1. MECHANISMS OF CELL
DEATH
ISHAK MAT, PhD
Translational Research Network
Centre,
Institut Perubatan dan Pergigian
Termaju

2. MECHANISMS OF CELL
DEATH
The mechanisms of cell
death and cell survival are
complex

3. The mechanisms of cell
death and cell survival are
complex
previously
apoptosis
necrosis

4. apoptosis
Due to the activation
of a cascade of
biochemical
reaction resulting in
cell death
“Cell
suicide”
necrosis

5. apoptosis
Due to the activation
of a cascade of
biochemical
reaction resulting in
cell death
“Cell
suicide”
necrosis
Due to adverse
conditions in
the cell
environment,
causing acute
injury leading
to “biological
accident”
“Death by injury”

6. apoptosis
Cells are induced to
commit suicide
“Cell
suicide”
necrosis
-mechanical
damage
-exposure to
toxic chemicals
“Death by injury”

7. apoptosis
Cell changes:
1. Formation of small blebs
2. Breakdown of nucleus
3. DNA fragmentation
4. Blebs contain cellular organelles
5. The cells break into several
apoptotic bodies with organelles
6. The organelles within the apoptotic
bodies are still functional
7. No tissue damage

8. apoptosis
-approximately 50 to 70 billion cells die
each day due to apoptosis in a
normal human being
-In a year, this amounts to the
proliferation and subsequent
destruction of a mass of cells equal
to an individual's body weight.

9. necrosis
Cell Processes:
1. Formation of small blebs
2. Changes in nuclear structure
3. The various blebs fused and
become larger
4. No organelles in the blebs
5. Rupture of cell membrane,
releasing content of cells
6. Organelles are non-functional
7. Induction of inflammation
8. Tissue damage

10. Normal cell
Small
blebs
Small
blebs
Big
blebs,no
organelles
DNA
fragmentat
ion,
organelles
in the
blebs
Cell membrane
ruptures,
organelles non
functional
necrosis
Inflammation of
surrounding
tissues
apoptosis
Apoptotic
bodies,
organelles
functional, no
inflammation

11. Why commit suicide (apoptosis)?
1. Needed for proper development to take
place, eg
-
resorption of the tadpole tails in its
metamorphosis into a frog occur via
apoptosis
-
The formation of the fingers and toes of the
fetus occur via apoptosis of the tissue
between them.
-
Sloughing of the inner lining of the uterus at
the start of menstruation.
-
Formation of proper synapses requires
apoptosis of excess neuron

12. Why commit suicide (apoptosis)?
2. To destroy cells threatening the integrity of
the organisms.
e.g Cells infected with viruses are killed by
cytotoxic T lymphocytes by apoptosis e.g via
Fas-Fas ligand interaction
A receptor
called CD95
[Fas] on
virus infected
cell

13. Why commit suicide (apoptosis)?
2. To destroy cells threatening the integrity of
the organisms.
e.g Cells infected with viruses are killed by
cytotoxic T lymphocytes by apoptosis e.g via
Fas-Fas ligand interaction
A receptor
called CD95
[Fas] on
virus infected
cell
Tc
Fasligand
on Tc
Fas-Fas-ligand binding
induces apotosis of virusinfected cells

14. Why commit suicide (apoptosis)?

15. Why commit suicide (apoptosis)?
2. To destroy cells threatening the integrity of
the organisms.
e.g Winding down of Effector T cells once the
immune response has been completed.
Teff
Self induced
apoptosis
Each
other
Teff

16. Why commit suicide (apoptosis)?
2. To destroy cells threatening the integrity of
the organisms.
e.g Winding down of Effector T cells once the
immune response has been completed.
Teff
Self induced
apoptosis
Each
other
Success:
no self
destruct
Teff
Failure:
autoimmune
diseases [eg
SLE,
rhematoid
arthritis]

17. Why commit suicide (apoptosis)?
3. Cells with DNA damage
Can lead to:
i. Distruption of proper development leading
to birth defect
ii. Formation of cancer
DNA damage
Increase
production of
normal p53
molecule
Potent inducer
of apoptosis
Mutation of
p53
Cell
suicide/death
Increase
cancer
incidence

18. Why commit suicide (apoptosis)?
4. Radiation and Chemotherapy
- have been shown to lead to apoptosis in
some types of cancer

19. What makes a cell to undergo
apoptosis?

20. What induces apoptosis?
Withdrawal of
positive
signals: eg
Receipt of
negative
signals:
-Growth factors
for neuron
-increase levels
of oxidants
-Interleukin-2 for
lymphocytes
-DNA damage
[UV, X-ray,
chemo]
-molecules that
induce
apoptosis

