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  1. Article: Renal oncometabolite L-2-hydroxyglutarate imposes a block in kidney tubulogenesis: Evidence for an epigenetic basis for the L-2HG-induced impairment of differentiation.

    Taub, Mary / Mahmoudzadeh, Nader H / Tennessen, Jason M / Sudarshan, Sunil

    Frontiers in endocrinology

    2022  Volume 13, Page(s) 932286

    Abstract: 2-Hydroxyglutarate (2HG) overproducing tumors arise in a number of tissues, including the kidney. The tumorigenesis resulting from overproduced 2HG has been attributed to the ability of 2HG alter gene expression by inhibiting α-ketoglutarate (αKG)- ... ...

    Abstract 2-Hydroxyglutarate (2HG) overproducing tumors arise in a number of tissues, including the kidney. The tumorigenesis resulting from overproduced 2HG has been attributed to the ability of 2HG alter gene expression by inhibiting α-ketoglutarate (αKG)-dependent dioxygenases, including Ten-eleven-Translocation (TET) enzymes. Genes that regulate cellular differentiation are reportedly repressed, blocking differentiation of mesenchymal cells into myocytes, and adipocytes. In this report, the expression of the enzyme responsible for L2HG degradation, L-2HG dehydrogenase (L2HGDH), is knocked down, using lentiviral shRNA, as well as siRNA, in primary cultures of normal Renal Proximal Tubule (RPT) cells. The knockdown (KD) results in increased L-2HG levels, decreased demethylation of 5mC in genomic DNA, and increased methylation of H3 Histones. Consequences include reduced tubulogenesis by RPT cells in matrigel, and reduced expression of molecular markers of differentiation, including membrane transporters as well as HNF1α and HNF1β, which regulate their transcription. These results are consistent with the hypothesis that oncometabolite 2HG blocks RPT differentiation by altering the methylation status of chromatin in a manner that impedes the transcriptional events required for normal differentiation. Presumably, similar alterations are responsible for promoting the expansion of renal cancer stem-cells, increasing their propensity for malignant transformation.
    MeSH term(s) Cell Differentiation/genetics ; Chromatin ; Dioxygenases/metabolism ; Epigenesis, Genetic ; Glutarates ; Histones/metabolism ; Ketoglutaric Acids/metabolism ; Kidney/metabolism ; Membrane Transport Proteins/metabolism ; Oxidoreductases/metabolism ; RNA, Small Interfering
    Chemical Substances Chromatin ; Glutarates ; Histones ; Ketoglutaric Acids ; Membrane Transport Proteins ; RNA, Small Interfering ; alpha-hydroxyglutarate (2889-31-8) ; Oxidoreductases (EC 1.-) ; Dioxygenases (EC 1.13.11.-)
    Language English
    Publishing date 2022-09-05
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 2592084-4
    ISSN 1664-2392
    ISSN 1664-2392
    DOI 10.3389/fendo.2022.932286
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: The Drosophila melanogaster enzyme glycerol-3-phosphate dehydrogenase 1 is required for oogenesis, embryonic development, and amino acid homeostasis.

    Rai, Madhulika / Carter, Sarah M / Shefali, Shefali A / Mahmoudzadeh, Nader H / Pepin, Robert / Tennessen, Jason M

    G3 (Bethesda, Md.)

    2022  Volume 12, Issue 8

    Abstract: As the fruit fly, Drosophila melanogaster, progresses from one life stage to the next, many of the enzymes that compose intermediary metabolism undergo substantial changes in both expression and activity. These predictable shifts in metabolic flux allow ... ...

