ausblenden:
Schlagwörter:
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
Zusammenfassung:
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.
