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Molecular Basis Of Disease > Mechanisms Of Disease 2 > Flashcards

Mechanisms Of Disease 2 Flashcards

1
Q

What is the function of necrosis?

A

Removes damaged cells from a organism
Failure to do so may lead to chronic inflammation (necrosis induces acute inflammation to clear cell debris via phagocytosis)

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2
Q

What causes necrosis?

A

Usually a lack of blood supply (injury, infection, cancer, infarction, inflammation)

This decreases the ppO2 in the affected area and a decrease in the pH

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3
Q

Describe the process of necrosis step by step.

A
  1. Result of an injurious agent or event
  2. Initial events are reversible, later ones die
  3. Lack of oxygen prevents ATP production
  4. As ATP require for ion pumps to work - cells swell due to a influx of water
  5. Lysosomes rupture; enzymes released degrade other organelles and nuclear material haphazardly
  6. Cellular debris released, triggering inflammation
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4
Q

What nuclear changes occur in NECROSIS under a microscope?

A

Nuclear changes:

  • chromatin condensation/shrink
  • fragmentation of nucleus
  • dissolution of chromatin by DNAse
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5
Q

What cytoplasmic changes occur during NECROSIS under a microscope?

A
  • opacification: protein denaturation and aggregation - turns white
  • complete digestion of cells by enzymes causing cell to liquify
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6
Q

What biochemical changes occur during NECROSIS under a microscope?

A
  • release of enzymes (creatine kinase and lactate dehydrogenase)
  • release of proteins (myoglobin)
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7
Q

What is the function of apoptosis?

A

Selective process for the deletion of superfluous, infected or transformed cells

Involved in:
- Embryogenesis
- Metamorphosis
- Normal tissue turn over

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8
Q

Describe the step by step process of apoptosis

A
  1. Programmed cell death of one or few cells
  2. Events are irreversible and is energy dependent (requires ATP)
  3. Cells shrink as the cytoskeleton is dissembled
  4. Orderly packaging of organelles and nuclear fragments into membrane bound vesicles
  5. New molecules are expressed on vesicle membranes that stimulate phagocytosis without causing a inflammatory response
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9
Q

What cytoplasmic changes occur during APOPTOSIS under a microscope?

A
  • shrinkage of cell + organelles packaged into membrane vesicles.
  • cell fragmentation + membrane bound vesicles bud off
  • phagocytosis of cell fragments by adjacent cells and macrophages
  • minimal leakage of cytosolic components so no inflammation
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10
Q

What nuclear changes occur during APOPTOSIS under a microscope?

A
  • nuclear chromatin condenses on the nuclear membrane
  • DNA cleavage
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11
Q

What biochemical changes occur during APOPTOSIS under a microscope?

A

- expression of charged sugar molecules on the outer surface of membrane of vesicles

  • protein cleavage l protease, caspases
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12
Q

What is metamorphosis?

A

Tadpoles tail is lost by apoptosis

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13
Q

What is interdigital web loss?

A

The webs between paws are lost in mouse paw development
Also occurs in humans (syndactyly)

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14
Q

What are the two types of apoptosis?

A

Intrinsic

  • viral infection (on,y once virus is in cell)
  • Inhibition of protein synthesis
  • DNA damage

Extrinsic

  • withdrawal of survival, factors
  • Extracellular signals
  • T cell or NK

RELATIVE TO THE CELL

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15
Q

What are capsases?

A

The point of convergence for causes of apoptosis.
They are cysteine proteases.
Arrange themselves to form a activation cascade, where one cleaves and activates the next.

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16
Q

What are the different type of caspases?

A

Initiator caspases

  • 8,9
  • few molecules

Effector caspases

  • 1,3,6,7
  • more and more molecules
17
Q

What occurs during a caspase cascade?

A
  1. A inactive procaspase Y is cleaved by active caspase X where a pro domain (NH2) is removed
  2. Caspase Y is now active and consists of a small and large subunit
  3. Active caspase Y can activate other caspases
18
Q

What is the function of the caspase cascade?

A

Cleavage of cytosolic proteins

Cleavage of nuclear lamina (nuclear membrane)

19
Q

What is the effect of caspase activation?

A

Leads to characteristic morphological changes:

  • shrinkage
  • chromatin condensation
  • DNA fragmentation
  • plasma membrane blabbing
20
Q

How are initiator caspases activated?

