CELL DEATH

 PROGRAMMED CELL DEATH (PCD)

Apoptosis type I cell death

Apoptosis = programmed cell death

• Main features:

➢ Chromatin condensation and DNA

fragmentation

➢ Formation of blebs on the cell surface

➢ Breakdown of cytoskeleton and nuclear

envelope

➢ Cell shrinkage and formation of apoptotic

bodies

    

Apoptosis (TEM): https://www.sciencedirect.com/science/article/pii/S0955067404001474

Apoptosis is mediated by intracellular proteolytic cascade

Caspases = family of protease enzymes - catalytic activity

Intracellular proteolytic cascade = irreversible amplifying chain reaction involve initiator and executioner caspases that is destructive

Procaspase = inactive caspase precursor 

Initiator procaspase = inactive caspase precursor activate downstream executioner caspase 

Executioner caspase = degrade proteins 

Intrinsic pathway (Mitochondrial pathway)	Extrinsic pathway
Triggered by cellular stressors  Oxidative stress free radicals and not enough antioxidants to neutralize Free radicals unstable atoms cause damage to cell	Induced by extracellular signals
Mitochondrial outer membrane permeabilization (MOMP)  Intrinsic pathway is regulated by the balance between activities of  pro apoptotic members and anti apoptotic members of B cell lymphoma 2 family.  Activation Pro apoptotic effectors (Bak & Bax) induce the release of mitochondrial protein cytochrome c into the cytosol Cytochrome c activates assemble of adaptor proteins into apoptosome and recruit initiator procaspase (procaspase 9) Activated initiator procaspase induce apoptosis	Activation of cell surface death receptors by recognizing membrane bound Fas ligand NK cells with Fas ligand structure recognized by death receptor expressed on target cell surface Cytoplasmic tails (death domains) of Fas death receptors bind with intracellular adaptor protein Initiator procaspases (procaspase 8) recruit to the complex to form a death inducing signaling complex (DISC) Activation of initiator caspases cleave downstream effector caspases (caspase 3) Activation of downstream executioner caspases
Inhibition by Bcl 2 Anti apoptotic effectors (Bcl 2) inactivate pro apoptotic members to prevent the release of cytochrome c  Apoptotic stimuli inactivate Bcl 2 and allow Bak to induce the release of cytochrome c and subsequently induce apoptosis
Inhibition by extracellular survival factors Extracellular survival factors bind to cell surface receptors Initiation of intracellular signaling pathway activates a transcription regulator in the cytosol Activated transcription regulator moves to the nucleus and activates the gene encoding Bcl 2 which inhibits apoptosis  Binding of survival factor to a specific receptor initiates intracellular signaling pathway BH3 only protein (Bad) becomes phosphorylated by Ser/Thr kinase (Akt)   Bcl 2 is released and activated to inhibit apoptosis