Programmed and unprogrammed cell death
Programmed cell death
mediated by specific cells
signaling system beneficial for the organism
has been described in plants and animals
participation in ensuring homeostasis
participation in developmental processes
removal of damaged / infected cells
Unprogrammed cell death
arises unregulated from external causes (insults)
Types of cell death
apoptosis (mediated by caspases during development, aging,
or in response to specific stimuli)
autophagy (degradation of cellular components in
lysosomes)
excitotoxicity (al cell death due to excessive activation of
receptors for neurotransmitters)
anoikis (result of the breakdown interactions that anchor
cell in the matrix)
necrosis (trauma-induced nonspecific)
necroptosis (necrosis induced by specific stimuli, without
the involvement of caspases)
Other types of cell death
Aponecrosis
- does not occur completion of cell death, in the end, there are signs of
necrosis
Paraptosis
- It has nothing to do with apoptosis
- striking vacuolation and swelling of mitochondria
Necroptosis
- Similarity to apoptosis
- Necrosis induced by external stimuli through
death receptors, if apoptosis does not occur
Pyroptosis
- Programmed cell death associated with antimicrobial responses
Autophagy
- Catabolic mechanism for the degradation of the cell and recycling of
cellular components
Mitotic catastrophe
Cornification
Anoikis
- Programmed cell death caused by loss of contact
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Different forms of cell death
Cell lysis
Necrosis Apoptosis
Autophagic Death
Blebbing
Chromatin copactation
Cell and nuclear
fragmentation
Apoptotic
bodies
Autolysosome
Lysosome
Preautophagosoma
structure
Autophagic vesicle
Autolysosome
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The potential dual role of
entosis.
When epithelial
cells lose their attachment to
the ECM, cells can undergo,
instead of anoikis, the process
of entosis, which is favored by
forces that are associated with
adherens junctions. In this
intermediate state, where one
cell is inside another, an
important decision can be
made: the internalized cell can
either die or be released from
the host cell, and potentially
reattach to ECM, pointing to a
protective role of entosis.
Bunecna smrt 2017
Physiological proces regulation of cell
homeostasis
(Counterpart to cell division)
Part of embryogenesis and organogenesis:
• It is necessary in the production of body
cavities during morphogenesis of fingers
and toes
• Neuronal death during the formation of
the CNS
• Cell death during the development of
limbs
• Hormonally regulated during the tadpole
tail loss
• Atrophy - atrophy of the mammary gland
in menopause, endometrial cell death
during menstruation
Apoptosis eliminates harmful cells:
• death of cells detected as cells infected
by virus
• cells with damaged DNA
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APOPTOSIS
• Insufficiency can lead to
malignancy, or
autoimmune diseases;
common are adhesions
toes (fig.)
• Conversely, excessive
apoptosis contributes to
neurodegenerative
diseases (Alzheimer,
Parkinson, Huntington's
disease), AIDS, certain
autoimmune diseases,
spinal muscular atrophy,
multiple sclerosis ...
Apoptosis in pathology insufficient
apoptosis
7
Programmed cell death during animal development
Sculpting
Deleting structures
A B
C D
E F G
Eliminating dangerous
or injured cells
Adjusting cell
numbers
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Apoptosis vs. necrosis
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Apoptosis
• Programmed cell death
• It affects individual cells
• Induction by physiological
stimuli
• No inflammatory reaction
• Active process - consumption
of ATP
Necrosis
• It refers to a group of
affected cells
• Caused by non-physiological
injury (viral infections,
hypoxia, metabolic poisons ...)
• inflammatory reaction
Morphological features:
Condensation of the cell and nucleus membrane pouch (,, blebbing ")
Condensation of chromatin, fragmentation of nuclei
Disintegration of cells to apoptotic bodies membrane does not lose
its integrity
Apoptotic bodies are phagocytosed by surrounding cells and
macrophages
Biochemical features:
• Strictly regulated active process requiring energy
• Nonrandom DNA fragmentation (charts electrophoresis)
• Release of specific factors from the mitochondria into the cytoplasm
• activation of caspases
Apoptosis
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Necrosis
Morphological features :
• It starts swelling cytoplasm and mitochondria
• Organelles disintegrate, they do not form vesicles
• Loss of integrity of the cell membrane
• Ends complete lysis
Biochemical features :
• Loss of homeostasis regulation
• Passive process (does not require energy)
• Random degradation and fragmentation of DNA
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Apoptotic cells under microscope
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Regulation of apoptosis
Apoptosis induced:
Loss of contact with the outside environment (anoikis)
irreparable damage
Simultaneous reception of signals for the division and
apoptosis
Receiving death signals
intrinsic
They come from their own cells
"Voluntary" death
extrinsic
They come from surrounding
cells from the external
environment
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Main apoptotic pathway
Extrinsic receptor: ligand binds to the death receptor
and proapoptotic signal is formed. This leads to the
activation of death domain for the participation of
other proteins. The goal is the activation of
procaspases 8.
