The Mitochondrial Carrier Protein Family

Palmieri, Ferdinando; Ommen, Ben van

doi:10.1007/978-1-4615-4843-0_20

Frontiers of Cellular Bioenergetics 1999

DOI: 10.1007/978-1-4615-4843-0_20

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The Mitochondrial Carrier Protein Family

Ferdinando Palmieri

Ben van Ommen

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Cited by 14 publications

(11 citation statements)

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“…So far, 11 members of the family have been identified and sequenced. They are the uncoupling protein, and carriers for adenine nucleotides (ANC), phosphate, oxoglutarate, citrate, dicarboxylates, carnitine, ornithine, succinate-fumarate, oxaloacetate-sulfate, and oxodicarboxylates (1)(2)(3)(4)(5)(6)(7). The functions of other family members found in genome sequences are unknown.…”

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confidence: 99%

The human mitochondrial deoxynucleotide carrier and its role in the toxicity of nucleoside antivirals

Dolce

Fiermonte

Runswick

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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182

157

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The synthesis of DNA in mitochondria requires the uptake of deoxynucleotides into the matrix of the organelle. We have characterized a human cDNA encoding a member of the family of mitochondrial carriers. The protein has been overexpressed in bacteria and reconstituted into phospholipid vesicles where it catalyzed the transport of all four deoxy (d) NDPs, and, less efficiently, the corresponding dNTPs, in exchange for dNDPs, ADP, or ATP. It did not transport dNMPs, NMPs, deoxynucleosides, nucleosides, purines, or pyrimidines. The physiological role of this deoxynucleotide carrier is probably to supply deoxynucleotides to the mitochondrial matrix for conversion to triphosphates and incorporation into mitochondrial DNA. The protein is expressed in all human tissues that were examined except for placenta, in accord with such a central role. The deoxynucleotide carrier also transports dideoxynucleotides efficiently. It is likely to be medically important by providing the means of uptake into mitochondria of nucleoside analogs, leading to the mitochondrial impairment that underlies the toxic side effects of such drugs in the treatment of viral illnesses, including AIDS, and in cancer therapy.

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mentioning

confidence: 99%

The human mitochondrial deoxynucleotide carrier and its role in the toxicity of nucleoside antivirals

Dolce

Fiermonte

Runswick

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

182

157

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“…A family of membrane proteins that transports metabolites involved in oxidative phosphorylation and in other important functions in mitochondria is found in the inner membranes of the organelle (1). The sequences of members of this family are made of three related domains of about 100 amino acids repeated in tandem, each probably being folded into two transmembrane ␣-helices joined by an extensive hydrophilic sequence.…”

mentioning

confidence: 99%

Identification in Saccharomyces cerevisiae of Two Isoforms of a Novel Mitochondrial Transporter for 2-Oxoadipate and 2-Oxoglutarate

Palmieri

Agrimi

Runswick

et al. 2001

Journal of Biological Chemistry

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104

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The nuclear genome of Saccharomyces cerevisiae encodes 35 members of a family of membrane proteins. Known members transport substrates and products across the inner membranes of mitochondria. We have localized two hitherto unidentified family members, Odc1p and Odc2p, to the inner membranes of mitochondria. They are isoforms with 61% sequence identity, and we have shown in reconstituted liposomes that they transport the oxodicarboxylates 2-oxoadipate and 2-oxoglutarate by a strict counter exchange mechanism. Intraliposomal adipate and glutarate and to a lesser extent malate and citrate supported [ 14 C]oxoglutarate uptake. The expression of Odc1p, the more abundant isoform, made in the presence of nonfermentable carbon sources, is repressed by glucose. The main physiological roles of Odc1p and Odc2p are probably to supply 2-oxoadipate and 2-oxoglutarate from the mitochondrial matrix to the cytosol where they are used in the biosynthesis of lysine and glutamate, respectively, and in lysine catabolism.A family of membrane proteins that transports metabolites involved in oxidative phosphorylation and in other important functions in mitochondria is found in the inner membranes of the organelle (1). The sequences of members of this family are made of three related domains of about 100 amino acids repeated in tandem, each probably being folded into two transmembrane ␣-helices joined by an extensive hydrophilic sequence. The three repeats are linked by shorter hydrophilic sequences. The repeats in the various family members are all related, and various sequence features are conserved (2, 3). The nuclear genome of Saccharomyces cerevisiae encodes 35 members of this family (4). They include three isoforms of the ADP/ATP translocase and the carriers for phosphate, citrate, dicarboxylate, ornithine, succinate-fumarate, oxaloacetate-sulfate, and carnitine (see Ref. 5 for a review; Refs. 6 and 7). Hitherto, the functions of other family members have been unknown. Two of them, Odc1p and Odc2p 1 are 61% identical in sequence. As described here, they have been overexpressed in S. cerevisiae and shown to be isoforms in the inner mitochondrial membrane where they transport C5-C7 oxodicarboxylic acids, including 2-oxoadipate and 2-oxoglutarate, by a counter exchange mechanism. The main physiological roles of these novel transporters are likely to be in cytoplasmic biosynthesis of lysine and glutamate by supplying 2-oxoadipate and 2-oxoglutarate from the mitochondrial matrix and in lysine catabolism. EXPERIMENTAL PROCEDURESYeast Strains and Growth Conditions-Deletion of the yeast nuclear genes ODC1 (ORF YPL134c) and ODC2 (ORF Y0R222w) was accomplished by sequential homologous recombination of the auxotrophic markers TRP1 and HIS3 at the respective loci of S. cerevisiae YPH499 strain (wild type: MATa ade2-101 his3-⌬200 leu2-⌬1 ura3-52 trp1-⌬63 lys2-801). Deletants were verified by polymerase chain reaction and Western blot analysis. Yeast cells were precultured on synthetic complete medium (8) supplemented with 3% glycerol and 0.1% ...

