Universität zu Köln

Kondadi, Arun Kumar ORCID: 0000-0002-5888-7834, Wang, Shuaiyu, Montagner, Sara, Kladt, Nikolay, Korwitz, Anne, Martinelli, Paola, Herholz, David, Baker, Michael J., Schauss, Astrid C., Langer, Thomas ORCID: 0000-0003-1250-1462 and Rugarli, Elena I. ORCID: 0000-0002-5782-1067 (2014). Loss of the m-AAA protease subunit AFG3L2 causes mitochondrial transport defects and tau hyperphosphorylation. Embo J., 33 (9). S. 1011 - 1027. HOBOKEN: WILEY. ISSN 1460-2075

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Abstract

The m-AAA protease subunit AFG3L2 is involved in degradation and processing of substrates in the inner mitochondrial membrane. Mutations in AFG3L2 are associated with spinocerebellar ataxia SCA28 in humans and impair axonal development and neuronal survival in mice. The loss of AFG3L2 causes fragmentation of the mitochondrial network. However, the pathogenic mechanism of neurodegeneration in the absence of AFG3L2 is still unclear. Here, we show that depletion of AFG3L2 leads to a specific defect of anterograde transport of mitochondria in murine cortical neurons. We observe similar transport deficiencies upon loss of AFG3L2 in OMA1-deficient neurons, indicating that they are not caused by OMA1-mediated degradation of the dynamin-like GTPase OPA1 and inhibition of mitochondrial fusion. Treatment of neurons with antioxidants, such as N-acetylcysteine or vitamin E, or decreasing tau levels in axons restored mitochondrial transport in AFG3L2-depleted neurons. Consistently, tau hyperphosphorylation and activation of ERK kinases are detected in mouse neurons postnatally deleted for Afg3l2. We propose that reactive oxygen species signaling leads to cytoskeletal modifications that impair mitochondrial transport in neurons lacking AFG3L2.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Kondadi, Arun Kumar UNSPECIFIED orcid.org/0000-0002-5888-7834 UNSPECIFIED Wang, Shuaiyu UNSPECIFIED UNSPECIFIED UNSPECIFIED Montagner, Sara UNSPECIFIED UNSPECIFIED UNSPECIFIED Kladt, Nikolay UNSPECIFIED UNSPECIFIED UNSPECIFIED Korwitz, Anne UNSPECIFIED UNSPECIFIED UNSPECIFIED Martinelli, Paola UNSPECIFIED UNSPECIFIED UNSPECIFIED Herholz, David UNSPECIFIED UNSPECIFIED UNSPECIFIED Baker, Michael J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schauss, Astrid C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Langer, Thomas UNSPECIFIED orcid.org/0000-0003-1250-1462 UNSPECIFIED Rugarli, Elena I. UNSPECIFIED orcid.org/0000-0002-5782-1067 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-438570
DOI:	10.1002/embj.201387009
Journal or Publication Title:	Embo J.
Volume:	33
Number:	9
Page Range:	S. 1011 - 1027
Date:	2014
Publisher:	WILEY
Place of Publication:	HOBOKEN
ISSN:	1460-2075
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Biology > Institute for Genetics
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language COMPLEX I INHIBITOR; OXIDATIVE STRESS; SPASTIC PARAPLEGIA; AXONAL-TRANSPORT; ALZHEIMERS-DISEASE; OPA1; NEURODEGENERATION; PHOSPHORYLATION; DEGENERATION; ACTIVATION Multiple languages Biochemistry & Molecular Biology; Cell Biology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/43857