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Correction of the consequences of mitochondrial 3243A>G mutation in the MT-TL1 gene causing the MELAS syndrome by tRNA import into mitochondria

Mutations in human mitochondrial DNA are often associated with incurable human neuromuscular diseases. Among these mutations, an important number have been identified in tRNA genes, including 29 in the gene MT-TL1 coding for the tRNA(Leu(UUR)). The m.3243A>G mutation was described as the major ca...

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Autores principales: Karicheva, Olga Z., Kolesnikova, Olga A., Schirtz, Tom, Vysokikh, Mikhail Y., Mager-Heckel, Anne-Marie, Lombès, Anne, Boucheham, Abdeldjalil, Krasheninnikov, Igor A., Martin, Robert P., Entelis, Nina, Tarassov, Ivan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2011
Materias:
RNA
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3185436/
https://www.ncbi.nlm.nih.gov/pubmed/21724600
http://dx.doi.org/10.1093/nar/gkr546
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author Karicheva, Olga Z.
Kolesnikova, Olga A.
Schirtz, Tom
Vysokikh, Mikhail Y.
Mager-Heckel, Anne-Marie
Lombès, Anne
Boucheham, Abdeldjalil
Krasheninnikov, Igor A.
Martin, Robert P.
Entelis, Nina
Tarassov, Ivan
author_facet Karicheva, Olga Z.
Kolesnikova, Olga A.
Schirtz, Tom
Vysokikh, Mikhail Y.
Mager-Heckel, Anne-Marie
Lombès, Anne
Boucheham, Abdeldjalil
Krasheninnikov, Igor A.
Martin, Robert P.
Entelis, Nina
Tarassov, Ivan
author_sort Karicheva, Olga Z.
collection PubMed
description Mutations in human mitochondrial DNA are often associated with incurable human neuromuscular diseases. Among these mutations, an important number have been identified in tRNA genes, including 29 in the gene MT-TL1 coding for the tRNA(Leu(UUR)). The m.3243A>G mutation was described as the major cause of the MELAS syndrome (mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes). This mutation was reported to reduce tRNA(Leu(UUR)) aminoacylation and modification of its anti-codon wobble position, which results in a defective mitochondrial protein synthesis and reduced activities of respiratory chain complexes. In the present study, we have tested whether the mitochondrial targeting of recombinant tRNAs bearing the identity elements for human mitochondrial leucyl-tRNA synthetase can rescue the phenotype caused by MELAS mutation in human transmitochondrial cybrid cells. We demonstrate that nuclear expression and mitochondrial targeting of specifically designed transgenic tRNAs results in an improvement of mitochondrial translation, increased levels of mitochondrial DNA-encoded respiratory complexes subunits, and significant rescue of respiration. These findings prove the possibility to direct tRNAs with changed aminoacylation specificities into mitochondria, thus extending the potential therapeutic strategy of allotopic expression to address mitochondrial disorders.
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spelling pubmed-31854362011-10-04 Correction of the consequences of mitochondrial 3243A>G mutation in the MT-TL1 gene causing the MELAS syndrome by tRNA import into mitochondria Karicheva, Olga Z. Kolesnikova, Olga A. Schirtz, Tom Vysokikh, Mikhail Y. Mager-Heckel, Anne-Marie Lombès, Anne Boucheham, Abdeldjalil Krasheninnikov, Igor A. Martin, Robert P. Entelis, Nina Tarassov, Ivan Nucleic Acids Res RNA Mutations in human mitochondrial DNA are often associated with incurable human neuromuscular diseases. Among these mutations, an important number have been identified in tRNA genes, including 29 in the gene MT-TL1 coding for the tRNA(Leu(UUR)). The m.3243A>G mutation was described as the major cause of the MELAS syndrome (mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes). This mutation was reported to reduce tRNA(Leu(UUR)) aminoacylation and modification of its anti-codon wobble position, which results in a defective mitochondrial protein synthesis and reduced activities of respiratory chain complexes. In the present study, we have tested whether the mitochondrial targeting of recombinant tRNAs bearing the identity elements for human mitochondrial leucyl-tRNA synthetase can rescue the phenotype caused by MELAS mutation in human transmitochondrial cybrid cells. We demonstrate that nuclear expression and mitochondrial targeting of specifically designed transgenic tRNAs results in an improvement of mitochondrial translation, increased levels of mitochondrial DNA-encoded respiratory complexes subunits, and significant rescue of respiration. These findings prove the possibility to direct tRNAs with changed aminoacylation specificities into mitochondria, thus extending the potential therapeutic strategy of allotopic expression to address mitochondrial disorders. Oxford University Press 2011-10 2011-06-30 /pmc/articles/PMC3185436/ /pubmed/21724600 http://dx.doi.org/10.1093/nar/gkr546 Text en © The Author(s) 2011. Published by Oxford University Press. http://creativecommons.org/licenses/by-nc/3.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle RNA
Karicheva, Olga Z.
Kolesnikova, Olga A.
Schirtz, Tom
Vysokikh, Mikhail Y.
Mager-Heckel, Anne-Marie
Lombès, Anne
Boucheham, Abdeldjalil
Krasheninnikov, Igor A.
Martin, Robert P.
Entelis, Nina
Tarassov, Ivan
Correction of the consequences of mitochondrial 3243A>G mutation in the MT-TL1 gene causing the MELAS syndrome by tRNA import into mitochondria
title Correction of the consequences of mitochondrial 3243A>G mutation in the MT-TL1 gene causing the MELAS syndrome by tRNA import into mitochondria
title_full Correction of the consequences of mitochondrial 3243A>G mutation in the MT-TL1 gene causing the MELAS syndrome by tRNA import into mitochondria
title_fullStr Correction of the consequences of mitochondrial 3243A>G mutation in the MT-TL1 gene causing the MELAS syndrome by tRNA import into mitochondria
title_full_unstemmed Correction of the consequences of mitochondrial 3243A>G mutation in the MT-TL1 gene causing the MELAS syndrome by tRNA import into mitochondria
title_short Correction of the consequences of mitochondrial 3243A>G mutation in the MT-TL1 gene causing the MELAS syndrome by tRNA import into mitochondria
title_sort correction of the consequences of mitochondrial 3243a>g mutation in the mt-tl1 gene causing the melas syndrome by trna import into mitochondria
topic RNA
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3185436/
https://www.ncbi.nlm.nih.gov/pubmed/21724600
http://dx.doi.org/10.1093/nar/gkr546
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