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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↗
PubMed1985

Steady-state kinetics of the overall oxidative phosphorylation reaction in heart mitochondria. Evidence for linkage of the energy-yielding and energy-consuming steps by freely diffusible intermediates and for an allosteric mechanism of respiratory control at coupling site 2.

The three coupling segments of the respiratory chain of bovine heart mitochondria were examined individually by steady-state kinetic methods to determine whether or not freely diffusible intermediates occur between the energy-yielding and energy-consuming steps involved in the oxidative phosphorylation of extramitochondrial ADP. The principal method employed was the dual inhibitor technique, for which an appropriate model is provided. The results indicate that in accordance with the chemiosmotic theory the intermediate reactants that link the energy-yielding rotenone-sensitive (Site 1), cytochrome bc1 (Site 2), and cytochrome aa3 (Site 3) reactions of the respiratory chain to the energy-consuming ATP synthetase, AdN transport, and Pi transport reactions are freely diffusible (delocalized). Site 2 was found to differ from the others in regard to the mechanism by which the energy-linked respiratory chain reaction is controlled by the energy-consuming steps. Whereas the Site 1 and Site 3 respiratory chain reactions are controlled primarily by the thermodynamic mechanism of reaction reversal, the Site 2 respiratory reaction is controlled primarily by a kinetic mechanism in which an intermediate that links it to the energy-consuming steps inhibits it allosterically. From the effects of nigericin and valinomycin the allosteric intermediate appears to be the electrical component of the protonmotive force.

Animals↗
PubMed1996

Cloning by functional complementation, and inactivation, of the Schizosaccharomyces pombe homologue of the Saccharomyces cerevisiae gene ABC1.

The Saccharomyces cerevisiae gene ABC1 is required for the correct functioning of the bc1 complex of the mitochondrial respiratory chain. By functional complementation of a S. cerevisiae abc1(-) mutant, we have cloned a Schizosaccharomyces pombe cDNA, whose predicted product is 50% identical to the Abc1 protein. Significant homology is also observed with bacterial, nematode, and even human amino acid sequences of unknown function, suggesting that the Abc1 protein is conserved through evolution. The cloned cDNA corresponds to a single S. pombe gene abc1Sp, located on chromosome II, expression of which is not regulated by the carbon source. Inactivation of the abc1Sp gene by homologous gene replacement causes a respiratory deficiency which is efficiently rescued by the expression of the S. cerevisiae ABC1 gene. The inactivated strain shows a drastic decrease in the bc1 complex activity. a decrease in cytochrome aa3 and a slow growth phenotype. To our knowledge, this is the first example of the inactivation of a respiratory gene in S. pombe. Our results highlight the fact that S. pombe growth is highly dependent upon respiration, and that S. pombe could represent a valuable model for studying nucleo-mitochondrial interactions in higher eukaryotes.

3-Isopropylmalate Dehydrogenase↗
PubMed2005

Identification of tyrosine-phosphorylated proteins of the mitochondrial oxidative phosphorylation machinery.

The role of some serine/threonine kinases in the regulation of mitochondrial physiology is now well established, but little is known about mitochondrial tyrosine kinases. We showed that tyrosine phosphorylation of rat brain mitochondrial proteins was increased by in vitro addition of ATP and H2O2, and also during in situ ATP production at state 3, and maximal reactive oxygen species production. The Src kinase inhibitor PP2 decreased tyrosine phosphorylation and respiratory rates at state 3. We found that the 39-kDa subunit of complex I was tyrosine phosphorylated, and we identified putative tyrosine-phosphorylated subunits for the other complexes. We also have strong evidence that the FoF1-ATP synthase alpha chain is probably tyrosine-phosphorylated, but demonstrated that the beta chain is not. The tyrosine phosphatase PTP 1B was found in brain but not in muscle, heart or liver mitochondria. Our results suggest that tyrosine kinases and phosphatases are involved in the regulation of oxidative phosphorylation.

Animals↗
PubMedDate not supplied

Characteristics of the aerobic respiratory chains of the microaerophiles Campylobacter jejuni and Helicobacter pylori.

