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mitochondria-mediated cell death

Tuesday 14 February 2006

- Apoptosis is a cell-autonomous mode of death that is activated to eradicate superfluous, damaged, mutated, or aged cells. In addition to their role as the cell’s powerhouse, mitochondria play a central role in the control of apoptosis.

- Numerous pro-apoptotic molecules act on mitochondria and provoke the permeabilization of mitochondrial membranes. Soluble proteins contained in the mitochondrial intermembrane space are released through the outer membrane and participate in the organized destruction of the cell.

- Several among these lethal proteins can activate caspases (CASPs), a class of cysteine proteases specifically activated in apoptosis, whereas others act in a caspase-independent fashion, by acting as nucleases (e.g., endonuclease G), nuclease activators (e.g., apoptosis-inducing factor), or serine proteases (e.g., Omi/HtrA2).

- In addition, mitochondria can generate reactive oxygen species (ROS), following uncoupling and/or inhibition of the respiratory chain. The diversity of mitochondrial factors participating in apoptosis emphasizes the central role of these organelles in apoptosis control and unravels novel mechanisms of cell death execution.

- The formation of the apoptosome in mammalian cells is triggered by cytochrome c released from the mitochondria. Many other mitochondrial proteins have been suspected to be part of a conspiracy to cause cell death.

Several mitochondrial death proteins have been identified:

- PDCD8 (AIF) (MIM.300169)
- ENDOG (MIM.600440)
- PPID (cyclophilin-D) (MIM.601753)
- BIT1 (MIM.608625)
- GRIM19 (MIM.609435)
- DAP3 (MIM.602074)
- NR4A1 (Nur77/TR3/NGFB-1) (MIM.139139)
- PRSS25 (HtrA2/Omi) (MIM.606441)
- SMAC (Diablo) (MIM.605219)

References

- Ekert PG, Vaux DL. The mitochondrial death squad: hardened killers or innocent bystanders? Curr Opin Cell Biol. 2005 Dec;17(6):626-30. PMID: 16219456

- Newmeyer DD, Ferguson-Miller S: Mitochondria: releasing power for life and unleashing the machineries of death. Cell 112:481, 2003.

- Ravagnan L, Roumier T, Kroemer G. Mitochondria, the killer organelles and their weapons. J Cell Physiol. 2002 Aug;192(2):131-7. PMID: 12115719