Lecture 24 Flashcards
ATP depletion
Increased anaerobic metabolism–> deplete the glycogen stores and intracellular pH becomes acidic–> decrease Na/K- ATPase pump–> increase in influx of Na and water–> accumulation of intracellular fluids–> other effects leads to detachment of ribosomes, decreased protein synthesis
Mitochondria damage
- opening of mitochondrial permeability transition pore—> breakdown of ionic gradients—> loss of membrane potential—> inability to generate ATP—> necrosis
- form channels that allow cytochrome C and pro apoptotic proteins—> apoptosis
Influx of calcium
levels of calcium 10,000 times lower inside the cell than outside
release from intracellular calcium stores
regulates a whole number of enzymes
activate ATPase, phospholipase, protease, endonuclease
Increased oxidative stress
Generated by inflammation, radiation, chemicals, injury, and reperfusion
cells have ways to reverse reactive oxygen species
Fatty acids become oxidized leads to disruption of plasma membrane
Proteins get oxidized leads to abnormal folding of chains
DNA gets oxidized which leads to mutations and breaks
DNA fragmentation
Thymine oxidation: base pairing between T and A is altered, leading to repair featuring mis-substitution
ssDNA breaks: breakage of phosphodiester backbone reduced replication and transcription
Defects in membrane permeability
mitochondrial membrane damage- decreased ATP production leading to apoptosis and necrosis
plasma membrane damage- loss of osmotic balance, influx of fluids and ions as well as cellular contents
lysosomal membrane damage- leakage of enzymes into cytoplasm
Physiological causes of apoptosis
programmed destruction of cells
hormone-dependent tissues upon hormone deprivation
cell loss in proliferating cell populations
elimination of potentially harmful self reactive lymphocytes
cell death induced by cytotoxic T lymphocytes
Pathological causes of apoptosis
DNA damage
misfolded proteins in the ER and cytoplasm
viral infections
Intrinsic pathway of apoptosis
Begins with cell injury which could be DNA damage by radiation, protein misfolding (ER stress) which is going to activate a pathway that leads to the cell committing suicide
p53 triggers sensor molecules
Extrinsic pathway of apoptosis
receptor is engaged by a ligand and when the ligand binds it generates
TNF receptor and a Fas receptor sitting in the plasma membrane
end product is cytoskeleton gets degraded, DNA gets broken down a phagocytic cells comes in and engulfs it
What increases mitochondria membrane permeability and cytochrome c release?
dimerization and oligomerization of Bax or Bak
Role of cytochrome c in activation of initiator caspase-3
cytochrome c interacts with Apaf-1 causing a conformational change allowing it to multimerize and form this machine to generate a apoptosome and take pro enzymes leading to procaspase-9 and trigger a cleavage of procaspase-3 to caspase-3
once caspase-3 is cleaved its GAME OVER
Bcl-2 family
Bcl-2 and Bcl-x can bind Bax family proteins and inhibit their function so they are known as anti-apoptotic proteins
Caspase executioner
caspase-3 and 7
Activated caspases can activate endonucleases
cleavage of DNA leading to DNA fragmentation
