Mammalian Bcl2 family proteins regulate the intrinsic pathway of apoptosis mainly by controlling the release of cytochrome c and other intermembrane mitochondrial proteins into the cytosol. Some Bcl2 family proteins are pro-apoptotic and promote apoptosis by enhancing the release, whereas others are antiapoptotic and inhibit apoptosis by blocking the release. The pro-apoptotic and anti-apoptotic proteins can bind to each other in various combinations to form heterodimers in which the two proteins inhibit each other’s function. The balance between the activities of these two functional classes of Bcl2 family proteins largely determines whether a mammalian cell lives or dies by the intrinsic pathway of apoptosis.
As illustrated in Figure 18–8, the anti-apoptotic Bcl2 family proteins, including Bcl2 itself (the founding member of the Bcl2 family) and BclXL, share four distinctive Bcl2 homology (BH) domains (BH1–4). The pro-apoptotic Bcl2 family proteins
Figure 18–6 Release of cytochrome c from mitochondria in the intrinsic pathway of apoptosis. Fluorescence micrographs of human cancer cells in culture. (A) the control cells were transfected with a gene encoding a fusion protein consisting of cytochrome c linked to green fluorescent protein (cytochromec-GFp); they were also treated with a red dye that accumulates in mitochondria. the overlapping distribution of the green and red indicates that the cytochromec-GFp is located in mitochondria.
(B) Cells expressing cytochrome-c-GFp were irradiated with ultraviolet (UV) light to induce the intrinsic pathway of apoptosis and were photographed 5 hours later. the six cells in the bottom half of this micrograph have released their cytochrome c from mitochondria into the cytosol, whereas the cells in the upper half of the micrograph have not yet done so  (Movie 18.1). (From J.C. Goldstein et al., Nat. Cell Biol. 2:156–162, 2000. With permission from Macmillan publishers Ltd.) activation of caspase-9, which cleaves and thereby activates executioner caspases
Figure 18–7 The intrinsic pathway of apoptosis. Intracellular apoptotic stimuli cause mitochondria to release cytochrome c, which interacts with Apaf1. the binding of cytochrome c causes Apaf1 to unfold partly, exposing a domain that interacts with the same domain in other activated Apaf1 molecules. Seven activated Apaf1 proteins form a large ring complex called the apoptosome. Each Apaf1 protein contains a caspase recruitment domain (CArD), and these are clustered above the central hub of the apoptosome. the CArDs bind similar domains in multiple caspase-9 molecules, which are thereby recruited into the apoptosome and activated. the mechanism of caspase-9 activation is not clear: it probably results from dimerization and cleavage of adjacent caspase-9 proteins, but it might also depend on interactions between caspase-9 and Apaf1. Once activated, caspase-9 cleaves and thereby activates downstream executioner caspases. Note that the CArD is related in structure  and function to the death effector domain of caspase-8 (see Figure 18–5). Some scientists use the term “apoptosome” to refer to the complex containing caspase-9.
(e.g., Bcl2, BclXL) (e.g., Bax, Bak) (e.g., Bad, Bim,
Bid, Puma, Noxa) consist of two subfamilies—the effector Bcl2 family proteins and the BH3-only proteins. The main effector proteins are Bax and Bak, which are structurally similar to Bcl2 but lack the BH4 domain. The BH3-only proteins share sequence homology with Bcl2 in only the BH3 domain.