INTRODUCTION
CELL STRESS
− alterations in the internal and external cell environment
− external: mechanical stress, infection, hyperthermia / hypothermia, toxins
− internal:
o storage disorders genetic mutations
o energy shortage hypoxia, mitochondrial disorders, starvation
o living and aging
− adaptation: possible / impossible → cell survival / cell death
− causes:
o oxygen deprivation
o physical trauma
o chemical agents
o infectious agents
o inflammation
o immunological reactions
o radiation
o genetic defects
o nutritional imbalances
→ ROS = main mediator of cell damage, electron transport in mitochondria
− hydroxyl radicals:
o cleared by antioxidants
o lipid peroxidation, protein oxidation, DNA damage
CELL DEATH
− apoptosis = programmed cell death process that eliminates damaged or unwanted cells in a
controlled manner
− necrosis = cell death caused by external factors leading to cell swelling and inflammation
− necroptosis = regulated programmed cell death pathway sharing features with both apoptosis and
necrosis
− autophagy = cellular process that degrades and recycles damaged or unnecessary cellular
components
− pryroptosis = highly inflammatory form of cell death associated with the release of pro-
inflammatory molecules
− ferroptosis = regulated cell death driven by iron-dependent lipid peroxidation
CELLULAR SENESCENCE
− state between cell survival and cell death
− a damaged cell can’t be fully restored but it also doesn’t die
− hallmarks:
o cell cycle arrest – irreversible, tumour suppressing
, o apoptosis resistant
o SASP – communicating the compromised state extracellularly
− causes:
o sublethal damage (oxidative stress, DNA damage)
o replicative stress (telomere shortening, dysfunction)
o oncogene activation
o defective apoptotic signalling
− senescent cell burden increases with age → increased damage rate & impaired immune-mediated
removal
CELL SURVIVAL
− atrophy = reduction in cell size and function
− hypertrophy = increase in cell size and function
− hyperplasia = increase in cell numbers
− metaplasia = reversible change in cell type
− dysplasia = abnormal growth and disorganization of cells within a tissue, cell function altered,
premalignant
− labile cells = continuous proliferation → skin and blood cells
− stabile cells = limited regeneration capacity under specific conditions → liver cells
− permanent cells = lost proliferation and regeneration ability in mature tissues → neurons, cardiac
muscle cells
− cancer:
o disturbed cell cycle check – p53/RB system
o disturbed regulation of apoptosis – Bc1 system (role of mitochondria)
o disrupted metabolism – VHL, IDH
LECTURE 2: BASIC MODES of CELL DEATH
− morphogenesis & tissue remodelling → sculpting, deleting unwanted structures
− homeostasis & protection → adjusting cell numbers, eliminating dangerous and injured cells
− terminal differentiation:
o suspended death program for a unique function
o skin cells → cornification
o lens cells → transparency
o red blood cells → oxygen transport
o platelets → blood coagulation
− apoptosis = initiation phase (extrinsic / intrinsic pathway) + execution phase + burial phase
, EXTRINSIC PATHWAY = DEATH RECEPTOR SIGNALLING
− TNF receptor family:
o CD95/Fas, DR4 & DR5 (TRAIL-R1 & TRAL-
R2), TNF
o extracellular receptor domain needs to
be oligomerized
o intracellular domain interacts with the
death proteins
o DD = death domain, DED = death
effector domain, FADD = Fas-associated
protein with DD
− Fas receptor:
o essential for removal of cells that threaten
homeostasis
o autoreactive T cells
o cells that are no longer needed at the
termination of an immune response
o inflammatory cells in a tumour or in immune
privileged tissues (brain, eyes)
o virus-infected cells
− Fas-mediated tumour escape:
o Fas ligand (FasL) is expressed on numerous
tumours of varying origin
o cancer progression associated with
progressively increased FasL expression
o FasL-expressing tumours can induce T cell
apoptosis
o cancer cells can be resistant to Fas-mediated
apoptosis
− CD95/Fas activation:
o regulators (IFN, TNF) bind to the receptors
o ligand oligomerization → activation of the
signalling cascade
o different proteins ligate to the intracellular part,
caspase 1 and 8 = death inducing signalling
complex (DISC)
o mitochondrial signalling
o inhibitors of apoptosis → FLIPs and IAPs →
safety switch
− TNF signalling:
o formation of homotrimers
o default pathway → NF-κB activation for
inflammation and survival
