PUBLICATION

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

Authors
Munro, B., Horvath, R., Müller, J.S.
ID
ZDB-PUB-181115-14
Date
2018
Source
Human molecular genetics   28(5): 796-803 (Journal)
Registered Authors
Horvath, Rita, Munro, Benjamin
Keywords
none
MeSH Terms
  • Animals
  • DNA Copy Number Variations*
  • Dietary Supplements*
  • Gene Expression Profiling
  • Genes, Mitochondrial
  • Genotype
  • Humans
  • Mitochondria/drug effects*
  • Mitochondria/genetics*
  • Mitochondria/metabolism
  • Mitochondrial Diseases/genetics
  • Mutation
  • Nucleosides/metabolism
  • Nucleosides/pharmacology*
  • Phenotype
  • Phosphotransferases (Alcohol Group Acceptor)/deficiency*
  • Zebrafish/genetics*
  • Zebrafish/metabolism
PubMed
30428046 Full text @ Hum. Mol. Genet.
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.
Genes / Markers
Figures
Show all Figures
Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes