Universität zu Köln

Dogan, Sukru Anil ORCID: 0000-0002-1800-2923, Pujol, Claire, Maiti, Priyanka ORCID: 0000-0003-4207-0341, Kukat, Alexandra, Wang, Shuaiyu, Hermans, Steffen, Senft, Katharina, Wibom, Rolf, Rugarli, Elena I. ORCID: 0000-0002-5782-1067 and Trifunovic, Aleksandra (2014). Tissue-Specific Loss of DARS2 Activates Stress Responses Independently of Respiratory Chain Deficiency in the Heart. Cell Metab., 19 (3). S. 458 - 470. CAMBRIDGE: CELL PRESS. ISSN 1932-7420

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Abstract

Adaptive stress responses activated upon mitochondrial dysfunction are assumed to arise in order to counteract respiratory chain deficiency. Here, we demonstrate that loss of DARS2 (mitochondrial aspartyl-tRNA synthetase) leads to the activation of various stress responses in a tissue-specific manner independently of respiratory chain deficiency. DARS2 depletion in heart and skeletal muscle leads to the severe deregulation of mitochondrial protein synthesis followed by a strong respiratory chain deficit in both tissues, yet the activation of adaptive responses is observed predominantly in cardiomyocytes. We show that the impairment of mitochondrial proteostasis in the heart activates the expression of mitokine FGF21, which acts as a signal for cell-autonomous and systemic metabolic changes. Conversely, skeletal muscle has an intrinsic mechanism relying on the slow turnover of mitochondrial transcripts and higher proteostatic buffering capacity. Our results show that mitochondrial dysfunction is sensed independently of respiratory chain deficiency, questioning the current view on the role of stress responses in mitochondrial diseases.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Dogan, Sukru Anil UNSPECIFIED orcid.org/0000-0002-1800-2923 UNSPECIFIED Pujol, Claire UNSPECIFIED UNSPECIFIED UNSPECIFIED Maiti, Priyanka UNSPECIFIED orcid.org/0000-0003-4207-0341 UNSPECIFIED Kukat, Alexandra UNSPECIFIED UNSPECIFIED UNSPECIFIED Wang, Shuaiyu UNSPECIFIED UNSPECIFIED UNSPECIFIED Hermans, Steffen UNSPECIFIED UNSPECIFIED UNSPECIFIED Senft, Katharina UNSPECIFIED UNSPECIFIED UNSPECIFIED Wibom, Rolf UNSPECIFIED UNSPECIFIED UNSPECIFIED Rugarli, Elena I. UNSPECIFIED orcid.org/0000-0002-5782-1067 UNSPECIFIED Trifunovic, Aleksandra UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-443587
DOI:	10.1016/j.cmet.2014.02.004
Journal or Publication Title:	Cell Metab.
Volume:	19
Number:	3
Page Range:	S. 458 - 470
Date:	2014
Publisher:	CELL PRESS
Place of Publication:	CAMBRIDGE
ISSN:	1932-7420
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Biology > Institute for Genetics
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language MITOCHONDRIAL PROTEIN-SYNTHESIS; GENE-EXPRESSION; MUSCLE; MICE; CARDIOMYOPATHY; MUTATIONS; AUTOPHAGY; MYOPATHY; EMBRYOGENESIS; TRANSCRIPTION Multiple languages Cell Biology; Endocrinology & Metabolism Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/44358