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Vermulst, Marc. "Untangling mitochondrial mutagenesis and aging in mice /." Thesis, Connect to this title online; UW restricted, 2008. http://hdl.handle.net/1773/6321.
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Kawashima, Tsuneaki. "Constitutive SIRT1 overexpression impairs mitochondria and reduces cardiac function in mice." Kyoto University, 2012. http://hdl.handle.net/2433/157426.
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Jugé, Romain. "Étude de la dynamique mitochondriale dans des cellules cutanées humaines : Mise en place de modèles pour des applications en cosmétologie." Thesis, Lyon, 2016. http://www.theses.fr/2016LYSEN007.
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La peau est un épithélium spécialisé vital et fragile, qui évolue avec l’âge et est influencé par l’environnement, notamment les radiations solaires. Des données sont disponibles sur la réponse du réseau mitochondrial et le devenir des mitochondries endommagées en réponse à des stress chimiques et environnementaux dans plusieurs systèmes expérimentaux, mais ces processus restent peu étudiés dans les cellules cutanées. Dans ce contexte, le projet de thèse visait à analyser l’effet (i) de l’irradiation UVB sur la dynamique mitochondriale (en particulier la fragmentation des mitochondries) dans des kératinocytes primaires humains normaux, qui constituent la première ligne de défense contre les agressions externes ; (ii) d’un traitement par des poisons mitochondriaux sur les mitochondries contenues dans des kératinocytes ou des fibroblastes primaires humains normaux. Dans un premier axe de la thèse, nous avons mis au point une méthode originale (Mitoshape) basée sur l’imagerie confocale, permettant d’estimer à la fois qualitativement et quantitativement la morphologie du réseau mitochondrial dans des cellules vivantes après irradiation UVB. Grâce à cette technologie, nous avons pu montrer que les UVB induisaient une fragmentation du réseau mitochondrial dans les kératinocytes primaires, dont nous avons étudié les acteurs biochimiques. Dans un deuxième axe, nous avons montré que les poisons mitochondriaux avaient la capacité d’endommager les mitochondries dans des kératinocytes et des fibroblastes humains primaires et induisaient une autophagie générale sans toutefois exclure la présence d’une mitophagie dépendante de la voie PINK1/PARKIN. Outre son intérêt fondamental, ce travail (réalisé en collaboration avec la société de cosmétologie SILAB dans le cadre d’un partenariat industriel CIFRE) ouvre la voie à l’identification d’actifs naturels capables de préserver et/ou restaurer les paramètres fonctionnels mitochondriaux suite à des stressThe skin is a specialized type of epithelium, both vital and fragile, which evolves with age and is continuously exposed to environmental stresses, such as solar radiations. While data is available about the response of the mitochondrial network and the fate of damaged mitochondria after chemical or environmental stresses in numerous experimental systems, little is known about these processes in skin cells. The aim of the present thesis was to study the impact (i) of UVB irradiation on mitochondrial dynamics (especially mitochondrial fragmentation) in normal human epidermal keratinocytes, which represent the first line of defence against environmental insults; (ii) of poisoning mitochondria of keratinocytes and normal human fibroblasts with chemical drugs. In a first axis, we developed an original method (called Mitoshape) based on confocal microscopy, to estimate qualitatively and quantitatively the morphology of the mitochondrial network within live cells following UVB irradiation. Using this technology, we demonstrated that UVB irradiation induces mitochondrial fragmentation in normal human keratinocytes, and studied the biochemical actors involved in this response. In a second axis, we showed that the use of mitochondrial poisons could damage mitochondria of keratinocytes and normal human fibroblasts and induce bulk autophagy, although it is not possible to formally rule out the involvement of a PINK1/PARKIN-dependent pathway of mitophagy. In addition to its fundamental interest, this work (performed in collaboration with the cosmetic company SILAB in the context of a CIFRE PhD fellowship from ANRT) paves the way for the screening of novel bioactive agents able to protect and restore mitochondria following stresses
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Puddick, Jonathan. "A comparative proteomics approach to studying skeletal muscle mitochondria from myostatin knockout mice." The University of Waikato, 2006. http://hdl.handle.net/10289/2254.
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Myostatin is a negative regulator of muscle growth. When it is not present or non-functional double-muscling occurs, the primary characteristic of this phenotype being an increase in muscle mass. Another characteristic of double-muscling is an increased proportion of type IIB muscle fibres, which rely on glycolysis as their primary energy source, as opposed to type IIA and type I fibres which rely on oxidative phosphorylation. This switch in muscle metabolism directly impacts on the mitochondria, as mitochondria from glycolytic muscle fibres have been shown to have differences in metabolic activity. The increased proportion of glycolytic muscle fibres present in myostatin knockout animals provides a unique model to investigate alterations in muscle fibre type metabolism. The mouse model of myostatin knockout utilised during this study was generated by genetic deletion of exon three of the myostatin gene. Verification of this knockout was attempted by western blot analysis, but only the latency associated protein (LAP) was detected. Interestingly, the LAP was barely detectable in the knockout muscle suggesting deletion of exon three affects binding of anti-myostatin antibodies to the LAP, as that part of the gene is not deleted. A comparison of the basal mitochondrial stress levels was made, also by western blot analysis. The knockout mitochondria showed no change in levels of heat shock protein 60 or superoxide dismutase 2, indicating that they are not being subjected to any increased stress due to the myostatin knockout phenotype. A comparative proteomics approach was used to detect changes in the mitochondrial proteome of myostatin knockout gastrocnemius muscle to gain clues to how mitochondria from glycolytic muscle fibres differ from those present in oxidative fibres. This was undertaken using two-dimensional electrophoresis (2-DE), in-gel tryptic digests and peptide mass fingerprinting by mass spectrometry. A 2-DE gel protein loading of 220 g was shown to give the best protein spot resolution and the most crucial step in the loading process was found to be the laying of the immobilized pH gradient, which had to be performed very carefully to obtain a consistent loading pattern. This study resolved only around 160 protein spots out of the estimated 1,000 to 2,000 proteins present in the mitochondria. Modulation of six proteins was seen at a plt0.1 level, but were unable to be identified using the current methodology. More abundant mitochondrial proteins were able to be identified, but showed no significant modulation. Malate dehydrogenase and 3-hydroxyacyl-CoA dehydrogenase, which were identified during this study, have been reported to have decreased activity in mitochondria from glycolytic muscle fibres. This study suggests that the change in activity observed by other researchers is due to inhibition of these enzymes in the glycolytic fibres or activation in the oxidative fibres.
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Pan, Minglin, Ying Han, Rui Si, Rui Guo, Ankit Desai, and Ayako Makino. "Hypoxia-induced pulmonary hypertension in type 2 diabetic mice." SAGE PUBLICATIONS INC, 2017. http://hdl.handle.net/10150/623894.
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Hypoxia-induced pulmonary hypertension (HPH) is a progressive disease that is mainly caused by chronic exposure to high altitude, chronic obstructive lung disease, and obstructive sleep apnea. The increased pulmonary vascular resistance and increased pulmonary arterial pressure result in increased right ventricular afterload, leading to right heart failure and increased morbidity. There are several clinical reports suggesting a link between PH and diabetes, insulin resistance, or obesity; however, it is unclear whether HPH is associated with diabetes as a progressive complication in diabetes. The major goal of this study is to examine the effect of diabetic ''preconditioning'' or priming effect on the progression of HPH and define the molecular mechanisms that explain the link between diabetes and HPH. Our data show that HPH is significantly enhanced in diabetic mice, while endothelium-dependent relaxation in pulmonary arteries is significantly attenuated in chronically hypoxic diabetic mice (DH). In addition, we demonstrate that mouse pulmonary endothelial cells (MPECs) isolated from DH mice exhibit a significant increase in mitochondrial reactive oxygen species (ROS) concentration and decreased SOD2 protein expression. Finally, scavenging mitochondrial ROS by mitoTempol restores endothelium-dependent relaxation in pulmonary arteries that is attenuated in DH mice. These data suggest that excessive mitochondrial ROS production in diabetic MPECs leads to the development of severe HPH in diabetic mice exposed to hypoxia.
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Barros, Susana Raquel Costa. "Metabolic adaptations in liver-specific OPA1 knockout mice." Doctoral thesis, Universitat de Barcelona, 2020. http://hdl.handle.net/10803/668803.
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OPA1 is a dynamin-related protein that is responsible for the fusion of the internal mitochondrial membrane and essential to control the morphology of the mitochondrial cristae. Thus, it directly impacts the efficiency of OxPhos and the stability of mitochondrial DNA. In this study, we have explored the effects of hepatic deletion of OPA1 on mitochondrial function and metabolism. We have shown that the ablation of OPA1 in the liver produces a mitochondrial dysfunction characterized by alterations in mitochondrial cristae structure, concomitant with a reduced respiratory capacity and mtDNA copy number, and perturbed mitochondrial proteostasis. The mitochondrial dysfunction caused by the ablation of OPA1 in liver triggers the activation of a mitochondrial stress response, including mitochondrial unfolded stress response (UPRmt) that is probably mediated by the transcription factor ATF5.
Interestingly, we have observed that OPA1 deficiency in the liver causes better glucose tolerance and protects against diet-induced obesity and insulin resistance concomitant to a high circulating levels of the metabolic modulator FGF21. Here we suggest that the systemic protective effects associated to OPA1 ablation are due to the action of FGF21, probably mediated by the mitochondrial stress response associated to OPA1 loss- of-function via ATF5 activation.OPA1 es una proteína relacionada con la dinamina que es responsable de la fusión de la membrana mitocondrial interna y esencial para controlar la morfología de las crestas mitocondriales, afectando directamente la eficiencia de OxPhos y la estabilidad del DNA mitocondrial. En este estudio, hemos explorado los efectos de la eliminación hepática de OPA1 sobre la función mitocondrial y el metabolismo. Hemos demostrado que la ablación de OPA1 en el hígado produce una disfunción mitocondrial caracterizada por alteraciones en la estructura de las crestas mitocondriales, concomitante con una capacidad respiratoria reducida y menor número de copias de DNA miocondrial, y perturbación en la proteostasis mitocondrial. La disfunción mitocondrial causada por la ablación de OPA1 en el hígado desencadena la activación de una respuesta al estrés mitocondrial, incluyendo la respuesta a las proteínas mal plegadas de la mitocondria, que probablemente es mediada por el factor de transcripción ATF5. Curiosamente, hemos observado que la deficiencia de OPA1 en el hígado causa una mejor tolerancia a la glucosa y protege contra la obesidad y resistencia a la insulina inducida por la dieta, en paralelo con un aumento de los niveles de FGF21 circulante, un factor involucrado en la modulación metabólica. Con este estudio proponemos que los efectos sistémicos protectores asociados a la ablación de OPA1 se deben a la acción de FGF21 que probablemente es mediada por la respuesta al estrés mitocondrial asociada a la pérdida de función de OPA1 a través de la activación de ATF5.
