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Dean P Jones - One of the best experts on this subject based on the ideXlab platform.
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mtor initiated metabolic switch and degeneration in the retinal pigment epithelium
The FASEB Journal, 2020Co-Authors: Jing Zhang, Jolyn Fernandes, Christopher Litwin, Rui Chen, Theodore G Wensel, Dean P Jones, Jiyang Cai, Yan ChenAbstract:The retinal pigment epithelium (RPE) is a particularly vulnerable tissue to age-dependent degeneration. Over the life span, the RPE develops an expanded endo-lysosomal compartment to maintain the high efficiency of phagocytosis and degradation of photoreceptor outer segments (POS) necessary for photoreceptor survival. As the assembly and activation of the mechanistic target of rapamycin complex 1 (mTORC1) occur on the lysosome surface, increased lysosome mass with aging leads to higher mTORC1 activity. The functional consequences of hyperactive mTORC1 in the RPE are unclear. In the current study, we used integrated high-resolution metabolomic and genomic approaches to examine mice with RPE-specific deletion of the tuberous sclerosis 1 (Tsc1) gene which encodes an upstream suppressor of mTORC1. Our data show that RPE cells with constitutively high mTORC1 activity were reprogramed to be hyperactive in glucose and lipid metabolism. Lipolysis was suppressed, mitochondrial Carnitine Shuttle was inhibited, while genes involved in fatty acid (FA) biosynthesis were upregulated. The metabolic changes occurred prior to structural changes of RPE and retinal degeneration. These findings have revealed cellular events and intrinsic mechanisms that contribute to lipid accumulation in the RPE cells during aging and age-related degeneration.
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MTOR‐initiated metabolic switch and degeneration in the retinal pigment epithelium
FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2020Co-Authors: Jing Zhang, Jolyn Fernandes, Christopher Litwin, Rui Chen, Theodore G Wensel, Dean P Jones, Jiyang Cai, Yan ChenAbstract:The retinal pigment epithelium (RPE) is a particularly vulnerable tissue to age-dependent degeneration. Over the life span, the RPE develops an expanded endo-lysosomal compartment to maintain the high efficiency of phagocytosis and degradation of photoreceptor outer segments (POS) necessary for photoreceptor survival. As the assembly and activation of the mechanistic target of rapamycin complex 1 (mTORC1) occur on the lysosome surface, increased lysosome mass with aging leads to higher mTORC1 activity. The functional consequences of hyperactive mTORC1 in the RPE are unclear. In the current study, we used integrated high-resolution metabolomic and genomic approaches to examine mice with RPE-specific deletion of the tuberous sclerosis 1 (Tsc1) gene which encodes an upstream suppressor of mTORC1. Our data show that RPE cells with constitutively high mTORC1 activity were reprogramed to be hyperactive in glucose and lipid metabolism. Lipolysis was suppressed, mitochondrial Carnitine Shuttle was inhibited, while genes involved in fatty acid (FA) biosynthesis were upregulated. The metabolic changes occurred prior to structural changes of RPE and retinal degeneration. These findings have revealed cellular events and intrinsic mechanisms that contribute to lipid accumulation in the RPE cells during aging and age-related degeneration.
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Metabolomics Analysis of Aspirin's Effects in Human Colon Tissue and Associations with Adenoma Risk.
Cancer prevention research (Philadelphia Pa.), 2020Co-Authors: Elizabeth L. Barry, Karan Uppal, Ken Liu, Veronika Fedirko, Leila A. Mott, Janet L. Peacock, Michael N. Passarelli, John A. Baron, Dean P JonesAbstract:Although substantial evidence supports aspirin9s efficacy in colorectal cancer chemoprevention, key molecular mechanisms are uncertain. An untargeted metabolomics approach with high-resolution mass spectrometry was used to elucidate metabolic effects of aspirin treatment in human colon tissue. We measured 10,269 metabolic features in normal mucosal biopsies collected at colonoscopy after approximately 3 years of randomized treatment with placebo, 81 or 325 mg/day aspirin from 325 participants in the Aspirin/Folate Polyp Prevention Study. Linear regression was used to identify aspirin-associated metabolic features and network analysis was used to identify pathways and predict metabolite identities. Poisson regression was used to examine metabolic features associations with colorectal adenoma risk. We detected 471 aspirin-associated metabolic features. Aside from the Carnitine Shuttle, aspirin-associated metabolic pathways were largely distinct for 81 mg aspirin (e.g., pyrimidine metabolism) and 325 mg (e.g., arachidonic acid metabolism). Among aspirin-associated metabolic features, we discovered three that were associated with adenoma risk and could contribute to the chemopreventive effect of aspirin treatment, and which have also previously been associated with colorectal cancer: creatinine, glycerol 3-phosphate, and linoleate. The last two of these are in the glycerophospholipid metabolism pathway, which was associated with 81 mg aspirin treatment and provides precursors for the synthesis of eicosanoids from arachidonic acid upstream of cyclooxygenase inhibition by aspirin. Conversely, Carnitine Shuttle metabolites were increased with aspirin treatment and associated with increased adenoma risk. Thus, our untargeted metabolomics approach has identified novel metabolites and pathways that may underlie the effects of aspirin during early colorectal carcinogenesis.
