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: Sukru Anil Dogan, Claire Pujol, Priyanka Maiti, Alexandra Kukat, Shuaiyu Wang, Steffen Hermans, Katharina Senft, Rolf Wibom, Elena I Rugarli, Aleksandra Trifunovic
• Journal: Cell metabolism (Cell Metab) Vol. 19 Issue 3 Pg. 458-69 (Mar 04 2014) ISSN: 1932-7420 [Electronic] United States
• PMID: 24606902 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• Mitochondrial Proteins
• fibroblast growth factor 21
• Fibroblast Growth Factors
• Aspartate-tRNA Ligase

Topics

• Animals
• Aspartate-tRNA Ligase (deficiency, genetics, metabolism)
• Cell Line
• Embryonic Development
• Fibroblast Growth Factors (genetics, metabolism)
• Genotype
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mitochondrial Diseases (metabolism, pathology)
• Mitochondrial Proteins (biosynthesis)
• Muscle, Skeletal (metabolism, pathology)
• Myocardium (metabolism, pathology)
• Phenotype
• Transfer RNA Aminoacylation