An AIF orthologue regulates apoptosis in yeast

Abstract

Apoptosis-inducing factor (AIF), a key regulator of cell death, is essential for normal mammalian development and participates in pathological apoptosis. The proapoptotic nature of AIF and its mode of action are controversial. Here, we show that the yeast AIF homologue Ynr074cp controls yeast apoptosis. Similar to mammalian AIF, Ynr074cp is located in mitochondria and translocates to the nucleus of yeast cells in response to apoptotic stimuli. Purified Ynr074cp degrades yeast nuclei and plasmid DNA. YNR074C disruption rescues yeast cells from oxygen stress and delays age-induced apoptosis. Conversely, overexpression of Ynr074cp strongly stimulates apoptotic cell death induced by hydrogen peroxide and this effect is attenuated by disruption of cyclophilin A or the yeast caspase YCA1. We conclude that Ynr074cp is a cell death effector in yeast and rename it AIF-1 (Aif1p, gene AIF1).

Cavitation of embryoid bodies requires optimal oxidative phosphorylation and AIF

“…These cells are identifiable as macrophages by their stereotypic distribution and enormous size, and by doubly labeling for Croquemort (Figure 1e), a macrophage-specific cell surface marker. 11,12 Identical results were obtained using the mitochondrial marker TMRE (not shown).…”

“…These results are consistent with observations by us and others that following exposure to UV irradiation, Croquemort-positive cells in the embryo become quite large owing to multiple engulfment events (R Hays, unpublished finding). 11 One would expect macrophages to undergo apoptosis like any other cell type, having been exposed to the same dose of radiation. However, they survive to engulf corpses for a period of at least several hours.…”

“…7 The AIF gene has been knocked out or knocked down in several species including in human cell lines, 8 mice, 9 Caenorhabditis elegans 10 and Saccharomyces cerevisiae. 11 In yeast, the knockout of AIF leads to a partial resistance to oxidative stress and influences replicative aging. 11 In nematodes, the knockdown of AIF leads to reduction of developmental cell death, in particular, in animals that bear loss-of-function mutations of caspases.…”

Mitochondrial factors with dual roles in death and survival

“…To the contrary, yeast Drp1/Dnm1 also promotes programmed cell death in yeast Ivanovska and Hardwick, 2005). Similarly, the yeast homologue of AIF promotes cell death in yeast (Vahsen et al, 2004;Wissing et al, 2004). These examples provide new evidence that indeed programmed cell death is an ancient process.…”

Redundant cell death mechanisms as relics and backups

“…A popular, plausible 46 yet speculative 47 scenario states that the ancestral cell death mechanism (which may have resembled 'necrosis') might stem from the intrusion of the bacterial precursor of the mitochondrion (the endosymbiont) into the precursor of the eukaryotic cell. In favor of the mitochondrial involvement in the emergence of cell death, it appears that some of the mitochondrial proteins which can be involved in mammalian cell death (such as AIF, cytochrome c, and the serine protease HtrA2/Omi) and in yeast cell death (AIF1) 48 are present in the genome of bacterial ancestors of mitochondria, 46,49 as are the evolutionary ancestors of caspases, the meta-caspases. 46 As additions to such an ancestral cell death mechanism, while autophagy emerged in evolution before apoptosis and possibly initially only as a restorative pathway, both apoptosis and autophagy might have entered cell death pathways at the dismantling stage, in order to facilitate the disposal of cell corpses ( Figure 3).…”