Cell Metab. doi:10.1016/j.cmet.2015.06.021; Cell Metab. doi:10.1016/j.cmet.2015.06.023

The metabolic enzymes isocitrate dehydrogenases 1 and 2 (IDH1/2) normally catalyze the interconversion of isocitrate and α-ketoglutarate (α-keto). Somatic gain-of-function mutations in IDH1/2 result in production of the D enantiomer of 2-hydroxyglutarate (D2HG), a known onco-metabolite that prevents differentiation of cancer cells. The levels of D2HG and of the L enantiomer L-2-hydroxyglutarate (L2HG) are further regulated by D-2-hydroxyglutarate dehydrogenase (D2HGDH) and L-2-hydroxyglutarate (L2HGDH), respectively, which convert D2HG and L2HG back to α-keto. However, the potential sources and functions of L2HG in normal and malignant cellular metabolism were poorly understood. In a search to identify metabolites that are regulated under low-oxygen conditions, Oldham et al. and Intlekofer et al. performed mass spectrometry analysis of mammalian cells under hypoxic conditions and detected elevated levels of 2-hydroglutarate (2-HG). Surprisingly, both groups resolved the 2-HG enantiomers and discovered that L2HG and not D2HG levels were increased in hypoxic cells. Consistent with this, inhibition of L2HGDH increased 2-HG production whereas overexpression of L2HGDH lowered 2-HG levels under low oxygen conditions. Both studies showed a contribution of malate dehydrogenase (MDH) towards L2HG production through reduction of 2-oxoglutarate. Knockdown of either MDH isoforms decreased hypoxia-mediated L2HG production. In addition, Intlekofer et al. proposed that lactate dehydrogenase served as a major enzymatic source of L2HG production by utilizing glutamate-derived α-KG. Using a genetically encoded fluorescent sensor, Oldham et al. found that L2HG altered the cellular redox status by increasing the NADH/NAD+ ratio while also functioning as a suppressor of oxygen consumption and glycolytic flux. Moreover, Intlekofer et al. demonstrated that hypoxia-induced L-2HG alters histone methylation by inhibiting α-keto-dependent histone demethylases. Overall, these findings suggest that manipulation of L2HG production represents a novel strategy to influence cellular responses to hypoxic stress.