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Mitochondrial transporters of the SLC25 family and associated diseases: a review

  • ICIEM Symposium 2013
  • Published:
Journal of Inherited Metabolic Disease

Abstract

To date, 14 inherited diseases (including phenotypes) associated to mitochondrial transporters of the SLC25 family have been well characterized biochemically and genetically. They are rare metabolic disorders caused by mutations in the SLC25 nuclear genes that encode mitochondrial carriers, a superfamily of 53 proteins in humans that shuttle a variety of solutes across the mitochondrial membrane. Mitochondrial carriers vary considerably in the nature and size of the substrates they transport, the modes of transport and driving forces. However, their substrate translocation mechanism at the molecular level is thought to be basically the same. Herein, the main structural and functional properties of the SLC25 mitochondrial carriers and the known carrier-related diseases are presented. Two of these disorders, ADP/ATP carrier deficiency and phosphate carrier deficiency, are caused by defects of the two mitochondrial carriers that provide mitochondria with ADP and phosphate, the substrates of oxidative phosphorylation; these disorders therefore are characterized by defective energy production by mitochondria. The mutations of SLC25 carrier genes involved in other cellular functions cause carnitine/acylcarnitine carrier deficiency, HHH syndrome, aspartate/glutamate isoform 1 and 2 deficiencies, congenital Amish microcephaly, neuropathy with bilateral striatal necrosis, congenital sideroblastic anemia, neonatal epileptic encephalopathy, and citrate carrier deficiency; these disorders are characterized by specific metabolic dysfunctions depending on the role of the defective carrier in intermediary metabolism.

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References

  • Agrimi G, Russo A, Scarcia P, Palmieri F (2012) The human gene SLC25A17 encodes a peroxisomal transporter of coenzyme A, FAD and NAD+. Biochem J 443:241–247

    Article  CAS  PubMed  Google Scholar 

  • Bricker DK, Taylor EB, Schell JC et al (2012) A mitochondrial pyruvate carrier required for pyruvate uptake in yeast, Drosophila, and Humans. Science 337:96–100

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Camacho JA, Obie C, Biery B et al (1999) Hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome is caused by mutations in a gene encoding a mitochondrial ornithine transporter. Nat Genet 22:151–158

    Article  CAS  PubMed  Google Scholar 

  • Cappello AR, Curcio R, Miniero DV et al (2006) Functional and structural role of amino acid residues in the even-numbered transmembrane α-helices of the bovine mitochondrial oxoglutarate carrier. J Mol Biol 363:51–62

    Article  CAS  PubMed  Google Scholar 

  • Catalina-Rodriguez O, Kolukula VK, Tomita Y et al (2012) The mitochondrial citrate transporter, CIC, is essential for mitochondrial homeostasis. Oncotarget 3:1220–1223

    PubMed Central  PubMed  Google Scholar 

  • Dolce V, Iacobazzi V, Palmieri F, Walker JE (1994) The sequences of human and bovine genes of the phosphate carrier from mitochondria contain evidence of alternatively spliced forms. J Biol Chem 269:10451–10460

    CAS  PubMed  Google Scholar 

  • Dolce V, Fiermonte G, Palmieri F (1996) Tissue-specific expression of the two isoforms of the mitochondrial phosphate carrier in bovine tissues. FEBS Lett 399:95–98

    Article  CAS  PubMed  Google Scholar 

  • Echaniz-Laguna A, Chassagne M, Ceresuela J et al (2012) Complete loss of expression of the ANT1 gene causing cardiomyopathy and myopathy. J Med Genet 49:146–150

    Article  CAS  PubMed  Google Scholar 

  • Edvardson S, Porcelli V, Jalas C et al (2013) Agenesis of corpus callosum and optic nerve hypoplasia due to mutations in SLC25A1 encoding the mitochondrial citrate transporter. J Med Genet 50:240–245

    Article  CAS  PubMed  Google Scholar 

  • Ersoy Tunali N, Marobbio CM,Tiryakioglu NO et al (2014) A novel mutation in the SLC25A15 gene in a Turkish patient with HHH syndrome: functional analysis of the mutant protein. Mol Genet Metab. doi:10.1016/j.ymgme.2014.03.002

