L28 Cell Death Flashcards
How do cells die?
Most cells die through Necrosis and apoptosis
What is Necrosis ?
Premature death of cells in living tissue. It’s an uncontrolled, chaotic process unlike apoptosis
What is apoptosis?
Programmed cell death, is a controlled process by which cells self-destruct
When does necrosis occur?
Physical damage:
- trauma e.g. cuts and burns
- extreme temperatures e.g. frostbite
Toxins:
- External e.g. snake venom
- Internal e.g. bacterial toxins
Acute hypoxia/ischaemia e.g. stroke
When does apoptosis occur?
Physiological situations:
- Tissue size maintenance
- Developmental cell loss - growth factors
- Removal of immune cells
Pathological situations:
- DNA damage e.g. radiation, oxidative stress
- Virally infected cells
What are the characteristics of necrosis?
Reversible:
- Membrane integrity compromised
- Organelle and cell swelling
Irreversible:
- Increased intracellular calcium
- Autolysis
- Cell bursting (cell lysis)
- Elicits an inflammatory response
What are the characteristics of apoptosis?
Shrinkage
Nuclear breakdown
Apoptotic bodies
Phagocytosis
No inflammatory response
Requires energy
Controlled cell death
Relationship with autophagy
Can both mechanisms be involved in the death of a cell?
Yes. In brain ischaemia, cells in the middle die through necrosis and cells at edge die through apoptosis. This restricts spread of cells death
What does developmental apoptosis mean?
- Developmental apoptosis is very controlled cell death where we can be precise on the count.
- It involves selective elimination of specific cells.
- In C.elegans 131 cells die for development.
How is developmental apoptosis initiated?
It is initiated through release of local signals.
What happens to the cell shape via apoptosis and necrosis?
Apoptosis - shrinkage, condensed
Necrosis - swelling
What happens to cellular content after apoptosis vs necrosis?
Apoptosis - packaged in apoptotic bodies
Necrosis - leakage to extra cellular fluid
Is ATP required for apoptosis and/or necrosis?
ATP required for apoptosis but not necrosis
Why is developmental apoptosis important?
Eliminates unnecessary cells which is important for processes like metamorphosis e.g. tadpole - frog
- Surge in thyroid hormone in the blood initiate apoptosis in tail cells
How would one study apoptotic pathways?
We would use C- elegans because they provide an excellent model for studying the pathways.
Ced genes involved from recognition of apoptotic signal to engulfment of apoptotic cell by phagocytes
What are caspases?
The executioners of cell death = essential for apoptosis
C = cysteine at their active site
asp = aspartic acid are the cleave site in target proteins
What are the Ced genes conserved in mammals?
- Ced 9
- Ced 4 - Inhibitors
- Ced 3 - The ones that inititae apoptosis.
What does the decrease in Ced 3 and Ced 9 cause in apoptosis?
Decrease in Ced3 causes excess adult cells existence
Decrease in Ced 9 gives massive cell death.
What are imitator caspases?
Activated by apoptotic signals
Activate executioner caspases
What happens when initiator caspases activates executioner caspases?
One initiator caspases can active multiple executioner caspases - amplified proteolytic cascade
Describe the mechanism behind initiator caspase activating the executioner caspases.
Initiator caspases (caspases 8,9) activated by apoptotic signals which activates executioner caspases
Executioner caspases (caspases 3,6,7) cleaves onto more than 1000 proteins
What are some of the caspase targets? (3)
- Cause breakdown of nucleus structure, cleavage of nuclear lamins
- Prevents DNA repair by cleaving the DNA repair enzyme PARP
- Cause cytoskeleton changes, cleaves cytoskeleton proteins like Gelsolin
What are the two main ways of initiating apoptosis?
Extrinsic pathways
Intrinsic pathways
What triggers extrinsic pathway of apoptosis?
Triggered by external signals, such as death receptors: These are proteins on the cell surface that, when activated by specific ligands (like Tumor Necrosis Factor - TNF), initiate a signaling cascade leading to apoptosis.
What does DISC stand for?
Death - induced signalling complex
What triggers intrinsic pathways?
Triggered by:
Stress signals e.g. DNA damage
Developmental signals
Describe how an apoptotic stimulus can lead to a caspase cascade leading to apoptosis?
An apoptotic stimulus triggers either the extrinsic or intrinsic pathway, leading to the activation of initiator caspases. These initiator caspases, in turn, activate executioner caspases, which dismantle the cell and lead to its demise.
What do pro and anti apoptotic factors do with cells?
- Pro- apoptotic factors:
Promote cell death (Bax, Bak) - Anti - apoptotic factors:
Inhibit cell death (Bcl2, BclXL)
