Summary BMS37. Cell death in life and disease
LE Introduction to the course
All diseases have its origin on the cellular level → cellular stress
Cell stress
= alterations in the internal and external cell environment
- Reaction to stress:
o Adaptation possible → cell survival
o Adaptation impossible → cell death (= apoptosis, necrosis, necroptosis, ferroptosis,
autophagy, pyroptosis) → inflammation?
o Cellular senescence = state between survival and death = damaged cell cannot be restored
but does not die yet
- Survival → adaptations
o Atrophy = reduction in size and function of a cell → when it is not used (for example muscle
cells)
o Hypertrophy = increase in cell size and function (for example in the heart, this will impact
pump function)
o Hyperplasia = increase in cell number
o Metaplasia = change in differentiation state → different structures of the (epithelial) cells, and
cells that are normally not present arise more
o Dysplasia = disorganized tissue structure → can be premalignant (monitor)
- Labile cells = continuously recycling as part of normal health
- Stabile cells = can proliferate but not continuously proliferation, upon specific trigger they will enter
cell cycle and proliferate
- Permanent cells = do not divide, if you lose them they are lost, neuron cells
Cellular senescence
Hallmarks
- Cell cycle arrest; cells have so much damage it is not safe to divide, effectively irreversible
- Apoptosis (intracellular machinery) resistance
- SASP (senescence-associated secretory phenotype) production; gives senescence cells the
ability to show there is something wrong
Caused by:
- (sublethal) oxidative stress
- (sublethal) DNA damage
- Replicative stress (telomere shortening/dysfunction)
- Oncogene activation/defective apoptotic signaling (prevent cancer)
Senescent cell burden accumulates strongly with age → increased rate of damage & impaired
immune-mediated removal
Cancer is a process of uncontrolled cell proliferation (over apoptosis) → cells that should go in
apoptosis or senescence don’t
- Check on cell cycle is disturbed (p53, RB system)
- Regulation of apoptosis is disturbed (Bcl system, role of mitochondria)
- Metabolism is disrupted (VHL, IDH)
1
,Cell cycle visualization (use staining on these factors)
- Cdt1 = licensing factor
→ degraded in S phase by geminin
- Geminin = DNA replication licensing inhibitor
- MCM = DNA helicase, crucial for DNA replication and elongation
Another way to impact progression in cell cycle → HDAC inhibitors (closed chromatin = genes off,
open = on); by blocking you push it towards open, and therefore transcription and differentiation
Causes of stress = oxygen deprivation (ischemia), physical trauma, chemical agents, infectious
agents, inflammation, immunological reactions, radiations, genetic defects ➔ ROS production
(superoxide and hydroxyl radical)
In the ETC: O2 → H2O (O2 accepts 4 electrons to form 2 H2O)
Superoxide → using SOD (antioxidant) → hydrogen peroxide → via CAT → H2O
No such mechanism for hydroxyl radical, some antioxidants but capacity is limited
Effects of hydroxyl radicals: lipid peroxidation, protein oxidation, DNA damage
Hemochromatosis = iron storage disease due to HFe mutation
- Dysregulated hepcidin expression (too low)
- Dysregulated iron uptake (no uptake stop in intestines/macrophages) → too much iron = problem
- Fe(II) is toxic to cells, Fe(III) is not
- In tissue; balance between vitamins, catalase, GSH – Fe(II) (Fenton reaction)
Disturbance leads to OH- hydroxyl radical
- Result of hemochromatosis on cellular and tissue level
o Chronic damage to membranes, proteins and DNA
o Most impact:
▪ Membrane disintegration → cell death and arachidonic acid formation (attraction
inflammatory cells → further damage by ROS release)
▪ Liver can induce cell regeneration (also immune cells involved)
= pathological cycle of necrosis – inflammation and repair – cell renewal
→ excessive scarring
- Increased chance of developing hepatic cancer with hemochromatosis → also damage to other
organs, but also cells with mutational environment will grow
