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miR-181c Regulates the Mitochondrial Genome, Bioenergetics, and Propensity for Heart Failure In Vivo

MicroRNAs (miRNAs) are small non-coding RNAs, which inhibit the stability and/or translation of a mRNA. miRNAs have been found to play a powerful role in various cardiovascular diseases. Recently, we have demonstrated that a microRNA (miR-181c) can be encoded in the nucleus, processed to the mature...

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Autores principales: Das, Samarjit, Bedja, Djahida, Campbell, Nathaniel, Dunkerly, Brittany, Chenna, Venugopal, Maitra, Anirban, Steenbergen, Charles
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4014556/
https://www.ncbi.nlm.nih.gov/pubmed/24810628
http://dx.doi.org/10.1371/journal.pone.0096820
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author Das, Samarjit
Bedja, Djahida
Campbell, Nathaniel
Dunkerly, Brittany
Chenna, Venugopal
Maitra, Anirban
Steenbergen, Charles
author_facet Das, Samarjit
Bedja, Djahida
Campbell, Nathaniel
Dunkerly, Brittany
Chenna, Venugopal
Maitra, Anirban
Steenbergen, Charles
author_sort Das, Samarjit
collection PubMed
description MicroRNAs (miRNAs) are small non-coding RNAs, which inhibit the stability and/or translation of a mRNA. miRNAs have been found to play a powerful role in various cardiovascular diseases. Recently, we have demonstrated that a microRNA (miR-181c) can be encoded in the nucleus, processed to the mature form in the cytosol, translocated into the mitochondria, and ultimately can regulate mitochondrial gene expression. However the in vivo impact of miR-181c is unknown. Here we report an in-vivo method for administration of miR-181c in rats, which leads to reduced exercise capacity and signs of heart failure, by targeting the 3′-end of mt-COX1 (cytochrome c oxidase subunit 1). We cloned miR-181c and packaged it in lipid-based nanoparticles for systemic delivery. The plasmid DNA complexed nanovector shows no apparent toxicity. We find that the mRNA levels of mitochondrial complex IV genes in the heart, but not any other mitochondrial genes, are significantly altered with miR-181c overexpression, suggesting selective mitochondrial complex IV remodeling due to miR-181c targeting mt-COX1. Isolated heart mitochondrial studies showed significantly altered O(2)-consumption, ROS production, matrix calcium, and mitochondrial membrane potential in miR-181c-treated animals. For the first time, this study shows that miRNA delivered to the heart in-vivo can lead to cardiac dysfunction by regulating mitochondrial genes.
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spelling pubmed-40145562014-05-14 miR-181c Regulates the Mitochondrial Genome, Bioenergetics, and Propensity for Heart Failure In Vivo Das, Samarjit Bedja, Djahida Campbell, Nathaniel Dunkerly, Brittany Chenna, Venugopal Maitra, Anirban Steenbergen, Charles PLoS One Research Article MicroRNAs (miRNAs) are small non-coding RNAs, which inhibit the stability and/or translation of a mRNA. miRNAs have been found to play a powerful role in various cardiovascular diseases. Recently, we have demonstrated that a microRNA (miR-181c) can be encoded in the nucleus, processed to the mature form in the cytosol, translocated into the mitochondria, and ultimately can regulate mitochondrial gene expression. However the in vivo impact of miR-181c is unknown. Here we report an in-vivo method for administration of miR-181c in rats, which leads to reduced exercise capacity and signs of heart failure, by targeting the 3′-end of mt-COX1 (cytochrome c oxidase subunit 1). We cloned miR-181c and packaged it in lipid-based nanoparticles for systemic delivery. The plasmid DNA complexed nanovector shows no apparent toxicity. We find that the mRNA levels of mitochondrial complex IV genes in the heart, but not any other mitochondrial genes, are significantly altered with miR-181c overexpression, suggesting selective mitochondrial complex IV remodeling due to miR-181c targeting mt-COX1. Isolated heart mitochondrial studies showed significantly altered O(2)-consumption, ROS production, matrix calcium, and mitochondrial membrane potential in miR-181c-treated animals. For the first time, this study shows that miRNA delivered to the heart in-vivo can lead to cardiac dysfunction by regulating mitochondrial genes. Public Library of Science 2014-05-08 /pmc/articles/PMC4014556/ /pubmed/24810628 http://dx.doi.org/10.1371/journal.pone.0096820 Text en © 2014 Das et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Das, Samarjit
Bedja, Djahida
Campbell, Nathaniel
Dunkerly, Brittany
Chenna, Venugopal
Maitra, Anirban
Steenbergen, Charles
miR-181c Regulates the Mitochondrial Genome, Bioenergetics, and Propensity for Heart Failure In Vivo
title miR-181c Regulates the Mitochondrial Genome, Bioenergetics, and Propensity for Heart Failure In Vivo
title_full miR-181c Regulates the Mitochondrial Genome, Bioenergetics, and Propensity for Heart Failure In Vivo
title_fullStr miR-181c Regulates the Mitochondrial Genome, Bioenergetics, and Propensity for Heart Failure In Vivo
title_full_unstemmed miR-181c Regulates the Mitochondrial Genome, Bioenergetics, and Propensity for Heart Failure In Vivo
title_short miR-181c Regulates the Mitochondrial Genome, Bioenergetics, and Propensity for Heart Failure In Vivo
title_sort mir-181c regulates the mitochondrial genome, bioenergetics, and propensity for heart failure in vivo
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4014556/
https://www.ncbi.nlm.nih.gov/pubmed/24810628
http://dx.doi.org/10.1371/journal.pone.0096820
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