Дисертації з теми "Phosphorylation oxidative"
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1
Carr, M. D. "NMR studies of oxidative phosphorylation." Thesis, University of Oxford, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.382584.
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Eijsden, Rudy Gerardus Elisabeth van. "Microarray analysis of oxidative phosphorylation disorders." [Maastricht] : Maastricht : Maastricht University ; University Library, Universiteit Maastricht [host], 2008. http://arno.unimaas.nl/show.cgi?fid=10708.
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3
Heiske, Margit. "Modeling the respiratory chain and the oxidative phosphorylation." Thesis, Bordeaux 2, 2012. http://www.theses.fr/2012BOR21965/document.
Повний текст джерелаАнотація:
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
4
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.
Повний текст джерелаАнотація:
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.
5
Luca, Corneliu Constantin. "MTERFD3 is a Mitochondrial Protein that Modulates Oxidative Phosphorylation." Scholarly Repository, 2008. http://scholarlyrepository.miami.edu/oa_dissertations/132.
Повний текст джерелаАнотація:
Mitochondrial function is critical for the survival of eukaryotes. Hence, mitochondrial dysfunctions are involved in numerous human diseases. An essential process for a normal mitochondrial function is mitochondrial gene expression which is tightly regulated in response to various physiological changes. The accurate control of mitochondrial gene expression is essential in order to provide the appropriate oxidative phosphorylation capacity for diverse metabolic demands. Recent findings in the basic mitochondrial replication and transcription regulation helped advance our understanding of organelle function and basic pathogenetic mechanisms of mitochondrial DNA mutations associated with oxidative phosphorylation defects. Mitochondrial transcription is regulated by the mitochondrial transcription termination factor (mTERF) both at the initiation and termination levels. A protein family containing highly conserved mTERF motifs has been identified recently and its members named generically as "terfins." In this work, one of these factors, mTERFD3, has been characterized in vitro and in vivo. The mTERFD3 protein is highly conserved throughout evolution. It is a mitochondrial protein localized to the matrix and is abundantly expressed in high energy demand tissues. We found that it contains 4 putative leucine zippers and is able to form dimers in vitro. We showed that mTERFD3 binds mtDNA at the transcription initiation site in the mtDNA regulatory region. These findings suggest that mTERFD3 may be involved in regulating mitochondrial gene expression at the transcriptional initiation level. In order to study the functional significance of mTERFD3 in vivo we developed a mouse deficient in mTERFD3 using a gene trapping strategy. The KO mice had a normal lifespan but showed decreased weight gain and decreased fat content in females. Fibroblasts isolated from KO mice displayed decreased growth rate when compared with WT in respiratory media, and had decreased complex IV activity. Consistent with the above findings, we found that muscle, one of the tissues with high energy demands, showed abnormal mitochondrial function, displaying features characteristic of mitochondrial myopathy such as decreased muscle strength and endurance. Muscle mitochondria of the KO mice showed a significant decrease in the complex II +III and complex IV activity. The decrease in OXPHOS complexes activity was associated with increased citrate synthase activity, suggesting mitochondrial proliferation, a feature typical for mitochondrial disorders. Another important finding was a decrease in the muscle mitochondrial transcripts in the KO animals associated with decreased steady state levels of OXPHOS subunits. Together these data suggest that mTERFD3 is a mitochondrial protein involved in the regulation of mtDNA transcription. mTERFD3 KO is not embryonic lethal suggesting that it is involved in the fine tuning of mitochondrial transcription. We conclude that mTERFD3 is a mitochondrial protein that modulates oxidative phosphorylation function, probably by directed interactions with the mtDNA regulatory region. This work shows the importance of mTERFD3, an mTERF family member, in the mitochondrial gene expression regulation.
6
Padovan, Anna Caterina. "The control of oxidative phosphorylation in isolated plant mitochondria /." Title page, table of contents and summary only, 1986. http://web4.library.adelaide.edu.au/theses/09SB/09sbp124.pdf.
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Schroeder, James Lee. "Acute and chronic regulation of oxidative phosphorylation in muscle." Thesis, University of Oxford, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.540256.
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8
Kavanagh, Norita Irene. "A quantitative analysis of the effect of calcium on oxidative phosphorylation." Thesis, University of Cambridge, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.624736.
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Žūkienė, Rasa. "Investigation of the effect of hyperthermic treatment on mitochondrial oxidative phosphorylation system." Doctoral thesis, Lithuanian Academic Libraries Network (LABT), 2008. http://vddb.library.lt/obj/LT-eLABa-0001:E.02~2008~D_20081120_151452-51127.
Повний текст джерелаАнотація:
The elucidation of the molecular mechanism of the cell response to moderate heating is of importance for understanding the events that occur in the cell upon use of heating for therapeutic purpose or during illnesses that are associated with fever. The aim of this work was to investigate and to compare the effects of mild (fever) and severe hyperthermia on functional properties of oxidative phosphorylation system in normal tissue mitochondria. Modular kinetic analysis for the first time was applied to evaluate effects of hyperthermia on oxidative phosphorylation in rat heart and liver mitochondria. We demonstrated that changes in mitochondrial functions induced by mild hyperthermia (42 ºC) are reversible but more severe hyperthermia (45 ºC) causes partially irreversible uncoupling and inhibition of mitochondrial respiration in state 3, hyperthermia remarkably (3.6-2.1 fold) activates ROS generation in heart mitochondria and that maximal increase in rate of H2O2 production and lipid peroxidation is observed in the fever temperature range. We show that the response of liver mitochondria and hepatocytes to hyperthermia is to certain extent dependent on gender and temperature. Specific differences of male rat liver and heart mitochondrial components phase transitions have been revealed by DSC analysis.Ląstelių atsako į nuosaikią hipertermiją molekulinio mechanizmo išaiškinimas yra labai svarbus norint suprasti procesus, kurie vyksta ląstelėse jas kaitinant gydymo tikslais ar organizmui karščiuojant. Šio darbo tikslas buvo nustatyti ir palyginti švelnios (karščiavimo) ir šiurkščios hipertermijos poveikį oksidacinės fosforilinimo sistemos funkcijoms normalių audinių mitochondrijose. Pirmą kartą panaudojome modulių kinetinę analizę hipertermijos poveikiui širdies ir kepenų mitochondrijų oksidacinio fosforilinimo sistemai tirti. Mes nustatėme, kad švelnios hipertermijos (42 ºC) poveikis širdies mitochondrijų funkcijoms yra grįžtamas, bet šiurkštesnė hipertermija (45 ºC) sukelia dalinai negrįžtamą kvėpavimo ir fosforilinimo atskyrimą bei mitochondrijų kvėpavimo greičio trečioje metabolinėje būsenoje slopinimą. Hipertermija didino ROS gamybos greitį ir lipidų peroksidaciją, kurie buvo didžiausi karščiavimo temperatūroje. Nustatėme, kad kepenų mitochondrijų ir hepatocitų atsakas į hipertermiją priklauso nuo žiurkės lyties ir temperatūros. Atlikome palyginamąjį širdies ir kepenų mitochondrijų sandų fazinių virsmų analizę diferencine skenuojamaja kalorimetrija ir nustatėme būdingus skirtumus.
10
Liu, Quan. "PHOSPHORYLATION AND SEQUENCE DEPENDENCY OF NEUROFILAMENT PROTEIN OXIDATIVE MODIFICATION IN ALZHEIMER DISEASE." Connect to text online, 2005. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=case1102024839.
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11
Fries, Anthony Charles. "The molecular evolution of mitochondrial oxidative phosphorylation genes in the Order Passeriformes." The Ohio State University, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=osu1258557488.
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12
El-Wadawi, Rukaya A. "Heat death and the development of thermotolerance in the blow fly Calliphora viicina : a study of flight muscle mitochondrial function." Thesis, Durham University, 1996. http://etheses.dur.ac.uk/5267/.
Повний текст джерелаАнотація:
The LD(_50) of 10-day-old blowflies differed significantly in two different stocks, and were found to be 38.12 ± 0.07ºC for the Durham stock and 40.8 ± 0.18ºC for the Cambridge stock. A transitory increase in heat resistance occurred following the exposure of adult blowflies to a sublethal heat shock. This thermotolerance was apparent 1h after the application of heat shock, was maximal 2-3 h later and had disappeared after 6 h. Oxidative phosphorylation by flight muscle mitochondria from non-thermotolerant control flies was impaired by an LD(_50) dose in vivo. Respiration using glycerol-3- phosphate was more heat sensitive than that with pyruvate plus proline. State III respiration was markedly inhibited, acceptor control (RCI) was lost with (G 3P) as substrate and so ADP:0 ratios were not measurable; whereas with pyruvate + proline as substrates, although State III respiration was inhibited by 50% and acceptor control was significantly reduced, ADP:0 remained measurable. Uncoupling of oxidative phosphorylation was obvious only with pyruvate + proline where State IV was significantiy increased. The development of thermotolerance protected oxidative phosphorylation against heat damage. With G-3-P respiration State III was largely restored and acceptor control was not significantly different from controls, but ADP:0 remained lower. With pyruvate + proline as substrates State III respiration was inhibited, but State IV was also lower without evidence of uncoupling of oxidative phosphorylation. Acceptor control was restored to control levels but ADP:0 values were lower. The lower ADP:0 ratios indicate some impairment of mitochondrial function occurred. The effect of experimental temperature in vitro on respiratory performance of mitochondria from non-pretreated control and thermotolerant LD(_50) flies was also determined between 19 and 39ºC. State III respiration was markedly temperature- dependent in mitochondria from non-pretreated control flies with both substrates; it was maximal at 24-29ºC and fell progressively at higher measuring temperatures. In mitochondria from thermotolerant flies, State III respiration was less temperature dependent with both substrates, but this effect was more marked for G-3-P. The effect of experimental temperature on State IV respiration was similar in mitochondria from non- pretreated control and thermotolerant LD(_50) flies with the same substrate, but differed between the two substrates. With G 3P as substrate, respiration rate rose with temperature with a Q(_10) of approximately 1.5; however, with pyruvate + proline as substrate, the trend was for respiration rate to fall as experimental temperature rose. Differences in the temperature sensitivities of mitochondria from control and thermotolerant flies, in terms of acceptor control, were found. Using G-3-P, acceptor control was lost in mitochondria from control flies above 29ºC, but was still measurable at 34ºC in mitochondria from thermotolerant flies. With pyruvate + proline as substrate acceptor control was demonstrable in mitochondria from both non-pre-treated control and thermotolerant flies at all experimental temperatures. The thermal sensitivities of the respiratory complexes were studied using the inhibitors rotenone and antimycin A. In mitochondria from LD(_50) treated control flies respiration uncoupled with FCCP was not restored to State II levels. However, in LD(_50) treated mitochondria from thermotolerant flies respiration uncoupled with FCCP was not different from State III respiration. These data suggest that the reduction in State III respiration after heating is owing to an inhibition of oxidation rather than phosphorylation. Complex I, NADH coenzyme Q reductase, was shown to be the most temperature sensitive of the respiratory complexes.
13
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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Hébert, Chatelain Etienne. "Impact des phosphorylations sur tyrosine sur le métabolisme mitochondrial : régulation et impacts fonctionnels des phosphorylations induites par la Src kinase." Thesis, Bordeaux 2, 2011. http://www.theses.fr/2011BOR21830/document.
