Beyond Isocitrate Dehydrogenase Mutations: Emerging Mechanisms for the Accumulation of the Oncometabolite 2-Hydroxyglutarate

Abstract

2-Hydroxyglutarate (2-HG) is an unconventional oncometabolite of α-ketoglutarate. Isocitrate dehydrogenase mutation is generally acknowledged to be the main cause of 2-HG accumulation. In isocitrate dehydrogenase mutant tumors, 2-HG accumulation inhibits α-ketoglutarate/ Fe(II)-dependent dioxygenases, resulting in epigenetic alterations. Recently, the increase of 2-HG has also been observed in the cases of mitochondrial dysfunction and hypoxia. In these cases, 2-HG not only inhibits αketoglutarate/Fe(II)-dependent dioxygenases to regulate epigenetics but also affects other cellular pathways, such as regulating hypoxia-inducible transcription factors and glycolysis. These provide a new perspective for the study of 2-HG.

Structural analysis of the 2-oxoglutarate binding site of the circadian rhythm linked oxygenase JMJD5

“…Previous reports have shown that inhibition of human 2OG oxygenases by both l - and d -2HG is possible 35 , 46 ; the concentration of d -2HG is elevated as a consequence of gain of function mutations to isocitrate dehydrogenases 1/2 (IDH 1/2) 47 , 48 . Mutations to the dehydrogenases converting l -2HG or d -2HG to 2OG can also result in elevations of l - or d -2HG levels 49 . Future work to systematically investigate the stereoselectivity of 2OG oxygenase inhibition by the 2HG enantiomers is therefore of interest.…”

Oncometabolite 2-hydroxyglutarate regulates anti-tumor immunity

“…This points to the existence of additional factors that contribute to the increased levels of 2-HG. In fact, several mechanisms independent of mIDH, leading to an increase in both D-2-HG and L-2-HG in tumors, have been reported [ 49 ].…”

“…Concurrently, a distinguishing characteristic of tumor metabolism is the increased uptake of glutamine, coupled with intensified glutaminolysis within the mitochondria, mediated by glutaminase 1 (GLS1) [ 51 ]. This metabolic shift leads to a heightened accumulation of glutamine-derived α-KG, which can subsequently serve as the substrate for the synthesis of both D-2-HG and L-2-HG [ 49 , 52 ]. In RCC, a noted reduction in L2HGDH expression correlates with the consequential accumulation of L-2-HG [ 53 ].…”