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Article

  • The EMBO Journal (2009) 28, 1757 - 1768
  • doi:10.1038/emboj.2009.90

Published online: 2 April 2009

Mitochondrial apoptosis induced by BH3-only molecules in the exclusive presence of endoplasmic reticular Bak

Martina Klee1, Kathrin Pallauf1, Sonia Alcalá1, Aarne Fleischer1 and Felipe X Pimentel-Muiños1

  1. Instituto de Biología Molecular y Celular del Cáncer, Centro de Investigación del Cáncer, CSIC-Universidad de Salamanca, Salamanca, Spain

Correspondence to:

Felipe X Pimentel-Muiños, Instituto de Biología Molecular y Celular del Cáncer, Centro de Investigación del Cáncer, CSIC-Universidad de Salamanca, Campus Miguel de Unamuno, Salamanca 37007, Spain. Tel.: +34 923 294 818; Fax: +34 923 294 795; E-mail: fxp@usal.es

Received 7 June 2008; Accepted 13 March 2009

Bak and Bax are critical apoptotic mediators that naturally localize to both mitochondria and the endoplasmic reticulum (ER). Although it is generally accepted that mitochondrial expression of Bak or Bax suffices for apoptosis initiated by BH3-only homologues, it is currently unclear whether their reticular counterparts may have a similar potential. In this study, we show that cells exclusively expressing Bak in endoplasmic membranes undergo cytochrome c mobilization and mitochondrial apoptosis in response to BimEL and Puma, even when these BH3-only molecules are also targeted to the ER. Surprisingly, calcium was necessary but not sufficient to drive the pathway, despite normal ER calcium levels. We provide evidence that calcium functions coordinately with the ER-stress surveillance machinery IRE1alpha/TRAF2 to transmit apoptotic signals from the reticulum to mitochondria. These results indicate that BH3-only mediators can rely on reticular Bak to activate an ER-to-mitochondria signalling route able to induce cytochrome c release and apoptosis independently of the canonical Bak,Bax-dependent mitochondrial gateway, thus revealing a new layer of complexity in apoptotic regulation.

  • Keywords:

    • Bak,
    • endoplasmic reticulum,
    • ER-to-mitochondria apoptotic communication,
    • mitochondrial apoptosis