Universität zu Köln

Merkwirth, Carsten ORCID: 0000-0001-8895-3495, Martinelli, Paola, Korwitz, Anne, Morbin, Michela ORCID: 0000-0001-8034-3123, Broenneke, Hella S., Jordan, Sabine D., Rugarli, Elena I. and Langer, Thomas ORCID: 0000-0003-1250-1462 (2012). Loss of Prohibitin Membrane Scaffolds Impairs Mitochondrial Architecture and Leads to Tau Hyperphosphorylation and Neurodegeneration. PLoS Genet., 8 (11). SAN FRANCISCO: PUBLIC LIBRARY SCIENCE. ISSN 1553-7404

Full text not available from this repository.

Abstract

Fusion and fission of mitochondria maintain the functional integrity of mitochondria and protect against neurodegeneration, but how mitochondrial dysfunctions trigger neuronal loss remains ill-defined. Prohibitins form large ring complexes in the inner membrane that are composed of PHB1 and PHB2 subunits and are thought to function as membrane scaffolds. In Caenorhabditis elegans, prohibitin genes affect aging by moderating fat metabolism and energy production. Knockdown experiments in mammalian cells link the function of prohibitins to membrane fusion, as they were found to stabilize the dynamin-like GTPase OPA1 (optic atrophy 1), which mediates mitochondrial inner membrane fusion and cristae morphogenesis. Mutations in OPA1 are associated with dominant optic atrophy characterized by the progressive loss of retinal ganglion cells, highlighting the importance of OPA1 function in neurons. Here, we show that neuron-specific inactivation of Phb2 in the mouse forebrain causes extensive neurodegeneration associated with behavioral impairments and cognitive deficiencies. We observe early onset tau hyperphosphorylation and filament formation in the hippocampus, demonstrating a direct link between mitochondrial defects and tau pathology. Loss of PHB2 impairs the stability of OPA1, affects mitochondrial ultrastructure, and induces the perinuclear clustering of mitochondria in hippocampal neurons. A destabilization of the mitochondrial genome and respiratory deficiencies manifest in aged neurons only, while the appearance of mitochondrial morphology defects correlates with tau hyperphosphorylation in the absence of PHB2. These results establish an essential role of prohibitin complexes for neuronal survival in vivo and demonstrate that OPA1 stability, mitochondrial fusion, and the maintenance of the mitochondrial genome in neurons depend on these scaffolding proteins. Moreover, our findings establish prohibitin-deficient mice as a novel genetic model for tau pathologies caused by a dysfunction of mitochondria and raise the possibility that tau pathologies are associated with other neurodegenerative disorders caused by deficiencies in mitochondrial dynamics.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Merkwirth, Carsten UNSPECIFIED orcid.org/0000-0001-8895-3495 UNSPECIFIED Martinelli, Paola UNSPECIFIED UNSPECIFIED UNSPECIFIED Korwitz, Anne UNSPECIFIED UNSPECIFIED UNSPECIFIED Morbin, Michela UNSPECIFIED orcid.org/0000-0001-8034-3123 UNSPECIFIED Broenneke, Hella S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Jordan, Sabine D. UNSPECIFIED UNSPECIFIED UNSPECIFIED Rugarli, Elena I. UNSPECIFIED UNSPECIFIED UNSPECIFIED Langer, Thomas UNSPECIFIED orcid.org/0000-0003-1250-1462 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-479259
DOI:	10.1371/journal.pgen.1003021
Journal or Publication Title:	PLoS Genet.
Volume:	8
Number:	11
Date:	2012
Publisher:	PUBLIC LIBRARY SCIENCE
Place of Publication:	SAN FRANCISCO
ISSN:	1553-7404
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language M-AAA PROTEASE; DOMINANT OPTIC ATROPHY; ALZHEIMERS-DISEASE; PROTEOLYTIC CLEAVAGE; AXONAL-TRANSPORT; SPFH DOMAIN; OPA1; FUSION; PHOSPHORYLATION; FISSION Multiple languages Genetics & Heredity Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/47925