APOPTOSIS
LECTURE 1 (SLIDE 1 T/M 29)
Cell death is important for proper functioning of the body. The average red blood cell life time is around 50 days. Sometimes
cell death needs to be initiated in order to grow the correct tissue. Apoptotic bodies will be cleared by neighboring cells.
Cell death can be programmed and it predictable in time and place. A feature from necrotic cells is that they swell and then
burst, but in apoptosis they saw that the cell shrink and then it was not called necrose anymore but apoptosis.
C.elegans is a very good model to study cell death. 15 genes involving cell death were identified and the healthy cells get a
decision to die. They then become committed to die and there is the execution of death. The dead cell is then engulfed by
phagocytes to remove the cell and in the phagocytes there are enzymes that degrade the cell parts. You can see that all
these genes play a role in the programmed cell death of C.elegans cells.
The pathway of the cell death pathway in C.elegans is conserved, in
mammals almost the same pathway is seen but with different genes.
Types of cell death
- Apoptosis: a controlled form of cell death
- Necrosis: an uncontrolled form of cell death (passive)
- Programmed cell death: genetically encoded cell death
- Anoikis: programmed cell death that is induced in
anchorage-dependent cells when they detach from the
surrounding ECM. Anoikis is the cell’s way of killing itself
when it’s in the wrong place, it prevents cells from floating around and growing where they should not grow.
- Autophagic cell death: dying cells displaying a large-scale accumulation of autophagosomes. Autophagy is
considered to be a pro-survival pathway in the dying cell. Cells die with autophagy, rather than by autophagy.
Autophagic cell death refers to cells that are dying while showing high levels of autophagy, which is a survival
response rather than the actual cause of death.
- Necroptosis: controlled form of necrosis
- Pyroptosis: a highly inflammatory form or programmed cell death that occurs most frequently upon infection with
intracellular pathogens and is likely to form part of the antimicrobial response. It is an intermediate between
apoptosis and necrosis, uniquely dependent on caspase-1. It happens when bacteria or viruses are living inside
the cell. Common in immune cells like macrophages
- Parthanatos: a form of programmed cell death caused by severe DNA damage, and it is dependent on PARP-1
which tries to repair the DNA. But when PARP-1 is overactivated it causes cellular energy collapse.
- Ferroptosis: it is a form of programmed cell death caused by excess iron which causes peroxidation of membrane
lipids and this damages the cell membrane and thus the cell dies. It is iron-dependent, non-apoptotic
, - Mitotic catastrophe: due to premature or inappropriate entry of cells into mitosis leading to programmed cell death,
often induced by radiation, chemotherapeutic drugs, or hyperthermia.
- NETosis: pathogen-induced cell death of neutrophils, which excrete their DNA leading to Neurophil Extracellular
Traps that are able to catch and kill extracellular pathogens
There are a lot of forms of cell death and they
can be regulated and this can be differentiated
into apoptotic or non-apoptotic cell death.
Each pathway is a form of cell “suicide”, where
specific pro-death proteins are expressed
and/or post-translationally modified to
promote death, or as a form of cell “sabotage”,
where cell death results from disruption of the
operation of an essential process, leading to
cellular dysfunction and death without the
involvement of dedicated cell death machinery.
Apoptosis is playing an important role in development for example for sculpting, digit formation, deleting unwanted
structures, controlling cell numbers and eliminating nonfunctional, harmful, abnormal or misplaced cells. The almost-dead
cells are specialized cells that undergo programmed cell death, for example skin tissue that constantly renew. Platelets
and red blood cells do not have a nucleus which means that they die in a certain time. This is good for their function because
they can transport oxygen or make sure that blood clots, and these cells have to be renewed again. So these are called
almost-dead cells.
When faced with potentially oncogenic alterations, individual cells can respond in several ways, depending on the
circumstances. Upon oncogenic activation followed by DNA damage accumulation and hyper-replication, normal cells
enter a pre- neoplastic state. If DNA damage is too extended, cells undergo apoptosis. Otherwise, a permanent cell cycle
arrest, distinctive of the senescent state, guarantees a tumorigenic barrier. Bypassing the senescence barrier leads cells to
transformation and cancer spreading. Restoration of senescence in cancer cells might represent a strategy to neutralize
tumor growth. So, depending on the damage that cells have when they are pre-neoplastic, they can have different fates.
