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

• Published in: The EMBO journal Vol. 28; no. 12; pp. 1757 - 1768
• Main Authors: Klee, Martina, Pallauf, Kathrin, Alcalá, Sonia, Fleischer, Aarne, Pimentel-Muiños, Felipe X
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 17.06.2009; Nature Publishing Group UK; Blackwell Publishing Ltd; Nature Publishing Group
• Subjects: Animals; Apoptosis; Apoptosis - drug effects; Apoptosis Regulatory Proteins - metabolism; Bak; bcl-2 Homologous Antagonist-Killer Protein - metabolism; Bcl-2-Like Protein 11; Calcium; Calcium - pharmacology; Calcium Signaling - drug effects; Cell Line; Cytochrome; Cytochromes b5 - metabolism; Cytochromes c - metabolism; EMBO07; EMBO37; endoplasmic reticulum; Endoplasmic Reticulum - drug effects; Endoplasmic Reticulum - metabolism; Enzyme Activation - drug effects; ER-to-mitochondria apoptotic communication; Fibroblasts - cytology; Fibroblasts - metabolism; Gene expression; Humans; JNK Mitogen-Activated Protein Kinases - metabolism; Membrane Proteins - metabolism; Mice; Mitochondria - drug effects; Mitochondria - enzymology; Mitochondria - metabolism; mitochondrial apoptosis; Molecular biology; Protein Transport - drug effects; Protein-Serine-Threonine Kinases - metabolism; Proteins; Proto-Oncogene Proteins - metabolism; Signal transduction; Stress, Physiological - drug effects; TNF Receptor-Associated Factor 2 - metabolism; Tumor Suppressor Proteins - metabolism; ER‐to‐mitochondria apoptotic communication; Bak; endoplasmic reticulum; mitochondrial apoptosis
• ISSN: 0261-4189; 1460-2075
• DOI: 10.1038/emboj.2009.90

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 IRE1α/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.