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 Llewelyn Williams, Nils Göran Larsson, James B. Stewart, Carlos T Moraes

Research output: Contribution to journalArticle

15 Citations (Scopus)

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.

Original languageEnglish (US)
JournalNature Medicine
DOIs
StateAccepted/In press - Jan 1 2018

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RNA, Transfer, Ala
Mitochondrial DNA
Mutation
Muscle
Myocardium
Intramuscular Injections
Oxidative Phosphorylation
Intraperitoneal Injections
Intravenous Injections
Tissue
Phenotype
Muscles
Defects

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

MitoTALEN reduces mutant mtDNA load and restores tRNAAla levels in a mouse model of heteroplasmic mtDNA mutation. / Bacman, Sandra R.; Kauppila, Johanna H.K.; Pereira, Claudia V.; Nissanka, Nadee; Miranda, Maria; Pinto, Milena; Williams, Sion Llewelyn; Larsson, Nils Göran; Stewart, James B.; Moraes, Carlos T.

In: Nature Medicine, 01.01.2018.

Research output: Contribution to journalArticle

Bacman, Sandra R. ; Kauppila, Johanna H.K. ; Pereira, Claudia V. ; Nissanka, Nadee ; Miranda, Maria ; Pinto, Milena ; Williams, Sion Llewelyn ; Larsson, Nils Göran ; Stewart, James B. ; Moraes, Carlos T. / MitoTALEN reduces mutant mtDNA load and restores tRNAAla levels in a mouse model of heteroplasmic mtDNA mutation. In: Nature Medicine. 2018.
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AU - Miranda, Maria

AU - Pinto, Milena

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