Drosophila larvae synthesize the putative oncometabolite L-2-hydroxyglutarate during normal developmental growth

摘要: 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 L-2HG to interfere with broad range cellular processes, this molecule often characterized metabolic waste product. Here, we demonstrate Drosophila larvae use conditions established by aerobic glycolysis both synthesize accumulate high concentrations during normal developmental growth. A majority larval pool derived from glucose dependent on estrogen-related receptor (dERR), which promotes synthesis up-regulating expression homolog lactate dehydrogenase (dLdh). We also show dLDH necessary sufficient for directly synthesizing (dL2HGDH), encodes enzyme breaks down L-2HG, required stage-specific degradation pool. In addition, indirectly accumulation via lactate, activates feed-forward mechanism inhibits dL2HGDH activity stabilizes levels. Finally, genetic approach influence position effect variegation DNA methylation, suggesting compound serves coordinate glycolytic flux epigenetic modifications. Overall, our studies growing animal tissues controlled manner, reveal coordinates catabolism synthesis, establish fly unique model system studying endogenous functions growth proliferation.