Metabolism and cell death
OXPHOS needs oxygen, but none is available with hypoxia → lack of ability to produce sufficient ATP
→ cell death
Ischemia = reduced blood flow (so less oxygen) → less ATP → decrease in transport via ATP
dependent Na/K exchanger → sodium increase in cells → calcium influx → necrosis
(via anaerobic glycolyisis also calcium influx
Oxidative stress → oxidation of LDL (also marker for oxidative stress) → OxLDL is toxic to
endothelium → macrophage recruitment → accumulation of foam cells → further accumulation of
inflammatory cells
Heart attack on cellular level, organ level and organism level → heart cells (cardiomyocytes) do not
regenerate so you can never fully recover from a heart attack (small scars are fine, very common, but
big can lead to complications)
Smokers lung
- Squamous metaplasia (different types of cells that are normally not there, to work in the best
interest of the body), hyperplasia (stimulate growth), impaired mucus removal → higher risk of
infection, increased inflammation, increased ROS, high DNA mutation load, dysplasia, and cancer
- Histology
normal – metaplasia – mild dysplasia – moderate dysplasia – severe dysplasia, carcinoma in situ
2
,Cell death
- Apoptosis
o Physiological or damage
o Tightly regulated
o Active process
o No inflammation (= better for maintaining homeostasis)
- Necrosis
o Always due to damage from outside
o Inflammation
o Necroptosis = regulated necrosis
Cell → apoptosis
→ autophagy = repairing (restoration of its role) itself after signal → regulated by mTORC1 (stress
signal → integrate signals)
* when there is stress/a lack of nutrients → mTOR is low → activation of autophagy → cleaning out
debris and recycling materials
When it is not safe to divide anymore → cellular senescence
LE Basic models of cell death
Historically there were 3 forms of cell death: apoptosis (type I), autophagy (type II) and necrosis (type
III) → classification is revised into RCD (regulated cell death):
ADCD: autophagy-dependent cell death
ICD: immunogenic cell death
LDCD: lysosome-dependent cell death
MPT: mitochondrial permeability
transition
Morphological and biological hallmarks:
- Apoptosis; normal → condensation (cell blebbing) → fragmentation → secondary necrosis
o Mitochondrial structure preserved, nuclear changes, intact membranes, apoptotic bodies
- Necro(pto)sis; normal → reversible swelling → irreversible swelling → disintegration
o Mitochondrial changes, chromatin pattern conserved, membrane breakdown
Programmed cell death in homeostasis and development
- Morphogenesis and tissue remodeling: sculpting and deleting unwanted structures
- Homeostasis and protection: adjusting cell number, eliminating dangerous cells, eliminating
injured cells
3
, - Terminal differentiation: some cells have a suspended death program for a unique function (skin
cells, lens cells, red blood cells, platelets) = ‘almost-death cells’
Apoptosis
- Initiation phase
o Extrinsic pathway → death receptor signaling
o Intrinsic pathway → mitochondrial signaling (cytochrome C)
- Execution phase
o Caspase cascade
Extrinsic pathway: Death receptor signaling
- TNF receptor family members
o CD95/Fas receptor → Fas pathway
o DR4 (TRAIL-R1) and DR5 (TRAIL-R2) receptors → Trail pathway
o TNF receptor → TNF pathway
The extrinsic Fas pathway
The binding of a death activator (such as FasL) to its
TNF receptor (such as Fas) activates the receptor. The
activated receptor then transmits the apoptotic signal to the
cytoplasm by recruiting FADD (Fas-Associated Death
Domain protein) via its cytoplasmic Death domain, to form
the death-inducing signaling complex (DISC). FADD
contains two domains: a Death domain that binds to the
Death domain on the Fas receptor, and a DED (Death
effector domain) that binds to DED on pro-caspase-8. The
proteolytic activation of caspase-8 leads to its dissociation
from the DISC complex. Active caspase-8 can then initiate
the caspase cascade that leads to apoptosis and
phagocytosis via the proteolytic activation of other
caspases, including caspases-3, -4, -6, -7, -9 and -10.