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Beauchamp, Brittany. "Low Birth Weight is Associated with Impaired Skeletal and Cardiac Muscle Energetics in Adult Mice." Thesis, Université d'Ottawa / University of Ottawa, 2015. http://hdl.handle.net/10393/32963.
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In utero undernutrition is associated with increased risk for insulin resistance, obesity, and cardiovascular disease during adult life. A common phenotype associated with low birth weight is reduced skeletal muscle mass. Given the central role of skeletal muscle in whole body metabolism, we hypothesized that predisposition to metabolic disease is, in part, due to low oxidative capacity and dysfunctional mitochondrial energetics in muscle. We used an experimental mouse model system of maternal undernutrition during late pregnancy to examine female offspring from undernourished dams (U) and control offspring from ad libitum fed dams (C). U have increased adiposity and decreased glucose tolerance compared to C. Strikingly, when U are put on a 4 week 40% calorie restricted diet they lose half as much weight as calorie restricted controls. Skeletal muscle mitochondria from U have decreased coupled and uncoupled respiration and increased maximal respiration compared to C. In permeabilized fiber preparations from mixed fiber type muscle, U have decreased mitochondrial content and decreased adenylate free leak respiration, fatty acid oxidative capacity, and state 3 respiratory capacity through complex I. Fiber maximal oxidative phosphorylation capacity does not differ between U and C.
We next aimed to determine if the impaired skeletal muscle energetics observed in U also exist in primary muscle cells derived from these mice. We measured oxidative and glycolytic capacities in primary myotubes from U and C using cellular bioenergetics. Myotubes from U have decreased resting respiration and increased glycolysis compared to myotubes from C. There was no difference in myotube mitochondrial content. Findings suggest that undernutrition in utero causes a primary muscle defect.
Energetics in cardiac muscle were also examined. U have impaired cardiac muscle homogenate energetics, including decreased fatty acid oxidative capacity, decreased maximum oxidative phosphorylation rate, and decreased proton leak respiration. Additionally, we measured plasma acylcarnitine levels and found that short-chain acylcarnitines are increased in U. Overall, results reveal that in utero undernutrition alters metabolic physiology through a profound effect on skeletal muscle and cardiac muscle energetics. These effects may be mediated by epigenetic mechanisms which could be explored in future research.
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Alshudukhi, Abdullah Ali. "Exploring the role of lipin1 in mitophagy process using lipin1 deficient-EGFP tagged LC3 transgenic mice." Wright State University / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=wright151377463726015.
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Luther, Daniel J. "The Role of Type VI Collagen In Cardiac Remodeling Following Myocardial Infarction In Mice." Kent State University / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=kent1376067347.
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Chen, Z. (Zhijun). "Characterization of the 2-enoyl thioester reductase of mitochondrial fatty acid synthesis type II in mammals." Doctoral thesis, University of Oulu, 2008. http://urn.fi/urn:isbn:9789514289804.
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Abstract
A data base search using the amino acid sequence of Saccharomyces cerevisiae Etr1p, the last enzyme of mitochondrial fatty acid synthesis type II (FAS II), revealed a highly similar human protein, NRBF-1. Expression of NRBF-1 in a yeast etr1Δ strain rescued its respiratory deficiency. NRBF-1 resides in mitochondria in cultured HeLa cells. The recombinant NRBF-1 is enzymatically active, reducing 2E-enoyl-CoAs to acyl-CoAs in an NADPH-dependent manner. Altogether, our data showed that NRBF-1 is a mitochondrial 2-enoyl-CoA reductase/2-enoyl thioester reductase (MECR/ETR1), the human functional counterpart of yeast Etr1p. In addition, MECR was also isolated from bovine heart. It turns out that mammals contain a mitochondrial FAS II pathway, in addition to cytoplasmic FAS I.
To investigate the functional mechanism of MECR/ETR1 at the molecular level, the protein was crystallized and the crystal structure determined. The apo-structure of MECR/ETR1 contains two sulfates in the nucleotide binding site and the domain arrangement resembles the NADPH-containing holo-structure of yeast Etr1p. The predicted mode of NADPH-binding and kinetic data suggest that Tyr94 and Trp311 play critical roles in catalysis. A pocket was found in the structure extending away from the catalytic site that can accommodate fatty acyl chains up to 16 carbons. An acyl carrier protein (ACP) binding site was also suggested.
To study the physiological function of mouse Mecr, two lines of transgenic mice overexpressing Mecr were generated. The Mecr transgenic mice developed cardiac and mitochondrial abnormalities. The phenotyping was carried out using echocardiography, heart perfusion, histology, and endurance testing. Our results suggest Mecr plays a role in mitochondrial and heart function. Therefore, inappropriate expression of the genes of FAS II may result in the development of cardiomyopathy.
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Miinalainen, I. (Ilkka). "Enoyl thioester reductases—enzymes of fatty acid synthesis and degradation in mitochondria." Doctoral thesis, University of Oulu, 2006. http://urn.fi/urn:isbn:9514282442.
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Fatty acids are one of the most essential categories of biological lipids and their synthesis and degradation are vital for all organisms. Severely compromised phenotypes of yeast mutants and human patients, which have defective components in their degradative or synthetic processes for fatty acid metabolism, have highlighted the importance of these processes for overall metabolism. Most fatty acids are degraded by β-oxidation, which occurs in mitochondria and peroxisomes in mammals, whereas synthesis is catalyzed by cytosolic multifunctional peptides, although a synthesis system involving individual enzymes in mitochondria has been also proposed.
In this study a novel mitochondrial 2-enoyl thioester reductase Etr1p from the yeast Candida tropicalis, its homolog Mrf1p from Saccharomyces cerevisiae, and their mammalian ortholog were identified and characterized. Observations indicating that mitochondrial localization as well as enzymatic activity is needed to complement the respiratory-deficient phenotype of the mrf1Δ strain from S. cerevisiae suggests that Etr1p and Mrf1p might act as a part of the mitochondrial fatty acid synthesis machinery, the proper function of which is essential for respiration and the maintenance of mitochondrial morphology in yeast. The mammalian enzyme, denoted Nrbf-1p, showed similar localization, enzymatic activity, and ability to rescue the growth of the mrf1Δ strain suggesting that mammals are also likely to possess the ability and required machinery for mitochondrial fatty acid synthesis.
This study further included the characterization of another mitochondrial thioester reductase, 2,4-dienoyl-CoA reductase, which acts as an auxiliary enzyme in the β-oxidation of unsaturated fatty acids. The function of this gene was analyzed by creating a knock-out mouse model. While unstressed mice deficient in 2,4-dienoyl-CoA reductase were asymptomatic, metabolically challenged mice showed symptoms including hypoglycemia, hepatic steatosis, accumulation of acylcarnitines, and severe intolerance to acute cold exposure. Although the oxidation of saturated fatty acids proceeds normally, the phenotype was in many ways similar to mouse models of the disrupted classical β-oxidation pathway, except that an altered ketogenic response was not observed. This mouse model shows that a proper oxidative metabolism for unsaturated fatty acids is important for balanced fatty acid and energy metabolism.
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Okuda, Junji. "Persistent Overexpression of Phosphoglycerate Mutase, a Glycolytic Enzyme, Modifies Energy Metabolism and Reduces Stress Resistance of Heart in Mice." Kyoto University, 2014. http://hdl.handle.net/2433/185197.
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Bermúdez, Mei-Ling. "Carnosine as a Mechanism-based Intervention in the Thy1-aSyn Mouse Model of Parkinson’s Disease: Neurobehavioral, Biochemical, and Bioinformatic Analyses." University of Cincinnati / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1543839362404126.
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So, Hon-fai, and 蘇漢暉. "Age-dependent effects of mitochondrial function in skin fibroblasts and skeletal muscle derived from a Parkinsonian LRRK2 R1441G knockinmouse model." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2013. http://hub.hku.hk/bib/B50162846.
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Parkinson's disease (PD) is an age-related neurodegenerative disease characterized by the selective loss of dopaminergic neurons in the substantia nigra of the brain. The pathogenesis and etiology of PD are unclear. Mitochondrial dysfunction occurs in PD, causing a decrease in complex I activity in postmortem brain, and exacerbating reactive oxygen species production and ATP deficiency contributing to neuronal cell death. Mutation of leucine-rich-repeat kinase 2 (LRRK2) gene is the most common genetic factor identified in both familial and sporadic PD cases. Several mutations in LRRK2 have been linked to PD, in which R1441G is the second commonest mutation after G2019S. LRRK2 protein is ubiquitously expressed in human body, in which a portion is localized to the mitochondria. Mutations of LRRK2 directly or indirectly cause mitochondria dysfunction. Dysfunction of mitochondrial respiratory complexes has been described in skin fibroblasts and skeletal muscle of PD patients. Therefore, these clinically accessible tissues are good for monitoring disease progression. The objectives of this study were to investigate how LRRK2 R1441G mutation affects normal mitochondrial function, and whether this specific LRRK2 mutation potentiates age-dependent deterioration of mitochondrial function.
To achieve these aims, colonies of skin fibroblast carrying LRRK2 R1441G mutation or wild-type LRRK2 were derived from a novel LRRK2 R1441G knock-in (KI) mouse model and its wild-type (WT) littermates. Skeletal muscles were dissected from the hind legs of WT and KI mice. The effects of aging and LRRK2 R1441G mutation on mitochondrial function were investigated in vitro using these derived skin fibroblast cultures, and ex vivo using skeletal muscle obtained from young (3-month-old) and aged (18-month-old) WT and KI mice. Reduction-oxidation activities of mitochondrial complex I and complex II in skin fibroblasts and skeletal muscle were measured spectrophotometrically. Intracellular ATP levels in skin fibroblasts were determined by bioluminescent assay.
Phase-contrast microscopy showed that aging and LRRK2 R1441G mutation did not affect cell morphology of the derived skin fibroblast cultures. Complex I activity determined in skin fibroblasts and skeletal muscle derived from KI and their WT littermates revealed that, aging caused a significant increase in complex I activity in WT but not KI skin fibroblasts. Conversely, a significant decrease in complex I activity was observed in both WT and KI skeletal muscle, demonstrating an aging effect ex vivo. LRRK2 R1441G mutation did not affect complex I activity in WT and KI skin fibroblasts and skeletal muscle. Moreover, complex II activity in these two tissues was neither affected by aging nor R1441G LRRK2 mutation. Intracellular ATP levels in the skin fibroblast cultures were also unaltered by aging and LRRK2 R1441G mutation.
