Intrinsic apoptosis is evolutionarily divergent among metazoans

Apoptosis is regulated cell death that depends on caspases. Upstream of each apoptotic signalling pathway is involved a specific initiator caspase. Characterised in nematode, fly and mammals, intrinsic apoptosis is considered to be ancestral and conserved among animals, and depends on shared initiators; caspase-9, Apaf-1 and Bcl-2. However, the biochemical role of mitochondria, the pivotal function of cytochrome c and the modality of caspase activation remain highly heterogeneous and hide profound molecular divergences among apoptotic pathways in animals. Uncovering the phylogenetic history of apoptotic actors, especially caspases, is crucial to shed light on intrinsic apoptosis evolutionary history. Here, we demonstrate by phylogenetic analyses, that caspase-9, the fundamental key of intrinsic apoptosis, is deuterostome-specific, while caspase-2 is ancestral to bilaterians. Our analysis of Bcl-2 and Apaf-1 confirm heterogeneity in functional organisation of apoptotic pathways in animals. Our results support emergence of distinct intrinsic apoptotic pathways during metazoan evolution.