MitoTALEN reduces mutant mtDNA load and restores tRNAAla levels in a mouse model of heteroplasmic mtDNA mutation

Sandra R. Bacman, Johanna H.K. Kauppila, Claudia V. Pereira, Nadee Nissanka, Maria Miranda, Milena Pinto, Sion L. Williams, Nils Göran Larsson, James B. Stewart, Carlos T. Moraes

Research output: Contribution to journalArticlepeer-review

76 Scopus citations


Mutations in the mitochondrial DNA (mtDNA) are responsible for several metabolic disorders, commonly involving muscle and the central nervous system1. Because of the critical role of mtDNA in oxidative phosphorylation, the majority of pathogenic mtDNA mutations are heteroplasmic, co-existing with wild-type molecules1. Using a mouse model with a heteroplasmic mtDNA mutation2, we tested whether mitochondrial-targeted TALENs (mitoTALENs)3,4 could reduce the mutant mtDNA load in muscle and heart. AAV9-mitoTALEN was administered via intramuscular, intravenous, and intraperitoneal injections. Muscle and heart were efficiently transduced and showed a robust reduction in mutant mtDNA, which was stable over time. The molecular defect, namely a decrease in transfer RNAAla levels, was restored by the treatment. These results showed that mitoTALENs, when expressed in affected tissues, could revert disease-related phenotypes in mice.

Original languageEnglish (US)
Pages (from-to)1696-1700
Number of pages5
JournalNature medicine
Issue number11
StatePublished - Nov 1 2018

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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