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.
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This work was supported primarily by the National Institutes of Health Grant 5R01EY010804, with additional support from 1R01AG036871 and 1R01NS079965 (NIH) and the Muscular Dystrophy Association (CTM). We also acknowledge support from The JDM Fund for Mitochondrial Research and the Biscardi family. N.N. is supported by an American Heart Association predoctoral fellowship (16PRE30480009). We are grateful to the University of Miami Flow Cytometry core facility (SCCC) for expert assistance.
The authors declare no competing interests.
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Bacman, S.R., Kauppila, J.H.K., Pereira, C.V. et al. MitoTALEN reduces mutant mtDNA load and restores tRNAAla levels in a mouse model of heteroplasmic mtDNA mutation. Nat Med 24, 1696–1700 (2018). https://doi.org/10.1038/s41591-018-0166-8
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