Apoptosis
Apoptosis is a type of cell death that is induced by a tightly regulated suicide
program in which cells destined to die activate intrinsic enzymes that degrade
the cells’ genomic DNA and nuclear and cytoplasmic proteins.
It serves important functions beyond embryogenesis, including the
elimination of unwanted or potentially harmful cells, such as those with
damaged DNA or infected by viruses. In contrast to necrosis, which is a
pathological process resulting from acute cell injury, apoptosis is a highly
regulated and controlled process that typically does not elicit an inflammatory
response.
Causes of Apoptosis
A. Apoptosis in Physiologic Situations
Apoptosis is a normal process used to remove cells that are no longer
needed, maintaining tissue homeostasis. Key physiologic situations where
apoptosis is important include:
1. Development: Removal of excess cells (supernumerary) during
embryogenesis, helping in tissue remodeling.
2. Hormone-dependent involution:
o Menstrual cycle: Endometrial breakdown after hormone withdrawal.
o Menopause: Ovarian follicular atresia.
o Lactating breast: Regression after weaning.
3. Cell turnover in proliferating tissues:
o Immature lymphocytes in bone marrow/thymus.
o B lymphocytes in germinal centers without useful antigen receptors.
o Epithelial cells in intestinal crypts for homeostasis.
4. Elimination of self-reactive lymphocytes: To prevent autoimmune
responses.
5. Apoptosis after immune/inflammatory responses:
o Neutrophils at the end of an acute inflammatory response.
o Lymphocytes after an immune response is completed.
B. Apoptosis in Pathologic Conditions
Apoptosis plays a protective role in many pathological conditions by
eliminating damaged or harmful cells without causing an inflammatory
response. Key pathologic conditions where apoptosis occurs include:
1. DNA damage: Radiation or chemotherapy: Causes DNA damage,
triggering apoptosis to prevent the survival of potentially malignant cells.
2. Accumulation of misfolded proteins: ER stress: Induced apoptosis due to
misfolded proteins, which can lead to cell death if not corrected.
3. Infections:
, Viral infections: Apoptosis may be induced by the virus (e.g., HIV) or
by host immune responses (e.g., viral hepatitis).
Cytotoxic T lymphocytes (CTLs): Target infected cells, tumors, and are
involved in transplant rejection and graft-versus-host disease.
4. Pathologic atrophy:
Duct obstruction: Causes apoptosis in organs like the pancreas, parotid
gland, and kidney.
Morphology of Apoptosis
Cells undergoing apoptosis display distinctive morphologic changes, best seen
under an electron microscope. Key features include:
1. Cell Shrinkage: The cell becomes smaller, with dense and eosinophilic
cytoplasm.
2. Chromatin Condensation: The most characteristic feature of apoptosis.
Chromatin aggregates under the nuclear membrane, forming dense masses
of various sizes and shapes. The nucleus may fragment into two or more
parts.
3. Cytoplasmic Blebs and Apoptotic Bodies: Surface membrane blebbing
occurs. The cell fragments into membrane-bound apoptotic bodies,
containing cytoplasm, organelles, and nuclear fragments.
4. Phagocytosis: Apoptotic bodies are quickly phagocytosed, typically by
macrophages. Phagocytic cells degrade these bodies with lysosomal
enzymes.
Mechanisms of Apoptosis
Apoptosis is driven by the activation of caspases, proteases that cleave proteins
after aspartic residues. Caspases exist as inactive proenzymes and become active
through cleavage. Apoptosis has two phases:
1. Initiation phase: Activates some caspases, triggering a cascade of other
caspases.
2. Execution phase: Terminal caspases cause cellular fragmentation. Two
pathways lead to caspase activation:
A. Mitochondrial (Intrinsic) Pathway: Triggered by increased
mitochondrial membrane permeability, releasing pro-apoptotic proteins
like cytochrome c. The BCL2 family of proteins regulates this pathway,
with anti-apoptotic proteins (BCL2, BCL-XL, MCL1) maintaining
membrane integrity, and pro-apoptotic proteins (BAX, BAK) promoting
membrane permeability. BH3-only proteins (BAD, BID, etc.) initiate
apoptosis by activating BAX and BAK, while blocking BCL2.
Cytochrome c release activates APAF-1, forming the apoptosome, which
activates caspase-9 and initiates the caspase cascade.
, B. Death Receptor (Extrinsic) Pathway: Involves receptor-ligand
interactions that directly activate caspases
The pathway starts with the engagement of plasma membrane death
receptors.
Death receptors belong to the TNF receptor family and contain a
cytoplasmic death domain crucial for apoptosis.
Key death receptors include TNFR1 and Fas (CD95).
Fas ligand (FasL) binds to Fas, leading to the recruitment of adaptor protein
FADD.
FADD binds to inactive caspase-8 or caspase-10.
Autocatalytic cleavage activates caspase-8.
Active caspase-8 triggers the executioner caspases, leading to apoptosis.
The pathway can be inhibited by FLIP, which blocks caspase-8 activation.