    Abstract As the fruit fly, Drosophila melanogaster, progresses from one life stage to the next, many of the enzymes that compose intermediary metabolism undergo substantial changes in both expression and activity. These predictable shifts in metabolic flux allow the fly meet stage-specific requirements for energy production and biosynthesis. In this regard, the enzyme glycerol-3-phosphate dehydrogenase 1 (GPDH1) has been the focus of biochemical genetics studies for several decades and, as a result, is one of the most well-characterized Drosophila enzymes. Among the findings of these earlier studies is that GPDH1 acts throughout the fly lifecycle to promote mitochondrial energy production and triglyceride accumulation while also serving a key role in maintaining redox balance. Here, we expand upon the known roles of GPDH1 during fly development by examining how depletion of both the maternal and zygotic pools of this enzyme influences development, metabolism, and viability. Our findings not only confirm previous observations that Gpdh1 mutants exhibit defects in larval development, lifespan, and fat storage but also reveal that GPDH1 serves essential roles in oogenesis and embryogenesis. Moreover, metabolomics analysis reveals that a Gpdh1 mutant stock maintained in a homozygous state exhibits larval metabolic defects that significantly differ from those observed in the F1 mutant generation. Overall, our findings highlight unappreciated roles for GPDH1 in early development and uncover previously undescribed metabolic adaptations that could allow flies to survive the loss of this key enzyme.
    MeSH term(s) Amino Acids/metabolism ; Animals ; Drosophila/metabolism ; Drosophila Proteins/genetics ; Drosophila Proteins/metabolism ; Drosophila melanogaster ; Embryonic Development/genetics ; Glycerolphosphate Dehydrogenase/genetics ; Glycerolphosphate Dehydrogenase/metabolism ; Homeostasis ; Oogenesis/genetics
    Chemical Substances Amino Acids ; Drosophila Proteins ; Glycerolphosphate Dehydrogenase (EC 1.1.-)
    Language English
    Publishing date 2022-05-10
    Publishing country England
    Document type Journal Article
    ZDB-ID 2629978-1
    ISSN 2160-1836 ; 2160-1836
    ISSN (online) 2160-1836
    ISSN 2160-1836
    DOI 10.1093/g3journal/jkac115
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Aging and memory are altered by genetically manipulating lactate dehydrogenase in the neurons or glia of flies.

    Frame, Ariel K / Robinson, J Wesley / Mahmoudzadeh, Nader H / Tennessen, Jason M / Simon, Anne F / Cumming, Robert C

    Aging

    2023  Volume 15, Issue 4, Page(s) 947–981

    Abstract: The astrocyte-neuron lactate shuttle hypothesis posits that glial-generated lactate is transported to neurons to fuel metabolic processes required for long-term memory. Although studies in vertebrates have revealed that lactate shuttling is important for ...

    Abstract The astrocyte-neuron lactate shuttle hypothesis posits that glial-generated lactate is transported to neurons to fuel metabolic processes required for long-term memory. Although studies in vertebrates have revealed that lactate shuttling is important for cognitive function, it is uncertain if this form of metabolic coupling is conserved in invertebrates or is influenced by age. Lactate dehydrogenase (Ldh) is a rate limiting enzyme that interconverts lactate and pyruvate. Here we genetically manipulated expression of
    MeSH term(s) Animals ; L-Lactate Dehydrogenase/genetics ; L-Lactate Dehydrogenase/metabolism ; Drosophila melanogaster/genetics ; Drosophila melanogaster/metabolism ; Neuroglia/metabolism ; Neurons/metabolism ; Astrocytes/metabolism ; Memory Disorders/metabolism ; Lactic Acid/metabolism ; Lipids
    Chemical Substances L-Lactate Dehydrogenase (EC 1.1.1.27) ; Lactic Acid (33X04XA5AT) ; Lipids
    Language English
    Publishing date 2023-02-26
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ISSN 1945-4589
    ISSN (online) 1945-4589
    DOI 10.18632/aging.204565
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  4. Article ; Online: Metabolomic analysis of Drosophila melanogaster larvae lacking pyruvate kinase.

