Mitochondrial pathway of apoptosis is ancestral in metazoans

Proc Natl Acad Sci U S A. 2012 Mar 27;109(13):4904-9. doi: 10.1073/pnas.1120680109. Epub 2012 Mar 13.


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).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Apoptosis* / radiation effects
  • Caspases / metabolism
  • Cell Extracts
  • Cytochromes c / metabolism
  • Enzyme Activation / radiation effects
  • Exocytosis / radiation effects
  • Gamma Rays
  • Mitochondria / metabolism*
  • Mitochondria / radiation effects
  • Mitochondrial Membranes / radiation effects
  • Permeability / radiation effects
  • Phosphatidylserines / metabolism
  • Planarians / metabolism*
  • Planarians / radiation effects*
  • Protein Transport / radiation effects
  • Saccharomyces cerevisiae / metabolism
  • Saccharomyces cerevisiae / radiation effects
  • Sea Urchins / cytology
  • Sea Urchins / metabolism
  • Sea Urchins / radiation effects
  • Signal Transduction* / radiation effects
  • bcl-2 Homologous Antagonist-Killer Protein / metabolism


  • Cell Extracts
  • Phosphatidylserines
  • bcl-2 Homologous Antagonist-Killer Protein
  • Cytochromes c
  • Caspases