The Human Gene SLC25A29, of Solute Carrier Family 25, Encodes a Mitochondrial Transporter of Basic Amino Acids

Porcelli, Vito; Fiermonte, Giuseppe; Longo, Antonella; Palmieri, Ferdinando

doi:10.1074/jbc.m114.547448

Cited by 78 publications

(70 citation statements)

References 56 publications

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“…In recent years many of these transporters have been investigated at the molecular and biochemical levels. They transport inorganic anions, amino acids, carboxylic acids, nucleotides, and coenzymes across the inner mitochondrial membrane and in a few cases across other membranes (1,(3)(4)(5). The importance of mitochondrial carriers is demonstrated by their wide distribution in all eukaryotes, their role in numerous metabolic pathways and cell functions, and the identification of several diseases caused by alterations of their genes (1, 2, 6 -8).…”

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confidence: 99%

The Human SLC25A33 and SLC25A36 Genes of Solute Carrier Family 25 Encode Two Mitochondrial Pyrimidine Nucleotide Transporters

Noia

Todisco

Cirigliano

et al. 2014

Journal of Biological Chemistry

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Background: SLC25A33 and SLC25A36 are two human uncharacterized proteins encoded by the mitochondrial carrier SLC25 genes. Results: Recombinant SLC25A33 and SLC25A36 transport cytosine, uracil, and thymine (deoxy)nucleotides with different efficiency. Conclusion: SLC25A33 and SLC25A36 are mitochondrial transporters for pyrimidine (deoxy)nucleotides. Significance: SLC25A33 and SLC25A36 are essential for mitochondrial DNA and RNA metabolism; other two members of the SLC25 superfamily responsible for 12 monogenic diseases were thoroughly characterized.

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confidence: 99%

The Human SLC25A33 and SLC25A36 Genes of Solute Carrier Family 25 Encode Two Mitochondrial Pyrimidine Nucleotide Transporters

Noia

Todisco

Cirigliano

et al. 2014

Journal of Biological Chemistry

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“…Ort1p exchanges ornithine, arginine, and lysine but can also catalyze ornithine/proton exchange, which was also shown to be the case for the purified ornithine carrier from rat liver (Indiveri et al 1999). The human "ornithine carriers" ORC1 (SLC25A15), ORC2 (SLC25A2), and SLC25A29 (Fiermonte et al 2003;Porcelli et al 2014), and the Arabidopsis thaliana carriers BAC1 and BAC2 (Hoyos et al 2003;Palmieri et al 2006b) were identified and characterized using recombinant expression and reconstitution methods; they were shown to have different substrate specificities. In this review, we summarize and discuss the knowledge about these six biochemically characterized MCs that all transport ornithine and related substrates.…”

Section: Xx[k/r]x[k/r] (20-30 Residues) [D/e]gxxxx[w/y/f][k/r]g (Prosmentioning

confidence: 99%

“…The transport characteristics of yeast Ort1p , Arabidopsis BAC1 (Hoyos et al 2003), and BAC2 (Palmieri et al 2006b) as well as of human ORC1, ORC2 (Fiermonte et al 2003), and SLC25A29 (Porcelli et al 2014) have been determined by expressing the proteins in bacteria, purifying the resulting inclusion bodies and reconstituting the MCs into liposomes followed by transport assays. The transport experiments were done by loading the MC-containing proteoliposomes with excess cold internal substrate and initiating substrate exchange by the addition of radioactive external substrate.…”

Section: Xx[k/r]x[k/r] (20-30 Residues) [D/e]gxxxx[w/y/f][k/r]g (Prosmentioning

confidence: 99%

“…The determinants for substrate specificity have been further deduced by the identification of specific and conserved residues in each subfamily transporting the same substrates (Palmieri et al 2011). Based on these analyses and the set of MCs biochemically characterized (Palmieri 2004(Palmieri , 2013Porcelli et al 2014;Todisco et al 2014;Di Noia et al 2014), the MC family can be divided into three major classes with carriers that transport nucleotides, carboxylic acids, and amino acids. Most MCs work as antiporters exchanging an intermembrane space/cytoplasmic substrate for a matrix substrate, but some of them can also work as uniporters or symporters, and they may be dependent on or independent of the electrical and pH gradients across the inner mitochondrial membrane (Monné and Palmieri 2014).…”

