title: Tissue-specific loss of DARS2 activates stress responses independently of respiratory chain deficiency in the heart.
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.
authors.affiliation: Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50674 Cologne, Germany.
authors.forename: Sukru Anil
authors.initials: SA
authors.lastname: Dogan
authors.affiliation: Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50674 Cologne, Germany.
authors.forename: Claire
authors.initials: C
authors.lastname: Pujol
authors.affiliation: Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50674 Cologne, Germany.
authors.forename: Priyanka
authors.initials: P
authors.lastname: Maiti
authors.affiliation: Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50674 Cologne, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Kukat
authors.affiliation: Institute of Zoology, University of Cologne, 50674 Cologne, Germany.
authors.forename: Shuaiyu
authors.initials: S
authors.lastname: Wang
authors.affiliation: Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50674 Cologne, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Hermans
authors.affiliation: Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50674 Cologne, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Senft
authors.affiliation: Department of Laboratory Medicine, Karolinska Institutet, 17165 Stockholm, Sweden.
authors.forename: Rolf
authors.initials: R
authors.lastname: Wibom
authors.affiliation: Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50674 Cologne, Germany; Institute of Zoology, University of Cologne, 50674 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), 50931 Cologne, Germany.
authors.forename: Elena I
authors.initials: EI
authors.lastname: Rugarli
authors.affiliation: Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50674 Cologne, Germany; Department of Laboratory Medicine, Karolinska Institutet, 17165 Stockholm, Sweden; Center for Molecular Medicine Cologne (CMMC), 50931 Cologne, Germany; Institute for Mitochondrial Diseases and Aging, Medical Faculty, University of Cologne, 50931 Cologne, Germany. Electronic address: aleksandra.trifunovic@uk-koeln.de.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Trifunovic
mesh_terms: D000818:Animals; D001226:Aspartate-tRNA Ligase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D047108:Embryonic Development; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism; D005838:Genotype; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D028361:Mitochondrial Diseases / Q000378:metabolism / Q000473:pathology; D024101:Mitochondrial Proteins / Q000096:biosynthesis; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D046249:Transfer RNA Aminoacylation
chemical_list: D024101:Mitochondrial Proteins; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D001226:Aspartate-tRNA Ligase