Cell Death And Cell Damage Flashcards
What is the purpose of necrosis?
Removes damaged cells from an organism
Why does necrosis cause acute inflammation?
Clear cell debris via phagocytosis
What are the causes of necrosis?
Lack of blood supply as a result of: Injury Infection Cancer Infarction Inflammation
What is the step by step of necrosis?
injurious agent or event
- > lack of oxygen prevents ATP production
- > cells swell due to influx of water
- > lysosomes rupture: enzymes degrade other organelles and nuclear material haphazardly
- > cellular debris is released, triggering inflammation
What are the three changes in the microscopic appearance of necrosis?
Nuclear, cytoplasmic and biochemical
What are the nuclear changes that happen in necrosis?
Chromatin condensation
Fragmentation of the nucleus
Dissolution of the chromatin by DNAase
What are the cytoplasmic changes that happen in necrosis?
Opacification: protein denaturation and aggregation
Complete digestion of cells by enzymes causing cells to liquefy
What are the biochemical changes that happen in necrosis?
Release of enzymes such as creatinine kinase or lactate dehydrogenase and other proteins like myoglobin
Why are biochemical changes useful in a clinical setting?
Measure the extent of tissue damage
What are the functions of apoptosis?
Deletion of superfluous, injected or transformed cells
What is apoptosis involved in?
Embryogenesis Metamorphosis Normal tissue turnover Endocrine-dependent tissue atrophy Variety of pathological conditions
What is the step by step of apoptosis?
Programmed cell death of one or a few cells
- > cells shrink as the cytoskeleton is disassembled
- > orderly packaging of organelles and nucelar fragments into membrane bound vesicles
- > new molecules are expressed on vesicular membranes that stimulate phagocytosis without an inflammatory response
Is necrosis reversible?
Initial events are reversible, later ones are not
Is apoptosis reversible?
No
What are the cytoplasmic changes in apoptosis?
Shrinkage of cell
organelles packaged into membrane vesicle
Phagocytosis of cell fragments by macrophages and adjacent cells
No leakage of cytosolic components
What are the nuclear changes in apoptosis?
Nuclear chromatin condenses on nuclear membranes
DNA cleavage
What are the biochemical changes in apoptosis?
Expression of charged sugar molecules on the outer surface of cell membranes
Protein cleavage by proteases
What are the two types of apoptosis?
Intrinsic and extrinsic
What causes intrinsic apoptosis (specifically)?
DNA damage interruption of the cell cycle Inhibition of protein synthesis Viral infection Change in redox state
What causes extrinsic apoptosis?
Survival factors
Extracellular signals
Tcell or natural killer
What are caspases?
Cysteine proteases
What is the caspase cascade?
Initiator caspases (8 and 9) activate other caspases which both cleave cytosolic proteins and activate more proteases which also cleave nuclear lamin
What are the effects of caspase activation?
Morphological changes: Shrinkage Chromatin condensation DNA fragmentation plasma membrane blebbing
What do initiator caspases do?
Activate themselves when in close proximity
What is extrinsic apoptosis induced by?
Ligand binding to receptors, causing receptor dimer(or multimer)isation
What are involved in ligand induced multimerisation?
Ligand
Receptor
Death adaptor
Procaspase-8
Which parts of ligand induced multimerisation share a death domain?
Receptor and death adaptor
Which parts of ligand induced multimerisation share the death effector domain?
Death adaptor and procaspase-8
What is an example of ligand induced multimerisation?
Tumour necrosis factor (TNF)
What does TNF do?
Binds to TNFreceptor - creates an environment for oligomerisation with other death domains
Causes FADD binding which forms an environment with a high concentration of death effector domain
Causes procaspase-8 binding
Causes autoproteolysis, activating the caspase and initiating the caspase cascade
What is intrinsic apoptosis induced by?
Cytochrome C release from the mitochondria
What does FADD stand for?
FAS- associated protein with death domain
What is cytochrome C?
Mitochondrial matrix protein
What is involved in cytochrome C induced apoptosis?
Cytochrome C, APAF-1, procaspase-9
What does APAF-1 stand for?
Apoptotic protease activating factor
What is APAF-1 made up of?
Cytochrome C binding site
APAF domain
Caspase recruitment domain
What is procaspase-9 made up of?
Caspase recruitment domain and protease domain
What is an apoptosome?
The whole cytochrome C induced apoptosis complex
How is the mitochondrial release of Cytochrome C regulated?
BCL-2 family protein pore
Are BCL-2 proteins pro or anti-apoptotic?
Can be either
What BCL-2 family proteins are anti-apoptotic?
BCL-2, BCL (and more!)
What is the job of anti-apoptotic BCL-2 proteins?
Repress cytochromes
Which of the BCL-2 family are pro-apoptotic?
BAX, BID, BAD etc
What is the function of pro-apoptotic BCL-2 proteins?
Facilitate cytochrome C release
What is the BH3 domain used for?
To allow the BCL-2 family proteins to form dimers
What regulates BCL-2 proteins?
TP53, growth factors
How does TP53 regulate BCL-2 proteins?
Increases BAX, so more membrane pore insertion
- > not enough BCL-2 to block the channels
- > cytochrome c is released
- > cell death
How do growth factors regulate BCL-2 proteins?
Activate PKB, which phosphorylates BAD
- > phosphorylated BAD can’t bind to BCL-2 so cytochrome c isn’t released
- > cell survives
What happens if only BAX is present?
Cytochrome C is released
What happens if BAX and BCL-2 is released?
Cytochrome C remains in the mitochondria
