Cell death in life and disease
INTRODUCTION
Alterations in the internal and external cell environment
- Mechanical stress
- Infection
- Hyperthermia
- Hypothermia
- Toxins
- Storage disorders (genetic mutations)
- Energy shortage (hypoxia, mitochondrial disorders, starvation)
- Living and ageing
If it is possible for cells to adapt in the case of stress, then we have cell
survival:
atrophy (reduction in size and function of cell)
hypotrophy (increase in cell size and function)
hyperplasia (increase in cell number) (Benign prostatic hyperplasia
which is age-related, has an unclear specific cause and androgens
are involved)
metaplasia (change in differentiation state) (Barret’s esophagus:
adaptation to chronic acid exposure which leads to stratified
squamous epithelial à simple columnar epithelium and goblet cells
occur which are present normally only in the intestine)
dysplasia (disorganized tissue structure) (dysplasia in the uterine
cervix which is premalignant and can be monitored)
Otherwise, we have cell death.
Cell death can be due to apoptosis, necrosis, necroptosis, ferroptosis,
autophagy and pyroptosis. This may lead to inflammation.
Cellular senescence: the damaged cell cannot be fully restored but it
cannot also die. During aging there is accumulation of these cells.
Hallmarks:
1. cell cycle arrest
2. apoptosis resistance
3. SASP (senescence associated secretory phenotype) production.
Causes:
1. Oxidative stress
2. DNA damage
3. Replicative stress (telomere shortening/dysfunction)
4. Oncogene activation/defective apoptotic signal
,The senescence cell burden accumulates strongly with age à increase
rate of damage & impaired immune mediated removal play important
roles.
Different type of cells:
labile: constantly proliferating.
stabile: only proliferate when they get a signal.
permanent: no division
In cancer we have uncontrolled cell proliferation, at bigger rates than
apoptosis.
Cell cycle visualization: Cdt1 (licensing factor) is expressed in G1 but
degraded by geminin (DNA replication licensing inhibitor) from S-phase on.
The main mediator of cell damage is ROS: reactive oxygen species. They
can be caused by oxygen deprivation, physical trauma, chemical agents,
infectious agents, inflammation, radiation, immunological reactions,
genetic defects and nutritional imbalances.
O2 needs to accept 4 electrons to form 2H 2O.
Effects of hydroxyl radicals:
- lipid peroxidation
- protein oxidation
- DNA damage
Hemochromatosis: iron storage disease due to HFe mutation à
dysregulation hepcidin expression (too low) and dysregulation in iron
uptake (no uptake stop in intestines). Fe (II) is toxic to cells while Fe (II) is
not. This oxidation is done via the Fenton reaction.
Results of hemochromatosis on the cellular and tissue level:
- Chronic damage to membranes, proteins and DNA in cells with Fe
(II)
- Membrane disintegration à cell death and arachidonic acid
formation
- Cell renewal leads to more necrosis of cells which leads to
inflammation and repair à excessive scarring.
Ischemia: no oxygen present, no oxidative phosphorylation, lower
amounts of ATP, ATP-dependent Na+ K+ exchanger doesn’t not work
anymore, increase of Na, pH goes down, the cell exports Na and imports
Ca2+, which is a trigger for phospholipase activity, massive cell membrane
damage, Ca influx, necrosis.
BASIC MODELS OF CELL DEATH
Why there are so many cell death mechanisms:
, - Homeostasis: morphogenesis and tissue remodeling à deleting
unwanted structures
- Protections: eliminating dangerous cells and injured cells
Terminal differentiation
Some cells have a suspended death program for a unique function:
Skin cells for cornification
Lens cells for transparency
Red blood cells for oxygen transport
Platelets for blood coagulation
Apoptotic pathway:
1. Initiation phase
- Extrinsic pathway controlled by the death receptor pathway.
o TNF family death receptors: death domain interact with death
effector domains à initiation of pathway. Crucial for immune
regulation, removal of cells that threaten homeostasis (either
immune cells or virus-infected cells)
o TNF receptor family members: CD95/Fas receptor, DR4 (TRAIL-
R1) and DR5 (TRAIL-R2) receptors, TNF receptors
o The Fas receptor is essential for the removal of cells that
threaten homeostasis. Those can be:
Immune cells: Autoreactive T cells with the potential to
attack "self" are removed by apoptosis. At the termination
of an immune response when they are no longer needed.
Inflammatory cells in immune privileged tissues (brain,
eyes, testis). Inflammatory cells in a tumor
Virus-infected cells
o Fas-mediated immune escape of tumors
FasL is de novo expressed on
numerous tumors of varying
origin.
Cancer progression is
associated with
progressively increased FasL
expression.
Injection of FasL-expressing
melanoma cells into Fas deficient mice results in delayed
tumor growth compared with that in wild-type mice.
FasL-expressing tumors can induce T cell apoptosis.
