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

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.Abbreviations AAC ADP/ATP carrier - AGC aspartate/glutamate carrier - ANC peroxisomal adenine nucleotide carrier - BKA bongkrekic acid - CAC carnitine/acylcarnitine carrier - CATR carboxyatractyloside - CoA coenzyme A - CIC citrate carrier - DIC dicarboxylate carrier - DNC deoxynucleotide carrier - GC glutamate carrier - GDC Graves disease carrier - i.m.m. inner mitochondrial membrane - MC mitochondrial carrier - MCF mitochondrial carrier family - MTSEA (2-aminoethyl)-methanethiosulphonate hydrobromide - OAA oxaloacetate - ODC oxodicarboxylate carrier - OGC oxoglutarate carrier - OMIM Online Mendelian Inheritance in Man (database) - ORC ornithine carrier - PEP phosphoenolpyruvate - PiC phosphate carrier - SLC25 name of the human mitochondrial solute carrier gene family, assigned by the Human Genome Organisation (HUGO) nomenclature committee - TMS transmembrane segment - UCP uncoupling protein This revised version was published in December 2003 because additional corrections were requested by the guest editor.