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1
Hansson, Anna. "Cellular responses to respiratory chain dysfunction /". Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-493-7/.
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2
Silva, José Pablo. "The pathophysiology of respiratory chain dysfunction /". Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-234-9/.
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3
Li, Xi. "The respiratory chain in Neisseria species". Thesis, University of York, 2013. http://etheses.whiterose.ac.uk/3989/.
Testo completoAbstract (sommario):
This work presents the organization of respiratory chain in Neisseria species. The localization of redox proteins was determined. Lipid-modified azurin (Laz) and nitrite reductase (AniA) are mainly associated with outer membrane. All c-type cytochrome proteins are mainly associated with inner membrane. Cytochrome c5 is the major electron donor to AniA. Reduced form cytochrome c5 is able to donate electrons to AniA at a physiologically relevant rate. In addition, the second haem domain of cytochrome c5 is the direct donor to AniA. It presents a potential problem for inter-electron transfer between c5 and AniA, which are associated with inner and outer membrane respectively. Trihaem CcoP is the alternative electron donor to AniA in N. gonorrhoeae. The 3rd haem domain of N. gonorrhoeae CcoP is able to donate electrons to AniA at a physiologically relevant rate, suggesting there is alternative route for nitrite reduction in N gonorrhoeae. N. elongata cytochrome is an electron donor to AniA. N. elongata cytochrome which has high degree of similarity with c5, is confirmed to donate electrons to AniA at a physiologically relevant rate, suggesting N. elongata has one other route for nitrite reduction. Laz is not involved in nitrite reduction. Laz is able to receive electrons from cytochrome c5 at physiological relevant rate, but cannot donate electrons to AniA. Based on laz mutagenesis study, laz mutant strain has limited affect on growth and nitrite usage compared to the wild type strain. Cytochrome cx is not involved in oxygen reduction. Cytochrome cx has presumably been found to be involved in oxygen reduction in N. meningitidis, but not in N. gonorrhoeae. N. meningitidis carrying an N. gonorrhoeae ccoP gene has a similar growth rate as the growth rate of the wild type strain and also cx mutant strains.
4
Chen, Walter W. "Pathological features of mitochondrial respiratory chain dysfunction". Thesis, Massachusetts Institute of Technology, 2016. http://hdl.handle.net/1721.1/104099.
Testo completoAbstract (sommario):
Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biology, 2016.This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.
Cataloged from student-submitted PDF version of thesis. "June 2016."
Includes bibliographical references.
Mitochondria are essential organelles that carry out a multitude of important metabolic processes in mammalian organisms. These processes include ATP generation by the respiratory chain, aspartate synthesis by matrix aminotransferases, and long-chain fatty acid catabolism by the beta oxidation pathway. Given the role of mitochondria in maintaining cellular physiology, mitochondrial dysfunction often leads to disease. One major class of mitochondrial pathologies is caused by defects in the mitochondrial respiratory chain (RC). Yet while the genetic etiologies of these RC disorders are well-studied, the molecular defects that actually link RC dysfunction with impaired cellular viability are still unclear. In the work described here, we demonstrate that loss of mitochondrial membrane potential and aspartate contributes significantly to cellular pathology during RC dysfunction. In addition, we develop a novel method for rapidly isolating mitochondria and profiling their metabolite contents to study the changes in mitochondrial metabolism across various states of RC function. From this work, we find numerous alterations in matrix metabolites that had been previously unappreciated using traditional profiling of whole-cells and identify new metabolic abnormalities downstream of RC dysfunction. Collectively, this work uncovers distinct molecular events connecting RC pathology with impaired cellular viability and expands our understanding of the metabolic processes affected by RC dysfunction, thus opening up new areas for exploration.
by Walter W. Chen.
Ph. D.
5
Capristo, Mariantonietta <1981>. "Respiratory chain complex I dysfunction in tumorigenesis". Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2012. http://amsdottorato.unibo.it/4798/1/Capristo_Mariantonietta_Tesi.pdf.
Testo completoAbstract (sommario):
Diseases due to mutations in mitochondrial DNA probably represent the most common form of metabolic disorders, including cancer, as highlighted in the last years. Approximately 300 mtDNA alterations have been identified as the genetic cause of mitochondrial diseases and one-third of these alterations are located in the coding genes for OXPHOS proteins. Despite progress in identification of their molecular mechanisms, little has been done with regard to the therapy. Recently, a particular gene therapy approach, namely allotopic expression, has been proposed and optimized, although the results obtained are rather controversial. In fact, this approach consists in synthesis of a wild-type version of mutated OXPHOS protein in the cytosolic compartment and in its import into mitochondria, but the available evidence is based only on the partial phenotype rescue and not on the demonstration of effective incorporation of the functional protein into respiratory complexes. In the present study, we took advantage of a previously analyzed cell model bearing the m.3571insC mutation in MTND1 gene for the ND1 subunit of respiratory chain complex I. This frame-shift mutation induces in fact translation of a truncated ND1 protein then degraded, causing complex I disassembly, and for this reason not in competition with that allotopically expressed. We show here that allotopic ND1 protein is correctly imported into mitochondria and incorporated in complex I, promoting its proper assembly and rescue of its function. This result allowed us to further confirm what we have previously demonstrated about the role of complex I in tumorigenesis process. Injection of the allotopic clone in nude mice showed indeed that the rescue of complex I assembly and function increases tumor growth, inducing stabilization of HIF1α, the master regulator of tumoral progression, and consequently its downstream gene expression activation.
6
Capristo, Mariantonietta <1981>. "Respiratory chain complex I dysfunction in tumorigenesis". Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2012. http://amsdottorato.unibo.it/4798/.
Testo completoAbstract (sommario):
Diseases due to mutations in mitochondrial DNA probably represent the most common form of metabolic disorders, including cancer, as highlighted in the last years. Approximately 300 mtDNA alterations have been identified as the genetic cause of mitochondrial diseases and one-third of these alterations are located in the coding genes for OXPHOS proteins. Despite progress in identification of their molecular mechanisms, little has been done with regard to the therapy. Recently, a particular gene therapy approach, namely allotopic expression, has been proposed and optimized, although the results obtained are rather controversial. In fact, this approach consists in synthesis of a wild-type version of mutated OXPHOS protein in the cytosolic compartment and in its import into mitochondria, but the available evidence is based only on the partial phenotype rescue and not on the demonstration of effective incorporation of the functional protein into respiratory complexes. In the present study, we took advantage of a previously analyzed cell model bearing the m.3571insC mutation in MTND1 gene for the ND1 subunit of respiratory chain complex I. This frame-shift mutation induces in fact translation of a truncated ND1 protein then degraded, causing complex I disassembly, and for this reason not in competition with that allotopically expressed. We show here that allotopic ND1 protein is correctly imported into mitochondria and incorporated in complex I, promoting its proper assembly and rescue of its function. This result allowed us to further confirm what we have previously demonstrated about the role of complex I in tumorigenesis process. Injection of the allotopic clone in nude mice showed indeed that the rescue of complex I assembly and function increases tumor growth, inducing stabilization of HIF1α, the master regulator of tumoral progression, and consequently its downstream gene expression activation.
7
Jackson, Margaret J. "Clinical and biochemical studies of respiratory chain disease". Thesis, University of Newcastle Upon Tyne, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.294642.
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8
Heiske, Margit. "Modeling the respiratory chain and the oxidative phosphorylation". Thesis, Bordeaux 2, 2012. http://www.theses.fr/2012BOR21965/document.