21. What induces apoptosis?
Withdrawal of
positive
signals: eg
-Growth factors
for neuron
-Interleukin-2 for
lymphocytes
Receipt of negative
signals:
-molecules that induce
apoptosis
Tumour
necrosis
factor-alpha
(TNFalpha)
TNFR
TNFbeta
TNFR
FasL
Bind to
cell
surface
Fas

22. Mechanisms of apoptosis?
1. The internal or intrinsic pathways
2. External molecules binding to cell
surface receptors.
3. Due to reactive oxygen species

23. Mechanisms of apoptosis?
1. The internal or intrinsic pathways
Healthy cell
Mitochondria
Bcl-2 displayed on
the outer
membrane of
mitochondria
Inhibits
apoptosis

24. Mechanisms of apoptosis?
1. The internal or intrinsic pathways
Internal damage to
healthy cell
Mitochondria
Bax protein,
a related
molecules
Migrates to the surface
and inhibits the protective
effects of Bcl-2
Bcl-2

25. Mechanisms of apoptosis?
1. The internal or intrinsic pathways
Internal damage to
healthy cell
Mitochondria
Bax protein,
a related
molecules
Insert itself to the outer
mitochondrial membranes
and punch holes
Bcl-2

26. Mechanisms of apoptosis?
1. The internal or intrinsic pathways
Internal damage to
healthy cell
Mitochondria
Bcl-2
Leaking of
cytochrome c
Apoptosomes bind to
and activate caspase
9 enzymes
Binds to apoptotic
protease activating factor1 (Apaf-1)
The complexes
aggregate to form
apoptosomes

27. Mechanisms of apoptosis?
1. The internal or intrinsic pathways
Internal damage to
healthy cell
Mitochondria
There are about a
dozen of
caspases
enzymes - all
proteases
Apoptosomes bind to
and activate caspase
9 enzymes
Bcl-2
Cleaves and activates
other enzyme [caspase 3
and 7]

28. Mechanisms of apoptosis?
1. The internal or intrinsic pathways
Cleaves and activates
other enzyme [caspase 3
and 7]
Internal damage to
healthy cell
Expanding activation
of proteolytic enzymes
leading to:
Digestion of
structural
proteins in
the
cytoplasm
Degradation of
chromosomal
DNA
Phagocytosis of
the cell

29. Mechanisms of apoptosis?
2. Induction by external signal
Fas
TNFR

30. Mechanisms of apoptosis?
2. Induction by external signal
Fas
FasL
TNF
TNFR

31. Mechanisms of apoptosis?
2. Induction by external signal
Fas
Transmit signal
to the
cytoplasms
FasL
[on
cells]
TNF
Activate
caspase 8
Leading to destruction
and phagocytosis
TNFR

32. Mechanisms of apoptosis?
3. Apoptosis-inducing factor AIF)
Neuron - self
destruct
without using
caspases
Induction
of cell
death
When the neuron
receives signal to
die
Trigger the
destruction of
the DNA
AIF is
released from
the
mitochondria
Migrate to
the nucleus
and bind to
DNA

33. Mechanisms of Necrosis?
Necrotic Cell Death
1. Loss of metabolic functions
2. Loss of the integrity of the cell
membranes
3. Cessation of the production of
proteins and ATP.
4. Cells organelles swell and
become nonfunctional.

34. Mechanisms of Necrosis?
1. Depletion of ATP-leads to
breakdown of the cell’s ion
balance
2. Reduce oxygen level (hypoxia)
3. Oxidative stress - the presence of
excess oxygen radicals

35. Other mechanisms of cell
death and cell survival:
3. Autophagy
4. Post-Mitotic Death
5. Entosis

36. Other mechanisms of cell
death and cell survival:
3. Autophagy
In cell biology, autophagy, or
autophagocytosis, is a catabolic
process involving the degradation of a
cell's own components through the
lysosomal machinery.

37. Other mechanisms of cell
death and cell survival:
3. Autophagy
-a tightly regulated process
-help maintain a balance between the
synthesis, degradation and subsequent
recycling of cellular products

38. Other mechanisms of cell
death and cell survival:
3. Autophagy: the main
mechanisms
- formation of a membrane around the
targeted region of a cell
-followed by fusion of the vesicle with
lysosome
-subsequent degradation of the contents

39. Other mechanisms of cell
death and cell survival:
5. Entosis

40. ENTOSIS
• Scientists have discovered a novel form of
cell death in which cells crawl inside other
cells to die.
• The process, dubbed entosis, may be a
method of suppressing tumors, the
researchers say, but others aren't so sure.

41. ENTOSIS
• http://www.youtube.com/watch?
v=Zp61OzvKRHY