Translocation of Apoptosis-Inducing Factor in Vulnerable Neurons after Transient Cerebral Ischemia and in Neuronal Cultures after Oxygen-Glucose Deprivation

Abstract

Loss of mitochondrial membrane integrity and the resulting release of apoptogenic factors may play a critical role in mediating hippocampal neurodegeneration after transient global ischemia. In the present study, the authors have cloned and characterized the rat cDNA encoding apoptosis-inducing factor (AIF), an intramitochondrial protein that promotes cell death in a caspase-independent manner upon release into nonmitochondrial compartments. In contrast to the expression patterns of a number of apoptosis-regulatory gene products during brain development, the expression of AIF protein increases gradually with brain maturation and peaks in adulthood. In a rat model of transient global ischemia, AIF was found to translocate from mitochondria to the nucleus in the hippocampal CA1 neurons after ischemia and to manifest a DNA-degrading activity that mimicked the purified AIF protein and was inhibitable by AIF immunodepletion. The temporal profile of AIF translocation after ischemia (24 to 72 hours) coincided with the induction of large-scale DNA fragmentation at the size of 50 kbp, a well-characterized hallmark of AIF-like activity but preceded the formation of internucleosomal DNA fragmentation (72 hours), a DNA degradation associated with the terminal stage of cell death. Further, the nuclear translocation of AIF after ischemia was not blocked by inhibiting caspase-3/-7 activities, but, as shown in neuronal cultures that were challenged with transient oxygen-glucose deprivation, it can be prevented by intracellular delivery of the mitochondria-associated antiapoptotic protein Bcl-xL. The results presented here strongly suggest that mitochondrial release of AIF may be an important factor, in addition to the previously reported cytochrome c and Smac, which could contribute to the selective vulnerability of CA1 neurons to transient global ischemic injury.

Cerebral Endothelial Cell Apoptosis after Ischemia—Reperfusion: Role of PARP Activation and AIF Translocation

“…Similarly, the earlier successes of PARP-1 inhibition or deletion strategies in reducing ischemic brain injury in vivo (Ding et al, 2001;Eliasson et al, 1997;Endres et al, 1997;Takahashi et al, 1999) may have their mechanistic basis in the secondary reduction in nuclear AIF translocation (Cao et al, 2003;Plesnila et al, 2004).…”

Irradiation-induced progenitor cell death in the developing brain is resistant to erythropoietin treatment and caspase inhibition

“…47 We observed increased nuclear translocation of AIF in irradiated TG-XIAP mice compared with WT animals. Translocation of AIF has been shown to correlate well with induction of cell death after hypoglycemia, 48 brain trauma 49 and after neonatal 24 as well as adult 23,50 ischemia. Seizure-induced, newborn neurons in the DG die, at least partly, through caspase-dependent mechanisms.…”

General versus Specific Actions of Mild-Moderate Hypothermia in Attenuating Cerebral Ischemic Damage

“…Conversely, proapoptotic proteins of the Bcl-2 family, Bax, Bid, and Bad, are highly expressed in dying cells after stroke (Graham and Chen, 2001). After ischemia, cytochrome c is released from the mitochondria into the cytosol causing caspase-9 and -3 activity, leading to apoptosis; apoptosis-inducing factor translocates from the mitochondria into the nuclei, generating large fragments of DNA (Cao et al, 2003;Colbourne et al, 1997;Graham and Chen, 2001;Zhao et al, 2004). However, other studies did not detect the typical apoptotic morphology of neuronal death in focal ischemia (van Lookeren Campagne and Gill, 1996) and global ischemia (Colbourne et al, 1999), and little convincing evidence for the protective effect of a caspase inhibitor has been reported.…”