Testo completoAbstract (sommario):
Mitochondria are cell organelles which play an essential role in the cell energy supply providing the universal high energetic molecule ATP which is used in numerous energy consuming processes. The core of the ATP production, oxidative phosphorylation (OXPHOS) consists of four enzyme complexes (respiratory chain) which establish, driven by redox reactions, a proton gradient over the inner mitochondrial membrane. The ATP-synthase uses this electrochemical gradient to phosphorylate ADP to ATP. Dysfunctioning of an OXPHOS complex can have severe consequences for the energy metabolism and cause rare but incurable dysfunctions in particular tissues with a high energy demand such as brain, heart, kidney and skeleton muscle. Moreover mitochondria are linked to widespread diseases like diabetes, cancer, Alzheimer and Parkinson. Further, reactive oxygen species which are a by-product of the respiratory chain, are supposed to play a crucial role in aging. The aim of this work is to provide a realistic model of OXPHOS which shall help understanding and predicting the interactions within the OXPHOS and how a local defect (enzyme deficiency or modification) is expressed globally in mitochondrial oxygen consumption and ATP synthesis. Therefore we chose a bottom-up approach. In a first step different types of rate equations were analyzed regarding their ability to describe the steady state kinetics of the isolated respiratory chain complexes in the absence of the proton gradient. Here Michaelis-Menten like rate equations were revealed to be appropriate for describing their behavior over a wide range of substrate and product concentrations. For the validation of the equations and the parameter estimation we have performed kinetic measurements on bovine heart submitochondrial particles. The next step consisted in the incorporation of the proton gradient into the rate equations, distributing its influence among the kinetic parameters such that reasonable rates were obtained in the range of physiological electrochemical potential differences. In the third step, these new individual kinetic rate expressions for the OXPHOS complexes were integrated in a global model of oxidative phosphorylation. The new model could fit interrelated data of oxygen consumption, the transmembrane potential and the redox state of electron carriers. Furthermore, flux inhibitor titration curves can be well reproduced, which validates its global responses to local effects. This model may be of great help to understand the increasingly recognized role of mitochondria in many cell processes and diseases as illustrated by some simulations proposed in this workLes mitochondries sont l’usine à énergie de la cellule. Elles synthétisent l’ATP à partir d’une succession de réactions d’oxydo-réduction catalysées par quatre complexes respiratoires qui forment la chaîne respiratoire. Avec la machinerie de synthèse d’ATP l’ensemble constitue les oxydations phosphorylantes (OXPHOS). Le but de ce travail est de bâtir un modèle des OXPHOS basé sur des équations de vitesse simples mais thermodynamiquement correctes, représentant l’activité des complexes de la chaîne respiratoire (équations de type Michaelis- Menten). Les paramètres cinétiques de ces équations sont identifiés en utilisant les cinétiques expérimentales de ces complexes respiratoires réalisées en absence de gradient de proton. La phase la plus délicate de ce travail a résidé dans l’introduction du gradient de protons dans ces équations. Nous avons trouvé que la meilleure manière était de distribuer l’effet du gradient de proton sous forme d’une loi exponentielle sur l’ensemble des paramètres, Vmax et Km pour les substrats et les produits. De cette manière, j’ai montré qu’il était possible de représenter les variations d’oxygène, de ΔΨ et de ΔpH trouvés dans la littérature. De plus, contrairement aux autres modèles, il fut possible de simuler les courbes de seuil observées expérimentalement lors de la titration du flux de respiration par l’inhibiteur d’un complexe respiratoire donné.Ce modèle pourra présenter un très grand intérêt pour comprendre le rôle de mieux en mieux reconnu des mitochondries dans de nombreux processus cellulaires, tels que la production d’espèces réactives de l’oxygène, le vieillissement, le diabète, le cancer, les pathologies mitochondriales etc. comme l’illustrent un certain nombre de prédictions présentées dans ce travail
9
Heiske, Margit. "Modeling the respiratory chain and the oxidative phosphorylation". Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2013. http://dx.doi.org/10.18452/16720.
Testo completoAbstract (sommario):
Die oxidative Phosphorylierung (OXPHOS) spielt eine zentrale Rolle im Energiestoffwechsel der Zelle. Sie besteht aus der Atmungskette, deren vier Enzymkomplexe einen Protonengradienten über die innere mitochondriale Membran aufbauen, und der ATP-Synthase, die diesen Gradienten zur Phosphorylierung von ADP zu ATP, der zelluläre Energieeinheit, nutzt. In der vorliegenden Arbeit wurde ein thermodynamisch konformes OXPHOS Modell erstellt, welches auf Differentialgleichungen basiert. Dazu wurden Gleichungen entwickelt, welche die Kinetiken jedes OXPHOS-Komplexes über weite Bereiche von Substrat- und Produktkonzentrationen sowie unterschiedlichster Werte des elektrochemischen Gradientens wiedergeben. Zunächst wurden für jeden Komplex der Atmungskette kinetische Messungen in Abwesenheit des Protonengradientens durchgeführt. Für deren Beschreibung erwiesen sich Gleichungen vom Typ Michaelis-Menten als adäquat; hierbei wurden verschiedene Gleichungstypen verglichen. Anschließend wurde der Einfluss des Protonengradientens auf die kinetischen Parameter so modelliert, dass physiologisch sinnvolle Raten in dessen Abhängigkeit erzielt werden konnten. Diese neuen Ratengleichungen wurden schließlich in ein OXPHOS Modell integriert, mit dem sich experimentelle Daten von Sauerstoffverbrauch, elektrischem Potential und pH-Werten sehr gut beschreiben ließen. Weiter konnten Inhibitor-Titrationskurven reproduziert werden, welche den Sauerstoffverbrauch in Abhängigkeit der relativen Hemmung eines OXPHOS-Komplexes darstellen. Dies zeigt, dass lokale Effekte auf globaler Ebene korrekt wiedergeben werden können. Das hier erarbeitete Modell ist eine solide Basis, um die Rolle der OXPHOS und generell von Mitochondrien eingehend zu untersuchen. Diese werden mit zahlreichen zellulären Vorgängen in Verbindung gebracht: unter anderem mit Diabetes, Krebs und Mitochodriopathien, sowie der Bildung von Sauerstoffradikalen, die im Zusammenhang mit Alterungsprozessen stehen.Oxidative phosphorylation (OXPHOS) plays a central role in the cellular energy metabolism. It comprises the respiratory chain, consisting of four enzyme complexes that establish a proton gradient over the inner mitochondrial membrane, and the ATP-synthase that uses this electrochemical gradient to phosphorylate ADP to ATP, the cellular energy unit. In this work a thermodynamically consistent OXPHOS model was built based on a set of differential equations. Therefore rate equations were developed that describe the kinetics of each OXPHOS complex over a wide concentration range of substrates and products as well for various values of the electrochemical gradient. In a first step, kinetic measurements on bovine heart submitochondrial particles have been performed in the absence of the proton gradient. An appropriate data description was achieved with Michaelis-Menten like equations; here several types of equations have been compared. The next step consisted in incorporating the proton gradient into the rate equations. This was realized by distributing its influence among the kinetic parameters such that reasonable catalytic rates were obtained under physiological conditions. Finally, these new individual kinetic rate expressions for the OXPHOS complexes were integrated in a global model of oxidative phosphorylation. This new model could fit interrelated data of oxygen consumption, the transmembrane potential and the redox state of electron carriers. Furthermore, it could well reproduce flux inhibitor titration curves, which validates its global responses to local perturbations. This model is a solid basis for analyzing the role of OXPHOS and mitochondria in detail. They have been linked to various cellular processes like diabetes, cancer, mitochondrial disorders, but also to the production of reactive oxygen species, which are supposed to be involved in aging.
10
Taylor, Claire Louise. "Biochemical investigations of defects of the mitochondrial respiratory chain". Thesis, University of Newcastle Upon Tyne, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.281706.
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11
Kwong, Jennifer Quo-Yee. "The mitochondrial respiratory chain is a modulator of apoptosis /". Access full-text from WCMC, 2007. http://proquest.umi.com/pqdweb?did=1441191921&sid=24&Fmt=2&clientId=8424&RQT=309&VName=PQD.
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12
Miley, Timothy Brian. "Studies of the respiratory chain of Methylococcus capsulatus (bath)". Morgantown, W. Va. : [West Virginia University Libraries], 2000. http://etd.wvu.edu/templates/showETD.cfm?recnum=1252.
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13
Brierley, Elizabeth Jane. "Defects of mitochondrial DNA and mitochondrial energy production in ageing". Thesis, University of Newcastle Upon Tyne, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.323477.
