title: Loss of m-AAA protease in mitochondria causes complex I deficiency and increased sensitivity to oxidative stress in hereditary spastic paraplegia.
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.
authors: Human Molecular Genetics Unit, Dibit-San Raffaele Scientific Institute, 20132 Milan, Italy.
authors: Luigia
authors: L
authors: Atorino
authors: Laura
authors: L
authors: Silvestri
authors: Mirko
authors: M
authors: Koppen
authors: Laura
authors: L
authors: Cassina
authors: Andrea
authors: A
authors: Ballabio
authors: Roberto
authors: R
authors: Marconi
authors: Thomas
authors: T
authors: Langer
authors: Giorgio
authors: G
authors: Casari
mesh_terms: D049069:ATP-Dependent Proteases; D000074183:ATPases Associated with Diverse Cellular Activities; D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism; D019069:Cell Respiration / Q000235:genetics; D002478:Cells, Cultured; D015536:Down-Regulation / Q000235:genetics; D042967:Electron Transport Complex I / Q000172:deficiency / Q000378:metabolism*; D005347:Fibroblasts; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D046911:Macromolecular Substances; D008666:Metalloendopeptidases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000201:enzymology*; D018384:Oxidative Stress / Q000235:genetics; D010802:Phylogeny; D017382:Reactive Oxygen Species / Q000494:pharmacology; D012441:Saccharomyces cerevisiae / Q000201:enzymology / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D012689:Sequence Homology, Nucleic Acid; D015419:Spastic Paraplegia, Hereditary / Q000201:enzymology* / Q000235:genetics
chemical_list: D046911:Macromolecular Substances; D017382:Reactive Oxygen Species; D029701:Saccharomyces cerevisiae Proteins; D049069:ATP-Dependent Proteases; C120699:AFG3L2 protein, human; D008666:Metalloendopeptidases; C112889:SPG7 protein, human; C114583:m-AAA proteases; D000251:Adenosine Triphosphatases; C090045:AFG3 protein, S cerevisiae; D000074183:ATPases Associated with Diverse Cellular Activities; D042967:Electron Transport Complex I