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MOLECULAR BASIS OF DISEASE > 3. MECHANISMS OF DISEASE II - CELL DEATH & DAMAGE > Flashcards

3. MECHANISMS OF DISEASE II - CELL DEATH & DAMAGE Flashcards

1
Q

What are the two types of cell death?

A
  1. Necrosis

2. Apoptosis

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2
Q

What is necrosis?

A
  • Necrosis is the process by which cells die when they are damaged due to harm such as toxins
  • The function of necrosis is to remove damaged cells
  • If necrosis doesn’t occur, there’s chronic inflammation. But necrosis itself does also cause inflammation to allow the cell debris to be cleared by phagocytosis
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3
Q

What are the causes of necrosis?

A
  • Normally a lack of blood supply to an area results in necrosis such as:
    1. Injury
    2. Cancer
    3. Inflammation
    4. Infarction
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4
Q

What are the steps of necrosis?

A
  1. Necrosis occurs due to an injurious agent affecting whole groups of cells. Initial/early events of necrosis are reversible but the later stages aren’t
  2. Necrosis results in a loss of oxygen or hypoxia
  3. ATP formation is reduced due to the loss of oxygen as oxygen is needed to produce ATP via metabollic pathways such as gylcolysis
  4. Reduced ATP means that the ATP dependent ion pumps aren’t as effective and are unable to maintain osmolality. There’s an influx of sodium ions followed by water
  5. The influx of water results in swelling of the cell. The cytoplasm osmolality changes putting pressure on the membrane
  6. Lysosomal enzymes rupture & degrade organelles & nuclear material rapidly when released into the cytoplasm
  7. Cellular debris are released into the extracellular environment triggering infllamation
  8. Inflammation allows cell debris to be phagocytosed
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5
Q

What are the nuclear changes in changes in necrotic cells?

A
  1. Chromatin condenses/shrinks
  2. Fragmentation of nucleus
  3. Degradation of chromatin DNAase
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6
Q

What are cytoplasmic changes in necrotic cells?

A
  1. OPACIFICATION - Cytoplasm becomes opaque rather than transparent due to protein denaturation & aggregation
  2. LIQUEFACTIVE NECROSIS - Lysosomal enzymes cause complete digestion of cells resulting in the cell liquefying
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7
Q

What are the biochemical changes in necrotic cells?

A
  1. Release of intracelular enzymes such as creatinine kinase or lactate dehydrogenase
  2. Release of intracellular proteins
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8
Q

What is apoptosis?

A
  • Apoptosis is a type of programmed cell death
  • It is a selective process for the deletion of damaged infected or transformed cells
  • Apoptosis is involved in embryogenesis, metamorphosis, nromal tissue turnover & pathogical conditions
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9
Q

What are the steps of apoptosis?

A
  1. Programmed cell death of one or few cells
  2. Events in apoptosis are IRREVERSIBLE & are ATP dependent
  3. Cells shrink due to disassembly of the cytoskeleton
  4. Organelles & nuclear fragments are packaged into the membrane bound vesicles
  5. New molecules (phsophatidyserine) are expressed on the membrane of vesicles to cause phagocytosis without an inflammatory response
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10
Q

What are the differences between necrosis & apoptosis?

A
  1. Necrosis affects groups of cells whereas apoptosis only affects a few cells
  2. Early stages of necrosis are reversible but all stages of apoptosis are irreversible
  3. The loss of ATP triggers necrosis, but the changes in Apoptosis are ATP dependent
  4. Cells undergoing necrosis swell but cells undergoing apoptosis shrink
  5. Cells undergoing necrosis release debri, but in apoptosis organelles are packed into vesicles
  6. Release of debris triggers inflammation in necrosis, but there’s minimal inflammation in apoptosis
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11
Q

What are the 4 cytoplasmic changes in apoptotoc cells?

A
  1. Cells shrink & organelles packed into vesicles
  2. Cell fragmentation, vesicles bud off via BLEBBING
  3. Phagocytosis of cell fragemnts by macrophages or adjacent cells
  4. No leakage of debris or minimal debris
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12
Q

What are the nuclear changes in apoptotic cells?

A
  1. Nucelar chromosme condenses on nuclear membrane

2. DNA cleavage

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13
Q

What are the biochemical changes in apoptotic cells?

A
  1. Expression of new molecules on vesicle membrane (e.g phosphatidyl serine) to enhance phagocytosis
  2. Protein cleavage by proteases (caspases)
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14
Q

Give some examples of apoptosis

A
  1. Cell death in embryonic handto form digits
  2. DNA damage/P53 mediated apoptosis
  3. Apoptosis mediated by removal of growth factors
  4. Death of neutrophils during acute infection
  5. Death of immune cells after depletion of cytokines
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15
Q

What are the two types of apoptosis?

A
  1. Extrinsic apoptosis - Pro-Caspase 8

2. Intrinsic apoptosis - Procaspase-9

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16
Q

What are examples of intrinsic apoptosis?

A
  1. DNA damage - P53 dependent pathway
  2. Interruption of the cell cycle
  3. Inhibition of protein synthesis
  4. Viral infection (virus is extrinisc, but it causes apoptosis once it’s inside the cell)
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17
Q

What are examples of extrinsic apoptosis?

A
  1. Removal of growth factors
  2. Extracellular signals (e.g TNF)
  3. T cell or Natural Killer
18
Q

What are caspases & what do they do?

A
  • Casapases are a type of protease - cysteine aspartate specifc proteases
  • Involved in both extrinsic & intrinsic apoptosis & therefore a converegnce point
19
Q

What are the two groups of caspases?

