AGC1/2, the mitochondrial aspartate-glutamate carriers

Abstract

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.

Multi-omic profiling of tyrosine kinase inhibitor-resistant K562 cells suggests metabolic reprogramming to promote cell survival

“…Ultimately, these metabolic adaptations seem to be relatively independent of the specific kinases or cancer type. (59), (60)(61) The metabolic adaptations we observed were not consistent with recently proposed models in which increased OXPHOS is a marker of early-stage non-response to chemotherapies (as opposed to apparent deficiency in OXPHOS, as in our case), (56,(62)(63) suggesting that longer time courses of exposure may be needed in order to understand longer term resistance. The detailed mechanisms of how the metabolic alterations enable cell survival in the presence of the three TKIs still need to be elucidated, and studies are ongoing to identify the key metabolic processes (e.g.…”

T-ALL Proliferation Relies on Glutamine Uptake and EAAT1-dependent Conversion of Glutamine to Aspartate and Nucleotides

“…Their activity depends on the mitochondrial membrane potential that is maintained by cytoplasmic ATP [69]. Both transporters are present in the majority of cells and tissues (reviewed in [70]). We found that SLC25A12 is expressed in all four T-ALL cell lines, while SLC25A13 was found only in DU.528.…”

“…One possibility is that EAAT1 has a higher Kd for glutamate than ARALAR1and CITRIN and therefore facilitates a higher rate of antiport across the mitochondrial membrane. Even though the kinetics of all three transporters are reported, the experiments were not performed in comparable experimental conditions and EAAT1 capacity was always addressed in respect to its membranous localisation [70][71][72]. The second possibility is that the intracellular conditions, such as the pH, ATP availability and mitochondrial action potential, are restrictive for ARALAR1 and CITRIN function, whereas EAAT1 is independent of these factors.…”

Functional Properties of the Mitochondrial Carrier System

“…As an example, the aspartate-glutamate carrier 1 (AGC1; SCL25A12 ), aspartate-glutamate carrier 2 ( AGC2 ; SLC25A13 ), glutamate carrier 1 (GC1; SLC25A22 ), and glutamate carrier 2 (GC2; SLC25A18 ) all import glutamate. AGC1 and AGC2 are calcium-stimulated exchangers that import glutamate while exporting aspartate [61]. This exchange activity is a key step in the malate-aspartate shuttle [62, 63].…”

“…Import through AGC1/2 is in exchange for aspartate export [61]. Import through GC1/2 is by proton (H + ) symport [66].…”