In conclusion, my current findings indicated a significant aging effect on mitochondrial complex I activity ex vivo, supporting the role of age-dependent deterioration of complex I activity in mitochondrial dysfunction of PD. LRRK2 R1441G mutation did not affect complex I and II activities in both skin fibroblasts and skeletal muscle. Also, this mutation did not potentiate the age-dependent deterioration of complex I activities as observed in skin fibroblasts and skeletal muscle of the LRRK2 R1441G knock-in mice.published_or_final_version
Medicine
Master
Master of Philosophy
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Alberici, Luciane Carla. "Camundongos hiperlipidemicos transgenicos para a apolipoproteina-III tem aumento de catabolismo corporal e atividade do canal mitocondrial de 'K POT.+' sensivel a ATP." [s.n.], 2006. http://repositorio.unicamp.br/jspui/handle/REPOSIP/313574.
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Orientadores: Anibal Eugenio Vercesi, Helena Coutinho Franco OliveiraTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas
Made available in DSpace on 2018-08-08T02:32:32Z (GMT). No. of bitstreams: 1 Alberici_LucianeCarla_D.pdf: 5846392 bytes, checksum: a41c4e31bbe1d1fa3a670c7a9956806e (MD5) Previous issue date: 2006
Resumo: Alterações no metabolismo energético mitocondrial promovidas por proteínas desacopladoras (UCPs) são frequentemente encontradas em desordens metabólicas. Recentemente demonstramos que camundongos hipertrigliceridêmicos (HTG) apresentam uma respiração mitocondrial de repouso elevada, não relacionada a UCPs. Neste trabalho, nós elucidamos o mecanismo responsável por esta elevação da respiração de repouso e demonstramos algumas conseqüências dessa resposta mitocondrial à hiperlipidemia no fígado e no metabolismo corporal total. Resultados: Mitocôndrias isoladas de fígados e de células mononucleares de baço de camundongos HTG apresentaram velocidades respiratórias elevadas comparadas aos camundongos controles. Mudanças no consumo de oxigênio em mitocôndrias de fígados de camundongos HTG foram sensíveis a ATP, diazóxido e ácido 5-hidroxidecanóico (5-HD) indicando que o consumo pode ser atribuído à atividade dos canais de K+ sensíveis a ATP (mitoKATP). Do mesmo modo, as mitocôndrias HTG apresentaram um maior inchamento na presença de íons K+, sensível aos agonistas e antagonistas do mitoKATP. Além disso, a ligação de glibenclamida marcada às mitocôndrias indica que os camundongos HTG expressaram maiores quantidades de receptores de sulfoniluréias, um componente os mitoKATP. Aumento da velocidade de metabolismo foi evidenciado por um aumento no consumo de oxigênio no fígado (sensível ao tratamento agudo in vivo pela administração de 5-HD), elevada temperatura retal e maior produção corporal de CO2 nesses camundongos. De acordo com a velocidade metabólica elevada, a ingestão alimentar foi significantemente maior em camundongos HTG, sem concomitante aumento de peso. Assim como verificado em camundongos HTG, mitocôndrias de fígados de animais submetidos à dietas ricas em substratos energéticos apresentaram também elevação da respiração mitocondrial de repouso. Conclusões: Esses resultados demonstram que a hiperlipidemia primária leva ao aumento da atividade dos mitoKATP em fígados, o que pode representar uma adaptação regulada para oxidar o excesso de ácidos graxos em camundongos HTG. Além disso, nossos resultados indicam que os mitoKATP, além das UCPs, podem estar envolvidos no controle do metabolismo energético e do peso corporal
Abstract: Changes in mitochondrial energy metabolism promoted by uncoupling proteins (UCPs) are often found in metabolic disorders. We have recently shown that hypertriglyceridemic (HTG) mice present higher mitochondrial resting respiration unrelated to UCPs. Here, we disclose the underlying mechanism and consequences, in tissue and whole body metabolism, of this mitochondrial response to hyperlipidemia. Results: As observed in HTG mice, liver mitochondria from animals submitted to the rich energy diets presented high resting respiration. Mitochondria isolated from the livers and spleen mononuclear cells of HTG mice presented enhanced respiratory rates compared to those from wild-type mice. Changes in oxygen consumption of liver mitochondria from HTG mice were sensitive to ATP, diazoxide and 5-hydroxydecanoate (5-HD), indicating they can be attributable to mitochondrial ATP-sensitive K+ channel (mitoKATP) activity. Indeed, mitochondria from HTG mice presented enhanced swelling in the presence of K+ ions, sensitive to mitoKATP agonists and antagonists. Furthermore, mitochondrial binding to fluorescent glibenclamide indicates that HTG mice expressed higher quantities of sulfonylurea receptors, a component of mitoKATP. An overall faster metabolic state was evidenced by increased liver oxygen consumption (sensitive to acute in vivo 5-HD administration), higher body CO2 release and temperature in these mice. In agreement with higher metabolic rates, food ingestion was significantly larger in HTG mice, without enhanced weight gain. Liver mitochondria isolated from rats fed glucose rich diet or from mice fed fat rich diet also presented higher resting respiration rates. Conclusions: These results demonstrate that primary hyperlipidemia leads to an elevation in liver mitoKATP activity, which may represent a regulated adaptation to oxidize excess fatty acids in HTG mice. Furthermore, our data indicate that mitoKATP, in addition to UCPs, may be involved in the control of energy metabolism and body weight
Doutorado
Ciencias Biomedicas
Doutor em Ciências Médicas
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Bergemalm, Daniel. "Mutant superoxide dismutase-1-caused pathogenesis in amyotrophic lateral sclerosis." Doctoral thesis, Umeå : Umeå university, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-31116.
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Littlejohns, Ben. "The role of mitochondria in increased vulnerability to insults of hearts and cardiomyocytes isolated from mice fed a "Western style" high-fat diet." Thesis, University of Bristol, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.618820.
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Cardiovascular diseases arc the most common cause of death in the world. One key contributory factor in cardiovascular diseases is the consumption of a high-fat diet. A high-fat diet can cause direct and indirect effects on the myocardium. Directly it can alter substrate supply and metabolism and indirectly it can cause obesity and associated comorbidities such as diabetes and hypertrophy. Preliminary work in Bristol has shown that a non-obesogenic high-fat diet renders the heart more vulnerable to ischaemia/reperfusion (IIR) injury compared to normal diet. Triggers of UR injury include calcium overload, oxidative stress and mitochondrial permeability transition pore (mPTP) opening. The aim of this thesis was 10 study cardiac remodelling in a mouse model of non-obesogenic high-fat diet and investigate the mechanism(s) responsible for the increased vulnerability to I1R. Male C57BU6 mice were fed cither a normal diet (13 % calories from fat) or a high-fat diet (45 % calories from fat) for 20 weeks. An array of techniques (e.g. echocardiography, fluorescence, electron microscopy, tissue and cell perfusion, western blotting and proteomics) and different preparations (in vivo and isolated hearts, cardiomyocytes and mitochondria) were used to address the stated aim of this thesis. Mice fed a high-fat diet did not become obese and did not show evidence of diabetes, coronary disease, cardiac hypertrophy or heart failure. The key findings are that in the highfat diet group there were changes in Ca2 + handling contributing to an increase in intracellular Ca2+, changes in the oxidative state during IIR, alterations in mitochondrial morphology and dissociation of hexokinase Il from the mitochondria. When the mPTP was inhibited in isolated perfused hearts subjected to IIR the increased vulnerability to IIR in the high-fat diet was abolished. In conclusion, the results suggest that a non-obesogenic high-fat diet increased the probability of mPTP opening which induced more damage during I/R.
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Maryam, Akramisomeabozorg. "Circulation of gut pre-activated naïve CD8+ T cells enhances anti-tumor immunity in B cell defective mice." Kyoto University, 2020. http://hdl.handle.net/2433/259729.
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Neher, Margret Feodora Maria [Verfasser], Lucia [Akademischer Betreuer] Tabares, Jochen [Akademischer Betreuer] Weishaupt, Silvio [Akademischer Betreuer] Rizzoli, and Margarete [Akademischer Betreuer] Schön. "Synaptic Vesicles, Mitochondria, and Actin Alterations in SMN-deficient Mice / Margret Feodora Maria Neher. Gutachter: Jochen Weishaupt ; Silvio Rizzoli ; Margarete Schön. Betreuer: Lucia Tabares." Göttingen : Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2015. http://d-nb.info/1071991604/34.
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Friederich, Persson Malou. "The Role of Mitochondrial Uncoupling in the Development of Diabetic Nephropathy." Doctoral thesis, Uppsala universitet, Integrativ Fysiologi, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-167815.
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Diabetes is closely associated with increased oxidative stress, especially originating from the mitochondria. A mechanism to reduce increased mitochondria superoxide production is to reduce the mitochondria membrane potential by releasing protons across the mitochondria membrane. This phenomenon is referred to as mitochondria uncoupling since oxygen is consumed independently of ATP being produced and can be mediated by Uncoupling Proteins (UCPs). However, increased oxygen consumption is potentially detrimental for the kidney since it can cause tissue hypoxia. Therefore, this thesis aimed to investigate the role of mitochondria uncoupling for development of diabetic nephropathy. UCP-2 was demonstrated to be the only isoform expressed in the kidney, and localized to tubular segments performing the majority of tubular electrolyte transport. Streptozotocin-induced diabetes in rats increased UCP-2 protein expression and correlated to increased non-transport dependent oxygen consumption in isolated proximal tubular cells. These effects were prevented by intense insulin treatment to the diabetic animals demonstrating a pivotal role of hyperglycemia. Importantly, elevated UCP-2 protein expression increased mitochondria uncoupling in mitochondria isolated from diabetic kidneys. Mitochondria uncoupling and altered morphology was also evident in kidneys from db/db-mice, a model of type-2 diabetes, together with proteinuria and glomerular hyperfiltration which are both clinical manifestations of diabetic nephropathy. Treatment with the antioxidant coenzyme Q10 prevented mitochondria uncoupling as well as morphological and functional alterations in these kidneys. Acute knockdown of UCP-2 paradoxically increased mitochondria uncoupling in a mechanism involving the adenosine nucleotide transporter. Increased uncoupling via adenosine nucleotide transporter decreased mitochondria membrane potential and kidney oxidative stress but did not affect glomerular filtration rate, renal blood flow, total kidney oxygen consumption or intrarenal tissue oxygen tension. The role of increased mitochondria oxygen consumption was investigated by administering the chemical uncoupler dinitrophenol to healthy rats. Importantly, increased mitochondria oxygen consumption resulted in kidney tissue hypoxia, proteinuria and increased staining of the tubular injury marker vimentin, demonstrating a crucial role of increased oxygen consumption per se and the resulting kidney tissue hypoxia for the development of nephropathy. Taken together, the data presented in this thesis establishes an important role of mitochondria uncoupling for the development of diabetic nephropathy.