4
LE Introduction to the course
All diseases have its origin on the cellular level → cellular stress
Cell stress
= alterations in the internal and external cell environment
- Reaction to stress:
o Adaptation possible → cell survival
o Adaptation impossible → cell death (= apoptosis, necrosis, necroptosis, ferroptosis,
autophagy, pyroptosis) → inflammation?
o Cellular senescence = state between survival and death = damaged cell cannot be restored
but does not die yet
- Survival → adaptations
o Atrophy = reduction in size and function of a cell → when it is not used (for example muscle
cells)
o Hypertrophy = increase in cell size and function (for example in the heart, this will impact
pump function)
o Hyperplasia = increase in cell number
o Metaplasia = change in differentiation state → different structures of the (epithelial) cells, and
cells that are normally not present arise more
o Dysplasia = disorganized tissue structure → can be premalignant (monitor)
- Labile cells = continuously recycling as part of normal health
- Stabile cells = can proliferate but not continuously proliferation, upon specific trigger they will enter
cell cycle and proliferate
- Permanent cells = do not divide, if you lose them they are lost, neuron cells
Cellular senescence
Hallmarks
- Cell cycle arrest; cells have so much damage it is not safe to divide, effectively irreversible
- Apoptosis (intracellular machinery) resistance
- SASP (senescence-associated secretory phenotype) production; gives senescence cells the
ability to show there is something wrong
Caused by:
- (sublethal) oxidative stress
- (sublethal) DNA damage
- Replicative stress (telomere shortening/dysfunction)
- Oncogene activation/defective apoptotic signaling (prevent cancer)
Senescent cell burden accumulates strongly with age → increased rate of damage & impaired
immune-mediated removal
Cancer is a process of uncontrolled cell proliferation (over apoptosis) → cells that should go in
apoptosis or senescence don’t
- Check on cell cycle is disturbed (p53, RB system)
- Regulation of apoptosis is disturbed (Bcl system, role of mitochondria)
- Metabolism is disrupted (VHL, IDH)
1
,Cell cycle visualization (use staining on these factors)
- Cdt1 = licensing factor
→ degraded in S phase by geminin
- Geminin = DNA replication licensing inhibitor
- MCM = DNA helicase, crucial for DNA replication and elongation
Another way to impact progression in cell cycle → HDAC inhibitors (closed chromatin = genes off,
open = on); by blocking you push it towards open, and therefore transcription and differentiation
Causes of stress = oxygen deprivation (ischemia), physical trauma, chemical agents, infectious
agents, inflammation, immunological reactions, radiations, genetic defects ➔ ROS production
(superoxide and hydroxyl radical)
In the ETC: O2 → H2O (O2 accepts 4 electrons to form 2 H2O)
Superoxide → using SOD (antioxidant) → hydrogen peroxide → via CAT → H2O
No such mechanism for hydroxyl radical, some antioxidants but capacity is limited
Effects of hydroxyl radicals: lipid peroxidation, protein oxidation, DNA damage
Hemochromatosis = iron storage disease due to HFe mutation
- Dysregulated hepcidin expression (too low)
- Dysregulated iron uptake (no uptake stop in intestines/macrophages) → too much iron = problem
- Fe(II) is toxic to cells, Fe(III) is not
- In tissue; balance between vitamins, catalase, GSH – Fe(II) (Fenton reaction)
Disturbance leads to OH- hydroxyl radical
- Result of hemochromatosis on cellular and tissue level
o Chronic damage to membranes, proteins and DNA
o Most impact:
▪ Membrane disintegration → cell death and arachidonic acid formation (attraction
inflammatory cells → further damage by ROS release)
▪ Liver can induce cell regeneration (also immune cells involved)
= pathological cycle of necrosis – inflammation and repair – cell renewal
→ excessive scarring
- Increased chance of developing hepatic cancer with hemochromatosis → also damage to other
organs, but also cells with mutational environment will grow
Metabolism and cell death
