title: Cytosolic signaling protein Ecsit also localizes to mitochondria where it interacts with chaperone NDUFAF1 and functions in complex I assembly.
abstract: Ecsit is a cytosolic adaptor protein essential for inflammatory response and embryonic development via the Toll-like and BMP (bone morphogenetic protein) signal transduction pathways, respectively. Here, we demonstrate a mitochondrial function for Ecsit (an evolutionary conserved signaling intermediate in Toll pathways) in the assembly of mitochondrial complex I (NADH:ubiquinone oxidoreductase). An N-terminal targeting signal directs Ecsit to mitochondria, where it interacts with assembly chaperone NDUFAF1 in 500- to 850-kDa complexes as demonstrated by affinity purification and vice versa RNA interference (RNAi) knockdowns. In addition, Ecsit knockdown results in severely impaired complex I assembly and disturbed mitochondrial function. These findings support a function for Ecsit in the assembly or stability of mitochondrial complex I, possibly linking assembly of oxidative phosphorylation complexes to inflammatory response and embryonic development.
authors.affiliation: Department of Paediatrics, Nijmegen Centre for Mitochondrial Disorders, Radboud University Nijmegen Medical Centre, Nijmegen 6500 HB, The Netherlands.
authors.forename: Rutger O
authors.initials: RO
authors.lastname: Vogel
authors.forename: Rolf J R J
authors.initials: RJ
authors.lastname: Janssen
authors.forename: Mariël A M
authors.initials: MA
authors.lastname: van den Brand
authors.forename: Cindy E J
authors.initials: CE
authors.lastname: Dieteren
authors.forename: Sjoerd
authors.initials: S
authors.lastname: Verkaart
authors.forename: Werner J H
authors.initials: WJ
authors.lastname: Koopman
authors.forename: Peter H G M
authors.initials: PH
authors.lastname: Willems
authors.forename: Wendy
authors.initials: W
authors.lastname: Pluk
authors.forename: Lambert P W J
authors.initials: LP
authors.lastname: van den Heuvel
authors.forename: Jan A M
authors.initials: JA
authors.lastname: Smeitink
authors.forename: Leo G J
authors.initials: LG
authors.lastname: Nijtmans
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D002460:Cell Line; D042967:Electron Transport Complex I / Q000378:metabolism*; D047108:Embryonic Development; D006367:HeLa Cells; D006801:Humans; D008928:Mitochondria / Q000737:chemistry / Q000378:metabolism*; D008969:Molecular Sequence Data; D009245:NADH Dehydrogenase / Q000032:analysis / Q000378:metabolism*; D010085:Oxidative Phosphorylation; D034622:RNA Interference
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C518657:Ecsit protein, human; D009245:NADH Dehydrogenase; D042967:Electron Transport Complex I; C506342:NDUFAF1 protein, human