely cerebral hemispheres (CH), cerebellum (CB), and brainstem (BS). Peripheral organs, such as liver and kidney, were also studied. Significant changes in these enzymic activities were observed. The analysis of such alterations is important in ultimately determining the basis of neuronal dysfunction during metabolic stress conditions, such as hypoglycemia, and also defining the nature of these changes may help to develop therapeutic means to cure metabolically stressed tissues.

Animals↗
PubMed2004

Structure-based engineering of Alcaligenes xylosoxidans copper-containing nitrite reductase enhances intermolecular electron transfer reaction with pseudoazurin.

The intermolecular electron transfer from Achromobacter cycloclastes pseudoazurin (AcPAZ) to wild-type and mutant Alcaligenes xylosoxidans nitrite reductases (AxNIRs) was investigated using steady-state kinetics and electrochemical methods. The affinity and the electron transfer reaction constant (k(ET)) are considerably lower between AcPAZ and AxNIR (K(m) = 1.34 mM and k(ET) = 0.87 x 10(5) M(-1) s(-1)) than between AcPAZ and its cognate nitrite reductase (AcNIR) (K(m) = 20 microM and k(ET) = 7.3 x 10(5) M(-1) s(-1)). A negatively charged hydrophobic patch, comprising seven acidic residues around the type 1 copper site in AcNIR, is the site of protein-protein interaction with a positively charged hydrophobic patch on AcPAZ. In AxNIR, four of the negatively charged residues (Glu-112, Glu-133, Glu-195, and Asp-199) are conserved at the corresponding positions of AcNIR, whereas the other three residues are not acidic amino acids but neutral amino acids (Ala-83, Ala-191, and Gly-198). Seven mutant AxNIRs with additional negatively charged residues surrounding the hydrophobic patch of AxNIR (A83D, A191E, G198E, A83D/A191E, A93D/G198E, A191E/G198E, and A83D/A191E/G198E) were prepared to enhance the specificity of the electron transport reaction between AcPAZ and AxNIR. The k(ET) values of these mutants become progressively larger as the number of mutated residues increases. The K(m) and k(ET) values of A83D/A191E/G198E (K(m) = 88 microM and k(ET) = 4.1 x 10(5) M(-1) s(-1)) are 15-fold smaller and 4.7-fold larger than those of wild-type AxNIR, respectively. These results suggest that the introduction of negatively charged residues into the docking surface of AxNIR facilitates both the formation of electron transport complex and the electron transfer reaction.

Achromobacter denitrificans↗
PubMed1985

Cooperation among electron-transfer complexes in ATP synthesis in chloroplasts.

We have investigated the extent to which redox reactions of thylakoid membranes cooperate in ATP synthesis. This was done by measuring the onset of ATP synthesis following a series of single-turnover light-flashes at various levels of electron transport inhibition. In the presence of antibiotics that prevent the formation of a membrane potential, the onset of ATP synthesis seems to depend entirely on the formation of an adequately large delta pH. Under our conditions, the accumulation of about 60 mmol H+ X mol chlorophyll-1 is then necessary to form the requisite delta pH, which in turn requires about 15 saturating flashes in uninhibited thylakoid samples. Inhibition of some of the electron transfer centers by limiting the light intensity of the flashes, by dichlorophenyldimethylurea, by heat treatment, or by NH2OH-treatment caused an increase in the number of flashes required for the onset of ATP synthesis. The increase in the requisite number of flashes reflected the decreased number of electrons transferred in each flash, almost exactly the same number of electrons being transferred before ATP synthesis could begin. This effect of inhibitors was true when the two photosystems were operating in unison and when either of the two photosystems was acting alone. However, when either photosystem acted alone, there was an increase in the number of flashes required for the onset of ATP synthesis, an increase which was consistent with the observed lower flash-induced proton accumulation. A mathematical analysis of the onset of flash-induced ATP synthesis shows that at least several hundred proton-translocating electron transport complexes must be cooperating to form the threshold delta pH. In spite of this evidence for extensive cooperation among different electron transport complexes in ATP formation, the implied pooling of H+ ions does not seem to involve inner vesicle regions accessible to exogenous buffers. Thus, even when the number of H+ ions accumulated per flash was reduced by 70% through attenuation of the intensity of the flashes, exogenous hydrogen ion buffers present within the lumen of the thylakoid vesicle had no effect on the number of flashes required for the onset of ATP synthesis.

