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-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.

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

This work was supported by National Institutes of Health grants AR049217 and AR048269 to R.M.P.

We thank M. Paniaqua and L. Reynolds from the Robert Lurie Cancer Center for assistance with flow cytometry and electron microscopy and N. Chandel and K. Machida for helpful discussions.