Universität zu Köln

AFG3L2 deficiency impairs axonal transport of mitochondria dependent on ROS and tau levels

Kondadi, Arun Kumar (2014) AFG3L2 deficiency impairs axonal transport of mitochondria dependent on ROS and tau levels. PhD thesis, Universität zu Köln.

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    The m-AAA protease, present in the inner mitochondrial membrane facing the mitochondrial matrix, degrades misfolded polypeptides and processes substrates. AFG3L2 is a subunit of m-AAA protease. In humans, heterozygous missense mutations in AFG3L2 lead to Spinocerebellar Ataxia type 28 (SCA28) whereas homozygous mutations in AFG3L2 cause a severe recessive form of spastic-ataxia with early-onset and rapid progression (SPAX5). While depletion of AFG3L2 causes mitochondrial fragmentation in non-polarised cells, the mechanisms of neurodegeneration associated with mitochondrial dynamics and trafficking were not studied in AFG3L2 deficient neurons. We showed that depletion of AFG3L2 in murine primary cortical neurons leads to a selective defect of anterograde transport of mitochondria. The impaired anterograde transport defect was also observed upon concomitant depletion of AFG3L2 and OMA1 demonstrating that OMA1-mediated degradation of OPA1 (to inhibit mitochondrial fusion) was not the reason for mitochondrial transport defects. Anterograde transport defect of mitochondria in AFG3L2 depleted neurons could be rescued by antioxidants, N-acetyl cysteine (NAC) and vitamin E. Interestingly, we also observed a partial rescue in mitochondrial transport by depleting tau, a microtubule-associated protein. Hence, we conclude that neurons employ ROS to couple cytoskeletal modifications and mitochondrial transport.

    Item Type: Thesis (PhD thesis)
    Kondadi, Arun Kumarshriarun@gmail.com
    URN: urn:nbn:de:hbz:38-56553
    Journal or Publication Title: The EMBO Journal / Loss of the m‐AAA protease subunit AFG3L2 causes mitochondrial transport defects and tau hyperphosphorylation
    ISBN: EMBO press
    Volume: 33
    Number: 9
    Subjects: Natural sciences and mathematics
    Life sciences
    Medical sciences Medicine
    Uncontrolled Keywords:
    Mitochondria, AFG3L2, transport, tauEnglish
    Faculty: Mathematisch-Naturwissenschaftliche Fakultät
    Divisions: Mathematisch-Naturwissenschaftliche Fakultät > Institut für Genetik
    Language: English
    Date: 05 May 2014
    Date Type: Publication
    Date of oral exam: 23 June 2014
    NameAcademic Title
    Rugarli, ElenaProf. Dr.
    Langer, ThomasProf. Dr.
    Full Text Status: Public
    Related URLs:
    Date Deposited: 14 Jul 2014 14:29:33
    NameAcademic Title
    Rugarli, ElenaProf. Dr.
    Langer, ThomasProf. Dr.
    URI: http://kups.ub.uni-koeln.de/id/eprint/5655

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