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Oxidative stress-induced mitophagy is suppressed by the miR-106b-93-25 cluster in a protective manner

Increased reactive oxygen species levels in the mitochondrial matrix can induce Parkin-dependent mitophagy, which selectively degrades dysfunctional mitochondria via the autolysosome pathway. Phosphorylated mitofusin-2 (MFN2), a receptor of parkin RBR E3 ubiquitin-protein ligase (Parkin), interacts...

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Autores principales: Zhang, Cheng, Nie, Pengqing, Zhou, Chunliu, Hu, Yue, Duan, Suling, Gu, Meijia, Jiang, Dongxu, Wang, Yunfu, Deng, Zixin, Chen, Jincao, Chen, Shi, Wang, Lianrong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904769/
https://www.ncbi.nlm.nih.gov/pubmed/33627622
http://dx.doi.org/10.1038/s41419-021-03484-3
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author Zhang, Cheng
Nie, Pengqing
Zhou, Chunliu
Hu, Yue
Duan, Suling
Gu, Meijia
Jiang, Dongxu
Wang, Yunfu
Deng, Zixin
Chen, Jincao
Chen, Shi
Wang, Lianrong
author_facet Zhang, Cheng
Nie, Pengqing
Zhou, Chunliu
Hu, Yue
Duan, Suling
Gu, Meijia
Jiang, Dongxu
Wang, Yunfu
Deng, Zixin
Chen, Jincao
Chen, Shi
Wang, Lianrong
author_sort Zhang, Cheng
collection PubMed
description Increased reactive oxygen species levels in the mitochondrial matrix can induce Parkin-dependent mitophagy, which selectively degrades dysfunctional mitochondria via the autolysosome pathway. Phosphorylated mitofusin-2 (MFN2), a receptor of parkin RBR E3 ubiquitin-protein ligase (Parkin), interacts with Parkin to promote the ubiquitination of mitochondrial proteins; meanwhile, the mitophagy receptors Optineurin (OPTN) and nuclear dot protein 52 (NDP52) are recruited to damaged mitochondria to promote mitophagy. However, previous studies have not investigated changes in the levels of OPTN, MFN2, and NDP52 during Parkin-mediated mitophagy. Here, we show that mild and sustained hydrogen peroxide (H(2)O(2)) stimulation induces Parkin-dependent mitophagy accompanied by downregulation of the mitophagy-associated proteins OPTN, NDP52, and MFN2. We further demonstrate that H(2)O(2) promotes the expression of the miR-106b-93-25 cluster and that miR-106b and miR-93 synergistically inhibit the translation of OPTN, NDP52, and MFN2 by targeting their 3’ untranslated regions. We further reveal that compromised phosphorylation of MYC proto-oncogene protein (c-Myc) at threonine 58 (T58) (producing an unstable form of c-Myc) caused by reduced nuclear glycogen synthase kinase-3 beta (GSK3β) levels contributes to the promotion of miR-106b-93-25 cluster expression upon H(2)O(2) induction. Furthermore, miR-106b-mediated and miR-93-mediated inhibition of mitophagy-associated proteins (OPTN, MFN2, and NDP52) restrains cell death by controlling excessive mitophagy. Our data suggest that microRNAs (miRNAs) targeting mitophagy-associated proteins maintain cell survival, which is a novel mechanism of mitophagy control. Thus, our findings provide mechanistic insight into how miRNA-mediated regulation alters the biological process of mitophagy.
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spelling pubmed-79047692021-03-11 Oxidative stress-induced mitophagy is suppressed by the miR-106b-93-25 cluster in a protective manner Zhang, Cheng Nie, Pengqing Zhou, Chunliu Hu, Yue Duan, Suling Gu, Meijia Jiang, Dongxu Wang, Yunfu Deng, Zixin Chen, Jincao Chen, Shi Wang, Lianrong Cell Death Dis Article Increased reactive oxygen species levels in the mitochondrial matrix can induce Parkin-dependent mitophagy, which selectively degrades dysfunctional mitochondria via the autolysosome pathway. Phosphorylated mitofusin-2 (MFN2), a receptor of parkin RBR E3 ubiquitin-protein ligase (Parkin), interacts with Parkin to promote the ubiquitination of mitochondrial proteins; meanwhile, the mitophagy receptors Optineurin (OPTN) and nuclear dot protein 52 (NDP52) are recruited to damaged mitochondria to promote mitophagy. However, previous studies have not investigated changes in the levels of OPTN, MFN2, and NDP52 during Parkin-mediated mitophagy. Here, we show that mild and sustained hydrogen peroxide (H(2)O(2)) stimulation induces Parkin-dependent mitophagy accompanied by downregulation of the mitophagy-associated proteins OPTN, NDP52, and MFN2. We further demonstrate that H(2)O(2) promotes the expression of the miR-106b-93-25 cluster and that miR-106b and miR-93 synergistically inhibit the translation of OPTN, NDP52, and MFN2 by targeting their 3’ untranslated regions. We further reveal that compromised phosphorylation of MYC proto-oncogene protein (c-Myc) at threonine 58 (T58) (producing an unstable form of c-Myc) caused by reduced nuclear glycogen synthase kinase-3 beta (GSK3β) levels contributes to the promotion of miR-106b-93-25 cluster expression upon H(2)O(2) induction. Furthermore, miR-106b-mediated and miR-93-mediated inhibition of mitophagy-associated proteins (OPTN, MFN2, and NDP52) restrains cell death by controlling excessive mitophagy. Our data suggest that microRNAs (miRNAs) targeting mitophagy-associated proteins maintain cell survival, which is a novel mechanism of mitophagy control. Thus, our findings provide mechanistic insight into how miRNA-mediated regulation alters the biological process of mitophagy. Nature Publishing Group UK 2021-02-24 /pmc/articles/PMC7904769/ /pubmed/33627622 http://dx.doi.org/10.1038/s41419-021-03484-3 Text en © The Author(s) 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Zhang, Cheng
Nie, Pengqing
Zhou, Chunliu
Hu, Yue
Duan, Suling
Gu, Meijia
Jiang, Dongxu
Wang, Yunfu
Deng, Zixin
Chen, Jincao
Chen, Shi
Wang, Lianrong
Oxidative stress-induced mitophagy is suppressed by the miR-106b-93-25 cluster in a protective manner
title Oxidative stress-induced mitophagy is suppressed by the miR-106b-93-25 cluster in a protective manner
title_full Oxidative stress-induced mitophagy is suppressed by the miR-106b-93-25 cluster in a protective manner
title_fullStr Oxidative stress-induced mitophagy is suppressed by the miR-106b-93-25 cluster in a protective manner
title_full_unstemmed Oxidative stress-induced mitophagy is suppressed by the miR-106b-93-25 cluster in a protective manner
title_short Oxidative stress-induced mitophagy is suppressed by the miR-106b-93-25 cluster in a protective manner
title_sort oxidative stress-induced mitophagy is suppressed by the mir-106b-93-25 cluster in a protective manner
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904769/
https://www.ncbi.nlm.nih.gov/pubmed/33627622
http://dx.doi.org/10.1038/s41419-021-03484-3
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