Inhibition of ADP/ATP exchange in receptor-interacting protein-mediated necrosis

Vladislav Temkin, Qiquan Huang, Hongtao Liu, Hiroyuki Osada, Richard M. Pope*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

159 Scopus citations

Abstract

Receptor-interacting protein (RIP) has been implicated in the induction of death receptor-mediated, non-apoptotic 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 over expression 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.

Original languageEnglish (US)
Pages (from-to)2215-2225
Number of pages11
JournalMolecular and cellular biology
Volume26
Issue number6
DOIs
StatePublished - Mar 2006

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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