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14
Eubel, Holger. "The supramolecular structure of the respiratory chain of higher plants". [S.l.] : [s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=975827413.
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15
Menezes, Minal Juliet. "Gene discovery and functional studies of mitochondrial respiratory chain disorders". Thesis, The University of Sydney, 2015. http://hdl.handle.net/2123/12688.
Testo completoAbstract (sommario):
Mitochondrial respiratory chain disorders (MRCD) are one of the most challenging inborn errors of metabolism to diagnose and treat, because of their phenotypic and genetic heterogeneity, and a paucity of validated therapies. The approach opted to diagnose our MRCD patient cohort was using next generation sequencing (NGS) technology, and in particular whole exome sequencing (WES). Using our research pipeline we were able to identify novel YARS2 variants in patients with a tissue specific MRCD. Novel disease gene discoveries (CYC1 and MRPS7) causing MRCD were identified using the WES approach, and the functional studies implemented confirmed the pathogenicity of the newly identified variants. Advances in NGS technologies lead to the identification of a novel mtDNA mutation in the MT_ND3 gene and therefore rapid genetic diagnosis of a patient with Leigh disease allowing timely acceptance into a Phase 2B clinical trial. Using WES, two patients initially suspected to have a mitochondrial myopathy were diagnosed with congenital myasthenia resulting in the successful treatment for one patient. Through the research presented in this thesis, we were able to gain more knowledge about the disease mechanisms of MRCDs, and we hope that these findings will be instrumental in research towards future therapy of MRCD.
16
Morris, Andrew Alan Myles. "Disorders of mitochondrial oxidation : clinical, biochemical & molecular studies". Thesis, University of Newcastle Upon Tyne, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.294810.
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17
Taylor, Robert William. "Mitochondrial respiratory chain dysfunction in human pathology : investigation, pathogenicity and treatment". Thesis, University of Newcastle Upon Tyne, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.577189.
Testo completoAbstract (sommario):
The work presented in this thesis comprises 100 peer-reviewed publications, mostly original research papers but some key review articles are included, which highlight my ongoing research in understanding the role of mitochondrial respiratory chain dysfunction and mitochondrial DNA (mtDNA) mutation in human pathologies over a twenty year period, and in no small part have contributed to the development of my laboratory as a national referral centre in the UK for diagnostic biochemical and molecular genetic testing, funded by the NHS Specialist Commissioners. A significant proportion (at least 50%) of all the papers which are included in this application are either first author or senior author publications. Mitochondrial respiratory chain disease exhibits marked clinical and genetic heterogeneity, often requiring the study of clinically-relevant, post-mitotic tissues to make a diagnosis which in many cases is made difficult on account of the peculiarities of mitochondrial genetics. Understanding this phenotypic diversity and elucidating the basic molecular mechanisms leading to cellular dysfunction continues to be challenging, with progress in the development of curative therapies hampered by our inability to manipulate the mitochondrial genome, and difficulties in obtaining alternative models of disease other than patients with pathogenic mtDNA mutations. . In an attempt to submit a cohesive application, the papers have been organised into relevant sections, beginning with general reviews of the clinical, biochemical and molecular features of mitochondrial genetic disease (Section A) followed by sections on the investigation and laboratory diagnosis of mitochondrial disease including epidemiology (Sections 8-0). The largest collection of papers document the molecular investigation of mitochondrial disorders, many describing novel mutations and disease mechanisms associated with both mtDNA- encoded and nuclear mitochondrial genes (Sections E-K). The next section describe studies investigating the role of somatic mtDNA abnormalities in neurodegenerative disease, cancer and ageing pathologies - including marking stem cell populations (Section L) - before a series of original research articles and invited reviews that focus on pharmacological and gene therapy strategies for the treatment of patients with mtDNA disease (Section M).
18
Lowerson, Shelagh Anne. "Defects of the mitochondrial respiratory chain : biochemical studies and mathematical modelling". Thesis, University of Newcastle Upon Tyne, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.297572.
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19
Owen, Mark R. "The mechanisms by which mild respiratory chain inhibitors regulate hepatic gluconeogenesis". Thesis, University of Bristol, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.358337.
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20
Nelson, Christy L. "Branched-chain amino acid nutrition and respiratory stability in premature infants". free to MU campus, others may purchase free online, 2002. http://wwwlib.umi.com/cr/mo/preview?3074432.
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21
Williams, Andrew. "Functional and molecular analysis of defects of the mitochondrial respiratory chain". Thesis, The University of Sydney, 1998. https://hdl.handle.net/2123/27688.
Testo completoAbstract (sommario):
The diagnosis of human mitochondrial respiratory chain defects is based on a
staged procedure including: screening tests, enzymology of tissues and cultured cells
and use of molecular techniques or cybrid technology to assign the site of the genetic
defect This thesis examines aspects of each of these stages and presents improved
methods for screening, enzymology and cybrid technology.
Analyses of enzymes and proteins in the detection of respiratory chain defects
are traditionally performed by manual assays. In chapters 2 and 3, I present
automated methods for total protein, citrate synthase, cytochrome c oxidase,
succinatezubiquinone oxidoreductase and lactate dehydrogenase. The automated
assays use less sample, are less labour intensive and show improved precision.
The second part of this thesis examines the levels of reactive oxygen
intermediates in cultured skin fibroblasts of patients with respiratory chain defects. A
flow cytometric technique was developed to examine the fluorescence of these cells
after application of a molecule which fluoresces when oxidised. Ten of the eleven cell
strains studied had significantly reduced levels of fluorescence when compared to
intra-batch controls. This technique may be usefiJl diagnostically in patients suspected
of having a respiratory chain defect.
Detection of the site of the genetic defect in respiratory chain disorders is
complicated by clinical heterogeneity, the numbers of proteins involved in the
normally functioning respiratory chain and the involvement of both the nuclear and
mitochondrial genomes. In chapter 5, I examine the effect of rhodamine-6G on the
structure of cultured skin fibroblasts and their organelles, the function of the electron
transport chain and the mitochondrial DNA. In chapter 6 I examine the utility of
generating cybrids to tentatively assign the site of the genetic defect to either the
mitochondrial or nuclear genome using rhodamine-6G to remove the mitochondria
from the cells of a patient with a known mitochondrial DNA defect. The assignment
of a defect to either the nuclear or mitochondrial genome has immediate implications
for genetic counselling.
22
Marshall, Douglas Charles Alexander. "Structural and functional studies of respiratory chain proteins using infrared spectroscopy". Thesis, University College London (University of London), 2007. http://discovery.ucl.ac.uk/1446092/.
Testo completoAbstract (sommario):
Attenuated total reflection Fourier transform infrared (FTIR) spectroscopy in the 4000-800 cm"1 range was applied to NADH:ubiquinone oxidoreductase (complex I) and cytochrome bc complex of the respiratory electron transfer chain. High signal:noise redox difference spectra were acquired using novel electrochemical and perfusion techniques to reversibly adjust protein redox state which, where appropriate, was monitored by simultaneous UV/visible spectroscopy. Interpretation of spectra was assisted by hydrogen-deuterium exchange, 15N labelling and redox titration. Model compound data, including protonation state/redox difference spectra of histidine, flavin mononucleotide and ferredoxins, were recorded and are presented as a comprehensive 'toolkit' for assisting in acquisition and interpretation of protein IR data in general. Electrochemically-induced difference spectra of bovine and Rhodobacter capsulatus cytochrome bc complex are comparable to published perfusion data but are at significantly higher signahnoise demonstrating the functionality of the electrochemical technique. Comparison of wild-type and E295V Rba. capsulatus difference spectra resulting from haem reduction/oxidation definitively rules out Glu-295 as the principal carboxylic acid residue responsive to haem b redox change. Full redox difference spectra of Yarrowia lipolytica and bovine complex I are similar to published E. coli transmission FTIR spectra where signals in the amide I and II region were interpreted as indictors of large scale conformational change. Comparison of complex I and ferredoxin difference spectra rules out this interpretation. Signals in the presented spectra are tentatively assigned to reduced flavin and to protonation state change of one or more histidine residues. In iron-sulphur centre N2 redox difference spectra, measured in intact complex I for the first time, signals from substrate ubiquinone/ubiquinol formation are clear a putative histidine protonation change signal is also present. Perfusion induced-difference spectra, using NADH as reductant, indicate that NADH does not reduce the full complement of iron-sulphur centres and no signals indicative of large scale conformational change were present.
