2-Hydroxyglutarate Inhibits ATP Synthase and mTOR Signaling

We discovered recently that the central metabolite α-ketoglutarate (α-KG) extends the lifespan of C. elegans through inhibition of ATP synthase and TOR signaling. Here we find, unexpectedly, that (R)-2-hydroxyglutarate ((R)-2HG), an oncometabolite that interferes with various α-KG-mediated processes, similarly extends worm lifespan. (R)-2HG accumulates in human cancers carrying neomorphic mutations in the isocitrate dehydrogenase (IDH) 1 and 2 genes. We show that, like α-KG, both (R)-2HG and (S)-2HG bind and inhibit ATP synthase and inhibit mTOR signaling. These effects are mirrored in IDH1 mutant cells, suggesting a growth-suppressive function of (R)-2HG. Consistently, inhibition of ATP synthase by 2-HG or α-KG in glioblastoma cells is sufficient for growth arrest and tumor cell killing under conditions of glucose limitation, e.g., when ketone bodies (instead of glucose) are supplied for energy. These findings inform therapeutic strategies and open avenues for investigating the roles of 2-HG and metabolites in biology and disease. [Display omitted] •2-HG, like α-KG, inhibits ATP synthase and extends the lifespan of C. elegans•IDH1(R132H) mutant cells have reduced ATP content, respiration, and mTOR signaling•IDH1(R132H) mutant cells exhibit an intrinsic vulnerability to glucose limitation•ATP synthase is a target of 2-HG’s growth-suppressive activity in IDH mutant cells Aberrant isocitrate dehydrogenase enzymes encoded by cancer-associated IDH1 and IDH2 gene mutations produce an oncometabolite, (R)-2HG. Fu et al. discover a growth-suppressive function of (R)-2-HG mediated by its binding and inhibition of ATP synthase. The resulting OXPHOS perturbation imparts extra vulnerability to glucose limitation in IDH mutant glioblastoma cells.