Regulation of Apoptosis by Mitochondrial
Apoptosis is an evolutionarily conserved type of programmed cell death essential for
development, homeostasis, and self-defense against infection. It can be triggered by a
number of factors including UV- or gamma-irradiation, chemotherapeutic drugs, or
signaling by death receptors. There are two major pathways in mammals that are involved
in the initiation of apoptosis. These are the 'extrinsic' death receptor pathway, and the
'intrinsic' mitochondrial pathway. These pathways can act independently to initiate the
death machinery, however there is delicate coordination and cross talk between these
pathways that leads to the activation of the caspase cascade , .
Activation of the death domain receptors, such as Tumor necrosis factor receptor
superfamily 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 death
agonist (Bid). Following cleavage, the carboxyl-terminal
fragment (tBid) of Bid
transmits the apoptotic signal from the death receptors to the
mitochondria. tBid targets the mitochondria and induces
oligomerization of BCL2-associated X protein (Bax) and
BCL2-antagonist/killer 1 (Bak) in the cellular outer
membrane , . However, oligomerization of both
Bax and Bak may occur
independently of the cleavage of Bid and/or translocation of Bid from cytosol to
mitochondria , . tBid also
forms oligomers in the mitochondrial membrane . The Bcl-2 family members
may function as pore-forming proteins (Bak-, Bax- and Bid-pores) , .
Cytochrome-c and the second mitochondria-derived
activator of caspases Smac/Diablo are released into cytosol
and pass through the Bak-, Bax- and Bid-pores. This leads to rupture of the outer
membrane , . Once released from mitochondria,
Cytochrome-c binds to and activates Apoptotic peptidase
activating factor 1 (Apaf-1). Activated
Apaf-1 then forms complexes with pro-Caspase
9. This results in the activation of caspase cascade and induction of
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. These
anti-apoptotic proteins selectively bind to Bax and
Bak, block their oligomerization and induce closing pores
, , , .
Mitochondrially encoded 16S RNA (Humanin) is another
anti-apoptotic peptide that was identified recently. It
prevents the translocation of Bax from cytosol to
mitochondria, blocks Bax association and suppresses Cytochrome
c release 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 apoptosis 1
(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, thereby initiating cell
death. Some BH3-only proteins exhibit binding to all the anti-apoptotic proteins, while
others exhibit marked selectivity. This selectivity accounts for differences in the
proapoptotic activity of the BH3-only proteins and apoptosis relies on selective
interactions between particular subsets of these proteins .
Mitochondria can also release factors involved in caspase-independent cell death
including Apoptosis-inducing factor, mitochondrion-associated 1
(Aif). This protein translocates to the nucleus and induces
DNA fragmentation in a caspase-independent manner .
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