Kaspar, Sophie ORCID: 0000-0002-0844-6432, Oertlin, Christian, Szczepanowska, Karolina ORCID: 0000-0003-4689-2350, Kukat, Alexandra, Senft, Katharina, Lucas, Christina ORCID: 0000-0002-6575-3877, Brodesser, Susanne, Hatzoglou, Maria, Larsson, Ola ORCID: 0000-0003-1412-1308, Topisirovic, Ivan ORCID: 0000-0002-5510-9762 and Trifunovic, Aleksandra (2021). Adaptation to mitochondrial stress requires CHOP-directed tuning of ISR. Sci. Adv., 7 (22). WASHINGTON: AMER ASSOC ADVANCEMENT SCIENCE. ISSN 2375-2548

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Abstract

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/EBP beta, 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/EBP beta 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Kaspar, SophieUNSPECIFIEDorcid.org/0000-0002-0844-6432UNSPECIFIED
Oertlin, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Szczepanowska, KarolinaUNSPECIFIEDorcid.org/0000-0003-4689-2350UNSPECIFIED
Kukat, AlexandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Senft, KatharinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lucas, ChristinaUNSPECIFIEDorcid.org/0000-0002-6575-3877UNSPECIFIED
Brodesser, SusanneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hatzoglou, MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Larsson, OlaUNSPECIFIEDorcid.org/0000-0003-1412-1308UNSPECIFIED
Topisirovic, IvanUNSPECIFIEDorcid.org/0000-0002-5510-9762UNSPECIFIED
Trifunovic, AleksandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-587300
DOI: 10.1126/sciadv.abf0971
Journal or Publication Title: Sci. Adv.
Volume: 7
Number: 22
Date: 2021
Publisher: AMER ASSOC ADVANCEMENT SCIENCE
Place of Publication: WASHINGTON
ISSN: 2375-2548
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
PROTEIN-SYNTHESIS; MICE LACKING; CELL-DEATH; C/EBP; GENE; METABOLISM; ATF4; LIP; BIOSYNTHESIS; MECHANISMSMultiple languages
Multidisciplinary SciencesMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/58730

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