Apoptosis
LEC 7
Prof- Baha’ M. Ewissat
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APOPTOSIS: PROGRAMMED CELL DEATH
important type of cell death: cell commits suicideنتحر
suicide ت
Physiological or pathological: “””mainly physiological”””
Examples:
1. Programmed destruction of cells during embryogenesis.
Congenital malformation ت شوهin which fingers fail in separation
--syndactyly
2. Hormone-dependent involution:
involution
e.g. physiological,
physiological as in endometrium during menstrual cycle
pathologic as in the prostate atrophy after castrationخصي
e.g. pathologic,
3.Cell deletion in proliferating tissues e.g. cell death in tumors 2
APOPTOSIS: PROGRAMMED CELL DEATH
Examples:
4. Immune cell death:
death
e.g. deletion of autoreactive T-lymphocytes in thymus
e.g. cell death induced by cytotoxic T cells
5. Mild injurious stimuli:
stimuli
e.g. mild heat, radiation, cytotoxic treatment.
6. Death of neurons in disease processes
e.g. Alzheimer disease 3
Mechanisms of apoptosis
The main players are:
Cytosolic proteins called Caspases
Mitochondrial proteins called BCL-2 family
BCL 2 prevent cytochrome C Liang
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Mechanisms of apoptosis: Caspases
• Enzymes which are present in the cytoplasm and
are key players in apoptosis
• Found in an inactive form in the cytoplasm.
• They are called Caspases from C; from Cysteine
active site, “asp”;
asp from cleavage after aspartic
asp
acid residue. 5
Mechanisms of apoptosis: Caspases
There are two types:
1. Initiators: signaling of these caspases results in
commitment ا لتزامof cells to apoptotic cell death.
death These
are found in certain معينcell types.
types
2. Effectors: these are proteases which bring about the
structural degradation انحال لof the cells to give the
classical morphology. They are present in all cell types.
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Mechanisms of apoptosis: BCL-2 family
• BCL-2 family are group of proteins that either:
– suppress apoptosis,
apoptosis like BCL-2 / BCL-XL
– enhance apoptosis like Bax / Bad
• BCL-2 protects from apoptosis by stabilizing the
mitochondrial membrane,
membrane thus preventing increase
permeability, by binding and sequestering عزلcytochrome-C,
cytochrome-C
and stabilizing proteins like the Apaf( Apoptotic protease
activating factor), thus preventing its activation.
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Mechanisms of apoptosis: BCL-2 family
• Factors that influence ي ؤثرmitochondrial membrane
permeability are important players in regulating
apoptosis in the cells.
(Apoptosis Inducing Factor)
Permeability Transition Pore Complex
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Mechanisms of apoptosis: mitochondrial damage
• Stimuli like toxins, or signalling will open permeability
transition pore complex (PTPC),
PTPC or mega channels,
channels which
will release material mainly cytochrome-C from the
mitochondria to cytosol.
• Cytochrome-C will bind to Apaf “apoptotic protease-
activating factor” and activate effector caspases.
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Mechanisms of apoptosis: mitochondrial damage
signalling
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Mechanisms of apoptosis
1. Signaling: intrinsic or extrinsic triggers محفزاتto induce apoptosis
2. Control and integration دمج: by the BCL-2 family that can either
inhibit or promote cell death.
3. Execution ت نفيذ: by caspases that activate cytoplasmic
endonuclease and proteases that degrade cytoskeletal & nuclear
proteins which results in breakdown of cytoskeleton and
fragmentation of nuclear chromatin.
4. Removal of dead cells:
cells the formation of apoptotic bodies
containing various intracellular organelles; they express new
ligands that mediate phagocytic cell binding and uptake. 11
Mechanisms of apoptosis
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Apoptosis: Morphology
• Single cells or groups of cells
• Cells show intensely مكثفeosinophilic cytoplasm
and condensed pyknotic nucleus
• Cells are not surrounded by inflammatory cells
• Rapidly removed by fragmentation and
engulfment by cells
Pyknosis: increased basophilia due to shrinkage of the nucleus
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Apoptosis: Morphology
Normal Apoptotic body
removed 14
Ultrastructural changes in necrosis & apoptosis
chromatin
chromatin condensation
clumping
organellar
chromatin
swelling
fragmentation
membrane cytoplasmic
damage budding
necrosis apoptosis 15
Feature Necrosis Apoptosis
Cell size Enlarged (swelling) Reduced (shrinkage)
Nucelus Pyknosis Fragmentation into
karyorrhexis nucleosome size
karyolysis fragments
Plasma membrane Disrupted ت عطل Intact;
Intact altered
structure, especially
orientation اتجاهof lipids
Cellular contents Enzymatic digestion;
digestion Intact;
Intact may be
may leak ت سريبout of released in apoptotic
cell bodies
Adjacent inflammation Frequent No
Physiologic or Invariablyب ثبات Often physiologic,
physiologic
pathologic role pathologic means of eliminating
(irreversible cell unwanted cells; may
injury) be pathologic after
some forms of cell
injury, especially DNA
damage 16
