title: Drosophila larvae synthesize the putative oncometabolite L-2-hydroxyglutarate during normal developmental growth.
abstract: L-2-hydroxyglutarate (L-2HG) has emerged as a putative oncometabolite that is capable of inhibiting enzymes involved in metabolism, chromatin modification, and cell differentiation. However, despite the ability of L-2HG to interfere with a broad range of cellular processes, this molecule is often characterized as a metabolic waste product. Here, we demonstrate that Drosophila larvae use the metabolic conditions established by aerobic glycolysis to both synthesize and accumulate high concentrations of L-2HG during normal developmental growth. A majority of the larval L-2HG pool is derived from glucose and dependent on the Drosophila estrogen-related receptor (dERR), which promotes L-2HG synthesis by up-regulating expression of the Drosophila homolog of lactate dehydrogenase (dLdh). We also show that dLDH is both necessary and sufficient for directly synthesizing L-2HG and the Drosophila homolog of L-2-hydroxyglutarate dehydrogenase (dL2HGDH), which encodes the enzyme that breaks down L-2HG, is required for stage-specific degradation of the L-2HG pool. In addition, dLDH also indirectly promotes L-2HG accumulation via synthesis of lactate, which activates a metabolic feed-forward mechanism that inhibits dL2HGDH activity and stabilizes L-2HG levels. Finally, we use a genetic approach to demonstrate that dLDH and L-2HG influence position effect variegation and DNA methylation, suggesting that this compound serves to coordinate glycolytic flux with epigenetic modifications. Overall, our studies demonstrate that growing animal tissues synthesize L-2HG in a controlled manner, reveal a mechanism that coordinates glucose catabolism with L-2HG synthesis, and establish the fly as a unique model system for studying the endogenous functions of L-2HG during cell growth and proliferation.
authors.affiliation: Department of Biology, Indiana University, Bloomington, IN 47405.
authors.forename: Hongde
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Biology, Indiana University, Bloomington, IN 47405.
authors.forename: Geetanjali
authors.initials: G
authors.lastname: Chawla
authors.affiliation: Department of Biology, Indiana University, Bloomington, IN 47405.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Hurlburt
authors.affiliation: Department of Biology, Indiana University, Bloomington, IN 47405.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Sterrett
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada M5S 3E1.
authors.forename: Olga
authors.initials: O
authors.lastname: Zaslaver
authors.affiliation: Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112.
authors.forename: James
authors.initials: J
authors.lastname: Cox
authors.affiliation: Department of Chemistry, Indiana University, Bloomington, IN 47405.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Karty
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada M5S 3E1.|Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada M5S 3E1.
authors.forename: Adam P
authors.initials: AP
authors.lastname: Rosebrock
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada M5S 3E1.|Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada M5S 3E1.
authors.forename: Amy A
authors.initials: AA
authors.lastname: Caudy
authors.affiliation: Department of Biology, Indiana University, Bloomington, IN 47405; jtenness@indiana.edu.
authors.forename: Jason M
authors.identifier: 0000-0002-3527-5683
authors.initials: JM
authors.lastname: Tennessen
mesh_terms: D000429:Alcohol Oxidoreductases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D019175:DNA Methylation; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics / Q000254:growth & development* / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D005977:Glutarates / Q000737:chemistry / Q000378:metabolism*; D006019:Glycolysis; D007770:L-Lactate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D007814:Larva / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D013237:Stereoisomerism
chemical_list: D029721:Drosophila Proteins; C475538:ERR protein, Drosophila; D005977:Glutarates; D011960:Receptors, Estrogen; C019417:alpha-hydroxyglutarate; D000429:Alcohol Oxidoreductases; D007770:L-Lactate Dehydrogenase; C023858:2-hydroxyglutarate dehydrogenase
keywords: 2-hydroxyglutarate; LDH; Warburg effect; estrogen-related receptor; lactate