Abstract
Under stress conditions, apoptogenic factors normally sequestered in the mitochondrial intermembrane space are released into the cytosol, caspases are activated and cells die by apoptosis. Although the precise mechanism that leads to the permeabilization of mitochondria is still unclear, the activation of multidomain pro-apoptotic proteins of the Bcl-2 family, such as Bax and Bak, is evidently crucial. Regulation of Bax and Bak by other members of the family has been known for a long time, but recent evidence suggests that additional unrelated proteins participate in the process, both as inhibitors and activators. The important rearrangements mitochondrial lipids undergo during apoptosis play a role in the permeabilization process and this role is probably more central than first envisioned.
Highlights
Programmed cell death is essential for the development of multicellular organisms, for tissue homeostasis, and to eliminate damaged and infected cells
Every mammalian cell type seems to require the expression of at least one anti-apoptotic Bcl-2-like protein to survive (Ranger et al, 2001). These proteins can protect cells from apoptosis at multiple levels (Cory et al, 2003; Gross et al, 1999). They can sequester BH3-only factors (Fig. 2B) (Cheng et al, 2001), and even though they do not appear to bind to inactive Bax and Bak, they can neutralize them if the latter have undergone conformational changes resulting in the exposure of their N-terminal domains, preventing their oligomerization and the release of apoptogenic factors from mitochondria (Desagher et al, 1999; Hsu and Youle, 1997; Perez and White, 2000; Ruffolo and Shore, 2003)
Cell death that follows the overexpression of mtCLIC/CLIC4 is independent of Bax but is inhibited by Bcl-2 (Suh et al, 2004), and downregulation of mtCLIC/CLIC4 inhibits p53-induced cell death (Fernandez-Salas et al, 2002). mtCLIC/CLIC4 could promote classical intrinsic apoptotic
Summary
Apoptogenic factors normally sequestered in the mitochondrial intermembrane space are released into the cytosol, caspases are activated and cells die by apoptosis. The precise mechanism that leads to the permeabilization of mitochondria is still unclear, the activation of multidomain pro-apoptotic proteins of the Bcl-2 family, such as Bax and Bak, is crucial. Regulation of Bax and Bak by other members of the family has been known for a long time, but recent evidence suggests that additional unrelated proteins participate in the process, both as inhibitors and activators. The important rearrangements mitochondrial lipids undergo during apoptosis play a role in the permeabilization process and this role is probably more central than first envisioned
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