Universität zu Köln

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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Abstract

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)
Creators:	Creators Email ORCID ORCID Put Code Kondadi, Arun Kumar shriarun@gmail.com UNSPECIFIED UNSPECIFIED
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
Volume:	33
Number:	9
Date:	5 May 2014
ISBN:	EMBO press
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 Medical sciences Medicine
Uncontrolled Keywords:	Keywords Language Mitochondria, AFG3L2, transport, tau English
Date of oral exam:	23 June 2014
Referee:	Name Academic Title Rugarli, Elena Prof. Dr. Langer, Thomas Prof. Dr.
Related URLs:	Publication
Funders:	NRW fellowship (IGSDHD) for Ph.D programme
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/5655