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APOPTOSIS

By
Dr.M.Anthony David
Professor of Physiology

Apoptosis is
Programmed cell death

ETYMOLOGY
Greek

Apo meaning away


from Ptosismeaning to
droop or to fall.
Apoptosis :Physiological: To fall
away : Cell suicide
Necrosis: a pathological
destruction of cells : Cell murder
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Necrosis or Apoptosis
NECROSIS
Cell Murder
Passive
Pathological
Swelling & Lysis
seen
Dissipated
Inflammation seen
Externally induced

APOPTOSIS
Cell Suicide
Active
Physiological
Condensation & Crosslinking seen
Phagocytosed
No inflammation
Internally or externally
induced
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PHYSIOLOGICAL :
APOPTOSIS
Common

in Fetal development as well


as in adulthood.
Common examples:
Many neurons undergo apoptosis
during remodelling of the CNS
Inappropriate clones in the immune
system.
Removing the webs between fingers
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PHYSIOLOGICAL :
APOPTOSIS
Disappearance

of the Mullerian System in

the males
Removal of the Endometrium during
menstruation
The epidermal layers of our skin are
continually replaced by germinal
epithelium.
Worn out cells removed by apoptosis
Same with the enterocytes on the
Intestinal villi and microvilli
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APOPTOSIS : Pathological
Autoimmune

diseases

Example : Systemic Lupus


Erythematosus
Neurodegenerative

diseasess :
Eg : Parkinsons disease
Carcinomas:

Cancers

Eg : Ovarian Cancer, Testicular


cancer

Mechanism of Apoptosis
1.

Death signal : Initiators of cell death:


i. External
ii. Internal

2.

Commitment to die : Regulators of


Apoptosis
i.

3.

BCL-2, BAD, BAX, p53etc

Execution of death : Caspase Pathways


i. Fas receptor activation
ii. Ceramide generation
iii. DNA damage

4.

Engulfment : Phagocytosis
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STAGES OF APOPTOSIS
Healthy cell
DEATH SIGNAL

Commitment to die (reversible)


EXECUTION (irreversible)

Dead cell (condensed, crosslinked)


ENGULFMENT / PHAGOCYTOSIS

DEGRADATION
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Cells are balanced between life and death


DAMAGE

Physiological death signals

DEATH SIGNAL
BAX
BAD

PROAPOPTOTIC
PROTEINS

BCL-2
BCL-XL

ANTI-APOPTOTIC
PROTEINS

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APOPTOSIS: Controlled Process


Physiological
receptor pathway

Intrinsic
damage pathway

MITOCHONDRIAL SIGNALS
Caspase cleavage cascade
Orderly cleavage of proteins and DNA
Apoptotic bodies

Crosslinking of proteins

PHAGOCYTOSIS
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APOPTOSIS: control
Receptor pathway:
Death receptors:
(FAS, TNF-R, etc)

FAS ligand

TNF

Death
domains

Adaptor proteins

Pro-caspase 8 (inactive)

Pro-execution caspase (inactive)

MITOCHONDRIA

Caspase 8 (active)

Execution caspase (active)

Death
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APOPTOSIS: control
Intrinsic pathway (damage):

BAX
BAD

BCL-XL
BCL-2

Mitochondria
Smac/DIABLO
Cytochrome c release
Pro-caspase 9 cleavage

Pro-execution caspase (3) cleavage

Caspase (3) cleavage of cellular proteins,


Nuclease activation,
Etc.

Death
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APOPTOSIS: in embryogenesis
Morphogenesis (eliminates excess cells):
e.g. web spaces between digits

Selection (eliminates non-functional cells):


e.g.neurons

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APOPTOSIS: in embryogenesis
Organ size (eliminates excess cells):

Regression of duct system during sex differentiation


e.g. Mullerian ducts

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APOPTOSIS: important in immunity


Immunity (eliminates dangerous cells):

Self antigen
recognizing cell

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APOPTOSIS: in adults
Tissue remodeling (eliminates cells no longer needed):

Virgin mammary gland

Apoptosis

Involution
Late pregnancy, lactation
(non-pregnant, non-lactating)

- Testosterone

Apoptosis
Prostate gland

Pregnant uterus

Apoptosis

Involution after delivery

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APOPTOSIS: in adults
Tissue remodeling (eliminates unnecessarycells):
Apoptosis

Resting lymphocytes + antigen (e.g. infection)

- antigen (e.g. recovery)

Steroid immunosuppressants: kill


Lymphocytes by apoptosis
Lymphocytes poised to die by apoptosis
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APOPTOSIS : in adults
Maintains organ size and function
Apoptosis
+ cell division

Cells lost by apoptosis are replaced by cell division

E.g. Cyclical shedding of endometrium

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APOPTOSIS: Role in
Aging

Aging

: Excessive & Less of apoptosis


Excessive Apoptosis due to accumulated
oxidative damage
Causes tissue degeneration
Less

Apoptosis due to defective


sensors/signals
Causes accumulation of dysfunctional cells
Hyperplasia (precancerous lesions)

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APOPTOSIS: Pathological (in Disease)


TOO MUCH: Tissue atrophy
Neurodegeneration
Thin skin
etc

TOO LITTLE: Hyperplasia


Cancer
Atherosclerosis
etc
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APOPTOSIS: Role in Disease


Neurodegeneration
Neurons

cannot replace themselves

normally
Die due to loss of proper connections, loss
of proper growth factors (e.g. NGF), or
damage (especially oxidative damage)
Neuronal dysfunction or damage results in
loss of synapses
Synaptosis (reversible)
Apoptosis (irreversible)
Neurodegenerative

diseases include:

PARKINSON'S DISEASE
ALZHEIMER'S DISEASE
HUNTINGTON'S DISEASE

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APOPTOSIS: Role in Disease


Cancer
Apoptosis

eliminates damaged cells


(damage => mutations => cancer
Tumor suppressor p53 controls senescence
and apoptotic responses to damage
Most cancer cells defective in apoptotic
response
High levels of anti-apoptotic proteins Or
Low levels of pro-apoptotic proteins
Causes CANCER
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Apoptosis : A Review
Programmed

cell death is physiological


It has a role to play in the fetal
development.
It also helps us in adult lives in the
recycling of certain tissues
It helps in the Menstrual cycle in women
In disease it is seen in cancers and in
neurodegenerative diseases
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