Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Mol Cell. 2013 Jul 25;51(2):236-48. doi: 10.1016/j.molcel.2013.05.003. Epub 2013 Jun 6.
The tricarboxylic acid cycle enzyme fumarate hydratase (FH) has been identified as a tumor suppressor in a subset of human renal cell carcinomas. Human FH-deficient cancer cells display high fumarate concentration and ROS levels along with activation of HIF-1. The underlying mechanisms by which FH loss increases ROS and HIF-1 are not fully understood. Here, we report that glutamine-dependent oxidative citric acid cycle metabolism is required to generate fumarate and increase ROS and HIF-1 levels. Accumulated fumarate directly bonds the antioxidant glutathione in vitro and in vivo to produce the metabolite succinated glutathione (GSF). GSF acts as an alternative substrate to glutathione reductase to decrease NADPH levels and enhance mitochondrial ROS and HIF-1 activation. Increased ROS also correlates with hypermethylation of histones in these cells. Thus, fumarate serves as a proto-oncometabolite by binding to glutathione which results in the accumulation of ROS.
三羧酸循环酶延胡索酸水合酶 (FH) 已被确定为人类肾细胞癌亚群中的肿瘤抑制因子。人类 FH 缺陷型癌细胞表现出高琥珀酸浓度和 ROS 水平，同时 HIF-1 被激活。FH 缺失增加 ROS 和 HIF-1 的潜在机制尚未完全阐明。在这里，我们报告谷氨酰胺依赖性氧化柠檬酸循环代谢对于产生琥珀酸和增加 ROS 和 HIF-1 水平是必需的。蓄积的琥珀酸直接与抗氧化剂谷胱甘肽在体外和体内结合，产生代谢物琥珀酰化谷胱甘肽 (GSF)。GSF 作为谷胱甘肽还原酶的替代底物，降低 NADPH 水平，并增强线粒体 ROS 和 HIF-1 的激活。这些细胞中 ROS 的增加也与组蛋白的超甲基化相关。因此，琥珀酸通过与谷胱甘肽结合作为原致癌代谢物，导致 ROS 的积累。
