The mitochondrial transporter family (SLC25): physiological and pathological implications

Abstract

The mitochondrial carriers (MCs) shuttle a variety of metabolites across the inner mitochondrial membrane (i.m.m.). In man they are encoded by the SLC25 genes. Some MCs have isoforms encoded by different SLC25 genes, whereas the phosphate carrier has two variants arising from an alternative splicing of SLC25A3. Six MCs have been sequenced after purification, and many more have been identified from their transport and kinetic properties following heterologous over-expression and reconstitution into liposomes. All MCs of known function belong to the same protein family, since their polypeptide chains consist of three tandemly related sequences of about 100 amino acids, and the repeats of the different carriers are homologous. They probably function as homodimers, each monomer being folded in the membrane into six transmembrane segments. The functional information obtained in studies with mitochondria and/or the reconstituted system has helped to gain an insight into the physiological role of the MCs in cell metabolism, as have tissue distribution, the use of knock-out mice (and/or yeast) and over-expression in human cell lines (or yeast) of individual carriers and isoforms. At the same time, the cloning and functional identification of many SLC25 genes has made it possible (i) to identify the genes (and their defects) responsible for some diseases, e.g. Stanley syndrome and Amish microcephaly, and (ii) where the genes were already known, to characterize the function of the gene products and hence understand the molecular basis and the symptoms of the diseases, e.g. hyperornithinaemia, hyperammonaemia and homocitrullinuria (HHH) syndrome and type II citrullinemia. It is likely that further extension and functional characterization of the SLC25 gene family will elucidate other diseases caused by MC deficiency.

AGC1 Deficiency Causes Infantile Epilepsy, Abnormal Myelination, and Reduced N-Acetylaspartate

“…This carrier transports only L-aspartate and L-glutamate, and its physiological role is to catalyze the exchange of intramitochondrial aspartate with cytosolic glutamate plus a proton (Palmieri 2004). To investigate whether the R353Q mutation of AGC1 affects protein function, we overexpressed the wild-type and mutant AGC1 proteins in Escherichia coli, purified the proteins, and reconstituted these purified proteins into phospholipid vesicles (liposomes).…”

“…SLC25A12 encodes a neuronal-specific mitochondrial aspartate-glutamate carrier (aspartate-glutamate carrier isoform 1, AGC1). AGC1 is an important component of the neuronal malate/aspartate shuttle (Palmieri 2004), which is a crucial system to export intramitochondrial aspartate and to transfer the reducing equivalents of NADH from cytosol to mitochondria and hence to support oxidative phosphorylation (Lasorsa et al 2003). A distinct disorder, AGC2 deficiency, results from SLC25A13 mutations that reduce aspartate-glutamate carrier isoform 2 (AGC2) function with impaired malate/aspartate shuttle activity in the liver (Saheki and Kobayashi 2002).…”

Isthmin targets cell-surface GRP78 and triggers apoptosis via induction of mitochondrial dysfunction

“…25 Four AAC isoforms have been identified in human with distinct expression patterns. 26,27 According to previous reports, [28][29][30] AAC2 and AAC3 are the dominant AACs in ECs. Co-IP confirmed that ISM interacts with AAC2/AAC3 (Figure 5a).…”

Mitochondrial carriers and pores: Key regulators of the mitochondrial apoptotic program?

“…Reconstitution into liposomes and complementation experiments in yeast revealed also common functional characteristics between the different MCs, although the substrates transported differ widely in their structure, charge and size [40].…”

“…The mitochondrial carrier (MC) protein family comprises of membrane embedded proteins that catalyze the exchange of solutes across the IMM (reviewed in [40,41]). These carriers provide a link between mitochondria and cytosol, which is indispensable for the metabolic activities performed by mitochondria.…”