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An Untargeted Metabolomic Study of the Effects of Vitamin D and/or Calcium Supplementation Among Individuals at High Risk for Colorectal Neoplasms
Current Developments in Nutrition, 2020Co-Authors: Paula-dene Nesbeth, Dean P Jones, Elizabeth L. Barry, Veronika Fedirko, Roberd M. Bostick, John A. BaronAbstract:Abstract Objectives To obtain preliminary data on the independent and synergistic anti-neoplastic effects of 1-year supplementation with vitamin D3 and/or calcium on the plasma metabolome and metabolic pathways among individuals at high risk for colorectal neoplasms. Methods This study was an untargeted metabolomic analysis that used data and biosamples from a completed, large, multicenter, randomized, placebo-controlled, clinical trial of vitamin D3 (1000 IU/d) and/or calcium (1200 mg/d via calcium carbonate) for preventing colorectal adenoma recurrence. High resolution liquid chromatography-mass spectrometry with positive and negative ion modes was used to measure >20,000 metabolites in the baseline and year 1 follow-up plasma samples from the four treatment groups (n = 30/group). The data were processed for peak extraction and quantification of ion intensities using xMSanalyzer software with apLCMS. Using repeated measures mixed models and false discovery rate adjustment, top features associated with each treatment combination were identified. Significant features (unadjusted P < 0.05) were analyzed in mummichog 2.0 to identify enriched metabolic pathways associated with each treatment agent. Results Following 1 year of treatment, in the calcium treatment group relative to placebo, pathways related to Carnitine Shuttle; prostaglandin formation from arachidonate; fructose and caffeine metabolism were significantly modulated (P < 0.05). Prostaglandin formation from arachidonate; Carnitine Shuttle; N-glycan and keratan sulfate degradation were significantly associated with calcium plus vitamin D3 treatment (P < 0.05). Metabolic pathways significantly modulated with vitamin D3 treatment were leukotriene, vitamin D3, vitamin E, vitamin A, arachidonic acid metabolism, and fatty acid activation (P < 0.05). Conclusions Our preliminary results suggest significant changes in prostaglandin formation pathway in plasma of individuals at high risk for colorectal cancer supplemented for 1 year with calcium alone and calcium plus vitamin D3. Vitamin D3 supplementation modulated the arachidonic acid pathway supporting its effects on inflammation. Our study supports continued investigation of vitamin D3 and calcium's anti-carcinogenic actions. Funding Sources National Cancer Institute.
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Reprint of "Metabolome Wide Association Study of Serum Poly and Perfluoroalkyl Substances (PFASs) in Pregnancy and Early Postpartum".
Reproductive toxicology (Elmsford N.Y.), 2020Co-Authors: Piera M. Cirillo, Dean P Jones, Vilinh Tran, Nickilou Y. Krigbaum, Barbara A. CohnAbstract:High-resolution metabolomics (HRM) profiling of metabolic fingerprints can improve understanding of how poly and perfluoroalkyl substances (PFASs) induce metabolic alterations of in utero environment and impact fetal health. HRM profiling and quantification of PFASs were performed for 397 maternal perinatal serum samples collected from 1959-1967 in the Child Health and Development Studies (CHDS). We used Metabolome-Wide Association Studies (MWAS) and pathway enrichment analysis for metabolic associations with PFOS, its precursor EtFOSAA, and EtFOSAA-to-PFOS ratio. Distinct metabolic profiles were found with EtFOSAA and PFOS. Urea cycle metabolites such as arginine, lysine and creatine had opposite associations with EtFOSAA (negative) and PFOS (positive); whereas, Carnitine Shuttle metabolites were found to be exclusively and positively associated with PFOS indicating perturbation in fatty acid metabolism. These differential metabolic associations for precursor and end-product represent an important first step in identifying how PFASs alter the in utero environment and potentially leads to disease risk.
