Drosophila larvae synthesize the putative oncometabolite L-2-hydroxyglutarate during normal developmental growth
Drosophila larvae synthesize the putative oncometabolite L-2-hydroxyglutarate during normal developmental growth
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DOI：
10.1073/pnas.1614102114
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发表时间：
2017-02-07
影响因子：
11.1
通讯作者：
Tennessen, Jason M.
中科院分区：
文献类型：
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作者：
Li, Hongde;Chawla, Geetanjali;Tennessen, Jason M.
L-2-羟基戊二酸（L-2 HG）是一种公认的代谢抑制剂，能够抑制参与代谢、染色质修饰和细胞分化的酶。然而，尽管L-2 HG能够干扰广泛的细胞过程，但这种分子通常被表征为代谢废物。在这里，我们证明了果蝇幼虫使用有氧糖酵解建立的代谢条件，在正常发育生长过程中合成和积累高浓度的L-2 HG。大多数幼虫L-2 HG库来自葡萄糖，并依赖于果蝇雌激素相关受体（dERR），其通过上调乳酸脱氢酶（dLdh）的果蝇同源物的表达来促进L-2 HG合成。我们还表明，dLDH是必要的和足够的直接合成L-2 HG和果蝇同源的L-2-羟戊二酸脱氢酶（dL 2 HGDH），它编码的酶，打破L-2 HG，是所需的阶段特异性降解的L-2 HG池。此外，dLDH还通过合成乳酸盐间接促进L-2 HG积累，这激活了抑制dL 2 HGDH活性并稳定L-2 HG水平的代谢前馈机制。最后，我们使用遗传方法来证明，dLDH和L-2 HG影响位置效应杂色和DNA甲基化，这表明该化合物用于协调糖酵解通量与表观遗传修饰。总之，我们的研究表明，生长中的动物组织合成L-2 HG以受控的方式，揭示了协调葡萄糖催化剂与L-2 HG合成的机制，并建立了苍蝇作为一个独特的模型系统，用于研究L-2 HG在细胞生长和增殖过程中的内源性功能。
L-2-hydroxyglutarate (L-2HG) has emerged as a putative oncome-tabolite 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.