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Molecular Investigation of Mitochondrial RNA19 Role in the Pathogenesis of MELAS Disease
In mammalian mitochondria, the processing of primary RNA transcripts involves a coordinated series of cleavage and modification events, leading to the formation of processing intermediates and mature mt-RNAs. RNA19 is an unusually stable unprocessed precursor, physiologically polyadenylated, which i...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10532844/ https://www.ncbi.nlm.nih.gov/pubmed/37763267 http://dx.doi.org/10.3390/life13091863 |
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author | Loguercio Polosa, Paola Capriglia, Francesco Bruni, Francesco |
author_facet | Loguercio Polosa, Paola Capriglia, Francesco Bruni, Francesco |
author_sort | Loguercio Polosa, Paola |
collection | PubMed |
description | In mammalian mitochondria, the processing of primary RNA transcripts involves a coordinated series of cleavage and modification events, leading to the formation of processing intermediates and mature mt-RNAs. RNA19 is an unusually stable unprocessed precursor, physiologically polyadenylated, which includes the 16S mt-rRNA, the mt-tRNALeu(UUR) and the mt-ND1 mRNA. These peculiarities, together with the alteration of its steady-state levels in cellular models with defects in mitochondrial function, make RNA19 a potentially important molecule for the physiological regulation of mitochondrial molecular processes as well as for the pathogenesis of mitochondrial diseases. In this work, we quantitatively and qualitatively examined RNA19 in MELAS trans-mitochondrial cybrids carrying the mtDNA 3243A>G transition and displaying a profound mitochondrial translation defect. Through a combination of isokinetic sucrose gradient and RT-qPCR experiments, we found that RNA19 accumulated and co-sedimented with the mitoribosomal large subunit (mt-LSU) in mutant cells. Intriguingly, exogenous expression of the isolated LARS2 C-terminal domain (Cterm), which was shown to rescue defective translation in MELAS cybrids, decreased the levels of mt-LSU-associated RNA19 by relegating it to the pool of free unbound RNAs. Overall, the data reported here support a regulatory role for RNA19 in mitochondrial physiopathological processes, designating this RNA precursor as a possible molecular target in view of therapeutic strategy development. |
format | Online Article Text |
id | pubmed-10532844 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-105328442023-09-28 Molecular Investigation of Mitochondrial RNA19 Role in the Pathogenesis of MELAS Disease Loguercio Polosa, Paola Capriglia, Francesco Bruni, Francesco Life (Basel) Article In mammalian mitochondria, the processing of primary RNA transcripts involves a coordinated series of cleavage and modification events, leading to the formation of processing intermediates and mature mt-RNAs. RNA19 is an unusually stable unprocessed precursor, physiologically polyadenylated, which includes the 16S mt-rRNA, the mt-tRNALeu(UUR) and the mt-ND1 mRNA. These peculiarities, together with the alteration of its steady-state levels in cellular models with defects in mitochondrial function, make RNA19 a potentially important molecule for the physiological regulation of mitochondrial molecular processes as well as for the pathogenesis of mitochondrial diseases. In this work, we quantitatively and qualitatively examined RNA19 in MELAS trans-mitochondrial cybrids carrying the mtDNA 3243A>G transition and displaying a profound mitochondrial translation defect. Through a combination of isokinetic sucrose gradient and RT-qPCR experiments, we found that RNA19 accumulated and co-sedimented with the mitoribosomal large subunit (mt-LSU) in mutant cells. Intriguingly, exogenous expression of the isolated LARS2 C-terminal domain (Cterm), which was shown to rescue defective translation in MELAS cybrids, decreased the levels of mt-LSU-associated RNA19 by relegating it to the pool of free unbound RNAs. Overall, the data reported here support a regulatory role for RNA19 in mitochondrial physiopathological processes, designating this RNA precursor as a possible molecular target in view of therapeutic strategy development. MDPI 2023-09-03 /pmc/articles/PMC10532844/ /pubmed/37763267 http://dx.doi.org/10.3390/life13091863 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Loguercio Polosa, Paola Capriglia, Francesco Bruni, Francesco Molecular Investigation of Mitochondrial RNA19 Role in the Pathogenesis of MELAS Disease |
title | Molecular Investigation of Mitochondrial RNA19 Role in the Pathogenesis of MELAS Disease |
title_full | Molecular Investigation of Mitochondrial RNA19 Role in the Pathogenesis of MELAS Disease |
title_fullStr | Molecular Investigation of Mitochondrial RNA19 Role in the Pathogenesis of MELAS Disease |
title_full_unstemmed | Molecular Investigation of Mitochondrial RNA19 Role in the Pathogenesis of MELAS Disease |
title_short | Molecular Investigation of Mitochondrial RNA19 Role in the Pathogenesis of MELAS Disease |
title_sort | molecular investigation of mitochondrial rna19 role in the pathogenesis of melas disease |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10532844/ https://www.ncbi.nlm.nih.gov/pubmed/37763267 http://dx.doi.org/10.3390/life13091863 |
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