Endoplasmic reticulum BIK initiates DRP1-regulated remodelling of mitochondrial cristae during apoptosis.
The endoplasmic reticulum (ER) can elicit proapoptotic signalling that results in transmission of Ca(2+) 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.
Germain
Marc
M
Department of Biochemistry, McGill University, Montréal, QC, Canada.
Mathai
Jaigi P
JP
McBride
Heidi M
HM
Shore
Gordon C
GC
D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D002118:Calcium / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D045304:Cytochromes c / Q000378:metabolism; D034281:Dynamins; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D004789:Enzyme Activation; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism*; D008564:Membrane Potentials; D008565:Membrane Proteins / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism / Q000648:ultrastructure; D024101:Mitochondrial Proteins / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
D051017:Apoptosis Regulatory Proteins; C096820:BIK protein, human; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; C498702:PMAIP1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D045304:Cytochromes c; D020169:Caspases; D020558:GTP Phosphohydrolases; C110768:DNM1L protein, human; D034281:Dynamins; D002118:Calcium