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See detailLiver proteomic response to hypertriglyceridemia in human-apolipoprotein C-III transgenic mice at cellular and mitochondrial compartment levels
Ehx, Grégory ULg; Gerin, Stéphanie ULg; Mathy, Grégory et al

in Lipids in Health and Disease (2014), 13

Background: Hypertriglyceridemia (HTG) is defined as a triglyceride (TG) plasma level exceeding 150 mg/dl and is tightly associated with atherosclerosis, metabolic syndrome, obesity, diabetes and acute ... [more ▼]

Background: Hypertriglyceridemia (HTG) is defined as a triglyceride (TG) plasma level exceeding 150 mg/dl and is tightly associated with atherosclerosis, metabolic syndrome, obesity, diabetes and acute pancreatitis. The present study was undertaken to investigate the impact of hypertriglyceridemia on the mitochondrial, sub-mitochondrial and cellular proteomes in the hepatocytes of a hypertriglyceridemic transgenic mouse model overexpressing the human apolipoproteinC-III. Methods: Quantitative comparative proteomics (2D-DIGE) was carried out in both “low-expressor” (LE) and “high-expressor” (HE) mice, respectively exhibiting moderate and severe HTG, to characterize the effect of the TG plasma level on the proteomic response. Results: The mitoproteome analysis revealed the occurrence of a large-scale adaptation in transgenic mice consisting of a general down-regulation of matricial proteins and up-regulation of inner membrane proteins. Remarkably, the magnitude of these proteomic changes appears to strongly depend on the TG plasma level. Altogether, our different analyses indicate that, in HE mice, the capacity of several metabolic pathways is altered to promote the availability of acetyl-CoA, glycerol-3-phosphate, ATP and NADPH for de novo TG biosynthesis. The up-regulation of several cytosolic ROS detoxifying enzymes also tend to confirm that the cytoplasm of HTG mice is subjected to oxidative stress as previously stated. The up-regulation of cytosolic ferritin indicates that iron over-accumulation could take place in the cytosol of HE mice hepatocytes and contribute to (i) enhance oxidative stress and (ii) promote cellular proliferation. Conclusions: The present analyses demonstrate that important TG dose-responsive metabolic adaptations are set up in human apolipoproteinC-III-overexpressing mice. Our results indicate that these adaptations could support the higher TG production rates which have been previously reported in this HTG model, and also suggest that cytosolic oxidative stress may result from FFA over-accumulation, iron overload and enhanced activity of some ROS-producing catabolic enzymes. [less ▲]

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See detailMécanismes de concentration du carbone (CCMs) chez les algues
Gerin, Stéphanie ULg

Scientific conference (2014, May 06)

Description des mécanismes de concentration du carbone (CCMs) développés par les algues pour augmenter la disponibilité en CO2 dans l'environnement local de la RubisCO. De tels mécanismes permettent de ... [more ▼]

Description des mécanismes de concentration du carbone (CCMs) développés par les algues pour augmenter la disponibilité en CO2 dans l'environnement local de la RubisCO. De tels mécanismes permettent de limiter l'activité oxygénase de l'enzyme et d'atteindre la vitesse de catalyse maximale (Vmax). La présente communication se focalise particulièrement sur les CCMs biophysiques des cyanobactéries et de l'algue verte unicellulaire modèle Chlamydomonas reinhardtii. [less ▲]

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See detailCumulative effect of Aox1 inactivation and N source modulation on the cellular proteome of Chlamydomonas reinhardtii - New insights in the metabolic interconnexion between respiration and photosynthesis
Gerin, Stéphanie ULg; Mathy, Grégory; Franck, Fabrice ULg

Conference (2014, April 14)

In Chlamydomonas reinhardtii, the Aox1 gene encoding the mitochondrial alternative oxidase (AOX) is tightly regulated by the N source: its transcription is stimulated by nitrate and repressed by ammonium ... [more ▼]

