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