Intrinsic (Mitochondrial) Pathway

of Apoptosis

Growth factors and other survival signals

stimulate production of anti-apoptotic proteins
(e.g. Bcl-2, Bcl-x, and Mcl-1)
These proteins normally reside in the cytoplasm and
in mitochondrial membranes, there they control
mitochondrial permeability and prevent leakage of
mitochondrial proteins that have the ability to trigger
cell death

Damage/Stress BH3-only (sensor) proteins

activated
Sensors: Bim, Bid, and Bad proteins

Pro-apoptotic effectors, Bax and Bak,

activated
Form oligomers that insert in to mitochondrial
membrane and create channels that allow leakage
May also block function of Bcl-2 and Bcl-x survival
signals

Capsase Cascade ACTIVATED

Release of cytochrome-c binding of Apaf-1
(apoptosis-activating factor-1) which forms a wheel
like hammer apoptosome apoptosome binds to
caspase-9 (critical initiator capsase) and cleaves
adjacent caspase-9 molecules setting up an autoamplification process
Other mitochondrial proteins, Smac/DIABLO, enter
the cytoplasm where they bind to and neutralize
cytoplasmic proteins that function as inhibitors of
apoptosis (IAPs)

Extrinsic (Death Receptor Initiated)

Pathway of Apoptosis

This pathway is initiated by engagement

of plasma membrane death receptors
(DRs)
FasL (Fas ligand) binds to Fas (death
receptor) 3 or more molecules of Fas
are brought together
The cytoplasmic death domains form a
binding site for an adapter protein (FADD)
FADD in turn binds an inactive form of
caspase-8 (-10)
Multiple pro-caspase-8 molecules are thus
brought into proximity and cleave on
another to generate active caspase-8
Enzyme then triggers a cascase of
caspase activation by cleving and therby
activating other pro-caspases leading
to the execution phases of apoptosis
*FLIP this pathway can be inhibited by
FLIP protein which binds to pro-caspase-8
preventing it from being cleaved and
activated
Used by some viruses and normal cells to
protect themselves from Fas-mediated
apoptosis

EXECUTION OF
APOPTOSIS