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Molecular Basis Of Disease > Cell Damage And Cell Death > Flashcards

Cell Damage And Cell Death Flashcards

1
Q

List the functions of necrosis

A
  • Removes damaged cells from an organism
  • Failure to do so may lead to chronic inflammation
  • Necrosis causes acute inflammation to clear cell debris via phagocytosis
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2
Q

List the causes of necrosis

A
  • Usually a lack of blood supply
  • Injury
  • Infection
  • Cancer
  • Infarction
  • Inflammation
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3
Q

Describe the causes of necrosis graph

A
  • Graph with distance from vessel (ùm) on X axis and pH on Y axis. On the right hand side, there’s partial pressure of O2
  • Going from 0 to 100 um, there’s a dramatic drop in PO2 from 12 to 4
  • From 100 to 200 um, there’s 0 PO2 so an anoxic environment (no O2), there’s a decrease in pH
  • As you move away from the blood vessel, the environment becomes more acidic
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4
Q

Describe the process of necrosis in steps

A
  1. Result of an injurious agent or event
  2. Initial events are reversible, later ones are not
  3. Lack of oxygen prevents ATP production
  4. Cell swell due to influx of water (ATP is required for ion pumps to work)
  5. Lysosomes rupture; enzymes degrade other organelles and nuclear material hapzardly
  6. Cellular debris released, triggering inflammation
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5
Q

How does necrosis appear under a microscope?

A
  • Can be divided into 2 groups
  • Nuclear changes
  • Cytoplasmic changes
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6
Q

Describe the nuclear changes of Necrosis appearance under a microscope

A
  • Chromatin condenses and shrinks
  • Nucleus begins to fragment
  • Dissolution of the chromatin by DNAse
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7
Q

Describe the Cytoplasmic changes of Necrosis appearance under a microscope

A
  • Opacification: Protein denaturation & aggregation
  • Complete digestion of cells by enzymes causing cells to liquify (liquefactive necrosis)
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8
Q

What are the biochemical changes that occur from necrosis?

A
  • Release of enzymes such as creatine kinase or lactate dehydrogenase
  • Release of other proteins such as myoglobin
  • These biochemical changes are useful in the clinic to measure the extent of tissue damage
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9
Q

Check diagram for the kidney stains of normal or necrotic cells

A
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10
Q

What are the functions of apoptosis?

A
  • Selective process for the deletion of superfluous, infected or transformed cells
  • Involved in:
  • Embryogenesis
  • Metamorphosis
  • Normal tissue turnover
  • Endocrine dependent tissue atrophy
  • A variety of pathological conditions
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11
Q

Describe the process of apoptosis in steps

A
  1. Programmed cell death of one or a few cells
  2. Events are irreversible and energy (ATP) dependent
  3. Cells shrink as the cytoskeleton is desassembled
  4. Orderly packaging of organelles and nuclear fragments into membrane bound vesicles
  5. New molecules are expressed on vesicles membranes that stimulate phagocytosis without an inflammatory response
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12
Q

Describe the cytoplasmic changes of Apoptosis appearance under a microscope

A
  • Cytoplasmic changes
  • Shrinkage of cell. Organelles packaged into membrane vesicles
  • Cell fragmentation. Membrane bound vesicles bud off
  • Phagocytosis of cell fragments by macrophages and adjacent cells
  • No leakage of cytotoxic components
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13
Q

What are the 2 types of electron microscopy images produced for apoptosis?

