Specific organelles, including mitochondria and the ER, have been identified as critical for the apoptotic process. In seminal work by Li, Wang, and colleagues, it was discovered that the mitochondrion integrates death signals engaged by proteins in the Bcl-2 family and releases molecules residing in the mitochondrial intermembrane space, such as cytochrome c, that complexes with cytoplasmic proteins (e.g., apoptotic protease activating factor 1, Apaf1) to activate caspase proteases leading to internucleosomal cleavage of DNA (Figure 1 and Figure 2) [125,126]. The ER, which regulates intracellular Ca2+ levels, participates in a loop with mitochondria to modulate mPT and cytochrome c release through the actions of Bcl-2 protein family members (Figure 1) [130].