23
Parmar, Gaganvir. "Protein Factors Regulating Mitochondrial Respiratory Supercomplexes". Thesis, Université d'Ottawa / University of Ottawa, 2021. http://hdl.handle.net/10393/42350.
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24
Neehaul, Yashvin. "Study of protein in the respiratory chain by IR spectroscopy and electrochemistry". Phd thesis, Université de Strasbourg, 2012. http://tel.archives-ouvertes.fr/tel-00827526.
Testo completoAbstract (sommario):
The field of molecular bioenergetics deals with the energy transduction in biological cells. In this project, respiration and more specifically proton and sodium pumping enzymes and their coupling to electron transfer have been in focus. First we have been interested in the Na+-pumping NADH:quinone reductase from Vibrio cholerae which is the entry site of electrons in the respiratory chain of several pathogens. The role of specific flavin cofactors and amino acids involved in Na+ transfer has been shown in a combined IR spectroscopic and electrochemical approach. The interaction between proteins, namely the cytochrome c552 and the CuA fragment from the terminal ba3 oxidase from the organism Thermus thermophilus was then investigated. Structural reorganization during electron transfer was revealed by IR spectroscopy. Finally, in the third part of the project the interaction within the bc1-aa3 supercomplex from the respiratory chain from Corynebacterium glutamicum was analyzed.
25
Pulkes, Teeratorn. "Studies on the genetics and molecular pathogenesis of mitochondrial respiratory chain disorders". Thesis, University College London (University of London), 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.411323.
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Pagnamenta, Alistair. "Identification of nuclear genes responsible for mitochondrial respiratory chain disorders in childhood". Thesis, University College London (University of London), 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.437288.
Testo completo
27
Tropeano, Concetta Valentina <1987>. "Respiratory Chain Complexes and Supercomplexes Organization in Cells with Defective Complex III". Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2016. http://amsdottorato.unibo.it/7634/1/tropeano_concettavalentina_tesi.pdf.
Testo completoAbstract (sommario):
Cytochrome b is the only subunit of complex III (CIII) encoded by the mitochondrial DNA. Constituting the central core of the enzyme, the protein is essential for both assembly and catalytic activity of the complex. CIII can associate with complex I (CI) and complex IV to form supercomplexes (SCs). MTCYB mutations can affect CIII only or both CIII and CI, as a consequence of the importance of CIII on the stability of CI. Here, we have investigated the effects of two pathogenic mutations affecting MTCYB: the p.278Y>C missense mutation, causing the substitution of conserved Tyr278 close to the QO site, and the ΔI300-P305 microdeletion, producing the loss of six aminoacids in the sixth transmembrane helix, but leaving the remaining of the MTCYB in frame. We have demonstrated that both MTCYB mutations severely impaired the activity of CIII: the missense mutation produced an oxidative damage of CIII due to increased superoxide production, whereas in cells bearing the ΔI300-P305 microdeletion, CIII was not detected, with consequent derangement also of CI. The detailed analysis of SCs organization revealed in both cases a strong perturbation of the CIII2+IV SC, together with an attempt to preserve the respirasome. These results favor the hypothesis that SCs not only preserve the structure and stability of respiratory complexes, but are essential for attenuating the mitochondrial dysfunction due to pathogenic mutations affecting the respiratory enzymes. Furthermore, the cells bearing ΔI300-P305 deletion showed a marked increase in complex II (CII) redox activity, associated with significant hydrogen peroxide production. It has been suggested that the enhanced CII activity is a compensatory mechanism due to the lacking of CI. Our results instead suggest that it might be a more general phenomenon for cell adaptation to respiratory chain dysfunction, being detected also in CIII-deficient cells where the hydrogen peroxide production is increased.
28
Tropeano, Concetta Valentina <1987>. "Respiratory Chain Complexes and Supercomplexes Organization in Cells with Defective Complex III". Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2016. http://amsdottorato.unibo.it/7634/.
Testo completoAbstract (sommario):
Cytochrome b is the only subunit of complex III (CIII) encoded by the mitochondrial DNA. Constituting the central core of the enzyme, the protein is essential for both assembly and catalytic activity of the complex. CIII can associate with complex I (CI) and complex IV to form supercomplexes (SCs). MTCYB mutations can affect CIII only or both CIII and CI, as a consequence of the importance of CIII on the stability of CI. Here, we have investigated the effects of two pathogenic mutations affecting MTCYB: the p.278Y>C missense mutation, causing the substitution of conserved Tyr278 close to the QO site, and the ΔI300-P305 microdeletion, producing the loss of six aminoacids in the sixth transmembrane helix, but leaving the remaining of the MTCYB in frame. We have demonstrated that both MTCYB mutations severely impaired the activity of CIII: the missense mutation produced an oxidative damage of CIII due to increased superoxide production, whereas in cells bearing the ΔI300-P305 microdeletion, CIII was not detected, with consequent derangement also of CI. The detailed analysis of SCs organization revealed in both cases a strong perturbation of the CIII2+IV SC, together with an attempt to preserve the respirasome. These results favor the hypothesis that SCs not only preserve the structure and stability of respiratory complexes, but are essential for attenuating the mitochondrial dysfunction due to pathogenic mutations affecting the respiratory enzymes. Furthermore, the cells bearing ΔI300-P305 deletion showed a marked increase in complex II (CII) redox activity, associated with significant hydrogen peroxide production. It has been suggested that the enhanced CII activity is a compensatory mechanism due to the lacking of CI. Our results instead suggest that it might be a more general phenomenon for cell adaptation to respiratory chain dysfunction, being detected also in CIII-deficient cells where the hydrogen peroxide production is increased.
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Tabrizi, Sarah Joanna. "Mitochondrial dysfunction in the pathogenesis of neurodegeneration". Thesis, University College London (University of London), 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.325866.
Testo completo
30
Reed, J. S. "The function of ubiquinone in mitochondrial electron transport". Thesis, University of Southampton, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.376174.
Testo completo
31
Bouverot, Romain. "Etudes structurales de la protéine ACAD9 et des facteurs d'assemblage du complexe 1 de la chaîne respiratoire mitochondriale pour établir leur implication dans les processus neurodégénératifs". Thesis, Université Grenoble Alpes (ComUE), 2019. http://www.theses.fr/2019GREAV005.
