Rapid directional shift of mitochondrial DNA heteroplasmy in animal tissues by a mitochondrially targeted restriction endonuclease

Maria Pilar Bayona-Bafaluy, Bas Blits, Brendan J. Battersby, Eric A. Shoubridge, Carlos T. Moraes

Research output: Contribution to journalArticlepeer-review

98 Scopus citations

Abstract

Frequently, mtDNA with pathogenic mutations coexist with wild-type genomes (mtDNA heteroplasmy). Mitochondrial dysfunction and disease ensue only when the proportion of mutated mtDNAs is high, thus a reduction in this proportion should provide an effective therapy for these disorders. We developed a system to decrease specific mtDNA haplotypes by expressing a mitochondrially targeted restriction endonuclease, ApaLI, in cells of heteroplasmic mice. These mice have two mtDNA haplotypes, of which only one contains an ApaLI site. After transfection of cultured hepatocytes with mitochondrially targeted ApaLI, we found a rapid, directional, and complete shift in mtDNA heteroplasmy (2-6 h). We tested the efficacy of this approach in vivo, by using recombinant viral vectors expressing the mitochondrially targeted ApaLI. We observed a significant shift in mtDNA heteroplasmy in muscle and brain transduced with recombinant viruses. This strategy could prevent disease onset or reverse clinical symptoms in patients harboring certain heteroplasmic pathogenic mutations in mtDNA.

Original languageEnglish (US)
Pages (from-to)14392-14397
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number40
DOIs
StatePublished - Oct 4 2005

Keywords

  • Gene therapy
  • Mitochondria

ASJC Scopus subject areas

  • Genetics
  • General

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