Повний текст джерелаАнотація:
La mitochondrie est une organelle très importante vu son implication dans plusieurs processus cellulaires. Elle produit notamment la majeure partie de l'énergie qui est consommée par la cellule, grâce aux processus d'oxydation phosphorylante (OXPHOS). La phosphorylation des enzymes impliquées dans les OXPHOS apparait comme une voie de régulation importante de la production énergétique. L'objectif de ce thèse était donc de comprendre comment les phosphorylations, et plus particulièrement, les phosphorylations sur tyrosine induites par la Src kinase influencent les OXPHOS. Il a donc été démontré qu'il existe, à l'intérieur des mitochondries, des voies de régulation de ces processus de phosphorylation induits par la Src kinase. Ces processus pouvant induire la phosphorylation de plusieurs enzymes mitochondriales, notamment plusieurs sous-unités des complexes du système des électrons et ainsi, grandement influencer les OXPHOS. Il a aussi été démontré que la Src kinase semble aussi présente dans les mitochondries de cellules cancéreuses, induisant la phosphorylation d'une sous-unité de la NADH-oxidoréductase et une augmentation du métabolisme énergétique mitochondrial. Cette régulation des OXPHOS dans les cellules cancéreuses par la Src kinase pourrait participer à l'établissement du phénotype hautement prolifératif de ces cellulesMitochondria are implicated in several key cellular processes. They are producing most part of the energy that is consumed by the cell via oxidative phosphorylation processes (OXPHOS). Phosphorylation of different components implicated in OXPHOS are known to constitute an important regulation pathway of energetic production. The objective of this thesis was to understand how tyrosine phosphorylation induced by the Src kinase could influence OXPHOS. First, it was shown that Src kinase mediated phosphorylation can be regulated directly in mitochondria, inducing phosphorylation of several mitochondrial proteins and different effects on OXPHOS. I also demonstrated that Src kinase is also present in mitochondria of cancer cells where it can lead to phosphorylation of NADH-oxidoreductase. This phosphorylation site is associated with increase of OXPHOS which could be implicated in the establishment of global phenotype of cancer cells
15
Apostolova, Nadezda. "Mitochondrial role of Apoptosis-Inducing Factor (AIF): Oxidative Phosphorylation and Reactive Oxygen Species." Doctoral thesis, Universitat de València, 2008. http://hdl.handle.net/10803/9775.
Повний текст джерелаАнотація:
The apoptotic function of Apoptosis-inducing factor (AIF) is well documented in theliterature, but its physiological role in the mitochondrion is less certain. Using a smallinterfering RNA (siRNA) strategy, we studied whether modulation of AIF expression incultured cells influenced the production of reactive oxygen species (ROS). We foundthat siAIF-transfected cells had reduced AIF protein levels and this was paralleled by asignificant increase in ROS. We tested the generality of this response by using twodifferent human cell lines, the hepatoma cell line Hep3B and cervix carcinoma lineHeLa, and also by employing a mouse ES AIF-KO cell line. The increased ROS weremitochondrial in origin as a similar silencing strategy in cells devoid of a functioningmitochondrial electron transport chain (ETC) did not result in a ROS-increase. Theaugmented ROS levels were sufficient to activate Hypoxia-inducible factor 1α (HIF-1α),a ROS-sensitive transcription factor, and this effect could be reversed usingantioxidants, both the broad-range general antioxidant (N-acetyl cysteine) and aspecific mitochondrial-targeted antioxidant (MitoQ), proving the implication of ROS inthe HIF-1α stabilization. We also studied another two redox-sensitive transcriptionfactor and thus observed up-regulation in the expression of Nuclear factor (erythroidderived2)-like 2 (Nrf2), however without major changes in Nuclear factor-kappa B(NF-κB) levels. Examination of the cellular oxygen consumption rate revealed that AIFdepletedcells had a major impairment of respiration, at Complex I in the ETC. Westernblot analysis also showed a loss of Complex I 39 and 20 kDa subunits. Studies usingthe antioxidants mentioned above, revealed that the respiratory competence could beregained in AIF-silenced cells. However, neither of the antioxidant treatments we usedcould recover Complex I assembly. Studies of the energetic state of siAIF cells showedthat despite a 30% decrease in the overall intact cell respiration, these cells maintainnormal basal levels of ATP, presumably due to a higher glycolytic capacity and a lowerproliferation rate. Moreover, we analyzed the expression of another redox-activeprotein, thioredoxin, by Western blot and found that the mitochondrial isoform, Trx2,was significantly decreased when AIF was silenced. Preliminary co-immunoprecipitationanalyses and proteomic studies failed to show any direct correlation between AIF andTrx2 at the protein level.Our results lead us to the conclusion that the defect in respiration in siAIF cells isdownstream of Complex I protein loss and is presumably due to ROS-mediateddamage to the ETC. This suggests an integral mitochondrial function of AIF, as a redoxmodifier and chaperone-like molecule, necessary for Complex I assembly. Additionalstudies are required to define the detailed mechanism of the AIF enzymatic activity inthe mitochondrion and to establish its binding partners.La función proapoptótica del Factor Inductor de Apoptosis (AIF) está biendocumentada, sin embargo su papel fisiológico en la mitocondria es menos conocido.Empleando la metodología de interferencia por ARN, estudiamos si la modulación de laexpresión proteica de AIF en cultivo celular modifica la producción celular de especiesreactivas de oxígeno (ROS). Observamos que el silenciamiento de AIF estaba seguidopor un incremento significativo en los niveles de las ROS. Estas ROS fueronmitocondriales de origen, puesto que el silenciamiento de AIF en células que carecende la cadena de transporte electrónico funcional (ETC) en la mitocondria no llevó a unincremento de ROS. Este incremento fue suficiente para activar el Factor inducible porhipoxia (HIF-1α), efecto que se puede revertir usando los antioxidantes, N-AcetilCisteina y MitoQ, demostrando así la implicación de los ROS en la estabilización deHIF1-α. Los análisis del consumo de oxigeno celular mostraron que las células de AIFsilenciado sufren una disminución en la respiración celular, al nivel del Complejo I de laETC, acompañada por una disminución significativa en la expresión de sus subunidades39 y la 20kDa. Tratamientos con los antioxidantes previamente nombrados mostraronque la tasa de respiración se puede recuperar, no siendo así con la expresión delComplejo I de la ETC. Estudios del estado energético de las células siAIF mostraronque a pesar de la disminución de 30% en la tasa de la respiración celular, estas célulasmantienen niveles normales de ATP, como resultado de un incremento en la capacidadglucolítica y una reducción en la tasa de proliferación. Posteriormente, analizamos laexpresión de la proteína tioredoxina y observamos una disminución significativa en laisoforma mitocondrial, la tioredoxina 2 (Trx2), aunque los análisis preliminares de coinmunoprecipitacióny proteómica no mostraron la existencia de una correlacióndirecta entre las proteínas AIF y Trx2.Concluyendo, nuestros resultados sugieren que el defecto de la respiración celular esposterior al defecto en el Complejo I, probablemente como consecuencia al daño de laETC por ROS. Esta observación apunta a un papel integrador de AIF en la mitocondria,como modulador del estatus redox y necesario para el ensamblaje del Complejo I.
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Winegarden, Neil Anthony. "The effect of inhibitors of oxidative phosphorylation on the Drosophila heat shock response." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/tape16/PQDD_0005/MQ29359.pdf.
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Paterson, Andrea Beth. "Mechanisms of acetaminophen-induced hepatotoxicity, effects of mitochondrial glutathione, protein thiols and oxidative phosphorylation." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/mq22375.pdf.
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Fukui, Hirokazu. "Mitochondrial Involvement in the Accumulation of Misfolded Proteins in Neurodegenerative Diseases." Scholarly Repository, 2008. http://scholarlyrepository.miami.edu/oa_dissertations/41.
Повний текст джерелаАнотація:
Mitochondrial respiratory chain deficiency and increased oxidative stress have been closely associated with major age-associated neurodegenerative diseases. I hypothesized that mitochondrial oxidative phosphorylation defects or elevated oxidative stress, which could arise in a stochastic manner during our normal aging process, might modulate the formation of protein aggregates or production of misfolded proteins, contributing to the initiation of these diseases. To test this hypothesis, we (i) have developed and characterized mouse and cellular models of Alzheimer's and Huntington's diseases expressing aggregate-prone pathogenic proteins, beta-amyloid and mutant huntingtin (Chapters 1 and 2), (ii) have developed mouse models that exhibit neuron-specific defects in mitochondrial oxidative phosphorylation (Chapters 2 and 3), and (iii) have evaluated the alterations in the amount of aggregate loads upon genetic and pharmacological manipulations of mitochondrial oxidative phosphorylation activities (Chapters 1 and 2). The evaluation of the impacts of mitochondrial defects on the amount of huntingtin aggregates has revealed that a defect in complex III promotes the accumulation of huntingtin aggregates via the impairment of proteasome activity (Chapter 1). On the other hand, ablation of complex IV activity in a subset of postmitotic neurons revealed that complex IV deficiency does not promote either oxidative stress or the deposition of amyloid plaques in a mouse model of Alzheimer's disease, questioning the mitochondrial origin of Alzheimer's disease (Chapter 2). However, as shown previously, the tight correlation between oxidative stress and accumulation of amyloid plaques was found. Chapter 3 involved the generation of an improved mouse model, in which mitochondrial defects can be induced in a subset of forebrain neurons (cortex, hippocampus, and striatum) in a doxycycline-dependent manner. This system relies on the regulated expression of a mitochondria-targeted restriction enzyme, PstI, which digests mitochondrial DNA and thereby impairs the activity of oxidative phosphorylation. In conclusion, our studies highlighted the disease-specific complex pathways that may modulate the accumulation of misfolded proteins during aging. Future studies employing the newly-developed mouse model may reveal a contribution of age-associated global defects of oxidative phosphorylation to oxidative stress and neurodegenerative diseases.
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Dahlberg, Anna-Karin. "Environmentally relevant chemical disruptors of oxidative phosphorylation in Baltic Sea biota : Exposure and toxic potentials." Doctoral thesis, Stockholms universitet, Institutionen för miljövetenskap och analytisk kemi, 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-115436.
Повний текст джерелаАнотація:
This thesis focuses on toxicity and occurrence of hydroxylated polybrominated diphenyl ethers (OH-PBDEs) in Baltic Sea biota. The aims were to assess OH-PBDEs potency for disruption of oxidative phosphorylation (OXPHOS) and determine their and related compounds exposure in Baltic blue mussel, herring and long-tailed duck. A method for analysis of OH-PBDEs in herring and long-tailed duck plasma was also evaluated. Relevant OH-PBDEs were tested in vitro for OXPHOS disruption, using a classic rat mitochondrial respiration assay and a cell mitochondrial membrane potential assay. All compounds were found to disrupt OXPHOS either by protonophoric uncoupling and/or via inhibition of the electron transport chain. 6-OH-BDE47 and 6-OH-BDE85, were identified as particularly potent OXPHOS disruptors. Strong synergism was observed when OH-PBDEs were tested as a mixture corresponding to what is present in Baltic blue mussels. Baltic blue mussel is main feed for several species of mussel feeding sea ducks which have decreased dramatically in numbers. To assess long-tailed ducks exposure to brominated substances, liver tissue from long-tailed ducks wintering in the Baltic Sea and blue mussels were analysed. The result confirms that long-tailed duck are exposed to OH-PBDEs via their diet. However, low concentrations were found in the duck livers, which suggest low retention of these compounds despite daily intake. How the nutritional value of blue mussels as feed for sea ducks are affected by OH-PBDE exposure still needs further studies. Other species of sea ducks foraging on Baltic blue mussels during summer months can also be more exposed due to seasonal variation in primary production. Herring sampled in the Baltic Proper and Bothnian Sea, were found to contain OH-PBDEs and high levels of their methylated counterpart, MeO-PBDEs. As demethylation of MeO-PBDEs is known to occur in fish, MeO-PBDEs may pose as additional source for more toxic OH-PBDEs in herring and their roe.At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: Manuscript. Paper 3: Manuscript.
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Ruas, Juliana Silveira 1989. "Metabolismo energético mitocondrial na proliferação de células de glioblastoma U-87MG e T98G em cultura." [s.n.], 2015. http://repositorio.unicamp.br/jspui/handle/REPOSIP/313030.