Testo completoAbstract (sommario):
Les mitochondries sont en charge de la bioénergétique cellulaire, tout particulièrement dans le cerveau humain, au sein duquel les neurones sont extrêmement demandeurs en énergie et hautement dépendant de la phosphorylation oxydative. En effet, celles-ci génèrent un potentiel énergétique grâce à une chaîne de transport d’électrons, ou chaîne respiratoire, composée de quatre complexes protéiques ancrés dans la membrane interne mitochondriale. La chaine respiratoire permet la production d’énergie via la phosphorylation oxydative d’ADP en ATP par l’ATP synthéase dans la matrice mitochondriale. Le premier complexe (CI) de la chaîne est composé de 45 sous-unités protéiques (dont 44 différentes). En tant que premier enzyme de la phosphorylation oxydative, il joue un rôle d’initiateur et est essentiel pour la production d'énergie cellulaire. Un défaut d’assemblage du CI se traduit par d’importantes conséquences sur la bioénergétique cellulaire et augmente la production d’espèces réactives de l’oxygène (ROS), pouvant être à l'origine de divers troubles mitochondriaux, parmi lesquels certains processus neurodégénératifs. La bonne intégration des sous-unités et cofacteurs composant le CI est par conséquent primordiales et requièrent la participation de facteurs d’assemblage jouant le rôle de chaperonnes afin de stabiliser les sous-unités et faciliter leur intégration au sein de l'enzyme complète. De plus, certaines fonctions additionnelles à leur rôle d’assemblage peuvent intervenir dans d’autres processus cellulaire régulant l’activité métabolique.Le fonctionnement des facteurs d'assemblage du CI au niveau moléculaire demeure encore obscur. Néanmoins, il est admis que la plupart des facteurs d'assemblages identifiés sont actifs dès le début de l'assemblage, particulièrement pour l'incorporation des sous-unités membranaires. Récemment un groupe de facteurs d’assemblage composés des protéines NDUFAF1 (NADH dehydrogenase [ubiquinone] 1 alpha subcomplex assembly factor 1), ACAD9 (Acyl-CoA dehydrogenase 9), ECSIT (Evolutionarily conserved signaling intermediate in Toll pathway), et potentiellement TMEM126B (Transmembrane protein 126B) and TIMMDC1 (Translocase of inner mitochondrial membrane domain-containing 1) est désigné sous l'appellation complexe d’assemblage du complexe mitochondrial I (MCIA). Cependant, la composition et la stœchiométrie de ce dernier restent inconnus, excluant ainsi toute compréhension satisfaisante de sa structure et de son importance dans les mécanismes à l'oeuvre dans l’assemblage du CI.Cette thèse a pour but les caractérisations des facteurs d’assemblage ACAD9, ECSIT and NDUFAF1 grâce à un ensemble d’approches biochimiques et biophysiques dans le but de déterminer les mécanismes moléculaires et la cartographie des interactions impliqués dans l’assemblage du complexe MCIAMitochondria are responsible for bioenergetics, particularly critical in the human brain, where neurons are extremely energy demanding and highly dependent on the oxidative phosphorylation (OXPHOS) system. They generate energetic potential through the electron transport chain (ETC), also named the respiratory chain, which is composed of four protein complexes embedded into the mitochondrial inner membrane (MIM) to enable the phosphorylation of ADP into ATP by the ATP synthase in the mitochondrial matrix. Together these complexes form the OXPHOS system. Complex I (CI), the first enzyme of the respiratory chain, is composed of 45 protein subunits (of which 44 are different) and initiates the OXPHOS system, being essential in cellular energy production. Defects in CI assembly severally impair ATP production, increase the production of reactive oxygen species (ROS) and are implicated in several mitochondrial disorders, including neurodegenerative diseases. The integration of the 45 subunits and the insertion of cofactors into the nascent complex requires the help of assembly factors. Assembly factors may act as chaperones that stabilize the intermediate complexes or subunits and help to attach them to other intermediate assemblies to build the complete enzyme. However, they may also have additional functions besides their requirement for CI assembly, in line with the emerging evidence that mitochondria are involved with various (sub)cellular processes that regulate cell metabolic activity.How CI assembly factors function at the molecular level is currently unclear, with very little structural information available. Nevertheless, it is thought that most identified assembly factors are involved in early assembly, more specifically in the incorporation of hydrophobic membrane subunits. Recently, the CI assembly factors NDUFAF1 (NADH dehydrogenase [ubiquinone] 1 alpha subcomplex assembly factor 1), ACAD9 (Acyl-CoA dehydrogenase 9), ECSIT (Evolutionarily conserved signaling intermediate in Toll pathway), and potentially TMEM126B (Transmembrane protein 126B) and TIMMDC1 (Translocase of inner mitochondrial membrane domain-containing 1) were proposed to form the so-called mitochondrial complex I assembly (MCIA) complex. However, the composition and stoichiometry of the MCIA complex are unknown, which precludes a proper understanding of the structural and mechanistic bases for building-up assembly intermediates and how the MCIA complex achieves specificity.This thesis pursues the characterisation of the MCIA core components ACAD9, ECSIT and NDUFAF1, mapping their interactions and characterising their structures using a combination of biophysical and biochemical approaches in order to elucidate the molecular mechanisms underlying the MCIA complex formation
32
Sabuncu, Sinan. "Investigation of enzymes from the respiratory chain by using electrochemical and spectroscopic techniques". Thesis, Strasbourg, 2017. http://www.theses.fr/2017STRAF017/document.
Testo completoAbstract (sommario):
Le présent travail porte sur l’étude de deux protéines de la famille des oxydases à hème-fer par des techniques de spectroscopie et d’électrochimie. Le premier chapitre décrit l’étude du cytochrome bo3 oxydase issue d’E. coli. Nous nous sommes intéressés à l’étude des interactions enzyme-quinone par l’utilisation de quinones avec des longueurs chaines isoprenyl différentes. Notre but est de mieux comprendre le rôle de la longueur de la chaine des quinones sur l’activité catalytique de l’enzyme et sur les propriétés redox des cofacteurs à hème. Dans l’étape suivante, on a étudié les résidus impliqués dans le site de liaison des quinones (haute affinité, QH). Plusieurs mutations de ces résidus sont étudiées pour mieux comprendre l’importance de chacun des résidus dans cette liaison. Dans la dernière partie de ce premier chapitre, la spectroscopie SEIRAS «spectroscopie d’absorption infrarouge exaltée de surface» est introduite comme une technique alternative pour l’étude des protéines membranaires. Dans le second chapitre, la protéine membranaire cNOR issue de P. denitrificans est étudiée. Nous nous sommes focalisés sur l’effet de différents environnements (pH, présence de protéo-liposomes) sur la stabilité de la cNOR. Pour ce faire, trois valeurs de pH (6.5, 7.5 et 8.5) sont choisies et quelques échantillons de cNOR sont reconstitués dans des protéo-liposomes. Enfin, le donneur de proton terminal (au centre binucléaire) dans la protéine cNOR était étudié. De plus, nous avons étudié les ligands des ions Ca2+ puisqu’il est proposé que le donneur de proton est situé proche de cette régionThis thesis is focused on the study of two members of the heme-copper oxidase family by using spectroscopic and electrochemical techniques. In the first chapter cytochrome bo3 oxidase from E. coli was studied. We focused on the quinone-enzyme interactions by using quinones with different isoprenyl chains. Our aim was to better understand the role of isoprenyl chain on the catalytic activity of the enzyme and the redox properties of the heme cofactors. In the next step we studied the residues that are suggested to be in the high-affinity (QH) quinone binding site. Several site-directed mutants of these residues were investigated in order to better understand the position of QH binding site and the importance of each residue. In the last part of this chapter surface-enhanced infrared absorption spectroscopy (SEIRAS) was introduced as an alternative technique to study the membrane proteins. In the second chapter cytochrome c dependent nitric oxide reducates (cNOR) from P. denitrificans was studied. We focused on the effect of different environment (pH, proteoliposomes) on the stability of cNOR. For that purpose three pH values (6.5, 7.5 and 8.5) was selected and some of the cNOR samples were reconstituted in liposomes. Finally, the terminal proton donor (to the binuclear center) in cNOR was investigated. We studied the ligands of the Ca2+ site in cNOR since it was suggested that the proton donor may be close to this area
33
Alderson, Jesse. "Studies on the aerobic respiratory chain of the human gastric pathogen Helicobacter pylori". Thesis, University of Sheffield, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.324459.
Testo completo
34
Pham, Nhu-An. "Generation of oxidative stress by the respiratory chain following treatment with DNA damaging agents". Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape7/PQDD_0003/MQ46064.pdf.
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35
Schweizer, Ina [Verfasser], e Thorsten [Akademischer Betreuer] Friedrich. "Studies on the Escherichia coli aerobic respiratory chain with an emphasis on complex I". Freiburg : Universität, 2016. http://d-nb.info/1122647670/34.
Testo completo
36
Sasarman, Florin. "Adult mitochrondrial myopathy associated with generalized respiratory chain deficiency : molecular mechanism and genetic basis". Thesis, McGill University, 2003. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=84321.
