Types & Mechanism

1. CELL DEATH: BENEFICIAL, DETRIMENTAL
OR NO EFFECT
By,
Md. Sabbir Hossain,
Dept. of Fish Health Management,
Sylhet Agricultural University, Sylhet-3100

2. Content
 Cell Death
 Type I Cell Death
 Type II Cell Death
 Type III Cell Death
 Cornification
 Consequences of Faulty Cell Death

3. Cell Death
 The rate of cell growth and cell death is balanced to maintain the
weight of the body.
 Cell death is a fundamental pathophysiological process and also an
essential event in normal life and development.
 Cell death is a critical and active process that maintains tissue
homeostasis and eliminates potentially harmful cells.
(Green and Llambi, 2015)
 This may be the result of the natural process of old cells dying and
being replaced by new ones, or may result from such factors as
disease, localized injury, or the death of the organism of which the
cells are part

4. Cell Death Types
 There are three major types of
morphologically distinct cell death:
(Galluzzi et al. 2007).
Apoptosis (type I),
Autophagic cell death (type II)
Necrosis (type III).
 Apoptosis or Type I cell-death, and
autophagy or Type II cell-death are
both forms of programmed cell death,
while necrosis is a non-physiological
process that occurs as a result of
infection or injury.

5.  Apoptosis is a form of programmed
cell death, or “cellular suicide.”
 ‘Apoptosis’ is the original term
introduced by Kerr et al. (1972) to
define a type of cell death with
specific morphological features.
 These changes include
Type I Cell Death - Apoptosis
• Plasma membrane blebbing
• Cell shrinkage
• Nuclear fragmentation (karyorrhexis)
• Chromatin condensation (pyknosis)
• Chromosomal DNA fragmentation etc.

6. Cause of Apoptosis
 Physiological Apoptosis
 Pathological Apoptosis
 Removal of excess cells during embryogenesis
 Elimination of potentially harmful cells
 Cell deletion in proliferating cell population
(intestinal epithelium) etc.
 Eliminating neoplastic cells
 Cells infected by virus
 Cells with damaged DNA caused by
radiation, hypoxia, anticancer drugs etc.

7. Caspase
# Apoptotic cell death accompanied by the activation of caspase proteases
(Galluzzi et al. 2012).
* Casepases are Family of Proteins- main executors of the apoptotic process.
* They belong to a group of enzymes known as cysteine proteases.
* Caspase 8 and 10- initiator (extrinsic)
* Caspase 9- initiator (intrinsic)
* Lead to effector caspase 3 and 6
* Cleave key cellular proteins

8. Apoptosis: Pathways
1. Extrinsic Pathway

Death Ligand

Death Receptors

DISC

Initiator Caspase 8

Effector Caspase 3

Cell Death
2. Intrinsic Pathway

Mitochondria

Cytochrome C

APAF-1

Apoptosome Complex

Initiator Caspase 9

Effector Caspase 3

Cell Death

9. Apoptosis: Pathways
Common Pathway
Initiator caspases (8,9,10)
Convert procaspase 3,6,7 to caspase 3,6,7
Activate Endonuclease
Degrades chromosomal DNA and chromatin condensation
Executional caspases causes disintegration of the cells into apoptotic body
Phagocytosis by macrophages







10. Type II Cell Death - Autophagy
# Autophagy is the natural, regulated mechanism of the
cell that disassembles unnecessary or dysfunctional
components.
# It allows the orderly degradation and recycling of
cellular components.
# Autophagy serves as a protective mechanism that
facilitates the degradation of superfluous or damaged
cellular constituents, although hyper activation of
autophagy can lead to cell death so-called type II
programmed cell death (PCD) or Autophagic Cell Death
(Esclatine et al., 2009; Klionsky, 2005).
# Distinct From type I PCD (apoptosis) and From
Necrosis