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Oktay, Yavuz. "Defining a novel role for hypoxia inducible factor-2 alpha (HIF-2a)/EPAS1 : maintenance of mitochondrial and redox homeostasis." Access to abstract only; dissertation is embargoed until after 12/20/2006, 2005. http://www4.utsouthwestern.edu/library/ETD/etdDetails.cfm?etdID=134.
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Koulintchenko, Milana. "Mise en évidence et analyse d'un mécanisme actif d'importation d'ADN dans les mitochondries de plante." Université Louis Pasteur (Strasbourg) (1971-2008), 2003. http://www.theses.fr/2003STR13032.
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Les génomes mitochondriaux des plantes supérieures ont une taille très importante. Cependant, 5 à 20% de ces séquences ont une origine chloroplastique, nucléaire ou virale et la moitié n'a aucune fonction ou origine reconnaissable (Notsu et al. , 2002, Mol. Genet. Genomics 268:434). Chez de nombreuses espèces de plante, les mitochondries ont également acquis des plasmides (Brown & Zhang, 1995, The molecular biology of plant mitochondria, Levings III & Vasil eds. , Kluwer Academic Publishers, pp. 61-91). Bien que tous ces processus se réalisent à l'échelle de l'évolution, ils suggèrent que les mitochondries des plantes aient une capacité importante de capture et d'intégration de séquences étrangères. En utilisant comme substrat-modèle le plasmide linéaire de 2,3 kpb naturellement présent dans les mitochondries du maïs (Leon et al. , 1989, Nucleic Acids Res. 17:4089), nous avons démontré l'existence d'un mécanisme actif d'importation d'ADN dans les mitochondries végétales. Le processus se limite à l'ADN double brin mais n'a aucune spécificité de séquence évidente. Il est le plus efficace avec des fragments linéaires de quelques kpb. Lorsqu'elles contiennent un promoteur approprié, les séquences importées sont transcrites dans les mitochondries. L'utilisation d'anticorps, de compétiteurs et d'inhibiteurs spécifiques indique l'implication du canal d'anions voltage-dépendant (VDAC) et du transporteur de nucléotides adénylés (ANT) qui sont les composants majeurs du complexe du pore de transition de perméabilité (PTPC) des mitochondries animales (Zamzami & Kroemer, 2001, Nat. Rev. Mol. Cell. Biol. 2:67). Cependant, les expériences montrent que l'importation de l'ADN ne fait pas intervenir de transition de perméabilité mitochondriale promue par le calcium et le stress oxydatif. L'importation d'ADN dans les mitochondries de plante représente un phénomène naturel qui pourrait avoir une signification dans les flux génétiques ou remplir des fonctions physiologiquesHigher plant mitochondrial genomes have a strikingly large size. From that wealth of sequences, 5 to 20% originate from plastids, nuclei or viruses and about half have no recognizable function and origin (Marienfeld et al. , 1999, Trends Plant Sci. 4:495; Kubo et al. , 2000, Nucleic Acids Res. 28:2571; Notsu et al. , 2002, Mol. Genet. Genomics 268:434). Mitochondria of numerous plant species have also acquired DNA plasmids (e. G. Brown & Zhang, 1995, in The molecular biology of plant mitochondria, Levings III & Vasil eds. , Kluwer Academic Publishers, pp. 61-91). Although all these processes occur at an evolutionary scale, they suggest that plant mitochondria have a high capacity to capture and integrate foreign sequences. Using the well defined maize mitochondrial 2. 3 kilobase-pair linear DNA plasmid (Leon et al. , 1989, Nucleic Acids Res. 17:4089) as a model substrate, we demonstrated the existence of an active, effector modulatable, mechanism of DNA import into plant mitochondria. The process is restricted to double-strand DNA, but has no obvious sequence specificity. It is most efficient with linear fragments up to a few kilobase-pairs. When containing appropriate promoter information, imported sequences are transcribed inside mitochondria. Inhibition studies of the uptake using antibodies, competitors and specific blockers point to an involvement of the voltage-dependent anion channel (VDAC) and the adenine nucleotide translocator (ANT), which are considered to be the core components of the mitochondrial permeability transition pore complex (PTPC) in animal cells (e. G. Zamzami & Kroemer, 2001, Nat. Rev. Mol. Cell. Biol. 2:67). However, the experiments show that the plant DNA uptake mechanism is not a calcium/oxidative stress-promoted mitochondrial permeability transition. We conclude that DNA import into plant mitochondria represents a natural phenomenon which might have some relevance in genetic fluxes or fulfil physiological functions
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Paterson, Andrew William James. "Mitochondrial abnormalities in PrP-null mice and Mecp2-null mice." Thesis, University of Edinburgh, 2007. http://hdl.handle.net/1842/29313.
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Evidence of a mitochondrial abnormality in PrP-null mice was sought by extensive assessment of the morphological and functional characteristics of isolated brain mitochondria. Study of isolated mitochondrial suspensions by electron microscopy revealed that PrP-null mitochondria were larger and, when cristae density was quantitatively measured using a novel technique, to have a reduced cristae density when compared to controls. A significant increase in respiratory capacity was detected in PrP-null mitochondria when metabolising Complex I substrates, but not when electrons entered downstream of complex 1. This implicates Complex 1 as a site for pathological change. As recent studies of the Mecp2-null mouse model of Rett syndrome detected increased transcription of Uqcrc1 (a core subunit of Complex III), mitochondrial morphology and respiration were studied in Mecp2-null mice. Whilst electron microscopy did not reveal any gross alterations in mitochondrial size or cristae density, respiration measurements revealed a severe phenotype in symptomatic, but not presymptomatic, Mecp2-null mice. Mitochondrial coupling was considerably reduced in isolated brain mitochondria from Mecp2-null mice indicating reduced mitochondrial efficiency. This effect was accompanied by an increase in respiratory capacity through Complex III. In order to determine if the overexpression of Uqcrc1 was causative in the production of the observed increase in respiratory capacity, the respiration rates of N2A cells overexpressing Uqcrc1 were measured. As transfected N2A cells showed significantly increased respiration rates through Complex III, the up-regulation of Uqcrc1 may be causative in producing the respiratory capacity increase observed in the animal model. These results enhance the evidence for dysfunctional mitochondria in both PrP-null and Mecp2-null mouse models and are discussed in relation to other investigations of prion disease, Rett syndrome and other models of neurodegenerative disease.
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Payette, Daniel. "Neuronal dysfunction and degeneration in Alzheimer's disease and brain trauma." Oklahoma City : [s.n.], 2008.
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Pretorius, Marianne. "Evaluation of metallothionein involvement in the modulation of mitochondrial respiration in mice / Marianne Pretorius." Thesis, North-West University, 2011. http://hdl.handle.net/10394/9195.
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Metallothioneins (MTs) are small, non-enzymatic proteins that are involved in cellular detoxification and metal homeostasis because of their high cysteine content. MTs have also been identified as one of the vast number of adaptive responses to mitochondrial respiratory chain (RC) deficiencies. Aside from this, numerous other studies have linked MTs to several mitochondrion-linked components, including reactive oxygen species (ROS) and oxidative stress, apoptosis, glutathione, energy metabolism and nuclear- and mitochondrial DNA transcription regulation. However, most of the reports concerning the putative link between MTs and mitochondria are from in vitro studies and relatively little supportive in vivo evidence has been reported. Information on the involvement of MTs with respiratory chain function is especially limited. Is was therefore the aim of this study to investigate the involvement of MTs in mitochondrial respiration and respiratory chain enzyme function by using an MT knockout (MTKO) mouse model, which was treated with the irreversible complex I inhibiting reagent, rotenone. The aim was achieved by implementing three objectives: firstly, the RC function was investigated as a complete working unit; secondly, the functional and structural properties of single units (enzymes) of the RC were investigated utilising enzyme activity assays and BN- PAGE/western blot analysis; and thirdly, the possible effect of MTs on mtDNA copy number was investigated. While some tendencies of variation in RC enzyme activity and expression were identified, no significant effect on the overall mitochondrial respiratory function, or any significant differences in the relative mtDNA copy number of MTKO mice were observed. Thus it is concluded, while MTs have in this study revealed relatively small changes in respiratory chain function, which may still prove to have biological ignificance in vivo, the exact nature of the putative role of MTs in mitochondrial respiration or oxidative phosphorylation remains undefined.Thesis (MSc (Biochemistry))--North-West University, Potchefstroom Campus, 2012.
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Tamassia, Manoel Augusto Monteiro. "Mise en évidence chez les bovins d'un effet maternel sur la production d'embryons in vitro : étude des mitochondries ovocytaires et des réserves en ATP." Paris, Institut national d'agronomie de Paris Grignon, 2003. http://www.theses.fr/2003INAP0028.
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L'objectif de cette thèse, a été tout d'abord, d'essayer de mettre en évidence l'influence de la femelle donneuse sur la qualité de l'ovocyte chez la vache. Afin d'isoler le rôle de l'ovocyte dans le taux de développement embryonnaire, l'influence du tractus génital femelle a été supprimée par collecte des ovocytes dans les follicules (par Ovum Pick-Up ; OPU) puis par maturation, fécondation et culture in vitro. Ce protocole expérimental a été appliqué à deux situations physiologiques permettant d'explorer l'influence maternelle sous plusieurs approches. Tout d'abord, nous avons utilisé des génisses issues de clonage embryonnaire. Dans un second temps, ce protocole expérimental a été appliqué à 10 vaches d'origines familiales différentes (non apparentées). Ce sperme ne pouvait donc pas être considéré comme le facteur limitant du taux de développement. Nous avons ainsi démontré scientifiquement l'existence d'un effet maternel, c'est-à-dire d'une influence des facteurs maternels ovocytaires, sur le développement embryonnaire (in vitro). Ce travail a permis d'isoler des vaches donneuses d'ovocytes de " bonne " et " mauvaise " qualité. Nos recherches ont ensuite porté sur le(s) mécanisme(s) pouvant être responsable(s) de ces différences d'aptitude au développement in vitro entre femelles. Cette recherche a été plus particulièrement axée sur le métabolisme énergétique : réserves d'ATP, quantité de mitochondries (d'ADN mitochondrial) et séquence de l'ADN mitochondrial. Seules les mutations de l'ADN mitochondrial ont réellement permis de différencier les deux phénotypes de qualité ovocytaire. Ces travaux de thèse ont donné lieu à la rédaction de 3 articles (2 publiés, 1 soumis)The main objective of this thesis was to show the influence that the oocyte donor cow has over the oocyte quality measured by the embryo production in vitro. In order to isolate the effect of the oocyte on embryo production, we used the techniques of ovum pick-up (OPU), in vitro fertilisation (IVF) and culture (IVC) of embryos. These procedures were used to test the influence of oocytes in two distinct situations. Initially, the purpose was to test the in vitro embryo production in cloned cows (embryonic cloning). A second purpose was performed using ten cows with diverse genetic origins. In order to avoid the sperm induced variation on embryo production, only semen with good IVF rates from the same bull and from the same ejaculate was used. The results of this second study demonstrated scientifically the existence of a maternal effect over in vitro embryo production. This work allowed the identification of cows that produce oocytes of "good" and "bad" quality. After showing the existence of a maternal effect over in vitro embryo production, the research focused on the exploration of mechanisms that could be involved in such differences. Thus, the third experiment centered on the energetic metabolism of the oocyte, studying the oocytes' ATP reserves and the quantity of mitochondrial DNA and polymorphisms in the control region of the mitochondrial DNA. Only the study of mutations of the mitochondrial DNA control region was successful in differentiating the phenotypic variation in oocyte quality. This work resulted in the publication of two articles and a third one that was submitted for publication in international pier-reviewed journals
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Rambau, Ramugondo Victor. "Molecular genetics of Rhabdomys subspecies boundaries : phylogeography of mitochondrial lineages and chromosomal fluorescence in situ hybridization." Thesis, Stellenbosch : Stellenbosch University, 2003. http://hdl.handle.net/10019.1/53504.
