Amoedo N D, Punzi G, Obre E, Lacombe D, De Grassi A, Pierri C L, Rossignol R
Univ. Bordeaux, U1211, Bordeaux, France; INSERM, U1211, Bordeaux, France; Instituto de Bioquímica Médica Leopoldo De Meis, UFRJ, Rio de Janeiro, Brazil.
Univ. Bordeaux, U1211, Bordeaux, France; INSERM, U1211, Bordeaux, France; Department of Biosciences, Biotechnologies and Biopharmaceutics, Laboratory of Biochemistry and Molecular Biology, University of Bari.
Biochim Biophys Acta. 2016 Oct;1863(10):2394-412. doi: 10.1016/j.bbamcr.2016.04.011. Epub 2016 Apr 28.
In this review we discuss the structure and functions of the aspartate/glutamate carriers (AGC1-aralar and AGC2-citrin). Those proteins supply the aspartate synthesized within mitochondrial matrix to the cytosol in exchange for glutamate and a proton. A structure of an AGC carrier is not available yet but comparative 3D models were proposed. Moreover, transport assays performed by using the recombinant AGC1 and AGC2, reconstituted into liposome vesicles, allowed to explore the kinetics of those carriers and to reveal their specific transport properties. AGCs participate to a wide range of cellular functions, as the control of mitochondrial respiration, calcium signaling and antioxydant defenses. AGC1 might also play peculiar tissue-specific functions, as it was found to participate to cell-to-cell metabolic symbiosis in the retina. On the other hand, AGC1 is involved in the glutamate-mediated excitotoxicity in neurons and AGC gene or protein alterations were discovered in rare human diseases. Accordingly, a mice model of AGC1 gene knock-out presented with growth delay and generalized tremor, with myelinisation defects. More recently, AGC was proposed to play a crucial role in tumor metabolism as observed from metabolomic studies showing that the asparate exported from the mitochondrion by AGC1 is employed in the regeneration of cytosolic glutathione. Therefore, given the central role of AGCs in cell metabolism and human pathology, drug screening are now being developed to identify pharmacological modulators of those carriers. This article is part of a Special Issue entitled: Mitochondrial Channels edited by Pierre Sonveaux, Pierre Maechler and Jean-Claude Martinou.
在本综述中，我们讨论了天冬氨酸/谷氨酸载体（AGC1-阿拉拉尔和AGC2-西曲林）的结构和功能。这些蛋白质将在线粒体基质中合成的天冬氨酸供应到细胞质中，以交换谷氨酸和一个质子。目前尚无AGC载体的结构，但已提出了比较性的三维模型。此外，通过使用重组AGC1和AGC2（重组到脂质体囊泡中）进行的转运测定，有助于探究这些载体的动力学并揭示其特定的转运特性。AGC参与多种细胞功能，如线粒体呼吸的控制、钙信号传导和抗氧化防御。AGC1可能还具有特殊的组织特异性功能，因为已发现它参与视网膜中的细胞间代谢共生。另一方面，AGC1参与神经元中谷氨酸介导的兴奋性毒性，并且在罕见的人类疾病中发现了AGC基因或蛋白质的改变。相应地，AGC1基因敲除的小鼠模型表现出生长延迟和全身性震颤，并伴有髓鞘形成缺陷。最近，从代谢组学研究观察到，AGC1从线粒体输出的天冬氨酸用于细胞质谷胱甘肽的再生，因此AGC被认为在肿瘤代谢中起关键作用。因此，鉴于AGC在细胞代谢和人类病理学中的核心作用，目前正在开展药物筛选以鉴定这些载体的药理学调节剂。本文是由皮埃尔·松沃、皮埃尔·梅克勒和让-克洛德·马蒂诺编辑的特刊《线粒体通道》的一部分。
