1. Apoptosis is a tightly regulated process of programmed cell death that removes unwanted or damaged cells through activation of intracellular enzymes that degrade a cell's own DNA and proteins. 2. There are two main pathways that initiate apoptosis - the extrinsic pathway which is activated by death receptors, and the intrinsic pathway which is activated by intracellular stress signals within mitochondria. 3. Disorders of apoptosis can result from too much or too little cell death. Excess apoptosis can lead to tissue atrophy while insufficient apoptosis allows damaged or mutated cells to survive and potentially cause diseases like cancer and neurodegeneration.

1. MODERATOR
DR. POONAM
MA’AM
LECTURER
PATHOLOGY DEPTT.
MRAMC
PRESENTED BY :
ABHISHEK KUMAR YADAV
R.NO. - 04

2. oIntroduction
oEtiopathogenesis
oMorphological, Biochemical changes
oMechanism
oIntrinsic pathway
oExtrinsic pathway
oDisorders of apoptosis
oConclusion

3. INTRODUCTION

4. Apoptosis - Definition
A pathway of cell death induced by a tightly
regulated suicidal program, in which the cells
destined to die activate enzymes that degrade
cells own nuclear DNA and nuclear,
cytoplasmic proteins.

5. Significance of apoptosis
• During development → many cells produced
in excess → programmed cell death →
contribute to sculpturing of organs & tissues.
• In human body about one lakh cells are
produced every second by mitosis and a
similar number die by apoptosis.

6. ETIOPATHOGENESI
S

7. Physiological apoptosis
Programmed cell death is as
needed for proper normal
development as mitosis is.
Examples:
• Formation of fingers & toes of
fetus requires removal by
apoptosis
• Sloughing off of endometrium at
the start of menstruation.

8. Apoptosis in physiologic situations
 Programmed destruction during embryogenesis
 Involution of hormone dependent tissues
 Cell loss in proliferating cell populations
 Elimination of harmful self- reactive lymphocytes
 Death of host cells

9. Apoptosis: in embryogenesis
Morphogenesis (eliminates excess cells):
Selection (eliminates non-functional cells):

10. Apoptosis: importance 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

11. Apoptosis: in immunity
Immunity (eliminates dangerous cells):
Self antigen
recognizing cell
Organ size (eliminates excess cells):

12. Apoptosis in pathological conditions
- DNA damage
- Accumulation of misfolded proteins
- Cell death in certain infections
- Pathological atrophy in parenchymal organs

13. MORPHOLOGICAL
&
BIOCHEMICAL CHANGES

14. CLASSIC CHANGES
• Cell shrinkage
• Nuclear fragmentation
• Chromatin condensation
• Chromosomal DNA fragmentation
• Formation of cytoplasmic blebs& apoptotic bodies
• Phagocytosis

15. Biochemical changes

16. MECHANISMS OF APOPTOSIS

17. 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

19. Initiation of apoptosis by activation of
signalling pathways :
There are two main signalling pathways in apoptosis :
(A) Extrinsic/death receptor-initiated pathway :

20. (A) EXTRINSIC PATHWAY
FLIP

21. Activation of
caspase
cascade
Release of
several mt
proteins
(B) INTRINSIC/MITOCHONDRIAL PATHWAY :

22. CONTD…

23. (B) INTRINSIC PATHWAY

24. Execution Phase

25. HISTOLOG
Y

26. Apoptotic bodies
 Round oval mass of intensely eosinophilic cytoplasm

27. Apoptotic bodies
 Fragmented nuclei with condensed chromatin

28. REGULATION OF
APOPTOSIS
• Release of mitochondrial pro-apoptotic
proteins tightly controlled by BCL2 family of
proteins.
• Antiapoptotic proteins : BCL2, BCLXL & MCL1
• Proapoptotic proteins : BAX and BAK
• BCL2 sensor proteins : BAD, BIM, BID, Puma, Noxa
(also called BH3 proteins)
• Also, cytoplasm of normal cells contains
inhibitors of apoptosis (IAP) which are
neutralized by proapoptotic factors.

30. DISORDERS OF
APOPTOSIS

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

32. Neurodegeneration
→Neurons are post-mitotic.
→Neuronal death caused by loss of proper
connections, loss of proper growth factors (e.g.
NGF), and/or damage (especially oxidative
damage).
→Neuronal dysfunction or damage results in loss of
synapses or loss of cell bodies (synaptosis, can be
reversible; apoptosis, irreversible)
→PARKINSON'S DISEASE
→ALZHEIMER'S DISEASE
→HUNTINGTON'S DISEASE etc.

34. CANCER
 Apoptosis eliminates damaged cells
(damage => mutations => cancer)
 Tumor suppressor p53 controls senescence and
apoptosis responses to damage.
 Most cancer cells are defective in apoptotic
response(damaged, mutant cells survive)
 High levels of anti-apoptotic proteins
or
 Low levels of pro-apoptotic proteins ===>
CANCER

35. CANCER
VIRUS ASSOCIATED CANCER
• Human papilloma viruses (HPV)
•causes cervical cancer
•produces a protein (E6)-binds & inactivates apoptosis promoter p53.
• Epstein-Barr Virus (EBV)
- cause of mononucleosis and a/w some lymphomas
–produces a protein similar to Bcl-2
–produces another protein that causes the cell to
increase its own production of Bcl-2. Both these actions
make the cell more resistant to apoptosis (thus enabling
a cancer cell to continue to proliferate).

36. • Some B-cell leukemia and lymphomas express high
levels of Bcl-2 → block apoptotic signals. The high
levels result from a translocation of BCL-2 gene into
an enhancer region for antibody production.
• Melanoma cells avoid apoptosis by inhibiting
expression of the gene encoding Apaf-1.
CANCER

37. ConClusion

38. DAMAGE Physiological death signals
DEATH SIGNAL
PROAPOPTOTIC
PROTEINS
(dozens!)
ANTIAPOPTOTIC
PROTEINS
(dozens!)
DEATH