  • Falk MJ, Li D, Gai X et al (2014) AGC1 deficiency causes infantile epilepsy, abnormal myelination, and reduced N-acetylaspartate. JIMD Rep. doi:10.1007/8904_2013_287

    Google Scholar 

  • Fiermonte G, Dolce V, Palmieri F (1998) Expression in Escherichia coli, functional characterization, and tissue distribution of isoforms A and B of the phosphate carrier from bovine mitochondria. J Biol Chem 273:22782–22787

    Article  CAS  PubMed  Google Scholar 

  • Fiermonte G, Palmieri L, Todisco S, Agrimi G, Palmieri F, Walker JE (2002) Identification of the mitochondrial glutamate transporter: bacterial expression, reconstitution, functional characterization, and tissue distribution of two human isoforms. J Biol Chem 277:19289–19294

    Article  CAS  PubMed  Google Scholar 

  • Fiermonte G, Dolce V, David L et al (2003) The mitochondrial ornithine transporter: bacterial expression, reconstitution, functional characterization, and tissue distribution of two human isoforms. J Biol Chem 278:32778–32783

    Article  CAS  PubMed  Google Scholar 

  • Fiermonte G, De Leonardis F, Todisco S, Palmieri L, Lasorsa FM, Palmieri F (2004) Identification of the mitochondrial ATP-Mg/Pi transporter: bacterial expression, reconstitution, functional characterization and tissue distribution. J Biol Chem 279:30722–30730

    Article  CAS  PubMed  Google Scholar 

  • Guernsey DL, Jiang H, Campagna DR et al (2009) Mutations in mitochondrial carrier family gene SLC25A38 cause nonsyndromic autosomal recessive congenital sideroblastic anemia. Nat Genet 41:651–653

    Article  CAS  PubMed  Google Scholar 

  • Herzig S, Raemy E, Montessuit S, Veuthey J-L, Zamboni N, Westermann B, Kunji ERS, Martinou J-C (2012) Identification and functional expression of the mitochondrial pyruvate carrier. Science 337:93–96

    Article  CAS  PubMed  Google Scholar 

  • Huizing M, Iacobazzi V, Ijlst L et al (1997) Cloning of the human carnitine-acylcarnitine carrier cDNA, and identification of the molecular defect in a patient. Am J Hum Genet 61:1239–1245

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Huizing M, Ruitenbeek W, van den Heuvel LP et al (1998) Human mitochondrial transmembrane metabolite carriers: tissue distribution and its implication for mitochondrial disorders. J Bioenerg Biomembr 30:277–284

    Article  CAS  PubMed  Google Scholar 

  • Indiveri C, Tonazzi A, Palmieri F (1992) Identification and purification of the ornithine/citrulline carrier from rat liver mitochondria. Eur J Biochem 207:449–454

    Article  CAS  PubMed  Google Scholar 

  • Indiveri C, Iacobazzi V, Tonazzi A et al (2011) The mitochondrial carnitine/acylcarnitine carrier: function, structure and physiopathology. Mol Aspects Med 32:223–233

    Article  CAS  PubMed  Google Scholar 

  • Infantino V, Convertini P, Cucci L et al (2011) The mitochondrial citrate carrier: a new player in inflammation. Biochem J 438:433–436

    Article  CAS  PubMed  Google Scholar 

  • Joseph JW, Jensen MV, Ilkayeva O, Palmieri F, Alárcon C, Rhodes CJ, Newgard CB (2006) The mitochondrial citrate/isocitrate carrier plays a regulatory role in glucose-stimulated insulin secretion. J Biol Chem 281:35624–35632

    Article  CAS  PubMed  Google Scholar 

  • Kaukonen J, Juselius JK, Tiranti V et al (2000) Role of adenine nucleotide translocator 1 in mtDNA maintenance. Science 289:782–785

    Article  CAS  PubMed  Google Scholar 

  • Klingenberg M (1979) The ADP, ATP shuttle of the mitochondrion. Trends Biochem Sci 4:249–252

    Article  CAS  Google Scholar 

  • Kobayashi K, Sinasac DS, Iijima M et al (1999) The gene mutated in adult-onset type II citrullinaemia encodes a putative mitochondrial carrier protein. Nat Genet 22:159–163