OXPHOS needs oxygen, but none is available with hypoxia → lack of ability to produce sufficient ATP
→ cell death
Ischemia = reduced blood flow (so less oxygen) → less ATP → decrease in transport via ATP
dependent Na/K exchanger → sodium increase in cells → calcium influx → necrosis
(via anaerobic glycolyisis also calcium influx
Oxidative stress → oxidation of LDL (also marker for oxidative stress) → OxLDL is toxic to
endothelium → macrophage recruitment → accumulation of foam cells → further accumulation of
inflammatory cells
Heart attack on cellular level, organ level and organism level → heart cells (cardiomyocytes) do not
regenerate so you can never fully recover from a heart attack (small scars are fine, very common, but
big can lead to complications)
Smokers lung
- Squamous metaplasia (different types of cells that are normally not there, to work in the best
interest of the body), hyperplasia (stimulate growth), impaired mucus removal → higher risk of
infection, increased inflammation, increased ROS, high DNA mutation load, dysplasia, and cancer
- Histology
normal – metaplasia – mild dysplasia – moderate dysplasia – severe dysplasia, carcinoma in situ
2
,Cell death
- Apoptosis
o Physiological or damage
o Tightly regulated
o Active process
o No inflammation (= better for maintaining homeostasis)
- Necrosis
o Always due to damage from outside
o Inflammation
o Necroptosis = regulated necrosis
Cell → apoptosis
→ autophagy = repairing (restoration of its role) itself after signal → regulated by mTORC1 (stress
signal → integrate signals)
* when there is stress/a lack of nutrients → mTOR is low → activation of autophagy → cleaning out
debris and recycling materials
When it is not safe to divide anymore → cellular senescence
LE Basic models of cell death
Historically there were 3 forms of cell death: apoptosis (type I), autophagy (type II) and necrosis (type
III) → classification is revised into RCD (regulated cell death):
ADCD: autophagy-dependent cell death
ICD: immunogenic cell death
LDCD: lysosome-dependent cell death
MPT: mitochondrial permeability
transition
Morphological and biological hallmarks:
- Apoptosis; normal → condensation (cell blebbing) → fragmentation → secondary necrosis
o Mitochondrial structure preserved, nuclear changes, intact membranes, apoptotic bodies
- Necro(pto)sis; normal → reversible swelling → irreversible swelling → disintegration
o Mitochondrial changes, chromatin pattern conserved, membrane breakdown
Programmed cell death in homeostasis and development
- Morphogenesis and tissue remodeling: sculpting and deleting unwanted structures
- Homeostasis and protection: adjusting cell number, eliminating dangerous cells, eliminating
injured cells
3
, - Terminal differentiation: some cells have a suspended death program for a unique function (skin
cells, lens cells, red blood cells, platelets) = ‘almost-death cells’
Apoptosis
- Initiation phase
o Extrinsic pathway → death receptor signaling
o Intrinsic pathway → mitochondrial signaling (cytochrome C)
- Execution phase
o Caspase cascade
Extrinsic pathway: Death receptor signaling
- TNF receptor family members
o CD95/Fas receptor → Fas pathway
o DR4 (TRAIL-R1) and DR5 (TRAIL-R2) receptors → Trail pathway
o TNF receptor → TNF pathway
The extrinsic Fas pathway
The binding of a death activator (such as FasL) to its
TNF receptor (such as Fas) activates the receptor. The
activated receptor then transmits the apoptotic signal to the
cytoplasm by recruiting FADD (Fas-Associated Death
Domain protein) via its cytoplasmic Death domain, to form
the death-inducing signaling complex (DISC). FADD
contains two domains: a Death domain that binds to the
Death domain on the Fas receptor, and a DED (Death
effector domain) that binds to DED on pro-caspase-8. The
proteolytic activation of caspase-8 leads to its dissociation
from the DISC complex. Active caspase-8 can then initiate
the caspase cascade that leads to apoptosis and
phagocytosis via the proteolytic activation of other
caspases, including caspases-3, -4, -6, -7, -9 and -10.
4
