APOPTOSIS
APOPTOSIS
The term “apoptosis” appears in biological literature in1972, to
describe a structurally distinctive mode of cell death leading to the cell loss
within living tissues.Now
a days, it is considered as a cellular the suicidal mechanism that occurs during development of plants, bacteria, invertebrates and
mammals including humans..In Multicellular organisms, apoptosis is
very important, because in these organisms homeostasis is maintained through a
balance between cell multiplication and apoptosis.
Apoptosis may be defined as the programmed
cell death in which the cell actively
participates in bringing about it’s death. During programmed cell death some
changes occur in the apoptotic cell, which are as follows…………….
(i) First a pronounced increase in cell
volume takes place.
(ii) Then the modification of the
cytoskeleton occurs
(iii)
The cell membrane starts to form blebs, or regions that balloon out
(iv)
The nucleus shrinks, condenses, and divides into smaller fragments.
(v)
Finally the entire cell shrinks and divides into large condensed fragments called
apoptotic bodies .
(vi)
Other cells engulf the debris by phagocytosis, thus cleaning up the remnants.
The proteins, lipids, and nucleic acids are all digested and recycled.
Developmental stages of programmed cell
death: Apoptosis
involves many biochemical and cytological events.Cell operates apoptosis
through the activation of “cell’s
intrinsic suicide program” system. Its important machinery appears to be
present in most cells at all times, but the activation of the suicide program
is regulated by many different signals that originate from both intracellular
and extracellular factor (stellar, 1995). Some components of apoptotic program
are established among worms, insects, and vertebrates (Stellar 1995).
Mechanism
of Apoptosis:Molecular
events associated with apoptosis are
(a) Apoptotic (death) signaling
(b)Binding
of apoptotic signal to death receptors and adaptors
(c) Activation of caspases (Death
enzyme)
(d) Cell death and clearance of cell
debris
(a)Apoptotic
(death) signaling:In
response to apoptotic (death) signal/ stimuli cell enters apoptic pathway.Death
receptors translate death signal into metabolic reactions by activating
prodeath enzymes.Death signals are not common to all types of cells. They vary
according to cell type. Death signals may originate from the cell itself or
outside of cell or combination of both.Some of the events that act as signals
for apoptosis are
1.
An increase in reactive oxygen species (ROS).
2.
Collapse of mitochondrial membrane potential that causes release of death
substance cytochromes.
3.
Increased intracellular calcium level.
4.
Loss of essential survival factors.
5.
Radiation exposure, hormones, drugs and toxins action on cell.
6.
Increased intracellular ceramide level.
7.
Increased expression of phosphatidyl serine on outer cell membrane.
8.
Environmental and developmental signals
(b)Binding of
apoptotic signal to death receptors and adaptors: Plasma membrane of most cells possess
different transmembrane proteins which
has the property of receiving extra-cellular signal and subsequently can
transmit these signals into the cytoplasm.These receptors are called death
receptors.The death receptor cannot
directly activate the cytoplasmic enzymes.They depend upon some othe protein
molecules called adaptor proteins.
Each death receptor has three types of domains-
(i)Ligand
or death factor binding domain located on extracellular side,
(ii)a
transmembrane domain and
(iii)death
domains (DDs) located on cytosolic side.
Some known death receptors
are Fas (Apo-1,or CD 95) the receptor for FasL, Tumor necrosis factor receptor
TNFR etc. Some (DEDs). Some known adaptor proteins are FADD (Fas associated
death domain. Apaf-1 (apoptosis protease activating factor-1) and factors released by mitochondria.
(c) Activation of caspases (Death
enzyme): In
addition with death receptor and adaptor apoptotic factors activate death Enzymes like caspases. The caspases, cysteine proteases are of
central importance in the apoptotic signalling network which are activated in
most cases of apoptotic cell death [Bratton, 2000]. Actually, strictly defined,
cell death only can be classified to follow a classical apoptotic mode if
execution of cell death is dependent on caspase activity.The term caspases is
derived from cysteine-dependent aspartate-specific
proteases.Their catalytical activity depends on a critical cysteine-residue
within a highly conserved active-site pentapeptide and the caspases
specifically cleave their substrates after Asp residues.
More than 15 different caspases are identified
in higher organisms.Among them Caspase-1 as well as caspases-4, -5, -11,and –12 appear to be mainly
involved in the proteolytic maturation of pro-inflammatory cytokines and their
contribution to the execution of apoptosis remains questionable In contrast,
gene knockout experiments targeting caspase-3 and caspase-9 resulted in
prenatal mortality, whereas caspase-8 deficient embryos died after day 12.This
and the observation that cell lines derived from those knockout experiments are
resistant to distinct apoptosis stimuli underlines the importance of caspases
as proapoptotic mediators. Indeed, caspase-3, caspase-9, caspase-8, and
additionally caspases-2, -6, -7, and –10 have been recognized to play an
important role in the apoptotic signalling machinery [Earnshaw, 1999].