In some cells, Fas signaling also activates the mitochondrial pathway,
amplifying apoptosis
Apoptosis is a type of cell death that is induced by a tightly regulated suicide
program in which cells destined to die activate intrinsic enzymes that degrade
the cells’ genomic DNA and nuclear and cytoplasmic proteins.
It serves important functions beyond embryogenesis, including the
elimination of unwanted or potentially harmful cells, such as those with
damaged DNA or infected by viruses. In contrast to necrosis, which is a
pathological process resulting from acute cell injury, apoptosis is a highly
regulated and controlled process that typically does not elicit an inflammatory
response.
Causes of Apoptosis
A. Apoptosis in Physiologic Situations
Apoptosis is a normal process used to remove cells that are no longer
needed, maintaining tissue homeostasis. Key physiologic situations where
apoptosis is important include:
1. Development: Removal of excess cells (supernumerary) during
embryogenesis, helping in tissue remodeling.
2. Hormone-dependent involution:
o Menstrual cycle: Endometrial breakdown after hormone withdrawal.
o Menopause: Ovarian follicular atresia.
o Lactating breast: Regression after weaning.
3. Cell turnover in proliferating tissues:
o Immature lymphocytes in bone marrow/thymus.
o B lymphocytes in germinal centers without useful antigen receptors.
o Epithelial cells in intestinal crypts for homeostasis.
4. Elimination of self-reactive lymphocytes: To prevent autoimmune
responses.
5. Apoptosis after immune/inflammatory responses:
o Neutrophils at the end of an acute inflammatory response.
o Lymphocytes after an immune response is completed.
B. Apoptosis in Pathologic Conditions
Apoptosis plays a protective role in many pathological conditions by
eliminating damaged or harmful cells without causing an inflammatory
response. Key pathologic conditions where apoptosis occurs include:
1. DNA damage: Radiation or chemotherapy: Causes DNA damage,
triggering apoptosis to prevent the survival of potentially malignant cells.
2. Accumulation of misfolded proteins: ER stress: Induced apoptosis due to
misfolded proteins, which can lead to cell death if not corrected.
3. Infections:
, Viral infections: Apoptosis may be induced by the virus (e.g., HIV) or
by host immune responses (e.g., viral hepatitis).
Cytotoxic T lymphocytes (CTLs): Target infected cells, tumors, and are
involved in transplant rejection and graft-versus-host disease.
4. Pathologic atrophy:
Duct obstruction: Causes apoptosis in organs like the pancreas, parotid
gland, and kidney.
Morphology of Apoptosis
Cells undergoing apoptosis display distinctive morphologic changes, best seen
under an electron microscope. Key features include:
1. Cell Shrinkage: The cell becomes smaller, with dense and eosinophilic
cytoplasm.
2. Chromatin Condensation: The most characteristic feature of apoptosis.
Chromatin aggregates under the nuclear membrane, forming dense masses
of various sizes and shapes. The nucleus may fragment into two or more
parts.
3. Cytoplasmic Blebs and Apoptotic Bodies: Surface membrane blebbing
occurs. The cell fragments into membrane-bound apoptotic bodies,
containing cytoplasm, organelles, and nuclear fragments.
4. Phagocytosis: Apoptotic bodies are quickly phagocytosed, typically by
macrophages. Phagocytic cells degrade these bodies with lysosomal
enzymes.
Mechanisms of Apoptosis
Apoptosis is driven by the activation of caspases, proteases that cleave proteins
after aspartic residues. Caspases exist as inactive proenzymes and become active
through cleavage. Apoptosis has two phases:
1. Initiation phase: Activates some caspases, triggering a cascade of other
caspases.
2. Execution phase: Terminal caspases cause cellular fragmentation. Two
pathways lead to caspase activation:
A. Mitochondrial (Intrinsic) Pathway: Triggered by increased
mitochondrial membrane permeability, releasing pro-apoptotic proteins
like cytochrome c. The BCL2 family of proteins regulates this pathway,
with anti-apoptotic proteins (BCL2, BCL-XL, MCL1) maintaining
membrane integrity, and pro-apoptotic proteins (BAX, BAK) promoting
membrane permeability. BH3-only proteins (BAD, BID, etc.) initiate
apoptosis by activating BAX and BAK, while blocking BCL2.
Cytochrome c release activates APAF-1, forming the apoptosome, which
activates caspase-9 and initiates the caspase cascade.
, B. Death Receptor (Extrinsic) Pathway: Involves receptor-ligand
interactions that directly activate caspases
The pathway starts with the engagement of plasma membrane death
receptors.
Death receptors belong to the TNF receptor family and contain a
cytoplasmic death domain crucial for apoptosis.
Key death receptors include TNFR1 and Fas (CD95).
Fas ligand (FasL) binds to Fas, leading to the recruitment of adaptor protein
FADD.
FADD binds to inactive caspase-8 or caspase-10.
Autocatalytic cleavage activates caspase-8.
Active caspase-8 triggers the executioner caspases, leading to apoptosis.
The pathway can be inhibited by FLIP, which blocks caspase-8 activation.
In some cells, Fas signaling also activates the mitochondrial pathway,
amplifying apoptosis
