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Possible A2E Mutagenic Effects on RPE Mitochondrial DNA from Innovative RNA-Seq Bioinformatics Pipeline

Mitochondria are subject to continuous oxidative stress stimuli that, over time, can impair their genome and lead to several pathologies, like retinal degenerations. Our main purpose was the identification of mtDNA variants that might be induced by intense oxidative stress determined by N-retinylide...

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Autores principales: Donato, Luigi, Scimone, Concetta, Alibrandi, Simona, Pitruzzella, Alessandro, Scalia, Federica, D’Angelo, Rosalia, Sidoti, Antonina
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699917/
https://www.ncbi.nlm.nih.gov/pubmed/33233726
http://dx.doi.org/10.3390/antiox9111158
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author Donato, Luigi
Scimone, Concetta
Alibrandi, Simona
Pitruzzella, Alessandro
Scalia, Federica
D’Angelo, Rosalia
Sidoti, Antonina
author_facet Donato, Luigi
Scimone, Concetta
Alibrandi, Simona
Pitruzzella, Alessandro
Scalia, Federica
D’Angelo, Rosalia
Sidoti, Antonina
author_sort Donato, Luigi
collection PubMed
description Mitochondria are subject to continuous oxidative stress stimuli that, over time, can impair their genome and lead to several pathologies, like retinal degenerations. Our main purpose was the identification of mtDNA variants that might be induced by intense oxidative stress determined by N-retinylidene-N-retinylethanolamine (A2E), together with molecular pathways involving the genes carrying them, possibly linked to retinal degeneration. We performed a variant analysis comparison between transcriptome profiles of human retinal pigment epithelial (RPE) cells exposed to A2E and untreated ones, hypothesizing that it might act as a mutagenic compound towards mtDNA. To optimize analysis, we proposed an integrated approach that foresaw the complementary use of the most recent algorithms applied to mtDNA data, characterized by a mixed output coming from several tools and databases. An increased number of variants emerged following treatment. Variants mainly occurred within mtDNA coding sequences, corresponding with either the polypeptide-encoding genes or the RNA. Time-dependent impairments foresaw the involvement of all oxidative phosphorylation complexes, suggesting a serious damage to adenosine triphosphate (ATP) biosynthesis, that can result in cell death. The obtained results could be incorporated into clinical diagnostic settings, as they are hypothesized to modulate the phenotypic expression of mtDNA pathogenic variants, drastically improving the field of precision molecular medicine.
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spelling pubmed-76999172020-11-29 Possible A2E Mutagenic Effects on RPE Mitochondrial DNA from Innovative RNA-Seq Bioinformatics Pipeline Donato, Luigi Scimone, Concetta Alibrandi, Simona Pitruzzella, Alessandro Scalia, Federica D’Angelo, Rosalia Sidoti, Antonina Antioxidants (Basel) Article Mitochondria are subject to continuous oxidative stress stimuli that, over time, can impair their genome and lead to several pathologies, like retinal degenerations. Our main purpose was the identification of mtDNA variants that might be induced by intense oxidative stress determined by N-retinylidene-N-retinylethanolamine (A2E), together with molecular pathways involving the genes carrying them, possibly linked to retinal degeneration. We performed a variant analysis comparison between transcriptome profiles of human retinal pigment epithelial (RPE) cells exposed to A2E and untreated ones, hypothesizing that it might act as a mutagenic compound towards mtDNA. To optimize analysis, we proposed an integrated approach that foresaw the complementary use of the most recent algorithms applied to mtDNA data, characterized by a mixed output coming from several tools and databases. An increased number of variants emerged following treatment. Variants mainly occurred within mtDNA coding sequences, corresponding with either the polypeptide-encoding genes or the RNA. Time-dependent impairments foresaw the involvement of all oxidative phosphorylation complexes, suggesting a serious damage to adenosine triphosphate (ATP) biosynthesis, that can result in cell death. The obtained results could be incorporated into clinical diagnostic settings, as they are hypothesized to modulate the phenotypic expression of mtDNA pathogenic variants, drastically improving the field of precision molecular medicine. MDPI 2020-11-20 /pmc/articles/PMC7699917/ /pubmed/33233726 http://dx.doi.org/10.3390/antiox9111158 Text en © 2020 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Donato, Luigi
Scimone, Concetta
Alibrandi, Simona
Pitruzzella, Alessandro
Scalia, Federica
D’Angelo, Rosalia
Sidoti, Antonina
Possible A2E Mutagenic Effects on RPE Mitochondrial DNA from Innovative RNA-Seq Bioinformatics Pipeline
title Possible A2E Mutagenic Effects on RPE Mitochondrial DNA from Innovative RNA-Seq Bioinformatics Pipeline
title_full Possible A2E Mutagenic Effects on RPE Mitochondrial DNA from Innovative RNA-Seq Bioinformatics Pipeline
title_fullStr Possible A2E Mutagenic Effects on RPE Mitochondrial DNA from Innovative RNA-Seq Bioinformatics Pipeline
title_full_unstemmed Possible A2E Mutagenic Effects on RPE Mitochondrial DNA from Innovative RNA-Seq Bioinformatics Pipeline
title_short Possible A2E Mutagenic Effects on RPE Mitochondrial DNA from Innovative RNA-Seq Bioinformatics Pipeline
title_sort possible a2e mutagenic effects on rpe mitochondrial dna from innovative rna-seq bioinformatics pipeline
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699917/
https://www.ncbi.nlm.nih.gov/pubmed/33233726
http://dx.doi.org/10.3390/antiox9111158
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