Hypoxia-Mediated Increases in L-2-hydroxyglutarate Coordinate the Metabolic Response to Reductive Stress.
Hypoxia-Mediated Increases in L-2-hydroxyglutarate Coordinate the Metabolic Response to Reductive Stress.
复制标题
缺氧介导的 L-2-羟基戊二酸增加可协调对还原应激的代谢反应。
DOI：
10.1016/j.cmet.2015.06.021
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发表时间：
2015-08-04
期刊：
影响因子：
29
通讯作者：
Loscalzo J
中科院分区：
文献类型：
--
作者：
Oldham WM;Clish CB;Yang Y;Loscalzo J
对缺氧的代谢适应对于后生动物物种的生存至关重要，因此它们已经开发了减轻其不良后果的细胞机制。在这里，我们已经确定L-2-羟基戊二酸（L2 HG）作为一个普遍的适应性决定因素的缺氧反应。L2 HG是一种功能未知的代谢产物，由苹果酸脱氢酶还原线粒体2-酮戊二酸产生。L2 HG响应于2-酮戊二酸的增加而积累，这是三羧酸循环功能障碍和线粒体还原电位增加的结果。这些变化与细胞氧化还原稳态密切相关，因为细胞L2 HG的增加会抑制电子传递和糖酵解，以抵消缺氧诱导的线粒体还原应激的不利后果。因此，L2 HG在细胞氧化还原调节的新模型中偶联线粒体和细胞质能量代谢。
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 previously 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 new model of cellular redox regulation.