title: Depletion of oxaloacetate decarboxylase FAHD1 inhibits mitochondrial electron transport and induces cellular senescence in human endothelial cells.
abstract: In this study we report the identification of FAH domain containing protein 1 (FAHD1), a recently described member of the fumarylacetoacetate hydrolase (FAH) superfamily of metabolic enzymes, as a novel player in the regulation of cellular senescence. FAHD1 was found in a proteomic screen searching for mitochondrial proteins, which are differentially regulated in mitochondria from young and senescent human endothelial cells, and subsequently identified as oxaloacetate decarboxylase. We report here that depletion of FAHD1 from human endothelial cells inhibited mitochondrial energy metabolism and subsequently induced premature senescence. Whereas senescence induced by FAHD1 depletion was not associated with DNA damage, we noted a reduction of mitochondrial ATP-coupled respiration associated with upregulation of the cdk inhibitor p21. These results indicate that FAHD1 is required for mitochondrial function in human cells and provide additional support to the growing evidence that mitochondrial dysfunction can induce cellular senescence by metabolic alterations independent of the DNA damage response pathway.
authors.affiliation: Institute for Biomedical Aging Research, Universität Innsbruck, Rennweg 10, A-6020 Innsbruck, Austria.
authors.forename: Michele
authors.initials: M
authors.lastname: Petit
authors.affiliation: Institute for Biomedical Aging Research, Universität Innsbruck, Rennweg 10, A-6020 Innsbruck, Austria.
authors.forename: Rafal
authors.initials: R
authors.lastname: Koziel
authors.affiliation: Institute for Biomedical Aging Research, Universität Innsbruck, Rennweg 10, A-6020 Innsbruck, Austria.
authors.forename: Solmaz
authors.initials: S
authors.lastname: Etemad
authors.affiliation: Institute for Biomedical Aging Research, Universität Innsbruck, Rennweg 10, A-6020 Innsbruck, Austria.
authors.forename: Haymo
authors.initials: H
authors.lastname: Pircher
authors.affiliation: Institute for Biomedical Aging Research, Universität Innsbruck, Rennweg 10, A-6020 Innsbruck, Austria. Electronic address: pidder.jansen-duerr@uibk.ac.at.
authors.forename: Pidder
authors.initials: P
authors.lastname: Jansen-Dürr
mesh_terms: D002460:Cell Line; D016922:Cellular Senescence / Q000235:genetics*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004249:DNA Damage; D004579:Electron Transport; D042783:Endothelial Cells / Q000166:cytology*; D004734:Energy Metabolism; D006801:Humans; D006867:Hydrolases / Q000235:genetics*; D008928:Mitochondria / Q000201:enzymology* / Q000235:genetics
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C000607392:FAHD1 protein, human; D006867:Hydrolases
keywords: DNA damage; Energy metabolism; FAHD1; Mitochondria; Oxaloacetate decarboxylase; Premature senescence