Functional Characterization of drim2, the Drosophila melanogaster Homolog of the Yeast Mitochondrial Deoxynucleotide Transporter

Da‐Ré, Caterina; Franzolin, Elisa; Biscontin, Alberto; Piazzesi, Antonia; Pacchioni, Beniamina; Gagliani, Maria Cristina; Mazzotta, Gabriella; Tacchetti, Carlo; Zordan, Mauro Agostino; Zeviani, Massimo; Bernardi, Paolo; Bianchi, Vera; Pittà, Cristiano De; Costa, Rodolfo

doi:10.1074/jbc.m113.543926

Cited by 13 publications

(14 citation statements)

References 48 publications

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“…The human PNC1 ortholog in yeasts (rim2) and flies (drim2) makes a critical contribution to the transport of dNTPs into the mitochondria, as evidenced by the loss of mtDNA in both organisms lacking the gene [ 56 , 57 ]. The yeast mtDNA abnormality can be rescued with either PNC1 or PNC2; and human PNC1 and PNC2, and yeast rim2, function as nucleotide transporters in reconstituted liposomes [ 48 , 58 ].…”

Section: Discussionmentioning

confidence: 99%

MPV17 Loss Causes Deoxynucleotide Insufficiency and Slow DNA Replication in Mitochondria

Rosa¹,

Cámara

Durigon³

et al. 2016

PLoS Genet

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MPV17 is a mitochondrial inner membrane protein whose dysfunction causes mitochondrial DNA abnormalities and disease by an unknown mechanism. Perturbations of deoxynucleoside triphosphate (dNTP) pools are a recognized cause of mitochondrial genomic instability; therefore, we determined DNA copy number and dNTP levels in mitochondria of two models of MPV17 deficiency. In Mpv17 ablated mice, liver mitochondria showed substantial decreases in the levels of dGTP and dTTP and severe mitochondrial DNA depletion, whereas the dNTP pool was not significantly altered in kidney and brain mitochondria that had near normal levels of DNA. The shortage of mitochondrial dNTPs in Mpv17-/- liver slows the DNA replication in the organelle, as evidenced by the elevated level of replication intermediates. Quiescent fibroblasts of MPV17-mutant patients recapitulate key features of the primary affected tissue of the Mpv17-/- mice, displaying virtual absence of the protein, decreased dNTP levels and mitochondrial DNA depletion. Notably, the mitochondrial DNA loss in the patients’ quiescent fibroblasts was prevented and rescued by deoxynucleoside supplementation. Thus, our study establishes dNTP insufficiency in the mitochondria as the cause of mitochondrial DNA depletion in MPV17 deficiency, and identifies deoxynucleoside supplementation as a potential therapeutic strategy for MPV17-related disease. Moreover, changes in the expression of factors involved in mitochondrial deoxynucleotide homeostasis indicate a remodeling of nucleotide metabolism in MPV17 disease models, which suggests mitochondria lacking functional MPV17 have a restricted purine mitochondrial salvage pathway.

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Section: Discussionmentioning

confidence: 99%

MPV17 Loss Causes Deoxynucleotide Insufficiency and Slow DNA Replication in Mitochondria

Rosa¹,

Cámara

Durigon³

et al. 2016

PLoS Genet

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“…Furthermore, analysis of nucleotide flow in cells with down-regulation of PNC1 and treated with labeled uridine or thymidine revealed a slower mitochondrial uptake of uridine triphosphate and a slower release of thymine nucleotides to the cytoplasm (13). Finally, it has recently been found that Drosophila S2R ϩ cells, silenced for drim2 (the Drosophila melanogaster homolog of the S. cerevisiae Rim2p), contained markedly reduced pools of both purine and pyrimidine dNTPs in mitochondria, whereas cytosolic pools were unaffected (14). Until now the biochemical characterization of purified PNC1 has been addressed in a single publication in which the recombinant SLC25A33, reconstituted into liposomes, was shown to transport pyrimidine nucleoside triphosphates with preference for UTP (11).…”

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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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“…Oxygen measurements were made using the XF24 Extracellular Flux Analyzer (Seahorse Bioscience) at 25 °C. S2R + Drosophila cells were seeded onto XF-24-well plates at 20,000 cells/well and cultured for 48 h ( 51 ). The following day, the culture medium was replaced with serum-free Schneider medium (Invitrogen).…”

Section: Methodsmentioning

confidence: 99%

Leigh Syndrome in Drosophila melanogaster

Da‐Ré

Stockum

Biscontin

et al. 2014

Journal of Biological Chemistry

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Background: Mutations in SURF1, a human gene important for the assembly of cytochrome-c-oxidase (COX) causes Leigh Syndrome, a mitochondrial encephalopathy.Results: Knockdown of Surf1 in Drosophila matches the biochemical features of the human disease.Conclusion: In Drosophila SURF1 is essential to maintain mitochondrial function and its silencing leads to COX deficiency.Significance: Drosophila offers new tools to investigate the pathogenic mechanism of Leigh Syndrome.

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Functional Characterization of drim2, the Drosophila melanogaster Homolog of the Yeast Mitochondrial Deoxynucleotide Transporter

Cited by 13 publications

References 48 publications

MPV17 Loss Causes Deoxynucleotide Insufficiency and Slow DNA Replication in Mitochondria

MPV17 Loss Causes Deoxynucleotide Insufficiency and Slow DNA Replication in Mitochondria

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

Leigh Syndrome in Drosophila melanogaster

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