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MitoTALEN reduces mutant mtDNA load and restores tRNA^Ala levels in a mouse model of heteroplasmic mtDNA mutation

Lookup NU author(s): Dr Jim StewartORCiD

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This is the authors' accepted manuscript of an article that has been published in its final definitive form by Nature Research, 2018.

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Abstract

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 RNA^Ala levels, was restored by the treatment. These results showed that mitoTALENs, when expressed in affected tissues, could revert disease-related phenotypes in mice.

Publication metadata

Author(s): Bacman SR, Kauppila JHK, Pereira CV, Nissanka N, Miranda M, Pinto M, Williams SL, Larsson NG, Stewart JB, Moraes CT

Publication type: Article

Publication status: Published

Journal: Nature Medicine

Year: 2018

Volume: 24

Issue: 11

Pages: 1696-1700

Print publication date: 01/11/2018

Online publication date: 24/09/2018

Acceptance date: 26/07/2018

Date deposited: 12/11/2020

ISSN (electronic): 1546-170X

Publisher: Nature Research

URL: https://doi.org/10.1038/s41591-018-0166-8

DOI: 10.1038/s41591-018-0166-8

PubMed id: 30250143

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