2: Cell Injury Flashcards
cells are stressed so severely that they are no longer able to adapt when exposed to damaging agents or abnormal changes within
cell injury
a cell that is constantly replicating
labile
a cell that needs a signal to replicate
stable
MPD
membranes (cell and organelle)
protein
DNA
mitochondrial damage —>
1) decrease in ATP: multiple downstream effects
2) increase in ROS: damage to lipids, proteins and DNA
entry of Ca2+ —>
1) increase in mitochondrial permeability
2) activation of multiple cellular enzymes
membrane damage —>
1) PM: loss of cellular components
2) lysosomal membrane: enzymatic digestion of cellular components
protein misfolding, DNA damage —->
activation of pro-apoptotic proteins
5 major biochemical mechanisms of cell injury
- influx of calcium into the cell and loss of calcium homeostasis
- mitochondrial damage
- depletion of ATP
- accumulation of ROS
- defects in membrane permeability
what is the downstream effect of increased mitochondrial permeability due to increased cytosolic Ca2+
decreased ATP
what cellular enzymes are activated by an increased cytosolic Ca2+
- phospholipase, protease –> membrane damage
- endonuclease —> nuclear damage
- ATPase –> decreased ATP
3 things that cause damage to the mitochondria
- increased calcium in cytosol
- ROS
- breakdown of phospholiipids
breakdown of phospholipids….
phospholipase A2 and sphingomyelin pathways may break down lipids.
- the breakdown products (FFA and ceramide) also damage mitochondria
How does H+ move in the CAC?
H+ is pumped out into the intermembrane space by ETC
H+ is taken in by the ATP synthase
( creation of energy ATP is dependent of H+ gradient in the mitochondria)
How is O2 important in the mitochondria?
it is the final electron acceptor
what mitochondrial attacks lead to necrosis v. apoptosis?
necrosis: decrease O2 supply, toxins, radiation
apoptosis: decrease survival signals, DNA or prtn damage
necrotic mitochondrial changes
decreased ATP production
increased ROS production
apoptotic mitochondrial changes
leakage of mitochondrial proteins
What are the three specific changes in the cell caused by a decrease in ATP production?
1) decreased Na pump
2) increased anaerobic glycolysis
3) detachment of ribosomes
decreased Na+ pump —>
increased influx of Ca2+, H2O, and Na+, increased efflux of K+ ——> swelling (ER, cell, loss of microvilli, blebs)
increased anaerobic glycolysis —>
decreased glycogen, increased lactic acid —> decreased pH —-> clumping of nuclear chromatin
detachment of ribosomes –>
decreased protein synthesis
mechanism of lipid peroxidation of membranes
double bond of unsaturated FA are attacked by oxygen-derived ROS–> peroxides formed —> peroxides react with membrane lipids —> damage and form more peroxides
how is the self-sustaining peroxidation of membranes stopped
free radicals are captured by free radical scavengers
examples of free radical scavengers
vitamin E (in membrane)
Vitamin C and A
Beta carotene
what changes does oxidation cause in proteins
- oxidation of side chains changes function/structure of proteins
- formation of disulfide bonds leads to cross-linking
- oxidation of some enzymes leads to inactivation
how do ROS cause ss breaks in DNA?
ROS interacts with thymine to cause ss breaks in DNA
SOD superoxide dismutase
- in mitochondria
- converts O2 –> H2O2
glutathione peroxidase
- in mitochondria
- converts OH–> H2O2
catalase
- in peroxisomes
- converts H2O2 —> H2O and O2
describe how PMNs use a respiratory burst of ROS to phagocytize bacteria
- O2 to O2- with NADPH oxidase
- O2- to H2O2 with SOD
- H2O2 activates PMN granules, is converted to HOCl by myeloperoxidase, is converted to OH radical by Fe2+ (fenton rxn)
________ prevents reacylationof phospholipids and diminishes synthesis so that the cell membrane can’t repair itself
lack of ATP
what activates phoshpolipases in cytosol
damage to membrane permeability
Observe:
- swelling of ER and mitochondria
- membrane blebs
- clumping of chromatin
reversible cell injury
Observe:
- swelling of ER and loss of ribosomes
- lysosome rupture
- myelin figures
- nuclear condensation
- swollen mitochondria w/ amorphous densities
irreversible injury