Jack T. Pronk - One of the best experts on this subject based on the ideXlab platform.
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Requirements for Carnitine Shuttle-Mediated Translocation of Mitochondrial Acetyl Moieties to the Yeast Cytosol
mBio, 2016Co-Authors: Harmen M. Van Rossum, Barbara U. Kozak, Matthijs S. Niemeijer, James C. Dykstra, Marijke A. H. Luttik, Jean-marc G. Daran, Antonius J. A. Van Maris, Jack T. PronkAbstract:In many eukaryotes, the Carnitine Shuttle plays a key role in intracellular transport of acyl moieties. Fatty acidgrown Saccharomyces cerevisiae cells employ this Shuttle to translocate acetyl units into their mitochondria. Mechanistically, the Carnitine Shuttle should be reversible, but previous studies indicate that Carnitine Shuttle-mediated export of mitochondrial acetyl units to the yeast cytosol does not occur in vivo. This apparent unidirectionality was investigated by constitutively expressing genes encoding Carnitine Shuttle-related proteins in an engineered S. cerevisiae strain, in which cytosolic acetyl coenzyme A (acetyl-CoA) synthesis could be switched off by omitting lipoic acid from growth media. Laboratory evolution of this strain yielded mutants whose growth on glucose, in the absence of lipoic acid, was L-Carnitine dependent, indicating that in vivo export of mitochondrial acetyl units to the cytosol occurred via the Carnitine Shuttle. The mitochondrial pyruvate dehydrogenase complex was identified as the predominant source of acetyl-CoA in the evolved strains. Whole-genome sequencing revealed mutations in genes involved in mitochondrial fatty acid synthesis (MCT1), nuclear-mitochondrial communication (RTG2), and encoding a Carnitine acetyltransferase (YAT2). Introduction of these mutations into the nonevolved parental strain enabled L-Carnitine-dependent growth on glucose. This study indicates intramitochondrial acetyl-CoA concentration and constitutive expression of Carnitine Shuttle genes as key factors in enabling in vivo export of mitochondrial acetyl units via the Carnitine Shuttle. IMPORTANCE This study demonstrates, for the first time, that Saccharomyces cerevisiae can be engineered to employ the Carnitine Shuttle for export of acetyl moieties from the mitochondria and, thereby, to act as the sole source of cytosolic acetyl-CoA. Further optimization of this ATP-independent mechanism for cytosolic acetyl-CoA provision can contribute to efficient, yeastbased production of industrially relevant compounds derived from this precursor. The strains constructed in this study, whose growth on glucose depends on a functional Carnitine Shuttle, provide valuable models for further functional analysis and engineering of this Shuttle in yeast and other eukaryotes.
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alternative reactions at the interface of glycolysis and citric acid cycle in saccharomyces cerevisiae
Fems Yeast Research, 2016Co-Authors: Harme M Van Rossum, Marijke A. H. Luttik, Antonius J. A. Van Maris, Arbara U Kozak, Matthijs S Niemeije, Hendrik J Duine, Pete Kotte, Jeanmarc Dara, Jack T. PronkAbstract:Pyruvate and acetyl-coenzyme A, located at the interface between glycolysis and TCA cycle, are important intermediates in yeast metabolism and key precursors for industrially relevant products. Rational engineering of their supply requires knowledge of compensatory reactions that replace predominant pathways when these are inactivated. This study investigates effects of individual and combined mutations that inactivate the mitochondrial pyruvate-dehydrogenase (PDH) complex, extramitochondrial citrate synthase (Cit2) and mitochondrial CoA-transferase (Ach1) in Saccharomyces cerevisiae . Additionally, strains with a constitutively expressed Carnitine Shuttle were constructed and analyzed. A predominant role of the PDH complex in linking glycolysis and TCA cycle in glucose-grown batch cultures could be functionally replaced by the combined activity of the cytosolic PDH bypass and Cit2. Strongly impaired growth and a high incidence of respiratory deficiency in pda1Δ ach1Δ strains showed that synthesis of intramitochondrial acetyl-CoA as a metabolic precursor requires activity of either the PDH complex or Ach1 . Constitutive overexpression of AGP2 , HNM1 , YAT2 , YAT1 , CRC1 and CAT2 enabled the Carnitine Shuttle to efficiently link glycolysis and TCA cycle in l-Carnitine-supplemented, glucose-grown batch cultures. Strains in which all known reactions at the glycolysis-TCA cycle interface were inactivated still grew slowly on glucose, indicating additional flexibility at this key metabolic junction.