Повний текст джерелаАнотація:
Orientador: Roger Frigério CastilhoDissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
Made available in DSpace on 2018-08-26T14:26:13Z (GMT). No. of bitstreams: 1 Ruas_JulianaSilveira_M.pdf: 1871713 bytes, checksum: a20e3cd08d0b770aed3b059541e382e3 (MD5) Previous issue date: 2015
Resumo: A maioria das células tumorais depende da glicólise para a ressíntese de ATP durante um processo de rápida proliferação, mesmo que haja disponibilidade de oxigênio para a transdução de energia mitocondrial (Efeito Warburg). O objetivo do presente estudo foi avaliar o papel do metabolismo oxidativo mitocondrial na proliferação de células de glioblastoma humano U-87MG e T98G. Quando as células foram cultivadas na presença de oligomicina (um inibidor da ATP sintase) ou antimicina A (um inibidor do complexo III da cadeia transportadora de elétrons), observou-se apenas uma inibição parcial da proliferação das células. Notadamente, a incubação dessas células com ambos os inibidores causou uma inibição quase completa na proliferação celular. Resultados semelhantes foram observados em cultura primária de astrócitos, havendo uma queda na proliferação celular somente quando ambos os inibidores mitocondriais estavam presentes. Medidas de consumo de oxigênio indicaram que células de glioblastoma utilizam parcialmente a fosforilação oxidativa para a ressíntese de ATP e apresentam uma respiração bem acoplada. Quando se inibiu, nestas células, a fosforilação oxidativa do ADP com oligomicina ou antimicina A, houve um pequeno aumento no consumo de glicose e na produção de lactato. No entanto, o tratamento com ambos os inibidores mitocondriais promoveu um menor consumo de glicose e produção de lactato, em comparação com os efeitos que a antimicina A promoveu. Isso indica que a cadeia transportadora de elétrons quando inibida pela presença de antimicina A, promove um funcionamento inverso da ATP sintase, promovendo a hidrólise de ATP para que haja um bombeamento de prótons para o espaço intermembranar mitocodrial. De acordo com os resultados acima descritos, uma queda quase completa do potencial de membrana mitocondrial foi observada apenas quando as células de glioblastoma foram incubadas na presença de ambos os inibidores mitocondriais, oligomicina e antimicina A. Quando a análise do ciclo celular foi realizada, observou-se uma diminuição da percentagem das células em G0-G1 e um aumento nas fases S e G2-M quando tratadas com oligomicina. Quando as células foram tratadas com antimicina A e oligomicina mais antimicina A foi constatado uma diminuição significativa nas fases G0-G1 e G2-M, e um aumento na fase S. Em conclusão, estes resultados indicam que a rápida proliferação de células de glioblastoma depende da existência do potencial de membrana mitocondrial, mas não da fosforilação oxidativa ou do transporte de elétrons na cadeia respiratória
Abstract: Most tumor cells rely on glycolysis for ATP resynthesis during rapid proliferation, despite the availability saturating levels of oxygen for mitochondrial energy transduction (Warburg effect). The aim of the present study was to evaluate the role of mitochondrial oxidative metabolism on proliferation of human glioblastoma cells U-87MG and T98G. When cells were cultured in the presence of oligomycin (ATP synthase inhibitor) or antimycin A (inhibitor of complex III of the electron transport chain), we observed only a partial inhibition of cell proliferation. Remarkably, incubation of cells with both inhibitors caused an almost complete inhibition of cell proliferation. Similar results were observed in primary culture of astrocytes, with a decrease in cell proliferation only when both mitochondrial inhibitors were present. Oxygen consumption measurements indicated that glioma cells partially rely on oxidative phosphorylation for ATP turnover and exhibit a well-coupled respiration. In fact, shutting down mitochondrial ADP phosphorylation in these glioma cells with either oligomycin or antimycin inhibitors slightly increased glucose consumption and lactate release. However, the treatment with both mitochondrial inhibitors promoted lower glucose consumption and lactate release as compared with the effects of antimycin alone, which indicates that ATP synthase is operating reversely and thus hydrolyzing ATP and pumping H+ out when the respiratory chain is inhibited by antimycin. In agreement, an almost complete collapse of mitochondrial membrane potential was only observed when the glioma cells were incubated in the presence of both antimycin and oligomycin, but not of only antimycin. When cell cycle analyses were performed in oligomycin-treated cells, a decrease in the percentage of cells in G0-G1 phase and an increase in S and G2-M phases were observed. When cells were treated with antimycin A or oligomycin plus antimycin A, it was observed a significant decrease in G0-G1 and G2-M cell phases and an increase in S phase. Overall, our results suggest that the rapid proliferation of glioblastoma cells is dependent on the mitochondrial membrane potential, but not on oxidative phosphorylation or electron transport in the respiratory chain
Mestrado
Biologia Estrutural, Celular, Molecular e do Desenvolvimento
Mestra em Ciências
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Du, Toit Hanli. "Biochemical analyses of deficiencies in the oxidative phosphorylation system in human muscle / by Hanli du Toit." Thesis, North-West University, 2007. http://hdl.handle.net/10394/743.
Повний текст джерелаАнотація:
MitochondriaI disorders are caused by biochemical abnormalities of the mitochondrial respiratory chain (RC), a key component of oxidative phosphorilation (OXPHOS). The diagnosis of a RC deficiency can be invasive, expensive, time consuming and labour intensive.
The corner stone for diagnosis of mitochondrial disorders and the only two definitive tests are DNA analysis and respiratory chain enzyme analysis (Naviaux, 2004).
The aim of this study was to use biochemical analysis (polarographic analysis and enzyme assay) to identify patients with an OXPHOS defect by setting up reference values from healthy control data. The most commonly used approach in many centres is the interpretation of enzyme activity data based on retrospectively compiled reference values obtained from the data from diseased children, because of the unavailability of muscle tissue from healthy children (Thorburn, 2004). Ethics approval (protocol 91/98) was given to obtain muscle biopsies from selected healthy children.
Biochemical tests were done on the muscle biopsies of the healthy children (control group) and those of the selected possible patients, based on their clinical phenotypes. The methods used in the literature differ significantly, so the first aim was to evaluate and partly standardise the method. Reference values were determined from the control group, based on four different approaches used in the literature. The most accurate approach was chosen, the patient data were compared to the reference range and the patients with OXPHOS deficiencies were diagnosed.
During this study 18 controls were collected and 26 possible patients identified. In 69% of the patients an OXPHOS defect could be diagnosed based on their enzymatic assay data. Only 11% of the enzymatic assay data were comparable with the respiratory analysis data. It is thus recommended that in future respiratory analysis is no longer utilised.Thesis (M.Sc. (Biochemistry))--North-West University, Potchefstroom Campus, 2008.
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Boël, Mélanie. "Influence de la masse corporelle au sein du triptyque mitochondrial "oxygène, ATP et radicaux libres." Thesis, Lyon, 2020. https://n2t.net/ark:/47881/m68c9vmt.
Повний текст джерелаАнотація:
Les mécanismes sous-jacents aux traits d’histoire de vie sont complexes et ne sont pas totalement compris à ce jour. De par leur capacité à générer de l’énergie cellulaire (ATP), des espèces réactives de l’oxygène (ROS) et de la chaleur, les mitochondries impactent les performances individuelles (taille, croissance et survie) et les traits d’histoire de vie des eucaryotes. La masse corporelle influence les processus et les structures biologiques, quelle que soit l’échelle biologique appréhendée. Cette thèse propose ainsi, par une approche écophysiologique, de comprendre le lien entre la bioénergétique mitochondriale et la masse corporelle, afin d’apporter une base physiologique aux traits d’histoire de vie des mammifères. Les résultats obtenus mettent en avant l’existence d’un patron allométrique général chez les mammifères. La consommation d’oxygène (O), la production radicalaire et la synthèse d’ATP mitochondriales, sont toutes corrélées négativement avec la masse corporelle ; alors que les rapports entre ces différents processus (ATP/O, ROS/O et ROS/ATP) sont indépendants de la masse corporelle. Malgré un couplage oxydation-phosphorylation (ATP/O) identique entre les espèces, les mammifères de grande taille sont plus efficaces, en produisant plus d’ATP par oxygène consommé, comparés aux petites espèces. Cette meilleure capacité est expliquée par des membranes mitochondriales moins perméables aux protons et permet aux mammifères de grande masse corporelle d’allouer plus d’énergie à leurs performances individuelles. Les données mettent aussi en évidence que les contraintes physiologiques, exigées par une très petite masse corporelle, peuvent entrainer des discordances d’une échelle biologique à une autre. Au niveau cellulaire seulement, Mus mattheyi (≈ 5 g) présente un profil bioénergétique similaire à celui d’une souris quatre fois plus lourde (Mus musculus, ≈ 20 g). Contrairement aux attendus allométriques, M. mattheyi présente des taux métaboliques faibles et une efficacité mitochondriale (ATP/O) élevée, lui permettant de produire plus d’ATP par oxygène consommé qu’une espèce de même masse corporelle. Enfin, cette thèse démontre que la dépendance de la production de ROS à l’activité mitochondriale est identique entre les espèces. En effet, une réduction de l’activité mitochondriale maximale, au-delà de 70-75%, entraine une production accrue de ROS dans la mitochondrie, quelle que soit l’espèce étudiée. L’invariance de cette valeur seuil et des stoechiométries entre processus bioénergétiques (ATP/O, ROS/O et ROS/ATP), montre une forte conservation de ces paramètres mitochondriaux au cours de l’évolutionNowadays, the mechanisms underlying life history traits are complexed and not fully understood. Through their ability to generate cellular energy (ATP), reactive oxygen species (ROS) and heat, mitochondria impact individual performances (size, growth and survival) and life history traits of organisms. Body mass influences a lot of biological processes and structures at all biological scales. Thus, this thesis proposes, through an eco-physiological approach, to understand the link between mitochondrial bioenergetics and body mass, in order to provide a physiological basis for mammalian life history traits. The results obtained highlight the existence of a general allometric pattern in mammals. Mitochondrial oxygen consumption (O), ROS production and ATP synthesis, correlate negatively with body mass; whereas ratios between these different processes (ATP/O, ROS/O and ROS/ATP) are independent of body mass. Despite identical oxidation-phosphorylation coupling (ATP/O) between species, large mammals are more efficient, producing more ATP per oxygen consumed, compared to smaller ones. This capacity allows large mammals to allocate more energy to their individual performances and is explained by mitochondrial membranes that are less permeable to protons. The data also show that physiological constraints imposed by a very small body mass can lead to inconsistencies from one biological scale to another. Only at the cellular level, Mus mattheyi (≈ 5 g) presents a bioenergetics profile similar to that of a mouse four times heavier (Mus musculus, ≈ 20 g). Contrary to allometric expectations, M. mattheyi has low metabolic rates and high mitochondrial efficiency (ATP/O), allowing it to produce more ATP per oxygen consumed than a species of the same body mass. Finally, this thesis demonstrates that the dependence of ROS production on mitochondrial activity is similar between species. A reduction in maximum mitochondrial activity, beyond 70-75%, leads to a drastic increased of mitochondrial ROS production. The invariance of this threshold value and of the stoichiometry between bioenergetics processes (ATP/O, ROS/O and ROS/ATP), suggests a strong conservation of these mitochondrial parameters during evolution
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Kuršvietienė, Lolita. "Riebalų rūgščių vaidmuo reguliuojant mitochondrijų kvėpavimą." Doctoral thesis, Lithuanian Academic Libraries Network (LABT), 2007. http://vddb.library.lt/obj/LT-eLABa-0001:E.02~2007~D_20070531.081711-68424.