The respiratory chain enzymes of microaerophilic bacteria should play a major role in their adaptation to growth at low oxygen tensions. The genes encoding the putative NADH:quinone reductases (NDH-1), the ubiquinol:cytochrome c oxidoreductases (bc1 complex) and the terminal oxidases of the microaerophiles Campylobacter jejuni and Helicobacter pylori were analysed to identify structural elements that may be required for their unique energy metabolism. The gene clusters encoding NDH-1 in both C. jejuni and H. pylori lacked nuoE and nuoF, and in their place were genes encoding two unknown proteins. The NuoG subunit in these microaerophilic bacteria appeared to have an additional Fe-S cluster that is not present in NDH-1 from other organisms; but C. jejuni and H. pylori differed from each other in a cysteine-rich segment in this subunit, which is present in some but not all NDH-1. Both organisms lacked genes orthologous to those encoding NDH-2. The subunits of the bc1 complex of both bacteria were similar, and the Rieske Fe-S and cytochrome b subunits had significant similarity to those of Paracoccus denitrificans and Rhodobacter capsulatus, well-studied bacterial bc1 complexes. The composition of the terminal oxidases of C. jejuni and H. pylori was different; both bacteria had cytochrome cbb3 oxidases, but C. jejuni also contained a bd-type quinol oxidase. The primary structures of the major subunits of the cbb3-type (terminal) oxidase of C. jejuni and H. pylori indicated that they form a separate group within the cbb3 protein family. The implications of the results for the function of the enzymes and their adaptation to microaerophilic growth are discussed.

Aerobiosis↗
PubMed1998

Genes coding for respiratory complexes map on all three chromosomes of the Paracoccus denitrificans genome.

The genome of Paracoccus denitrificans (strain Pd1222) consists of three distinct DNA molecules when separated by standard pulsed-field gel electrophoresis with apparent molecular sizes of approximately 2, 1.1, and 0.64 Mb. When the separated chromosomes are digested by restriction enzymes and sizes of resulting fragments are summed up, the three chromosomes are composed of 1.83, 1.16, and 0.67 Mb. Since their migration behavior relative to size standards is largely independent of electrophoresis conditions, at least the two smaller chromosomes most likely represent linear molecules. The size analysis presented here allows an unequivocal distinction between groups of different strains of P. denitrificans and of Thiosphaera pantotropha, confirming an earlier cytochrome c analysis. When the genome was analyzed with different probes coding for respiratory enzymes, essential genes were found spread over all three chromosomes without any obvious clustering on any of the three forms.

Chromosome Mapping↗
PubMed1997

Increase in oxidative key enzymes in a case of muscle ubiquinol-cytochrome c reductase deficiency.

In a 29-year-old patient suffering from exertional muscle intolerance with a ubiquinol-cytochrome c reductase deficiency related to a cytochrome b gene point mutation of the mitochondrial DNA, we conducted a study of the aims of which were: (1) to test whether changes in the maximum activities of muscle key enzymes of the main energy-producing pathways occur, (2) to address the issue of whether fibers of different types are equally affected in their enzymatic machinery involved in energy production, and (3) to correlate the results obtained with histochemical and 31P NMR spectroscopy data. When compared to results obtained in six normal subjects, our study clearly shows that the type I fibers of the patient virtually all contained subsarcolemmal mitochondrial aggregates and increased activities of succinate dehydrogenase and cytochrome c oxidase; microdissected type I fibers also displayed a significant increase in both citrate synthase and beta-hydroxyacyl-CoA dehydrogenase, two key enzymes of mitochondrial oxidative metabolism. Despite these changes in the patient's muscle, its whole energy-producing machinery remained impaired as revealed by a slowed post-exercise recovery of phosphocreatine.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed2005

Electrostatics of Cytochrome-c assemblies.

