APOPTOSIS

Pathway of cell death in which cells activate enzymes that degrade the cells’ own nuclear DNA and nuclear and cytoplasmic proteins

Apoptosis in Physiologic Situations

• The programmed destruction of cells during embryogenesis

• Involution of hormone-dependent tissues upon hormone deprivation

• Cell loss in proliferating cell populations

• Elimination of cells that have served their useful purpose

• Elimination of potentially harmful self-reactive lymphocytes

• Cell death induced by cytotoxic T lymphocytes

Apoptosis in Pathologic Conditions

• DNA damage - radiation, cytotoxic anticancer drugs, extremes of temperature, and even hypoxia

• Accumulation of misfolded proteins

• Cell injury in certain infections - especially viral

• Pathologic atrophy in parenchymal organs after duct obstruction

Normal cell proliferation is important for • Growth and development • Replacement of destroyed cells

APOPTOSIS important for • Programmed death of ‘cells not needed’, after a certain point in development • Removal of potentially dangerous damaged cells

Morphological changes• Shrinkage of cell volume and shape

• Chromatin condensation and DNA fragmentation (most characteristic feature of apoptosis)

• Formation of surface blebs

• Fragmentation into apoptotic bodies

• Phagocytosis of apoptotic bodies by macrophages

Apoptosis in acute viral hepatitis

Mechanisms of Apoptosis

• The Mitochondrial (Intrinsic) Pathway of Apoptosis

• The Death Receptor (Extrinsic) Pathway of Apoptosis

• Activation and Function of Caspases

• Clearance of Apoptotic Cells

Intrinsic (mitochondrial) pathway of apoptosis

triggered by

• loss of survival signals• DNA damage• accumulation of misfolded

proteins (ER stress)

Inhibited by

• survival signals – growth factors

BCL gene family and intrinsic pathway

• Anti-apoptotic genes (BCL-2 gene) and Pro-apoptotic genes (BAX, BAK genes)

– BCL-2 proteins • maintain mitochondrial membrane integrity and prevent leakage of

mitochondrial proteins that can trigger apoptosis (e.g., cytochrome c)

– BAX and BAK - proapoptotic genes• activated by damage to DNA, misfolded proteins, FR damage, viral

infections, and other injurious events • produces protein products that form channels in the mitochondrial

membrane that cause leakage of cytochrome c into the cytosol

Extrinsic (death receptor initiated) pathway

responsible for elimination of self-reactive lymphocytes and damage bycytotoxic T lymphocytes

Examples of Apoptosis

• Growth Factor Deprivation– Hormone-sensitive cells deprived of the relevant hormone– Lymphocytes not stimulated by antigens and cytokines– Neurons deprived of nerve growth factor

• DNA Damage - exposure of cells to radiation/chemotherapy

• Accumulation of Misfolded Proteins: ER Stress

• Apoptosis of Self-Reactive Lymphocytes

• Cytotoxic T Lymphocyte–Mediated Apoptosis

Disorders Associated with Dysregulated Apoptosis

• Defective apoptosis and increased cell survival– Cancer – Autoimmune disorders

• Increased apoptosis and excessive cell death– Neurodegenerative diseases– Ischemic injury– Death of virus infected cells

Necroptosis

• Morphologically - resembles necrosis (loss of ATP, cell swelling, ROS, lysosomal enzymes, rupture of plasma membrane)

• Mechanism : like apoptosis, triggered by genetically programmed signal transduction events

• Unlike apoptosis, the genetic program that drives necroptosis does not result in caspase activation

Necroptosis

Both physiologic and pathologic

• during formation of bone growth plate associated with cell death in • Steatohepatitis• Acute pancreatitis• Reperfusion injury• Neurodegenerative diseases

• Backup mechanism in host defense against certain viruses that encode caspase inhibitors (e.g., CMV)

Pyroptosis

• Pro-inflammatory programmed cell death different than apoptosis– Involves activation of caspase-1 which cleaves the precursor form of IL-1 to

generate biologically active IL-1 (fever inducing cytokine)

• Important in the host defense system for fighting microbial pathogens– In monocytes, macrophages, and dendritic cells infected with certain microbes– Microbial pathogens that may be killed by pyroptosis - Salmonella typhimurium,

Shigella flexneri, Legionella pneumophila, Pseudomonas aeruginosa, Candida albicans, Adenovirus, and Influenza virus

• Also implicated in pathogenesis of– Myocardial infarction (MI), Neurodegenerative diseases, Inflammatory Bowel

Disease (IBD), Cerebral Ischemia, and Endotoxic Shock

The unfolded protein response and ER stress

Diseases Caused by Misfolding of Proteins

Autophagy

Adaptive response enhanced during nutrient deprivation, allows the cell to cannibalize itself to survive

Dysregulation of autophagy occurs in • Cancers• Inflammatory bowel diseases• Neurodegenerative disorders• Host defense against certain microbes