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.

癌代谢物 L-2-羟基戊二酸 (L-2HG) 被认为是中央碳代谢的异常产物，能够破坏染色质结构、线粒体代谢和细胞分化。在大多数情况下，哺乳动物组织很容易处理这种化合物，因为异常的 L-2HG 积累会诱导神经代谢紊乱并促进肾细胞癌。有趣的是，黑腹果蝇最近发现幼虫在正常生长条件下会积累高水平的 L-2HG，这增加了 L-2HG 在昆虫代谢中发挥独特作用的可能性。在这里，我们通过分析 18 种昆虫的 L-2HG 水平来探索这一假设。虽然 L-2HG 在大多数这些物种中以低至中等水平存在（<100 pmol/mg；与小鼠肝脏相当），但双翅目幼虫表现出积累高 L-2HG 浓度（>100 pmol/mg）的趋势, 与蚊子埃及伊蚊, 吹蝇Phormia regina , 和三个代表果蝇浓度超过 1 nmol/mg 的物种——与在无法降解 L-2HG 的突变小鼠中测得的水平相当。总体而言，我们的研究结果表明，地球上最大的动物群体之一通常在幼体生长期间产生高浓度的癌代谢物，暗示 L-2HG 在双翅目发育进化中的作用，并提高了 L-2HG 代谢的可能性可以有针对性地限制关键病媒和农业害虫的生长。