Повний текст джерелаАнотація:
Šiame darbe siekta išsiaiškinti riebalų rūgščių vaidmenį reguliuojant oksidacinį fosforilinimą saponinu permeabilizuotose žiurkės širdies raumens skaidulose. Pagrindiniai darbo uždaviniai: 1).Įvertinti įvairios struktūros riebalų rūgščių vaidmenį reguliuojant oksidacinį fosforilinimą saponinu permeabilizuotose žiurkės širdies raumens skaidulose;2) Naudojant egzogeninę ADP-suvartojančią piruvato kinazės ir fosfoenolpiruvato sistemą įvertinti, ar oksiduojantis riebalų rūgštims kinta išorinės mitochondrijų membranos laidumas ADP-ui; 3) Tirti, ar riebalų rūgščių oksidacija veikia funkcinę sąveiką tarp kreatino kinazės ir ADP/ATP nešiklio; 4).Nustatyti riebalų rūgščių oksidacijos poveikį mitochondrijų in situ morfologijai bei įvertinti dekstrano T70 poveikį mitochondrijų in situ kvėpavimo parametrams ir morfologijai.
Mitochondrijose in situ oksiduojantis įvairios struktūros riebalų rūgštims, vienoms ar mišinyje su piruvatu+malatu, oksidacinio fosforilinimo tariamoji KmADP sumažėja panašiu laipsniu lyginant su piruvato+malato oksidacija. Šis poveikis yra grįžtamas, t.y. riebalų rūgščių oksidacija nedaro įtakos po jos vykstančiai neriebalinės kilmės substratų oksidacijai. Oksiduojantis riebalų rūgštims išsaugoma funkcinė sąveika tarp kreatino kinazės ir ANT, nepaisant ženklaus tar. KmADP reikšmės sumažėjimo. Elektroninės mikroskopijos metodu įvertinome, kad riebalų rūgščių sąlygotas KmADP sumažėjimas gali būti susijęs su mitochondrijų struktūros pokyčiais, kuriuos sukelia riebalų... [to full text]The aim of this study was to investigate the influence of fatty acid oxidation on the regulation of oxidative phosphorylation in permeabilized rat cardiac fibers. The objectives of the study:1). To evaluate the influence of different fatty acids in the regulation of oxidative phosphorylation in fibers; 2). To evaluate the changes in outer mitochondrial membrane permeability for ADP during fatty acid oxidation by the means of exogenous ADP consuming system consisting of pyruvate kinase and phosphoenolpyruvate;3); To investigate the effect of fatty acid oxidation on the functional coupling between mitochondrial creatine kinase and adenine nucleotide translocase; 4). To investigate the effects of fatty acid oxidation and dextran T70 on the morphology and respiration of mitochondria in saponin-permeabilized rat cardiac fibers. The apparent Km of oxidative phosphorylation for ADP in saponin-permeabilized rat cardiac fibers is decreased several fold during oxidation of fatty acids alone or in the mixture with pyruvate compared to oxidation of pyruvate+malate. This effect is reversible, and fatty acid oxidation does not influence the subsequent oxidation of non-fatty substrates. The functional coupling between creatine kinase and adenine nucleotide translocase is not influenced by fatty acid oxidation and the efficiency of creatine kinase system does not depend on the nature of respiratory substrates. Analysis of electron microscopy images of fibres indicates that morphological... [to full text]
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Goto, Toshihiko. "Liver specific Prox1 inactivation causes hepatic injury and glucose intolerance in mice." Kyoto University, 2017. http://hdl.handle.net/2433/225976.
Повний текст джерела
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Iguchi, Eriko. "DNA methyltransferase 3B plays a protective role against hepatocarcinogenesis caused by chronic inflammation via maintaining mitochondrial homeostasis." Doctoral thesis, Kyoto University, 2021. http://hdl.handle.net/2433/265187.
Повний текст джерела
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Gaignard, Pauline. "Métabolisme mitochondrial cérébral chez les mâles et les femelles : rôle des stéroïdes endogènes et effet de la progestérone après ischémie transitoire focale." Thesis, Paris 11, 2015. http://www.theses.fr/2015PA11T029.
Повний текст джерелаАнотація:
Les stéroïdes sexuels ne sont pas impliqués uniquement dans la reproduction, ils sont également actifs dans le système nerveux où ils exercent des effets neuroprotecteurs. La mitochondrie a un rôle central dans la synthèse de l’énergie cellulaire et le contrôle du stress oxydant. Ces fonctions mitochondriales seraient une cible potentielle des effets des stéroïdes sexuels dans le cerveau. Deux approches ont été développées au cours de ce travail de thèse : une approche physiologique avec l’étude de l’influence des stéroïdes endogènes sur la fonction mitochondriale cérébrale et une approche thérapeutique en utilisant le modèle expérimental de l’ischémie cérébrale et du traitement par la progestérone. Pour analyser l’influence des stéroïdes endogènes, nous avons comparé le fonctionnement de la phosphorylation oxydative (consommation d’oxygène ou « respiration » et activités enzymatiques) ; le niveau du stress oxydant (pool de glutathion mitochondrial et inactivation oxydative de l’aconitase mitochondriale) et les taux cérébraux de stéroïdes dans des groupes de souris mâles et femelles soit jeunes adultes intactes ou gonadectomisées (3 mois) ; soit âgées (20 mois). Nous avons montré que la respiration NADH-dépendante est plus importante et que le stress oxydant mitochondrial est moins important chez les femelles que chez les mâles jeunes. Cette différence n’existe plus chez les souris âgées et est abolie après ovariectomie mais pas après orchidectomie, ce qui démontre l’influence des stéroïdes ovariens. Les taux cérébraux importants de prégnènolone et de progestérone chez les souris jeunes femelles par rapport aux jeunes mâles pourraient être impliqués dans le dimorphisme sexuel observé.Les modifications de la respiration mitochondriale induites par l’ischémie cérébrale sont également différentes entre les mâles et les femelles dans notre modèle. La respiration NADH-dépendante est diminuée dans les deux sexes, mais la respiration FADH2-dépendante est diminuée spécifiquement chez les femelles. Le stress oxydant mitochondrial est augmenté dans les deux sexes. L’administration de progestérone permet de restaurer la respiration FADH2-dépendante chez les femelles et la respiration NADH-dépendante ainsi que le pool de glutathion mitochondrial dans les deux sexes. Ce travail a permis de mettre en évidence des différences de fonctionnement mitochondrial cérébral chez les souris mâles et femelles jeunes et d’identifier la phosphorylation oxydative et le stress oxydant mitochondrial comme cibles d’action des effets neuroprotecteurs de la progestérone lors de l’ischémie cérébraleBesides the reproduction control, sex steroids also act on nervous system and exert neuroprotective effects. The mitochondria are centrally involved in cellular energy synthesis and oxidative stress regulation and constitute a potential target of steroids effects on brain. The aim of our study was twofold: (1) to study the influence of endogenous steroids on brain mitochondrial function in physiological conditions ; (2) to determine the effects of progesterone on mitochondrial function when used as therapeutic agent in an experimental model of cerebral ischemia. To analyze the influence of endogenous sex steroids, the oxidative phosphorylation system (oxygen consumption or “respiration” and enzymatic activities) and mitochondrial oxidative stress (glutathione pool and mitochondrial aconitase oxidative inactivation) were analyzed in brain mitochondria of young adult male and female mice (3-month-old), intact and after gonadectomy, and of aged male and female mice (20-month-old). Our results showed that young adult females have lower oxidative stress and a higher NADH-linked respiration rate as compared to young adult males. This sex difference was suppressed by ovariectomy but not by orchidectomy and no longer existed in aged mice. Concomitant analysis of brain steroids suggest that the major male/female differences in brain pregnenolone and progesterone levels may contribute to the sex differences observed in brain mitochondrial function.We have also shown that the decrease of brain mitochondrial respiration induced by ischemia is different according to sex in our experimental model. The NADH-linked respiration decreased after ischemia in males and female but a decrease of FADH2-linked respiration only occurred in females. Ischemia induced oxidative damages in both males and females. Progesterone restored NADH-linked respiration in both sexes and FADH2-linked respiration in females. Progesterone also preserved mitochondrial glutathione pool in both sexes. Our findings point to a sex difference in brain mitochondrial function of young male and female mice and identify the oxidative phosphorylation system and the mitochondrial oxidative stress as targets of the neuroprotective effects of progesterone
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Nguyen, Hien-Anh. "Découverte d'une nouvelle famille de protéine kinases bactériennes : mécanismes de fonctionnement et rôle cellulaire de YdiB, un archétype chez Baccillus subtilis." Thesis, Grenoble, 2012. http://www.theses.fr/2012GRENV017/document.
Повний текст джерелаАнотація:
Les données de séquençage des génomes ont révélé une nouvelle famille de protéines UPF0079, comprenant des protéines de fonction inconnue qui sont exclusivement et largement présentes chez les bactéries et qui possèdent un motif A de Walker dans leur séquence. La caractérisation biochimique et l'élucidation du rôle physiologique de cette famille contribueront à élargir nos connaissances en biologie fondamentale, et sont également un préalable vers le développement de nouveaux composés antimicrobiens. Notre étude sur YdiB, un archétype de cette famille chez Bacillus subtilis a révélé à la fois l‟autophosphorylation de YdiB et son activité de protéine kinase. L‟activité kinase de double spécificité Ser/ Thr et Tyr de YdiB semble nécessiter son oligomérisation et semble être stimulée par des molécules basiques telles que des polyamines naturelles ou la poly-L-lysine. Les 10 résidus les plus conservés chez cette famille ont été étudiés afin de mieux comprendre le mécanisme moléculaire de YdiB. Concernant la caractérisation fonctionnelle de la phosphorylation liée à YdiB, l‟étude de l‟opéron ydiA-B-C-D-E de B. subtilis nous a permis de montrer que YdiB et YdiC fonctionnent comme un couple de protéine kinase/phosphatase de deux protéines substrats dont les fonctions seraient liées aux ribosomes, YdiD et YdiE. Une co-localisation partielle entre YdiB et les ribosomes a été observée. En outre, YdiB est capable de phosphoryler des protéines ribosomiques appartennant aux deux sous-unités 50S et 30S, ainsi que deux GTPases impliquées dans la biogénèse des ribosomes, EngA et EngB. Nous avons également démontré que EngA phosphorylée par YdiB est un substrat in vitro de la phosphatase YdiC. Enfin, basé sur le phosphoprotéome de Bacillus subtilis, des peptides mimant des sites de phosphorylation in vivo ont été utilisés. Certains entre eux sont phosphorylés in vitro par YdiB. Deux de ces peptides appartiennent à la superoxyde dismutase, SodA, dont l'activité in vitro et après purification est régulée positivement via la phosphorylation par YdiB. Nous avons ensuite constaté que les cellules de B. subtilis dépourvues du gène ydiB sont plus sensibles aux agents oxidants tels que le paraquat ou la norfloxacine. Nous proposons que, in vivo, YdiB fonctionne comme une protéine kinase impliquée dans l‟activité et/ou la stabilité des ribosomes dans des conditions physiologiques normales, et YdiB contribuerait à protéger les cellules contre les dommages du stress oxydatifGenome sequencing data has revealed genes encoding uncharacterized protein family UPF0079 which are exclusively found in bacteria; broadly distributed in this kingdom and possess an ATP-binding motif in their sequences. Biochemical characterization and physiological role elucidation of UPF0079 will undoubtedly increase our fundamental biology knowledge, and also remain a prerequisite towards the development of new antimicrobial compounds. Our investigation on YdiB, an archetype of this family in Bacillus subtilis revealed both autophosphorylating and protein phosphotransferase activities. The dual-specificity Ser/Thr and Tyr kinase activity of YdiB seems to require oligomerization is upregulated by basic molecule activators such as natural polyamines or poly-L-lysine. The 10 most conserved residues were studied to gain insights into molecular mechanism of the kinase YdiB. To characterize the function of phosphorylation events linked to YdiB, starting with the B. subtilis ydiA-B-C-D-E operon we showed that YdiB and YdiC function as cognate protein kinase/phosphatase towards two ribosome-related protein substrates YdiD and YdiE. Some co-localization between YdiB and ribosomes were observed. Furthermore, YdiB is capable of phosphorylating both ribosomal 50S and 30S subunits as well as two ribosome-binding GTPases EngA and EngB. We also demonstrated that phosphorylated EngA by YdiB is an in vitro substrate of the phosphatase YdiC. Finally, based on the phosphoproteome pf Bacillus subtilis, peptides mimicking the in vivo phosphorylation sites were used. Some of them were found to be phosphorylated in vitro by YdiB, including two peptides which belongs to the superoxide dismutase SodA. The activity of purified SodA was then shown to be upregulated via phosphorylation by YdiB. We furthermore found that B. subtilis cells lacking ydiB become more sensitive to oxidative stress-causing agents such as paraquat or norfloxacin. We propose that in vivo, YdiB functions as a protein kinase involved in ribosome function in normal condition; and in protecting cells from oxidative stress damage
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Akie, Thomas E. "Regulation of Metabolism by Hepatic OXPHOS: A Dissertation." eScholarship@UMMS, 2010. http://escholarship.umassmed.edu/gsbs_diss/857.