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Thesis (PhD)--University of Stellenbosch, 2003.ENGLISH ABSTRACT: The geographic genetic population structure and evolutionary history of the African four-striped mouse, Rhabdomys pumilio, was investigated using mitochondrial (mtDNA) cytochrome b gene (1140 bp) and control region (994 bp) sequences and a combination of cytogenetic banding techniques (G- and C-banding), and fluorescence in situ hybridization. Two cytotypes (2n = 46 and 2n = 48) were identified by cytogenetic analysis. No evidence of diploid number variation within populations was found nor were there differences in gross chromosome morphology, or subtle interchromosomal rearrangements at levels detected by ZOO-FISH. The comparative painting data (using the complete suite, N = 20, of Mus musculus chromosome specific painting probes) show that 10 mouse chromosomes have been retained as chromosomal arms, or intact chromosome blocks within the R. pumilio genome, six produced double signals, while the remaining four hybridized to three or more R. pumilio chromosomes. In total, the 20 mouse chromosome paints detected 40 segments of conserved synteny. Their analysis revealed eight R. pumilio specific contiguous segment associations, a further two that were shared by R. pumilio and other rodents for which comparable data are available, the Black (Rattus rattus) and Norwegian (Rattus nONegicus) rats, but not by the Chinese hamster, Cricetulus grise us. The results suggest that mouse chromosomes 1, 10, and 17 have undergone extensive rearrangements during genome evolution in the murids and may be useful markers for enhancing our understanding of the mode and tempo of chromosome evolution in rodents. Following initial studies using control region sequences, the phylogeographic appraisal of R. pumilio was done using cytochrome b gene sequences. Analyses based on a variety of analytical procedures resulted in the detection of two major mtDNA lineages that correspond roughly to the xeric and mesic biotic zones of southern Africa. One clade comprises specimens with 2n = 48, and the other representatives of two cytotypes (2n = 48 and 2n = 46). The mean sequence divergence (12.0%, range 8.3% -15.6%) separating the two mtDNA clades is comparable to among-species variation within murid genera suggesting their recognition as distinct species, the prior names for which would be R. dilecfus and R. pumilio. Low sequence divergences and the diploid number dichotomy within the mesic lineage support the recognition of two subspecies corresponding to R. d. dilecfus (2n = 46) and R. d. chakae (2n = 48). The data do not support subspecific division within the nominate, R. pumilio. Molecular dating places cladogenesis of the two putative species at less than 5 million years, a period characterised by extensive climatic oscillations which are thought to have resulted in habitat fragmentation throughout much of the species' range.
AFRIKAANSE OPSOMMING: Die geografiesebevolkingsstruktuur en evolusionêre verwantskappe binne die Afrika streepmuis, Rhabdoys pumilio, is ondersoek deur middel van mitochondriale ONS volgordebepaling van die geenfragment sitochroom b (1140 basispare) en die reguleerstreek (994 bp) in kombinasie met sitogenetiese tegnieke (G- en Cbandkleuring en f1uoreseerende in situ hibridisasie). Twee sitotipes (2n = 46 en 2n = 48) is geidentifiseer deur sitogenetiese analasie. Geen bewys van variasie in die 2n chromosoomgetal binne bevolkings is gevind nie. Verder is daar ook geen verskil in die morfologies struktuur van chromosome aanwesig binne bevolkings nie. Vergelykende data (verkry met behulp van die N = 20 Mus musculus chromosoomspesifiekepeilers) dui daarop dat 10 muis chromosome behoud gebly het as chromosoomarms of chromosoomblokke binne die R. pumilio genoom. Ses peilers het dubbel seine gelewer terwyl die oorblywende vier peilers gehibridiseer het aan drie of meer R. pumilio chromosome. In totaal het die 20 muischromosoomverwe 40 konserwatiewe segmente geidentifiseer. Die analise dui agt R. pumilio spesifieke aaneenlopende segmentassosiasies aan, met 'n addisionele twee wat deur R. pumilio en ander muisagtiges vir wie vergelykende data beskikbaar is, byvoorbeeld die swart (Rattus rattus) en Noorweegse (R. norvegicus) rot maar nie die Chinese hamster, Cricetulus grise us, gedeel word. Die resultate stel voor dat muischromosoom 1, 10 en 17 ekstensiewe herrangskikkings ondergaan het gedurende die genoom evolusie binne die Muridae en dat hulle waarskynlik waardevolle merkers kan wees om beide die patroon en tempo van chromosome evolusie in muisagtiges verder te kan verstaan. Die filogeografiese verwantskappe binne R. pumilio is ondersoek deur middel van ONS volgordebepalings van die reguleerstreek asook sitochroom b. Die resultate van hierdie studie het twee divergente mitochondriale ONS eenhede ontdek wat gekorreleer kan word met xeriese en mesiese klimaatsones binne suidelike Afrika. Een groep bestaan uit diere met 2n = 48, terwyl die ander genetiese groep twee sitotipes (2n = 46 en 2n= 48) insluit. 'n Gemiddelde genetiese divergensie van 12.0% (varieer tussen 8.3% - 15.5%) verdeel die twee mtDNS-groepe en is vergelykbaar met tussenspesievariasie binne ander muisagtige genera, wat moontlik daarop dui dat twee verskillende spesies teenwoordig is; die voorgestelde name is R. di/ectus en R. pumilio. Lae genetiese divergensie binne die mesiese groep versterk die moontlike teenwoordigheid van twee subspesies, R. d. di/ectus (2n = 46) en R. d. chakae (2n = 48). Die data verleen egter nie steun aan die divisie binne R. pumilio nie. Molekulêre datering van die twee spesies dui daarop dat die divergensie ten minste 5 miljoen jaar gelede plaasgevind het. Die periode was gekarakteriseer deur ekstensiewe klimaatsossilasies, wat gely het tot habitat fragmentasie in die spesie se verspreidingsgebied.
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Wang, Jianming. "Life without mitochondrial DNA : studies of transgenic mice /." Stockholm, 2000. http://diss.kib.ki.se/2000/91-628-4491-1/.
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Somers, Christopher Michael Quinn James S. "Germline mutations at expanded simple tandem repeat DNA loci in sentinel mice /." *McMaster only, 2004.
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Lemercier, Gabriel. "Conception et réalisation de microdispositifs électrochimiques, pour l'analyse de l'activité bioénergétique de mitochondries isolées, dans le cadre de la mise au point de traitements innovants des leucémies aiguës myéloïdes." Thesis, Toulouse 3, 2018. http://www.theses.fr/2018TOU30054/document.
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La mitochondrie est restée longtemps cantonnée au rôle de centrale énergétique cellulaire. On sait désormais qu'elle est aussi la principale source d'espèces réactives oxygénées, impliquées dans le stress oxydant et la signalisation inter- cellulaire. Le dérèglement de l'activité mitochondriale est ainsi susceptible d'être la cause de l'apparition et de la progression de maladies associées au vieillissement, comme le cancer et les maladies neurodégénératives. Dans le cadre de la leucémie aiguë myéloïde, des études menées par l'équipe dirigée par Jean-Emmanuel Sarry du Centre de Recherche en Cancérologie de Toulouse, ont montré qu'il est possible de sensibiliser les cellules jusqu'alors résistantes à la chimiothérapie, en ciblant préalablement la fonction mitochondriale. C'est dans ce contexte que s'inscrit le sujet de cette de thèse, portant sur la conception et la réalisation de micro-capteurs électrochimiques dédiées à l'analyse du métabolisme mitochondrial, à l'échelle de la mitochondrie isolée. La fabrication des microsystèmes s'est déroulée dans la salle blanche du Laboratoire d'Analyse et d'Architecture des Systèmes de Toulouse, sous l'encadrement des chercheurs Jérôme Launay et Pierre Temple-Boyer, spécialisés dans la conception de capteurs pour la détection d'espèces en phase liquide. Finalement, un système complet assurant le couplage à la microscopie et à la gestion des fluides a été fabriqué, validé, et breveté. Les résultats obtenus nous permettent d'envisager l'analyse à l'échelle de la mitochondrie unique par une approche parallélisée, ce qui n'a encore jamais été réaliséThe role of mitochondria have been restricted to oxidative phosphorylation for a long time. Now it is clear that they are also the main sources of reactive oxygen species, implied in oxidative stress and cell-to-cell signaling. Thus, mitochondrial malfunction is potentially the cause of the appearance and the progression of diseases linked to ageing like cancers and neurodegenerative troubles. In the frame of acute myeloid leukemia, studies governed by Jean-Emmanuel Sarry of the Cancer Research Center of Toulouse, showed that it is possible to improve the efficacy of current chemotherapies by targeting mitochondria's function. In this context, the objective of the thesis presented here consist in the design and the manufacturing of electrochemical micro-sensors, dedicated to the analysis of the metabolic activity of isolated mitochondria. The manufacturing occurred in the clean room facilities of the Laboratory for Analysis and Architecture of Systems of Toulouse under the supervision of Jérôme Launay and Pierre Temple-Boyer, researchers specialized in the development of solutions aiming the detection of species diluted in solution. Finally, a complete system ensuring the coupling with microscopy and fluidics have been realized, validated, and patented. The results obtained allow us to consider the analysis at the scale of the single mitochondrion with a parallelized approach, thing that have never been made
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Jones, Catherine S. "Mitochondrial DNA variation in British house mice (Mus domesticus, Rutty)." Thesis, University College London (University of London), 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.426183.
