Classic programmed cell death (PCD) involves activation of caspases. Increasing evidence, however, suggests that caspase-independent pathways also exist. Nuclear translocation of the mitochondrial flavoprotein apoptosis-inducing factor (AIF) might be key to one such pathway, but its role is controversial. Karl Csaky and co-workers now provide strong evidence for a caspase-independent AIF pathway in retinal pigment epithelial (RPE) cells,which undergo oxidative-stress-induced PCD in several degenerative diseases(see p. 1915). Comparing oxidant-induced PCD of U937 leukaemia cells and ARPE-19 RPE cells, the authors observe that U937 cells exhibit cleavage of caspase-3 and caspase-9 and DNA laddering – characteristics of caspase-dependent PCD. By contrast, they see none of this in ARPE-19 cells, although the cells show other signs of PCD,such as mitochondrial depolarization and membrane blebbing. Csaky and co-workers note that AIF translocates to the nucleus in the ARPE-19 cells and that this can be inhibited by pretreatment with hepatocyte growth factor(HGF/SCF), which...

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