11. Type II Cell Death - Autophagy
 In addition to stress management, autophagy is
involved in
 Cancer
 Myopathies
 Neurodegeneration
 Heart and Liver Diseases
 Gastrointestinal Disorders
 Autophagy also has a role in many
pathophysiologies, such as
 Normal Development
 Senescence
 Lifespan Extension
 Immunity and Defense against
Microbial Invasion

12. Autophagic Cell Death
 ‘Autophagic cell death’ is morphologically defined (especially by
transmission electron microscopy) as a type of cell death that occurs in the
absence of chromatin condensation but accompanied by massive autophagic
vacuolization of the cytoplasm.
 Although the expression ‘autophagic cell death’ is a linguistic invitation to
believe that cell death is executed by autophagy, the term simply describes
cell death with autophagy.
(Galluzzi et al., 2008; Levine and Yuan, 2005; Galluzzi et al., 2007)

13. Types of Autophagy
 According to the different pathways by which
cargo is delivered to the lysosome or vacuole,
Autophagy is divided into three main types:
Chaperone-mediated autophagy (CMA),
Microautophagy & Macroautophagy.
(Klionsky, 2005)
 Macroautophagy,- Macroautophagy is the
main pathway, used primarily to eradicate
damaged cell organelles or unused proteins
(Levine et al., 2011)
 Microautophagy, Microautophagy, involves the
direct engulfment of cytoplasmic material into
the lysosome
(Castro-Obregon and Susana, 2010)

14.  Chaperone-mediated autophagy, or CMA, is a very complex and specific
pathway, which involves the recognition by the hsc70-containing complex
(Česen et al., 2012; Bandyopadhyay et al., 2008)
 This means that a protein must contain the recognition site for this hsc70
complex to bind with chaperone, forming the CMA- substrate/chaperone
complex (K.S.
Homma, 2011)
 This complex then moves to the lysosomal membrane-bound protein that will
recognize and bind with the CMA receptor, allowing it to enter the cell.
 Although autophagy is generally considered to be nonspecific, there are many
examples of selective autophagy including
 Mitophagy (for mitochondria)
 Ribophagy (for ribosomes)
 Pexophagy (for peroxisomes) and
 Reticulophagy (for the endoplasmic reticulum, ER) (He and Klionsky,
2009)

15. Autophagy: Mechanism
 Autophagy is characterized by the sequestration of cytoplasmic material
within autophagosomes for bulk degradation by lysosomes.
 Autophagosomes, are two-membraned and contain degenerating cytoplasmic
organelles or cytosol
 The fusion between autophagosomes and lysosomes generates
autolysosomes, in which both the autophagosome inner membrane and its
luminal content are degraded by acidic lysosomal hydrolases.
 This catabolic process marks the completion of the autophagic pathway.
 The process of autophagy involves four key steps—

16. Autophagy: Mechanism
 Initiation
 Nucleation and
Elongation
 Fusion of autophagosome
and lysosome
 Hydrolyzation (Chen et al.
2018)

17. Type III Cell Death - Necrosis
# The death of most or all of the cells in an organ or tissue due to disease,
injury, or failure of the blood supply.
# A classical positive definition of
necrosis based on morphological criteria
(early plasma membrane rupture and
dilatation of cytoplasmic organelles, in
particular mitochondria)
# The idea that necrosis constitutes a
default cell death pathway is supported
by the observation that inhibition of
essential apoptotic events plus inhibition
of autophagy can induce necrosis

18. Type III Cell Death - Necrosis
 Causes of Necrosis
 Necrotic changes in tissues are caused by
 Anoxia
 Ischemia
 Physical agents
 Chemical agents
 Biological agents
 Hypersenstivity
 Digestion of cell by enzymes
 Denaturation of proteins
 Changes in Necrosis
 Changes inside the Cell
 Changes in Mitochondria
 Changes in Nucleus
 Changes in Cytoplasm

