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Nucleoside supplementation modulates mitochondrial DNA copy number in the dguok-/- zebrafish.

Published version
Peer-reviewed

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Authors

Munroe, Benjamin 
Muller, Juliane S 

Abstract

Deoxyguanosine kinase (dGK) is an essential rate limiting component of the mitochondrial purine nucleotide salvage pathway, encoded by the nuclear gene DGUOK. Mutations in DGUOK lead to mitochondrial DNA (mtDNA) depletion typically in the liver and brain, causing a hepatocerebral phenotype. Previous work has shown thatin cultured DGUOK patient cellsit 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 to wild-type fish. When supplemented with only one purine nucleoside (dGuo), mtDNA copy number in both mutant and wild-type juvenile animals was significantly reduced,contrasting with previous cell culture studies, possibly due to 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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Journal Title

Human Molecular Genetics

Conference Name

Journal ISSN

1460-2083

Volume Title

Publisher

OUP
Sponsorship
MRC Research Grant MR/N025431/1 Newton Fund MR/N027302/1 Wellcome Investigator Award 109915/Z/15/Z