A
  1. Initiator caspases - activate effector caspases via cleavage
  2. Effector caspases - cause the effects of apoptosis
20
Q

Describe the process of caspase activation

A
  • Caspase cascade involves signal amplification with the activation of multiple effector caspases
  • Effector caspases are activated by cleavage which also produces substrates
  • Substrates responsibel for effects
21
Q

Give some substrates that caspases cleave & their functions

A
  • Lamin A& B = nuclear envelope
  • PARP, DNA-PK = DNA Repair
  • Top III = DNA replication
  • Raf 1, STAT1 = Signalling
  • Akt/PKB = Cell survival
  • elF4 = Translation
22
Q

What is the effect of caspase activation?

A
  • Caspases are responsible for the biochemical changes of apoptosis through cleavage
  • Includes blebbing, DNA fragmentation, chromatin condensation
23
Q

How are initiator caspases activated?

A
  • Intiator caspases are also known as pro-caspases.
  • They are activated by AUTOPROTEOLYSIS
  • When they come into cose proximity with each other, they cleave themselves
24
Q

What is extrinsic apoptosis?

A
  • Extrinsic apoptosis occurs when a ligand binds to a receptor resulting in receptor dimerisation or multimerisation
25
Q

What are the three molecules involved in apoptosis?

A
  1. RECEPTOR - has a ligand binding domain & death domain
  2. DEATH ADAPTOR - has a death domain & death effector domain
  3. PRO-CASPASE 8 - has a death effector domain & protease domain
26
Q

Describe the mechanism of extrinsic apoptosis using TNF as an example

A
  1. TNF binds to ligand binding domain of TNF receptor
  2. Results in dimerisation fo TNF receptor via death domain
  3. Dimerised death domain recruits death domain (FADD) of Death adaptor protein
  4. Death effector domain recruits Pro-caspase 8 via detah effector dimerisation
  5. Pro-caspase 8 brought into close proximity with other resulting in activation to Caspase 8 via autoproteolysis
  6. Casapse 8 triggers cascade signalling cascade & forms a DEATH-INDUCING SIGNALLING COMPLEX (DISC)
27
Q

What is intrinsic apoptosis?

A
  • The intrinsic apoptosis pathway is triggred by the release of Cytochrome C
  • However, the removal of growth factors also involves the release of Cytochrome C which is an exception
28
Q

What is Cytochrome C?

A
  • Cytochrome C is a mitochondrial matrix protein which is released in response to oxidative stress, resulting in a change in permeability
  • Anything that causes a change in permeability can cause apoptosis
29
Q

What are the three molecules involved in intrinsuc apoptosis?

A
  1. Cytochrome C
  2. APAF 1 (Apoptotoc protease activating factor)
    - has a cytochrome C binding site, APAF domain & Caspase recruitment domain (CARD)
  3. Pro-caspase 9
30
Q

Describe the mechanism for intrinsic apoptosis

A
  1. Cytochrome C binds to cytochrome C bidning site on APAF 1
  2. CARD on many APAF1 molecules brought into close proximity causing dimerisation
  3. Dimerised CARD recruits Pro-caspase 9
  4. Forms apoptosome
  5. Pro-caspase 9 activated to Caspase 9 through autoproteolysis of protease domain
  6. Caspase 9 triggers signalling cascade resulting the release of Cytochrome C
31
Q

What are the initiator caspases for intrinsic & extrinsic apoptosis?

A
  • Intrinsic apoptosis = Pro-caspase 9

- Extrinsic apoptosis = Pro-caspase 8

32
Q

What are BCL2 family proteins & their properties?

A
  • The BCL2 family proteins can be anti-apoptotoc or pro-apoptotic
  • These proteins from a pore through which Cytochrome C is released
33
Q

What are the pro-apoptotic proteins?

A
  • BAX
  • BAD
  • BID
  • promote apoptosis/ cell death
34
Q

What are the anti-apoptotic proteins?

A
  • BLC2
  • BCL2-X
  • Promite cell survival, inhibiting apoptosis
35
Q

What is the effect of the Bax protein on Cytochrome C release?

A
  • Bax protein is a pro-apoptotic protein

- Bax forms a pore, allowing the release of Cytochrome C causing apoptosis

36
Q

What is the effect of the BCL2 protein on Cytochrome C release?

A
  • BCL2 protein is anti-apoptotoc, can block the Bax pore to prevent the release of Cytochrome C
  • Prevents apoptosis & prevents cell survival
37
Q

What is the effect of the BAD protein on Cytochrome C release?

A
  • Bad is a pro-apoptotic protein
  • Bad can bidn to BCL2 & displace it form the Bax pore
  • Cytochrome C can then be released from the Bax pore causing apoptosis
38
Q

What two things regulate BCL2 protein activity?

A
  1. Transcription

2. Phopshorylation

39
Q

How does TP53 regulate BCL2 activity?

A
  1. P53 activated in response to DNA damage & P53 target genes are transcribed including Bax
  2. Bax inserts itself into the membrane froming new pores
  3. Not enough BCL2 to block the now increased number of Bax proteins so they won’t all be blocked
  4. Cytochrome C is released
40
Q

How is BCL2 activity regulated through Bad phopshorylation?

A
  1. Growth factors trigger activation of serine threonine kinase Akt/PKB
  2. Akt/PKB phosphorylates BAD
  3. Phosphorylated BAD can no longer displace BCL2 from the pore, so BCL2 continues to block pre
  4. No cytochrome C release therefore no apoptosis
41
Q

Describe the extrinsic pathway (removal of growth factors) which involves Cytochrome C

A
  1. Removal of growth factors means no activation of serine threonine kinase Akt/PKB
  2. No phosphorylation of BAD -> BAD can displace BCL2 from BAX pore
  3. BAX pore is unblocked & cytochrome C is released leading to apoptosis

MOLECULAR BASIS OF DISEASE (4 decks)

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