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Published online 17 November 2003. doi:10.1083/jcb.200304112
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© The Rockefeller University Press, 0021-9525/2003/11/777 $8.00
The Journal of Cell Biology, Volume 163, Number 4, 777-787

Article

 Loss of m-AAA protease in mitochondria causes complex I deficiency and increased sensitivity to oxidative stress in hereditary spastic paraplegia

Luigia Atorino1, Laura Silvestri1, Mirko Koppen2,3, Laura Cassina1, Andrea Ballabio4, Roberto Marconi5, Thomas Langer2,3 and Giorgio Casari1

1 Human Molecular Genetics Unit, Dibit-San Raffaele Scientific Institute, 20132 Milan, Italy
2 Institute for Genetics, University of Cologne, 50923 Cologne, Germany
3 Center for Molecular Medicine, University of Cologne, 50923 Cologne, Germany
4 Telethon Institute of Genetics and Medicine, 80131 Naples, Italy
5 Division of Neurology, Ospedale Misericordia, 58100 Grosseto, Italy

Address correspondence to Giorgio Casari, Human Molecular Genetics Unit, Dibit-San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milan, Italy. Tel.: 39-02-26433502. Fax: 39-02-26434767. email: g.casari{at}hsr.it

Mmutations in paraplegin, a putative mitochondrial metallopeptidase of the AAA family, cause an autosomal recessive form of hereditary spastic paraplegia (HSP). Here, we analyze the function of paraplegin at the cellular level and characterize the phenotypic defects of HSP patients' cells lacking this protein. We demonstrate that paraplegin coassembles with a homologous protein, AFG3L2, in the mitochondrial inner membrane. These two proteins form a high molecular mass complex, which we show to be aberrant in HSP fibroblasts. The loss of this complex causes a reduced complex I activity in mitochondria and an increased sensitivity to oxidant stress, which can both be rescued by exogenous expression of wild-type paraplegin. Furthermore, complementation studies in yeast demonstrate functional conservation of the human paraplegin–AFG3L2 complex with the yeast m-AAA protease and assign proteolytic activity to this structure. These results shed new light on the molecular pathogenesis of HSP and functionally link AFG3L2 to this neurodegenerative disease.

Key Words: spasticity; mitochondria; respiratory complex; neurodegeneration; AAA protease

L. Atorino and L. Silvestri contributed equally to this work.

Abbreviations used in this paper: BN-PAGE, blue native PAGE; HSP, hereditary spastic paraplegia; ROS, reactive oxygen species.


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