Повний текст джерелаАнотація:
Non-alcoholic fatty liver disease (NAFLD) is an increasingly prevalent issue in the modern world, predisposing patients to serious pathology such as cirrhosis and hepatocellular carcinoma. Mitochondrial dysfunction, and in particular, diminished hepatic oxidative phosphorylation (OXPHOS) capacity, have been observed in NAFLD livers, which may participate in NAFLD pathogenesis.
To examine the role of OXPHOS in NAFLD, we generated a model of enhanced hepatic OXPHOS using mice with liver-specific transgenic expression of LRPPRC, a protein which activates mitochondrial transcription and augments OXPHOS capacity. When challenged with high-fat feeding, mice with enhanced hepatic OXPHOS were protected from the development of liver steatosis and inflammation, critical components in the pathogenesis of NAFLD. This protection corresponded to increased liver and whole-body insulin sensitivity. Moreover, mice with enhanced hepatic OXPHOS have increased availability of oxidized NAD+, which promotes complete fatty acid oxidation in hepatocytes.
Interestingly, mice with enhanced hepatic OXPHOS were also protected from obesogenic effects of long-term high-fat feeding. Consistent with this, enhanced hepatic OXPHOS increased energy expenditure and adipose tissue oxidative gene expression, suggesting a communication between the liver and adipose tissue to promote thermogenesis. Examination of pro-thermogenic molecules revealed altered bile acid composition in livers and serum of LRPPRC transgenic mice. These mice had increased expression of bile acid synthetic enzymes, genes which are induced by NAD+ dependent deacetylase SIRT1 activation of the transcriptional co-regulator PGC-1a. These findings suggest that enhanced hepatic OXPHOS transcriptionally regulates bile acid synthesis and dictates whole-body energy expenditure, culminating in protection from obesity.
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Akie, Thomas E. "Regulation of Metabolism by Hepatic OXPHOS: A Dissertation." eScholarship@UMMS, 2015. https://escholarship.umassmed.edu/gsbs_diss/857.
Повний текст джерелаАнотація:
Non-alcoholic fatty liver disease (NAFLD) is an increasingly prevalent issue in the modern world, predisposing patients to serious pathology such as cirrhosis and hepatocellular carcinoma. Mitochondrial dysfunction, and in particular, diminished hepatic oxidative phosphorylation (OXPHOS) capacity, have been observed in NAFLD livers, which may participate in NAFLD pathogenesis.
To examine the role of OXPHOS in NAFLD, we generated a model of enhanced hepatic OXPHOS using mice with liver-specific transgenic expression of LRPPRC, a protein which activates mitochondrial transcription and augments OXPHOS capacity. When challenged with high-fat feeding, mice with enhanced hepatic OXPHOS were protected from the development of liver steatosis and inflammation, critical components in the pathogenesis of NAFLD. This protection corresponded to increased liver and whole-body insulin sensitivity. Moreover, mice with enhanced hepatic OXPHOS have increased availability of oxidized NAD+, which promotes complete fatty acid oxidation in hepatocytes.
Interestingly, mice with enhanced hepatic OXPHOS were also protected from obesogenic effects of long-term high-fat feeding. Consistent with this, enhanced hepatic OXPHOS increased energy expenditure and adipose tissue oxidative gene expression, suggesting a communication between the liver and adipose tissue to promote thermogenesis. Examination of pro-thermogenic molecules revealed altered bile acid composition in livers and serum of LRPPRC transgenic mice. These mice had increased expression of bile acid synthetic enzymes, genes which are induced by NAD+ dependent deacetylase SIRT1 activation of the transcriptional co-regulator PGC-1a. These findings suggest that enhanced hepatic OXPHOS transcriptionally regulates bile acid synthesis and dictates whole-body energy expenditure, culminating in protection from obesity.
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Bi, Chongshan. "The role of caveolin-1 phosphorylation in AQP4 membrane expression in a model of oxidative stress in primary astrocyte cultures." Thesis, University of British Columbia, 2011. http://hdl.handle.net/2429/37065.
Повний текст джерелаАнотація:
Astrocytes play an important role in a wide variety of physiological processes and in
disease states such as ischemia. Ischemic damage in the brain involves apoptotic cell death of
neurons as well as astrocytes and it has been suggested that reactive oxygen species (ROS)
generated as a consequence of ischemia are a major factor in triggering cell death. The waterpermeable
channel, aquaporin 4 (AQP4), which is expressed at high concentrations in astrocytes,
is an important determinant of mortality and morbidity in mice subjected to ischemia, however
the effects of ROS on AQP4 expression and the underlying mechanisms are still obscure. In the
present study, we used primary astrocyte cultures to examine the expression of AQP4 under
oxidative stress using hydrogen peroxide. First, we showed that H₂O₂ induces a significant
increase of both AQP4 mRNA and protein levels and that this effect is inhibited by the antioxidant
N-acetylcysteine. Second, we demonstrated using cell surface biotinylation that H₂O₂
increases AQP4 plasma membrane expression independently of the newly synthesized pool of
AQP4. In parallel, we found that caveolin-1 undergoes a dose- and time-dependent
phosphorylation in astrocytes treated with H₂O₂ and that this effect is inhibited by the src kinase
inhibitor PP2. More importantly, PP2 inhibits the H₂O₂-induced increase in AQP4 cell surface
expression, suggesting that the phosphorylation of caveolin-1 and possibly other proteins may
play a role in this process. To investigate this further, we used MDA-435 cells expressing Y14F
and Y14D caveolin-1 mutants transfected with AQP4 and found that these cells exhibit a
decrease and an increase in AQP4 membrane expression, respectively. Furthermore, caveolin-1
knock down in astrocytes inhibits H₂O₂-induced increase in AQP4 cell surface expression.
Together these findings show that the phosphorylation of caveolin-1 Y14 is a key regulator of
AQP4 cell surface expression in oxidative stress possibly by altering AQP4 internalization and
trafficking resulting in its redistribution within different compartments of the cell.
31
Heiske, Margit [Verfasser], David [Akademischer Betreuer] Fell, Barbara [Akademischer Betreuer] Bakker, Edda [Akademischer Betreuer] Klipp, and Jean-Pierre [Akademischer Betreuer] Mazat. "Modeling the respiratory chain and the oxidative phosphorylation / Margit Heiske. Gutachter: David Fell ; Barbara Bakker ; Edda Klipp ; Jean-Pierre Mazat." Berlin : Humboldt Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2013. http://d-nb.info/1033837261/34.
Повний текст джерела
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Heiske, Margit [Verfasser], David Akademischer Betreuer] Fell, Barbara [Akademischer Betreuer] Bakker, Edda [Akademischer Betreuer] [Klipp, and Jean-Pierre [Akademischer Betreuer] Mazat. "Modeling the respiratory chain and the oxidative phosphorylation / Margit Heiske. Gutachter: David Fell ; Barbara Bakker ; Edda Klipp ; Jean-Pierre Mazat." Berlin : Humboldt Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2013. http://nbn-resolving.de/urn:nbn:de:kobv:11-100208865.
Повний текст джерела
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Chang, Jihye S. "Relationships among Processing Speed, Attention, and Biochemical Features in Children Identified with Mitochondrial Disease." Digital Archive @ GSU, 2011. http://digitalarchive.gsu.edu/psych_theses/80.
Повний текст джерелаАнотація:
Mitochondrial Diseases (MD) are disorders of function in cellular oxidative phosphorylation caused by diverse nuclear DNA and mtDNA mutations and seen in 1/5,000 births. The purpose of this study was to examine relationships across medical indices, biochemical measures, and neurobehavioral functioning in children with MD. Findings from Western Blot, Native Gels, High Resolution Respirometry, and the Nijmegen diagnostic criteria were assessed in relation to children’s processing speed and attention, based on the prediction that impaired functioning of proteins, complexes, and cellular respiration, that are critical in ATP production, will impact neurodevelopment and related neuropsychological processes in children with MD. Twenty-five children (ages 4-13) were administered subtests from the DAS-II and NEPSY-II. Results from multiple regression analyses suggest that processing speed and attention deficits may be markers of abnormal protein expression that interferes with the production of ATP in the oxidative phosphorylation process; implications for future research are presented.
34
Baliūtytė, Giedrė. "Dviskiaučių ginkmedžių (ginkgo biloba l.) Lapų ekstraktų poveikis mitochondrijų oksidacinio fosforilinimo sistemai." Doctoral thesis, Lithuanian Academic Libraries Network (LABT), 2011. http://vddb.laba.lt/obj/LT-eLABa-0001:E.02~2011~D_20110922_122213-85776.
Повний текст джерелаАнотація:
Vieni populiariausių vaistinių preparatų Europoje yra dviskiaučių ginkmedžių (Ginkgo biloba L.) lapų preparatai. Nors Ginkgo biloba lapų ekstraktai pasižymi plačiu farmakologiniu pritaikymu, tačiau nėra daug duomenų apie jų poveikį mitochondrijoms. Todėl darbo tikslas buvo ištirti dviskiaučių ginkmedžių lapų ekstraktų poveikį žiurkės širdies ir kepenų mitochondrijų oksidacinio fosforilinimo sistemai. Darbo uždaviniai: 1. Ištirti dviskiaučių ginkmedžių lapų ekstraktų poveikį žiurkės širdies permeabilizuotų skaidulų bei izoliuotų širdies ir kepenų mitochondrijų kvėpavimui. 2. Ištirti dviskiaučių ginkmedžių lapų tinktūros poveikio oksidaciniam fosforilinimui širdies mitochondrijose mechanizmą. 3. Įvertinti dviskiaučių ginkmedžių lapų tinktūros poveikį izoliuotos žiurkės širdies elektromechaniniam aktyvumui ir nustatyti kaip greit tinktūros komponentai patenka į ląstelę ir mitochondrijas. 4. Ištirti ar dviskiaučių ginkmedžių lapų tinktūra apsaugo širdies mitochondrijas nuo žalingo išemijos/reperfuzijos poveikio. 5. Ištirti dviskiaučių ginkmedžių lapų tinktūros poveikį mitochondrijų oksidacinio fosforilinimo sistemai in vivo, įvedant ją per os.Ginkgo biloba-derived preparations have become widely used in medical practice. Thougt extracts of Ginkgo biloba leaves have a wide pharmacological application, little is known about extract effects on mitochondria. Therefore, the aim of this study was to investigate the influence of extracts of Ginkgo biloba leaves on mitochondrial oxidative phosphorylation system. The tasks of the study were following: 1. To investigate the effects of extract of Ginkgo biloba leaves on the respiration of isolated heart and liver mitochondria and permeabilized heart fibers. 2. To analyze the mechanism(s) of extract of Ginkgo biloba leaves on mitochondrial oxidative phosphorylation system. 3. To determine the effect of extract of Ginkgo biloba leaves on perfused rat heart electromechanical activity and to analyze how GBE given to isolated perfused rat hearts readily can penetrate into the heart cells and mitochondria. 4. To test whether perfusion with Ginkgo biloba extract protects heart mitochondria against ischemia/reperfusion damage. 5. To investigate the effect of extract of Ginkgo biloba leaves on mitochondrial oxidative phosphorylation system in vivo.
