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

Atorino, L., Silvestri, L., Koppen, M., Cassina, L., Ballabio, A., Marconi, R., et al. (2003). Loss of m-AAA protease in mitochondria causes complex I deficiency and increased sensitivity to oxidative stress in hereditary spastic paraplegia. J Cell Biol, 163(4), 777-87. doi:10.1083/jcb.200304112.

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Atorino, L., Author
Silvestri, L., Author
Koppen, M., Author
Cassina, L., Author
Ballabio, A., Author
Marconi, R., Author
Langer, T.1, Author           
Casari, G., Author
Affiliations:
1Department Langer - Mitochondrial Proteostasis, Max Planck Institute for Biology of Ageing, Max Planck Society, ou_3393994              

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Free keywords: ATP-Dependent Proteases ATPases Associated with Diverse Cellular Activities Adenosine Triphosphatases/genetics/metabolism Cell Respiration/genetics Cells, Cultured Down-Regulation/genetics Electron Transport Complex I/deficiency/*metabolism Fibroblasts Humans Intracellular Membranes/metabolism Macromolecular Substances Metalloendopeptidases/*deficiency/genetics/*metabolism Mitochondria/*enzymology Oxidative Stress/genetics Phylogeny Reactive Oxygen Species/pharmacology Saccharomyces cerevisiae/enzymology/genetics Saccharomyces cerevisiae Proteins/genetics/metabolism Sequence Homology, Nucleic Acid Spastic Paraplegia, Hereditary/*enzymology/genetics
 Abstract: 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.

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 Dates: 2003-11-242003-11-19
 Publication Status: Issued
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 Identifiers: Other: 14623864
DOI: 10.1083/jcb.200304112
ISSN: 0021-9525 (Print)0021-9525 (Linking)
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Title: J Cell Biol
Source Genre: Journal
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Pages: - Volume / Issue: 163 (4) Sequence Number: - Start / End Page: 777 - 87 Identifier: -