    Heidarian, Yasaman / Tourigny, Jason P / Fasteen, Tess D / Mahmoudzadeh, Nader H / Hurlburt, Alexander J / Nemkov, Travis / Reisz, Julie A / D'Alessandro, Angelo / Tennessen, Jason M

    G3 (Bethesda, Md.)

    2023  Volume 14, Issue 1

    Abstract: Pyruvate kinase (Pyk) is a rate-limiting enzyme that catalyzes the final metabolic reaction in glycolysis. The importance of this enzyme, however, extends far beyond ATP production, as Pyk is also known to regulate tissue growth, cell proliferation, and ... ...

    Abstract Pyruvate kinase (Pyk) is a rate-limiting enzyme that catalyzes the final metabolic reaction in glycolysis. The importance of this enzyme, however, extends far beyond ATP production, as Pyk is also known to regulate tissue growth, cell proliferation, and development. Studies of this enzyme in Drosophila melanogaster are complicated by the fact that the fly genome encodes 6 Pyk paralogs whose functions remain poorly defined. To address this issue, we used sequence distance and phylogenetic approaches to demonstrate that the gene Pyk encodes the enzyme most similar to the mammalian Pyk orthologs, while the other 5 Drosophila Pyk paralogs have significantly diverged from the canonical enzyme. Consistent with this observation, metabolomic studies of 2 different Pyk mutant strains revealed that larvae lacking Pyk exhibit a severe block in glycolysis, with a buildup of glycolytic intermediates upstream of pyruvate. However, our analysis also unexpectedly reveals that pyruvate levels are unchanged in Pyk mutants, indicating that larval metabolism maintains pyruvate pool size despite severe metabolic limitations. Consistent with our metabolomic findings, a complementary RNA-seq analysis revealed that genes involved in lipid metabolism and protease activity are elevated in Pyk mutants, again indicating that loss of this glycolytic enzyme induces compensatory changes in other aspects of metabolism. Overall, our study provides both insight into how Drosophila larval metabolism adapts to disruption of glycolytic metabolism as well as immediate clinical relevance, considering that Pyk deficiency is the most common congenital enzymatic defect in humans.
    MeSH term(s) Animals ; Humans ; Drosophila melanogaster/genetics ; Drosophila melanogaster/metabolism ; Pyruvate Kinase/genetics ; Pyruvate Kinase/metabolism ; Phylogeny ; Glycolysis/genetics ; Drosophila/metabolism ; Pyruvates ; Mammals
    Chemical Substances Pyruvate Kinase (EC 2.7.1.40) ; Pyruvates
    Language English
    Publishing date 2023-10-04
    Publishing country England
    Document type Journal Article
    ZDB-ID 2629978-1
    ISSN 2160-1836 ; 2160-1836
    ISSN (online) 2160-1836
    ISSN 2160-1836
    DOI 10.1093/g3journal/jkad228
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  5. Article: Metabolomic analysis of

    Heidarian, Yasaman / Tourigny, Jason P / Fasteen, Tess D / Mahmoudzadeh, Nader H / Hurlburt, Alexander J / Nemkov, Travis / Reisz, Julie A / D'Alessandro, Angelo / Tennessen, Jason M

    bioRxiv : the preprint server for biology

    2023  

    Abstract: Pyruvate kinase (Pyk) is a rate-limiting enzyme that catalyzes the final metabolic reaction in glycolysis. The importance of this enzyme, however, extends far beyond ATP production, as Pyk is also known to regulate tissue growth, cell proliferation, and ... ...

    Abstract Pyruvate kinase (Pyk) is a rate-limiting enzyme that catalyzes the final metabolic reaction in glycolysis. The importance of this enzyme, however, extends far beyond ATP production, as Pyk is also known to regulate tissue growth, cell proliferation, and development. Studies of this enzyme in
    Language English
    Publishing date 2023-06-19
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.06.05.543743
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Inter-library loan at ZB MED

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  6. Article ; Online: The oncometabolite L-2-hydroxyglutarate is a common product of dipteran larval development.