They can become transformed into cancer, they can go into senescence, or they can go into apoptosis. During senescence,
cells undergo an apparently permanent growth arrest but remain in a stable and metabolically viable state accompanied
by some characteristic features (flattened and enlarged appearance).
Necrosis is just rupturing of the cells so there is no biochemical process
involved in necrosis. In apoptosis specialized programs need to be
executed to kill these cells. Cells are maintained by a complex of
signaling including growth factors, cytokines, nutrients, and other
information derived from their association with ECM or other cells. These
signals are countered by various stimuli, such as toxins, catabolic
hormones, death domain signaling molecules, and several physiological
parameters. These signals are integrated and the cell commits to a death
pathway. Cell death proceeds most frequently through apoptosis via
caspase-9 activation and a mitochondrial route or via caspase 8 to
caspase 3 as a primary effector caspase (here energy is needed for
apoptosis!!, if energy is depleted then it shifts to necrosis). If the cell is
severely injured so that its membrane permeability is compromised, it
might become necrotic. The cell may also deplete its energy resources
and starts an apoptotic pathway but can then revert to necrosis and this
happens most often when phagocytosis is compromised by massive toxic
death.
Apoptosis is a controlled process to deplete cells without cell lysis, so
cellular contents is not released in extracellular space. Apoptosis is
important for development, growth, maintenance, and the immune
system.
, During apoptosis cells shrink. There is membrane blebbing op apoptotic cells. Mitochondrial networks become fragmented
and there is condensation of the nuclear material leading to more condensed structures.
In apoptosis, the plasma
membrane remains
intact during apoptosis,
and in necrosis the
membrane breaks
down. By necrosis the
cell swells by taking up
water and then the
mitochondrion changes
and then the membrane
breakdown and the
intracellular contents
will be released. There
will be no inflammatory
response in apoptosis,
unless there is
secondary necrosis
where apoptotic bodies
are ruptured and will be
removed by secondary
necrosis.
LECTURE 1 (SLIDE 1 T/M 29)
Cell death is important for proper functioning of the body. The average red blood cell life time is around 50 days. Sometimes
cell death needs to be initiated in order to grow the correct tissue. Apoptotic bodies will be cleared by neighboring cells.
Cell death can be programmed and it predictable in time and place. A feature from necrotic cells is that they swell and then
burst, but in apoptosis they saw that the cell shrink and then it was not called necrose anymore but apoptosis.
C.elegans is a very good model to study cell death. 15 genes involving cell death were identified and the healthy cells get a
decision to die. They then become committed to die and there is the execution of death. The dead cell is then engulfed by
phagocytes to remove the cell and in the phagocytes there are enzymes that degrade the cell parts. You can see that all
these genes play a role in the programmed cell death of C.elegans cells.
The pathway of the cell death pathway in C.elegans is conserved, in
mammals almost the same pathway is seen but with different genes.
Types of cell death
- Apoptosis: a controlled form of cell death
- Necrosis: an uncontrolled form of cell death (passive)
- Programmed cell death: genetically encoded cell death
- Anoikis: programmed cell death that is induced in
anchorage-dependent cells when they detach from the
surrounding ECM. Anoikis is the cell’s way of killing itself
when it’s in the wrong place, it prevents cells from floating around and growing where they should not grow.
- Autophagic cell death: dying cells displaying a large-scale accumulation of autophagosomes. Autophagy is
considered to be a pro-survival pathway in the dying cell. Cells die with autophagy, rather than by autophagy.
Autophagic cell death refers to cells that are dying while showing high levels of autophagy, which is a survival
response rather than the actual cause of death.
- Necroptosis: controlled form of necrosis
- Pyroptosis: a highly inflammatory form or programmed cell death that occurs most frequently upon infection with
intracellular pathogens and is likely to form part of the antimicrobial response. It is an intermediate between
apoptosis and necrosis, uniquely dependent on caspase-1. It happens when bacteria or viruses are living inside
the cell. Common in immune cells like macrophages
- Parthanatos: a form of programmed cell death caused by severe DNA damage, and it is dependent on PARP-1
which tries to repair the DNA. But when PARP-1 is overactivated it causes cellular energy collapse.
