Nuclear expression of mitochondrial ND4 leads to the protein assembling in complex I and prevents optic atrophy and visual loss

Abstract : Leber hereditary optic neuropathy is due to mitochondrial DNA mutations; in ~70% of all cases, a point mutation in the mitochondrial NADH dehydrogenase subunit 4, ND4, gene leads to central vision loss. We optimized allotopic expression (nuclear transcription of a gene that is normally transcribed inside the mitochondria) aimed at designing a gene therapy for ND4; its coding sequence was associated with the cis-acting elements of the human COX10 mRNA to allow the efficient mitochondrial delivery of the protein. After ocular administration to adult rats of a recombinant adeno-associated viral vector containing the human ND4 gene, we demonstrated that: (i) the sustained expression of human ND4 did not lead to harmful effects, instead the human protein is efficiently imported inside the mitochondria and assembled in respiratory chain complex I; (ii) the presence of the human protein in the experimental model of Leber hereditary optic neuropathy significantly prevents retinal ganglion cell degeneration and preserves both complex I function in optic nerves and visual function. Hence, the use of optimized allotopic expression is relevant for treating mitochondrial disorders due to mutations in the organelle genome.
Keywords : Metabolic disorders
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Article dans une revue
Molecular Therapy, Nature Publishing Group, 2015, 2, pp.15003. 〈10.1038/mtm.2015.3〉
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Hélène Cwerman-Thibault, Sébastien Augustin, Christophe Lechauve, Jessica Ayache, Sami Ellouze, et al.. Nuclear expression of mitochondrial ND4 leads to the protein assembling in complex I and prevents optic atrophy and visual loss. Molecular Therapy, Nature Publishing Group, 2015, 2, pp.15003. 〈10.1038/mtm.2015.3〉. 〈hal-01121801〉

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