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Adaptation to mitochondrial stress requires CHOP-directed tuning of ISR
In response to disturbed mitochondrial gene expression and protein synthesis, an adaptive transcriptional response sharing a signature of the integrated stress response (ISR) is activated. We report an intricate interplay between three transcription factors regulating the mitochondrial stress respon...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for the Advancement of Science
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8153728/ https://www.ncbi.nlm.nih.gov/pubmed/34039602 http://dx.doi.org/10.1126/sciadv.abf0971 |
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author | Kaspar, Sophie Oertlin, Christian Szczepanowska, Karolina Kukat, Alexandra Senft, Katharina Lucas, Christina Brodesser, Susanne Hatzoglou, Maria Larsson, Ola Topisirovic, Ivan Trifunovic, Aleksandra |
author_facet | Kaspar, Sophie Oertlin, Christian Szczepanowska, Karolina Kukat, Alexandra Senft, Katharina Lucas, Christina Brodesser, Susanne Hatzoglou, Maria Larsson, Ola Topisirovic, Ivan Trifunovic, Aleksandra |
author_sort | Kaspar, Sophie |
collection | PubMed |
description | In response to disturbed mitochondrial gene expression and protein synthesis, an adaptive transcriptional response sharing a signature of the integrated stress response (ISR) is activated. We report an intricate interplay between three transcription factors regulating the mitochondrial stress response: CHOP, C/EBPβ, and ATF4. We show that CHOP acts as a rheostat that attenuates prolonged ISR, prevents unfavorable metabolic alterations, and postpones the onset of mitochondrial cardiomyopathy. Upon mitochondrial dysfunction, CHOP interaction with C/EBPβ is needed to adjust ATF4 levels, thus preventing overactivation of the ATF4-regulated transcriptional program. Failure of this interaction switches ISR from an acute to a chronic state, leading to early respiratory chain deficiency, energy crisis, and premature death. Therefore, contrary to its previously proposed role as a transcriptional activator of mitochondrial unfolded protein response, our results highlight a role of CHOP in the fine-tuning of mitochondrial ISR in mammals. |
format | Online Article Text |
id | pubmed-8153728 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | American Association for the Advancement of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-81537282021-06-07 Adaptation to mitochondrial stress requires CHOP-directed tuning of ISR Kaspar, Sophie Oertlin, Christian Szczepanowska, Karolina Kukat, Alexandra Senft, Katharina Lucas, Christina Brodesser, Susanne Hatzoglou, Maria Larsson, Ola Topisirovic, Ivan Trifunovic, Aleksandra Sci Adv Research Articles In response to disturbed mitochondrial gene expression and protein synthesis, an adaptive transcriptional response sharing a signature of the integrated stress response (ISR) is activated. We report an intricate interplay between three transcription factors regulating the mitochondrial stress response: CHOP, C/EBPβ, and ATF4. We show that CHOP acts as a rheostat that attenuates prolonged ISR, prevents unfavorable metabolic alterations, and postpones the onset of mitochondrial cardiomyopathy. Upon mitochondrial dysfunction, CHOP interaction with C/EBPβ is needed to adjust ATF4 levels, thus preventing overactivation of the ATF4-regulated transcriptional program. Failure of this interaction switches ISR from an acute to a chronic state, leading to early respiratory chain deficiency, energy crisis, and premature death. Therefore, contrary to its previously proposed role as a transcriptional activator of mitochondrial unfolded protein response, our results highlight a role of CHOP in the fine-tuning of mitochondrial ISR in mammals. American Association for the Advancement of Science 2021-05-26 /pmc/articles/PMC8153728/ /pubmed/34039602 http://dx.doi.org/10.1126/sciadv.abf0971 Text en Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). https://creativecommons.org/licenses/by-nc/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license (https://creativecommons.org/licenses/by-nc/4.0/) , which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited. |
spellingShingle | Research Articles Kaspar, Sophie Oertlin, Christian Szczepanowska, Karolina Kukat, Alexandra Senft, Katharina Lucas, Christina Brodesser, Susanne Hatzoglou, Maria Larsson, Ola Topisirovic, Ivan Trifunovic, Aleksandra Adaptation to mitochondrial stress requires CHOP-directed tuning of ISR |
title | Adaptation to mitochondrial stress requires CHOP-directed tuning of ISR |
title_full | Adaptation to mitochondrial stress requires CHOP-directed tuning of ISR |
title_fullStr | Adaptation to mitochondrial stress requires CHOP-directed tuning of ISR |
title_full_unstemmed | Adaptation to mitochondrial stress requires CHOP-directed tuning of ISR |
title_short | Adaptation to mitochondrial stress requires CHOP-directed tuning of ISR |
title_sort | adaptation to mitochondrial stress requires chop-directed tuning of isr |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8153728/ https://www.ncbi.nlm.nih.gov/pubmed/34039602 http://dx.doi.org/10.1126/sciadv.abf0971 |
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