Mitochondrial l-2-hydroxyglutarate is a physiological signalling metabolite

• 成果类型: Article
• 署名作者: 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.
• 署名单位: Northwestern University; Feinberg School of Medicine; Harvard University; Harvard Medical School; Northwestern University; Feinberg School of Medicine; Northwestern University; Feinberg School of Medicine; Ann & Robert H. Lurie Children's Hospital of Chicago; Northwestern University; Feinberg School of Medicine; Northwestern University; Feinberg School of Medicine; University of California System; University of California San Francisco
• 刊物名称: NATURE
• ISSN/ISSBN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-026-10564-x
• 发表日期: 2026-07-23
• 关键词: ALPHA-KETOGLUTARATE; ONCOMETABOLITE 2-HYDROXYGLUTARATE; PUTATIVE ONCOMETABOLITE; reductive carboxylation; gene-expression; dehydrogenase; generation; S-2-HYDROXYGLUTARATE; quantification; itaconate

摘要

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 accumulation(1). In humans, a lack of L2HGDH activity leads to l-2-HG accumulation and causes l-2-hydroxyglutaric aciduria(2). Thus, l-2-HG is often classified as a toxic metabolite(2, 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 dehydrogenase 2 (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.