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MitoTALEN reduces mutant mtDNA load and restores tRNAAla 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 RNAAla 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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