文献类型：期刊文献

英文题名：Hypoxia-Mediated Increases in L-2-hydroxyglutarate Coordinate the Metabolic Response to Reductive Stress

作者：Oldham, William M.[1,2];Clish, Clary B.[3];Yang, Yi[4];Loscalzo, Joseph[2,5,6]

机构：[1]Brigham & Womens Hosp, Dept Med, Pulm & Crit Care Med, Boston, MA 02115 USA;[2]Harvard Univ, Sch Med, Boston, MA 02115 USA;[3]Broad Inst Massachusetts Inst Technol & Harvard U, Metabolite Profiling, Cambridge, MA 02142 USA;[4]E China Univ Sci & Technol, Sch Pharm, Synthet Biol & Biotechnol Lab, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R China;[5]Brigham & Womens Hosp, Dept Med, Cardiovasc Med, Boston, MA 02115 USA;[6]Harvard Univ, Sch Med, Lab Syst Pharmacol, Boston, MA 02115 USA

年份：2015

卷号：22

期号：2

起止页码：291

外文期刊名：CELL METABOLISM

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000359000500014)】；

基金：This work was supported by the NIH/NHLBI (HL007633 to W.M.O.; HL048743, HL061795, GM107618, and HL108630 to J.L.), the Natural Science Foundation of China (31225008 and 91313301 to Y.Y.), and the Brigham and Women's Hospital Department of Medicine. The authors declare no conflicts of interest.

语种：英文

摘要：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.