CELL STRESS
− alterations in the internal and external cell environment
− external: mechanical stress, infection, hyperthermia / hypothermia, toxins
− internal:
o storage disorders genetic mutations
o energy shortage hypoxia, mitochondrial disorders, starvation
o living and aging
− adaptation: possible / impossible → cell survival / cell death
− causes:
o oxygen deprivation
o physical trauma
o chemical agents
o infectious agents
o inflammation
o immunological reactions
o radiation
o genetic defects
o nutritional imbalances
→ ROS = main mediator of cell damage, electron transport in mitochondria
− hydroxyl radicals:
o cleared by antioxidants
o lipid peroxidation, protein oxidation, DNA damage
CELL DEATH
− apoptosis = programmed cell death process that eliminates damaged or unwanted cells in a
controlled manner
− necrosis = cell death caused by external factors leading to cell swelling and inflammation
− necroptosis = regulated programmed cell death pathway sharing features with both apoptosis and
necrosis
− autophagy = cellular process that degrades and recycles damaged or unnecessary cellular
components
− pryroptosis = highly inflammatory form of cell death associated with the release of pro-
inflammatory molecules
− ferroptosis = regulated cell death driven by iron-dependent lipid peroxidation
CELLULAR SENESCENCE
− state between cell survival and cell death
− a damaged cell can’t be fully restored but it also doesn’t die
− hallmarks:
o cell cycle arrest – irreversible, tumour suppressing
, o apoptosis resistant
o SASP – communicating the compromised state extracellularly
− causes:
o sublethal damage (oxidative stress, DNA damage)
o replicative stress (telomere shortening, dysfunction)
o oncogene activation
o defective apoptotic signalling
− senescent cell burden increases with age → increased damage rate & impaired immune-mediated
removal
CELL SURVIVAL
− atrophy = reduction in cell size and function
− hypertrophy = increase in cell size and function
− hyperplasia = increase in cell numbers
− metaplasia = reversible change in cell type
− dysplasia = abnormal growth and disorganization of cells within a tissue, cell function altered,
premalignant
− labile cells = continuous proliferation → skin and blood cells
− stabile cells = limited regeneration capacity under specific conditions → liver cells
− permanent cells = lost proliferation and regeneration ability in mature tissues → neurons, cardiac
muscle cells
− cancer:
o disturbed cell cycle check – p53/RB system
o disturbed regulation of apoptosis – Bc1 system (role of mitochondria)
o disrupted metabolism – VHL, IDH
LECTURE 2: BASIC MODES of CELL DEATH
− morphogenesis & tissue remodelling → sculpting, deleting unwanted structures
− homeostasis & protection → adjusting cell numbers, eliminating dangerous and injured cells
− terminal differentiation:
o suspended death program for a unique function
o skin cells → cornification
o lens cells → transparency
o red blood cells → oxygen transport
o platelets → blood coagulation
− apoptosis = initiation phase (extrinsic / intrinsic pathway) + execution phase + burial phase
, EXTRINSIC PATHWAY = DEATH RECEPTOR SIGNALLING
− TNF receptor family:
o CD95/Fas, DR4 & DR5 (TRAIL-R1 & TRAL-
R2), TNF
o extracellular receptor domain needs to
be oligomerized
o intracellular domain interacts with the
death proteins
o DD = death domain, DED = death
effector domain, FADD = Fas-associated
protein with DD
− Fas receptor:
o essential for removal of cells that threaten
homeostasis
o autoreactive T cells
o cells that are no longer needed at the
termination of an immune response
o inflammatory cells in a tumour or in immune
privileged tissues (brain, eyes)
o virus-infected cells
− Fas-mediated tumour escape:
o Fas ligand (FasL) is expressed on numerous
tumours of varying origin
o cancer progression associated with
progressively increased FasL expression
o FasL-expressing tumours can induce T cell
apoptosis
o cancer cells can be resistant to Fas-mediated
apoptosis
− CD95/Fas activation:
o regulators (IFN, TNF) bind to the receptors
o ligand oligomerization → activation of the
signalling cascade
o different proteins ligate to the intracellular part,
caspase 1 and 8 = death inducing signalling
complex (DISC)
o mitochondrial signalling
o inhibitors of apoptosis → FLIPs and IAPs →
safety switch
− TNF signalling:
o formation of homotrimers
o default pathway → NF-κB activation for
inflammation and survival
