Modulation of mitochondrial function and morphology by interaction of Omi/HtrA2 with the mitochondrial fusion factor OPA1.

TitleModulation of mitochondrial function and morphology by interaction of Omi/HtrA2 with the mitochondrial fusion factor OPA1.
Publication TypeJournal Article
Year of Publication2010
AuthorsKieper, N, Holmstrom, KM, Ciceri, D, Fiesel, FC, Wolburg, H, Ziviani, E, Whitworth, AJ, L Martins, M, Kahle, PJ, Krüger, R
JournalExp Cell Res
Volume316
Issue7
Pagination1213-24
Date Published2010 Apr 15
ISSN1090-2422
KeywordsAnimals, Cells, Cultured, Drosophila, Embryo, Mammalian, GTP Phosphohydrolases, HeLa Cells, Humans, Membrane Fusion Proteins, Membrane Potential, Mitochondrial, Mice, Mice, Knockout, Mitochondria, Mitochondrial Membranes, Mitochondrial Proteins, Organelle Shape, Protein Binding, Reactive Oxygen Species, Serine Endopeptidases
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.

DOI10.1016/j.yexcr.2010.01.005
Alternate JournalExp. Cell Res.
Citation Key10.1016/j.yexcr.2010.01.005
PubMed ID20064504
PubMed Central IDPMC3063334
Grant List081987 / / Wellcome Trust / United Kingdom
081987 / / Wellcome Trust / United Kingdom
089698 / / Wellcome Trust / United Kingdom
G-0713 / / Parkinson's UK / United Kingdom