MCM Final - Cell Death and Adaptations Flashcards
apoptotic bodies
small, membrane-bound vesicles occur from membrane blebbing from cell
apoptosis
programmed cell death
no inflammation
cell shrinks, degrades, forms apoptotic bodies, induces membrane signaling (phosphatidylserine
membrane signaling during apoptosis?
phosphatidylserine from inner leaflet to outer leaflet
-signals for phagocytes
no inflammation response**
necrosis
cell death due to trauma
-cells swells and ruptures
**leads to inflammation response
when does apoptosis occur?
eliminate unwanted cells
-development loss of cells to form digits
quality control
-get rid of nonfunctional cells
homestasis of cell death and cell division important
caspase
protease during apoptosis
active site - cysteine - cleaves target aspartic acid
synthesized as zymogen (pro-caspase)
-activated by other caspases
initiator caspases
cleave and activate downstream caspase
have CARD domain that assemble in activation complex
executioner caspases
cleave and activate other caspases and target proteins
target proteins: nuclear lamins, endonuclease inhibiting enzyme, cytoskeleton, adhesion proteins
endonuclease inhibiting enzyme
cleaved by executioner caspase in apoptosis
endonuclease is activated and can cleave DNA
Extrinsic Pathway
one type of apoptosis initiation
from an external signal
death receptor binds is activated
- recruits FADD - recruits initiator procaspases 8 and 10 - DISC is formed - initiator caspases activate executioner
death receptor
of the tumor necrosis factor (TNF) family
homotrimer activated by homotrimer ligand
what happens during lymphocyte mediated cell death?
Fas death receptor activated by Fas ligand on lymphocyte
-juxtacrine signaling
Adaptor protein FADD recruited
- recruits procaspase 8 and 10 * *these two form the Death Inducing Signal Complex (DISC)
procaspases then activate executioner caspases
DISC
death inducing signaling complex
association of FADD with initiator procaspases 8 and 10
which caspases are involved in lymphocyte apoptosis (extrinsic)?
procaspases 8 and 10
Intrinsic Pathway
pathway of apoptosis
-result of injury (intracellular)
cytochrome c from mitochondria released into cytosol
- binds APAF-1 protease - oligomerizes into a heptamer called apoptosome - recruits initiator procaspase 9
caspase 9 recruits executioner caspases > apoptosis
Cytochrome C
released from the intermembrane space of mitochondria in response to high oxidative stress
binds APAF-1
APAF-1
binds cytochrome C
apoptotic protease
oligomerizes into a heptamer called apoptosome
apoptosome
oligermized (heptamer) APAF-1 that recruits initiator procaspase 9
what procaspase is involved in the intrinsic pathway of apoptosis?
procaspase 9
Bcl2 family of proteins
regulate apoptosis
-control release of cytochrome C
include pro-apoptotic BH123 and anti-apoptotic Bcl2
BH123 proteins
pro-apoptotic
Bax and Bak
form oligomers in the membrane and form pores for leakage of cytochrome C
Bak
BH123 protein involved in apoptosis signaling
-bound to mito membrane
form oligomer (with Bax) that is a pore for cytochrome release)
Bax
involved in the BH123 protein release of cytochrome C into the cytoplasm
translocated to mitochondria from the cytosol and associates with Bak to form a cytochrome C leak pore
Bcl2 proteins
anti-apoptotic
-bind and inhibit pro-apoptotic proteins
on the surface of mitochondria
-Bcl2 and Bcl-XI
BH3 only proteins
inhibit anti-apoptotic proteins
enable aggregation of Bax and Bak (leak pore cytochome C)
activated via signal transduction
-MAPK and p53
Bid protein activated by caspase 8
Bid protein
link between the extrinsic and intrinsic pathways of apoptosis
activated by caspase 8
-inhibits anti-apoptotic Bcl2 and stimulate pro-apoptotic BH123 proteins
Inhibitors of Apoptosis (IAP)
bind and inhibit caspases (or polyubiquitylate)
inhibit apoptosis
Anti-IAPs
released from mitochondria during intrinsic pathway
bind and inhibit IAPs - promoting apoptosis
survival factors
most cells need continuous signaling to avoid apoptosis
ex./ neurons need neurotrophins
necrosis
releases intracellular components we can detect
ischemia
inhibition of blood supply
decrease both metabolites and oxygen
acute injury
myocardial infarction cell death?