Section: Xx[k/r]x[k/r] (20-30 Residues) [D/e]gxxxx[w/y/f][k/r]g (Prosmentioning

confidence: 99%

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Mitochondrial transporters for ornithine and related amino acids: a review

et al. 2015

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Among the members of the mitochondrial carrier family, there are transporters that catalyze the translocation of ornithine and related substrates, such as arginine, homoarginine, lysine, histidine, and citrulline, across the inner mitochondrial membrane. The mitochondrial carriers ORC1, ORC2, and SLC25A29 from Homo sapiens, BAC1 and BAC2 from Arabidopsis thaliana, and Ort1p from Saccharomyces cerevisiae have been biochemically characterized by transport assays in liposomes. All of them transport ornithine and amino acids with side chains terminating at least with one amine. There are, however, marked differences in their substrate specificities including their affinity for ornithine (KM values in the mM to μM range). These differences are most likely reflected by minor differences in the substrate binding sites of these carriers. The physiological role of the above-mentioned mitochondrial carriers is to link several metabolic pathways that take place partly in the cytosol and partly in the mitochondrial matrix and to provide basic amino acids for mitochondrial translation. In the liver, human ORC1 catalyzes the citrulline/ornithine exchange across the mitochondrial inner membrane, which is required for the urea cycle. Human ORC1, ORC2, and SLC25A29 are likely to be involved in the biosynthesis and transport of arginine, which can be used as a precursor for the synthesis of NO, agmatine, polyamines, creatine, glutamine, glutamate, and proline, as well as in the degradation of basic amino acids. BAC1 and BAC2 are implicated in some processes similar to those of their human counterparts and in nitrogen and amino acid metabolism linked to stress conditions and the development of plants. Ort1p is involved in the biosynthesis of arginine and polyamines in yeast.

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“…Another gene of the same family, SLC25A29, encodes a mitochondrial transporter that was also proposed to vicariate the function of ORNT1 and was named ORNT3 (Camacho and Rioseco-Camacho 2009). However, this protein presents less than 50% of sequence similarity and a recent work showed that SLC25A29 transports preferentially lysine and arginine and to a much lesser extent histidine and ornithine when expressed in phospholipid vesicles (Porcelli et al 2014).…”

Section: Introductionmentioning

confidence: 97%

Heterologous Expression in Yeast of Human Ornithine Carriers ORNT1 and ORNT2 and of ORNT1 Alleles Implicated in HHH Syndrome in Humans

et al. 2015

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Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is an autosomal recessive metabolic disorder usually presenting in the neonatal period with intermittent episodes of hyperammonemia, psychomotor delay, and progressive encephalopathy. Adult cases usually evolve into frank spastic paraparesis. The syndrome is caused by mutations in SLC25A15/ORNT1 encoding the mitochondrial ornithine transporter; a second ornithine transporter, ORNT2 of unknown function, is also present in most placental mammals. ORNT2 is believed to originate from an ancient retro-transposition event. In yeast Saccharomyces cerevisiae the major function of the transporter (encoded by Arg11) is to shuttle ornithine from the mitochondrial matrix to the cytosol. Its inactivation abolishes growth in the absence of arginine.In this work, we used functional complementation in S. cerevisiae to characterize the function of human ORNT2 and to test the pathogenicity of ORNT1 mutations found in HHH patients. Notably, we found that human ORNT1 but not ORNT2 complements the deletion of the yeast gene, despite their high level of homology. However, we identified some key residues in ORNT2, which may recover its functional competence when replaced with the corresponding residues of ORNT1, suggesting that roles of the two transporters are different. Moreover, we used this system to test a series of missense mutations of ORNT1 identified in patients with HHH syndrome. All mutations had a detrimental effect on the functionality of the human gene, without however clear genotype-phenotype correlations. Our data support yeast as a simple and effective model to validate missense mutations occurring in patients with HHH.

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The Human Gene SLC25A29, of Solute Carrier Family 25, Encodes a Mitochondrial Transporter of Basic Amino Acids

Cited by 78 publications

References 56 publications

The Human SLC25A33 and SLC25A36 Genes of Solute Carrier Family 25 Encode Two Mitochondrial Pyrimidine Nucleotide Transporters

The Human SLC25A33 and SLC25A36 Genes of Solute Carrier Family 25 Encode Two Mitochondrial Pyrimidine Nucleotide Transporters

Mitochondrial transporters for ornithine and related amino acids: a review

Heterologous Expression in Yeast of Human Ornithine Carriers ORNT1 and ORNT2 and of ORNT1 Alleles Implicated in HHH Syndrome in Humans

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