1. APOPTOSIS Dr.Dinesh T Junior resident Department of Physiology JIPMER sclero dinesh

3. Introduction sclero dinesh

5. Kerr Wyllie and Currie paper, British Journal of Cancer, 1972 Aug;26(4):239-57 "We are most grateful to Professor James Cormack of the Department of Greek, University of Aberdeen, for suggesting this term. The word "apoptosis" (ἁπόπτωσισ) is used in Greek to describe the "dropping off" or "falling off" of petals from flowers, or leaves from trees. To show the derivation clearly, we propose that the stress should be on the penultimate syllable, the second half of the word being pronounced like "ptosis" (with the "p" silent), which comes from the same root "to fall", and is already used to describe the drooping of the upper eyelid sclero dinesh

10. Cell death mechanisms Death by suicide Death by injury sclero dinesh

11. sclero dinesh APOPTOSIS NECROSIS NATURAL YES NO EFFECTS BENEFICIAL DETRIMENTAL Physiological or pathological Always pathological Single cells Sheets of cells Energy dependent Energy independent Cell shrinkage Cell swelling Membrane integrity maintained Membrane integrity lost

12. sclero dinesh APOPTOSIS NECROSIS Role for mitochondria and cytochrome C No role for mitochondria No leak of lysosomal enzymes Leak of lysosomal enzymes Characteristic nuclear changes Nuclei lost Apoptotic bodies form Do not form DNA cleavage No DNA cleavage Activation of specific proteases No activation Regulatable process Not regulated Evolutionarily conserved Not conserved Dead cells ingested by neighboring cells Dead cells ingested by neutrophils and macrophages

14. Etiopathogenesis sclero dinesh

19. Apoptosis: in embryogenesis Morphogenesis (eliminates excess cells): Selection (eliminates non-functional cells): sclero dinesh

20. Apoptosis: in embryogenesis Immunity (eliminates dangerous cells): Self antigen recognizing cell Organ size (eliminates excess cells): sclero dinesh

21. Apoptosis: importantance in adults Tissue remodeling (eliminates cells no longer needed): Virgin mammary gland Late pregnancy, lactation Involution (non-pregnant, non-lactating) Apoptosis Apoptosis - Testosterone Prostate gland sclero dinesh

22. Apoptosis: importantance in adults Tissue remodeling (eliminates cells no longer needed): Resting lymphocytes + antigen (e.g. infection) - antigen (e.g. recovery) Apoptosis sclero dinesh

28. Morphological & Biochemical changes sclero dinesh

31. Bio chemical changes sclero dinesh

32. Mechanisms of apoptosis sclero dinesh

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37. STAGES OF CLASSIC APOPTOSIS Healthy cell DEATH SIGNAL / STIMULI (extrinsic or intrinsic) Commitment to die (reversible) EXECUTION (irreversible) Dead cell (condensed, crosslinked) ENGULFMENT (macrophages, neighboring cells) DEGRADATION sclero dinesh

38. Receptor pathway (physiological): Death receptors: (FAS, TNF-R, etc) FAS ligand TNF Death domains Adaptor proteins Pro-caspase 8 (inactive) Caspase 8 (active) Pro-execution caspase (inactive) Execution caspase (active) Death MITOCHONDRIA sclero dinesh

39. Apoptosis triggered by external signals: the extrinsic or death receptor pathway sclero dinesh

41. Intrinsic pathway (damage): Mitochondria Cytochrome c release Pro-caspase 9 cleavage Pro-execution caspase (3) cleavage Caspase (3) cleavage of cellular proteins, nuclease activation, etc. Death BAX BAK BOK BCL-Xs BAD BID B IK BIM NIP3 BNIP3 BCL-2 BCL-XL BCL-W MCL1 BFL1 DIVA NR-13 Several viral proteins sclero dinesh

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44. Intracellular signals Oxidative damage from free radicals, Radiation, Virus infection, Nutrient deprivation, Pro-apoptotic Factors Damage to the mitochondrial membrane increasing permeability Entry of Cytochrome C into the cytoplasm Cytochrome C binds to Apaf-1 forming an apoptosome Apoptosome activates procaspase-9 to caspase-9 Caspase-9 cleaves and activates caspase-3 and caspase-7. This executioner caspases activate a cascade of proteolytic activity that leads to: Chromatin condensation, DNA fragmentation, Protein cleavage, Membrane permeability sclero dinesh

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46. Physiological Intrinsic receptor pathway damage pathway MITOCHONDRIAL SIGNALS Caspase cleavage cascade Orderly cleavage of proteins and DNA CROSSLINKING OF CELL CORPSES; ENGULFMENT (no inflammation) sclero dinesh

47. Steps sclero dinesh

48. Disorders of apoptosis sclero dinesh

49. Apoptosis: Role in Disease TOO MUCH: Tissue atrophy TOO LITTLE: Hyperplasia Neurodegeneration Thin skin etc Cancer Athersclerosis etc sclero dinesh

55. Apoptosis: Role in Disease Aging Aging --> both too much and too little apoptosis (evidence for both) Too much (accumulated oxidative damage?) ---> tissue degeneration Too little (defective sensors, signals? ---> dysfunctional cells accumulate hyperplasia (precancerous lesions) sclero dinesh

58. Conclusion sclero dinesh

59. Cells are balanced between life and death DAMAGE Physiological death signals DEATH SIGNAL PROAPOPTOTIC PROTEINS (dozens!) ANTIAPOPTOTIC PROTEINS (dozens!) DEATH sclero dinesh

60. Thank u…. sclero dinesh