title: Inhibition of ADP/ATP exchange in receptor-interacting protein-mediated necrosis.
abstract: Receptor-interacting protein (RIP) has been implicated in the induction of death receptor-mediated, nonapoptotic cell death. However, the mechanisms remain to be elucidated. Here we show that tumor necrosis factor alpha induced RIP-dependent inhibition of adenine nucleotide translocase (ANT)-conducted transport of ADP into mitochondria, which resulted in reduced ATP and necrotic cell death. The inhibition of ADP/ATP exchange coincided with the loss of interaction between ANT and cyclophilin D and the inability of ANT to adopt the cytosolic conformational state, which prevented cytochrome c release. Neither overexpression of Bcl-xL nor inhibition of reactive oxygen species prevented necrosis. In contrast, the ectopic expression of ANT or cyclophilin D was effective at preventing cell death. These observations demonstrate a novel mechanism initiated through death receptor ligation and mediated by RIP that results in the suppression of ANT activity and necrosis.
authors.affiliation: Division of Rheumatology, Northwestern University Feinberg School of Medicine, 240 E. Huron, Suite 2300, Chicago, IL 60611, USA.
authors.forename: Vladislav
authors.initials: V
authors.lastname: Temkin
authors.forename: Qiquan
authors.initials: Q
authors.lastname: Huang
authors.forename: Hongtao
authors.initials: H
authors.lastname: Liu
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Osada
authors.forename: Richard M
authors.initials: RM
authors.lastname: Pope
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000590:Amino Acid Chloromethyl Ketones / Q000378:metabolism / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000494:pharmacology; D003545:Cysteine / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007425:Intracellular Membranes; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D000226:Mitochondrial ADP, ATP Translocases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D009336:Necrosis; D010539:Permeability; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D000590:Amino Acid Chloromethyl Ketones; C494811:BCL2L1 protein, human; D000081406:Peptidyl-Prolyl Isomerase F; D015853:Cysteine Proteinase Inhibitors; D017382:Reactive Oxygen Species; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins; D014409:Tumor Necrosis Factor-alpha; D051020:bcl-X Protein; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D000226:Mitochondrial ADP, ATP Translocases; D017346:Protein Serine-Threonine Kinases; C506249:RIPK1 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D021983:Cyclophilins; D003545:Cysteine