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Requirements for Carnitine Shuttle-Mediated Translocation of Mitochondrial Acetyl Moieties to the Yeast Cytosol
American Society for Microbiology, 2016Co-Authors: Harmen M. Van Rossum, Barbara U. Kozak, Matthijs S. Niemeijer, James C. Dykstra, Marijke A. H. Luttik, Jean-marc G. Daran, Antonius J. A. Van Maris, Jack T. PronkAbstract:In many eukaryotes, the Carnitine Shuttle plays a key role in intracellular transport of acyl moieties. Fatty acid-grown Saccharomyces cerevisiae cells employ this Shuttle to translocate acetyl units into their mitochondria. Mechanistically, the Carnitine Shuttle should be reversible, but previous studies indicate that Carnitine Shuttle-mediated export of mitochondrial acetyl units to the yeast cytosol does not occur in vivo. This apparent unidirectionality was investigated by constitutively expressing genes encoding Carnitine Shuttle-related proteins in an engineered S. cerevisiae strain, in which cytosolic acetyl coenzyme A (acetyl-CoA) synthesis could be switched off by omitting lipoic acid from growth media. Laboratory evolution of this strain yielded mutants whose growth on glucose, in the absence of lipoic acid, was l-Carnitine dependent, indicating that in vivo export of mitochondrial acetyl units to the cytosol occurred via the Carnitine Shuttle. The mitochondrial pyruvate dehydrogenase complex was identified as the predominant source of acetyl-CoA in the evolved strains. Whole-genome sequencing revealed mutations in genes involved in mitochondrial fatty acid synthesis (MCT1), nuclear-mitochondrial communication (RTG2), and encoding a Carnitine acetyltransferase (YAT2). Introduction of these mutations into the nonevolved parental strain enabled l-Carnitine-dependent growth on glucose. This study indicates intramitochondrial acetyl-CoA concentration and constitutive expression of Carnitine Shuttle genes as key factors in enabling in vivo export of mitochondrial acetyl units via the Carnitine Shuttle
Jaco Franken - One of the best experts on this subject based on the ideXlab platform.
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Carnitine Requires Choline to Exert Physiological Effects in Saccharomyces cerevisiae
Frontiers Media S.A., 2018Co-Authors: Michelle Du Plessis, Jaco Franken, Florian F. BauerAbstract:L-Carnitine is a key metabolite in the energy metabolism of eukaryotic cells, functioning as a shuttling molecule for activated acyl-residues between cellular compartments. In higher eukaryotes this function is essential, and defects in Carnitine metabolism has severe effects on fatty acid and carbon metabolism. Carnitine supplementation has been associated with an array of mostly beneficial impacts in higher eukaryotic cells, including stress protection and regulation of redox metabolism in diseased cells. Some of these phenotypes have no obvious link to the Carnitine Shuttle, and suggest that Carnitine has as yet unknown Shuttle-independent functions. The existence of Shuttle-independent functions has also been suggested in Saccharomyces cerevisiae, including a beneficial effect during hydrogen peroxide stress and a detrimental impact when Carnitine is co-supplemented with the reducing agent dithiothreitol (DTT). Here we used these two distinct yeast phenotypes to screen for potential genetic factors that suppress the Shuttle independent physiological effects of Carnitine. Two deletion strains, Δcho2 and Δopi3, coding for enzymes that catalyze the sequential conversion of phosphatidylethanolamine to phosphatidylcholine were identified for suppressing the phenotypic effects of Carnitine. Additional characterisation indicated that the suppression cannot be explained by differences in phospholipid homeostasis. The phenotypes could be reinstated by addition of extracellular choline, but show that the requirement for choline is not based on some overlapping function or the structural similarities of the two molecules. This is the first study to suggest a molecular link between a specific metabolite and Carnitine-dependent, but Shuttle-independent phenotypes in eukaryotes
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DOI 10.1007/s00294-008-0191-0RESEARCH ARTICLE Carnitine and Carnitine acetyltransferases in the yeast Saccharomyces cerevisiae: a role for Carnitine in stress protection
