Apoptosis and survival Regulation of Apoptosis by Mitochondrial Proteins
Regulation of Apoptosis by Mitochondrial Proteins Apoptosis is an evolutionarily conserved type of programmed cell death essential fordevelopment, homeostasis, and self-defense against infection. It can be triggered by anumber of factors including UV- or gamma-irradiation, chemotherapeutic drugs, orsignaling by death receptors. There are two major pathways in mammals that are involvedin the initiation of apoptosis. These are the 'extrinsic' death receptor pathway, and the'intrinsic' mitochondrial pathway. These pathways can act independently to initiate thedeath machinery, however there is delicate coordination and cross talk between thesepathways that leads to the activation of the caspase cascade , . Activation of the death domain receptors, such as Tumor necrosis factor receptorsuperfamily member 1A ( TNF-R1 ) and Fas TNF receptor superfamily member 6 (FasR(CD95) ) leads to the cleavage and activation of the pro- Caspase-8, . Caspase-8 cleaves BH3 interacting domain deathagonist ( Bid ). Following cleavage, the carboxyl-terminal fragment ( tBid) of Bid transmits the apoptotic signal from the death receptors to themitochondria. tBid targets the mitochondria and induces oligomerization ofBCL2-associated X protein ( Bax ) and BCL2-antagonist/killer 1 ( Bak ) inthe cellular outer membrane , . However, oligomerizationof both Bax and Bak may occur independently of the cleavage of Bid and/ortranslocation of Bid from cytosol to mitochondria , .tBid also forms oligomers in the mitochondrial membrane . TheBcl-2 family members may function as pore-forming proteins (Bak-, Bax- and Bid-pores), . Cytochrome-c and the second mitochondria-derived activator of caspasesSmac/Diablo are released into cytosol and pass through the Bak-, Bax- andBid-pores. This leads to rupture of the outer membrane , . Once released from mitochondria, Cytochrome-c binds to and activatesApoptotic peptidase activating factor 1 ( Apaf-1 ). Activated Apaf-1 thenforms complexes with pro- Caspase 9. This results in the activation of caspasecascade and induction of apoptosis . Anti-apoptotic proteins B-cell CLL/lymphoma 2 ( Bcl-2 ), BCL2-like 1 (Bcl-XL ), BCL2-like 2 ( Bcl-W ), BCL2-like 10 ( Bcl-B ),BCL2-related protein A1 ( BFL1 ), and Myeloid cell leukemia sequence 1 (Mcl-1 ) suppress apoptosis induced by either Bax or Bak. Theseanti-apoptotic proteins selectively bind to Bax and Bak, block theiroligomerization and induce closing pores , , , . Mitochondrially encoded 16S RNA (Humanin ) is another anti-apoptotic peptidethat was identified recently. It prevents the translocation of Bax fromcytosol to mitochondria, blocks Bax association and suppresses Cytochrome crelease from mitochondria into cytosol . The BH3-only proteins ( Bid, Harakiri BCL2 interacting protein ( HRK ),Phorbol-12-myristate-13-acetate-induced protein 1 ( NOXA ), Modulator of apoptosis1 ( MAP1 ), BCL2-like 11 ( BIM ), Bcl2 modifying factor ( BMF ),BCL2-interacting killer ( BIK ), BCL2-associated agonist of cell death (BAD ), and BCL2 binding component 3 ( Puma )) monitor cellular well being.Different damage signals trigger their binding to anti-apoptotic proteins, therebyinitiating cell death. Some BH3-only proteins exhibit binding to all the anti-apoptoticproteins, while others exhibit marked selectivity. This selectivity accounts fordifferences in the proapoptotic activity of the BH3-only proteins and apoptosis relies onselective interactions between particular subsets of these proteins . Mitochondria can also release factors involved in caspase-independent cell deathincluding Apoptosis-inducing factor, mitochondrion-associated 1 ( Aif ). Thisprotein translocates to the nucleus and induces DNA fragmentation in acaspase-independent manner .