Adenosine Triphosphate↗
PubMed2000

Increased mitochondrial superoxide generation in neurons from trisomy 16 mice: a model of Down's syndrome.

Increased neuronal cell death in neurodegenerative diseases has been suggested to result from an increased mitochondrial generation of radical oxygen species (ROS). To test this hypothesis, we investigated superoxide formation in cultured hippocampal neurons from diploid and trisomy 16 mice (Ts16), a model of Down's syndrome. Microflurometric techniques were used to measure superoxide-induced oxidation rate of hydroethidine (HEt) to ethidium and reduced nicotinamide adenine dinucleotide (NADH) and reduced nicotinamide adenine dinucleotide phosphate (NADPH) autofluorescence signal to monitor changes in neuronal energy metabolism. We found an increase in superoxide formation by more than 50% in Ts16 neurons in comparison with diploid control neurons. In the presence of the mitochondrial respiratory chain complex I inhibitor rotenone superoxide production was blocked in diploid neurons, but the increased superoxide generation in Ts16 neurons remained. Uncoupling of mitochondrial oxidative phosphorylation using carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP) caused irreversible deficiency in the energy metabolism, monitored by NAD(P)H autofluorescence in Ts16 neurons, but not in diploid control neurons. These results suggest an increased basal generation of superoxide in Ts16 neurons, probably caused by a deficient complex I of mitochondrial electron transport chain, which leads to an impaired mitochondrial energy metabolism and finally neuronal cell death.

Animals↗
PubMed1994

Aminoethylcysteine ketimine decarboxylated dimer inhibits mitochondrial respiration by impairing electron transport at complex I level.

The product of the spontaneous dimerization and decarboxylation of aminoethylcysteine ketimine (simply named the dimer in this note) has been investigated for a possible biochemical activity. It has been found that the dimer inhibits the ADP-dependent oxidation of NAD(+)-linked substrates in rat liver mitochondria and electron transport from NADH to O2 in bovine heart submitochondrial particles (SMP). Oxidation of succinate by SMP is not impaired by concentrations of the dimer inhibiting almost totally NADH oxidation. Furthermore, the dimer did not affect the rotenone-insensitive electron transfer from NADH to menadione. These results give a preliminary indication suggesting that the dimer inhibits electron flow from NADH dehydrogenase to ubiquinone at or near the rotenone binding site(s). The dimer inhibition falls in the same range exhibited by some neurotoxins which are known to interact with the rotenone binding site.

Animals↗
PubMed2005

Carbenoxolone induces oxidative stress in liver mitochondria, which is responsible for transition pore opening.

Carbenoxolone (Cbx), a derivative of glycyrrhetinic acid, which has been found to affect mineralocorticoid and glucocorticoid receptors, induces swelling and membrane potential collapse when added to Ca(2+)-loaded liver mitochondria at 10 microM concentrations. These effects are strictly correlated with hydrogen peroxide generation, increase in oxygen uptake, and sulfhydryl and pyridine nucleotide oxidation. Cyclosporin A, bongkrekic acid, and N-ethylmaleimide completely abolish all the above-described effects, suggesting that Cbx can be considered an inducer of mitochondrial permeability transition by means of oxidative stress. Cbx can also trigger the apoptotic pathway because the above events are also correlated with the loss of cytochrome c. These effects are probably related to the conjugated carbonyl oxygen in C-11, which produces reactive oxygen species by interacting with the mitochondrial respiratory chain, mainly at the level of complex I but, most likely, also with complex III. The oxidative stress induced by Cbx, which is responsible for pore opening, excludes that this is related to a genomic effect of the compound.

Animals↗
PubMed2003

Essential role of complex II of the respiratory chain in hypoxia-induced ROS generation in the pulmonary vasculature.