35
O'Brien, Laura. "Mitochondrial biogenesis and electrical properties of hPSC-derived motor neurons." VCU Scholars Compass, 2015. http://scholarscompass.vcu.edu/etd/3804.
Повний текст джерелаАнотація:
Human pluripotent stem cells (hPSCs), including human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) hold great promise in the fields of drug development and regenerative medicine. If iPSCs reprogrammed from patient cells replicate what is seen in vivo they may be used as a model of disease. A process that is disrupted in many neurodegenerative diseases is mitochondrial biogenesis. One of these diseases is amyotrophic lateral sclerosis (ALS), which is characterized by loss of motor neurons in the brain and spinal cord. Differentiation of hPSCs into motor neurons offers a way to study a previous unavailable cell type and may further our understanding of human motor neuron biology. The aims of the present study were to differentiate motor neurons from hESCs and iPSCs in low oxygen conditions and to explore mitochondrial biogenesis and electrical maturation during this process. After three weeks of treatment with retinoic acid and purmorphamine, a sonic hedgehog agonist, cells increased expression of post mitotic spinal motor neuron markers. One week later electrophysiological analysis revealed voltage-gated currents and action potential generation. Mitochondrial biogenesis signaling and expression of respiratory chain proteins increased with motor neuron differentiation. Respiration analysis revealed a decrease in glycolysis in motor neurons compared to neural stem cells. Interestingly, this was not accompanied by an increase in basal respiration or mitochondrial mass. These findings enhance our understanding of motor neuron mitochondrial biogenesis, a process impaired in ALS.
36
Woschnagg, Charlotte. "The oxidative metabolism by eosinophils : Effects of allergen exposure and interleukin-5." Doctoral thesis, Uppsala University, Department of Medical Sciences, 2000. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-514.
Повний текст джерелаАнотація:
In this thesis the oxidative metabolism by blood eosinophils from birch pollen allergic subjects was studied and compared to that by eosinophils from healthy controls, during and out of the pollen season. The effects and mechanisms of in vitro IL-5 priming on blood eosinophils were investigated and compared to the effects of in vivo priming during pollen exposure.
The main findings of this work were that the oxidative metabolism by blood eosinophils taken from pollen allergic subjects is reduced during the pollen season. The eosinophils taken from asymptomatic allergics have a reduced capacity to produce oxygen free radicals as compared to non-allergic controls. The oxidative metabolism by blood eosinophils from allergic subjects is primed in vivo during the pollen season, as compared to the healthy controls and as compared to out of season. IL-5 primed the oxidative metabolism by eosinophils from allergic subjects in a similar way as eosinophils from healthy controls, both during and out of pollen exposure. The total and tyrosine phosphorylation patterns obtained were identical in eosinophils from allergic subjects and non-allergic controls during the pollen season. Spontaneous phosphorylation was the same in both groups and different from that after IL-5 priming. The oxidative metabolism of blood eosinophils is composed of different stages. The initial stage, measured as the t½rises of the CL curves, is an indication of the state of priming of the cell, while the end stage, measured as the peaks of the CL curves, is an estimate of the total radical production by the cells. IL-5 priming affected these two stages differently and the two stages are regulated by different signal transduction pathways and IL-5 priming causes a by-passing of MEK.
In conclusion, in this thesis it is shown that blood eosinophils from allergic subjects are primed in vivo during exposure to their allergen. This in vivo priming leads on one hand to a reduced oxidative metabolism during the pollen season, but also to a faster onset of radical production as a response to certain stimuli. Our data do not provide any evidence of IL-5 involvement in the in vivo priming of blood eosinophils from allergic patients during pollen exposure.
37
Annunen-Rasila, J. (Johanna). "Molecular and cell phenotype changes in mitochondrial diseases." Doctoral thesis, University of Oulu, 2007. http://urn.fi/urn:isbn:9789514284427.
Повний текст джерелаАнотація:
Abstract
The mitochondrial oxidative phosphorylation system (OXPHOS) generates energy but also deleterious reactive oxygen species (ROS). Changes in the cytoskeleton, composed mainly of microfilaments, microtubules and intermediate filaments, have been observed in OXPHOS deficiency. The 3243A>G point mutation in mitochondrial DNA (mtDNA) leads to mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), which is the most common mitochondrial disease. Interestingly, mitochondrial aberrations have been demonstrated in patients with a mutation in NOTCH3, the genetic cause of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).
Randomization of vimentin intermediate filament direction and length together with slower population growth was observed in myoblasts with 3243A>G, with no difference in the amount of apoptotic cell death. Upon complex IV inhibition (with or without the microtubule-depolymerizing compound nocodazole) or a lack of mtDNA (ρ0) in osteosarcoma cells the vimentin network collapsed perinuclearly, forming thick bundles, whereas complex I inhibition led to thinner vimentin network bundles. Furthermore, the amount of vimentin was increased in ρ0 cells. Mitochondria accumulated around the nucleus upon complex IV inhibition and in ρ0 cells. Analysis of the total proteome revealed that specific OXPHOS deficiencies led to changes in the expression of cytoskeletal proteins and proteins involved in apoptosis, OXPHOS, glycolysis and oxidative stress response. Muscle histochemical and genetic analysis showed ragged red fibres and cytochrome c oxidase-negative fibres to be associated with 5650G>A in a patient with R133C in NOTCH3 and 5650G>A in MTTA. Immunolabelling of cells with R133C and 5650G>A revealed a sparse tubulin network with asters and less abundant mitochondria by comparison with control cell lines. Comparison of nucleotide diversity between CADASIL pedigrees and controls showed increased mtDNA sequence variation in the CADASIL patients. Also maternal relatives in two CADASIL pedigrees differed from each other in their mtDNA.
These findings suggest that defects in OXPHOS lead to selective changes in the vimentin network, which may have a role in the pathophysiology of mitochondrial diseases. They also suggest a relationship between NOTCH3 and mtDNA, and establish the pathogenicity of 5650G>A. The overall results emphasize that a deficiency in the energy converting system together with oxidative stress can lead to cytoskeletal changes.
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Parmar, Gaganvir. "Protein Factors Regulating Mitochondrial Respiratory Supercomplexes." Thesis, Université d'Ottawa / University of Ottawa, 2021. http://hdl.handle.net/10393/42350.
Повний текст джерела
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N'gadjaga, Maimouna Djamila Sadio. "Influence and reliance of Chlamydia trachomatis on host glucose metabolism." Electronic Thesis or Diss., Sorbonne université, 2021. http://www.theses.fr/2021SORUS486.
Повний текст джерелаАнотація:
Les microorganismes à développement intracellulaire exercent une pression importante sur le métabolisme de leur hôte, car ils obtiennent tous leurs nutriments de son cytoplasme. Les bactéries intracellulaires obligatoires Chlamydia trachomatis en sont une illustration extrême : elles dépendent de leur hôte non seulement pour l’apport en glucose, leur source principale de carbone, mais probablement aussi, au moins partiellement, pour l’obtention de la monnaie énergétique issue du catabolisme du glucose, l’adénosine triphosphate (ATP). Ces bactéries effectuent un cycle de développement biphasique: les bactéries infectieuses, ou corpsélémentaires (EBs), adhèrent à la membrane d’une cellule hôte, typiquement une cellules épithéliale du tractus génital, et provoquent leur internalisation. Une fois à l’intérieur d’un compartiment délimité par une membrane, appelé inclusion, les bactéries expriment un nouveau jeu de gènes et se transforment en corps réticulés (RBs). Le métabolisme des RBs, qui constitue la seule forme réplicative des bactéries, est plus élevé que celui des EBs. Les bactéries se multiplient plusieurs fois dans l’inclusion jusqu’à ce que les RBs se convertissent en EBs, qui, une fois relargués de la cellule-hôte, peuvent initier un nouveau cycle infectieux. La pressionmétabolique exercée par les bactéries sur leur hôte évolue donc tout au cours du temps. Savoir si l’infection module le métabolisme de son hôte, et dans quelle mesure les différentes étapes du cycle de développement dépendent de ce métabolisme, demeurent des questions ouvertes. Dans ce travail, en utilisant des cellules épithéliales primaires et une lignée cellulaire d’origine non tumorale, nous avons montré que les deux voies métaboliques principales pour la production d’ATP chez l’hôte, la glycolyse et la phosphorylation oxydative, restaient largement stables durant l’infection. Ces résultats indiquent que contrairement à nos attentes, il n’y a pasde basculement significatif du métabolisme de l’hôte vers la glycolyse durant l’infection. L’inhibition de l’une ou l’autre de ces deux voies diminue fortement la capacité des bactéries à effectuer leur cycle de développement. Bien que les EBs démontrent un certain degré d’autonomie énergétique pour la synthèse des protéines exprimées dans la phase initiale de l’infection, une glycolyse fonctionnelle est requise pour accompagner la formation des inclusions, tandis que la phosphorylation oxydative est moins nécessaire à ce stade précoce du développement. L’importance relative des deux voies pour soutenir les étapes initiales de l’infection corrèle avec leur contribution respective à maintenir le niveau d’ATP dans les cellules épithéliales, la glycolyse étant le contributeur principal. En conclusion, ce travail confirme la dépendance des bactéries vis à vis de la capacité de production d’ATP de l’hôte. Cependant, la consommation d’ATP par les bactéries semble en équilibre avec la production normale des cellules épithéliales et la production autonome par les bactéries, en sorte que le métabolisme de l’hôte ne nécessite pas de remodelage profond pour répondre aux besoins des bactériesMicroorganisms with an intracellular development lifestyle exert a strong pressure on the metabolism of their host, since they obtain all their nutriments from its cytoplasm. The obligate intracellular bacteria Chlamydia trachomatis provides an extreme illustration of this: they rely on the host not only for the supply of glucose, their main carbon source, but probably also, at least partially, for the supply of the energy currency generated through glucose catabolism, adenosine triphosphate (ATP). These bacteria undergo a particular biphasic developmental cycle: the infectious bacteria, or elementary bodies (EBs), adhere to the membrane of a host cell, typically of the epithelium of the genital tract, and trigger their internalization. Once inside a membrane-bound compartment, called an inclusion, the bacteria express a new set of genes and convert to reticulate bodies (RBs). This only replicative form of the bacteria has a higher metabolism than EBs. Bacteria multiply in the inclusion several times until RBs convert back to EBs, which, once released, can initiate a new infectious cycle. The metabolic pressure exerted by the bacteria on their host thus evolves with time. However, whether infection modulates the metabolism of its host, and the degree of the reliance of individual steps of the bacterial development cycle on host metabolism, remain largely unknown. In this work, using primary epithelial cells and a cell line of non tumoral origin, we showed that the two main ATP producing pathways of the host, glycolysis and oxidative phosphorylation, remained fairly stable during infection. These results suggest that, against our expectations, there is no significant shift of the host metabolism towards glycolysis during infection. Inhibition of either pathway strongly reduced the capacity of the bacteria to undergo a developmental cycle. While EBs showed some degree of energetic autonomy in the synthesis of the first proteins expressed at the onset of infection, a functional glycolysis was necessary for the establishment of early inclusions, while oxidative phosphorylation is less needed at this early stage of development. The relative importance of the two pathways to sustain the initial steps of infection correlates with their relative contribution in maintaining ATP levels in epithelial cells, glycolysis being the main contributor. Altogether, this work confirms the dependence of the bacteria on the ATP production capacity of the host. However, ATP consumption by the bacteria appears to be fairly balanced with the normal production capacity of the host, and the autonomous production capacity of the bacteria, so that no major shift in host metabolism is required to meet bacterial needs
40
Naumenko, Nataliia [Verfasser], Peter [Akademischer Betreuer] Rehling, Blanche [Gutachter] Schwappach, and Reinhard [Gutachter] Luehrmann. "Function of the INA complex in assembly of the mitochondrial oxidative phosphorylation system / Nataliia Naumenko ; Gutachter: Blanche Schwappach, Reinhard Luehrmann ; Betreuer: Peter Rehling." Göttingen : Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2017. http://d-nb.info/1136785132/34.
