Apoptosis

INTRODUCTION
Programmed cell death that occur in
multicellular organisms
Apoptosis plays major role in
embryogenesis to senescence
Apoptosis differ from necrosis
 Necrosis
Cellular swelling
lysis of cell after infection
No cell signallinig is there
undergo cell lysis by other
factors
No blebbing occurs
Membranes are broken
Membranes are expanded
and thus loss of function
ATP is depleted
Necrotic cells are bursted to
cell envt
inflammatory reaction
DNA fragmentation is
random, or smeared
In vivo, whole areas of the
tissue are affected
Immune response
Apoptosis
Cellular condensation
Programmed cell death
Undergo apoptosis only after
recieving cell signal
Blebbing occurs
Membranes remain intact
Organelles are condensed
and loss of function
Requires ATP
Cell is phagocytosed, no
tissue reaction
No inflammatory responses
Ladder-like DNA
fragmentation
In vivo, individual cells
appear affected
No immune response
NECROSIS Vs
APOPTOSIS

Wilde, 1999
Death by Injury vs. Death by Suicide
(Necrosis vs. Apoptosis)
What makes a cell commit suicide?
withdrawal of positive signals (growth factors, Il-2)

receipt of negative signals (increased levels of oxidants, DNA damage

via X-ray or UV light, chemotherapeutic drugs, accumulation of
improperly folded proteins, death activators such as: TNF-a, TNF-b,
Fas/FasL)

Steps in apoptosis:
the decision to activate the pathway;
"suicide" of the cell;
engulfment of the cell remains by specialized immune cells called
phagocytes;
degradation of engulfed cell.
 The changes in cell death :
condensing of the cell nucleus and breaking it
into pieces
condensing and fragmenting of cytoplasm into
membrane bound apoptotic bodies;
breaking chromosomes into fragments
containing multiple number of nucleosomes (a
nucleosome ladder)
Apoptosis Triggered via Two Pathways
Intrinsic or mitochondrial pathway
Extrinsic or death receptor pathway
STAGES OF APOPTOSIS
Healthy cell

DEATH SIGNAL (extrinsic or intrinsic)

Commitment to die (reversible)

EXECUTION (irreversible)

Dead cell (condensed, crosslinked)

ENGULFMENT (macrophages, neighboring cells)

DEGRADATION
STAGES OF APOPTOSIS

Induction of apoptosis related genes, signal transduction

Sherman et al., 1997

 APOPTOSIS: Morphological events
cell
shrinkage
organelle reduction
mitochondrial leakage
chromatin
condensation
nuclear fragmentation
membrane blebbing &
changes
 Apoptosis:
Pathways
Extrinsic Pathway

Death Death Initiator

Ligands Receptors Caspase 8

Effector
Intrinsic Pathway
Caspase 3 PCD

DNA Initiator
Mitochondria/
damage Caspase 9
Cytochrome C
& p53
Extrinsic or Binding of Fas by FasL
Death Receptor induces recruitment of
Pathway FADD to the cytoplasmic
tail of Fas
The opposite end of FADD
contains a death effector
domain (hatched boxes);
recruitment of either
procaspase-8 or c-FLIP
Caspase-8 can cleave Bid
truncated Bid (tBid) can
inactivate Bcl-2 in the
mitochondrial membrane.
This allows the escape of
cytochrome c, which
clusters with Apaf-1 and
caspase-9 in the presence
of dATP to activate
caspase-9.
Smac/DIABLO is also
released from the
mitochondria and
inactivates inhibitors of
apoptosis (IAPs).
breakdown of several
cytoskeletal proteins and
degradation of the inhibitor
of caspase-activated
 SIGNIFICANCE OF APOPTOSIS
Important in normal physiology
Development: Immune systems
maturation, Morphogenesis
Adult: DNA Damage and wound repair.

Excess apoptosis
Neurodegenerative diseases

Deficient apoptosis
Cancer
Autoimmunity
 CANCER
Apoptosis eliminates damaged cells(damage => mutations
=> cancer

Tumor suppressor p53 controls senescence and apoptosis

responses to damage

Most cancer cells are defective in apoptotic

response(damaged, mutant cells survive)

High levels of anti-apoptotic proteins or Low levels of pro-

apoptotic proteins CANCER
 NEURODEGNERATION
Neurons are post-mitotic (cannot replace themselves; neuronal stem cell

replacement is inefficient)
Neuronal death caused by loss of proper connections, loss of proper growth factors

(e.g. NGF), and/or damage (especially oxidative damage)

Neuronal dysfunction or damage results in loss of synapses or loss of cell bodies

(synaptosis, can be reversible; apoptosis, irreversible)

PARKINSON'S DISEASE
ALZHEIMER'S DISEASE
HUNTINGTON'S DISEASE etc.