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Morphometric, karyological and historical evidence indicates that Caithness and Orkney House mice (Mus.domesticus Rutty) are genetically distinct from other British mice, suggesting they are descended from introductions. Mitochondrial DNA is a small, rapidly evolving, maternally inherited molecule; hence each mtDNA molecule carries in its sequence the history of its lineage uncomplicated by recombination. Thus, mtDNA RFLPs can be used for analysing possible patterns of colonisation and gene flow in these populations. Highly purified mtDNA was isolated from each mouse and mapped, using the high resolution restriction method, with respect to the published sequence of mouse mtDNA. This allowed the types and incidence of mutational change by which mtDNA evolves in the House mouse to be evaluated. A total of 23 mtDNA composite genotypes, assayed using 14 restriction enzymes, were recognised among the British mice examined and a genetic "break" observed between individuals from the north of Britain (Orkney, Ireland and N.E. Scotland; N.W lineage) and those from the south (British mainland, south of Caithness and Sutherland; S.E lineage)~ The approximate location of this "break" corresponds with the Great Glen fault, which marks a boundary between inhospitable moorland, occupied by Apode7ltus. Geographic orientation of mtDNA variability is concordant with data from other sources, including the paternal Y-chromosome DNA. The House mouse is unlikely to have survived the 1ast glaciation, dating the earliest possible British colonisation to about 10,000 B.P. An integrated approach, using evidence from anthropological, palaeontological, genetical and historical sources, permits the progression of the house mouse to be followed through Europe. These data indicate that Mus domesticus probably reached North-West Europe and Britain in the Iron
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Gonzalez, Malinda Wallentine. "Phylogenetic relationships of forest spiny pocket mice (Genus Heteromys) inferred from mitochondrial and nuclear markers with implications for species boundaries /." Diss., CLICK HERE for online access, 2005. http://contentdm.lib.byu.edu/ETD/image/etd777.pdf.
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Igoudjil, Anissa. "Effets métaboliques de la stavudine chez la souris : mise en évidence de mécanismes indépendants d'une altération de la chaîne respiratoire mitochondriale." Paris 7, 2006. http://www.theses.fr/2006PA077226.
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Les analogues nucléosidiques (NUC) tels que la zidovudine (AZT) et la stavudine (d4T) sont des médicaments importants dans le traitement de l'infection par le VIH. Malheureusement, leur utilisation est assombrie par l'existence d'effets secondaires tels que stéatose hépatique, myopathie et lipodystrophie. Ces effets secondaires pourraient être liés à une toxicité mitochondriale des NUC, par inhibition de la réplication de l'ADN mitochondrial (ADNmt). Cependant, les NUC semblent également avoir des effets mitochondriaux et métaboliques indépendamment d'une depletion de l'ADNmt. Des travaux antérieurs réalisés au laboratoire ont montré de façon inattendue que l'administration de 100 mg/kg/j de d4T ou d'AZT chez la souris était susceptible de stimuler l'oxydation des acides gras (OAG) dans le foie. Mes travaux de thèse ont visé à poursuivre les investigations sur l'AZT et le d4T. Dans une 1ere étude, la stimulation de l'OAG hépatique était associée à une diminution de la masse grasse (MG) chez la souris. Dans une 2ème étude, nous avons observé qu'une augmentation de la-dose de d4T (500 mg/kg/j) pouvait aggraver la perte de MG, alors que l'OAG hépatique était inhibée. Nos résultats indiquent que les effets métaboliques des analogues de la thymidine sont complexes et peuvent être indépendants d'une depletion de l'ADNmt. Ils suggèrent aussi que la toxicité précoce du d4T est dépendante de la dose, et que la lipoatrophie pourrait avoir indirectement des effets délétères sur le foie. Nous espérons que nos travaux participeront à une meilleure compréhension de la physiopathologie des lipoatrophies et des stéatoses induites par les NUCNucleoside reverse transcriptase inhibitors (NRTI) such as stavudine (d4T) and zidovudine (AZT) are antiretroviral drugs frequently used in HIV-infected patients. In some patients these drugs can unfortunately induce different side effects as hepatic steatosis, myopathy and lipodystrophy. Although it is widely acknowledged that NRTI are toxic for the mitochondrial DNA (mtDNA) and the respiratory chain, other mechanisms seem to be involved. Recently, we reported that 100 mg/kg/d of d4T and AZT (two thymidine analogs) stimulated fatty acid oxidation (PAO) in mouse liver. The aim of the investigations was to complete the study on AZT and d4T, in order to study the consequences of this PAO stimulation. In a first study, hepatic PAO stimulation was associated with fat wasting in mice treated with d4T and AZT 100mg/kg/j. In a second study, higher d4T doses (500 mg/kg/j) reduced further adiposity, while hepatic PAO was inhibited. Our results indicate that metabolic effects of thymidine analogues are difficult to understand and can be independent of mtDNA depletion. Moreover, d4T effects are dependent of the dose, and fat wasting could have indirect liver toxic effects. We hope that our results will help to prevent some NRTI-induced side effects and will prove useful to gain an insight into the physiopathology of these drug-induced mitochondrial diseases
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Al-Fadda, Assim. "Metabolic consequences of deleting the mitochondrial glycerol-3-phosphate dehydrogenase gene in mice." Thesis, McGill University, 2003. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=80162.
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To define the role of mitochondrial glycerol-3-phosphate dehydrogenase (EC 1.1.99.5; mGPD) in energy balance and intermediary metabolism, we studied female transgenic mice lacking the mGPD gene (mGPD-/-). These mice had higher serum glycerol and triglycerides; lower body weight, blood glucose, and energy expenditure (QO2); and higher glycerol-3-phosphate and lactate/pyruvate ratio in muscle than controls with wild type genotype (WT). When given a high fat/low carbohydrate diet, mGPD-/- mice gain more weight than WT, without the genotype differentially affecting QO2 or calorie intake. On a low fat/high carbohydrate diet, mGPD-/- mice failed to increase QO2 as the WT and gained more weight. After a 30-hour fasting or food restriction to 70% for 10 days, WT lost significantly more weight than mGPD-/- mice, but these latter had lower body temperature and QO2. Thus, mGPD-/- mice exhibit a thrifty phenotype largely resulting from reduced obligatory thermogenesis.
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Monemdjou, Shadi. "Mitochondrial proton leak and uncoupling protein expression in transgenic mice and human obesity." Thesis, University of Ottawa (Canada), 2002. http://hdl.handle.net/10393/6433.
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The significance of the uncoupling protein-1 (UCP1) in brown adipose tissue (BAT) thermogenesis has been well defined. However, the absence of significant amounts of BAT in adult humans, and the desire to reveal the mechanisms modulating skeletal muscle thermogenesis, led to the search for other proteins homologous to UCP1 which could also mediate thermogenesis by uncoupling oxidative phosphorylation. This search led to the discovery of Ucp2 and Ucp3 genes, as well as Ucp4 and brain mitochondrial carrier protein-1 (BMCP1). Ucp3 is of particular interest as a potential mediator of thermogenesis because it is selectively expressed at moderately high levels in human skeletal muscle, a tissue that contributes significantly to resting energy expenditure. In this thesis we attempt to elucidate the true physiological role of the UCP1 homologues, and of UCP3 specifically, by examining mitochondrial proton leak and UCP3 protein expression in: (1) mice that do not express Ucp3 ( Ucp3-knockout mice), (2) transgenic mice that overexpress human Ucp3 in their skeletal muscle (UCP-3Tg mice), (3) and finally in a distinct population of women who differ in their rate of weight loss. Our studies with the Ucp3-knockout mice show that the mitochondrial proton conductance is reduced in skeletal muscle mitochondria when UCP3 is absent. This result supports the hypothesis that UCP3 is a significant contributor to proton leak in skeletal muscle, and that the remaining UCPs in muscle (e.g., UCP2) do not compensate for the loss of UCP3. Mice overexpressing human UCP3 in skeletal muscle have total Ucp3 mRNA expression that is 66-fold greater than normal, and despite an increase in food intake, they are more lean than controls. Our results from human studies have provided the first ever measurements of proton leak in human muscle mitochondria. We examined the role of UCP3 and mitochondrial proton leak in patients on an energy restricted diet (900 kcal/day) who were identified as either diet-responsive or diet-resistant. Our results indicate that the state 4 oxygen consumption is 51% higher in the diet-responsive subjects compared to the diet-resistant ones. In addition, Ucp3 mRNA expression was found to be 25% greater in skeletal muscle of diet-responsive compared to diet-resistant individuals, suggesting that the upregulation of this protein could be responsible for the differences seen in the rate of weight loss. (Abstract shortened by UMI.)
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Dovydenko, Ilya. "Mise au point d'aptamères aux capacités thérapeutiques basés sur les ARN importables dans les mitochondries humaines." Thesis, Strasbourg, 2015. http://www.theses.fr/2015STRAJ046/document.
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Les défauts de génome mitochondrial provoquent des maladies neuromusculaires, pour lequel aucun traitement efficace n'a été mis au point. La plupart des mutations mitochondriales sont hétéroplasmique, ce qui signifie que l'ADN mitochondrial (ADNmt) de type sauvage et muté coexistent dans la même cellule, et le changement de proportion entre deux types d'ADNmt pourrait rétablir les fonctions mitochondriales. Le but du projet était le développement du système pour cibler l'ARN thérapeutique dans les cellules humaines vivantes. Au cours de ma thèse j'ai synthétisé une série de nouveaux ARN anti-réplicatifs contenant modifications chimiques pour augmenter leur stabilité dans la cellule, et mis au point la nouvelle méthode de synthèse chimique des molécules d'ARN contenant cholestérol fixé par l'intermédiaire d'un pont biodégradable. Ces ARN étaient capable de pénétrer dans les cellules humains, d'être adressées dans les mitochondries et de diminuer la proportion d' ADNmt mutéDefects in mitochondrial genome cause neuromuscular diseases, for which no efficient therapy has been developed. Since most mitochondrial mutations are heteroplasmic, wild type and mutated mitochondrial DNA (mtDNA) coexist in the same cell, and the shift in proportion between two mtDNA types could restore mitochondrial functions. The aim of the project was development of carrier-free system for targeting the therapeutic mitochondrially importable RNA into living human cells. During my PhD study, I have synthesized a set of new anti-replicative RNAs containing various chemical modifications, aiming to increase their stability in the cell, and developed a new method for the chemical synthesis of RNA molecules containing cholesterol attached through a biodegradable bridge. Cholesterol containing antireplicative RNAs were characterised by efficient cellular uptake, partial colocalisation with mitochondria and ability to decrease the proportion of mutant mtDNA
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Niot, Isabelle. "Régulation de l'oxydation mitochondriale des acides gras dans le foie du rat Zucker obèse ou mince : effets de régimes enrichis en acides gras en n-3 : mise en évidence d'un mécanisme régulateur impliquant le réticulum endoplasmique." Dijon, 1991. http://www.theses.fr/1991DIJOS047.
