Article
- The EMBO Journal (2005) 24, 1546 - 1556
- doi:10.1038/sj.emboj.7600592
Published online: 24 March 2005
Subject Categories:
Endoplasmic reticulum BIK initiates DRP1-regulated remodelling of mitochondrial cristae during apoptosis
Marc Germain1,a, Jaigi P Mathai1,a, Heidi M McBride2 and Gordon C Shore1,3
- Department of Biochemistry, McGill University, Montréal, QC, Canada
- University of Ottawa Heart Institute, Ottawa, ON, Canada
- McGill Cancer Center, McGill University, Montréal, QC, Canada
Correspondence to:
Gordon C Shore, Department of Biochemistry, McIntyre Medical Sciences Building, McGill University, Montreal, Quebec, Canada H3G 1Y6. Tel.: +1 514 398 7282; Fax: +1 514 398 7384; E-mail: gordon.shore@mcgill.ca
Heidi M McBride, University of Ottawa Heart Institute, Ottawa, ON, Canada K1Y 4W7. Tel.:+1 613 761 4701; Fax: +1 613 761 5281; E-mail: hmcbride@ottawaheart.ca
aThese authors contributed equally to this work
Received 25 June 2004; Accepted 1 February 2005
Abstract
The endoplasmic reticulum (ER) can elicit proapoptotic signalling that results in transmission of Ca2+ to the mitochondria, which in turn stimulates recruitment of the fission enzyme DRP1 to the surface of the organelle. Here, we show that BH3-only BIK activates this pathway at the ER in intact cells, resulting in mitochondrial fragmentation but little release of cytochrome c to the cytosol. The BIK-induced transformations in mitochondria are dynamic in nature and involve DRP1-dependent remodelling and opening of cristae, where the major stores of cytochrome c reside. This novel function for DRP1 is distinct from its recognized role in regulating mitochondrial fission. Selective permeabilization of the outer membrane with digitonin confirmed that BIK stimulation results in mobilization of intramitochondrial cytochrome c. Of note, BIK can cooperate with a weak BH3-only protein that targets mitochondria, such as NOXA, to activate BAX by a mechanism that is independent of DRP1 enzyme activity. When expressed together, BIK and NOXA cause rapid release of mobilized cytochrome c and activation of caspases.
Keywords:
- Bax,
- calcium,
- caspase,
- fission,
- NOXA
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