BAX and BAK Regulation of Endoplasmic Reticulum Ca2+: A Control Point for Apoptosis
Luca Scorrano,12*
Scott A. Oakes,1*
Joseph T. Opferman,1
Emily H. Cheng,1
Mia D. Sorcinelli,1
Tullio Pozzan,23
Stanley J. Korsmeyer1
BAX and BAK are "multidomain" proapoptotic proteins
that initiate mitochondrial dysfunction but also localize to the
endoplasmic reticulum (ER). Mouse embryonic fibroblasts deficient for
BAX and BAK (DKO cells) were found to have a reduced resting
concentration of calcium in the ER ([Ca2+]er)
that results in decreased uptake of Ca2+ by mitochondria
after Ca2+ release from the ER. Expression of SERCA
(sarcoplasmic-endoplasmic reticulum Ca2+ adenosine
triphosphatase) corrected [Ca2+]er and
mitochondrial Ca2+ uptake in DKO cells, restoring apoptotic
death in response to agents that release Ca2+ from
intracellular stores (such as arachidonic acid,
C2-ceramide, and oxidative stress). In contrast, targeting
of BAX to mitochondria selectively restored apoptosis to "BH3-only"
signals. A third set of stimuli, including many intrinsic signals,
required both ER-released Ca2+ and the presence of
mitochondrial BAX or BAK to fully restore apoptosis. Thus, BAX and BAK
operate in both the ER and mitochondria as an essential gateway for
selected apoptotic signals.
1 Howard Hughes Medical Institute, Dana-Farber
Cancer Institute, Brigham and Women's Hospital, Department of
Pathology and Medicine, Harvard Medical School, Boston, MA 02115, USA.
2 Venetian Institute for Molecular Medicine, 35121 Padova, Italy.
3 Department of Biomedical Sciences,
University of Padova, 35121 Padova, Italy.
*
These authors contributed equally to this work.
To whom correspondence should be addressed. E-mail:
stanley_korsmeyer{at}dfci.harvard.edu
