UCP2 transports C4 metabolites out of mitochondria, regulating glucose and glutamine oxidation
UCP2 transports C4 metabolites out of mitochondria, regulating glucose and glutamine oxidation
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DOI：
10.1073/pnas.1317400111
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发表时间：
2014-01-21
影响因子：
11.1
通讯作者：
Fiermonte, Giuseppe
中科院分区：
文献类型：
--
作者：
Vozza, Angelo;Parisi, Giovanni;Fiermonte, Giuseppe
解偶联蛋白2（UCP2）参与多种生理和病理过程，如胰岛素分泌、干细胞分化、癌症和衰老。然而，它的生理和生化功能仍然存在争议。UCP2是一种代谢物转运蛋白，调节线粒体中的底物氧化。为了阐明其生物化学作用，我们首先研究了其沉默对葡萄糖和谷氨酰胺的线粒体氧化的影响。与野生型相比，UCP2沉默的人肝细胞癌（HepG2）细胞，生长在葡萄糖的存在下，表现出较高的线粒体内膜电位和ATP：ADP的比例与较低的乳酸释放。在谷氨酰胺而不是葡萄糖存在下获得相反的结果。在脂质囊泡中重组的UCP2催化苹果酸、草酰乙酸和天冬氨酸与来自膜两侧的磷酸盐和质子的交换。与野生型细胞相比，siUCP2HepG2细胞线粒体中发现的柠檬酸循环中间体水平更高，除了运输数据外，还表明通过将C4化合物输出线粒体，UCP2限制了乙酰辅酶A产生底物（如葡萄糖）的氧化，并增强了谷氨酰胺分解，防止了来自谷氨酰胺的C4代谢物的线粒体积累。我们的工作揭示了一个独特的调节机制，在细胞生物能量学，并引发了大量的重新考虑的生理和病理功能归因于UCP2的基础上，其声称的解偶联性能。
Uncoupling protein 2 (UCP2) is involved in various physiological and pathological processes such as insulin secretion, stem cell differentiation, cancer, and aging. However, its biochemical and physiological function is still under debate. Here show that UCP2 is a metabolite transporter that regulates substrate oxidation in mitochondria. To shed light on its biochemical role, we first studied the effects of its silencing on the mitochondrial oxidation of glucose and glutamine. Compared with wild-type, UCP2-silenced human hepatocellular carcinoma (HepG2) cells, grown in the presence of glucose, showed a higher inner mitochondrial membrane potential and ATP: ADP ratio associated with a lower lactate release. Opposite results were obtained in the presence of glutamine instead of glucose. UCP2 reconstituted in lipid vesicles catalyzed the exchange of malate, oxaloacetate, and aspartate for phosphate plus a proton from opposite sides of the membrane. The higher levels of citric acid cycle intermediates found in the mitochondria of siUCP2HepG2 cells compared with those found in wild-type cells in addition to the transport data indicate that, by exporting C4 compounds out of mitochondria, UCP2 limits the oxidation of acetyl-CoA-producing substrates such as glucose and enhances glutaminolysis, preventing the mitochondrial accumulation of C4 metabolites derived from glutamine. Our work reveals a unique regulatory mechanism in cell bioenergetics and provokes a substantial reconsideration of the physiological and pathological functions ascribed to UCP2 based on its purported uncoupling properties.