Electrostatic potentials along with computational mutagenesis are used to obtain atomic level insights into Cytochrome-c in order to design efficient bionanosensors. The electrostatic properties of wild type and mutant Cytochrome-c are examined in the context of their assembly, i.e. are examined in the absence and presence of neighboring molecules from the assembly. An intense increase in the positive potential ensues when the neighboring molecules are taken into account. This suggests that in the extrapolation of electric field effects upon the design of assemblies, considering the properties of only the central molecule may not be sufficient. Additionally, the influence of the uncharged residues becomes quite diminished when the molecule is considered in an assembly. This could pave the way for making mutants that might be more soluble in different media used in the construction of devices. [Figure: see text]. The electrostatic potential, calculated using the program DELPHI mapped on to the surface of Cytochrome-c when it is considered by itself (in the left column) and in the presence of the electrostatic field generated by the presence of the surrounding 4 molecules on the right. The potentials range from -10kT in red to +10kT in blue. The central figure shows the regions that have been mutated to positively charged residues by placing a unit positive charge at the terminal atom of the respective side chain. The figures range from the wild type in the first row, followed by the Gln12, Asn70, Asp50, Glu90 and Ala83 mutants.

Cytochromes c↗
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↗
PubMed2006

Protection of mitochondria during cold storage of liver and following transplantation: comparison of the two solutions, University of Wisconsin and Eurocollins.

Injury to allografts during ischaemia/reperfusion contribute to the development of graft failure following transplantation with significant morbidity and mortality to patients. The development of University of Wisconsin solution has significantly improved the quality of graft preservation and transplant outcome relative to formerly used solutions such as Eurocollins. The aim of this study was to further characterize mitochondrial structural and functional alterations occurring in rat livers following cold storage and transplantation. Mitochondrial impairment after prolonged storage in Eurocollins included decreased cyt. c+c1, cyt. b and cyt. a+a3 concentration and dramatic falls in the activities of the respiratory chain enzymes ubiquinol-cyt. c oxidoreductase and cytochrome oxidase. Under the same conditions the highest hydroperoxide but lowest vitamin E concentrations were also found. Although both the Eurocollins and University of Wisconsin preservation solutions have limitations in preventing oxidative injuries following cold storage and reperfusion, our data indicate that mitochondrial impairment was higher in Eurocollins- than in University of Wisconsin-stored livers. Further improvements are necessary in maintaining the stability of mitochondria in order to optimize preservations solutions used in transplantations.

Adenosine↗
PubMed2003

Mitochondrial disorders.

We present here a discussion on the most relevant recent publications on mitochondrial disease. In addition to many papers concerning the description of the genotype-to-phenotype correlations in mitochondrial DNA-related disorders, this very broad area of neurogenetics includes a number of novel observations on the basic aspects of mitochondrial biogenesis that can be relevant in explaining the molecular mechanisms of mitochondrial abnormalities. The completion of the human genome project and the wealth of knowledge gained on the genetics of oxidative phosphorylation in yeast have promoted a substantial acceleration in the discovery of a remarkable number of nuclear genes associated with specific mitochondrial disorders. A further development of these contributions has been the generation of several cellular and animal models of disease that can now be exploited for testing both pathogenetic hypotheses and therapeutic strategies. Most of the latter are based on the use of chemical compounds aimed at reducing the negative impact of mitochondrial defects on both energy production and generation of reactive oxygen species. The first successful attempts for gene therapy of some mitochondrial diseases have recently been achieved and will hopefully increase in the near future.

Animals↗
PubMed1989

The response of individual polypeptides of the mammalian respiratory chain to thyroid hormone.

The effects of thyroid hormone on the accumulation of inner membrane polypeptides in rat liver mitochondria have been investigated using Western blot analysis. Respiration and mitochondrial protein synthesis were also measured. Levels of the subunits of cytochrome oxidase, the cytochrome bc1 complex, and the beta-subunit of F1-ATPase increase relatively late, requiring 3-6 days of treatment and high doses of hormone. In contrast, respiration increases under conditions in which no significant accumulation of individual subunits is observed. Our results indicate that increased oxidative capacity of mitochondria can be divided into an early response which probably involves metabolic regulation of mitochondrial respiration by hormone and a later response which is due to elevated mitochondrial protein synthesis and the accumulation of polypeptides of the respiratory chain.

Animals↗
PubMed1990

Stimulation of the electron transport chain in mitochondria isolated from rats treated with mannoheptulose or glucagon.

