Construction of transgenic mice with tissue-specific acceleration of mitochondrial DNA mutagenesis

Dekui Zhang, Justin L. Mott, Shin Wen Chang, Grace Denniger, Zehua Feng, Hans Peter Zassenhaus

Research output: Contribution to journalArticlepeer-review

104 Scopus citations

Abstract

Transgenic mice having rapid accumulation of mitochondrial DNA (mtDNA) mutations specifically in the heart were created. These mice contained a transgene encoding a proofreading-deficient, mouse mitochondrial DNA polymerase (pol γ) driven by the promoter for the cardiac-specific α-myosin heavy chain. Starting shortly after birth greater than 95% of all pol γ mRNA in the heart was transgene derived; expression in other tissues was low or absent. Mutations in cardiac mtDNA began to accumulate by 7 days after birth. At 1 month of age the frequency of point mutations was 0.014% as determined by DNA sequencing of cloned mtDNA. By long-extension PCR multiple different deletion mutations that had removed several thousand basepairs of genomic sequence were also detected. Sequencing of two deletion molecules showed thai one was flanked at the breakpoint by direct repeat sequences. The expression of proofreading-deficient pol γ had no apparent deleterious effect on mitochondrial DNA and protein content, gene expression, or respiratory function. However, associated with the rise in mtDNA mutation levels was the development of cardiomyopathy as evidenced by enlarged hearts in the transgenic mice. These mice may prove to be useful models to study the pathogenic effects of elevated levels of mitochondrial DNA mutations in specific tissues. (C) 2000 Academic Press.

Original languageEnglish (US)
Pages (from-to)151-161
Number of pages11
JournalGenomics
Volume69
Issue number2
DOIs
StatePublished - Oct 15 2000

ASJC Scopus subject areas

  • Genetics

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