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La recherche de facteurs susceptibles d'influencer l'activité carnitine palmitoyltransferase I (cpt i) qui permet l'entrée des acides gras dans la mitochondrie vers l'oxydation, est effectuée sur des rats Zucker obèses et minces en raison de leur capacité différente à oxyder les acides gras. Dans l'introduction sont rappelées les étapes de la dégradation des acides gras, jusqu'aux derniers acquis concernant la localisation de la cpt i et le concept moléculaire de sa régulation selon mcgarry et foster. La première partie présente une étude des différentes fractions mitochondriales et de leurs membranes externes dans le foie des phénotypes Zucker, et souligne l'existence d'une population mitochondriale méconnue, parce qu'inextractible, et dont la voie de l'oxydation des acides gras serait fortement régulée. Le cholestérol des membranes ne semble pas devoir être implique dans cette régulation. La deuxième partie a trait à l'influence de régimes qui, par leur apport lipidique, modifient la composition en acides gras des phospholipides des membranes externes ou l'enzyme cpt i est localisée. On y formule un mode d'action possible des huiles de poisson au niveau de l'organisme qui utilise alors mieux les lipides, grâce à un environnement particulier de l'enzyme. Dans la troisième partie, sont testées les capacités d'un certain nombre d'acides gras, présents dans les lipides des régimes, à être transférés et oxydes dans la mitochondrie, leur disparition des membranes pouvant ensuite se répercuter sur les activités enzymatiques. Dans la quatrième partie, le mécanisme par lequel les mitochondries peuvent s'attacher aux microsomes, est analyse en utilisant la papaine, puis est reconstitue en définissant les conditions optimales de son déclenchement. On suggère ainsi l'existence possible d'une régulation à court terme de l'oxydation des acides gras par une sorte de mise au repos d'une partie de la population mitochondriale lorsque la production d'énergie est excessive.
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Blanc, Valérie. "Editing des ARNs mitochondriaux de plantes. Approche biochimique du processus de conversion C-U. Mise en évidence d'une réaction spécifique de désamination." Bordeaux 2, 1996. http://www.theses.fr/1996BOR28421.
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Lejay, Anne. "Ischémie critique chronique des membres inférieurs : implication mitochondriale chez l'Homme et mise au point d'un modèle murin permettant l'évaluation de conditionnements pharmacologiques." Thesis, Strasbourg, 2014. http://www.theses.fr/2014STRAJ078/document.
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L’ischémie critique chronique définit un stade avancé d’insuffisance artérielle chronique. Le diagnostic d’ischémie critique chronique nécessite trois éléments : des signes cliniques, des mesures de perfusion artérielle témoignant de l’ischémie, ainsi qu’une durée des symptômes supérieure à 15 jours. Nous avons mis au point un modèle d’ischémie critique chronique valide chez la souris, et reproduisant au plus proche les lésions observées chez l’homme, en réalisant une ligature fémorale droite associée à une ligature iliaque droite 4 jours plus tard. Nous avons ensuite étudié à partir de ce modèle l’atteinte mitochondriale liée à l’ischémie critique chronique, notamment l’altération de la fonction respiratoire mitochondriale, la diminution de la capacité de rétention calcique, et la production de radicaux libres. Nous avons testé différents protocoles de conditionnement pharmacologique et avons mis en évidence un effet protecteur de la N acétyl cystéine, des statines et de la L arginine. Les voies de protection RISK et SAFE seraient potentiellement impliquées dans cet effet protecteurCritical limb ischemia defines an advances stage of peripheral arterial disease and peripheral arterial insufficiency. The diagnosis of critical limb ischemia requires three elements: clinical signs, arterial perfusion measures demonstrating the level of ischemia, as well as a duration of symptoms for more than 15 days. We developed a critical limb ischemia model in mice, nearly mimicking human pathology, by right femoral artery ligatuon followed by right artery ligation 4 days later. We then studied from this model the mitochondrial impairment associted with critical limb ischemia, including impaired mitochondrial respiratory function, reduced calcium retention capacity, and increased production of free radicals. Once these changes highlighted, we wanted to test different pharmacological conditioning, in order to identify protective molecules in critical limb ischemia. We thus demonstrated a protective effetct of N acetyl cysteine, statins and L-arginine. The protection pathways RISK and SAFE may be involved in this protective effect
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Williamson, Melina C. "Molecular systematics of spiny pocket mice (subfamily Heteromyinae) inferred from mitochondrial and nuclear sequence data /." Diss., CLICK HERE for online access, 2009. http://contentdm.lib.byu.edu/ETD/image/etd2891.pdf.
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Williamson, Melina Crystal. "Molecular Systematics of Spiny Pocket Mice (Subfamily Heteromyinae) Inferred from Mitochondrial and Nuclear Sequence Data." BYU ScholarsArchive, 2009. https://scholarsarchive.byu.edu/etd/1718.
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This study aims to determine species-level relationships within the genus Heteromys, as well as generic-level relationships among members of the subfamily Heteromyinae using a phylogenetic framework. Molecular sequence data were generated from two mitochondrial genes (cytochrome b and cytochrome oxidase I) and three nuclear gene segments (β-fibrinogen, engrailed protein II, and myosin heavy chain II), and analyzed under maximum parsimony, maximum likelihood, and Bayesian optimality criteria to infer relationships. Chapter 1 focuses on the phylogenetic and taxonomic implications for Heteromys from the analyses of sequence data. Phylogenies also provided a framework for delimiting species boundaries within the wide-ranging Heteromys desmarestianus complex using the Wiens and Penkrot method. Several well-supported clades within this complex were recovered, including H. goldmani, H. nubicolens, and H. oresterus, as well as five groups identified as candidate species. Heteromys oasicus was not found to be genetically diagnosable from H. anomalus, and was relegated to subspecific status. I present a revised taxonomy as follows: the monotypic subgenus Xylomys is maintained (H. nelsoni); the subgenus Heteromys is divided into three species groups – anomalus (H. anomalus [including H. oasicus], H. australis, and H. teleus), desmarestianus (H. desmarestianus, H. goldmani, H. nubicolens, H. oresterus, and the five candidate species), and gaumeri (H. gaumeri). Chapter 2 describes phylogenetic inferences made from analyses of heteromyine taxa, genera Heteromys and Liomys. Many studies have recovered Liomys as paraphyletic relative to Heteromys, and the goal of this chapter was to address this taxonomic problem. The Liomys pictus species group (L. irroratus, L. pictus, and L. spectabilis) was recovered as sister to Heteromys rather than to the L. salvini group (L. adspersus and L. salvini). I recommend a revised taxonomy for the subfamily as follows: the genus Heteromys is retained as delineated in Chapter 1; the genus Liomys is reduced in scope to include only L. irroratus, L. pictus, and L. spectabilis; the subgeneric name Schaeferia is elevated to generic rank and includes S. adspersus and S. salvini. This classification better reflects the phyletic diversity within the subfamily Heteromyinae, and requires fewer name changes; thus providing nomenclatural stability.
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Vélot, Christian. "Identification chez la levure Saccharomyces cerevisiae, d'un gène (GOAI) necessaire à l'expression basale de l'aconitase en conditions de repression catabolique: mise en évidence d'une seconde isoforme mitochondriale de l'aconitase." Bordeaux 2, 1995. http://www.theses.fr/1995BOR28383.
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Monemdjou, Shadi. "Metabolic control and regulation of mitochondrial proton leak, effects of UCP1 deficiency and aging in mice." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp01/MQ36727.pdf.
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Monemdjou, Shadi. "Metabolic control and regulation of mitochondrial proton leak: Effects of UCP1 deficiency and aging in mice." Thesis, University of Ottawa (Canada), 1998. http://hdl.handle.net/10393/4293.
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The overall objective of this thesis was to examine various aspects of the metabolic significance and regulation of the mitochondrial proton leak. The research conducted specifically assesses the influence that leak has on age-associated changes in mitochondria, and the role that the leak plays in facultative energy expenditure of transgenic mice which lack uncoupling protein-1 (UCP1), a well known mediator of the proton leak. Proton leak in mitochondria has been studied for over ten years, but its exact mechanism has not yet been elucidated and only recently has it been realized that it might be mediated by uncoupling proteins (UCPs). UCPs may confer a mechanism for proton leakage and thus affect the efficiency of oxidative phosphorylation. Mice deficient in the gene for mitochondrial UCP1 (Ucp1-deficient mice) are cold-sensitive despite their abundant expression of genes for the isoforms (Ucp2 and Ucp3), and do not become more obese than controls when fed a high fat diet (Enerback et al. 1997) The objective of our work was to analyse the metabolic control and characteristics of proton leak in mitochondria from brown adipose tissue (BAT) of Ucp1-deficient mice and of heterozygote controls in order to establish the role of the UCPs in facultative thermogenesis. (Abstract shortened by UMI.)
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Dong, Hongbin. "Knock-in Mouse Lines Expressing Microsomal or Mitochondrial CYP1A1: Variations in Response to Oral Benzo[a]pyrene." University of Cincinnati / OhioLINK, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1245449157.
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Guittaut, Michaël. "Mise en évidence et caractérisation d'un gène cytotoxique emboîté dans le gène de la Galectine-3 humaine." Orléans, 2001. http://www.theses.fr/2001ORLE2030.
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La Galectine-3 est une lectine spécifique des ?-galactosides impliquée dans de nombreux phénomènes tels que l'épissage des ARNm, la prolifération cellulaire et les phénomènes apoptotiques. Nous avons montré l'existence d'un second gène, dénommé galig (galectin-3 internal gene), emboîté dans les séquences du gène de la Galectine-3. Les transcrits de galig, initiés dans le second intron du gène de la Galectine-3, sont principalement détectés dans les leucocytes et à un niveau moindre dans le placenta, le cœur, les muscles, l'estomac et les testicules. L'ARNm de galig présente l'originalité de posséder deux phases ouvertes de lecture décalées et chevauchantes qui permettent la traduction de deux protéines entièrement différentes. Cette structure génique constitue, à notre connaissance, un cas unique parmi les gènes d'eucaryotes supérieurs. Les deux protéines distribuées dans le cytosol et le noyau ou dans les mitochondries ont été dénommées, respectivement, Cytogaligine et Mitogaligine. Le signal mitochondrial de cette dernière protéine a été localisé en position centrale de la molécule entre les résidus 31 et 54. D'un point de vue biologique, la Mitogaligine produit de profonds changements morphologiques dans les cellules transfectées (forme arrondie et condensation des mitochondries), effet qui est accentué quand la Cytogaligine est exprimée avec la Mitogaligine. D'autres expériences ont permis de mettre en évidence que la toxicité cellulaire ou bactérienne peut également être induite par un peptide couvrant la région centrale de la Mitogaligine (position 35-54). Il apparaît donc que la région toxique de la molécule est située dans la région contenant le signal de localisation mitochondriale. Si l'effet cytotoxique de la Mitogaligine est lié à sa localisation intracellulaire, l'activation de l'expression du gène galig pourrait induire un phénomène apoptotique via son intervention sur les mitochondries.
