Pubblicazione scientifica

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

FILONE TECNOLOGICO	TEMA
trasformazione e commercializzazione

RIASSUNTO

Abstract

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.

DATA

Data di pubblicazione: 14/11/2018

AUTORI

MUNRO BENJAMIN
HORVATH RITA
MULLER JULIANE S

ENTE DI AFFERENZA

WELLCOME TRUST CTR MITOCHONDRIAL RSCH INST GENETIC MEDICINE NEWCASTLE UNIV NEWCASTLE UPON TYNE NE1 3BZ UK
DEPT CLINICAL NEUROSCIENCES UNIV CAMBRIDGE JOHN VAN GEEST CTR BRAIN REPAIR ED ADRIAN BLDG FORVIE SITE ROBINSON WAY CAMBRIDGE CB2 0PY UK

RIVISTA

Human Molecular Genetics, 28(5), 796-803

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