Apoptosis

APOPTOSIS
Prof. Dr. Sampene Ossei

OVERVIEW
• Definition
• Types
• Mechanisms
• Morphological changes in Apoptosis
• Diagnosis of Apoptosis
• Differences from necrosis
DEFINITION
• It is a pathway of cell death that is induced by a tightly

regulated intracellular program in which cells destined
to die activate enzymes (caspase) to degrade the cells
own nuclear DNA and cytoplasmic proteins.
• The cell is phagoctosed
• There is no leakage outside
• So there is no inflammation
• It is a way of elimination of unwanted cells and those which are
damaged beyond repair capacity of the cell
• Apoptosis generally involves a single cell in contrast to necrosis

that usually involve a group of cells.
• It is the ‘programmed cell death’
• It is genetically programmed.
TYPES OF APOPTOSIS
• Physiological → Programmed cell death
• Pathological → Unprogrammed cell death

EXAMPLES OF PHYSIOLOGICAL APOPTOSIS
• Embryogenesis
• Elimination of potentially self reacting lymphocytes
• Hormone dependent involution of the uterus and breast
• Death of cells that have completed their functions
EXAMPLES OF PATHOLOGICAL APOPTOSIS
• Cell death in tumors exposed to chemotherapeutic

agents.
• Progressive depletion of CD4+T cells in the

pathogenesis of AIDS
• Cell death in viral infections e.g. formation of

Councilman bodies in viral hepatitis.
MECHANISM OF APOPTOSIS
• Apoptosis can be induced through two distinct but convergent
pathways.
1. Extrinsic pathway – It is initiated by extracellular stimulus
with help of specific receptors called death receptors.
2. Intrinsic pathway – It is result of increased mitochondrial
membrane permeability and release of pro-apoptotic markers
like cytochrome C into the cytoplasm.
EXTRINSIC PATHWAY → INITIATION PHASE
• It is initiated through specific receptors called death

receptors
1. Fas Protein (CD95)

2. TNF receptors
FAS PROTEIN (CD95)
Fas protein (CD95)

↓
Fas receptor (Death receptor)
↓
Multiple Fas Proteins come together
↓
Cytoplasmic death domains combine to form death domain FADD
↓
Activate pro-caspase 8 to activate caspase
TNF RECEPTORS
TNF
↓
TNF receptor
↓
Multiple Fas Proteins come together
↓
Cytoplasmic death domains combine to form death domain TRADD
↓
Activate pro-caspsase 8 to activate caspase
INTRINSIC PATHWAY → INITIATION PHASE
• The intrinsic signaling pathways that initiate apoptosis

involve a diverse array of non-receptor-mediated stimuli
that produce intracellular signals within the cell and are
mitochondrial initiated events.
INTRINSIC PATHWAY → INITIATION PHASE
Stimuli
↓
Anti apoptotic molecules Bcl-2 and Bcl-x are lost
↓
Replaced by pro-apoptotic molecules like Bak, Bax, Bim
↓
Increased mitochondrial permeability (MPT)
↓
Release to cytochrome C into cytoplasm
↓
Activates Apaf-1 along with procaspase 9
↓
Activated caspase-9
EXECUTION PHASE FOR EXTRINSIC AND
INTRINSIC PATHWAYS
•It is a convergence point for both extrinsic

and intrinsic pathways
Extrinsic Pathway Intrinsic Pathway
↓ ↓
Caspase 8 Caspase 9
Activates caspase 3 and 7

↓
Sequentially activates all other caspase
↓
Caspases cleave cytoskeletal and nuclear matrix proteins
↓
Cell degenerate / apoptotic bodies
REMEMBER
• Initiation Caspase → Caspase 8 and 9
• Execution Caspase → Caspase 3 and 7

PHAGOCYTOSIS
Phosphatidylserine is a phospholipid normally present on inner surface
membrane
↓
During apoptosis
↓
Flipped to outer surface
↓
Externalization of phosphatidylserine causes its tagging
↓
Phagocytes ingulf it
Apoptotic Cell Death and
PS Externalization
• The process of apoptotic cells is so efficient that dead cells
disappear without leaving a trace and inflammation is
virtually absent
• Essential feature is immediate, specific and non-
inflammatory nature of phagocytosis
MORPHOLOGICAL CHANGES IN APOPTOSIS
1. Cellular shrinkage is earliest change. It is due to

damage to the cytoskeletal proteins
2. Cellular organelles are tightly packed thus imparting
intense eosinophilic color to cytoplasm
3. Pyknosis i.e. Chromatin condensation or nuclear compaction.
4. Karyorrhexis i.e.. Nuclear fragmentation. It is due to activity
of endonuclease and caspases.
• It is the most characteristic feature
5. Cytoplasmic membrane shows multiple surface blebs.
• It is the end stage of apoptosis.
• Cell membrane intact thus preventing leaking out of cellular
contents.
6. Nuclear fragments and cytoplasmic organelles form membrane bound
apoptotic bodies.
• These are membrane bound round masses of eosinophilic cytoplasm
with tightly packed organelles which contain nuclear debris
• These apoptotic bodies are recognized by phagocytes and are destroyed
• Characteristically, unlike necrosis, there is no acute inflammatory
reaction around apoptosis.
7. Phagocytosis
DIAGNOSIS OF APOPTOSIS
There are 2 ways of diagnosis apoptosis.

• Apoptosis markers
• Agarose gel electrophoresis
1. APOPTOSIS MARKERS
• This laddered pattern is a characteristic but not
specific for apoptosis.
DIFFERENCES BETWEEN APOPTOSIS AND
NECROSIS

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APOPTOSIS

Prof. Dr. Sampene Ossei

• It is a pathway of cell death that is induced by a tightly

• Apoptosis generally involves a single cell in contrast to necrosis

• It is the ‘programmed cell death’

• Physiological → Programmed cell death

• Pathological → Unprogrammed cell death

• Cell death in tumors exposed to chemotherapeutic

• Progressive depletion of CD4+T cells in the

• Cell death in viral infections e.g. formation of

• It is initiated through specific receptors called death

1. Fas Protein (CD95)

Fas protein (CD95)

• The intrinsic signaling pathways that initiate apoptosis

•It is a convergence point for both extrinsic

Activates caspase 3 and 7

• Initiation Caspase → Caspase 8 and 9

• Execution Caspase → Caspase 3 and 7

1. Cellular shrinkage is earliest change. It is due to

There are 2 ways of diagnosis apoptosis.

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