In Chlamydomonas reinhardtii, the Aox1 gene encoding the mitochondrial alternative oxidase (AOX) is tightly regulated by the N source: its transcription is stimulated by nitrate and repressed by ammonium. AOX has been proposed to play a key role in regards to the N source by acting as a trigger factor for the TCA cycle to promote the production of reduced cofactors which, together with photo-generated reductant, could contribute to support nitrate assimilation. In the present work, the cellular proteomes of wild-type and AOX-deficient strains grown either on nitrate or ammonium in the presence of acetate have been compared using two dimensional-differential in-gel electrophoresis (2D-DIGE) coupled to hierarchical clustering and ANOVA-2 statistical analyses in order to further investigate the physiological role(s) of AOX, particularly in regards to the N source. The dramatic up-regulation of chloroplastic components of the carbon-concentrating mechanism (CCM) in response to Aox1 inactivation importantly suggests that AOX plays a key role in the CCM in both N sources by allowing the production of CO2 through the TCA cycle. The concomitant down-regulation of photorespiratory enzymes in cells lacking AOX indicates that such an induction of the CCM could actually be sufficient to over-compensate the effects of AOX deficiency on CO2 availability in the local environment of Rubisco and maintain high rates of inorganic carbon fixation despite lower TCA cycle-mediated CO2 production. The global overexpression of diverse photosynthetic chain and Calvin cycle components in cells lacking AOX further evidences that a tight functional relationship exists between mitochondrial and chloroplastic processes of energy transduction, and that there could be a global redirection of bioenergetics towards photosynthesis to limit the harmful consequences (particularly oxidative stress) of mitochondrial deficiency. The observation that numerous N-responsive proteomic modifications are strongly attenuated (or even abolished) in response to Aox1 inactivation supports that AOX also exerts a more specific role as a central effector of the metabolic plasticity induced by modulating the N source in the growth medium. Our proteomic results tend notably to confirm that respiration (through AOX activity) and photosynthesis collaborate to provide nitrate reduction with electrons in mixotrophic condition and that acetate oxidation could be promoted to support AOX involvement in this context. [less ▲]

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See detailModeling the dependence of respiration and photosynthesis upon light, acetate, carbon dioxide, nitrate and ammonium in Chlamydomonas reinhardtii using design of experiments and multiple regression
Gerin, Stéphanie ULg; Mathy, Gregory; Franck, Fabrice ULg

in BMC Systems Biology (2014), 8(96),

Background: In photosynthetic organisms, the influence of light, carbon and inorganic nitrogen sources on the cellular bioenergetics has extensively been studied independently, but little information is ... [more ▼]

Background: In photosynthetic organisms, the influence of light, carbon and inorganic nitrogen sources on the cellular bioenergetics has extensively been studied independently, but little information is available on the cumulative effects of these factors. Here, sequential statistical analyses based on design of experiments (DOE) coupled to standard least squares multiple regression have been undertaken to model the dependence of respiratory and photosynthetic responses (assessed by oxymetric and chlorophyll fluorescence measurements) upon the concomitant modulation of light intensity as well as acetate, CO2, nitrate and ammonium concentrations in the culture medium of Chlamydomonas reinhardtii. The main goals of these analyses were to explain response variability (i.e. bioenergetic plasticity) and to characterize quantitatively the influence of the major explanatory factor(s). Results: For each response, 2 successive rounds of multiple regression coupled to one-way ANOVA F-tests have been undertaken to select the major explanatory factor(s) (1st-round) and mathematically simulate their influence (2nd-round). These analyses reveal that a maximal number of 3 environmental factors over 5 is sufficient to explain most of the response variability, and interestingly highlight quadratic effects and second-order interactions in some cases. In parallel, the predictive ability of the 2nd-round models has also been investigated by k-fold cross-validation and experimental validation tests on new random combinations of factors. These validation procedures tend to indicate that the 2nd-round models can also be used to predict the responses with an inherent deviation quantified by the analytical error of the models. Conclusions: Altogether, the results of the 2 rounds of modeling provide an overview of the bioenergetic adaptations of C. reinhardtii to changing environmental conditions and point out promising tracks for future in-depth investigations of the molecular mechanisms underlying the present observations. [less ▲]

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See detailModelization of photosynthetic and respiratory maximal activities as a function of culture parameters in Chlamydomonas reinhardtii using design of experiment and data analysis by JMP (SAS Institute)
Gerin, Stéphanie ULg; Mathy, Grégory; Franck, Fabrice ULg

Poster (2013, August)

We aimed to modelize the dependence of photosynthetic as well as cytochromial and alternative respiratory maximal activities upon different culture parameters, i.e. light intensity and acetate, carbon ... [more ▼]