    Mahmoudzadeh, Nader H / Fitt, Alexander J / Schwab, Daniel B / Martenis, William E / Nease, Lauren M / Owings, Charity G / Brinkley, Garrett J / Li, Hongde / Karty, Jonathan A / Sudarshan, Sunil / Hardy, Richard W / Moczek, Armin P / Picard, Christine J / Tennessen, Jason M

    Insect biochemistry and molecular biology

    2020  Volume 127, Page(s) 103493

    Abstract: The oncometabolite L-2-hydroxyglutarate (L-2HG) is considered an abnormal product of central carbon metabolism that is capable of disrupting chromatin architecture, mitochondrial metabolism, and cellular differentiation. Under most circumstances, ... ...

    Abstract The oncometabolite L-2-hydroxyglutarate (L-2HG) is considered an abnormal product of central carbon metabolism that is capable of disrupting chromatin architecture, mitochondrial metabolism, and cellular differentiation. Under most circumstances, mammalian tissues readily dispose of this compound, as aberrant L-2HG accumulation induces neurometabolic disorders and promotes renal cell carcinomas. Intriguingly, Drosophila melanogaster larvae were recently found to accumulate high L-2HG levels under normal growth conditions, raising the possibility that L-2HG plays a unique role in insect metabolism. Here we explore this hypothesis by analyzing L-2HG levels in 18 insect species. While L-2HG was present at low-to-moderate levels in most of these species (<100 pmol/mg; comparable to mouse liver), dipteran larvae exhibited a tendency to accumulate high L-2HG concentrations (>100 pmol/mg), with the mosquito Aedes aegypti, the blow fly Phormia regina, and three representative Drosophila species harboring concentrations that exceed 1 nmol/mg - levels comparable to those measured in mutant mice that are unable to degrade L-2HG. Overall, our findings suggest that one of the largest groups of animals on earth commonly generate high concentrations of an oncometabolite during juvenile growth, hint at a role for L-2HG in the evolution of dipteran development, and raise the possibility that L-2HG metabolism could be targeted to restrict the growth of key disease vectors and agricultural pests.
    MeSH term(s) Aedes/growth & development ; Aedes/metabolism ; Animals ; Calliphoridae/growth & development ; Calliphoridae/metabolism ; Drosophila/growth & development ; Drosophila/metabolism ; Glutarates/metabolism ; Larva/growth & development ; Larva/metabolism
    Chemical Substances Glutarates ; alpha-hydroxyglutarate (2889-31-8)
    Language English
    Publishing date 2020-11-03
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 1483248-3
    ISSN 1879-0240 ; 0965-1748
    ISSN (online) 1879-0240
    ISSN 0965-1748
    DOI 10.1016/j.ibmb.2020.103493
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Lactate dehydrogenase and glycerol-3-phosphate dehydrogenase cooperatively regulate growth and carbohydrate metabolism during

    Li, Hongde / Rai, Madhulika / Buddika, Kasun / Sterrett, Maria C / Luhur, Arthur / Mahmoudzadeh, Nader H / Julick, Cole R / Pletcher, Rose C / Chawla, Geetanjali / Gosney, Chelsea J / Burton, Anna K / Karty, Jonathan A / Montooth, Kristi L / Sokol, Nicholas S / Tennessen, Jason M

    Development (Cambridge, England)

    2019  Volume 146, Issue 17

    Abstract: The dramatic growth that occurs ... ...

