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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...

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Autores principales: Kaspar, Sophie, Oertlin, Christian, Szczepanowska, Karolina, Kukat, Alexandra, Senft, Katharina, Lucas, Christina, Brodesser, Susanne, Hatzoglou, Maria, Larsson, Ola, Topisirovic, Ivan, Trifunovic, Aleksandra
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2021
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.
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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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