Apoptosis

Definition
Programmed cell death

Causes of Apoptosis
Physiological
Embryogenesis (mullerian structures Withdrawal of hormone (e.g. menstrual cycles)

Pathological
Death of tumour cells and virus infected cells Damage to cell DNA (e.g. radiation, Free radicals) Removal of acute inflammatory cells from healing sites

Pharmacological
Corticosteroids cause apoptosis of B and T lymphocytes

Mechanism of Apoptosis
Intrinsic Mechanism
Some information first:
BSL-2 gene is anti-apoptotic (it want to prevent apoptosis)
Its gene is on chromosome 18 The protein product of this gene sits in the mitochondrial membrane and plugs holes so that cytochrome c cannot escape. These genes code for proteins that form channels in the mitochondrial membrane.

BAX and BAK genes are pro-apoptotic (they want to induce apoptosis)

Mechanism
Damage to DNA, missfolded proteins, FR damage, viral infection and over injuries activate BCL-2 sensor genes. These release factors that activate BAX and BAK genes This results in channels forming in the mitochondrial membrane allowing cytochrome c to leak out. This activates initiator caspases (caspase 9) This activates effector caspases (endonucleases and proteases) which mediate the execution phase of apoptosis (see later)

Extrinsic Mechanism
Death receptors = cell surface receptors that induce apoptosis when stimulated. Specific ligands bind to them (mainly Fas and TNF-) TNF receptor-1 (TNFR1) is the best known death receptor and is activated by TNF-. Activation of the death receptor results in activation of initiator caspases (caspase 8 and 10) in the cytosol. These in turn activate effector caspases (proteases and endonucleases) which mediate the execution phase of apoptosis (see later)

Mechanism of Apoptosis
Execution phase
Proteases destroy the cytoskeleton Endonucleases destroy the nucleus (Pyknosis) Cytoplasmic buds form on the cell membrane containing nuclear fragments and organelles These break off forming apoptotic bodies Apoptotic bodies are phagocytosed by neighbouring cells

TNF-
Produced in:
Systemic inflammation Autoimmune disease Cancer (causing cachexia)

Produced by:
Macrophages (main source) T-cells Mast cells] Endothelial cells Cardiac cells Neurons