Universität zu Köln

Mitochondrial Aspartyl-tRNA Synthetase (DARS2) Deficiency and Tissue-Specific Consequences of Defective Mitochondrial Translation

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:
    CreatorsEmail
    Dogan, Sükrü Anilanil.dogan@uni-koeln.de
    URN: urn:nbn:de:hbz:38-55516
    Subjects: Natural sciences and mathematics
    Life sciences
    Uncontrolled Keywords:
    KeywordsLanguage
    mitochondria, DARS2, translation, unfolded protein responseEnglish
    Faculty: Mathematisch-Naturwissenschaftliche Fakultät
    Divisions: Mathematisch-Naturwissenschaftliche Fakultät > Institut für Genetik
    Language: English
    Date: 05 November 2013
    Date Type: Publication
    Date of oral exam: 28 January 2014
    Full Text Status: Public
    Date Deposited: 28 Apr 2014 08:42:47
    Referee
    NameAcademic Title
    Trifunovic, AleksandraProf. Dr.
    Rugarli, ElenaProf. Dr.
    URI: http://kups.ub.uni-koeln.de/id/eprint/5551

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