Hypoxia-Mediated Increases in l-2-hydroxyglutarate Coordinate the Metabolic Response to Reductive Stress

• Published in: Cell metabolism Vol. 22; no. 2; pp. 291 - 303
• Main Authors: Oldham, William M., Clish, Clary B., Yang, Yi, Loscalzo, Joseph
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 04.08.2015
• Subjects: Adaptation, Physiological - physiology; Cell Hypoxia - physiology; Citric Acid Cycle - physiology; Glutarates - metabolism; Glycolysis - physiology; HEK293 Cells; Hep G2 Cells; Humans; Malate Dehydrogenase - metabolism; Oxidation-Reduction; Stress, Physiological
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2015.06.021

Metabolic adaptation to hypoxia is critical for survival in metazoan species for which reason they have developed cellular mechanisms for mitigating its adverse consequences. Here, we have identified l-2-hydroxyglutarate (L2HG) as a universal adaptive determinant of the hypoxia response. L2HG is a metabolite of unknown function produced by the reduction of mitochondrial 2-oxoglutarate by malate dehydrogenase. L2HG accumulates in response to increases in 2-oxoglutarate, which occur as a result of tricarboxylic acid cycle dysfunction and increased mitochondrial reducing potential. These changes are closely coupled to cellular redox homeostasis, as increased cellular L2HG inhibits electron transport and glycolysis to offset the adverse consequences of mitochondrial reductive stress induced by hypoxia. Thus, L2HG couples mitochondrial and cytoplasmic energy metabolism in a model of cellular redox regulation. [Display omitted] •Hypoxia increases cellular l-2-hydroxyglutarate (L2HG)•L2HG accumulates in response to mitochondrial dysfunction•This accumulation is independent of hypoxia-inducible factor activation•L2HG inhibits electron transport and glycolysis to mitigate reductive stress The oncometabolite D-2-hydroxyglutarate (D-2HG) generated via mutant isocitrate dehydrogenase contributes to cancer pathogenesis. Intlekofer et al. and Oldham et al. now show that the enantiomer L-2HG is selectively produced in hypoxic cells to regulate histone methylation levels and to help mitigate cellular reductive stress through inhibition of glycolysis and electron transport.