 Execution phase: other caspases trigger the

degradation of critical cellular components

Physiologic Apoptosis
 To eliminate cells no longer needed
 To maintain a steady number of various cell
population in tissues

Examples:
 Embryogenesis: death of specific cells types
during development
 Involution of hormone-dependent tissues upon
Reversible Cell Injury Irreversible Cell Injury
 Generalized swelling of  Increased Swelling of hormone withdrawal
the cell and its the cell  Cell loss in proliferating cell populations
organelles  Swelling and disruption
 Blebbing of the plasma of lysosomes  Elimination of potentially harmful self-reactive
membrane  Presence of large lymphocytes
 Detachment of amorphous densities
ribosomes from ER  Profound nuclear  Death of host cells that have served their
 Clumping of nuclear changes: purpose
chromatin  Pyknosis
 Karyorrhexis
Pathologic Apoptosis
 Karyolysis
 Cells injured beyond repair to limit collateral
Nuclear Changes tissue damage

Examples:
*Apoptosis can be pathologic and physiologic; Necrosis
always pathologic.
Apoptosis – “program cell death”
 A pathway of cell death that is induced by a
tightly regulated suicide program
 Results from the activation of enzymes called
Caspases
 Fragmentation into apoptotic bodies with intact
PM
 devoured rapidly by phagocytes
*Pro-apoptotic proteins (will induced apoptosis) like
caspase and cytochrome C
*intact membrane = no inflammation
 DNA damage - radiation, anticancer drugs,
hypoxia / aided by tumor-suppressor gene, p53
(for cell damage) if absent/mutated  meaning
cell will survive (pero damaged cell) —> induce
neoplasms (enhance cancer)
**DNA DAMAGE IF MILD: p53 accumulation in
cells: arrests cell cycle (at the G1 phase) to
allow the DNA to be repaired before it is
replicated
**DNA DAMGE IF SEVERE: p53 triggers
apoptosis  stimulate sensors that will activate
BAK and BAX and by increasing synthesis of the
Bcl-2 family
 Accumulation of misfolded proteins
 Infections usually viral: to eliminate reservoirs
 Pathologic atrophy after duct obstruction

The process of apoptosis may be divided into:

 Initiation phase: some caspases become
catalytically active
*have two types: Intrinsic and Extrinsic
Normal Protein Synthesis
1. Chaperones in the ER (control the proper
folding of the synthesized proteins.
2. Misfolded proteins (ubiquitinated and targeted
for proteolysis
3. Accumulated misfolded proteins in ER (induce
protective response called UNFOLDED PROTEIN
RESPONSE which functions to increase
production of chaperones and protein
translation to reduce the level of misfolded
proteins in the ER)
4. ER Stress – too much accumulation of misfolded
proteins (activates caspases and ultimately
apoptosis)
Mechanism of Apoptosis
Intrinsic Pathway
- The intrinsic pathway to apoptosis is triggered by
stress or damage to the cell. Types of stress and
damage that can lead the cell to apoptosis include
damage to its DNA, oxygen deprivation, and other
stresses that impair a cell’s ability to function.
1. Stimuli (ex. Hypoxia)  activates BH3-only proteins
(senses damage)
2. BH3-only proteins  activates BAX and BAK proteins
( has 2 effects; First effect, Mitochondrial damage;
Second effect, stop or block BCL-2, BCL-X or MCL 1 [
which are anti-apoptotic proteins] )
** Mitochondrial damage effect: It will draw out
CYTOCHROME C and SMAC (second mitochondrial
derived activator of caspase) [ which are pro apoptotic
proteins ]
3. Cytochrome C will form a structure with APAF1 (
apoptosis activating factor 1 )  produce
APOPTOSOME. While, SMAC will inhibit XIAP ( x-linked
inhibitor of apoptosis protein)
3. Apoptosome will activate  CASPASE 9  will
activate CASPASE 3 & 7 (executioners)  APOPTOSIS
Extrinsic Pathway
- The extrinsic pathway of apoptosis starts with a signal
molecule binding to a receptor on the outside of the cell
membrane. 
1. Ligand from another cell will bind to another cells
receptor ( LIGAND + RECEPTOR ) activates FADD (fas-
associated death domain protein)  then will activate
CASPASE 8 & 10 (initiators)
3. CASPASE 8 & 10 (has 2 effects; First effect, activate
BID then it will formed to tBID which activates BAK
and BAX; Second effect, it can activate CASPASE 3 & 7
and directly results in apoptosis .
Removal of Dead cells
 Formation of Apoptotic bodies - edible to
phagocytes and exposure of phosphatidylserine
in the outer layer of the membrane
 Release of soluble factor to recruit phagocytes
 Macrophage produced protein that bind to
apoptotic cells
 Dead cells disappear within minutes without a
trace
WHY DO WE NEED TO UNDERGO APOPTOSIS?
 limit neoplastic growth
 does not stimulate inflammation response