We aimed to modelize the dependence of photosynthetic as well as cytochromial and alternative respiratory maximal activities upon different culture parameters, i.e. light intensity and acetate, carbon dioxide, nitrate and ammonium concentrations, in the model unicellular green alga Chlamydomonas reinhardtii. Culture parameters were submitted to a dedicated statistical software (JMP 10.0, SAS Institute) for the generation of a design of experiment. Measurements of oxygen concentrations were carried out to quantify maximal activities. JMP was further used to detect culture parameters exerting a statistically significant effect on maximal activities and to modelize the dependence of maximal activities upon these culture parameters of interest. [less ▲]

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See detailMetabolic plasticity of wild-type and AOX-deficient Chlamydomonas reinhardtii cells related to the inorganic nitrogen source (nitrate or ammonium), as revealed by a 2D-DIGE comparative proteomic analysis
Gerin, Stéphanie ULg; Mathy, Grégory; Franck, Fabrice ULg

Poster (2012, June 15)

In the model unicellular green alga Chlamydomonas reinhardtii, both nitrate and ammonium can be used as primary inorganic nitrogen sources. Interestingly, the expression of the mitochondrial alternative ... [more ▼]

In the model unicellular green alga Chlamydomonas reinhardtii, both nitrate and ammonium can be used as primary inorganic nitrogen sources. Interestingly, the expression of the mitochondrial alternative oxidase (AOX), an "energy-dissipating" ubiquinol-oxygen oxidoreductase of the mitochondrial electron transport chain, is under the control of the exogenous nitrogen source : it is activated in nitrate-grown cells and repressed in ammonium-grown cells at both transcriptional and translational levels. This regulation of AOX by nitrogen is Chlamydomonas-specific and currently its bioenergetic and metabolic significance is poorly understood. In order to get clues to this peculiar phenomenon, we characterized the global metabolic response of a wild-type strain (WT) and an AOX-deficient mutant (AOX-) obtained by RNA interference grown either on nitrate or ammonium. For this purpose, we used a highly accurate 2D electrophoresis-based comparative proteomic approach (2D-DIGE) to compare the cellular proteomes of nitrate and ammonium-grown WT and AOX- Chlamydomonas. The analysis was performed in the middle of the exponential growth phase in mixotrophic conditions. It revealed many proteomic modifications between WT and AOX- cells and a smaller number between nitrate and ammonium-grown cells. In nitrate-grown cells, we notably observed an important up-regulation of glutamine synthetase. Interestingly, in AOX- cells, we respectively detected a general down-regulation and a general up-regulation of mitochondrial and chloroplastic bioenergetic enzymes, and also an important up-regulation of glutathione-dependent oxidative stress defense systems together with a remarkable down-regulation of methionine synthase. Altogether these results and previous studies provide new features in understanding the metabolic adaptations occurring in response to the inorganic nitrogen source with emphasis on the role played by AOX. [less ▲]

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See detailEtude protéomique de l'incidence d'une hypertriglycéridémie sur la mitochondrie de foie de souris
Gerin, Stéphanie ULg

Master's dissertation (2010)

L’hypertriglycéridémie est une pathologie largement répandue chez l’homme sédentarisé. Elle se définit comme un taux de triglycérides (TAG) supérieur à 200 mg/dl. Les souris HuApoC-III sont des souris ... [more ▼]