A

Activate themselves when in close proximity

21
Q

How is extrinsic apoptosis induced?

A

By ligand binding to receptors, causing receptor multierisation, which leads to the activation of the initiation caspase

22
Q

What are the molecules involved in the ligand induced multimerisation?

A

Outside cell/on surface:
- receptor
- ligand

Inside cell:
- death adaptor
- procapase-8

23
Q

What is the structure of the receptor?

A

Ligand binding domain

DEATH DOMAIN

24
Q

What is the structure of the death adaptor?

A

DEATH DOMAIN

DEATH EFFECTOR DOMAIN

25
Q

What is the structure of the procaspase-8?

A

DEATH EFFECTOR DOMAIN

protease domain

26
Q

Describe ligand induced multimerisation using TNF (tumour necrosis factor)

A
  1. TNF binds to TNFR
  2. Brings together per the death domains of the receptors in close proximity which creates a environment for other proteins containing these domains is favoured.
  3. Death adapter protein (FADD) associates/dimerises with the receptors death domain
  4. This leads to a high concentration of death effector proteins, inducing a environment for other molecules with the death effector domain to bind
  5. Procaspase-8 then binds/dimerises with FADD
  6. A death inducing signalling complex (DISC) is formed
  7. Procaspase-8 is then released through auto proteolysis and can induce a caspase cascade in the cell
27
Q

How is intrinsic apoptosis induced?

A

By cytochrome c released from mitochondria.

(One form of extrinsic apoptosis can also use cytochrome C)

28
Q

What is cytochrome c?

A

Mitochondrial matrix protein

Released in response to oxidative stress by a “permeability transition”

29
Q

What molecules are induced in cytochrome c induced apoptosis?

A

Cytochrome

APAF-1

Procaspase-9

30
Q

What is the structure of APAF-1?

A
  • cytochrome binding site
  • APAF domain
  • CASPASE RECRUITING DOMAIN
31
Q

What is the structure of procaspase-9?

A
  • CASPASE RECRUITING DOMAIN
  • protease domain
32
Q

Describe cytochrome c induced apoptosis.

A
  1. Cytochrome binds to APAF-1
  2. Creates a environment of high caspase recruitment domain affinity
  3. Procaspase-9 binds to APAF-1 and a Apostosome forms
  4. Auto proteolysis activates caspase 9
33
Q

How is the real ease of cytochrome c from the mitochondria regulated?

A

By a pore made of BCL-2 family of proteins

Some are not membrane proteins

All have a BH3 domain used to form dimers

34
Q

What are the 2 types of BCL-2 proteins and they’re function?

A

Pro-apoptotic:
- facilitate cytochrome c release

Anti-apoptotic:
- repress cytochrome c release

35
Q

Describe the example of BAX and BCL-2 and BAD

A
  1. BAX only - cytochrome c is released
  2. BAX and BCL-2 - cytochrome c remains in mitochondria (BCL-2 is not a membrane protein and blocks the use of the BAX channel)
  3. BAX and BCL-2 and BAD - cytochrome c can leave mitochondria as BAD has a greater affinity for BCL-2 it displaces it and prevents it from binding to BAX
36
Q

How does TP53 regulate BCL-2?

A
  1. Transcription is driven by TP53
  2. Increased BAX production
  3. More BAX inserted into membrane
  4. Increased permiability of cytochrome c

5. Cytochrome c leaves mitochondria and cell death occurs

37
Q

How do growth factors regulate BCL-2 by phsophorylation?

A
  1. Growth factors from survival signals activate Akt/PKB which phosphorylated BAD
  2. BAD cannot bind to BCL-2
  3. Cell survives ac cytochrome c cannot leave the mitochondria
38
Q

Why is necrosis usually more damaging then apoptosis?

A

Apoptosis is a controlled process where the cell contents are packaged in membrane and not released. This means the surrounding tissue is protected from damaging molecules such as proteases.

39
Q

Explain why lack of oxygen causes cells to swell as part of necrosis

A

Lack of oxygen prevents oxidative phosphorylation

Less ATP production

Lack of ATP prevents normal function of sodium channels

Leads to a altered ionic balance across the membrane leading to the entry of water into the cytoplasm.

Molecular Basis Of Disease (32 decks)

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