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

  • The ABC of Solute Carriers
  • Guest Editor: Matthias A. Hediger
  • Published:
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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.

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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

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Acknowledgements

Research in the author’s laboratory was supported by grants from the Ministero dell’Istruzione, dell’Università e della Ricerca (MIUR), the Italian Consiglio Nazionale delle Ricerche (CNR), Centre of Excellence “Genomics: genes involved in pathopysiological processes in the biomedical and agricultural fields” (CEGBA), and the European Social Fund.

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Palmieri, F. The mitochondrial transporter family (SLC25): physiological and pathological implications. Pflugers Arch - Eur J Physiol 447, 689–709 (2004). https://doi.org/10.1007/s00424-003-1099-7

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