A
  • Transmission EM: Produces a slice through the cell, 2D section, not much cytoplasm but mainly nucleus
  • Scanning EM: Shows the surface of the membrane
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14
Q

Describe the nuclear changes of apoptosis appearance under a microscope

A
  • Nuclear changes
  • Nuclear chromatin condenses on nuclear membrane
  • DNA cleavage
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15
Q

Describe the Biochemical changes of apoptosis appearance under a microscope

A
  • Biochemical changes
  • Expression of charged sugar molecules on outer surface of cell membranes (recognised by macrophages to enhance phagocytosis)
  • Protein cleavage by proteases, caspases
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16
Q

Give an example of metamorphosis

A
  • Tadpole’s tail lost by apoptosis
  • At first the tadpole has a long tail
  • But once it starts to grow properly, it loses this tail by apoptosis
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17
Q

Describe interdigital web loss

A
  • In certain animals, the fingers are a lot more attached to eachother
  • Apoptosis then occurs to separate the fingers a lot more
  • E.g. Mouse paw development
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18
Q

The cell constantly undergoes a balance between life or death
What are the balancing factors of a cell between survival and apoptosis?

A
  • Survival factors: Growth factors, Cytokines, cell-cell or cell-matrix contacts
  • Apoptosis factors: Lack of growth factors, DNA damaging agents, Death domain ligands, Disruption of cell-cell or cell-matrix contacts
19
Q

What are the 2 types of apoptosis?

A
  • Intrinsic
  • Extrinsic
20
Q

Describe the intrinsic features of apoptosis

A
  • DNA damage: p53 dependent pathway
  • Interruption of cell cycle
  • Inhibition of protein synthesis
  • Viral infection
  • Change in redox state
21
Q

Describe the extrinsic features of apoptosis

A
  • Withdrawal of survival factors
  • Extracellular signals
  • T cell or NK (natural killer)
22
Q

Describe caspases

A
  • Caspases are the point of convergence for causes of apoptosis
  • For e.g. Extrinsic causes + intrinsic causes -> caspases -> apoptosis
  • Caspases are cysteine proteases
  • Caspases form an activation cascade, where one cleaves and activates the next (analogues to kinase cascades)
  • Caspase - activates caspase Y
23
Q

Describe the caspase cascade

A
  • At the top there’s an initiator caspase which has a few molecules
  • This activates downstream Caspases
  • Which in turn will activate more downstream Caspases
  • These downstream Caspases have additional Caspases known as cleavage of nuclear lamin
  • These downstreams with additional Caspases are known as effector Caspases
24
Q

What happens when you have large amounts of many substrates?

A
  • Hundreds of substances for activated Caspases
  • Substrates fall into most classes of important genes
  • Death by a thousand cuts occur
25
Q

What is the effect of caspase activation?

A
  • Caspase activation leads to characteristic morphological changes, such as shrinkage, chromatin condensation, DNA fragmentation and plasma membrane blebbing
26
Q

How is the initiator caspase activated?

A
  • Initiator Caspases activate themselves when in close proximity
  • Activation, therefore means bringing initiator Caspases together
27
Q

Describe extrinsic apoptosis

A
  • Induced by ligand binding to receptor causing a receptor diner or (multimer) isation
28
Q

Describe the ligand induced multimerisation: the players

A
  • You have a ligand which will bind to its transmembrane receptor on the cell membrane
  • You then have an intermediate protein which can be classified as a group of death adaptive proteins
  • You then finally have the initiator caspase which is the procaspase-8
29
Q

What does the ligand receptor and the death adaptor share in common?
What does the death adaptor and procaspase-8 share in common?

A
  • Receptor and death adaptor share the death domain
  • Death adaptor and procaspase-8 share the death effector domain
  • These shared domains usually allow the proteins to bind together
30
Q

Give a specific example of these binding domain stuff

A
  • There’s the tumour necrosis factor signal
  • There’s also a TNFR (tumour necrosis factor receptor which is above the membrane
  • The death adaptor protein (4 in total) is know as the FADD (Fas associated protein with death domain)
  • This creates an environment of high death adaptor concentration
  • The death adaptor then recruits procaspase 8
  • When you add all these together, it creates a death inducing signalling complex
  • When bought into close proximity, autoproteolysis occurs which is how these Caspases become active
31
Q

Describe the intrinsic form of apoptosis

A
  • Induced by cytochrome C released from mitochondria
  • Note: Growth factor withdrawal (extrinsic apoptosis) is an exception that uses cytochrome C
32
Q

What is Cytochrome C?

