Toxic proteins released from mitochondria in cell death

Oncogene. 2004 Apr 12;23(16):2861-74. doi: 10.1038/sj.onc.1207523.


A plethora of apoptotic stimuli converge on the mitochondria and affect their membrane integrity. As a consequence, multiple death-promoting factors residing in the mitochondrial intermembrane space are liberated in the cytosol. Pro- and antiapoptotic Bcl-2 family proteins control the release of these mitochondrial proteins by inducing or preventing permeabilization of the outer mitochondrial membrane. Once released into the cytosol, these mitochondrial proteins activate both caspase-dependent and -independent cell death pathways. Cytochrome c was the first protein shown to be released from the mitochondria into the cytosol, where it induces apoptosome formation. Other released mitochondrial proteins include apoptosis-inducing factor (AIF) and endonuclease G, both of which contribute to apoptotic nuclear DNA damage in a caspase-independent way. Other examples are Smac/DIABLO (second mitochondria-derived activator of caspase/direct IAP-binding protein with low PI) and the serine protease HtrA2/OMI (high-temperature requirement protein A2), which both promote caspase activation and instigate caspase-independent cytotoxicity. The precise mode of action and importance of cytochrome c in apoptosis in mammalian cells has become clear through biochemical, structural and genetic studies. More recently identified factors, for example HtrA2/OMI and Smac/DIABLO, are still being studied intensively in order to delineate their functions in apoptosis. A better understanding of these functions may help to develop new strategies to treat cancer.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Apoptosis Inducing Factor
  • Apoptosis Regulatory Proteins
  • Apoptosis*
  • Carrier Proteins / metabolism
  • Caspases / physiology
  • Chromatin / metabolism
  • Cytochromes c / metabolism
  • DNA Fragmentation
  • Endodeoxyribonucleases / metabolism
  • Flavoproteins / metabolism
  • High-Temperature Requirement A Serine Peptidase 2
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins / metabolism
  • Mitochondria / metabolism*
  • Mitochondrial Proteins / metabolism
  • Serine Endopeptidases / metabolism


  • AIFM1 protein, human
  • Apoptosis Inducing Factor
  • Apoptosis Regulatory Proteins
  • Carrier Proteins
  • Chromatin
  • DIABLO protein, human
  • Flavoproteins
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Mitochondrial Proteins
  • Cytochromes c
  • Endodeoxyribonucleases
  • endonuclease G
  • Serine Endopeptidases
  • HTRA2 protein, human
  • High-Temperature Requirement A Serine Peptidase 2
  • Caspases