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Molecular and Cellular Biology, March 2006, p. 2215-2225, Vol. 26, No. 6
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.6.2215-2225.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

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

Division of Rheumatology, Department of Medicine, Northwestern University Feinberg School of Medicine,¹ Jesse Brown Veteran Administration Medical Center, Chicago, Illinois,³ Antibiotics Laboratory, Discovery Research Institute, RIKEN, Wako, Saitama 351-0198, Japan²

Received 31 August 2005/ Returned for modification 18 October 2005/ Accepted 21 December 2005

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-x_L 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.

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