Universität zu Köln

Croon, Marijana ORCID: 0000-0001-5797-5413, Szczepanowska, Karolina ORCID: 0000-0003-4689-2350, Popovic, Milica ORCID: 0000-0002-8762-6967, Lienkamp, Christina, Senft, Katharina ORCID: 0000-0003-2294-6481, Brandscheid, Christoph Paul ORCID: 0000-0001-9739-6643, Bock, Theresa ORCID: 0000-0002-8308-4021, Gnatzy-Feik, Leoni ORCID: 0000-0003-3999-5976, Ashurov, Artem ORCID: 0000-0002-5206-7413, Acton, Richard James ORCID: 0000-0002-2574-9611, Kaul, Harshita, Pujol, Claire, Rosenkranz, Stephan, Krueger, Marcus and Trifunovic, Aleksandra ORCID: 0000-0002-5472-3517 (2022). FGF21 modulates mitochondrial stress response in cardiomyocytes only under mild mitochondrial dysfunction. Sci. Adv., 8 (14). WASHINGTON: AMER ASSOC ADVANCEMENT SCIENCE. ISSN 2375-2548

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Abstract

The mitochondrial integrated stress response (mitoISR) has emerged as a major adaptive pathway to respiratory chain deficiency, but both the tissue specificity of its regulation, and how mitoISR adapts to different levels of mitochondrial dysfunction are largely unknown. Here, we report that diverse levels of mitochondrial cardiomyopathy activate mitoISR, including high production of FGF21, a cytokine with both paracrine and endocrine function, shown to be induced by respiratory chain dysfunction. Although being fully dispensable for the cell-autonomous and systemic responses to severe mitochondrial cardiomyopathy, in the conditions of mild-tomoderate cardiac OXPHOS dysfunction, FGF21 regulates a portion of mitoISR. In the absence of FGF21, a large part of the metabolic adaptation to mitochondrial dysfunction (one-carbon metabolism, transsulfuration, and serine and proline biosynthesis) is strongly blunted, independent of the primary mitoISR activator ATF4. Collectively, our work highlights the complexity of mitochondrial stress responses by revealing the importance of the tissue specificity and dose dependency of mitoISR.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Croon, Marijana UNSPECIFIED orcid.org/0000-0001-5797-5413 UNSPECIFIED Szczepanowska, Karolina UNSPECIFIED orcid.org/0000-0003-4689-2350 UNSPECIFIED Popovic, Milica UNSPECIFIED orcid.org/0000-0002-8762-6967 UNSPECIFIED Lienkamp, Christina UNSPECIFIED UNSPECIFIED UNSPECIFIED Senft, Katharina UNSPECIFIED orcid.org/0000-0003-2294-6481 UNSPECIFIED Brandscheid, Christoph Paul UNSPECIFIED orcid.org/0000-0001-9739-6643 UNSPECIFIED Bock, Theresa UNSPECIFIED orcid.org/0000-0002-8308-4021 UNSPECIFIED Gnatzy-Feik, Leoni UNSPECIFIED orcid.org/0000-0003-3999-5976 UNSPECIFIED Ashurov, Artem UNSPECIFIED orcid.org/0000-0002-5206-7413 UNSPECIFIED Acton, Richard James UNSPECIFIED orcid.org/0000-0002-2574-9611 UNSPECIFIED Kaul, Harshita UNSPECIFIED UNSPECIFIED UNSPECIFIED Pujol, Claire UNSPECIFIED UNSPECIFIED UNSPECIFIED Rosenkranz, Stephan UNSPECIFIED UNSPECIFIED UNSPECIFIED Krueger, Marcus UNSPECIFIED UNSPECIFIED UNSPECIFIED Trifunovic, Aleksandra UNSPECIFIED orcid.org/0000-0002-5472-3517 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-682030
DOI:	10.1126/sciadv.abn7105
Journal or Publication Title:	Sci. Adv.
Volume:	8
Number:	14
Date:	2022
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 SYNTHETASE GENES; EXPRESSION; DEFICIENCY; MECHANISMS; STARVATION; PGC-1-ALPHA; MEDIATOR; PATHWAY; DISEASE; OBESITY Multiple languages Multidisciplinary Sciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/68203