L’hypertriglycéridémie est une pathologie largement répandue chez l’homme sédentarisé. Elle se définit comme un taux de triglycérides (TAG) supérieur à 200 mg/dl. Les souris HuApoC-III sont des souris transgéniques exprimant la protéine apoC-III humaine. Elles sont hypertriglycéridémiques et constituent un modèle pour l’étude de cette pathologie. Leur taux de TAG plasmatiques dépend du nombre de copies du transgène : on distingue les individus « low expressor » (modérément hypertriglycéridémiques) et « high expressor » (sévèrement hypertriglycéridémiques). Une caractéristique spécifique aux « high expressor » est le taux de production accru de TAG par les hépatocytes. Lors de ce mémoire, nous avons caractérisé, par une analyse protéomique en 2D-DIGE, les adaptations du métabolisme mitochondrial hépatique à une hypertriglycéridémie modérée et sévère chez la souris HuApoC-III afin d’établir la dépendance de la réponse métabolique vis-à-vis du niveau d’hypertriglycéridémie. Cette analyse a révélé que la proportion relative des protéines de la matrice et de la membrane interne est respectivement diminuée et augmentée de manière proportionnelle au taux de TAG plasmatiques. Il pourrait s’agir d’un mécanisme adaptatif permettant de conserver un équilibre bioénergétique entre les taux de production, par les voies métaboliques matricielles, et de consommation, par l’appareil de la phosphorylation oxydative, des cofacteurs réduits. Nous avons ensuite caractérisé les réponses protéomiques de la matrice et de la membrane interne de manière indépendante. Pour ce faire, nous avons utilisé deux types d’approches : une approche mathématique et une approche expérimentale. Les résultats obtenus montrent que de nombreuses adaptations métaboliques supplémentaires sont présentes chez les souris HuApoC-III sévèrement hypertriglycéridémiques et permettent probablement d’augmenter le taux de production d’acétyl-CoA, de glycérol-3-phosphate et d’ATP afin de supporter la production accrue de TAG. Ces nouvelles informations nous ont amenés à émettre l’hypothèse qu’au niveau organismique, l’hydrolyse et l’oxydation des TAG par le tissu adipeux brun pourraient constituer une stratégie visant à limiter le niveau d’hypertriglycéridémie. [less ▲]

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See detailProteomic and functional characterization of a Chlamydomonas reinhardtii mutant lacking the mitochondrial alternative oxidase 1
Mathy, Grégory ULg; Cardol, Pierre ULg; Dinant, Monique et al

in Journal of Proteome Research (2010), 9

In the present work we have isolated by RNA interference and characterized at the functional and the proteomic levels a Chlamydomonas reinhardtii strain devoid of the mitochondrial alternative oxidase ... [more ▼]

In the present work we have isolated by RNA interference and characterized at the functional and the proteomic levels a Chlamydomonas reinhardtii strain devoid of the mitochondrial alternative oxidase (AOX). The AOX-deficient strain displays a doubling of the cell volume and biomass without any alteration of the generation time, a significantly higher ROS production, no change in total respiration rate, and a slight decrease of the photosynthesis efficiency. In order to identify the molecular adaptation underlying these phenotypical effects, we carried out a comparative proteomic study at the level of the mitochondrial and cellular soluble proteomes. Our results indicate a strong up-regulation of the ROS scavenging systems and important modifications of proteins involved in the primary metabolism, namely an increase of enzymes involved in anabolic pathways and a concomitant general down-regulation of enzymes of the main catabolic pathways. [less ▲]

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See detailPlasticity of the mitoproteome to nitrogen sources (nitrate and ammonium) in Chlamydomonas reinhardtii: the logic of Aox1 gene localization
Gérin, Stéphanie ULg; Mathy, Grégory ULg; Blomme, Arnaud ULg et al

in Biochimica et Biophysica Acta-Bioenergetics (2010), 1797

Nitrate and ammonium constitute primary inorganic nitrogen sources that can be incorporated into carbon skeletons in photosynthetic eukaryotes. In Chlamydomonas, previous studies and the present one ... [more ▼]

Nitrate and ammonium constitute primary inorganic nitrogen sources that can be incorporated into carbon skeletons in photosynthetic eukaryotes. In Chlamydomonas, previous studies and the present one showed that the mitochondrial AOX is up-regulated in nitrate-grown cells in comparison with ammonium-grown cells. In this work, we have performed a comparative proteomic analysis of the soluble mitochondrial proteome of Chlamydomonas cells growth either on nitrate or ammonium. Our results highlight important proteomics modifications mostly related to primary metabolism in cells grown on nitrate. We could note an up-regulation of some TCA cycle enzymes and a down-regulation of cytochrome c1 together with an up-regulation of l-arginine and purine catabolism enzymes and of ROS scavenging systems. Hence, in nitrate-grown cells, AOX may play a dual role: (1) lowering the ubiquinone pool reduction level and (2) permitting the export of mitochondrial reducing power under the form of malate for nitrate and nitrite reduction. This role of AOX in the mitochondrial plasticity makes logical the localization of Aox1 in a nitrate assimilation gene cluster. [less ▲]

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