- Ferroptosis: it is a form of programmed cell death caused by excess iron which causes peroxidation of membrane
lipids and this damages the cell membrane and thus the cell dies. It is iron-dependent, non-apoptotic
, - Mitotic catastrophe: due to premature or inappropriate entry of cells into mitosis leading to programmed cell death,
often induced by radiation, chemotherapeutic drugs, or hyperthermia.
- NETosis: pathogen-induced cell death of neutrophils, which excrete their DNA leading to Neurophil Extracellular
Traps that are able to catch and kill extracellular pathogens
There are a lot of forms of cell death and they
can be regulated and this can be differentiated
into apoptotic or non-apoptotic cell death.
Each pathway is a form of cell “suicide”, where
specific pro-death proteins are expressed
and/or post-translationally modified to
promote death, or as a form of cell “sabotage”,
where cell death results from disruption of the
operation of an essential process, leading to
cellular dysfunction and death without the
involvement of dedicated cell death machinery.
Apoptosis is playing an important role in development for example for sculpting, digit formation, deleting unwanted
structures, controlling cell numbers and eliminating nonfunctional, harmful, abnormal or misplaced cells. The almost-dead
cells are specialized cells that undergo programmed cell death, for example skin tissue that constantly renew. Platelets
and red blood cells do not have a nucleus which means that they die in a certain time. This is good for their function because
they can transport oxygen or make sure that blood clots, and these cells have to be renewed again. So these are called
almost-dead cells.
When faced with potentially oncogenic alterations, individual cells can respond in several ways, depending on the
circumstances. Upon oncogenic activation followed by DNA damage accumulation and hyper-replication, normal cells
enter a pre- neoplastic state. If DNA damage is too extended, cells undergo apoptosis. Otherwise, a permanent cell cycle
arrest, distinctive of the senescent state, guarantees a tumorigenic barrier. Bypassing the senescence barrier leads cells to
transformation and cancer spreading. Restoration of senescence in cancer cells might represent a strategy to neutralize
tumor growth. So, depending on the damage that cells have when they are pre-neoplastic, they can have different fates.
They can become transformed into cancer, they can go into senescence, or they can go into apoptosis. During senescence,
cells undergo an apparently permanent growth arrest but remain in a stable and metabolically viable state accompanied
by some characteristic features (flattened and enlarged appearance).
Necrosis is just rupturing of the cells so there is no biochemical process
involved in necrosis. In apoptosis specialized programs need to be
executed to kill these cells. Cells are maintained by a complex of
signaling including growth factors, cytokines, nutrients, and other
information derived from their association with ECM or other cells. These
signals are countered by various stimuli, such as toxins, catabolic
hormones, death domain signaling molecules, and several physiological
parameters. These signals are integrated and the cell commits to a death
pathway. Cell death proceeds most frequently through apoptosis via
caspase-9 activation and a mitochondrial route or via caspase 8 to
caspase 3 as a primary effector caspase (here energy is needed for
apoptosis!!, if energy is depleted then it shifts to necrosis). If the cell is
severely injured so that its membrane permeability is compromised, it
might become necrotic. The cell may also deplete its energy resources
and starts an apoptotic pathway but can then revert to necrosis and this
happens most often when phagocytosis is compromised by massive toxic
death.
Apoptosis is a controlled process to deplete cells without cell lysis, so
cellular contents is not released in extracellular space. Apoptosis is
important for development, growth, maintenance, and the immune
system.
, During apoptosis cells shrink. There is membrane blebbing op apoptotic cells. Mitochondrial networks become fragmented
and there is condensation of the nuclear material leading to more condensed structures.
In apoptosis, the plasma
membrane remains
intact during apoptosis,
and in necrosis the
membrane breaks
down. By necrosis the
cell swells by taking up
water and then the
mitochondrion changes
and then the membrane
breakdown and the
intracellular contents
will be released. There
will be no inflammatory
response in apoptosis,
unless there is
secondary necrosis
where apoptotic bodies
are ruptured and will be
removed by secondary
necrosis.
