title: Modulation of mitochondrial function and morphology by interaction of Omi/HtrA2 with the mitochondrial fusion factor OPA1.
abstract: Loss of Omi/HtrA2 function leads to nerve cell loss in mouse models and has been linked to neurodegeneration in Parkinson's and Huntington's disease. Omi/HtrA2 is a serine protease released as a pro-apoptotic factor from the mitochondrial intermembrane space into the cytosol. Under physiological conditions, Omi/HtrA2 is thought to be involved in protection against cellular stress, but the cytological and molecular mechanisms are not clear. Omi/HtrA2 deficiency caused an accumulation of reactive oxygen species and reduced mitochondrial membrane potential. In Omi/HtrA2 knockout mouse embryonic fibroblasts, as well as in Omi/HtrA2 silenced human HeLa cells and Drosophila S2R+ cells, we found elongated mitochondria by live cell imaging. Electron microscopy confirmed the mitochondrial morphology alterations and showed abnormal cristae structure. Examining the levels of proteins involved in mitochondrial fusion, we found a selective up-regulation of more soluble OPA1 protein. Complementation of knockout cells with wild-type Omi/HtrA2 but not with the protease mutant [S306A]Omi/HtrA2 reversed the mitochondrial elongation phenotype and OPA1 alterations. Finally, co-immunoprecipitation showed direct interaction of Omi/HtrA2 with endogenous OPA1. Thus, we show for the first time a direct effect of loss of Omi/HtrA2 on mitochondrial morphology and demonstrate a novel role of this mitochondrial serine protease in the modulation of OPA1. Our results underscore a critical role of impaired mitochondrial dynamics in neurodegenerative disorders.
authors.affiliation: Center of Neurology and Hertie Institute for Clinical Brain Research, Tübingen, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Kieper
authors.forename: Kira M
authors.initials: KM
authors.lastname: Holmström
authors.forename: Dalila
authors.initials: D
authors.lastname: Ciceri
authors.forename: Fabienne C
authors.initials: FC
authors.lastname: Fiesel
authors.forename: Hartwig
authors.initials: H
authors.lastname: Wolburg
authors.forename: Elena
authors.initials: E
authors.lastname: Ziviani
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Whitworth
authors.forename: L Miguel
authors.initials: LM
authors.lastname: Martins
authors.forename: Philipp J
authors.initials: PJ
authors.lastname: Kahle
authors.forename: Rejko
authors.initials: R
authors.lastname: Krüger
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004330:Drosophila; D004622:Embryo, Mammalian; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D000074923:High-Temperature Requirement A Serine Peptidase 2; D006801:Humans; D050576:Membrane Fusion Proteins / Q000235:genetics / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism / Q000502:physiology*; D051336:Mitochondrial Membranes / Q000378:metabolism / Q000502:physiology; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D053140:Organelle Shape / Q000235:genetics / Q000502:physiology; D011485:Protein Binding / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*
chemical_list: D050576:Membrane Fusion Proteins; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; D012697:Serine Endopeptidases; C000615914:HTRA2 protein, human; D000074923:High-Temperature Requirement A Serine Peptidase 2; C000615915:Htra2 protein, mouse; D020558:GTP Phosphohydrolases; C498809:Opa1 protein, mouse