Post on 16-Jul-2015
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MECHANISMS OF CELL DEATH
ISHAK MAT, PhD
Translational Research Network Centre,
Institut Perubatan dan Pergigian Termaju
MECHANISMS OF CELL DEATH
The mechanisms of cell death and cell survival are
complex
The mechanisms of cell death and cell survival are
complex
previously
apoptosis necrosis
apoptosis necrosis
Due to the activation of a cascade of biochemical reaction resulting in cell death
“Cell suicide”
apoptosis necrosis
Due to the activation of a cascade of biochemical reaction resulting in cell death
“Cell suicide”
Due to adverse conditions in the cell environment, causing acute injury leading to “biological accident”
“Death by injury”
apoptosis necrosis
Cells are induced to commit suicide
“Cell suicide”
-mechanical damage
-exposure to toxic chemicals
“Death by injury”
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
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.
necrosisCell 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
Normal cellSmall blebs
Big blebs,no organelles
Cell membrane ruptures, organelles non functional
Apoptotic bodies, organelles functional, no inflammation
DNA fragmentation, organelles in the blebs
Small blebs
necrosis apoptosis
Inflammation of surrounding tissues
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
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
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
TcFas-ligand on Tc
Fas-Fas-ligand binding induces apotosis of virus-infected cells
Why commit suicide (apoptosis)?
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.
TeffTeffEach other
Self induced apoptosis
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.
TeffTeffEach other
Self induced apoptosis
Success: no self destruct
Failure: autoimmune diseases [eg SLE, rhematoid arthritis]
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
Increase cancer incidence
Cell suicide/death
Why commit suicide (apoptosis)?
4. Radiation and Chemotherapy
- have been shown to lead to apoptosis in some types of cancer
What makes a cell to undergo apoptosis?
What induces apoptosis?
Withdrawal of positive signals: eg
-Growth factors for neuron
-Interleukin-2 for lymphocytes
Receipt of negative signals:
-increase levels of oxidants
-DNA damage [UV, X-ray, chemo]
-molecules that induce apoptosis
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
TNF-beta
TNFR
FasL
Bind to cell surface Fas
Mechanisms of apoptosis?
1. The internal or intrinsic pathways
2. External molecules binding to cell surface receptors.
3. Due to reactive oxygen species
Mechanisms of apoptosis?
1. The internal or intrinsic pathways
Healthy cell
Bcl-2 displayed on the outer membrane of mitochondria
Mitochondria
Inhibits apoptosis
Mechanisms of apoptosis?
1. The internal or intrinsic pathways
Internal damage to healthy cell
Bcl-2Mitochondria
Migrates to the surface and inhibits the protective effects of Bcl-2
Bax protein, a related molecules
Mechanisms of apoptosis?
1. The internal or intrinsic pathways
Internal damage to healthy cell
Bcl-2Mitochondria
Insert itself to the outer mitochondrial membranes and punch holes
Bax protein, a related molecules
Mechanisms of apoptosis?
1. The internal or intrinsic pathways
Internal damage to healthy cell
Bcl-2Mitochondria
Binds to apoptotic protease activating factor-1 (Apaf-1)
Leaking of cytochrome c
The complexes aggregate to form apoptosomes
Apoptosomes bind to and activate caspase 9 enzymes
Mechanisms of apoptosis?
1. The internal or intrinsic pathways
Internal damage to healthy cell
Bcl-2Mitochondria
Cleaves and activates other enzyme [caspase 3 and 7]
There are about a dozen of caspases enzymes - all proteases
Apoptosomes bind to and activate caspase 9 enzymes
Mechanisms of apoptosis?
1. The internal or intrinsic pathways
Internal damage to healthy cell
Cleaves and activates other enzyme [caspase 3 and 7]
Expanding activation of proteolytic enzymes leading to:
Digestion of structural proteins in the cytoplasm
Degradation of chromosomal DNA
Phagocytosis of the cell
Mechanisms of apoptosis?
2. Induction by external signalFas
TNFR
Mechanisms of apoptosis?
2. Induction by external signalFas
TNFR
FasL
TNF
Mechanisms of apoptosis?
2. Induction by external signalFas
TNFR
FasL [on cells]
TNF
Transmit signal to the cytoplasms
Activate caspase 8
Leading to destruction and phagocytosis
Mechanisms of apoptosis?
3. Apoptosis-inducing factor AIF)
Neuron - self destruct without using caspases
When the neuron receives signal to die
AIF is released from the mitochondria
Migrate to the nucleus and bind to DNA
Trigger the destruction of the DNA
Induction of cell death
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.
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
Other mechanisms of cell death and cell survival:
3. Autophagy4. Post-Mitotic Death5. Entosis
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.
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
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
Other mechanisms of cell death and cell survival:
5. Entosis
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.
ENTOSIS
• http://www.youtube.com/watch?v=Zp61OzvKRHY