In the pulmonary vasculature, the mechanisms responsible for oxygen sensing and the initiation of hypoxia-induced vasoconstriction and vascular remodeling are still unclear. Nitric oxide (NO) and reactive oxygen species (ROS) are discussed as early mediators of the hypoxic response. Here, we describe a quantitative analysis of NO- and ROS-producing cells within the vascular walls of murine lung sections cultured at normoxia or hypoxia. Whereas the number of NO-producing cells was not changed by hypoxia, the number of ROS-generating cells was significantly increased. Addition of specific inhibitors revealed that mitochondria were the source of ROS. The participation of the individual mitochondrial complexes differed in normoxic and hypoxic ROS generation. Whereas normoxic ROS production required complexes I and III, hypoxic ROS generation additionally demanded complex II. Histochemically demonstrable succinate dehydrogenase activity of complex II in the arterial wall decreased during hypoxia. Inhibition of the reversed enzymatic reaction, i.e., fumarate reductase, by application of succinate, specifically abolished hypoxic, but not normoxic, ROS generation. Thus complex II plays an essential role in hypoxic ROS production. Presumably, its catalytic activity switches from succinate dehydrogenase to fumarate reductase at reduced oxygen tension, thereby modulating the directionality of the electron flow.

Animals↗
PubMed2002

Mitochondrial dysfunction in patients with hypotonia, epilepsy, autism, and developmental delay: HEADD syndrome.

A group of 12 children clinically presenting with hypotonia, intractable epilepsy, autism, and developmental delay, who did not fall into previously described categories of mitochondrial encephalomyopathy, were evaluated for mitochondrial respiratory enzyme activity levels, mitochondrial DNA, and mitochondrial structural abnormalities. Reduced levels in specific respiratory activities were found solely in enzymes with subunits encoded by mitochondrial DNA in seven of eight biopsied skeletal muscle specimens evaluated. Five cases exhibited increased levels of large-scale mitochondrial DNA deletions, whereas pathogenic point mutations previously described in association with mitochondrial encephalomyopathies were not found. Mitochondrial structural abnormalities were present in three of four patients examined. Our findings suggest that mitochondrial dysfunction, including extensive abnormalities in specific enzyme activities, mitochondrial structure, and mitochondrial DNA integrity, may be present in children with a clinical constellation including hypotonia, epileptic seizures, autism, and developmental delay. The acronym HEADD is presented here to facilitate pursuit of mitochondrial defects in patients with this clinical constellation after other causes have been excluded.

Adolescent↗
PubMedDate not supplied

The mitochondrial production of reactive oxygen species: mechanisms and implications in human pathology.

Mitochondria are major sources of reactive oxygen species (ROS); the main sites of superoxide radical production in the respiratory chain are Complexes III and I; however, other mitochondrial enzymes, such as Complex II, glycerol-1-phosphate dehydrogenase, and dihydroorotate dehydrogenase, are also involved in production of ROS. ROS appear to be released both in the matrix and in the intermembrane space; however, their appearance outside the mitochondria may not be physiologically relevant. ROS production is increased in State 4 and in all conditions when the respiratory components are substantially in the reduced form. Accordingly, defects inducing decrease of electron transfer in the respiratory chain, as in many pathological conditions, are bound to enhance ROS production.

Dihydroorotate Dehydrogenase↗
PubMed1996

Determination of the activities of the enzyme complexes of the electron transport chain in human fibroblasts.

In order to improve the determination of the activities of the enzyme complexes of the electron transport chain (ETC) in fibroblasts, we characterized the isolation of mitochondria and measured enzyme activities in mitochondrial preparations from fibroblasts of control subjects and patients with suspected mitochondrial cytopathy. The isolation procedure yielded 54% of the citrate synthase activity in fibroblasts, with a 6-fold enrichment in this mitochondrial marker enzyme. The activities of the complexes of the ETC were linear with time and with the mitochondrial protein concentration used. The coefficients of variation for the enzyme activities determined were in the range of 10% in mitochondria from identical fibroblast cultures and between 30 and 70% in mitochondria from different fibroblast cultures of the same or of different patients. Decreased activities of one or more enzyme complexes (defined as an activity below the 95% confidence limit of control values) were found in 15 of 22 patients investigated. When compared with activities obtained in liver or skeletal muscle obtained at autopsy, the results were identical in three but different in two patients. The studies show that the activities of the enzyme complexes of the ETC can be determined reliably and reproducibly in mitochondria isolated from fibroblasts and that the results obtained are potentially useful for the diagnosis of mitochondrial cytopathies in patients with suggestive symptoms and signs.

