On the origins and evolution of apoptosis: the predator–mitochondrial prey hypothesis

Different types of programmed cell death (PCD) have been described both in unicellular and multicellular organisms. The fundamental mode of eukaryotic cell death is PCD initiated by mitochondria, which is frequently referred to as apoptosis (or mitochondrial apoptosis). It is initiated by mitochondria through mitochondrial permeability transition and the release of apoptotic factors. It is widely thought that mitochondrial apoptosis evolved concurrently with mitochondrial domestication. PCD initiated by mitochondria is observed in various multicellular and unicellular eukaryotes. We discuss key hypotheses-namely, the "pleiotropy," "addiction," "immunological," and our "predator-mitochondrial prey" hypotheses-to explain the mechanisms of mitochondrial domestication that lead to apoptosis. In this perspective paper, we present evidence from various phylogenetic and experimental studies that strongly indicate our hypothesis is the most plausible. For the first time, we also present evidence that challenges the assumptions underlying all other hypotheses.