美国西北大学范伯格医学院Navdeep S. Chandel小组宣布他们的最新研究揭示了线粒体l-2-羟戊二酸是一种生理信号代谢产物。相关论文于2026年5月20日发表在《自然》杂志上。

在这里，该课题组通过测试三个标准来研究l-2-HG是否有资格作为生理信号代谢物：调节水平、确定的分子靶点和可测量的生理功能。研究团队报道线粒体NADH/NAD⁺比值的增加驱动苹果酸脱氢酶2 （MDH2）将2-Og还原为l-2-HG。

此外，L2HGDH在不需要功能性电子传递链的情况下将线粒体基质中的l-2-HG氧化回2-OG。通过蛋白质组积分溶解度改变测定，小组发现KDM4家族的H3K9去甲基化酶是l-2-HG响应的靶标。l-2-HG抑制同位胚胎干细胞中特定基因的新生转录，并增加这些位点上的H3K9me3（一种抑制性组蛋白标记）。在体内，小鼠胚胎早期L2HGDH过表达会系统性降低l-2-HG水平，损害出生后生长，增加死亡率，并产生选择性功能和组织学肾脆弱性。在出生后的肾脏中，L1MdTf逆转录转座子上的l-2-HG三聚体H3K9me3缺失的减少及其抑制，与综合应激反应和炎症途径的激活相一致。他们的发现证实了线粒体l-2-HG是一种生理信号代谢物，并表明以前被认为是有毒的代谢物也可能具有关键的生理功能。

据悉，l-2-羟戊二酸（l-2-HG）是哺乳动物体内的低丰度代谢物，因为线粒体酶l-2-HG脱氢酶（L2HGDH）将l-2-HG氧化为2-氧戊二酸（2-OG）以防止其积累。在人类中，缺乏L2HGDH活性会导致l-2-汞的积累和氨基糖-2-羟基戊二酸的产生。因此，l-2-HG通常被归类为有毒代谢物。然而，l-2-HG是否有任何生理功能尚不清楚。

附：英文原文

Title: Mitochondrial l-2-hydroxyglutarate is a physiological signalling metabolite

Author: Chakrabarty, Ram P., Van Vranken, Jonathan G., Aoi, Yuki, Poor, Taylor A., McElroy, Gregory S., Vasan, Karthik, Soliman, Shimaa H. A., Iwanaszko, Marta, Grant, Rogan A., Howard, Benjamin C., Reczek, Colleen R., Chandel, Anjali D., Kahl, Michael, Xu, Zhaofa, Helmin, Kathryn A., Jin, Qiushi, Wang, Dongmei, Gao, Peng, Blum, Jenna L. E., Sebo, Zachary L., Yue, Feng, Ma, Yongchao C., Davidson, Shawn M., Gygi, Steven P., Weinberg, Samuel E., Singer, Benjamin D., Han, SeungHye, Shilatifard, Ali, Chandel, Navdeep S.

Issue&Volume: 2026-05-20

Abstract: l-2-Hydroxyglutarate (l-2-HG) is a low-abundance metabolite in mammals because the mitochondrial enzyme l-2-HG dehydrogenase (L2HGDH) oxidizes l-2-HG to 2-oxoglutarate (2-OG) to prevent its accumulation1. In humans, a lack of L2HGDH activity leads to l-2-HG accumulation and causes l-2-hydroxyglutaric aciduria2. Thus, l-2-HG is often classified as a toxic metabolite2,3,4,5. However, whether l-2-HG has any physiological function is unclear. Here we investigate whether l-2-HG qualifies as a physiological signalling metabolite by testing three criteria: regulated levels, defined molecular targets and a measurable physiological function. We report that an increase in mitochondrial NADH/NAD+ ratio drives malate dehydrogenase2 (MDH2) to reduce 2-OG into l-2-HG. Moreover, L2HGDH oxidizes l-2-HG back to 2-OG in the mitochondrial matrix without requiring a functional electron transport chain. Through proteome integral solubility alteration assays, we show that the KDM4 family of H3K9 demethylases are l-2-HG-responsive targets. l-2-HG represses the nascent transcription of specific genes in mouse embryonic stem cells and increases H3K9me3 (a repressive histone mark) at these loci. In vivo, early embryonic L2HGDH overexpression in mice systemically reduces l-2-HG levels, impairs postnatal growth, causes mortality and produces selective functional and histological renal vulnerabilities. In postnatal kidneys, this reduction in l-2-HG causes H3K9me3 loss at L1MdTf retrotransposons and their derepression, which coincides with the activation of the integrated stress response and inflammation pathways. Our findings establish mitochondrial l-2-HG as a physiological signalling metabolite and indicate that metabolites previously regarded as toxic may also have crucial physiological functions.

DOI: 10.1038/s41586-026-10564-x

Source: https://www.nature.com/articles/s41586-026-10564-x