title: Tumor necrosis factor is delivered to mitochondria where a tumor necrosis factor-binding protein is localized.
abstract: The roles of the known tumor necrosis factor (TNF) receptors (TNFR-I and TNFR-II) and their associated signaling pathways in mediating the diverse actions of TNF remain incompletely defined. We have found that a proportion of exogenous TNF is delivered to mitochondria as well as to lysosomes. Using confocal and immunoelectron microscopy and Western blotting of subcellular fractions, we have identified a 60-kd protein in the inner mitochondrial membrane that is recognized by a monoclonal antibody to TNFR-II. In isolated mitochondria, this protein binds [125I]-TNF. This provides evidence of a mitochondrial binding protein for an extracellular ligand and demonstrates the presence of a pathway capable of delivering TNF from the cell surface to mitochondria. These findings suggest that TNF effects on cells may be due in part to a direct effect on mitochondria.
authors.affiliation: Department of Medicine, University of Cambridge, Addenbrooke's Hospital, United Kingdom.
authors.forename: E C
authors.initials: EC
authors.lastname: Ledgerwood
authors.forename: J B
authors.initials: JB
authors.lastname: Prins
authors.forename: N A
authors.initials: NA
authors.lastname: Bright
authors.forename: D R
authors.initials: DR
authors.lastname: Johnson
authors.forename: K
authors.initials: K
authors.lastname: Wolfreys
authors.forename: J S
authors.initials: JS
authors.lastname: Pober
authors.forename: S
authors.initials: S
authors.lastname: O'Rahilly
authors.forename: J R
authors.initials: JR
authors.lastname: Bradley
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000378:metabolism* / Q000648:ultrastructure; D000911:Antibodies, Monoclonal; D002352:Carrier Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D006801:Humans; D007150:Immunohistochemistry; D007425:Intracellular Membranes / Q000378:metabolism* / Q000648:ultrastructure; D007457:Iodine Radioisotopes; D008247:Lysosomes / Q000378:metabolism / Q000648:ultrastructure; D016253:Microscopy, Immunoelectron; D008928:Mitochondria / Q000378:metabolism* / Q000648:ultrastructure; D018124:Receptors, Tumor Necrosis Factor / Q000032:analysis / Q000276:immunology; D047888:Receptors, Tumor Necrosis Factor, Type I; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D020298:U937 Cells
chemical_list: D000911:Antibodies, Monoclonal; D002352:Carrier Proteins; D007457:Iodine Radioisotopes; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha; C069521:recombinant human tumor necrosis factor-binding protein-1