    Article  CAS  PubMed  Google Scholar 

  • Kolukula VK, Sahu G, Wellstein A et al (2014) SLC25A1, or CIC, is a novel transcriptional target of mutant p53 and a negative tumor prognostic marker. Oncotarget 5:1212–1225

  • Lasorsa FM, Pinton P, Palmieri L, Fiermonte G, Rizzuto R, Palmieri F (2003) Recombinant expression of the Ca2+-sensitive aspartate/glutamate carrier increases mitochondrial ATP production in agonist-stimulated Chinese hamster ovary cells. J Biol Chem 278:38686–38692

    Article  CAS  PubMed  Google Scholar 

  • Lindhurst MJ, Fiermonte G, Song S et al (2006) Knockout of Slc25a19 causes mitochondrial thiamine pyrophosphate depletion, embryonic lethality, CNS malformations, and anemia. Proc Natl Acad Sci U S A 103:15927–15932

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Mayr JA, Merkel O, Kohlwein SD et al (2007) Mitochondrial phosphate-carrier deficiency: a novel disorder of oxidative phosphorylation. Am J Hum Genet 80:478–484

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Mayr JA, Zimmermann FA, Horváth R et al (2011) Deficiency of the mitochondrial phosphate carrier presenting as myopathy and cardiomyopathy in a family with three affected children. Neuromuscul Disord 21:803–808

    Article  PubMed  Google Scholar 

  • Molinari F, Raas-Rothschild A, Rio M et al (2005) Impaired mitochondrial glutamate transport in autosomal recessive neonatal myoclonic epilepsy. Am J Hum Genet 76:334–339

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Molinari F, Kaminska A, Fiermonte G et al (2009) Mutations in the mitochondrial glutamate carrier SLC25A22 in neonatal epileptic encephalopathy with suppression bursts. Clin Genet 76:188–194

    Article  CAS  PubMed  Google Scholar 

  • Monné M, Palmieri F, Kunji ERS (2013) The substrate specificity of mitochondrial carriers: mutagenesis revisited. Mol Membr Biol 30:149–159

    Article  PubMed  Google Scholar 

  • Nota B, Struys EA, Pop A et al (2013) Deficiency in SLC25A1, encoding the mitochondrial citrate carrier, causes combined D-2- and L-2-hydroxyglutaric aciduria. Am J Hum Genet 92:627–631

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Palmieri F (2004) The mitochondrial transporter family (SLC25): physiological and pathological implications. Pflugers Arch-Eur J Physiol 447:689–709

    Article  CAS  Google Scholar 

  • Palmieri F (2008) Diseases caused by defects of mitochondrial carriers: a review. Biochim Biophys Acta 1777:564–578

    Article  CAS  PubMed  Google Scholar 

  • Palmieri F (2013) The mitochondrial transporter family SLC25: identification, properties and physiopathology. Mol Aspects Med 34:465–484

    Article  CAS  PubMed  Google Scholar 

  • Palmieri F, Pierri CL (2010a) Structure and function of mitochondrial carriers - Role of the transmembrane helix P and G residues in the gating and transport mechanism. FEBS Lett 584:1931–1939

    Article  CAS  PubMed  Google Scholar 

  • Palmieri F, Pierri CL (2010b) Mitochondrial metabolite transport. Essays Biochem 47:37–52

    Article  CAS  PubMed  Google Scholar 

  • Palmieri F, Indiveri C, Bisaccia F, Iacobazzi V (1995) Mitochondrial metabolite carrier proteins: purification, reconstitution and transport studies. Methods Enzymol 260:349–369

    Article  CAS  PubMed  Google Scholar 

  • Palmieri L, Pardo B, Lasorsa FM et al (2001) Citrin and aralar1 are Ca2+-stimulated aspartate/glutamate transporters in mitochondria. EMBO J 20:5060–5069

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Palmieri L, Alberio S, Pisano I et al (2005) Complete loss-of-function of the heart-/muscle-specific adenine nucleotide translocator is associated with mitochondrial myopathy and cardiomyopathy. Hum Mol Genet 14:3079–3088

  • Palmieri F, Agrimi G, Blanco E et al (2006) Identification of mitochondrial carriers in Saccharomyces cerevisiae by transport assay of reconstituted recombinant proteins. Biochim Biophys Acta 1757:1249–1262