Testo completoAbstract (sommario):
Cellular ATP is synthesized by the mitochondrial oxidative phosphorylation (OXPHOS) system, composed of five enzyme complexes (Complexes I--V), which consist collectively of over 80 subunits. The majority of these subunits are encoded by nuclear genes, and 13 of them, by mitochondrial DNA (mtDNA). OXPHOS deficiencies resulting in mitochondrial disorders can be caused by either nuclear or mitochondrial mutations; however, most pathogenic mutations reported in adults occur in mtDNA. Such mutations often impair mitochondrial translation and are associated with a characteristic muscle pathology consisting of a mosaic pattern of normal fibers interspersed with fibers displaying mitochondrial proliferation and decreased OXPHOS activity. In this thesis, the molecular basis for a severe mitochondrial myopathy in two adult patients was investigated. All patient muscle fibers showed mitochondrial proliferation and barely detectable Complex IV activity (a measure of OXPHOS activity), a pattern never before reported. Biochemical studies demonstrated decreased activities of Complexes I and IV (5% of control) and Complex II+III (41% of control) in patient muscle. Immunoblot analysis of nuclear and mitochondrial subunits of Complexes 1, III and IV showed a greater than 90% decrease in the steady-state level of these subunits in mature muscle, but no change in nuclear-encoded subunits of Complexes II and V. A generalized mitochondrial translation defect was identified by pulse-label experiments in myotubes, but not in myoblasts cultured from both patients. This defect moved with the nucleus in patient cybrid cells. Myoblasts from one patient transplanted into the muscle bed of SCID mice differentiated into mature muscle fibers that displayed a defect similar to that seen in the patient muscle. Mapping of the defective gene in this patient was attempted using a functional complementation approach. Microcell-mediated transfer of mouse chromosomes in patient
37
Hwang, Ming. "The role of complex II of the mitochondrial respiratory chain in cell death induction". Thesis, Imperial College London, 2014. http://hdl.handle.net/10044/1/25068.
Testo completoAbstract (sommario):
Complex II of the respiratory chain (RC) recently emerged as a prominent regulator of cell death. In both cancer as well as neurodegenerative diseases, mutations in its subunits have been found along with other genetic alterations indirectly affecting this complex. Moreover, anticancer compounds were developed that target complex II and cause cell death in a tumour-specific way. I found evidence that this protein assembly is specifically activated for cell death via the dissociation of its SDHA and SDHB subunits from the membrane-anchoring proteins through mitochondrial Ca2+ influx. The relationship between Ca2+ and cell death activation has been under intense investigation, but not much has been identified on the associated mechanisms. Ca2+ influx into mitochondria plays a significant role in cell death induction, but it was unknown how the observed massive Ca2 accumulation activates the organelle for cell destruction. The disintegration of complex II subunits is prevented in vitro when cardiolipin is substituted with a lipid devoid of Ca2+ binding. Cardiolipin is known to associate with complex II, but coalesces into tight homotypic clusters upon Ca2+ binding. When complex II is deprived of this lipid, it disintegrates for ROS formation and cell death induction. My results reveal Ca2+ binding to cardiolipin and subsequent complex II disintegration as a crucial step for oxidative stress and cell death induction. Ultimately, it emphasizes the important role that Ca2+ plays in ROS-induced cell death via the respiratory chain, which can be used for many translational investigations. For instance, future studies on Ca2+ and its binding to cardiolipin for cell death induction will further elucidate complex II as a target for cancer treatment as well as neurodegenerative diseases and reveal its role as a nexus for many diverse stimuli in cell death signalling.
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Homberg, Bettina [Verfasser]. "Regulation of Respiratory Chain Supercomplex Formation and the Involvement of Rcf-proteins / Bettina Homberg". Göttingen : Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2021. http://d-nb.info/1235222667/34.
Testo completo
39
Nunoura, Takuro. "Study of Aerobic Respiratory Chain of Novel Facultative Aerobic and Hyperthermophilic Archaeon Pyrobaculum oguniense". Kyoto University, 2002. http://hdl.handle.net/2433/149916.
Testo completoAbstract (sommario):
Kyoto University (京都大学)0048
新制・課程博士
博士(農学)
甲第9630号
農博第1258号
新制||農||844(附属図書館)
学位論文||H14||N3662(農学部図書室)
UT51-2002-G388
京都大学大学院農学研究科応用生物科学専攻
(主査)教授 内田 有恆, 教授 加藤 暢夫, 助教授 左子 芳彦
学位規則第4条第1項該当
40
Desmard, Mathieu. "Effets antibactériens sur Pseudomonas aeruginosa des donneurs de monoxyde de carbone". Thesis, Paris Est, 2010. http://www.theses.fr/2010PEST0039.
Testo completoAbstract (sommario):
La recherche de nouvelles molécules pour combattre Pseudomonas.aeruginosa est d'une grande importance. L'utilisation des antibiotiques a spectre large a grandement accru la résistance de P.aeruginosa aux antibiotiques. Malgré cette situation, aucune nouvelle drogue active sur P.aeruginosa n'a été introduite en pratique clinique durant les 2 dernières décennies. Le monoxyde de carbone (CO) pourrait agir comme un inhibiteur efficace de la chaîne respiratoire de P.aeruginosa mais l'utilisation pratique de ce gaz comme molécule antibactérienne est gênée par sa toxicité et les difficultés de manipulation. Une avancée fondamentale récente dans le domaine de la recherche sur le CO a été la découverte des « carbon monoxide releasing molecules » (CO-RMs), qui servent de transporteur et délivre des quantités contrôlées de CO aux systèmes biologiques.Nous montrons ici que les CO-RMs possèdent des propriétés antibactériennes contre P.aeruginosa. Cet effet antibactérien des CO-RMs à lieu à des concentrations non toxiques pour les cellules eucaryotes et passe par une interaction du CO libérer par le transporteur avec la chaîne respiratoire bactérienne. Nous présentons des résultats in vivo montrant que les CO-RMs diminuent l'inoculum bactérien et augmentent la survie des souris après une bactériémie à P.aeruginosa. La comparaison de 4 CO-RMs ayant différente structures chimiques suggère que la précence d'un métal de transition joue un rôle important dans l'activité antibactérienne des CO-RMs. Une autre découverte importante présentée dans ce travail est l'inhibition de l'activité antibactérienne de certain CO-RMs par les molécules contenant des résidus thiols. Cette découverte limite la possibilité d'utiliser les CO-RMs concernés comme des agents anti-infectieux.En considérant les résultats présentés dans ce travail, l'inhibition de la chaîne respiratoire pourrait être considérée comme un nouveau mécanisme prometteur pour la recherche de nouveaux agents pharmaceutique pour combattre les infections à P.aeruginosaThe search of new molecules to fight Pseudomonas.aeruginosa is of paramount importance. The use of broad spectrum antibiotics has greatly increased the antibiotic resistance of P.aeruginosa. In spite of this situation, no new drug against P.aeruginosa has been successfully introduced into the clinic in the past 2 decades. Carbon monoxide (CO) could act as an effective inhibitor of the respiratory chain in P. aeruginosa but the practical use of this gas as an antibacterial molecule is hampered by its toxicity and difficulty to manipulate. A recent fundamental development in the field of CO research has been the discovery of carbon monoxide-releasing molecules (CO-RMs), which serve as carriers for the delivery of controlled amounts of CO in biological systems.Here, we show that CO-RMs possesse bactericidal properties against P.aeruginosa. This antimicrobial effect of CO-RMs occurs at non toxic concentrations for eukaryotic cells and is mediated by an interaction of CO liberated by the carrier with bacterial respiratory chain. We present in vivo results showing that CO-RMs decrease bacterial inoculum and increase survival in mice following P.aeruginosa bacteraemia. A comparison of 4 CO-RMs with different chemical structures suggests that the presence of a transition metal center plays an important role in the antibacterial activity of CO-RMs. Another important finding presented in this work is the inhibition of the antibacterial activity of some CO-RMs by thiol containing molecules. This finding could deserve the possibility to use concerning CO-RMs as anti-infective agent.Considering results presented in this work, inhibition of respiratory chain could be considered as a promising new mechanism for the research in new pharmaceutical agent to fight P.aeruginosa infections
41
Bowman, Amy. "Investigating the role of mitochondrial respiratory chain activity and mitochondrial DNA damage in skin ageing". Thesis, University of Newcastle upon Tyne, 2014. http://hdl.handle.net/10443/2502.