2014Co-Authors: Curr Genet, Jaco Franken, Jan H. Swiegers, Florian F. BauerAbstract:Abstract To date, the only reported metabolic and physi-ological roles for Carnitine in Saccharomyces cerevisiae are related to the activity of the Carnitine Shuttle. In yeast, the Shuttle transfers peroxisomal activated acetyl-residues to the mitochondria. However, acetyl-CoA can also be metab-olised by the glyoxylate cycle to form succinate. The two pathways, therefore, provide a metabolic bypass for each other, and Carnitine-dependent phenotypes have only been described in strains with non-functional peroxisomal citrate synthase, Cit2p. Here, we present evidence for a role of car-nitine in stress protection that is independent of CIT2 and of the Carnitine Shuttle. Data show that Carnitine improves growth during oxidative stress and in the presence of weak organic acids in wt and in CAT deletion strains. Our data also show that strains with single, double and triple dele-tions of the three CAT genes generally present identical phenotypes, but that the deletion of CAT2 decreases sur-vival during oxidative stress in a Carnitine-independent manner. Overexpression of single CAT genes does not lead to cross-complementation, suggesting a highly speciWc metabolic role for each enzyme. The data suggest that Carnitine protects cells from oxidative and organic acid stress, while CAT2 contributes to the response to oxidative stress
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Carnitine supplementation has protective and detrimental effects in Saccharomyces cerevisiae that are genetically mediated
FEMS yeast research, 2010Co-Authors: Jaco Franken, Florian BauerAbstract:l-Carnitine plays a well-documented role in eukaryotic energy homeostasis by acting as a shuttling molecule for activated acyl residues across intracellular membranes. This activity, supported by Carnitine acyl-transferases and transporters, is referred to as the Carnitine Shuttle. However, several pleiotropic and often beneficial effects of Carnitine in humans have been reported that appear to be unrelated to shuttling activity, but little conclusive evidence regarding molecular mechanisms exists. We have recently demonstrated a role of Carnitine, independent of the Carnitine Shuttle, in yeast stress protection. Here, we show that Carnitine specifically protects against oxidative stress caused by H(2)O(2) and the superoxide-generating agent menadione. Surprisingly, Carnitine has a detrimental effect on survival when combined with thiol-modifying agents. Central elements of the oxidative stress response, specifically the transcription factors Yap1p and Skn7p, are shown to be required for Carnitine's protective effect, but several downstream effectors are dispensable. A DNA microarray-based analysis identifies Cyc3p, a cytochrome c heme lyase, as being important for Carnitine's impact during oxidative stress. These findings establish a direct genetic link to a Carnitine-related phenotype that is independent of the Shuttle system and suggests that Saccharomyces cerevisiae should provide a useful model for further elucidation of Carnitine's physiological roles.
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Carnitine and Carnitine acetyltransferases in the yeast Saccharomyces cerevisiae: a role for Carnitine in stress protection
Current Genetics, 2008Co-Authors: Jaco Franken, Sven Kroppenstedt, Jan H. Swiegers, Florian F. BauerAbstract:To date, the only reported metabolic and physiological roles for Carnitine in Saccharomyces cerevisiae are related to the activity of the Carnitine Shuttle. In yeast, the Shuttle transfers peroxisomal activated acetyl-residues to the mitochondria. However, acetyl-CoA can also be metabolised by the glyoxylate cycle to form succinate. The two pathways, therefore, provide a metabolic bypass for each other, and Carnitine-dependent phenotypes have only been described in strains with non-functional peroxisomal citrate synthase, Cit2p. Here, we present evidence for a role of Carnitine in stress protection that is independent of CIT2 and of the Carnitine Shuttle. Data show that Carnitine improves growth during oxidative stress and in the presence of weak organic acids in wt and in CAT deletion strains. Our data also show that strains with single, double and triple deletions of the three CAT genes generally present identical phenotypes, but that the deletion of CAT2 decreases survival during oxidative stress in a Carnitine-independent manner. Overexpression of single CAT genes does not lead to cross-complementation, suggesting a highly specific metabolic role for each enzyme. The data suggest that Carnitine protects cells from oxidative and organic acid stress, while CAT2 contributes to the response to oxidative stress.
