Universität zu Köln

Dogan, Sükrü Anil (2013). Mitochondrial Aspartyl-tRNA Synthetase (DARS2) Deficiency and Tissue-Specific Consequences of Defective Mitochondrial Translation. PhD thesis, Universität zu Köln.

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Abstract

Cells try to counteract mitochondrial respiratory chain deficiencies via various kinds of largely unknown compensatory mechanisms, which play a central role in determining the extent of tissue-specific defects leading to disease phenotypes. In this study, we directly disrupted mitochondrial protein synthesis in mice by deleting the mitochondrial aspartyl-tRNA synthetase (Dars2) gene in a tissue- specific manner. We generated DARS2 deficiency in three different tissues (heart, skeletal muscle and forebrain neurons) and followed the dynamics and extent of pathological changes that occurred. Deficiency of this essential protein leads to severe deregulation of mitochondrial protein synthesis in both heart and skeletal muscle. Yet, mitochondrial stress responses, like increased biogenesis, decreased autophagy, upregulation of mitochondrial unfolded protein response and mitokine FGF21, are only observed in DARS2-deficient cardiomyocytes. Surprisingly, the initiation of these stress responses is stemming from perturbed mitochondrial proteostasis, rather than the respiratory deficiency. Skeletal muscle, on the other hand, has intrinsic protective mechanisms that make it better equipped for folding and turnover of mitochondrial proteins, as well as slow turnover of mitochondrial transcripts that is coupled with possible upregulation of muscle regeneration. As a result, skeletal muscle is able to cope with increased levels of unassembled proteins better. Although DARS2 depletion leads to very strong, deleterious respiratory deficiency in heart and skeletal muscle, causing animals to die within 7-8 weeks, its deficiency in forebrain neurons seems to have a milder effect that takes much longer time to develop. Defective mitochondrial translation in forebrain neurons caused abnormal behavior, and severe forebrain atrophy, which is caused by neuronal cell apoptosis and accompanied by activation of inflammatory responses such as microgliosis and reactive astrogliosis. Surprisingly, neurodegeneration occurred in an age-dependent manner and affected cortex and hippocampal regions differently.

Item Type:	Thesis (PhD thesis)
Creators:	Creators Email ORCID ORCID Put Code Dogan, Sükrü Anil anil.dogan@uni-koeln.de UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-55516
Date:	5 November 2013
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Biology > Institute for Genetics
Subjects:	Natural sciences and mathematics Life sciences
Uncontrolled Keywords:	Keywords Language mitochondria, DARS2, translation, unfolded protein response English
Date of oral exam:	28 January 2014
Referee:	Name Academic Title Trifunovic, Aleksandra Prof. Dr. Rugarli, Elena Prof. Dr.
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/5551