Autophagic cell death: the story of a misnomer

Abstract

Dying cells often display a large-scale accumulation of autophagosomes and hence adopt a morphology called autophagic cell death. In many cases, it is agreed that this autophagic cell death is cell death with autophagy rather than cell death by autophagy. Here, we evaluate the accumulating body of literature that argues that cell death occurs by autophagy. We also list the caveats that must be considered when deciding whether or not autophagy is an important effector mechanism of cell death.

Figure 1. ‘cell death with autophagy’ versus ‘cell death by autophagy’

In both scenarios, a death stimulus results in morphological features of autophagy, and in both cases, pharmacological or genetic inhibitors of autophagy block these morphological features. a | In cell death with autophagy, the inhibition of autophagy does not alter the fate of the cell (that is, cell death), although it might change the kinetics of this fate and the morphological appearance of the dying cell, as well as the read-outs of some assays used to measure cell death, the type of cell death pathway used by the cell and/or the rate of degradation of the cell. If inhibition of autophagy accelerates cell death, autophagy is considered to be a pro-survival pathway in the dying cell. b | If cell death were to occur by autophagy, the inhibition of autophagy would alter the fate of the cell and result in long-term cellular survival. Note that the blockade of autophagy only leads to the disappearance of autophagosomes if it intervenes at the level of autophagosome formation.