Testo completoAbstract (sommario):
Ageing describes the progressive functional decline of an organism over time, leading to an increase in susceptibility to age-related diseases and eventually to death, and it is a phenomenon observed across a wide range of organisms. Despite a vast repertoire of ageing studies performed over the past century, the exact causes of ageing remain unknown. For over 50 years it has been speculated that mitochondria play a key role in the ageing process, due mainly to correlative data showing an increase in mitochondrial dysfunction, mitochondrial DNA (mtDNA) damage, and reactive oxygen species (ROS) with age. Therefore, a major aim of the current project was to assess mitochondrial dysfunction, in the form of complex II activity, in the skin cells of differently aged humans. Mitochondrial complex II of the electron transport chain (ETC) was chosen to be examined, as it has recently been implicated in the generation of ROS, as well as in the ageing process of lower organisms, and is the least studied complex of the ETC. Complex II activity was found in the present study to decline in an age-dependant manner in human skin fibroblast cells, which may have been partially related to an observed decrease in the expression of specific nuclear-encoded complex II subunits with age. Further investigations into the cause of the decrease in complex II activity with age revealed that the decline was specific to senescent cells, and was not present in non-senescent cells, which was determined following sorting into subpopulations via fluorescence-activated cell sorting (FACS). The decrease in activity with age was not reflected in another mitochondrial complex examined, complex IV, for which there was no alteration in activity with age for either unsorted, senescent, or non-senescent cells. This finding could suggest the specific targeting of complex II in senescent cells only for future age-related therapeutics. Interestingly, an age-dependant decrease in complex II activity was not observed for human skin keratinocytes, despite being observed in human skin fibroblasts. In the present study, it was also observed that different cell types undergo differing rates of maximal complex II activity, which could have important consequences in terms of the rate of ageing of specific cell types. In addition to the observed decrease in mitochondrial complex II activity with age, it was demonstrated in the present study that mtDNA damage is increased with age in the skin of both humans and a taxonomic group for which age- 3 related changes have not been previously studied, the whales. It was confirmed that the T414G mutation, which is a general biomarker for mtDNA mutations, was higher in human skin fibroblasts from older individuals when compared to younger individuals. Furthermore, an increase in mtDNA damage with age was also found in multiple whale species, for which mtDNA damage was measured in the form of strand breaks within a large region of the mitochondrial genome, using novel primers designed and optimised through the present study. Whales from three distinct species were chosen to be examined based on their differing levels of UV exposure, as a model for different ages. It was found that the level of mtDNA damage increased with both natural age and increased UV exposure. The three whale species studied appeared to have developed alternative mechanisms of coping with UV-induced damage. MtDNA damage was found to be lowest in those whales with the highest expression of heat shock protein 70 (Hsp70), suggesting that this UV-defensive mechanism may be useful in future studies for the prevention of age-related phenotypes. Overall, the present study provides important new insights into the potential role of mitochondria in ageing.
42
El, Khoury Youssef. "Mid and far infrared spectroelectrochemical studies on the metal−ligand interactions in respiratory chain enzymes". Strasbourg, 2010. https://publication-theses.unistra.fr/public/theses_doctorat/2010/EL_KHOURY_Youssef_2010.pdf.
Testo completoAbstract (sommario):
La thèse contient trois parties principales, la coordination du Cu, l'inhibition par le Zn, et le lointain infrarouge. Les vibrations de complexes de cuivre ont été étudiées en moyen et lointain infrarouge. Les spectres des complexes Cu- poly-L- histidine ont été enregistrés en fonction du pH en moyen et lointain infrarouge. De même, les vibrations métal- ligand ont été observées dans le lointain infrarouge. La coordination du Cu par l'amyloïde- beta16 est une étape déterminante dans l'apparition de la maladie d'Alzheimer. Les complexes cuivre- amyloïde- beta16 ont été étudiés dans le moyen infrarouge à différentes valeurs de pH. L'utilisation d'échantillons marqués isotopiquement pour cette étude a permis de déterminer les modes de coordination du cuivre. Dans la deuxième partie de la thèse, nous avons utilisé le moyen infrarouge pour étudier des protéines de la chaîne respiratoire. Les cations Zn2+ sont connus pour leur pouvoir inhibiteur vis-à-vis du pompage de protons par les enzymes respiratoires. Pour mieux comprendre l'effet de l'inhibition par le Zn sur les complexes III et IV, la spectroscopie différentielle IRTF induite par l'électrochimie a été utilisée. L'étude montre que le chélation du Zn par le complexe III a lieu via le résidu E295. L'inhibition du complexe IV se fait probablement dans deux sites de chélation. On a montré que le résidu E78 de la sous-unité II intervient dans la chélation du Zn. Enfin, le lointain infrarouge a été développé, y compris une approche électrochimique. Le domaine du lointain infrarouge offre un outil pour observer les vibrations métal- ligand, la signature amide VI et la signature des liaisons hydrogèneThe thesis is constituted of three main parts, the Cu coordination, the Zn inhibition and the far infrared. The vibrations of the Cu-poly-L-Histidine complexes have been studied in the mid and far infrared ranges as a function of pH. The Cu coordination by the amyloid-beta 16 peptide is a critical step in the development of Alzheimer' s. La coordination du Cu par l'amyloïde- beta16 est une étape déterminante dans l' apparition de la maladie d'Alzheimer. The spectra of the Cu-amyloid-beta16 complexes have been recorded in the mid infrared domain and the use of isotopically labelled samples allowed revealing the coordination sphere of Cu within the amyloid-beta16. Ln the second part, the mid infrared domain was used to study the respiratory chain enzymes. Zn cations are known to inhibit the proton pumping by the respiratory complexes. To better understand the effect of the inhibition by Zn on the complexes III and IV, the FTIR difference spectroscopy was used. The data shows that the chelation of Zn by the complex III takes places via E295 residue. The inhibition of the complex VI takes place via two binding sites, one of theme corresponds to the E78 residuee of the subunit JI. Finally, the far infrared spectroscopy of proteins has been developed. This spectral domain offers a unique tool to observe the metal-ligand vibration, the amide VI band, as weil as the hydrogen bonding signature of proteins
43
Ozeir, Mohammad. "Etude de la voie du coenzyme Q¦ chez la levure Saccharomyces cerevisiae". Phd thesis, Université de Grenoble, 2012. http://tel.archives-ouvertes.fr/tel-00859892.
Testo completoAbstract (sommario):
Le coenzyme Q (ubiquinone ou Q) est une molécule organique lipophile composée d'une benzoquinone substituée et d'une chaîne polyisoprényle contenant 6 unités chez Saccharomyces cerevisiae (Q6), 8 chez Escherichia coli (Q8) et 10 chez l'homme (Q10). Q a un rôle bien connu de transporteur d'électrons dans les chaînes respiratoires et fonctionne également comme un antioxydant membranaire. La déficience primaire en Q10 a maintenant été attribuée à des mutations dans 6 gènes de la biosynthèse de Q10 et cause des pathologies sévères. La biosynthèse de Q6 est mitochondriale et nécessite au moins 9 protéines organisées au sein d'un complexe multiprotéique chez la levure (Coq1-Coq9). L'acide 4-hydroxybenzoique (4-HB) et l'acide para-aminobenzoique (pABA) sont les deux précurseurs connus du noyau aromatique de Q6. Malgré de nombreuses recherches et l'importance cruciale de Q dans le métabolisme eucaryote, certaines étapes de la voie de biosynthèse de Q ne sont pas connues. L'étude présentée dans ce manuscrit a permis de montrer l'implication de la protéine Coq6, proposée comme étant une mono-oxygénase à flavine, dans une seule des trois réactions d'hydroxylation que compte la voie de biosynthèse de Q6: l'hydroxylation en C5. De plus, notre étude sur Coq8, une protéine kinase dont sa surexpression stabilise le complexe multiprotéique, nous a permis de confirmer les fonctions de certaines protéines Coq (Coq5, Coq7), de découvrir la fonction de Coq6 et d'éclaircir le rôle des autres (Coq4, Coq9). Nous rapportons également que des analogues hydroxylés ou méthoxylés de 4-HB et du pABA peuvent court-circuiter des étapes déficientes des mutants particuliers conduisant ainsi à la synthèse du coenzyme Q6 dans ces derniers. Ce résultat ouvre de nouvelles perspectives pour traiter les déficiences en coenzyme Q10 qui jusqu'à présent sont traitées par supplémentation en Q. Finalement, la réaction de déamination, essentielle à la biosynthèse de Q6 à partir du pABA, reste incomprise mais nos résultats suggèrent fortement l'implication de Coq6 dans cette étape.
