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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...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2011
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Materias: | |
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. |
format | Online Article Text |
id | pubmed-3185436 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
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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