Mitochondria have important roles in cellular energy generating processes. However, in cellular stress, mitochondria participate in cell death signaling by releasing pro-death proteins such as cytochrome c, AIF, Smac/Diablo, and Omi/ HtrA2 (Green and Kroemer 2004; Newmeyer and Ferguson-Miller 2003; Suzuki et al. 2001; Verhagen et al. 2000). Among these, Smac/Diablo and Omi/HtrA2 proteins act as inhibitors of cytosolic inhibitor apoptosis proteins (IAPs), which act by inhibiting caspase 9, 3, and 7 (Richter and Duckett 2000). Thus, the release of Smac/Diablo and Omi/HtrA2 into cytoplasm ensures that the brake that IAPs provide on caspase activation is removed. Release of cytochrome c in the cytosol leads to apaf-1 binding and initiates cell death through assembly of the apoptosome complex. Besides cytochrome c and Apaf-1, the apoptosome requires pro-caspase 9 (initiator caspase) and dATP. In this complex, caspase 9 gets cleaved and activated, which in turn activates downstream caspases that include the effector caspase, cas-pase 3. Active caspase 3 has many cellular substrates, including alpha foldrin, PARP-1, PMCA (plasma membrane Ca2+ pump) and ICAD (Inhibitor of caspase-activated DNase). CAD (caspase-activated DNase) is normally sequestered to an inactive form in a complex with ICAD (CAD-ICAD complex). On ICAD degradation by caspases, CAD is activated to induce large scale DNA-fragmentation and cell death (Liu et al. 1997; Sakahira et al. 1998).
AIF, on the other hand, does not seem to activate a proteolytic cascade but it directly translocates to the nucleus to initiate large scale chromatin condensation and caspase-independent cell death (Cregan et al. 2004; Krantic et al. 2007; Modjtahedi et al. 2006; Wang et al. 2004; Yu et al. 2002). In certain models of cell death, AIF release from mitochondria can be mediated through caspase activation. AIF is a mitochondrial flavoprotein with important functions in oxidative phosphorylation (Pospisilik et al. 2007). Originally, AIF was discovered as a death inducing factor (Susin et al. 1999). Numerous studies have clearly demonstrated that AIF induces cell death upon its translocation to the nucleus (Krantic et al. 2007; Modjtahedi et al. 2006). AIF as a cell death effector in PARP-1 toxicity became evident through studies using AIF-neutralizing antibodies or genetic knock down of AIF (Culmsee et al. 2005; Yu et al. 2006; Yu et al. 2002). In the mitochondria, AIF is involved in oxidative phosphorylation and energy production. Although mitochondrial localization of AIF is required for cell survival, recent studies indicate that nuclear translocation is a required factor to induce cell death and chromatin condensation. Along these lines, it was shown that recombinant AIF induced nuclear shrinkage in isolated nuclear preparations, which strengthens the concept that AIF is a factor that induces chromatin condensation. It still remains unclear how AIF induces chromatin condensation given that AIF has no intrinsic nuclease activity and nuclear AIF translocation is required for chromatin condensation and PARP-1 dependent cell death. It is likely that AIF in the nucleus activates certain proteins that either directly act as nucleases or indirectly activate nuclear condensation systems. PARP-1 activation induces mitochondrial AIF release through PAR polymer acting as a death signal. PAR is generated in the nucleus and signals the mitochondria to release AIF. It is not yet clear how PAR induces AIF release. Recent data suggests that PARP-1 activation induces mitochondrial permeability transition (mPT). Inhibition of mPT protects against PARP-1 dependent cell death (Alano et al. 2004; Cregan et al. 2004). It remains to be determined how PARP-1 activation induces mPT and whether mPT is critical for AIF release. The data that PAR in the cytosol localizes with mitochondria and induces AIF release hints at the role of PAR as a mediator of mPT. Recent discoveries also suggest that BAX/BAK activation is a required factor for AIF release (Arnoult et al. 2003; Arnoult et al. 2002). However, it remains to be determined whether BAX/BAK and mPT are activated as a consequence of PARP-1 toxicity or whether they act as by-standers in PARP-1 dependent cell death. The intriguing aspect emerging from these studies is how PAR is related to BAX/BAK and mPT activation in PARP-1 toxicity and mitochondrial AIF release (Fig. 5.3).
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