44
劉永棠 e Wing-tong Ricky Lau. "Multiplex RT-PCR for typing and subtyping influenza and respiratory syncytial viruses". Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2002. http://hub.hku.hk/bib/B31970667.
Testo completo
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Lau, Wing-tong Ricky. "Multiplex RT-PCR for typing and subtyping influenza and respiratory syncytial viruses". Hong Kong : University of Hong Kong, 2002. http://sunzi.lib.hku.hk/hkuto/record.jsp?B25151599.
Testo completo
46
Brewer, Judy. "Metabolic Modeling of Inborn Errors of Metabolism: Carnitine Palmitoyltransferase II Deficiency and Respiratory Chain Complex I Deficiency". Thesis, Harvard University, 2015. http://nrs.harvard.edu/urn-3:HUL.InstRepos:24078365.
Testo completoAbstract (sommario):
The research goal was to assess the current capabilities of a metabolic modeling environment to support exploration of inborn errors of metabolism (IEMs); and to assess whether, drawing on evidence from published studies of EMs, the current capabilities of this modeling environment correlate with clinical measures of energy production, fatty acid oxidation, accumulation of toxic by-products of defective metabolism, and mitigation via therapeutic agents.
IEMs comprise several hundred disorders of energy production, often with significant impact on morbidity and mortality. Despite advances in genomic medicine, currently the majority of therapeutic options for IEMs are supportive only, and most only weakly evidenced. Metabolic modeling could potentially offer an in silico alternative for exploring therapeutic possibilities.
This research established models of two inborn errors of metabolism (IEMs), carnitine palmitoyltransferase (CPT) II deficiency and respiratory chain complex I deficiency, allowing exploration of combinations of IEMs at different degrees of enzyme deficiency. It utilized a modified version of the human metabolic network reconstruction, Recon 2, which includes known metabolic reactions and metabolites in human cells, and which allows constraint-based modeling within a computational and mathematical representation of human metabolism. It utilized the Matlab-based COBRA (Constraint-based Reconstruction and Analysis) Toolbox 2.0, and a customized suite of functions, to model ATP production, long-chain fatty acid oxidation (LCFA), and acylcarnitine accumulation in response to varying defect levels, inputs and a simulated candidate therapy.
Following significant curation of the metabolic network reconstruction and customization of COBRA/Matlab functions, this study demonstrated that ATP production and LCFA oxidation were within expected ranges, and correlated with clinical data for enzyme deficiencies, while acylcarnitine accumulation inversely correlated with the degree of enzyme deficiency; and that it was possible to simulate upregulation of enzyme activity with a therapeutic agent.
Results of the curation effort contributed to development of an updated version of the metabolic reconstruction Recon 2. Customization of modeling approaches resulted in a suite of re-usable Matlab functions and scripts usable with COBRA Toolbox methods available for further exploration of IEMs.
While this research points to potentially greater suitability of kinetic modeling for some aspects of metabolic modeling of IEMs, it helps to demonstrate potential viability of constraint-based steady state modeling as a means to explore some clinically relevant measures of metabolic function for single and combined inborn errors of metabolism.
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Bursby, Timothy Patrick. "Investigations of the mitochondrial #beta#-oxidation trifunctional protein and its association with complex 1 of the respiratory chain". Thesis, University of Newcastle Upon Tyne, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.364807.
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Schimpf, Johannes [Verfasser], e Thorsten [Akademischer Betreuer] Friedrich. "Towards the structure of complex I and bo3 oxidase from Escherichia coli and exploring its aerobic respiratory chain". Freiburg : Universität, 2020. http://d-nb.info/1222436450/34.
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Li, Xu-Wen. "Bio-inspired formal synthesis of the antitubercular hirsutellones & Biomimetic synthetic studies toward the respiratory chain inhibitors aurachins". Paris 6, 2013. http://www.theses.fr/2013PA066738.
Testo completoAbstract (sommario):
Hirsutellones are fungal polyketides with beautiful structures including a decahydrofluorene (tricyclic) core and a highly strained 12- or 13-membered macrocycle. Inspired by a biosynthetic hypothesis concerning their skeletons, we envisaged a biomimetic strategy for the total synthesis of hirsutellone B, via a coupling and a cascade cyclization from a tetramic acid moiety and a linear polyunsaturated precursor. In this dissertation, we will describe the synthesis of several tetramic acids and linear polyene building blocks, as well as the attempts on their coupling and macrocyclization. Furthermore, through a designed linear polyene precursor with both nucleophilic and electrophilic functional groups, we will present the biomimetic electrophilic cyclization followed by an IMDA reaction towards the tricyclic core of hirsutellone B and thus the achievement of the formal total synthesis of hirsutellones A, B and C. In the context of searching for biologically active compounds, the respiratory chain inhibitory isoprenoid quinoline alkaloids aurachins captured our attention for their synthesis, which was inspired by another biosynthetic hypothesis. Therefore, as an international collaboration project, the first total synthesis of the natural product aurachin D and its analogues with chain length or aromatic cycle variations will be presented, using a key Conrad-Limpach process. An interesting reductive epoxide-opening cascade will be described towards the synthesis of aurachin H analogues. A new biosynthetic hypothesis will also be presented from aurachin C to B. Furthermore, their biological activity was extensively studied by our collaborators and will be summarizedLes hirsutellones sont des polycétides fongiques possédant une structure intéressante avec un noyau decahydrofluorène (tricycliques) et un macrocycle particulièrement contraint à 12- ou 13- chaînons. S'inspirant d'une hypothèse de biosynthèse sur le squelette des hirsutellones, nous avons envisagé une stratégie biomimétique pour la synthèse totale de l'hirsutellone B, par l'intermédiaire d'un précurseur polyinsaturé linéaire. Dans cette thèse, nous décrirons la synthèse de plusieurs acides tétramiques et polyènes linéaires intermédiaires, ainsi que les tentatives de leur couplage et de macrocyclisation. En outre, grâce à un précurseur polyène linéaire porteur de groupes fonctionnels nucléophile et électrophile, nous présenterons la cyclisation électrophile biomimétique suivie d'une réaction IMDA vers le noyau tricyclique de hirsutellone B, et donc la réalisation d'une synthèse totale formelle des hirsutellones A, B et C. Dans le cadre de la recherche de composés biologiquement actifs, des alcaloïdes inhibiteurs de la chaîne respiratoire, les aurachines de type isoprénoïde-quinoléine, ont attiré notre attention pour réaliser leur synthèse qui a été inspiré par une autre hypothèse biosynthétique. Par conséquent, la première synthèse totale de l'aurachine D et de ses analogues de chaîne ou de cycle aromatique sera présentée. Une cascade d'ouverture d'époxyde suite à une hydrogénation sera décrite vers la synthèse d'analogues de l'aurachine H. Une nouvelle hypothèse de biosynthèse sera également présentée de l’aurachine C au B. Enfin, leurs activités biologiques ont été extensivement étudiées par nos collaborateurs et seront résumées
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Kwan, See-wai Grace. "Detection of human coronavirus infections by reverse transcription PCR in children hospitalized with respiratory disease in Hong Kong /". View the Table of Contents & Abstract, 2005. http://sunzi.lib.hku.hk/hkuto/record/B31494274.
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