Caspase Independent Pathways

AIF represents another component of the intrinsic cell death mechanism. However, this pathway does not require the activation of caspases. AIF normally functions as an oxidoreductase in mitochondria, and knockdown of AIF is associated with impaired oxidative phosphorylation and cerebellar granule cell degeneration during aging (163,164). Oxidative damage of DNA can cause AIF to be translocated to the nucleus, where it initiates large-scale DNA fragmentation and cell death (Fig. 3). The exact mechanism involved in the execution of AIF-induced DNA fragmentation is not known, although endonuclease G is postulated to be involved in some forms of cell death (165,166). Release of AIF can be suppressed by Bcl-2 (167), and crosstalk signaling between the AIF and the caspase-dependent cell death pathways likely occurs at various levels of signaling. Increased nuclear AIF has been reported after hypoxia-ischemia in immature rats (168 ), global ischemia in mature rats (169 ), and hypoglycemia (170). With NMDA-induced excitotoxicity in neurons, AIF translocation to the nucleus occurs rapidly and depends on activation of poly(ADP-ribose) polymerase (PARP) activity (171,172). In contrast, AMPA-induced injury is not dependent on PARP activation (173). PARP-1 normally participates in DNA repair by temporarily elongating the helical strands to permit access by other repair enzymes. However, hyperactivation of this DNA repair enzyme from excessive DNA damage leads to formation of an abundant amount of poly(ADP-ribose) (PAR) and consumption of NAD+. Moreover, hyperactivation of PARP-1 can cause mitochondrial state 4 respiration, followed by loss of mitochondrial membrane potential and release of AIF and cytochrome c (174). Release of PAR from the nucleus is involved in triggering release of AIF from the nucleus (175). Partial neuroprotection after cardiac arrest by PARP-1 gene deletion supports a role for PARP-1 in global ischemic cell death (176), although another PARP isoform, PARP-2, may have a different functional role (177). Because some of the injury from global ischemia is dependent on AMPA receptor activation and because AMPA-mediated excitotoxicity does not depend on PARP activation, the precise role of PARP enzymes and AIF in mediating neuronal death in global cerebral ischemia in vivo remains to be elucidated.

A mechanism of regulated cell death with necrotic morphology has been identified in the TNF-a extrinsic pathway that is independent of caspases, mitochondria transition pore, PARP, and AIF (178). This pathway has been implicated in focal ischemic injury, but its role in global ischemia is yet to be explored.

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