Routes to Cell Death Flashcards
Where is the mitochondrial permeability transition pore (mPTP) located?
Inner mitochondrial membrane
What causes mPTP opening?
Oxidants
High [Ca2+]
High [Pi]
What inhbiits mPTP opening?
ATP
Cyclosporin A (CsA)
Sanglifehrin (SfA)
What binds to mPTP to cause opening and where is it located?
Cyclophilin D
Matrix
What are the effects of mPTP opening?
H+ moves in - gradient removed - no ATP synthesis
Intramitochondrial enzymes and Ca2+ move out
Osmotic swelling - ruptures outer membrane - cytochrome C released from intermembrane space
What modulates cyclophilin D binding to mPTP?
Ca2+
What is the O2 paradox?
Reperfusion repolarises mitochondria
Easier to accumulate Ca2+
Increases mPTP opening
What are the triggers of apoptosis?
Withdrawal of neurotrophin trophic support
‘Death receptor’ activation
DNA damage
What are the cell membrane changes involved in apoptosis?
Phosphatidylserine moves from inner to outer side of membrane - makes resistant to detergent permeabilisation - acts as signal to cause phagocytotic removal to fragments by macrophages - limits inflammatory response
What is used experimentally to bind to and visualise phosphatidylserine?
Annexin V
What are the events in the pathway to apoptosis?
Cytochrome C release from mitochondria - primary initiator - binds Apaf1 protein
Apaf1 binds caspase9 and ATP - forms apoptosome
Caspase9 initiates caspase cascade
Which form of cytochrome C initiates apoptosis?
Holoenzyme
What is added to apocytochrome to form cytochrome C and where does this occur?
Haem
In mitochondria
What is the role of bax?
Dimerises
Forms pores in membranes
Translocates from cytosol to mitochondria in early apoptosis
Which protein prevents bax insertion into mitochondrial membrane?
Bcl-2
