Autophagy-dependent cell death: where, how and why a cell eats itself to death

Autophagy as a means of cell killing was first advanced by Clark's phenotypic description of 'Type II autophagic cell death' in 1990. However, this phenomenon later came into question, because the presence of autophagosomes in dying cells does not necessarily signify that autophagy is the cause of demise, but rather may reflect the efforts of the cell to prevent it. Resolution of this issue comes from a more careful definition of autophagy-dependent cell death (ADCD) as a regulated cell death that is shown experimentally to require different components of the autophagy machinery without involvement of alternative cell death pathways. Following these strict criteria, ADCD has been validated in both lower model organisms and mammalian cells, highlighting its importance for developmental and pathophysiological cell death. Recently, researchers have defined additional morphological criteria that characterize ADCD and begun to explore how the established, well-studied autophagy pathway is subverted from a survival to a death function. This Review explores validated models of ADCD and focuses on the current understanding of the mechanisms by which autophagy can kill a cell.