Cells, Cultured↗
PubMed2003

Neonatal liver failure and Leigh syndrome possibly due to CoQ-responsive OXPHOS deficiency.

CoQ transfers electrons from complexes I and II of the mitochondrial respiratory chain to complex III. There are very few reports on human CoQ deficiency. The clinical presentation is usually characterized by: epilepsy, muscle weakness, ataxia, cerebellar atrophy, migraine, myogloblinuria and developmental delay. We describe a patient who presented with neonatal liver and pancreatic insufficiency, tyrosinemia and hyperammonemia and later developed sensorineural hearing loss and Leigh syndrome. Liver biopsy revealed markedly reduced complex I+III and II+III. Addition of CoQ to the liver homogenate restored the activities, suggesting CoQ depletion. Histological staining showed prominent bridging; septal fibrosis and widening of portal spaces with prominent mixed inflammatory infiltrate, associated with interface hepatitis, bile duct proliferation with numerous bile plugs. Electron microscopy revealed a large number of mitochondria, which were altered in shape and size, widened and disordered intercristal spaces. This may be the first case of Leigh syndrome with liver and pancreas insufficiency, possibly caused by CoQ responsive oxphos deficiency.

Biopsy↗
PubMed1999

Involvement of oxidative stress on the impairment of energy metabolism induced by A beta peptides on PC12 cells: protection by antioxidants.

Alzheimer's disease is widely held to be associated with oxidative stress due, in part, to the membrane action of amyloid beta-peptide (A beta) aggregates. In this study, the involvement of oxidative stress on A beta-induced energy metabolism dysfunction was evaluated on PC12 cells. It was shown that A beta peptides (A beta25-35 and A beta1-40) induce a concentration-dependent accumulation of reactive oxygen species (ROS), decrease the cellular redox activity, and lead to the depletion of ATP levels. The observed inhibition by A beta of mitochondrial function and of glycolysis is blocked by the antioxidants vitamin E, idebenone, and GSH ethyl ester. Taken together, these data suggest that exposure of PC12 cells to A beta results in an impairment of energy metabolism, leading to a deficit in ATP levels and to the compromise of cellular viability. Furthermore, the generation of ROS seems to be a crucial event responsible for the energetic metabolic dysfunction induced by A beta.

Adenosine Triphosphate↗
PubMed1999

Adult onset limb-girdle type mitochondrial myopathy with a mitochondrial DNA np8291 A-to-G substitution.

We analyzed mitochondrial DNA (mtDNA) from 7 patients in four families with adult onset limb-girdle type mitochondrial myopathy to clarify their genetic background. The patients, 2 men and 5 women, showed common clinical features, characterized by isolated skeletal myopathy, high serum creatine kinase level, ragged-red fibers and cytochrome c oxidase-defective fibers. Analysis of muscle biopsy specimens indicated that cytochrome c oxidase activity was decreased relative to that of citrate synthase in 5 of the 7 patients. Southern blotting and direct sequence analyses showed an A-to-G homoplasmic transition at np8291 and intergenic COII/tRNA (Lys) 9bp deletion in all patients. This substitution was detected in only 2 of 600 control individuals including healthy subjects and patients with other neuromuscular disorders; these 2 individuals had diabetes mellitus and myotonic dystrophy, respectively. Consequently, the mtDNA transition at np8291 was a rare polymorphism. However, the 7 patients we studied had identical clinical, pathological, biochemical, and genetic features. Therefore, limb-girdle type mitochondrial myopathy with this rare polymorphism may form a subgroup of adult onset mitochondrial myopathy.

Adult↗