期刊
NUCLEIC ACIDS RESEARCH
卷 43, 期 21, 页码 10338-10352出版社
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkv1139
关键词
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资金
- National Institutes of Health [R00ES015555, 5P20RR024485-02, 8 P20 GM103542-02]
- Medical University of South Carolina
- South Carolina Clinical and Translational Research Institute/Medical University of South Carolina CTSA
- National Institutes of Health/National Center for Research Resources [UL1RR029882, UL1 TR000062]
DNA polymerase gamma (POLG) is essential for replication and repair of mitochondrial DNA (mtDNA). Mutations in POLG cause mtDNA instability and a diverse range of poorly understood human diseases. Here, we created a unique Polg animal model, by modifying polg within the critical and highly conserved polymerase domain in zebrafish. polg(+/-) offspring were indistinguishable from WT siblings in multiple phenotypic and biochemical measures. However, polg(-/-) mutants developed severe mtDNA depletion by one week post-fertilization (wpf), developed slowly and had regenerative defects, yet surprisingly survived up to 4 wpf. Anin vivo mtDNA polymerase activity assay utilizing ethidium bromide (EtBr) to deplete mtDNA, showed thatpolg(+/-) and WT zebrafish fully recover mtDNA content two weeks post-EtBr removal. EtBr further reduced already low levels of mtDNA in polg(-/-) animals, but mtDNA content did not recover following release from EtBr. Despite significantly decreased respiration that corresponded with tissue-specific levels of mtDNA, polg(-/-) animals had WT levels of ATP and no increase in lactate. This zebrafish model of mitochondrial disease now provides unique opportunities for studying mtDNA instability from multiple angles, as polg(-/-) mutants can survive to juvenile stage, rather than lose viability in embryogenesis as seen in Polg mutant mice.
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