Florian F. Bauer - One of the best experts on this subject based on the ideXlab platform.
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Carnitine Requires Choline to Exert Physiological Effects in Saccharomyces cerevisiae
Frontiers Media S.A., 2018Co-Authors: Michelle Du Plessis, Jaco Franken, Florian F. BauerAbstract:L-Carnitine is a key metabolite in the energy metabolism of eukaryotic cells, functioning as a shuttling molecule for activated acyl-residues between cellular compartments. In higher eukaryotes this function is essential, and defects in Carnitine metabolism has severe effects on fatty acid and carbon metabolism. Carnitine supplementation has been associated with an array of mostly beneficial impacts in higher eukaryotic cells, including stress protection and regulation of redox metabolism in diseased cells. Some of these phenotypes have no obvious link to the Carnitine Shuttle, and suggest that Carnitine has as yet unknown Shuttle-independent functions. The existence of Shuttle-independent functions has also been suggested in Saccharomyces cerevisiae, including a beneficial effect during hydrogen peroxide stress and a detrimental impact when Carnitine is co-supplemented with the reducing agent dithiothreitol (DTT). Here we used these two distinct yeast phenotypes to screen for potential genetic factors that suppress the Shuttle independent physiological effects of Carnitine. Two deletion strains, Δcho2 and Δopi3, coding for enzymes that catalyze the sequential conversion of phosphatidylethanolamine to phosphatidylcholine were identified for suppressing the phenotypic effects of Carnitine. Additional characterisation indicated that the suppression cannot be explained by differences in phospholipid homeostasis. The phenotypes could be reinstated by addition of extracellular choline, but show that the requirement for choline is not based on some overlapping function or the structural similarities of the two molecules. This is the first study to suggest a molecular link between a specific metabolite and Carnitine-dependent, but Shuttle-independent phenotypes in eukaryotes
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DOI 10.1007/s00294-008-0191-0RESEARCH ARTICLE Carnitine and Carnitine acetyltransferases in the yeast Saccharomyces cerevisiae: a role for Carnitine in stress protection
2014Co-Authors: Curr Genet, Jaco Franken, Jan H. Swiegers, Florian F. BauerAbstract:Abstract To date, the only reported metabolic and physi-ological roles for Carnitine in Saccharomyces cerevisiae are related to the activity of the Carnitine Shuttle. In yeast, the Shuttle transfers peroxisomal activated acetyl-residues to the mitochondria. However, acetyl-CoA can also be metab-olised by the glyoxylate cycle to form succinate. The two pathways, therefore, provide a metabolic bypass for each other, and Carnitine-dependent phenotypes have only been described in strains with non-functional peroxisomal citrate synthase, Cit2p. Here, we present evidence for a role of car-nitine in stress protection that is independent of CIT2 and of the Carnitine Shuttle. Data show that Carnitine improves growth during oxidative stress and in the presence of weak organic acids in wt and in CAT deletion strains. Our data also show that strains with single, double and triple dele-tions of the three CAT genes generally present identical phenotypes, but that the deletion of CAT2 decreases sur-vival during oxidative stress in a Carnitine-independent manner. Overexpression of single CAT genes does not lead to cross-complementation, suggesting a highly speciWc metabolic role for each enzyme. The data suggest that Carnitine protects cells from oxidative and organic acid stress, while CAT2 contributes to the response to oxidative stress
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Carnitine and Carnitine acetyltransferases in the yeast Saccharomyces cerevisiae: a role for Carnitine in stress protection
Current Genetics, 2008Co-Authors: Jaco Franken, Sven Kroppenstedt, Jan H. Swiegers, Florian F. BauerAbstract:To date, the only reported metabolic and physiological roles for Carnitine in Saccharomyces cerevisiae are related to the activity of the Carnitine Shuttle. In yeast, the Shuttle transfers peroxisomal activated acetyl-residues to the mitochondria. However, acetyl-CoA can also be metabolised by the glyoxylate cycle to form succinate. The two pathways, therefore, provide a metabolic bypass for each other, and Carnitine-dependent phenotypes have only been described in strains with non-functional peroxisomal citrate synthase, Cit2p. Here, we present evidence for a role of Carnitine in stress protection that is independent of CIT2 and of the Carnitine Shuttle. Data show that Carnitine improves growth during oxidative stress and in the presence of weak organic acids in wt and in CAT deletion strains. Our data also show that strains with single, double and triple deletions of the three CAT genes generally present identical phenotypes, but that the deletion of CAT2 decreases survival during oxidative stress in a Carnitine-independent manner. Overexpression of single CAT genes does not lead to cross-complementation, suggesting a highly specific metabolic role for each enzyme. The data suggest that Carnitine protects cells from oxidative and organic acid stress, while CAT2 contributes to the response to oxidative stress.
