Inhibition of ADP/ATP Exchange in Receptor-Interacting Protein-Mediated Necrosis

• DOI: 10.1128/mcb.26.6.2215-2225.2006
• Publication Date: 2006-03-01T00:02:41Z
• Authors: Vladislav Temkin; Qiquan Huang; Hongtao Liu; Hiroyuki Osada; Richard M. Pope
• Keywords: 0301 basic medicine; Cell Death; Biological Transport; Intracellular Membranes; Cysteine Proteinase Inhibitors; Protein Serine-Threonine Kinases; Permeability; Amino Acid Chloromethyl Ketones; Membrane Potentials; Mitochondria; Adenosine Diphosphate; Cyclophilins; Necrosis; 03 medical and health sciences; Adenosine Triphosphate; Receptor-Interacting Protein Serine-Threonine Kinases; Peptidyl-Prolyl Isomerase F; Humans; Cysteine; Reactive Oxygen Species; Mitochondrial ADP, ATP Translocases; Cells, Cultured

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.