Повний текст джерела
41
Rennison, Julie Helene. "Effects of High Saturated Fat on Myocardial Contractile and Mitochondrial Function in Heart Failure." Case Western Reserve University School of Graduate Studies / OhioLINK, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=case1214425351.
Повний текст джерела
42
Gracia-Maldonado, Gabriel. "Exploiting the MLL-rearranged leukemia gene signature to identify molecular targets for novel therapies." University of Cincinnati / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1573570752309466.
Повний текст джерела
43
Sutton, Selina Kaye. "How does mitochondrial heteroplasmy affect cell proliferation?" Thesis, University of Canterbury. Biological Sciences, 2006. http://hdl.handle.net/10092/1306.
Повний текст джерелаАнотація:
Mitochondrial mutations and heteroplasmy have been associated with disease states that result from inadequate cellular energy production. As mitochondrial DNA (mtDNA) encodes many of the polypeptides involved in oxidative phosphorylation (OXPHOS), mtDNA mutations may lower energy production which is required for cell division and sustained ATP synthesis. In order to test the relationship between mtDNA mutations and the rate of cell division, a mammary epithelial cancer cell line, MCF-7, is used as a model. Nine proliferate single cell clones have been isolated from MCF-7. Population doubling times of six single cell clones and the MCF-7 stock have been determined. Clones with distinctly different growth rates were selected for mutational analysis. Growth rates of these clones appeared to be different from each other. Using polymerase chain reaction (PCR) and DNA sequencing, three cases of heteroplasmy have been identified in the mitochondrial genes of the MCF-7 stock and four single cell clones (ATPase C9119T, ND6 T14300G, Cytb G15807A). Heteroplasmy present in the Cytb gene is differs between single cell clones. Differences between the growth rates may be indicative of metabolic variations in these single cell clones. The OXPHOS enzymes encoded by the mutated genes were quantified by standard enzymatic assays. The assays demonstrated significant differences in specific activity between the clones, but were not correlated with mitochondrial heteroplasmy. This thesis determines that the differences in specific activity observed between clones is of nuclear origin.
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Bumbliauskinė, Jankauskaitė Lina. "Study of Perilla L. species and varieties cultivation, phytochemical composition and biological effect." Doctoral thesis, Lithuanian Academic Libraries Network (LABT), 2011. http://vddb.laba.lt/obj/LT-eLABa-0001:E.02~2011~D_20110309_111240-41438.
Повний текст джерелаАнотація:
Perilla L. are significant for multi-pharmacological effect. The aim of this work is to study Perilla L. growth and develop¬ment tendencies, productivity; composition of biologically active compounds and their variations during the vegetation period, and the biological effect of the extracts; to select perspective plants for cultivation in Lithuania and for production of medicinal preparations. The objectives of the Study: To investigate and determine growth dynamics of Perilla L. species and varieties during the vegetation period and to assess the influence of climate conditions on the vegetation rhythmic. To assess the quantity dynamics of Perilla L. species and varieties herbal medicinal raw material and to compare the productivity of Perilla L. species and varieties. To determine the quantity of the essential oil in Perilla L. species and varieties and to identify the chemotypes of the plants. To determine the qualitative composition and variation dynamics of the phenolic acids in Perilla L. species and varieties. To determine the composition and variation dynamics of the flavone complex in Perilla L. species and varieties. To determine the composition and variation dynamics of antho¬cyanidines in Perilla L. species and varieties. To assess the radical scavenging activity of the extracts of Perilla L. species and varieties raw materials. To research the effect of Perilla L. extracts on the oxidative phosphorylation in the rat heart mitochondria.Perilla L. genties vienmečiai vaistiniai augalai yra augaliniai imunomoduliatoriai, pasižymintys daugeliu farmakologinių poveikių. Darbo tikslas: Ištirti Vidurio Lietuvoje auginamų Perilla L. rūšių ir varietetų augimo ir vystymosi dėsningumus, biologiškai aktyvių junginių sudėtį ir jų įvai¬ravimą vegetacijos metu bei ekstraktų biologinį poveikį; atrinkti perspek¬tyvius augalus auginimui Lietuvoje. Uždaviniai: Ištirti ir nustatyti Perilla L. augimo dinamiką vegetacijos metu ir įvertinti klimatinių veiksnių įtaką augalų vegetacijai. Įvertinti Perilla L. vaistinės augalinės žaliavos kiekio dinamiką vege¬tacijos metu ir palyginti Perilla L. rūšių ir varietetų produk¬tyvumą. Nustatyti Perilla L. rūšių ir varietetų eterinio aliejaus kiekį auga¬luose vegetacijos metu ir identifikuoti augalų chemotipus. Nustatyti Perilla L. rūšių ir varietetų fenolinių rūgščių kokybinę sudėtį ir jų kitimo dėsningumus vegetacijos metu. Nustatyti Perilla L. rūšių ir varietetų flavonų komplekso sudėtį ir kitimo dinamiką vegetacijos metu. Nustatyti Perilla L. rūšių ir varietetų antocianidinų sudėtį bei kitimo dinamiką vegetacijos metu. Įvertinti Perilla L. rūšių ir varietetų žaliavų ekstraktų antiradikalinį aktyvumą. Ištirti Perilla L. rūšių ir varietetų ekstraktų poveikį žiurkės širdies mitochondrijų oksidaciniam fosforilinimui. Tyrimų rezultatai ir poveikiu pasižyminčių junginių identifikavimas atveria perspektyvas ateities tyrimams, kurie reikalingi kuriant preparatus iš perilių augalinių žaliavų.
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Potter, Michelle. "Development of models and methods to assess the efficacy of anti-cancer drugs targeted to the mitochondria." Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:6a847ae9-3664-437e-ad26-c1ae3d94f7c0.
Повний текст джерелаАнотація:
Background: Malignant transformation of cells is typically characterised by aerobic glycolysis, resulting in supressed mitochondrial function, a state that helps resistance to apoptosis. This characteristic has been widely accepted as a hallmark of cancer and has been shown to be of critical importance in tumour development. The bioenergetic differences between normal and malignant cells are being exploited to identify potential cancer specific therapeutics. Improved in-vitro models are required to aid the identification and assessment of candidate drugs. In this project, we investigated the bioenergetic phenotypes of a panel of adult and paediatric cancer cell lines and evaluated the potential of 3D models as a platform for testing drugs that target cancer metabolism. We also investigated a novel method to assess mitochondrial function that enables the quantification of the level of oxygenation within the cell. Results: The results presented in this thesis show that not all cancers display this aerobic glycolytic phenotype. We found that while some cell lines displayed the Warburg phenotype others displayed high levels of oxidative metabolism. These bioenergetic profiles need to be considered when deciding which anti-cancer drugs to use in a chemotherapeutic regime. If a bioenergetic pattern can be identified it may one day form the basis of a screening strategy for tumours. Dichloroacetate (DCA) is a small molecule PDK inhibitor that was investigated in this study. It was found to be relatively non-toxic to cells cultured in 2D but had improved toxicity when the cells were cultured in a 3D environment. Lastly, we evaluated a new oxygen sensing nanoprobe, Mito-Xpress Intra, and the results demonstrate its potential as a non-invasive means of measuring oxygen concentrations within the cell in real time as well as highlighting some striking differences between applied ambient and measured intracellular oxygen concentrations. Conclusion: The findings suggest that not all cancers display the characteristic glycolytic phenotype. They also highlight the importance of controlling oxygen and glucose levels when evaluating metabolism and when drug testing.
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Žūkienė, Rasa. "Hipertermijos poveikio mitochondrijų oksidacinio fosforilinimo sistemai tyrimas." Doctoral thesis, Lithuanian Academic Libraries Network (LABT), 2008. http://vddb.library.lt/obj/LT-eLABa-0001:E.02~2008~D_20080721_124917-64300.
Повний текст джерелаАнотація:
Ląstelių atsako į nuosaikią hipertermiją molekulinio mechanizmo išaiškinimas yra labai svarbus norint suprasti procesus, kurie vyksta ląstelėse jas kaitinant gydymo tikslais ar organizmui karščiuojant. Šio darbo tikslas buvo nustatyti ir palyginti švelnios (karščiavimo) ir šiurkščios hipertermijos poveikį oksidacinės fosforilinimo sistemos funkcijoms normalių audinių mitochondrijose. Pirmą kartą panaudojome modulių kinetinę analizę hipertermijos poveikiui širdies ir kepenų mitochondrijų oksidacinio fosforilinimo sistemai tirti. Mes nustatėme, kad švelnios hipertermijos (42 ºC) poveikis širdies mitochondrijų funkcijoms yra grįžtamas, bet šiurkštesnė hipertermija (45 ºC) sukelia dalinai negrįžtamą kvėpavimo ir fosforilinimo atskyrimą bei mitochondrijų kvėpavimo greičio trečioje metabolinėje būsenoje slopinimą. Hipertermija didino ROS gamybos greitį ir lipidų peroksidaciją, kurie buvo didžiausi karščiavimo temperatūroje. Nustatėme, kad kepenų mitochondrijų ir hepatocitų atsakas į hipertermiją priklauso nuo žiurkės lyties ir temperatūros. Atlikome palyginamąjį širdies ir kepenų mitochondrijų sandų fazinių virsmų analizę diferencine skenuojamaja kalorimetrija ir nustatėme būdingus skirtumus.The elucidation of the molecular mechanism of the cell response to moderate heating is of importance for understanding the events that occur in the cell upon use of heating for therapeutic purpose or during illnesses that are associated with fever. The aim of this work was to investigate and to compare the effects of mild (fever) and severe hyperthermia on functional properties of oxidative phosphorylation system in normal tissue mitochondria. Modular kinetic analysis for the first time was applied to evaluate effects of hyperthermia on oxidative phosphorylation in rat heart and liver mitochondria. We demonstrated that changes in mitochondrial functions induced by mild hyperthermia (42 ºC) are reversible but more severe hyperthermia (45 ºC) causes partially irreversible uncoupling and inhibition of mitochondrial respiration in state 3, hyperthermia remarkably (3.6-2.1 fold) activates ROS generation in heart mitochondria and that maximal increase in rate of H2O2 production and lipid peroxidation is observed in the fever temperature range. We show that the response of liver mitochondria and hepatocytes to hyperthermia is to certain extent dependent on gender and temperature. Specific differences of male rat liver and heart mitochondrial components phase transitions have been revealed by DSC analysis.
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Gollihue, Jenna L. "MITOCHONDRIAL TRANSPLANTATION AFTER SPINAL CORD INJURY: EFFECTS ON TISSUE BIOENERGETICS AND FUNCTIONAL NEUROPROTECTION." UKnowledge, 2017. http://uknowledge.uky.edu/physiology_etds/35.
