Department of Biology, Indiana University, Bloomington, IN 47405, USA.
RNA Biology Laboratory, School of Biological Sciences, University of Nebraska, Lincoln, NE 68588, USA.
Development. 2019 Sep 12;146(17):dev175315. doi: 10.1242/dev.175315.
The dramatic growth that occurs during larval development requires rapid conversion of nutrients into biomass. Many larval tissues respond to these biosynthetic demands by increasing carbohydrate metabolism and lactate dehydrogenase (LDH) activity. The resulting metabolic program is ideally suited for synthesis of macromolecules and mimics the manner by which cancer cells rely on aerobic glycolysis. To explore the potential role of LDH in promoting biosynthesis, we examined how mutations influence larval development. Our studies unexpectedly found that mutants grow at a normal rate, indicating that LDH is dispensable for larval biomass production. However, subsequent metabolomic analyses suggested that mutants compensate for the inability to produce lactate by generating excess glycerol-3-phosphate (G3P), the production of which also influences larval redox balance. Consistent with this possibility, larvae lacking both LDH and G3P dehydrogenase (GPDH1) exhibit growth defects, synthetic lethality and decreased glycolytic flux. Considering that human cells also generate G3P upon inhibition of lactate dehydrogenase A (LDHA), our findings hint at a conserved mechanism in which the coordinate regulation of lactate and G3P synthesis imparts metabolic robustness to growing animal tissues.
幼虫发育过程中的急剧生长需要将营养物质迅速转化为生物量。许多幼虫组织通过增加碳水化合物代谢和乳酸脱氢酶（LDH）活性来响应这些生物合成需求。由此产生的代谢程序非常适合合成大分子，并模仿癌细胞依赖有氧糖酵解的方式。为了探讨 LDH 在促进生物合成中的潜在作用，我们研究了 突变如何影响幼虫发育。我们的研究出人意料地发现， 突变体以正常速度生长，这表明 LDH 对于幼虫生物量的产生不是必需的。然而，随后的代谢组学分析表明， 突变体通过产生过量的甘油-3-磷酸（G3P）来弥补不能产生乳酸的能力，G3P 的产生也会影响幼虫的氧化还原平衡。与这种可能性一致的是，缺乏 LDH 和甘油-3-磷酸脱氢酶 1（GPDH1）的幼虫表现出生长缺陷、合成致死性和糖酵解通量降低。考虑到人类细胞在抑制乳酸脱氢酶 A（LDHA）后也会产生 G3P，我们的发现暗示了一种保守机制，即协调调节乳酸和 G3P 的合成赋予了生长中的动物组织代谢稳健性。