Cancer cells can be resistant to Fas-mediated apoptosis.
o DISC: death inducing signaling complex binds to the FAS
receptor and leads to apoptosis and mitochondrial signaling.
o TNF: tumor necrosis signaling pathway. NF-κB (p55+p65) is
activated and promotes survival by recruiting inflammatory
factors. Inflammation factors are needed to recruit immune cells
and combat inflammation. Prolonged activation leads to the
INTRODUCTION
Alterations in the internal and external cell environment
- Mechanical stress
- Infection
- Hyperthermia
- Hypothermia
- Toxins
- Storage disorders (genetic mutations)
- Energy shortage (hypoxia, mitochondrial disorders, starvation)
- Living and ageing
If it is possible for cells to adapt in the case of stress, then we have cell
survival:
atrophy (reduction in size and function of cell)
hypotrophy (increase in cell size and function)
hyperplasia (increase in cell number) (Benign prostatic hyperplasia
which is age-related, has an unclear specific cause and androgens
are involved)
metaplasia (change in differentiation state) (Barret’s esophagus:
adaptation to chronic acid exposure which leads to stratified
squamous epithelial à simple columnar epithelium and goblet cells
occur which are present normally only in the intestine)
dysplasia (disorganized tissue structure) (dysplasia in the uterine
cervix which is premalignant and can be monitored)
Otherwise, we have cell death.
Cell death can be due to apoptosis, necrosis, necroptosis, ferroptosis,
autophagy and pyroptosis. This may lead to inflammation.
Cellular senescence: the damaged cell cannot be fully restored but it
cannot also die. During aging there is accumulation of these cells.
Hallmarks:
1. cell cycle arrest
2. apoptosis resistance
3. SASP (senescence associated secretory phenotype) production.
Causes:
1. Oxidative stress
2. DNA damage
3. Replicative stress (telomere shortening/dysfunction)
4. Oncogene activation/defective apoptotic signal
,The senescence cell burden accumulates strongly with age à increase
rate of damage & impaired immune mediated removal play important
roles.
Different type of cells:
labile: constantly proliferating.
stabile: only proliferate when they get a signal.
permanent: no division
In cancer we have uncontrolled cell proliferation, at bigger rates than
apoptosis.
Cell cycle visualization: Cdt1 (licensing factor) is expressed in G1 but
degraded by geminin (DNA replication licensing inhibitor) from S-phase on.
The main mediator of cell damage is ROS: reactive oxygen species. They
can be caused by oxygen deprivation, physical trauma, chemical agents,
infectious agents, inflammation, radiation, immunological reactions,
genetic defects and nutritional imbalances.
O2 needs to accept 4 electrons to form 2H 2O.
Effects of hydroxyl radicals:
- lipid peroxidation
- protein oxidation
- DNA damage
Hemochromatosis: iron storage disease due to HFe mutation à
dysregulation hepcidin expression (too low) and dysregulation in iron
uptake (no uptake stop in intestines). Fe (II) is toxic to cells while Fe (II) is
not. This oxidation is done via the Fenton reaction.
Results of hemochromatosis on the cellular and tissue level:
- Chronic damage to membranes, proteins and DNA in cells with Fe
(II)
- Membrane disintegration à cell death and arachidonic acid
formation
- Cell renewal leads to more necrosis of cells which leads to
inflammation and repair à excessive scarring.
Ischemia: no oxygen present, no oxidative phosphorylation, lower
amounts of ATP, ATP-dependent Na+ K+ exchanger doesn’t not work
anymore, increase of Na, pH goes down, the cell exports Na and imports
Ca2+, which is a trigger for phospholipase activity, massive cell membrane
damage, Ca influx, necrosis.
BASIC MODELS OF CELL DEATH
Why there are so many cell death mechanisms:
, - Homeostasis: morphogenesis and tissue remodeling à deleting
unwanted structures
- Protections: eliminating dangerous cells and injured cells
Terminal differentiation
Some cells have a suspended death program for a unique function:
Skin cells for cornification
Lens cells for transparency
Red blood cells for oxygen transport
Platelets for blood coagulation
Apoptotic pathway:
1. Initiation phase
- Extrinsic pathway controlled by the death receptor pathway.
o TNF family death receptors: death domain interact with death
effector domains à initiation of pathway. Crucial for immune
regulation, removal of cells that threaten homeostasis (either
immune cells or virus-infected cells)
o TNF receptor family members: CD95/Fas receptor, DR4 (TRAIL-
R1) and DR5 (TRAIL-R2) receptors, TNF receptors
o The Fas receptor is essential for the removal of cells that
threaten homeostasis. Those can be:
Immune cells: Autoreactive T cells with the potential to
attack "self" are removed by apoptosis. At the termination
of an immune response when they are no longer needed.
Inflammatory cells in immune privileged tissues (brain,
eyes, testis). Inflammatory cells in a tumor
Virus-infected cells
o Fas-mediated immune escape of tumors
FasL is de novo expressed on
numerous tumors of varying
origin.
Cancer progression is
associated with
progressively increased FasL
expression.
Injection of FasL-expressing
melanoma cells into Fas deficient mice results in delayed
tumor growth compared with that in wild-type mice.
FasL-expressing tumors can induce T cell apoptosis.
Cancer cells can be resistant to Fas-mediated apoptosis.
o DISC: death inducing signaling complex binds to the FAS
receptor and leads to apoptosis and mitochondrial signaling.
o TNF: tumor necrosis signaling pathway. NF-κB (p55+p65) is
activated and promotes survival by recruiting inflammatory
factors. Inflammation factors are needed to recruit immune cells
and combat inflammation. Prolonged activation leads to the
