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Nucleoside supplementation modulates mitochondrial DNA copy number in the dguok (−/−) zebrafish

Deoxyguanosine kinase (dGK) is an essential rate-limiting component of the mitochondrial purine nucleotide salvage pathway, encoded by the nuclear gene encoding deoxyguanosine kinase (DGUOK). Mutations in DGUOK lead to mitochondrial DNA (mtDNA) depletion typically in the liver and brain, causing a h...

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Autores principales: Munro, Benjamin, Horvath, Rita, Müller, Juliane S
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6381312/
https://www.ncbi.nlm.nih.gov/pubmed/30428046
http://dx.doi.org/10.1093/hmg/ddy389
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author Munro, Benjamin
Horvath, Rita
Müller, Juliane S
author_facet Munro, Benjamin
Horvath, Rita
Müller, Juliane S
author_sort Munro, Benjamin
collection PubMed
description Deoxyguanosine kinase (dGK) is an essential rate-limiting component of the mitochondrial purine nucleotide salvage pathway, encoded by the nuclear gene encoding deoxyguanosine kinase (DGUOK). Mutations in DGUOK lead to mitochondrial DNA (mtDNA) depletion typically in the liver and brain, causing a hepatocerebral phenotype. Previous work has shown that in cultured DGUOK patient cells it is possible to rescue mtDNA depletion by increasing substrate amounts for dGK. In this study we developed a mutant dguok zebrafish (Danio rerio) line using CRISPR/Cas9 mediated mutagenesis; dguok(−/−) fish have significantly reduced mtDNA levels compared with wild-type (wt) fish. When supplemented with only one purine nucleoside (dGuo), mtDNA copy number in both mutant and wt juvenile animals was significantly reduced, contrasting with previous cell culture studies, possibly because of nucleotide pool imbalance. However, in adult dguok(−/−) fish we detected a significant increase in liver mtDNA copy number when supplemented with both purine nucleosides. This study further supports the idea that nucleoside supplementation has a potential therapeutic benefit in mtDNA depletion syndromes by substrate enhancement of the purine nucleoside salvage pathway and might improve the liver pathology in patients.
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spelling pubmed-63813122019-02-25 Nucleoside supplementation modulates mitochondrial DNA copy number in the dguok (−/−) zebrafish Munro, Benjamin Horvath, Rita Müller, Juliane S Hum Mol Genet General Article Deoxyguanosine kinase (dGK) is an essential rate-limiting component of the mitochondrial purine nucleotide salvage pathway, encoded by the nuclear gene encoding deoxyguanosine kinase (DGUOK). Mutations in DGUOK lead to mitochondrial DNA (mtDNA) depletion typically in the liver and brain, causing a hepatocerebral phenotype. Previous work has shown that in cultured DGUOK patient cells it is possible to rescue mtDNA depletion by increasing substrate amounts for dGK. In this study we developed a mutant dguok zebrafish (Danio rerio) line using CRISPR/Cas9 mediated mutagenesis; dguok(−/−) fish have significantly reduced mtDNA levels compared with wild-type (wt) fish. When supplemented with only one purine nucleoside (dGuo), mtDNA copy number in both mutant and wt juvenile animals was significantly reduced, contrasting with previous cell culture studies, possibly because of nucleotide pool imbalance. However, in adult dguok(−/−) fish we detected a significant increase in liver mtDNA copy number when supplemented with both purine nucleosides. This study further supports the idea that nucleoside supplementation has a potential therapeutic benefit in mtDNA depletion syndromes by substrate enhancement of the purine nucleoside salvage pathway and might improve the liver pathology in patients. Oxford University Press 2019-03-01 2018-11-14 /pmc/articles/PMC6381312/ /pubmed/30428046 http://dx.doi.org/10.1093/hmg/ddy389 Text en © The Author(s) 2018. Published by Oxford University Press. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle General Article
Munro, Benjamin
Horvath, Rita
Müller, Juliane S
Nucleoside supplementation modulates mitochondrial DNA copy number in the dguok (−/−) zebrafish
title Nucleoside supplementation modulates mitochondrial DNA copy number in the dguok (−/−) zebrafish
title_full Nucleoside supplementation modulates mitochondrial DNA copy number in the dguok (−/−) zebrafish
title_fullStr Nucleoside supplementation modulates mitochondrial DNA copy number in the dguok (−/−) zebrafish
title_full_unstemmed Nucleoside supplementation modulates mitochondrial DNA copy number in the dguok (−/−) zebrafish
title_short Nucleoside supplementation modulates mitochondrial DNA copy number in the dguok (−/−) zebrafish
title_sort nucleoside supplementation modulates mitochondrial dna copy number in the dguok (−/−) zebrafish
topic General Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6381312/
https://www.ncbi.nlm.nih.gov/pubmed/30428046
http://dx.doi.org/10.1093/hmg/ddy389
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