19. Type III Cell Death - Necrosis
 Changes inside the Cell  Changes in Mitochondria
 Changes in Nucleus
 Changes in Cytoplasm
 Endoplasmic reticulum is
disorganized
 There is rupture of membrane
 Ribosomes are shed off
 Disorganization of polysomes &
their structures
 Mitochondria become swallow
 Loss of intra-mitochondrial granules
 Loss of cristae & change their shape
 Rupture of outer membrane of
Mitochondria
 Pyknosis (Chromatin
Condensation)
 Karyorrhexis (Nuclear
Fragmentation)
 Karyolysis (dissolution of
a cell nucleus
 Cytoplasm becomes more
eosinophilic
 Cytoplasm becomes opaque.

20. Types of Necrosis
There are six distinctive morphological patterns of necrosis:
 Coagulative necrosis
 Liquefactive necrosis
 Gangrenous necrosis
 Caseous necrosis
 Fat necrosis
 Fibrinoid necrosis
(Kumar et al., 2010).

21.  Coagulative necrosis - formation of a gelatinous (gel-like) substance
in dead tissues
 Typically seen in hypoxic (low-oxygen) environments, such as
infarction.
 Occurs in kidney, heart and adrenal glands
 Coagulative necrosis
 Liquefactive necrosis
Liquefactive necrosis (or colliquative necrosis)-digestion of dead
cells to form a viscous liquid mass
 Necrotic liquid mass is frequently creamy yellow due to the
presence of dead leukocytes and is commonly known as pus
Hypoxic infarcts in the brain presents as this type of necrosis
 Gangrenous necrosis
Resembles mummified tissue
It is characteristic of ischemia of lower limb and the gastrointestinal
tracts

22.  Caseous necrosis
 Fat necrosis
 Fibrinoid necrosis
Fat necrosis is specialized necrosis of fat tissue
Resulting from the action of activated lipases on fatty tissues such
as the pancreas
It leads to acute pancreatitis
 A combination of coagulative and liquefactive necrosis
 Typically caused by mycobacteria (e.g. tuberculosis), fungi and
some foreign substances.
 The necrotic tissue appears as white and friable, like clumped
cheese
A special form of necrosis usually caused by immune-mediated
vascular damage.
It is marked by complexes of antigen and antibodies, sometimes
referred to as ‘immune complexes’ within arterial walls with Fibrin

23. Another Type of Cell Death: Cornification
 The process by which squamous epithelial cells in vertebrate animals develop
into tough protective layers or structures such as hair, hooves, and the outer
layer of skin;
 The final stage of keratinization.
 Cornification is a very specific form of PCD that occurs in the epidermis,
morphologically and biochemically distinct from apoptosis
 It leads to the formation of corneocytes (dead keratinocytes containing an
amalgam of specific proteins and lipids)
 Which are necessary for the function of the cornified skin layer (mechanical
resistance, elasticity, water repellence and structural stability)

24. Cornification follows a specific
mechanism of epithelial
differentiation.
This process needs Enzyme
(Transglutaminase types 1, 3 and
5) & Substrates (loricrin, SPR,
involucrin and SP100) for building
up the epithelial barrier
Cornification: Mechanism
Proteases are required for impermeability and desquamation.
Synthesised specific lipids are released into the extracellular space and
attached with cornified enveloped protiens.

25. Consequences of Faulty Cell Death during Development
 Deregulation of the signaling pathways trigger cell death that can lead to
the development of catastrophic diseases. Such as-
 Too little cell death – Cancer, Autoimmunity, Atherosclerosis
 Too much cell death - Neurodegenerative diseases, Tissue atrophy
 A variety of human congenital conditions such as
• Syndactyly ally
• Failure of neural tube closure
• Cleft palate
• Congenital heart defects
 The existence of diverse regulated cell death pathways implicates the
complexity of cell death programs but also provides novel therapeutic
targets.

26. HAVE ANY QUESTIONS?
K