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miR-24-mediated knockdown of H2AX damages mitochondria and the insulin signaling pathway
Mitochondrial deficits or altered expressions of microRNAs are associated with the pathogenesis of various diseases, and microRNA-operated control of mitochondrial activity has been reported. Using a retrovirus-mediated short-hairpin RNA (shRNA) system, we observed that miR-24-mediated H2AX knockdow...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5420797/ https://www.ncbi.nlm.nih.gov/pubmed/28386126 http://dx.doi.org/10.1038/emm.2016.174 |
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author | Jeong, Jae Hoon Cheol Kang, Young Piao, Ying Kang, Sora Pak, Youngmi Kim |
author_facet | Jeong, Jae Hoon Cheol Kang, Young Piao, Ying Kang, Sora Pak, Youngmi Kim |
author_sort | Jeong, Jae Hoon |
collection | PubMed |
description | Mitochondrial deficits or altered expressions of microRNAs are associated with the pathogenesis of various diseases, and microRNA-operated control of mitochondrial activity has been reported. Using a retrovirus-mediated short-hairpin RNA (shRNA) system, we observed that miR-24-mediated H2AX knockdown (H2AX-KD) impaired both mitochondria and the insulin signaling pathway. The overexpression of miR-24 decreased mitochondrial H2AX and disrupted mitochondrial function, as indicated by the ATP content, membrane potential and oxygen consumption. Similar mitochondrial damage was observed in shH2AX-mediated specific H2AX-KD cells. The H2AX-KD reduced the expression levels of mitochondrial transcription factor A (TFAM) and mitochondrial DNA-dependent transcripts. H2AX-KD mitochondria were swollen, and their cristae were destroyed. H2AX-KD also blocked the import of precursor proteins into mitochondria and the insulin-stimulated phosphorylation of IRS-1 (Y632) and Akt (S473 and T308). The rescue of H2AX, but not the nuclear form of ΔC24-H2AX, restored all features of miR-24- or shH2AX-mediated impairment of mitochondria. Hepatic miR-24 levels were significantly increased in db/db and ob/ob mice. A strong feedback loop may be present among miR-24, H2AX, mitochondria and the insulin signaling pathway. Our findings suggest that H2AX-targeting miR-24 may be a novel negative regulator of mitochondrial function and is implicated in the pathogenesis of insulin resistance. |
format | Online Article Text |
id | pubmed-5420797 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-54207972017-05-19 miR-24-mediated knockdown of H2AX damages mitochondria and the insulin signaling pathway Jeong, Jae Hoon Cheol Kang, Young Piao, Ying Kang, Sora Pak, Youngmi Kim Exp Mol Med Original Article Mitochondrial deficits or altered expressions of microRNAs are associated with the pathogenesis of various diseases, and microRNA-operated control of mitochondrial activity has been reported. Using a retrovirus-mediated short-hairpin RNA (shRNA) system, we observed that miR-24-mediated H2AX knockdown (H2AX-KD) impaired both mitochondria and the insulin signaling pathway. The overexpression of miR-24 decreased mitochondrial H2AX and disrupted mitochondrial function, as indicated by the ATP content, membrane potential and oxygen consumption. Similar mitochondrial damage was observed in shH2AX-mediated specific H2AX-KD cells. The H2AX-KD reduced the expression levels of mitochondrial transcription factor A (TFAM) and mitochondrial DNA-dependent transcripts. H2AX-KD mitochondria were swollen, and their cristae were destroyed. H2AX-KD also blocked the import of precursor proteins into mitochondria and the insulin-stimulated phosphorylation of IRS-1 (Y632) and Akt (S473 and T308). The rescue of H2AX, but not the nuclear form of ΔC24-H2AX, restored all features of miR-24- or shH2AX-mediated impairment of mitochondria. Hepatic miR-24 levels were significantly increased in db/db and ob/ob mice. A strong feedback loop may be present among miR-24, H2AX, mitochondria and the insulin signaling pathway. Our findings suggest that H2AX-targeting miR-24 may be a novel negative regulator of mitochondrial function and is implicated in the pathogenesis of insulin resistance. Nature Publishing Group 2017-04 2017-04-07 /pmc/articles/PMC5420797/ /pubmed/28386126 http://dx.doi.org/10.1038/emm.2016.174 Text en Copyright © 2017 The Author(s) http://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/ |
spellingShingle | Original Article Jeong, Jae Hoon Cheol Kang, Young Piao, Ying Kang, Sora Pak, Youngmi Kim miR-24-mediated knockdown of H2AX damages mitochondria and the insulin signaling pathway |
title | miR-24-mediated knockdown of H2AX damages mitochondria and the insulin signaling pathway |
title_full | miR-24-mediated knockdown of H2AX damages mitochondria and the insulin signaling pathway |
title_fullStr | miR-24-mediated knockdown of H2AX damages mitochondria and the insulin signaling pathway |
title_full_unstemmed | miR-24-mediated knockdown of H2AX damages mitochondria and the insulin signaling pathway |
title_short | miR-24-mediated knockdown of H2AX damages mitochondria and the insulin signaling pathway |
title_sort | mir-24-mediated knockdown of h2ax damages mitochondria and the insulin signaling pathway |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5420797/ https://www.ncbi.nlm.nih.gov/pubmed/28386126 http://dx.doi.org/10.1038/emm.2016.174 |
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