Living with death: the evolution of the mitochondrial pathway of apoptosis in animals

Abstract

The mitochondrial pathway of cell death, in which apoptosis proceeds following mitochondrial outer membrane permeabilization, release of cytochrome c, and APAF-1 apoptosome-mediated caspase activation, represents the major pathway of physiological apoptosis in vertebrates. However, the well-characterized apoptotic pathways of the invertebrates C. elegans and D. melanogaster indicate that this apoptotic pathway is not universally conserved among animals. This review will compare the role of the mitochondria in the apoptotic programs of mammals, nematodes, and flies, and will survey our knowledge of the apoptotic pathways of other, less familiar model organisms in an effort to explore the evolutionary origins of the mitochondrial pathway of apoptosis.

Figure 1

Mammalian cytochrome-c dependent apoptotic pathways and their homologs in flies and worms. Leftmost panel depicts the proteins upstream and downstream of cytochrome c release in mammals. Panels on the right show homologs of these proteins found in Drosophila and C.elegans; the degree to which homologs conserve the function of their mammalian counterparts varies, and is summarized in the text. Cytochrome c release is controversial in the fly, and is not observed in the worm. Note that this figure depicts only cytochrome c dependent caspase activation; effects of IAPs and their inhibitors, as well as other released mitochondrial factors, are omitted.

Figure 2

Animal phylogeny. MOMP is well characterized only in vertebrates. The apoptotic programs of the nematode ecdysozoan C.elegans and the arthropod ecdysozoan D.melanogaster have been studied extensively, and show varying degrees of mitochondrial involvement but lack direct evidence of MOMP. This leaves open the question of whether MOMP arose in vertebrates, or arose earlier but was lost in ecdysozoans. Much-need additional information from more basal phyla is emerging (surveyed in the text).