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“…These processes require traffic of substrates across the inner mitochondrial membrane. S. cerevisiae encodes 35 members of the mitochondrial carrier family (1)(2)(3)(4), including the dicarboxylate and succinate-fumarate carriers (5,6). The former catalyzes the import into mitochondria of succinate (or malate) in exchange for phosphate, producing a net uptake of succinate and supply of a substrate to the Krebs cycle (7).…”

mentioning

confidence: 99%

Identification of the Yeast Mitochondrial Transporter for Oxaloacetate and Sulfate

Palmieri

Vozza

Agrimi

et al. 1999

Journal of Biological Chemistry

Self Cite

107

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Saccharomyces cerevisiae encodes 35 members of the mitochondrial carrier family, including the OAC protein. The transport specificities of some family members are known, but most are not. Saccharomyces cerevisiae has two principal pathways for replenishing the intermediates of the Krebs cycle that have been withdrawn for biosynthesis. They are the glyoxylate cycle and the carboxylation of pyruvate to oxaloacetate, catalyzed by two cytosolic isozymes of pyruvate carboxylase. (Mammalian pyruvate carboxylase is in the mitochondrial matrix.) These processes require traffic of substrates across the inner mitochondrial membrane. S. cerevisiae encodes 35 members of the mitochondrial carrier family (1-4), including the dicarboxylate and succinate-fumarate carriers (5, 6). The former catalyzes the import into mitochondria of succinate (or malate) in exchange for phosphate, producing a net uptake of succinate and supply of a substrate to the Krebs cycle (7). The latter exchanges external succinate for fumarate and is required for gluconeogenesis (6,8). Yeast gene disruption strains (⌬-DIC1 and ⌬-SFC1) cannot grow on either ethanol or acetate as sole carbon source, but they grow well on glycerol, pyruvate and other nonfermentable substrates (7, 9). Growth of the ⌬-DIC1 strain on ethanol or acetate is restored by both low concentrations of oxaloacetate and other compounds that start the tricarboxylate cycle (and the oxidation of the acetyl-CoA unconsumed by the glyoxylate cycle) by generating either intramitochondrial oxaloacetate or other Krebs cycle intermediates (7). Therefore, does oxaloacetate enter yeast mitochondria, and if so, how?The S. cerevisiae gene OAC1 1 (formerly known as PMT or YKL120w) encodes a member of the mitochondrial carrier family of hitherto unknown function that is 29% identical to the yeast DIC, its closest relative in yeast and 30% identical to the bovine 2-oxoglutarate/malate carrier. OAC and the dicarboxylate carrier are the only carriers that cluster on a phylogenetic tree with the bovine oxoglutarate/malate carrier (10, 11). Disruption of the OAC1 gene produced no phenotype on rich glycerol medium (12), and its transcript level was higher in synthetic than in rich medium (13).We have overexpressed the OAC in E. coli, reconstituted it into phospholipid vesicles, and shown that it transports oxaloacetate, sulfate, and thiosulfate both in vitro and in vivo. One of its main functions is probably to carry oxaloacetate produced by cytoplasmic pyruvate carboxylase into the mitochondrial matrix.

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The Mitochondrial Carrier Protein Family

Cited by 14 publications

References 128 publications

The human mitochondrial deoxynucleotide carrier and its role in the toxicity of nucleoside antivirals

The human mitochondrial deoxynucleotide carrier and its role in the toxicity of nucleoside antivirals

Identification in Saccharomyces cerevisiae of Two Isoforms of a Novel Mitochondrial Transporter for 2-Oxoadipate and 2-Oxoglutarate

Identification of the Yeast Mitochondrial Transporter for Oxaloacetate and Sulfate

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