    Abstract The dramatic growth that occurs during
    MeSH term(s) Adenosine Triphosphate/metabolism ; Animals ; Animals, Genetically Modified ; Drosophila melanogaster/physiology ; Female ; Glycerolphosphate Dehydrogenase/genetics ; Glycerolphosphate Dehydrogenase/metabolism ; Glycolysis/genetics ; Homeostasis/genetics ; L-Lactate Dehydrogenase/genetics ; L-Lactate Dehydrogenase/metabolism ; Lactic Acid/biosynthesis ; Larva/growth & development ; Larva/metabolism ; Male ; Mutation ; NAD/metabolism ; Oxidation-Reduction ; Sugars/metabolism
    Chemical Substances Sugars ; NAD (0U46U6E8UK) ; Lactic Acid (33X04XA5AT) ; Adenosine Triphosphate (8L70Q75FXE) ; Glycerolphosphate Dehydrogenase (EC 1.1.-) ; L-Lactate Dehydrogenase (EC 1.1.1.27)
    Language English
    Publishing date 2019-09-12
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 90607-4
    ISSN 1477-9129 ; 0950-1991
    ISSN (online) 1477-9129
    ISSN 0950-1991
    DOI 10.1242/dev.175315
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    In stock of ZB MED Cologne/Königswinter

    Ub I Zs.183: Show issues Location:
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    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)
    Zs.MG 91: Show issues

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  8. Article: The oncometabolite L-2-hydroxyglutarate is a common product of dipteran larval development

    Mahmoudzadeh, Nader H / Fitt, Alexander J / Schwab, Daniel B / Martenis, William E / Nease, Lauren M / Owings, Charity G / Brinkley, Garrett J / Li, Hongde / Karty, Jonathan A / Sudarshan, Sunil / Hardy, Richard W / Moczek, Armin P / Picard, Christine J / Tennessen, Jason M

    Insect biochemistry and molecular biology. 2020 Dec., v. 127

    2020  

    Abstract: The oncometabolite L-2-hydroxyglutarate (L-2HG) is considered an abnormal product of central carbon metabolism that is capable of disrupting chromatin architecture, mitochondrial metabolism, and cellular differentiation. Under most circumstances, ... ...

    Abstract The oncometabolite L-2-hydroxyglutarate (L-2HG) is considered an abnormal product of central carbon metabolism that is capable of disrupting chromatin architecture, mitochondrial metabolism, and cellular differentiation. Under most circumstances, mammalian tissues readily dispose of this compound, as aberrant L-2HG accumulation induces neurometabolic disorders and promotes renal cell carcinomas. Intriguingly, Drosophila melanogaster larvae were recently found to accumulate high L-2HG levels under normal growth conditions, raising the possibility that L-2HG plays a unique role in insect metabolism. Here we explore this hypothesis by analyzing L-2HG levels in 18 insect species. While L-2HG was present at low-to-moderate levels in most of these species (<100 pmol/mg; comparable to mouse liver), dipteran larvae exhibited a tendency to accumulate high L-2HG concentrations (>100 pmol/mg), with the mosquito Aedes aegypti, the blow fly Phormia regina, and three representative Drosophila species harboring concentrations that exceed 1 nmol/mg – levels comparable to those measured in mutant mice that are unable to degrade L-2HG. Overall, our findings suggest that one of the largest groups of animals on earth commonly generate high concentrations of an oncometabolite during juvenile growth, hint at a role for L-2HG in the evolution of dipteran development, and raise the possibility that L-2HG metabolism could be targeted to restrict the growth of key disease vectors and agricultural pests.
    Keywords Aedes aegypti ; Drosophila melanogaster ; Phormia regina ; carbon metabolism ; cell differentiation ; chromatin ; evolution ; insect biochemistry ; insects ; juveniles ; larval development ; liver ; mitochondria ; molecular biology ; mutants
    Language English
    Dates of publication 2020-12
    Publishing place Elsevier Ltd
    Document type Article
    Note NAL-AP-2-clean
    ZDB-ID 1483248-3
    ISSN 1879-0240 ; 0965-1748
    ISSN (online) 1879-0240
    ISSN 0965-1748
    DOI 10.1016/j.ibmb.2020.103493
    Database NAL-Catalogue (AGRICOLA)

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