Ki-hye Kim - One of the best experts on this subject based on the ideXlab platform.
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Environmental Cadmium Enhances Lung Injury by Respiratory Syncytial Virus Infection.
The American journal of pathology, 2019Co-Authors: Ki-hye Kim, Jolyn Fernandes, Youri Lee, Matthew R. Smith, Yu-jin Jung, Michael Orr, Sang-moo Kang, Dean P JonesAbstract:Cadmium (Cd) is a naturally occurring environmental toxicant that disrupts mitochondrial function at occupational exposure levels. The impacts of Cd exposure at low levels through dietary intake remain largely uncharacterized. Human respiratory syncytial virus (RSV) causes severe morbidity, which can require hospitalization and result in death in young children and elderly populations. The impacts of environmental Cd exposure on the severity of RSV disease are unknown. Herein, we used a mouse model to examine whether Cd pre-exposure at a level of dietary intake potentiates pulmonary inflammation on subsequent infection with RSV. Mice were given Cd or saline in drinking water for 28 days. Subsets of these mice were infected with RSV at 5 days before the end of the study. Cd pre-exposure caused relatively subtle changes in lung; however, it elevated the IL-4 level and altered metabolites associated with fatty acid metabolism. After RSV infection, mice pre-exposed to Cd had elevated lung RSV titer and increased inflammation, as measured by histopathology, immune cell infiltration, cytokines, and chemokines. RSV infection after Cd pre-exposure also caused widespread perturbation in metabolism of glycerophospholipids and amino acids (Trp, Met, and Cys, branched-chain amino acids), as well as Carnitine Shuttle associated with mitochondrial energy metabolism. The results show that Cd burden by dietary intake potentiates RSV infection and severe disease with associated mitochondrial metabolic disruption.
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Environmental cadmium enhances respiratory syncytial virus infection-caused lung injury via mitochondrial metabolic disruption and oxidative stress
Free Radical Biology and Medicine, 2018Co-Authors: Ki-hye Kim, Jolyn Fernandes, Youri Lee, Matthew R. Smith, Yu-jin Jung, Michael Orr, Sang-moo Kang, Dean P JonesAbstract:Cadmium (Cd) is a naturally occurring environmental toxicant that disrupts mitochondrial function at occupational exposure levels. The impacts of Cd exposure at low levels through dietary intake remain largely uncharacterized. Human respiratory syncytial virus (RSV) causes severe morbidity which can require hospitalization and result in death in young children and elderly populations. The impacts of environmental Cd exposure on the severity of RSV disease are unknown. Herein, we used a mouse model to examine whether Cd pre-exposure at a level of dietary intake potentiates pulmonary inflammation upon subsequent infection with RSV. Mice were given Cd or saline in drinking water for 28 days. Subsets of these mice were infected with RSV at 5 days before the end of the study. After RSV infection, mice that were pre-exposed to Cd had elevated lung RSV titer and increased inflammation as measured by histopathology, immune cell infiltration, cytokines and chemokines. RSV infection following Cd pre-exposure also caused widespread perturbation in metabolism of glycerophospholipids and amino acids (Trp, Met, Cys, branched chain amino acids), as well as Carnitine Shuttle associated with mitochondrial energy metabolism. The results show that Cd burden by dietary intake potentiates RSV infection and severe disease with associated mitochondrial metabolic disruption and oxidative stress.