(d) Cell death and clearance of cell
debris: Apoptosis occurs via a cascade of different enzymes from two
different pathways mainly
(1)Intrinsic apoptosis pathways: Perforin Granzyme Pathway:
This mechanism is discovered by electron microscopy of cultuired CTLS
(cytotoxic T- lymphocyte).Analysis reveal that apoptosis is initiated by pore
forming protein- perforin and several proteases like Granzymes or Fragmentins. The
cells having mannose-6-phosphate receptor, are able to bind with granzyme-B.
Granzyme-B enters in to the cell by the perforin mediated process.After
entry it forms a complex and internalized
in to the cell and appears as vesicles. This apoptotic vesicle initiates
apoptotic pathway.
Besides this,
mitochondria also play a central role in the integration and propagation of
death signals originating from inside the cell such as DNA damage, oxidative
stress, starvation, as well as those induced by chemotherapeutic drugs. Most
apoptosis-inducing conditions involve the disruption of the mitochondrial inner
transmembrane potential (Δψ) as well as the so called permeability transition
(PT). A sudden increase of the inner mitochondrial membrane permeability results
mitochondrial swelling and eventual rupture of the outer mitochondrial
membrane. This is resulting in the release of proapoptotic proteins from the
mitochondrial intermembrane space into the cytoplasm. Released proteins include
cytochrome c, which activates the apoptosome and therefore the caspase cascade.
Other factors such as the apoptosis-inducing factor, inhibitor of ATP synthesis,
redox molecules such as NADH, NADPH, and glutathione are oxidized, and reactive
oxygen species (ROS) are increasingly enhancing apoptotic pathways.
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In case of cell
mediated apoptosis granzyme-B activate procaspase-8 in to active caspase-8,which
in turn activates procaspase-3 in to active caspase-3.Active caspase-3
catalyses whole cell destruction.In other hand, mitochondria act as a target of
granzyme-B,which causes the release of cytochrome-c. Cytochrome-c binds with
the proenzyme forms of caspase-9 and
stimulate its proteolytic activation.The
caspase-9 the activates caspase-3 and active caspase-3 catalyses whole cell
destruction.
(i) Signalling of death is mediated by the
cytoplasmic part of the death receptor which contains a conserved sequence
termed the death domain (DD).
(ii)Adapter molecules like FADD or TRADD
themselves possess their own DDs by which they are recruited to the DDs of the
activated death receptor, thereby forming the so-called death inducing
signalling complex (DISC).
(iii)In addition to its DD, the adaptor FADD
also contains a death effector domain (DED) which through homotypic
DED-DED interaction sequesters procaspase-8 to the DISC.
(iv)As the local concentration of several
procaspase-8 molecules at the DISC leads to their autocatalytic activation and
release of active caspase-8.
(v)Active caspase-8 then processes downstream
effector caspases which subsequently cleave specific substrates resulting in
cell death.
Significance:
1.
Apoptosis
is a process involved in many physiological and developmental processes. It is
a cellular suicidal mechanism that occurs during development. It plays major
role in controlling cell number of
living tissues. It is responsible for removal of unwanted cell.
2.
It plays crucial role in tissue sculpting,
pattern formation and tissue homeostasis.
3.
It
is involved in immunity and inflammation. It has a role in lymphocytes
turnover.Decreased apoptosis is a cause for cancer, autoimmune diseases like
rheumatoid arthritis(RA), systemic lupus erythromatosus etc.
4.
It
is responsible gaps between the human
fingers. It is also responsible for loss of
tadpoles’s tail during amphibian metamorphosis
5. In plants, PCD is a facet of a wide range of
developmental programmes which vary from the beginning of the plant's life
cycle, through essential development ( like xylogenesis), right until the end
of the plant life cycle(senescence) (Beers, 1997; Rogers, 2005)
6. Apoptosis is also important
for senescence and abscission of plant parts.
7. It is also important for
the modification of plant parts.
Q. Distinguish between
Necrosis and Apoptosis. 8
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Necrosis |
Apoptosis |
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1)Necrosis
is a passive, catabolic, pathological cell death process which generally
occurs in response to external toxic factors such as inflammation, ischaemic
or toxic injury 2)
It is not thought to ever occur under physiological conditions 3)
Necrosis is characterized by early rupture of the plasma membrane. 4)
During this dispersed chromatin and early destruction of the intact structure
of the cell. 5)The
swelling of mitochondria and other organelles take place. 6)Loss
of regulation of ion homeostasis takes
place. 7)Usually
necrosis affects a group of cells at a time. 8)Activation
of caspase cascade is not occur. |
1)Apoptosis is
an active,metabolic, genetically encoded and evolutionarily selected death
pathway. 2)
It occurs under either physiological or pathological conditions. 3)
This suicidal pathway is characterized by membrane blebbing, but there is no
loss of membrane integrity 4) During this the appearance of highly
condensed chromatin and activation of an endonucleolytic process, which leads
to the sequential cleavage of chromosomal DNA. 5)Shrinkage
of cytoplasm takes place. Mitochondria becomes leaky. 6)
Ion homeostasis is tightly regulated. 7)Usually
apoptosis affects an individual cell at a time. 8)
Activation of caspase cascade is occur. |
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