We investigated the kinetics of the mitochondrial respiratory chain, proton leak, and phosphorylating subsystems of liver mitochondria from mannoheptulose-treated and control rats. Mannoheptulose treatment raises glucagon and lowers insulin; it had no effect on the kinetics of the mitochondrial proton leak or phosphorylating subsystems, but the respiratory chain from succinate to oxygen was stimulated. Previous attempts to detect any stimulation of cytochrome c oxidase by glucagon are shown by flux control analysis to have used inappropriate assay conditions. To investigate the site of stimulation of the respiratory chain we measured the relationship between the thermodynamic driving force and respiration rate for the span succinate to coenzyme Q, the cytochrome bc1 complex and cytochrome c oxidase. Hormone treatment of rats altered the kinetics of electron transport from succinate to coenzyme Q in subsequently isolated mitochondria and activated succinate dehydrogenase. The kinetics of electron transport through the cytochrome bc1 complex were not affected. Effects on cytochrome c oxidase were small or nonexistent.

Animals↗
PubMed1980

A comparison of the respiratory chain in particles from Paracoccus denitrificans and bovine heart mitochondria by EPR spectroscopy.

A study is presented on the EPR characteristics of the paramagnetic groups in the respiratory chain present in membrane particles of Paracoccus denitrificans, the respiratory system of which is very similar to that in submitochondrial particles from beef heart. All paramagnetic prosthetic groups of the mitochondrial system are also found in the bacterial plasma membrane. Their properties suggest that the respiratory groups are embedded in very similar protein environments in the two systems.

Animals↗
PubMed1990

Monomer-dimer structure of cytochrome-c oxidase and cytochrome bc1 complex from the thermophilic bacterium PS3.

Molecular weights of three membrane proteins have been measured in the presence of 0.1% octaethylene glycol n-dodecyl ether (C12E8) by the measuring system in which a membrane protein eluted from a gel chromatography column is monitored sequentially for ultraviolet absorption, light scattering and refractive index. The relative molecular mass (Mr) and amount of bound detergent per protein (delta) can be calculated from these data, if instrumental constants are measured using a set of appropriate water-soluble proteins which does not bind nonionic surfactants. The molecular masses of cytochrome c oxidase and cytochrome bc1 complex from the thermophilic bacterium PS3 were determined to be 127 kDa and 185 kDa, respectively, indicating that the oxidase is monomeric, while the bc1 complex dimeric in the presence of C12E8. The larger apparent molecular mass of about 310 kDa of the PS3 oxidase obtained from the retention time of the gel chromatography (Sone, N., Sekimachi, M. and Kutoh, E. (1987) J. Biol. Chem. 262, 15386-15391) turned out to be due to a high binding ability with the detergent (delta = 1.25 g/g) of this very hydrophobic protein. Analyses of bovine heart cytochrome oxidase, on which monomer/dimer properties have been reported, showed that the enzyme is mainly dimeric (Mr = 374,000), while a small portion is monomeric (Mr = 191,000). Mild alkaline treatment of this enzyme caused monomerization of the enzyme with accompanying aggregate formation. These results, thus, show that this method is suitable to analyze monomer/dimer conversion of membrane protein as well as to estimate structure of membrane proteins.

Animals↗
PubMed1990

The molecular pathology of respiratory-chain dysfunction in human mitochondrial myopathies.

Some of the different molecular pathologies of respiratory-chain dysfunction in human mitochondrial myopathies will be reviewed in relation to the findings in 58 cases. Deletions of mitochondrial DNA were identified in 21 cases [36%]. There was some correlation between the sites of the deletion and the mitochondrial biochemistry in patients with defects of Complex I but not in cases with more extensive loss of respiratory chain activity. Complex I and Complex IV polypeptides were usually normal in deleted cases. Non-deleted cases, however, often showed specific subunit deficiencies which involved the products of both nuclear and mitochondrial genes. Immunoblots of respiratory-chain polypeptides in one case pointed to defective translocation of the Rieske precursor from the cytosol into the mitochondria. The pathogenic role of circulating autoantibodies to specific matrix proteins and the nature of the target antigens in two patients with mitochondrial encephalomyopathies and respiratory-chain dysfunction will also be discussed.

Autoantibodies↗