Apoptosis is a programmed cell death process where cells activate enzymes to degrade their own DNA and proteins. It is essential for development, homeostasis, and defense against cancer. The molecular mechanisms of apoptosis involve caspase-dependent pathways - the extrinsic pathway triggered by death receptors and the intrinsic pathway initiated within mitochondria by stress signals. These pathways activate initiator caspases that then activate executioner caspases to degrade cellular proteins and induce apoptosis. Tight regulation of apoptosis is important as its dysfunction can lead to degenerative diseases or cancer.

1. APOPTOSIS

2. What is apoptosis.
A energy dependent mechanism of programmed cell
death, in which cells are destined to die by activating
enzymes that degrade cells own nuclear DNA and
cytoplasmic proteins.
Molecular mechanism of apoptosis is discovered by
Hortviz in 1990.

3. Apoptosis vs necrosis
Apoptosis Necrosis
 Cell shrinkage cell swelling
 Pyknosis and karyorrhexis karyolysis, pyknosis and karyorrhexis
 Intact cell membrane & blebbing disrupted cell membrane
occurs.
 Cytoplasm retained in apoptotic cytoplasm released
bodies.
 No inflammation. inflammation usually present
 Energy dependent cell death. Energy independent cell death

4. Fig:- Apoptosis

5. Purpose of apoptosis.
 It is essential for embryogenesis, metamorphosis and aging.
 To prevent cancer.
 To remove vestigial organs.
 As defence mechanism.
Chemical changes occurs during apoptosis:-
 Chemical changes on the surface of apoptotic cells or bodies serves as a marker of these cells
to recognize by surrounding cells and macrophages and engulf them.
 The negatively charged phospholipid phosphatidylserine is normally located in the inner
leaflet of the plasma membrane, but it flips to the outer leaflet in apoptotic, and work as a
marker of these cells.

6. Mechanism of apoptosis:-
 The mechanism of apoptosis are highly complex and regulated, involving an engery-
dependent cascade of molecular events.
 The classical caspase dependent apoptosis is initiated either by extrinsic or intrinsic factors.
 There are two main caspase dependent apoptotic pathways:-
1) The extrinsic or death receptor pathway
2) The intrinsic or mitochondrial pathway
 Apoptosis is initiated by hormones, growth factors, heat, radiation, chemicals etc.

7. Caspase:-
 Caspase are cysteine dependent aspartate specific protease. They contain a key cysteine
residue in the catalytic site and selectively cleave proteins at sites just c- terminal to
aspartate residue.
 Caspase involved in apoptosis are classified in to two groups:-
1) Initiator caspase (caspases 2, 8, 9, 10)
2) executioner caspase (caspases 3, 6, 7)
 Procaspase are activated by dimerization which further activates executioner caspase.

8. Other important proteins:-
 BCL-2 family helps regulate the activation of procaspases.
 The family of protein consists of :-
Anti-apoptotic members – BCL-2 itself, BCL-X and BCL-B
Pro-apoptotic members – BAX, BAD, BIK
 The pro-apoptotic BCL-2 proteins consists of two subfamilies –
BH123 proteins -(BAX and BAK) promotes MOMP and release of cytochrome c.
BH3- only proteins – (BID, BIM, BIK, BAD, PUMA and NOXA) inhibition of of the anti-
apoptotic proteins and direct activation of the pro-apoptotic proteins.
 IAP inhibit caspases by promoting the degradation of active caspases.

9. The extrinsic pathway:-
 A number of extra cellular signal molecules is specialized to induce apoptosis. These extra
cellular signal molecules bind with cell surface receptors(death receptors).
 The intraction of FasL & FasR on the target cell triggers apoptosis. This intarction recruit
Fas-Assciated protein with Death Domain.
 FADD recruits procaspse-8 which I cleaved to generate active caspase-8. this complex is
called DISC (death inducing signal complex).
 In turn caspase-8 activates executioner caspase-3 or -7
 Which triggers apoptosis or cell death.

10. The intrinsic pathway:-
 It is induced by intracellular death signal. Mitochondria plays a central role by releasing
cytochrome c
 The events during the intrinsic apoptotic pathway:-
 Mitochondrial outer membrane permeabilization (MOMP)
 release of cytochrome c in the cytosol
 Cytochrome c binds to adaptor protein APAF-1
 Formation of apoptosome (heptameric complex) by hydrolysis of ATP into ADP
 Activation of procaspase-9 into caspase-9
 Activation of procaspase-3 into caspase-3
 Caspase-3 triggers apoptosis

11. Fig:- Molecular mechanism of apoptosis

12. Apoptosis and cancer:-
DNA damage & chromosome abnormalities
P53
cell cycle arrest apoptosis unlimited cell
proliferation
DNA repair Death & elimination
of damaged cells cancer
Loss of P53 function

13. Refrences :-
 https://www.annualreviews.org/doi/abs/10.1146/annurev.biochem.73.011303.07370.
 https://www.genome.gov/genetics-glossary/apoptosis.
 https://www.ewg.or.g/research/hallmarks-cancer/evading-apoptosis.