The modulation of inter-organelle cross-talk to control apoptosis

Med Chem. 2006 Jan;2(1):1-12. doi: 10.2174/157340606775197787.


Mitochondria fulfill a wide array of functions dedicated to the energetic metabolism as well as the control of cell death. These functions imply that mitochondria can be activated by a variety of signals and can integrate them to trigger a process called mitochondrial membrane permeabilization (MMP), which induces the ultimate events of apoptosis. MMP consists in a sudden increase in the permeability of mitochondrial membrane that results in the release of critical proapoptotic intermembrane space effectors into the cytosol such as cytochrome c, apoptosis-inducing factor (AIF), Smac/Diablo, Endo G, and pro-caspases. In many models of apoptosis, mitochondrial translocation of proteins and/or lipids concomitantly with alterations of the intracellular milieu has been shown to activate MMP. This applies to tumor suppressors of the Bax/Bcl-2 family (Bax, Bad, Bid, Bim), several protein kinases (Akt, ASK1, hexokinase), p53, NF-kappaB, and nuclear orphan receptors such as TR3/Nur77. After mitochondrial membrane association, these proteins target constitutive mitochondrial proteins including the permeability transition pore complex (PTPC), Bcl-X(L), HSP70, and/or the lipid interphase. Subsequently, they switch their vital function into a lethal function to promote membrane permeabilization and protein release. In this review, we will describe some general rules of inter-organelle cross-talk activating MMP and will review selected examples of pro-apoptotic protein translocation. Finally, we will propose new pharmacological strategies to modulate this process in a therapeutic perspective.

Publication types

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

MeSH terms

  • Animals
  • Apoptosis / physiology*
  • Apoptosis Inducing Factor / metabolism
  • Apoptosis Regulatory Proteins / metabolism
  • Caspases / metabolism
  • Endoplasmic Reticulum / metabolism
  • Humans
  • Mitochondrial Proteins / metabolism
  • NF-kappa B / metabolism
  • Organelles / metabolism*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Tumor Suppressor Protein p53 / metabolism
  • Tumor Suppressor Proteins / metabolism*
  • bcl-X Protein / metabolism


  • Apoptosis Inducing Factor
  • Apoptosis Regulatory Proteins
  • Mitochondrial Proteins
  • NF-kappa B
  • Proto-Oncogene Proteins c-bcl-2
  • Receptors, Cytoplasmic and Nuclear
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • bcl-X Protein
  • Caspases