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Thursday 16 February 2006

Cytochrome c (CYCS) (MIM.123970) released from the mitochondrial intermembrane space triggers a major caspase activation cascade through the cytochrome c/APAF1/CASP9 pathway.

Cytochrome c is located in the mitochondria of all aerobic cells and is involved in the electron transport system that functions in oxidative phosphorylation. It accepts electrons from cytochrome b and transfers them to cytochrome oxidase. In the process, the iron of the heme group, which is identical to that of hemoglobin and myoglobin, shifts from the ferrous to the ferric state.

Upon its release to the cytosol, cytochrome c (CYCS) binds to APAF1 (MIM.602233) in the presence of dATP or ATP. The cytochrome c/APAF1 complex then recruits procaspase-9 (CASP9) (MIM.602234), inducing its autoactivation and leading to the activation of downstream caspases (CSPs).

Proteins of the BCL2 (MIM.603167) families and inhibitor of apoptosis proteins (IAPs) are major regulators of the cytochrome c/APAF1/CASP9 pathway. SMAC (Diablo) promotes caspase activation in this pathway.

Apoptosis and anti-apoptosis

In a viable cell, the proapoptotic Bcl-2 family members Bax (BAX), Bak (BAK), and BH3-only proteins are antagonized by antiapoptotic members such as Bcl-2 (BCL2).

In response to an apoptotic stimulus, BH3-only members are activated by transcriptional upregulation (Bax, Noxa, Puma), subcellular relocalization (Bim, Bmf), dephosphorylation (Bad), or proteolysis (Bid).

Activated BH3-only proteins prevent antiapoptotic Bcl-2 members from inhibiting proapoptotic members. In addition, they might directly induce a conformational change of Bax and Bak which subsequently oligomerize and insert into the mitochondrial membrane where they form pores either by themselves or by associating with the permeability transition pore complex.

In consequence, proapoptotic factors are released from the inner mitochondrial membrane into the cytosol, such as cytochrome c which contributes to the formation of the apoptosome and the subsequent activation of the caspase cascade.

See also



- Scorrano L, Korsmeyer SJ: Mechanisms of cytochrome release by proapoptotic BCL-2 family members. Biochem Biophys Res Commun 304:437, 2003.

- Ravagnan L, Roumier T, Kroemer G: Mitochondria, the killer organelles and their weapons. J Cell Physiol 192:131, 2002.

- Cory S, Adams JM: The Bcl2 family: regulators of the cellular life-or-death switch. Nature Rev Cancer 2:647, 2002.

- Reed JC: Cytochrome c: can’t live with it - can’t live without it. Cell 91:559, 1997.