Intrinsic pathway: by signaling (e.g. via p53) is
initiated apoptosis, whose component is the Bcl-2/Bax,
key organelle is mitochondria, apoptosome complex is
formed and the goal is the activation of procaspases
9.
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Caspase activation by the extrinsic and intrinsic pathways
Smac
IAP
Cyt C
ATP
Apaf-1
Procaspase 9
Apoptosome
Procaspase 3
Caspase 3
Caspase 8
Procaspase 8
DISC
FADD
Fas
FasL
Cleavage of proteins leading to cell death
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adapter protein FADDinteracts
with
monomers of procaspase 8
and stimulates its
oligomerization
DISC („death-inducing signalig complex“),
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Extrinsic (the receptor) pathway of apoptosis
• activated by extrinsic („death“) ligands
• registration of ligand by death receptors
(TNF family) – Fas and TRAIL
• receptors form trimers after activation
• 2 or 3 trimers are connected by ligands
• intracellular domain of death receptors are
activated
• – they interact with other proteins – etc.
adapter protein FADD
• FADD interacts with
monomers of procaspase 8 and stimulates its
dimerization
dimerizatio activates caspases 8, which
activates executioner caspases
(procaspase-3).
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Death receptors
- transmembrane surface receptors
- transmits signals induced
apoptotic death ligands they belong
to the family of receptors TNF
(tumor necrosis factor)
- They can activate caspases within
seconds of ligands binding, causing
removal of the cell within a few
hours
- contain homologous cytoplasmic
death domain, which allows them to
directly interact with apoptotic
apparatus
- extracellular cysteine-rich
domains (in number of two to five
copies)
- intracellular death domain
20
Signaling pathways in apoptosis
21Bunecna smrt 2017
TNFR and DR3 signalization
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Caspases
- group of proteins which function
in initation and progress of
apoptosis
- cysteine proteases
-specifically cleaves aspartic acid
in their substrates
- synthesized in an inactive form
as zymogens
- dividing by the physiological role:
inflammatory and apoptotic
- division according apoptosis: the
initiator and effector
-initiator caspases are -2,-8,-9
and -10
-effector caspases are -3,-6 and
-7
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The main elements are the
mitochondria and
cytochrome c in the space
between the outer and inner
membrane
translocation of cytochrome c
into the cytosol
It is a critical event path
Intrinsic (mitochondrial) signal
apoptosis pathway
Bad
Cytochrome c
Apoptosome
caspases
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Cytochrome c is normally located in the
space between the inner and outer
membrane of mitochondria,
which is involved in electron transport in
oxidative phosphorylation
permeabilized external mit. membrane
diffuses into the intermembrane space
cytosol
Cytochrome c binds to Apaf-1
( "Apoptotic protease activating factor")
Apaf-1 alters the conformation-enable links
dATP
bond dATP conformation with Apaf-1 below
changes - baring oligomerization domain
7 molecules of Apaf-1-links formed
apoptosome
apoptosome binds initiation procaspases 9
molecules procaspases 9 in apoptosome
come in close proximity,
leading to their activation
caspase-9 activates the execution caspases
(caspase 3 and 7
cytochrome c
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cytochrome c released from the mitochondria into the cytosol
binds to Apaf-1
Apaf-1 alters the conformation and oligomerized
in the presence of dATP complex of cytochrome c/Apaf-1
binds and activates procaspases 9 ( "apoptosome")
activated caspase 9 activates another caspase responsible
for apoptotic cell death (caspase 3 or 7)
Apoptosome
Apoptosome is formed in
Cytosol, Cytochrome C is released
from mitochondria
and associates with Apaf-1, So
creates a seven-branched round
wherein the arms are formed
seven subunits Apaf-
1 and their vertices form
cytochrome C (red).
This round attracted
procaspases 9 which binds
the middle/wheel axis (blue)
and activated caspase 9
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proteins Bcl-2
the ratio of anti-apoptotic ( "pro-survival") and proapoptotic
proteins act mutually heterodimers and
mitochondrial permeability
membrane cytochrome c
What decides the cytochrome c
release?
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through BH3 domains or homodimers
heterodimers
homodimers Bax induce apoptosis
Bcl-2 constitutes a protein Bax heterodimer, thereby its
proapoptotic
activity inhibit
ratios factors "pro-death" and
"Pro-survival" Bcl-2 family decisions about cell death
Bcl-2 protein forms dimers
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- pro-apoptotic signals causes
depolarization of the external
mitochondrial membrane and the
assembly of such dimers of
proteins Bcl-2,
which facilitate transfer membrane
cytochrome c into the cytosol,
where it combines with other
proteins and initiates a cascade of
reactions leading to apoptosis
anti-apoptotic signals, leading to
compiling such complexes
Bcl-2 family that cytochrome c
release outside mitochondria
do not allow
Bcl-2 family
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