necrosis of cardiac myocytes
look for cardiac troponins and creatine kinase (CK-MB) in blood
apoptosis
clean cell death
can either have too much or too little apoptosis
neurodegeneration
due to too much apoptosis
neurons undergoing programmed cell deatah
ex/glaucoma
glaucmoma
loss of visual bc apoptosis of retinal ganglion cells
cause unknown
autoimmune disease
too little apoptosis
autoimmune lymphoproliferative syndrome (ALPS)
-mutation in Fas ligand
-accumulation of autoreactive lymphocytes
cancer cells
resistance to apoptosis
-due to mutations in apoptosis control genes
ex/ Bcl2 (b cell lymphoma) proto-oncogene
ex/ p53 tumor supressor
loss of p53
no cycle checkpoint for DNA damage
-cells with damage proliferate
cells escape apoptosis
cells can resist chemo and radiation therapy
reversible cell injury
can be reversed if stimulus removed
irreversible cell injury
cell is committed to cell death
free radicals
unpaired electron and is highly reactive
causes chain propagation > keeps reacting
reactive oxygen species
oxygen derived free radical
normal mitochondria byproduct
also from peroxisomes and lysosomes
reactive nitrogen species
NO is source of RNS
-signaling species in cell
lipid peroxidation
occurs at membranes
synthesizes free radicals
can become reactive peroxide (oxygen species + unsaturated FAs)
Fenton Reaction
Iron reacts with H2O2 to produce hydroxyl radicals
source of ROS
UV light and radiation
have ionizing properties that can form ROS
oxidative stress
ROS and free radicals can lead to damage in the cell
protein modification
DNA lesion
necrosis and ROS?
acute irreversible damage
apoptosis and ROS?
chronic slow ROS damage
antioxidants
molecules that can scavange or inactivate ROS
free unpaired electron
ex/estrogens (conjugated ring structure)
catalase
H2O2 > H2O and O2
peroxisomal enzyme
superoxide dismutase (SOD)
cytosolic and mitochondrial
convert superoxide to H2O2
glutathione peroxidase
break H2O2 down into OH- by oxidizing itself into a homodimer
oxidized from GSSG
reduced from GSH
GSSG
dimer - oxidized form of glutathione peroxidase
GSH
monomer reduced form
ratio of these can detect presence of oxidative stress
ischemia
insufficient blood flow
-no oxygen OR metabolic substrates
halts both aerobic AND anaerobic metabolism
hypoxia
reduce in available oxygen
only affects aerobic metabolism
anoxia
absence of oxygen
mechanism of hyopxia
less O2 to cell
loss of aerobic metabolism > decrease ATP
1 sodium pump failure
-cell swells
2 calcium pump failure
-accumulate intracellular Ca2 (leads to activation of pathways)
-can induce apoptosis
-activates ATPases, endonuclease, proteases, phospholipases
mechanism of ischemia
same as hypoxia
extra effect - no substrates for glycolysis
in addition - accumulate lactic acid (changes pH)
Hif1
hypoxia-inducible factor-1
produced in response to hypoxia
promotes angiogenesis (blood vessel formation)
Von Hippel Lindau
bonds to and degrades Hif-1
results in inhibition of angiogenesis
ischemia-reperfusion injury
return of blood flow to hypoxic tissue is even more damaging
- generate even more ROS (more substrates ex/Iron)
- induces inflammation
adaptation to stimulus
reversible change in a cell
hypertrophy
increase in cell size
in non-dividing or senescent cells
can be caused by functional demand or stimulation signals
(growth factors)
hypertrophy heart
increase in protein synthesis of proteins allowing contraction of heart
hyperplasia
occurs in dividing cells
increase in cell number
not cancer
ex/ endometrium of uterus - hyperplasia is normal
however, some patients have too much hyperplasia
-leads to dysfunction
glandular epithelial of breast
undergoing both hypertrophy and hyperplasia
agenesis
failure to form embryonic cell mass
entire missing organ
aplasia
part of organ missing
failure to differentiate into organ specific tissues
dysgenesis
missing tissue of an organ
hypoplasia
not growing to a full size
atrophy
decrease in cell size and number
normal during development
also pathological
involution
decrease in number of cell compared to the normal number
non-pathological
ex/ breast and uterus, thymus
metaplasia
substitution of one cell for another
-reprogramming of stem cells due to environmental stimulus
ex/ barrets esophagus - caused by regurgitation of acid from stomach
intracellular accumulations - categories?
endogenous
exogenous
steatosis
accumulation of triglycerides in the cell
atherosclerosis
cholesterol accumulation in the cell
xanthoma
cholesterol accumulation in the cell
protein deposits
can be extracellular or intracellular
calcification
deposition of calcium phosphate
usually associated with dying cells (necrosis)
-intracellular calcium interacts with membrane phospholipids
cell starvation
will undergo autophagy
- digest its own components - in autophagic vacuole
residual body
debris in a vacuole that we cannot digest in lysosome
lipofuscin
sign of free radical injury
caused by lipid peroxidation
