Universität zu Köln

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

Full text not available from this repository.

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:	Creators Email ORCID ORCID Put Code Kaspar, Sophie UNSPECIFIED orcid.org/0000-0002-0844-6432 UNSPECIFIED Oertlin, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Szczepanowska, Karolina UNSPECIFIED orcid.org/0000-0003-4689-2350 UNSPECIFIED Kukat, Alexandra UNSPECIFIED UNSPECIFIED UNSPECIFIED Senft, Katharina UNSPECIFIED UNSPECIFIED UNSPECIFIED Lucas, Christina UNSPECIFIED orcid.org/0000-0002-6575-3877 UNSPECIFIED Brodesser, Susanne UNSPECIFIED UNSPECIFIED UNSPECIFIED Hatzoglou, Maria UNSPECIFIED UNSPECIFIED UNSPECIFIED Larsson, Ola UNSPECIFIED orcid.org/0000-0003-1412-1308 UNSPECIFIED Topisirovic, Ivan UNSPECIFIED orcid.org/0000-0002-5510-9762 UNSPECIFIED Trifunovic, Aleksandra UNSPECIFIED UNSPECIFIED UNSPECIFIED
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:	Keywords Language PROTEIN-SYNTHESIS; MICE LACKING; CELL-DEATH; C/EBP; GENE; METABOLISM; ATF4; LIP; BIOSYNTHESIS; MECHANISMS Multiple languages Multidisciplinary Sciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/58730