Cell Death Flashcards
What is necrosis ?
The death of tissues following bioenergetic failure and loss of plasma membrane integrity.
Induces inflammation and repair.
What is apoptosis ?
Usually involves DNA fragmentation.
Apoptosis is an active process.
State some features of necrosis
Pathological process
Affects cell groups
Cell membrane integrity is lost
Cell swelling and lysis
Inflammatory response
Dead cells are phagocytosed by inflammatory cells
Abnormal ion homeostasis
State some features of apoptosis
Physiological or Pathological induced
Affects single cells
Cell membrane integrity is maintained
Cell shrinkage and fragmentation
NO inflammatory response
Dead cells are phagocytosed by neighbouring cells
Energy-dependent fragmentation of DNA
State some features of reversible cell injury
REVERSIBLE
Increased intracellular volume
Mitochondrial swelling and calcification
What is key to the homeostasis of a cell ?
The mitochondria
Function of the mitochondria
They oxidise things, as oxygen is dangerous to the cell.
This process produces free radicals (e.g. hydrogen peroxide), due to burning glucose.
Free radical
Any species with an unpaired electron.
Goes to things that like an electron, for example DNA, RNA, membranes. This can cause damage to any of these.
What happens if metabolism (respiration) is not properly controlled ?
You can risk further damage to the cell.
Function of mitochondria in reversible injury
The mitochondria is important to generate energy, to maintain the cells homeostasis, to keep water out.
Also because the mitochondria can be a potent source of molecules e.g. SOD, which can cause secondary damage.
Describe lethal injury
Reversible injury
Not able to restore e.g. membrane pumps to keep water and sodium out
Mitochondria may release oxygen free radicals, causing further damage.
Not enough energy produced.
Cell dies via necrosis.
Causes of necrosis
Ischaemia
Metabolic
Trauma
Coagulative necrosis
Commonest type
Firm, pale area with ghost outlines in microscopy
Colliquative necrosis
Seen in the brain
Dead area is liquefied
Caseous necrosis
Seen in tuberculosis
Pale yellow semi-solid material
Gangrene necrosis
Necrosis with putrefaction
Follows vascular occlusion or certain infections and is black.
Fibrinoid necrosis
Microscopic feature in arterioles in malignant hypertension
Fat necrosis
May follow trauma and cause a mass
OR
May follow pancreatitis visible as multiple white spots.
Key feature of necrosis
Evokes an inflammatory response
Loss of energy
Why don’t you get inflammation in apoptosis ?
As cell membrane integrity is maintained. No cell contents are spilled.
Fragments are phagocytosed and quickly sucked up by adjacent cells.
Give some examples of apoptosis
Embryology - lumen of tubules e.g. oesophagus
Inflammation - resolution and death of neutrophils
How to end inflammation ?
Acute inflammation can be controlled by neutrophils.
Neutrophils have a limited lifespan, they only stay around for <20hrs and then die.
So after 20hrs there is no inflammation, unless you recruit new cells.
How do neutrophils die ?
Apoptosis
What does clearance of apoptotic cells require ?
Clearance of apoptotic cells by macrophages requires reorganisation of phosphatidylserine.
State the 2 types of causes of apoptosis
Extrinsic - receptor triggered
Intrinsic - something from within damage the nucleus/ damage to DNA/ mitochondria
Extrinsic causes of apoptosis
Receptors
T cells
Intrinsic causes of apoptosis
Stress
Metabolic
DNA damage and p53
State the key features of extrinsic caused apoptosis
- Receptor interaction
- Cytoplasmic signals
- Caspase cascade
State some examples of extrinsic triggers
Tumour necrosis factor - cytokines produced by macrophages
Inflammation
This triggers apoptosis through the receptors.
Caspases function
Chew up the cell, chew up/ lead to the chewing up of DNA into chunks.
Help fragment the cytoskeleton, membrane is flipped inside out.
Describe some key features of T cell mediated apoptosis
- Touch the target cell and inject enzymes
- Perforin and granzymes
- Cytoplasmic activation, caspase activation
Examples of T cell mediated apoptosis
Viral infection
Transplantation rejection
Tumour cell destruction
State some key features of intrinsic apoptosis
- Endogenous activation
- Mitochondrial involvement
- Caspase activation which breaks up the cell
(response to DNA damage/ damage to the mitochondria)
What is a key step in intrinsic pathway of apoptosis ?
Release of cytochrome C from the mitochondria.
Apoptosome
A whole series of proteins which speeds up the biochemistry that chews up the cell into smaller parts.
AUGMENTS, AMPLIFIES, SPEEDS up the whole process.
Releases activated caspases, causing the cell to fragment.
Cells response to DNA damage
- Stop proliferating, cell doesn’t grow anymore, cell doesn’t die
- Sequence of events, hitting the mitochondrion, causing apoptosis
Control of apoptosis
Bcl2 family
- family of factors that either stick to each other, or stick to other members of the family
Describe the BCL-2 family
A. Anti-apoptotic Bcl2 protein
B. Pro-apoptotic BH123 protein
C. Pro-apoptotic BH3-only protein
BH3-only protein
Pro-apoptotic
Bcl2 protein
Anti-apoptotic
Stabilises the mitochondria
BH123 protein
Pro-apoptotic
What does abnormal Bcl2 expression lead to ?
Can contribute to cancer
- translocation and rearrangement
- too much Bcl2
- cell doesn’t die
- too much B cells
State the multiple layers of control of apoptosis
Caspases
Mitochondria
Bcl2 + family
Inhibitors of apoptosis (IAP proteins)
Describe caspase structure
Cysteine in the active site: ‘C’
Cleavage after aspartate: ‘asp’
Protease: ‘ase’
What are caspases ?
Key effectors of apoptosis
Function of cleaving ICAD
Destroy genetic information
Function of cleaving PARP
Prevents DNA repair
Function of cleaving lamin
Breaks down nuclear architecture
Function of cleaving keratin
Breaks down cytoplasmic architecture
Importance of apoptosis in carcinogenesis
Apoptosis is :
- discrete
- specific
- targeted
- a morphological diagnosis
State the 3 survival factors to block apoptosis
- Increased production of the anti-apoptotic Bcl2 protein
- Inactivation of pro-apoptotic BH3-only Bcl2 protein
- Inactivation of anti-IAPs
What lengthens the lifespan of cells ?
Calorie restriction
State some examples when apoptosis goes wrong
Autoimmune disease
Cancer
Neurodegeneration
Can pathway components be drug targets ?
Bcl2 in lymphoma
Caspase 3 in Alzheimer Type Dementia
IAP in cancer
State some other variants of cell death
Anoikis
Pyroptosis
Ferroptosis
Necroptosis
Trigger of pyroptosis
Microbial trigger
e.g. Salmonella
Pyroptosis
Features similar to apoptosis and necrosis
- Caspase 1 activation not 3
- nuclear fragmentation
- no cytoplasmic blebbing
- pro-inflammatory
Anoikis
Death after losing contact with basement membrane / extra-cellular matrix
