APOPTOSIS

DIFFERENCE BETWEEN NECROSIS AND APOPTOSIS

NECROSIS APOPTOSIS
Often in contagious cells Single cells/cell cluster
ATP is depleted Requires ATP
Karyolysis, pyknosis, karyorrhexis Pyknosis , karyorrhexis
Cellular swelling Cellular condensation
Membranes are broken Membranes are intact
Cytoplasm released Cytoplasm remain inside cell
Often cause inflammation No inflammation

APOPTOSIS

Is a destructive and important mode of programmed cell death.

It involves genetically determined elimination of cells.

It normally occurs in development and aging cells.

Has homeostatic mechanism to maintain cell population in tissue.

Also occurs as a defense mechanism such as immune reaction or when cells are damaged by a disease or
noxious agents.

STIMULI LEADING TO APOPTOSIS

Both physiological for example in growing and pathological cells killed by microorganisms like bacteria,
virus, parasites.

Stimuli can trigger apoptosis and same stimuli may kill different types of cells for example irradiation,
cancer chemotherapy.

Process is energy dependent that involves activation of a group of system protease called ‘caspases’

Some cells express Fas and TNF receptors where apoptosis happen via ligand binding or cross linking.

This produces cell fragments called apoptotic bodies, phagocytic cells engulf and quickly remove them,
cell content don’t spill out to surrounding cells and thus cause damage.

The process does not stop once started because it regulated.

EARLY APOPTOSIS

Cells shrinkage and pyknosis happens which are visible by light microscope.

Cells are smaller in size, the cytoplasm is dense and organelles more tightly packed, so solutes of cell
organelles are not lost.

Pyknosis is as a result of chromatin condensation.

Apoptotic cell appears round or oval mass with dark eosinophilic cytoplasm and dense purple nuclear
chromatin fragment.

There is also mitochondria shrinkage.

Since there is no breaking of plasma membranes, extensive plasma blebbing occurs followed by
karyorrhexis and separation of cell fragments into apoptotic bodies by budding

Apoptotic bodies are phagocytosed by macrophages, parenchymal cells or neoplastic cells and dragged
with in phagolysosomes.

Macrophages that engulf and digest apoptotic cells are called tangible body macrophages.

APOPTOSIS TO NECROSIS

Factors that enable include,

1. Decrease in the availability of caspase and intracellular ATP.

2. Nature of the cell death signal.
3. Tissue type.
4. Developmental stage of tissue and physiological milieu.

APOPTOTIC PATHWAYS

3 pathways which converge on the terminal execution pathway.

Extrinsic pathway.

Initiated by death receptor {TNFR, Fas-CD95}. Starts with death ligand binding, clustering or aggregation
of death receptors.

Cytoplasmic tails of death receptor bind adaptor proteins. Adaptor proteins recruits and activates
procaspase 8 to yield caspase 8{active}.

Caspase 8 triggers downstream effector caspase such as caspase 3.

Activation of death receptor may also activate intrinsic pathway.

Death ligand for example TNF will bind to the death receptor example TNF receptor, then adaptor
protein come into conduct with the receptor. Adaptor protein chain forms hard disk and thus caspase 8
{initiation pathway} is activated which also activates caspase 3 the execution pathway.

Intrinsic pathway.

In case of hypoxia, toxins, radiations in the body, it causes change in the mitochondria forming
apoptosomes in the process.

This will activate caspase 9 which will in turn activate caspase 3.

Perforin/granzyme pathway.
This happens in cytotoxic T-cells which bind to perforin proteins and two pathways are activated that’s
granzyme A, which activate caspase 10 the initiation pathway which also activates caspase 3 the
execution pathway or granzyme B can also activate caspase 3.

Granzyme A involves endoplasm reticulum complex which causes DNA cleavage.

Activation of caspase 3 cause endonuclease activation that breaks down DNA and protease activation
that cause degradation of nuclear and cytoskeletal proteins.

New cytomorphological changes happen where chromatin and cytoplasmic condensation occurs and
nuclear fragmentation leading to formation of apoptotic bodies which undergoes phagocytosis and
apoptosis is completed.

Importance of apoptosis

1. Immune system maturation

2. Neural development
3. DNA damage and wound repair.
4. Degenerative diseases: Parkinson disease, Alzheimer’s disease, Huntington’s disease
5. Cancer and autoimmune diseases.

Biological roles

 Development
 Metamorphosis
 Regulation of cell number in tissue
 Immune defense
 Diseases: cancer, autoimmunity, infections.

Examples of apoptosis

 Formation of gap between human fingers and toes.

 Loss of larval cells during metamorphosis
 Destruction of cells in thymus
 Destruction of virus infected cells
 Elimination of surplus cells during formation of synapse in brain
 Disintegration and sloughing of endometrium
 DNA damage and destruction of cancer cells