Abstract
Mitochondrial carriers catalyse the translocation of numerous metabolites across the inner mitochondrial membrane, playing a key role in different cell functions. For this reason, mitochondrial carrier gene expression needs tight regulation. The human SLC25A13 gene, encoding for the mitochondrial aspartate/glutamate carrier isoform 2 (AGC2), catalyses the electrogenic exchange of aspartate for glutamate plus a proton, thus taking part in many metabolic processes including the malate-aspartate shuttle. By the luciferase (LUC) activity of promoter deletion constructs we identified the putative promoter region, comprising the proximal promoter (−442 bp/−19 bp), as well as an enhancer region (−968 bp/−768 bp). Furthermore, with different approaches, such as in silico promoter analysis, gene silencing and chromatin immunoprecipitation, we identified two transcription factors responsible for SLC25A13 transcriptional regulation: FOXA2 and USF1. USF1 acts as a positive transcription factor which binds to the basal promoter thus ensuring SLC25A13 gene expression in a wide range of tissues. The role of FOXA2 is different, working as an activator in hepatic cells. As a tumour suppressor, FOXA2 could be responsible for SLC25A13 high expression levels in liver and its downregulation in hepatocellular carcinoma (HCC).
Highlights
The human aspartate/glutamate carrier isoform 2 (AGC2), encoded by the SLC25A13 gene, is a member of the mitochondrial carrier family [1,2]
We have investigated the transcriptional regulation of SLC25A13 and identified two transcriptional factors, USF1 and FOXA2, that act as positive regulators of the SLC25A13 gene expression
When FOXA2 or USF1 genes were silenced we obtained a great reduction in NAD+/NADH ratio; this reduction was even greater in the presence of FOXA2/USF1 double gene silencing (Figure 5B). These findings suggest a role for FOXA2 and USF1 as regulators of AGC2 activity implying their control of the NADH redox status
Summary
The human aspartate/glutamate carrier isoform 2 (AGC2), encoded by the SLC25A13 gene, is a member of the mitochondrial carrier family [1,2] This family of transporters translocates a variety of metabolites across the mitochondrial membrane, linking biological and metabolic processes occurring in both mitochondria and cytosol [3,4]. Humans possess another isoform of the aspartate-glutamate carrier, AGC1, which is encoded by the SLC25A12 gene. A specific involvement of AGC1 in hepatocellular carcinoma (HCC) and N-acetylaspartate synthesis in mice lacking AGC1 has been reported [21,22]
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