A
  • Mitochondrial matrix protein
  • Known for many years to be released in response to oxidative stress by a “permanent transition”
  • Any inducers of the permanent transition also eventually induce apoptosis
33
Q

Describe the cytochrome C induced apoptosis in a schematic way in the intrinsic pathway**

A
  • In this case, there’s a similar type of death adaptor protein called APAF 1 (apoptotic protease activating factor)
  • There is also the initiator caspase which is procaspase 9 in this case
  • The common domain shared between APAF 1 and procaspase 9 is the caspase recruitment domain
34
Q

What happens when cytochrome c is released? In relation to the last card

A
  • Cytochrome C is released from mitochondria
  • It binds to its binding domain in APAF 1 bringing these molecules together
  • Dimerisation, multimerisation, recruitment of procaspase 9 come together and is referred to as an apoptosome
  • The proteolytic domain of procaspase 9 is in close proximity allowing it to target itself, cleave itself
  • Resulting in active caspase 9 which can enter the cytoplasm and trigger a caspase cascade
35
Q

How is the release of cytochrome C from the mitochondria regulated?

A
  • Through a family of proteins called the BCL-2 family
  • BCL-2 is both a member of the family and the family itself
36
Q

What does the BCL-2 proteins form?

A
  • They form the permeability pore through which cytochrome C can be released
  • BCL-2 proteins can be pro or anti apoptotic
37
Q

Give some examples of anti apoptotic and pro apoptotic proteins

A
  • Anti apoptotic: Repress cytochrome C release (bcl-2, bcl-XL)
  • Pro-apoptotic: Facilitate cytochrome C release (Bax, Bad, Bid, others)
  • Some are not membrane proteins
  • All have a BH3 domain used to form dimers
38
Q

Give an example of how BAX is expressed

A
  1. BAX is pro apoptotic
  2. Creates a pore
  3. Outgoes cytochrome C is released through the Bax membrane
  4. Leading to cell death
39
Q

Give an example of how BAX + BCL-2 is expressed

A
  1. BCL 2 is anti apoptotic, not a membrane protein
  2. It binds to Bax and acts like a gate
  3. It closes the door and stops cytochrome C being released from mitochondria
  4. Promotes survival
40
Q

Give an example of how BAX + BCL-2 + BAD is expressed

A
  1. BAD is a pro apoptotic protein that binds very strongly to BCL-2. More strongly than BCL-2 binds to Bax
  2. BAD displaces all the BCL-2 from the pore
  3. This allows the Cytochrome C to be released again
41
Q

If the BCL-2 family proteins regulate the cytochrome C release from mitochondria, what regulates BCL-2 proteins?

A

Mainly down to gene expression and Post transcriptional modification

42
Q

How does transcription factor TP-53 activated by DNA damage and various other things activate apoptosis?

A
  • If there’s DNA damage, that triggers activation of TP53 and the expression of TP53 target genes
    1. If there’s a lot of BAX protein, it will start to insert into the membrane
    2. Ultimately, it results in a situation where you’re forming new pores that cannot be blocked by the BCL-2 family members
    3. This causes the release of Cytochrome C and death
43
Q

How does phosphorylation activate apoptosis?

A
  • BAD is able to bind to BCL-2, displacing it from the pore
  • This allows the release of cytochrome C and causes cell death
44
Q

What happens if the cell is enriched in an environment with growth factors?

A
  • These growth factors acting as survival signals will activate a serine threonine kinase called AKT OR pKB
  • This kinase phosphorylase’s BAD
  • Phosphorylated BAD becomes sequestered in the cytoplasm and becomes no available to bind to bcl2
  • Can’t displace it from the pore so cytochrome C is not released and the cell survives

Molecular Basis Of Disease (30 decks)

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