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Mol. Cell. Biol. 26 (6): 2215-2225

Copyright © 2006 by the American Society for Microbiology. All rights reserved.

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

Vladislav Temkin,1 Qiquan Huang,1 Hongtao Liu,1 Hiroyuki Osada,2, and Richard M. Pope1,3*

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 for publication 31 August 2005. Revision received 18 October 2005. Accepted for publication 21 December 2005.

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.

* Corresponding author. Mailing address: Division of Rheumatology, Northwestern University Feinberg School of Medicine, 240 E. Huron, Suite 2300, Chicago, IL 60611. Phone: (312) 503-8003. Fax: (312) 503-0994. E-mail: rmp158{at}northwestern.edu.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

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