On the evolutionary conservation of the cell death pathway: Mitochondrial release of an apoptosis-inducing factor during Dictyostelium discoideum cell death

Mitochondria play a pivotal role in apoptosis in multicellular organisms by releasing apoptogenic factors such as cytochrome c that activate the caspa ses effector pathway, and apoptosis-inducing factor (AIF) that is involved in a caspase-independent cell death pathway. Here we report that cell death in the single-celled organism Dictyostelium discoideum involves early disr uption of mitochondrial transmembrane potential (Delta Psim) that precedes the induction of several apoptosis-like features, including exposure of the phosphatidyl residues at the external surface of the plasma membrane, an i ntense vacuolization, a fragmentation of DNA into large fragments, an autop hagy, and the release of apoptotic corpses that are engulfed by neighboring cells. We have cloned a Dictyostelium homolog of mammalian AT that is loca lized into mitochondria and is translocated from the mitochondria to the cy toplasm and the nucleus after the onset of cell death. Cytoplasmic extracts from dying Dictyostelium cells trigger the breakdown of isolated mammalian and Dictyostelium nuclei in a cell-free system, and this process is inhibi ted by a polyclonal antibody specific for Dictyostelium discoideum apoptosi s-inducing factor (DdAIF), suggesting that DdAIF is involved in DNA degrada tion during Dictyostelium cell death. Our findings indicate that the cell d eath pathway in Dictyostelium involves mitochondria and an AIF homolog, sug gesting the evolutionary conservation of at least part of the cell death pa thway in unicellular and multicellular organisms.