Повний текст джерелаАнотація:
Contusion spinal cord injury (SCI) results in devastating life-long debilitation in which there are currently no effective treatments. The primary injury site presents a complex environment marked by subsequent secondary pathophysiological cascades involving excessive reactive oxygen and nitrogen species (ROS/RNS) production, glutamate-induced excitotoxicity, calcium dysregulation, and delayed neuronal apoptosis. Many of these cascades involve mitochondrial dysfunction, thus a single mitochondrial-centric therapy that targets a variety of these factors could be far reaching in its potential benefits after SCI. As such, this dissertation examines whether transplantation of exogenous mitochondria after SCI can attenuate secondary injury cascades to decrease the spread and severity of the injury.
Our first experiment tested the dose-dependent effects of mitochondrial transplantation on the ability to maintain acute overall bioenergetics after SCI. We compared transplantation of mitochondria originating from two different sources-cultured PC12 cells or rat soleus leg muscle. 24 hours after injury, State III oxygen consumption rates were maintained to over 80% of sham levels when 100ug of mitochondria was transplanted, regardless of the origin of the mitochondria. Complex I enzyme activity assays corroborated our findings that the 100ug dosage gave optimal benefits compared to vehicle injection.
We also analyzed the rostral-caudal distribution and cell-type colocalization of transplanted transgenically-labeled tGFP mitochondria after SCI. There were greater volumes and rostral-caudal spread of tGFP mitochondria at the 24 hour time point compared to 7 days post injection. tGFP mitochondria had the greatest propensity to colocalize with macrophages and pericytes. Colocalization was evident in endothelial cells, oligodendrocytes and astrocytes, though no such colabeling was present in neurons. Further, colocalization of tGFP was always greater at the 24 hour time compared to 48 hour or 7days post injection time points. These data indicate that there is a cell-type difference in incorporation potential of exogenous mitochondria which changes over time.
Finally, we tested the effects of mitochondrial transplantation on long term functional recovery. Animals were injected with either vehicle, 100ug cell-derived mitochondria, or 100ug muscle-derived mitochondria immediately after contusion SCI. Functional analyses including BBB overground locomotor scale and von Frey mechanical sensitivity tests did not show any differences between treatment groups. Likewise, there were no differences in tissue sparing when mitochondria were transplanted compared to vehicle injections, though there were higher neuronal cell counts in tGFP mitochondria injected groups caudal of the injury site.
These studies present the potential of mitochondrial transplantation for therapeutic intervention after SCI. While our acute measures do not correspond into long term recovery, we show that at 24 hours transplanted mitochondria do have an effect on bioenergetics and that they are taken into host cells. We believe that further investigation into caveats and technical refinement is necessary at this time to translate the evident acute bioenergetic recovery into long term functional recovery.
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Foster, Cerrone R., Laura L. Daniel, Christopher R. Daniels, Suman Dalal, Mahipal Singh, and Krishna Singh. "Deficiency of Ataxia Telangiectasia Mutated Kinase Modulates Cardiac Remodeling Following Myocardial Infarction: Involvement in Fibrosis and Apoptosis." Digital Commons @ East Tennessee State University, 2013. https://dc.etsu.edu/etsu-works/8570.
Повний текст джерелаАнотація:
Ataxia telangiectasia mutated kinase (ATM) is a cell cycle checkpoint protein activated in response to DNA damage. We recently reported that ATM plays a protective role in myocardial remodeling following β-adrenergic receptor stimulation. Here we investigated the role of ATM in cardiac remodeling using myocardial infarction (MI) as a model. Methods and Results: Left ventricular (LV) structure, function, apoptosis, fibrosis, and protein levels of apoptosisand fibrosis-related proteins were examined in wild-type (WT) and ATM heterozygous knockout (hKO) mice 7 days post-MI. Infarct sizes were similar in both MI groups. However, infarct thickness was higher in hKO-MI group. Two dimensional M-mode echocardiography revealed decreased percent fractional shortening (%FS) and ejection fraction (EF) in both MI groups when compared to their respective sham groups. However, the decrease in %FS and EF was significantly greater in WT-MI vs hKO-MI. LV end systolic and diastolic diameters were greater in WT-MI vs hKO-MI. Fibrosis, apoptosis, and α-smooth muscle actin staining was significantly higher in hKO-MI vs WT-MI. MMP-2 protein levels and activity were increased to a similar extent in the infarct regions of both groups. MMP-9 protein levels were increased in the non-infarct region of WT-MI vs WT-sham. MMP-9 protein levels and activity were significantly lower in the infarct region of WT vs hKO. TIMP-2 protein levels similarly increased in both MI groups, whereas TIMP-4 protein levels were significantly lower in the infarct region of hKO group. Phosphorylation of p53 protein was higher, while protein levels of manganese superoxide dismutase were significantly lower in the infarct region of hKO vs WT. In vitro, inhibition of ATM using KU-55933 increased oxidative stress and apoptosis in cardiac myocytes.
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Kaaman, Maria. "Role of inflammatory and mitochondria genes in adipose tissue and obesity /." Stockholm, 2007. http://diss.kib.ki.se/2007/978-91-7357-331-3/.
Повний текст джерела
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Vahlas, Zoï. "Régulation métabolique de l'infection des cellules T CD4 par VIH-1 : vers de nouvelles cibles thérapeutiques." Thesis, Montpellier, 2020. http://www.theses.fr/2020MONTT009.
Повний текст джерелаАнотація:
La susceptibilité des lymphocytes T CD4 (LT) à l'infection par VIH-1 est régulée par le métabolisme du glucose et de la glutamine. Cependant, les contributions relatives de ces nutriments à l'infection étaient peu connues lorsque j’ai débuté ma thèse. Au cours de mes travaux, j'ai identifié la glutaminolyse comme une voie majeure alimentant la phosphorylation oxydative (OXPHOS) dans les sous-populations de LT activés naïves et mémoires, et j'ai découvert que l'induction de ce réseau métabolique est nécessaire pour une infection optimale par VIH-1. J’ai constaté qu’en condition limitante en glutamine, l’α-kétoglutarate (α-KG), un intermédiaire du cycle TCA (TriCarboxylic Acid) issu de la glutaminolyse, constitue un facteur clé de l'infection des LT CD4 par VIH-1. L'ajout d’α-KG exogène induit une augmentation rapide du ratio OXPHOS/glycolyse et rend les LT naïfs et mémoires plus susceptibles à l’infection. Par ailleurs, l’inhibition du flux glycolytique du pyruvate vers le lactate induit une augmentation de l'OXPHOS et de l'infection des LT CD4 par VIH-1. En accord avec ces données, les LT CD4 infectés présentent une augmentation de la biomasse et de l'activité mitochondriale en comparaison à leurs homologues non infectés. Ces données identifient l'équilibre OXPHOS/glycolyse aérobie comme un élément clé de l'infection des LT par VIH-1.Afin de mieux appréhender les voies métaboliques régulant l'infection des LT par VIH-1, j'ai développé une approche complémentaire basée sur l’utilisation de shRNA ciblant spécifiquement les transporteurs de nutriments GLUT1, ASCT2 et CAT1, permettant notamment le transport du glucose, glutamine et arginine dans la cellule, respectivement. Ainsi, j’ai observé une diminution de la survie d’environ 80% des cellules shRNA+, témoignant ainsi de l’importance de ces transporteurs lors de l’activation de ces cellules. Cependant, la permissivité des LT CD4 à l’infection par VIH-1 est impactée différemment par la diminution de l’expression des transporteurs de nutriments. Conformément aux données présentées ci-dessus, l’inhibition de GLUT1 n'a pas eu d'impact significatif sur l'infection par VIH-1, tandis que l’inhibition de CAT1 a réduit de manière significative l’OXPHOS ainsi que l'infection par VIH-1 (de 35 %). Il est toutefois surprenant de constater que l’inhibition d’ASCT2 entraîne une augmentation de l'infection de 20 %. Cela était associé à une persistance significativement plus élevée des cellules T naïves dont l’expression d’ASCT2 était inhibée, par rapport aux LT mémoires. Ces données mettent ainsi en évidence l’importance relative de ces 3 transporteurs de nutriments dans la survie des LT naïfs par rapport aux LT mémoires et démontrent leur impact spécifique sur la permissivité de ces populations à l'infection par VIH-1.En conclusion, en utilisant deux approches complémentaires, mes travaux de thèse révèlent l'impact critique de l'état énergétique d'une cellule T CD4 sur sa susceptibilité à l'infection par VIH-1. Mes données mettent en évidence l'importance du métabolisme mitochondrial, avec un environnement riche en intermédiaires du cycle du TCA comme l’α-KG, dans la régulation de la sensibilité des LT à l'infection par VIH-1. En outre, l'expression des transporteurs de nutriments impacte différentiellement la sensibilité des LT naïfs et mémoires à l'infection par VIH-1. Ces études offrent donc de nouvelles perspectives utilisant le métabolisme pour le développement de stratégies thérapeutiques ciblées contre l'infection par VIH-1The susceptibility of CD4 T cells to HIV-1 infection is regulated by glucose and glutamine metabolism, but the relative contributions of these nutrients to infection are not known. During my PhD, I identified glutaminolysis as a major pathway fueling oxidative phosphorylation (OXPHOS) in activated naïve as well as memory CD4 cell subsets, and found that induction of this metabolic network is required for optimal HIV-1 infection. Moreover, we determined that under conditions of attenuated glutaminolysis, the α-ketoglutarate (αKG) TCA (tricarboxylic acid) cycle intermediate is a rate-limiting step in infection; exogenous α-KG directly increased OXPHOS and rendered both naïve and memory CD4 T cells significantly more sensitive to infection. Furthermore, blocking the glycolytic flux of pyruvate to lactate resulted in an increased OXPHOS and a significantly augmented level of HIV-1 infection. In agreement with these data, infected CD4 T cells exhibited increased mitochondrial biomass and respiration as compared to their non-infected counterparts. These data identify the OXPHOS/ aerobic glycolysis balance as a major regulator of HIV-1 infection in CD4 T lymphocytes.In order to gain more insight into the metabolic pathways regulating HIV-1 infection in CD4 T cells, we developed a complementary approach to target upstream processes, specifically altering glucose (GLUT1), glutamine (ASCT2), and arginine (CAT1) transporter expression by lentiviral-mediated delivery of specific shRNAs. Testifying to the importance of these transporters, CD4 T cells with downregulated expression of either GLUT1, ASCT2 or CAT1 were negatively selected, resulting in a loss of approximately 80% of shRNA-transduced cells within 14 days. Notably, the permissivity of CD4 T cells to HIV-1 infection was differentially impacted by inhibition of specific nutrient transporters. Consistent with the data presented above, knockdown of GLUT1 did not significantly impact HIV-1 infection whereas knockdown of CAT1 significantly decreased both OXPHOS as well as HIV-1 infection (by 35%). Surprisingly though, ASCT2 knockdown resulted in a significantly augmented infection, by approximately 20%. Mechanistically, we found that this was associated with a markedly higher persistence of naïve, as compared to memory, T cells with downregulated ASCT2 levels. These data highlight differences in the relative importance of distinct nutrient transporters in the survival of naïve vs memory CD4 T cell subsets and demonstrate their specific impact on the sensitivity of these populations to HIV-1 infection.In conclusion, using two complementary approaches, my PhD research has revealed the critical impact of a CD4 T cell’s energetic state on its susceptibility to HIV-1 infection. My data identify the importance of mitochondrial metabolism, with an environment rich in TCA cycle intermediates such as α-KG, in regulating the susceptibility of CD4 T cells to HIV-1 infection. Furthermore, I find that nutrient transporter expression differentially impacts the sensitivity of naïve and memory CD4 T cells to HIV-1 infection. These studies therefore provide new prospects for the development of targeted metabolic therapeutic strategies against HIV-1 infection