title: Mitochondrial pathway of apoptosis is ancestral in metazoans.
abstract: The mitochondrial pathway of apoptosis is the major mechanism of physiological cell death in vertebrates. In this pathway, proapoptotic members of the Bcl-2 family cause mitochondrial outer membrane permeabilization (MOMP), allowing the release of cytochrome c, which interacts with Apaf-1 to trigger caspase activation and apoptosis. Despite conservation of Bcl-2, Apaf-1, and caspases in invertebrate phyla, the existence of the mitochondrial pathway in any invertebrate is, at best, controversial. Here we show that apoptosis in a lophotrochozoan, planaria (phylum Platyhelminthes), is associated with MOMP and that cytochrome c triggers caspase activation in cytosolic extracts from these animals. Further, planarian Bcl-2 family proteins can induce and/or regulate cell death in yeast and can replace Bcl-2 proteins in mammalian cells to regulate MOMP. These results suggest that the mitochondrial pathway of apoptosis in animals predates the emergence of the vertebrates but was lost in some lineages (e.g., nematodes). In further support of this hypothesis, we surveyed the ability of cytochrome c to trigger caspase activation in cytosolic extracts from a variety of organisms and found this effect in cytosolic extracts from invertebrate deuterostomes (phylum Echinodermata).
authors.affiliation: Apoptosis and Cell Death Program, Burnham Institute for Medical Research, La Jolla, CA 92037, USA.
authors.forename: Cheryl E
authors.initials: CE
authors.lastname: Bender
authors.forename: Patrick
authors.initials: P
authors.lastname: Fitzgerald
authors.forename: Stephen W G
authors.initials: SW
authors.lastname: Tait
authors.forename: Fabien
authors.initials: F
authors.lastname: Llambi
authors.forename: Gavin P
authors.initials: GP
authors.lastname: McStay
authors.forename: Douglas O
authors.initials: DO
authors.lastname: Tupper
authors.forename: Jason
authors.initials: J
authors.lastname: Pellettieri
authors.forename: Alejandro
authors.initials: A
authors.lastname: Sánchez Alvarado
authors.forename: Guy S
authors.initials: GS
authors.lastname: Salvesen
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Green
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D020169:Caspases / Q000378:metabolism; D002457:Cell Extracts; D045304:Cytochromes c / Q000378:metabolism; D004789:Enzyme Activation / Q000528:radiation effects; D005089:Exocytosis / Q000528:radiation effects; D005720:Gamma Rays; D008928:Mitochondria / Q000378:metabolism* / Q000528:radiation effects; D051336:Mitochondrial Membranes / Q000528:radiation effects; D010539:Permeability / Q000528:radiation effects; D010718:Phosphatidylserines / Q000378:metabolism; D010932:Planarians / Q000378:metabolism* / Q000528:radiation effects*; D021381:Protein Transport / Q000528:radiation effects; D012441:Saccharomyces cerevisiae / Q000378:metabolism / Q000528:radiation effects; D012617:Sea Urchins / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects; D015398:Signal Transduction / Q000528:radiation effects; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism
chemical_list: D002457:Cell Extracts; D010718:Phosphatidylserines; D050998:bcl-2 Homologous Antagonist-Killer Protein; D045304:Cytochromes c; D020169:Caspases