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Höres, Timm [Verfasser]. "Characterisation of the pulmonary vascular response to hypoxia in mitochondrial uncoupling protein 2 deficient mice / Timm Höres." Gießen : Universitätsbibliothek, 2014. http://d-nb.info/1065479611/34.
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Tang, Man Ho. "Effects of schisandrin B on hepatic mitochondrial glutathione antioxidant status and heat shock protein production in mice /." View Abstract or Full-Text, 2002. http://library.ust.hk/cgi/db/thesis.pl?BICH%202002%20TANG.
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Thesis (M. Phil.)--Hong Kong University of Science and Technology, 2002.Includes bibliographical references (leaves 78-89). Also available in electronic version. Access restricted to campus users.
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Chaignepain, Stéphane. "Etude fonctionnelle et structurale de la sous-unité 4 de l'ATP synthase mitochondriale de la levure Saccharomyces Cerevisiae. Mise en évidence in vitro de l'interaction entre le domaine C-terminal de la sous-unité 4 et l'OSCP. Etude de l'organisation du pied de l'ATP synthase." Bordeaux 2, 1997. http://www.theses.fr/1997BOR28550.
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Dali-Youcef, Nassim. "Generation of mouse models for SIRT genes conditional knock-outs : Phenogenomics of adipocyte-specific retinoblastoma deficient mice." Université Louis Pasteur (Strasbourg) (1971-2008), 2007. http://www.theses.fr/2007STR13155.
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Chez les mammifères, les protéines SIRT, appelées aussi sirtuines, appartiennent à la famille des histones désacétylases (HDAC) de classe III et ont été nommées ainsi pour leur homologie avec le gène de la levure Saccharomyces cerevisiae Sir2. Il est clairement établi que le gène Sir2 joue un rôle primordial dans l’extension de la durée de vie de la levure induite par la restriction calorique et que des copies supplémentaires de ce gène retardent le vieillissement chez la levure. Contrairement aux HDAC de classe I et II, les protéines SIRT nécessitent un cofacteur, le NAD+, pour désacetyler les histones ainsi que d’importants facteurs régulateurs de la transcription. Le chef de file des sirtuines, SIRT1, semble impliqué dans des pathologies variées telles le diabète, l’obésité, l’insuffisance cardiaque, le SIDA et les maladies neurodégénératives. Même si le rôle de SIRT1 n’a pas encore été clairement établi in vivo, il apparaît indissociable de la régulation de différents processus biologiques allant de l’apoptose à la différentiation adipocytaire et musculaire ainsi que dans le métabolisme glucidique en régulant la néoglucogenèse. La fonction des autres SIRT n’est pas encore élucidée. Le sujet de ma thèse de doctorat est d’essayer de comprendre les fonctions biologiques des gènes SIRT en les inactivant de façon spatio-temporelle par l’utilisation de la stratégie du « knock-out conditionnel » (inactivation conditionnelle) et le système Cre/Lox. Cette technologie permet d’inactiver de façon contrôlée le gène d’intérêt dans un organe donné d’une souris adulte afin d’éviter les problèmes liés aux anomalies que l’absence du gène pourrait provoquer au cours du développement de l’animal lors d’un « knock-out classique ». Pour parvenir à notre objectif, nous avons réalisé des constructions modifiées des différents gènes SIRT. La particularité de ces constructions consiste à introduire des séquences Lox autour du domaine du gène codant pour la partie catalytique de l’enzyme. Les Lox sont des séquences nucléotidiques de 34 paires de bases qui sont excisées par l’enzyme Cre-recombinase lors de l’inactivation du gène. Les vecteurs contenant les gènes SIRT modifiés ont été électroporés dans des cellules souches embryonnaires (ES) de souris 129/Sv afin de s’intégrer au génome par recombinaison homologue. Les clones positifs ont été injectés par la suite dans des blastocystes. Nous avons obtenu ainsi des souris transgéniques pour le gène d’intérêt. Ces souris doivent par la suite être croisées avec des souris exprimant une protéine de fusion Cre-ERT sous le contrôle d’un promoteur spécifique d’un organe donné. La protéine Cre-ERT est une fusion entre la Cre-recombinase et le récepteur aux oestrogènes ayant une affinité élevée pour le ligand tamoxifène. En cas d’injection de tamoxifène, il y a activation de la Cre qui induit l’inactivation du gène d’intérêt à un moment donné de la vie de la souris et permet d’étudier ainsi les effets biologiques qui en résultent. A l’heure actuelle, les constructions pour les gènes SIRT1-7 ont été réalisées. Nous disposons des souris transgéniques pour le gène SIRT2 « floxé » et les croisements sont en cours avec des souris transgéniques CMV-Cre-ERT2 (inactivation de SIRT2 dans tous les tissus) et Syn-Cre-ERT2 (inactivation de SIRT2 dans les cellules nerveuses). Les autres constructions ont été électroporées dans les cellules ES et sont en cours d’analyse. Partie II : Etude de la fonction du gène Rb dans la différentiation adipocytaire et le métabolisme énergétique. Le gène du rétinoblastome Rb est le premier gène suppresseur de tumeur identifié et a été largement étudié. Son rôle a bien été démontré dans différents processus biologiques tels le contrôle du cycle cellulaire, l’apoptose, la prolifération et la différenciation cellulaires. Récemment, des études in vitro ont montré que la protéine pRb avait un rôle important dans la différentiation adipocytaire et qu’un déficit en pRb provoque un changement dans le programme de différentiation d’adipocytes blancs de souris en adipocytes bruns. Dans notre étude, nous avons utilisé le système Cre-lox pour inactiver spécifiquement le gène Rb dans le tissu adipeux. Soumises à un régime riche en graisses, des souris déficientes en pRb restent maigres par rapport à leurs congénères qui voient leurs poids augmenter de manière significative. L’analyse histologique et en microscopie électronique du tissu adipeux blanc (WAT) des souris déficientes en pRb montre une transformation d’une partie du WAT en tissu adipeux brun (BAT) avec une augmentation significative du nombre de mitochondries suggérant une activité métabolique élevée. L’analyse moléculaire a démontré une augmentation de l’expression des gènes impliqués dans la dépense énergétique tels UCP-1, PGC-1a et Dio2. Ceci se traduit physiologiquement par une augmentation de la consommation en O2 et de la production de CO2 démontrant une élévation de la dépense énergétique chez les souris pRb-déficientes. Ces données confirment que l’absence de pRb provoque la conversion d’une partie du WAT en BAT, un tissu connu pour son rôle actif dans la dépense énergétique. Le gène Rb devient ainsi une cible thérapeutique potentielle dans le but d’induire une perte de poids chez les patients obèsesIn mammals, the sirtuin family of histone deacetylases (HDACs) family was named after their homology to the yeast Saccharomyces cerevisiae gene Sir2. In yeast, it has been shown that Sir2 mediates the effects of calorie restriction on the extension of lifespan and that high levels of Sir2 activity promote longevity. Like their yeast homologs, the mammalian sirtuins (SIRT1-7) are class III HDACs and require NAD+ as a cofactor to deacetylate substrates such as histones and transcription regulators. Through this activity, sirtuins are shown to regulate important biological processes ranging from apoptosis, adipocyte and muscle differentiation, and energy expenditure to gluconeogenesis. SIRT1, the most studied sirtuin, seems to be implicated in several pathologies such as diabetes, obesity, heart failure and neurodegenerative disorders. The aim of this Ph. D. Thesis was to help understand the biological function of SIRT genes through their inactivation in mice in a spatial and temporal controlled manner, using the Cre/Lox technology. This system allows the controlled inactivation of a gene of interest in a given organ of an adult mouse to avoid abnormalities that could occur during the development when using a “classical knock-out”. We have generated genetically modified constructs for all SIRT genes by introducing 2 LoxP sequences flanking the catalytic domain of the enzyme. LoxP sites are sequences of 34 nucleotides that can be recognized and excised by the Cre-recombinase enzyme. Vectors containing the modified SIRT gene constructs were electroporated in embryonic stem cells (ES) of 129/Sv mice in order to be integrated in their genome by homologous recombination. Positif clones were then injected in blastocysts of C57BL/6J pseudopregnant mice. We obtained transgenic mice for the gene of interest. These mice will be crossed with mice expressing the Cre recombinase fused to a modified estrogen receptor with high affinity for the synthetic ligand tamoxifen, under the control of a cell specific promoter that targets Cre expression in a specific organ or cell type (promoter-Cre-ERT2). After tamoxifen injection, the Cre recombinase is activated and subsequently the SIRT gene of interest will be inactivated in a specific cell type (e. G. Adipocytes), whilst its activity remains in other cells, allowing the study of the biological effects that result from such gene inactivation. At present, we have completed the constructs for all SIRT(1-7) genes. We obtained mice with a floxed SIRT2 allele that were crossed with a CMV-Cre-ERT2 and Synapsin-Cre-ERT2 transgenic mice to generate cohorts of double transgenic mice expressing the floxed SIRT2 allele and the Cre-ERT2 either in all cell types or specifically in neurons. Constructs for other SIRT genes have been electroporated in ES cells and the generation of mice is underway. PART 2: Phenogenomics of adipocyte-specific retinoblastoma deficient miceThe role of the tumor suppressor retinoblastoma protein (pRb) has been firmly established in the control of cell cycle, apoptosis, and differentiation. Recently, it was demonstrated that lack of pRb promotes a switch from white to brown adipocyte differentiation in vitro. We used the Cre-Lox system to specifically inactivate pRb in adult adipose tissue. Under a high-fat diet, pRb-deficient (pRbad-/-) mice failed to gain weight because of increased energy expenditure. This protection against weight gain was caused by the activation of mitochondrial activity in white and brown fat as evidenced by histologic, electron microscopic, and gene expression studies. Moreover, pRb(-/-) mouse embryonic fibroblasts displayed higher proliferation and apoptosis rates than pRb(+/+) mouse embryonic fibroblasts, which could contribute to the altered white adipose tissue morphology. Taken together, our data support a direct role of pRb in adipocyte cell fate determination in vivo and suggest that pRb could serve as a potential therapeutic target to trigger mitochondrial activation in white adipose tissue and brown adipose tissue, favoring an increase in energy expenditure and subsequent weight loss