MPV17 Loss Causes Deoxynucleotide Insufficiency and Slow DNA Replication in Mitochondria.
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 numb...
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Public Library of Science (PLoS)
2016-01-01
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| Series: | PLoS Genetics |
| Online Access: | https://doi.org/10.1371/journal.pgen.1005779 |
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| author | Ilaria Dalla Rosa Yolanda Cámara Romina Durigon Chloe F Moss Sara Vidoni Gokhan Akman Lilian Hunt Mark A Johnson Sarah Grocott Liya Wang David R Thorburn Michio Hirano Joanna Poulton Robert W Taylor Greg Elgar Ramon Martí Peter Voshol Ian J Holt Antonella Spinazzola |
| author_facet | Ilaria Dalla Rosa Yolanda Cámara Romina Durigon Chloe F Moss Sara Vidoni Gokhan Akman Lilian Hunt Mark A Johnson Sarah Grocott Liya Wang David R Thorburn Michio Hirano Joanna Poulton Robert W Taylor Greg Elgar Ramon Martí Peter Voshol Ian J Holt Antonella Spinazzola |
| author_sort | Ilaria Dalla Rosa |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-fd0c8fb28a5f40f98a92dee74e9682c6 |
| institution | DOAJ |
| issn | 1553-7390 1553-7404 |
| language | English |
| publishDate | 2016-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj-art-fd0c8fb28a5f40f98a92dee74e9682c62025-08-20T03:10:08ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042016-01-01121e100577910.1371/journal.pgen.1005779MPV17 Loss Causes Deoxynucleotide Insufficiency and Slow DNA Replication in Mitochondria.Ilaria Dalla RosaYolanda CámaraRomina DurigonChloe F MossSara VidoniGokhan AkmanLilian HuntMark A JohnsonSarah GrocottLiya WangDavid R ThorburnMichio HiranoJoanna PoultonRobert W TaylorGreg ElgarRamon MartíPeter VosholIan J HoltAntonella SpinazzolaMPV17 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.https://doi.org/10.1371/journal.pgen.1005779 |
| spellingShingle | Ilaria Dalla Rosa Yolanda Cámara Romina Durigon Chloe F Moss Sara Vidoni Gokhan Akman Lilian Hunt Mark A Johnson Sarah Grocott Liya Wang David R Thorburn Michio Hirano Joanna Poulton Robert W Taylor Greg Elgar Ramon Martí Peter Voshol Ian J Holt Antonella Spinazzola MPV17 Loss Causes Deoxynucleotide Insufficiency and Slow DNA Replication in Mitochondria. PLoS Genetics |
| title | MPV17 Loss Causes Deoxynucleotide Insufficiency and Slow DNA Replication in Mitochondria. |
| title_full | MPV17 Loss Causes Deoxynucleotide Insufficiency and Slow DNA Replication in Mitochondria. |
| title_fullStr | MPV17 Loss Causes Deoxynucleotide Insufficiency and Slow DNA Replication in Mitochondria. |
| title_full_unstemmed | MPV17 Loss Causes Deoxynucleotide Insufficiency and Slow DNA Replication in Mitochondria. |
| title_short | MPV17 Loss Causes Deoxynucleotide Insufficiency and Slow DNA Replication in Mitochondria. |
| title_sort | mpv17 loss causes deoxynucleotide insufficiency and slow dna replication in mitochondria |
| url | https://doi.org/10.1371/journal.pgen.1005779 |
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