    Article  CAS  PubMed  Google Scholar 

  • Palmieri F, Pierri CL, De Grassi A, Nunes-Nesi A, Fernie AR (2011) Evolution, structure and function of mitochondrial carriers: a review with new insights. Plant J 66:161–181

    Article  CAS  PubMed  Google Scholar 

  • Palmisano A, Zara V, Hönlinger A et al (1998) Targeting and assembly of the oxoglutarate carrier: general principles for biogenesis of carrier proteins of the mitochondrial inner membrane. Biochem J 333:151–158

    CAS  PubMed Central  PubMed  Google Scholar 

  • Pebay-Peyroula E, Dahout-Gonzalez C, Kahn R, Trézéguet V, Lauquin G, Brandolin G (2003) Structure of mitochondrial ADP/ATP carrier in complex with carboxyatractyloside. Nature 426:39–44

    Article  CAS  PubMed  Google Scholar 

  • Poduri A, Heinzen EL, Chitsazzadeh V et al (2013) SLC25A22 is a novel gene for migrating partial seizures in infancy. Ann Neurol 74:873–882

    Article  CAS  PubMed  Google Scholar 

  • Robinson A, Kunji E (2006) Mitochondrial carriers in the cytoplasmic state have a common substrate binding site. Proc Natl Acad Sci U S A 103:2617–2622

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Robinson A, Overy C, Kunji E (2008) The mechanism of transport by mitochondrial carriers based on analysis of symmetry. Proc Natl Acad Sci U S A 105:17766–17771

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Rosenberg MJ, Agarwala R, Bouffard G et al (2002) Mutant deoxynucleotide carrier is associated with congenital microcephaly. Nat Genet 32:175–179

    Article  CAS  PubMed  Google Scholar 

  • Ruprecht JJ, Hellawell AM, Harding M, Crichton PG, McCoy AJ, Kunji ERS (2013) Structures of yeast mitochondrial ADP/ATP carriers support a domain-based alternating-access transport mechanism. Proc Natl Acad Sci U S A 105:17766–17771

    Google Scholar 

  • Spiegel R, Shaag A, Edvardson S et al (2009) SLC25A19 mutation as a cause of neuropathy and bilateral striatal necrosis. Ann Neurol 66:419–424

    Article  CAS  PubMed  Google Scholar 

  • Stanley CA, Palmieri F, Bennett MJ (2014) Disorders of the mitochondrial carnitine shuttle. OMMBID; in press

  • Tessa A, Fiermonte G, Dionisi-Vici C et al (2009) Identification of novel mutations in the SLC25A15 gene in hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome: a clinical, molecular, and functional study. Hum Mutat 30:741–748

    Article  CAS  PubMed  Google Scholar 

  • Wibom R, Lasorsa FM, Töhönen V et al (2009) AGC1 deficiency associated with global cerebral hypomyelination. N Engl J Med 361:489–495

    Article  PubMed  Google Scholar 

  • Zara V, Ferramosca A, Robitaille-Foucher P, Palmieri F, Young JC (2009) Mitochondrial carrier protein biogenesis: role of the chaperone Hcs70 and Hsp90. Biochem J 419:369–375

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

Due to limited space many excellent references could not be included. This work was supported by grants from MIUR, Italian Human ProteomeNet and Comitato Telethon Fondazione Onlus No. GGP11139. The valuable assistance of Dr. Magnus Monné in designing the figures of this study is much appreciated.

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This article is a review summarizing the results and conclusions of available publications that include previously performed studies on human or animal subjects.

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Authors and Affiliations

  1. Department of Biosciences, Biotechnologies and Biopharmaceutics, Laboratory of Biochemistry and Molecular Biology, University of Bari “A. Moro”, via E. Orabona, 4, 70125, Bari, Italy

    Ferdinando Palmieri

  2. Center of Excellence in Comparative Genomics, University of Bari “A. Moro”, via E. Orabona, 4, 70125, Bari, Italy

    Ferdinando Palmieri

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Correspondence to Ferdinando Palmieri.

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Communicated by: Shamima Rahman

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Palmieri, F. Mitochondrial transporters of the SLC25 family and associated diseases: a review. J Inherit Metab Dis 37, 565–575 (2014). https://doi.org/10.1007/s10545-014-9708-5

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  • DOI: https://doi.org/10.1007/s10545-014-9708-5

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