Apoptosis is a great topic of research.Presenting herewith the PPT on apoptosis

1. Dr.Shabnam N Shah
II Yr.MSc.Medical Physiology
JNUIMSRC,Jaipur
Dr.Shabnam N Shah
II Yr.MSc.(Medical Physiology)
JNUIMSRC,Jaipur

2. CELL –THE BUILDING BLOCKS OF HUMAN LIFE.

3. Specific Learning Objectives
 To define apoptosis.
 Explain Apoptosis in Physiological conditions.
 Explain Apoptosis Pathological conditions.
 Morphological features in Apoptosis.
 Molecular mechanism of apoptosis.

4. Apoptosis --Greek word
Apo -- Seperation
Ptosis – Falling offIntroduction

5. Introduction
 Carl Vogt(1842) –Cell death ,a completely normal process.
 Richard Lockshin(1964)-- Programmed cell death
 --The term apoptosis -- first used-- Kerr et al, Wyllie, and
Currie in 1972 (described a morphologically distinct
form of cell death).

9. Apoptosis or programmed cell
death (PCD)
A mode of cell death that occurs under normal physiological
or pathological conditions and the cell is an active
participant in its own demise.
An energy-dependent, asynchronous, genetically controlled
process.
Important for the development of multicellular organism
(embryonic development) and homeostasis of their tissues
(adult).
.

10. Apoptosis or programmed cell death (PCD)
 Takes about 15min.
 In the tissue only about 5% cells is
affected by the PCD.
 Physiological changes and phagocytosis
is very fast.

12. Role of Apoptosis in Physiological
conditions
 Development of Embryo: cell destruction in sculpting of
tissues and organs.
 Physiological involution of cells in hormone dependent
tissues. : e.g endometrial shedding, regression of lactating
breast.
 Intestinal epithelium: replacement proliferation.
 Loss of immature B cells and T cells.
 Elimination of blood cells. Eg neutrophil in acute
inflammation.

13. Apoptosis in Physiological
conditions
 Development of Embryo: cell destruction in
sculpting of tissues and organs.
 Physiological involution of cells in hormone
dependent tissues. : e.g endometrial shedding,
regression of lactating breast.
 Intestinal epithelium: replacement proliferation.
 Loss of immature B cells and T cells.
 Elimination of blood cells. Eg neutrophil in acute
inflammation.

19. Role of Apoptosis in Pathological conditions
1) DNA damage. Radiation, cytotoxic anticancer drugs, and
hypoxia can damage DNA, either directly or via
production of free radicals.
2) Accumulation of misfolded proteins - in the ER leads to ER
stress, which leads to apoptotic cell death.
3) Cell death in tumours exposed to chemotherapeutic
agents.

20. 4) Progressive depletion of CD4+T cells in the pathogenesis of AIDS.
5) Cell death in viral infections e.g. formation of Councilman
bodies in viral hepatitis.
6) Pathologic atrophy of organs e.g. prostatic atrophy after
orchiectomy, atrophy of kidney or salivary gland on
obstruction of ureter or ducts, respectively.

24. Necrotic cells Apoptotic cells
 Loss of regulation of ion
homeostasis
 No energy requirement
 Affects groups of contiguous cells
 Evoked by non-physiological
disturbances (lytic viruses, hypoxia)
 Phagocytosis by macrophages
 Significant inflammatory response
 Tightly regulated process
 Energy(ATP)- dependent
 Release of various factors into
cytosol by mitochondria
 Activation of caspase cascade
 Affects single cells or small
clusters of cells
 Induced by physiological
stimuli(lack of growth factors,
DNA damage)
 Rapidly phagocytized by
adjacent epithelial cells or
macrophages
 No inflammatory response

25. MECHANISM OF APOPTOSIS
Caspases= Cysteinyl aspartate specific proteases
(Main Player)
 Present as inactive zymogens.
During activation, the zymogen pro-proteins are cleaved to
generate the large and small subunits of the active enzymes.

26. Three pathways
The extrinsic pathway
 The intrinsic pathway
The granzyme pathway

28. The extrinsic pathway
Death receptors -- tumor necrosis factor (TNF) receptor.
similar extracellular domains --“death domain”
plays a critical role in transmitting the death signal from
the cell surface to the intracellular signaling pathways.
The best-characterized ligands and corresponding death
receptors include FasL/FasR, TNF-α/TNFR1, Apo3L/DR3,
Apo2L/DR4 and Apo2L/DR5

29. The extrinsic phase is characterized with FasL/FasR and TNF-
α/TNFR1 models.
 There is clustering of receptors and binding with the ligand.
Upon ligand binding, cytplasmic adapter proteins recruited
 At this point, a death-inducing signaling complex (DISC) is
formed, resulting in the autocatalytic activation of procaspase-8.
 Once caspase-8 is activated, the execution phase of apoptosis
is triggered.

30. TNF-like weak inducer of apoptosis -- TWEAK
TNF-related apoptosis-inducing ligand --TRAIL

33. Intrinsic Pathway
Withdrawal of growth factors, loss of apoptotic
suppression, and subsequent activation
of apoptosis.
Other stimuli are radiation, toxins, hypoxia,
hyperthermia, viral infections, and free radicals.

35. These stimuli cause changes in the inner mitochondrial
membrane that results in loss of the mitochondrial
transmembrane potential and release of cytochrome c,
Smac, and the serine protease from the intermembrane
space into the cytosol.

36. 2nd grp. of pro-apoptotic protein-- endonuclease G and CAD
– causes DNA fragmentation & chromatin condensation.
The control and regulation of these apoptotic mitochondrial
events occurs through members of the Bcl-2 proteins.
(Bcl-x,Bcl-XL, Bcl-XS, Bcl-w, BAG, and some of the pro-
apoptotic proteins include Bcl-10, Bax, Bak, Bid, Bad, Bim,
Bik, and Blk).
Special significance as they determine if the cell commits to
apoptosis or aborts the process.

38. Perforin/granzyme Pathway
Involves secretion of the transmembrane pore-forming
molecule perforin with release of cytoplasmic granules
The serine proteases granzyme A and granzyme B are
the most important component within the granules.

39. Granzyme B will
 Cleave proteins at aspartate residues and activate pro-
caspase-10.
Utilize the mitochondrial pathway for amplification of
the death signal.
Directly activate caspase-3.

40. Granzyme A
Activates DNA nicking via DNAse,a tumor suppressor
gene.
Which important role in immune surveillance to
prevent cancer through the induction of tumor cell
apoptosis.

43. Take home massege
 An energy-dependent, asynchronous, genetically
controlled process.
 Important for the development of multicellular organism
(embryonic development) and homeostasis of their tissues
(adult).
 Extrinsic pathway
 Intrinsic pathway
 Disturbance will lead to pathology.