期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 289, 期 19, 页码 13323-13334出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M113.528968
关键词
Fibroblast; Mitochondrial Diseases; Mitochondrial DNA; Mitochondrial Transport; Respiratory Chain; RNA Transport; Heteroplasmy; RNA-based Therapeutics; Cybrid Cells
资金
- CNRS
- University of Strasbourg
- Association Francaise contre les Myopathies
- Agence Nationale de la Recherche [ANR-06-MRAR-37-01, BLAN08-2-309449]
- Fondation pour la Recherche Medicale [DEQ20081214003]
- ARCUS/Suprachem Collaboration Program
- LIA Collaboration Program (ARNmitocure)
- French National Research Agency
- Fondation pour la Recherche Medicale
Background: Point mutations in mitochondrial genome cause severe clinical disorders. Results: We designed recombinant RNA molecules imported into mitochondria of human cells, which are able to decrease the proportion of mitochondrial DNA molecules bearing a pathogenic point mutation. Conclusion: Imported recombinant RNAs can function as anti-replicative agents in human mitochondria. Significance: This is a new approach for therapy of mitochondrial diseases. Defects in mitochondrial genome can cause a wide range of clinical disorders, mainly neuromuscular diseases. Presently, no efficient therapeutic treatment has been developed against this class of pathologies. Because most of deleterious mitochondrial mutations are heteroplasmic, meaning that wild type and mutated forms of mitochondrial DNA (mtDNA) coexist in the same cell, the shift in proportion between mutant and wild type molecules could restore mitochondrial functions. Recently, we developed mitochondrial RNA vectors that can be used to address anti-replicative oligoribonucleotides into human mitochondria and thus impact heteroplasmy level in cells bearing a large deletion in mtDNA. Here, we show that this strategy can be also applied to point mutations in mtDNA. We demonstrate that specifically designed RNA molecules containing structural determinants for mitochondrial import and 20-nucleotide sequence corresponding to the mutated region of mtDNA, are able to anneal selectively to the mutated mitochondrial genomes. After being imported into mitochondria of living human cells in culture, these RNA induced a decrease of the proportion of mtDNA molecules bearing a pathogenic point mutation in the mtDNA ND5 gene.
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