Compromised mitochondrial function irreversibly leads to cell death in both a caspase-dependent and -independent manner (Fig. 2.1). Mitochondrial breakdown is mainly the consequence of either extrinsic or intrinsic signals. Caspase-independent processes induce mitochondrial outer membrane permeabilization (MOMP). Although the precise mechanisms remain controversial, the involvement of Bcl-2 family proteins, among them the BH3-only proteins, is crucial in triggering MOMP (Green and Kroemer 2004). BH3-only proteins either activate or inhibit (Bcl-2 and Bcl-xL) the proapoptotic Bcl-2 family members Bax and Bak. Oligomerization of these proteins generates pores in the outer membrane of mitochondria, releasing cell death factors from the intermembrane space to the cytoplasm (Kim et al. 2006). The process of MOMP initiated through Bax and Bak has been investigated intensively (Antignani and Youle 2006).
The C. elegans gene ced-9 has been identified as an ortholog of the antiapoptotic members of the Bcl-2 family. CED-9 is anchored to the membrane of mitochondria and acts upstream of CED-3 and CED-4, negatively regulating the caspase-dependent cell death machinery (Igaki and Miura 2004). On the other hand, egl-1 encodes a protein that belongs to the BH3-only protein subfamily also functioning upstream of CED-3 and CED-4, inducing cell death. CED-4 is released from the CED-4/CED-9 complex, which is localized to mitochondria by EGL-1, inducing caspase-dependent cell death (del Peso et al. 2000; Lettre and Hengartner 2006).
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