al., 2001; Wang et al., 2001). Annis et al. (2002) observed that Bcl-2cb5 confers
protection against apoptotic stimuli (Myc, C2 ceramide) that cause an obvious
mitochondrial depolarization prior to the release of Cyt.c, but not against stimuli
that induce Cyt.c in the absence of large mitochondrial depolarizations. Therefore,
Ca2+ exchange between the two organelles may be required for Cyt.c release in some,
but not all, pathways. Of note, Lee et al. (1999) could not detect ER Ca2+ release
during Myc-induced apoptosis, but Bcl-2cb5 still blocked Cyt.c release and apoptosis,
suggesting that in some cases ER-mitochondria cross-talk might be mediated by other
Figure 2. Regulation of the mitochondrial phase of apoptosis by ER Ca2+ spikes.
Mitochondria are sensitized to PTP opening by proapoptotic stimuli, possibly mediated by
BH3-only proteins. Apoptotic stimuli may also activate clusters of IP 3 R or RyR channels at
the ER, generating Ca2+ spikes. The elevated [Ca2+]c at ER-mitochondria junctions activates
the IMM uniporter (UP), leading to accumulation of Ca2+ in the mitochondrial matrix. Bcl-2
prevents ER Ca2+ release either directly or by lowering the steady-state [Ca2+]ER. The high
mitochondrial Ca2+ load activates PTP opening, facilitating BH3-only protein-dependent
cristae remodeling and release of Cyt.c into unstructured regions of the IMS. Cyt.c (circles)
and other IMS proteins, including SMAC, endonuclease G, and AIF, may traverse the OMM
through BAX/BAK pores and activate cytosolic caspases and degradation of nuclear DNA.
Alternatively, IMS proteins may be released through BAX/VDAC channels, or by
mitochondrial swelling and OMM rupture caused by solute uptake during PTP opening.
Opening of the PTP also releases mitochondrial Ca2+, which is taken up by neighboring
mitochondria, propagating an apoptotic wave of mitochondrial transition throughout the cell.
THE ROLE OF THE ENDOPLASMIC RETICULUM IN APOPTOSIS 113