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Molecular and Cellular Biology, January 2007, p. 758-767, Vol. 27, No. 2
0270-7306/07/$08.00+0     doi:10.1128/MCB.01470-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Variable and Tissue-Specific Subunit Composition of Mitochondrial m-AAA Protease Complexes Linked to Hereditary Spastic Paraplegia ^,

Mirko Koppen,^1, Metodi D. Metodiev,^1, Giorgio Casari,² Elena I. Rugarli,³ and Thomas Langer^1*

Institute for Genetics and Center for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany,¹ Department of Neuroscience, DIBIT, San Raffaele Scientific Institute, Milan, Italy,² Division of Biochemistry and Genetics, Istituto Nazionale Neurologico "C. Besta," Milan, Italy³

Received 8 August 2006/ Returned for modification 18 September 2006/ Accepted 30 October 2006

The m-AAA protease, an ATP-dependent proteolytic complex in the mitochondrial inner membrane, controls protein quality and regulates ribosome assembly, thus exerting essential housekeeping functions within mitochondria. Mutations in the m-AAA protease subunit paraplegin cause axonal degeneration in hereditary spastic paraplegia (HSP), but the basis for the unexpected tissue specificity is not understood. Paraplegin assembles with homologous Afg3l2 subunits into hetero-oligomeric complexes which can substitute for yeast m-AAA proteases, demonstrating functional conservation. The function of a third paralogue, Afg3l1 expressed in mouse, is unknown. Here, we analyze the assembly of paraplegin into m-AAA complexes and monitor consequences of paraplegin deficiency in HSP fibroblasts and in a mouse model for HSP. Our findings reveal variability in the assembly of m-AAA proteases in mitochondria in different tissues. Homo-oligomeric Afg3l1 and Afg3l2 complexes and hetero-oligomeric assemblies of both proteins with paraplegin can be formed. Yeast complementation studies demonstrate the proteolytic activity of these assemblies. Paraplegin deficiency in HSP does not result in the loss of m-AAA protease activity in brain mitochondria. Rather, homo-oligomeric Afg3l2 complexes accumulate, and these complexes can substitute for housekeeping functions of paraplegin-containing m-AAA complexes. We therefore propose that the formation of m-AAA proteases with altered substrate specificities leads to axonal degeneration in HSP.

Published ahead of print on 13 November 2006.

Supplemental material for this article may be found at http://mcb.asm.org/.

Both authors contributed equally.

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