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Molecular Basis of Disease > Mechanisms Of Disease 2: Cell Damage And Cell Death > Flashcards

Mechanisms Of Disease 2: Cell Damage And Cell Death Flashcards

1
Q

What is the function of necrosis?

A

Remove damaged cells

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2
Q

When does chronic inflammation occur associated to necrosis?

A

If damaged cells aren’t removed by necrosis, damaged cells release components causing chronic inflammation.

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3
Q

When does acute inflammation occur associated to necrosis?

A

Necrosis causes acute inflammation to clear cell debris via phagocytosis

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4
Q

Why is necrosis important?

A

If damaged cells not removed, chronic inflammation would occur

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5
Q

What is the cause of necrosis? + examples

A

Lack of blood supply = lack of O2 supply to tissue and decrease pH

  • injury
  • infection
  • cancer
  • infarction
  • inflammation
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6
Q

What are the steps of necrosis?

A

1) Injury resulting in WHOLE GROUP OF CELLS affected
2) Initial events reversible - can undo damage, later cannot
3) Lack of oxygen = lack of ATP production
4) No ATP = ion pumps can’t work and influx of water cause cells to swell
5) Swollen cells and organelles increase pressure and osmolarity changes
6) Osmolarity changes cause lysosome rupture - enzymes degrade organelles and nuclear material haphazardly
7) Cellular debris release and triggers acute inflammation till cleared by phagocytosis

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7
Q

When does necrosis become irreversible?

A

Irreversible swelling and pressure causes lysosome rupture - chromatin structure won’t be preserved - breaks down

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8
Q

What are the 3 stages of nuclear changes during necrosis?

A

1) Chromatin condensation/shrinkage
2) Fragmentation of nucleus
3) Dissolution of the chromatin by DNAse (no more DNA material)

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9
Q

How does the cytoplasm change during necrosis?

A

Opacification - protein denaturation and aggregation

Complete digestion of cells by enzymes cause cell to liquify (liquefaction necrosis) and structures are lost

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10
Q

How can me measure extent of tissue damage?

A

Biochemical changes such as release of enzymes (creatinine kinase, lactate dehydrogenase) and other proteins (myoglobin) into the blood then urine can be measured to identify extent of damage.

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11
Q

What is astrocytoma?

A

Necrosis caused by cancer (grown tumour destroys vascularisation so has to form its own)

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12
Q

What is apoptosis?

A

Selective process for the deletion of superfluous, infected or transformed cells. (cells that are dangerous and must be removed)

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13
Q

Give examples of where apoptosis might take place.

A 
Embryogenesis
Metamorphosis
Normal tissue turnover
Endocrine dependent tissue atrophy
A variety of pathological conditions
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14
Q

What are the steps in apoptosis?

A

1) Programmed cell death of one or a few cells.
2) Events are irreversible and is energy (ATP) dependent
3) Cells shrink as cytoskeleton is disassembled
4) Orderly packaging of organelles and nuclear fragments into membrane bound vesicles.
5) New molecules expressed on vesicle membranes that stimulate phagocytosis WITHOUT AN INFLAMMATORY RESPONSE.

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15
Q

What are the differences between the steps in necrosis vs apoptosis?

A

1) In necrosis and whole group of cells are affected by apoptosis occurs to one or a few cells (programmed).
2) No stage of apoptosis is reversible unlike necrosis.
3) In necrosis enzymes degrade other organelles and nuclear material haphazardly but in apoptosis, there is ORDERLY packaging into vesicles.
4) There is no inflammatory response after phagocytes stimulated in apoptosis unlike necrosis.

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16
Q

What cytoplasmic changes occur in apoptosis?

A

1) Shrinkage of cell (+ organelles packaged into membrane vesicles) - cytoplasm shrinks around nucleus
2) Cell fragmentation. Membrane bound vesicles bud off
3) Phagocytosis of cell fragments by macrophage and adjacent cell.
4) No leakage of cytosolic components (or else would result in inflammation)

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17
Q

What nuclear changes occur in apoptosis?

A
  • Nuclear chromatin condenses on nuclear envelope.

- DNA cleavage

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18
Q

What biochemical changes occur in apoptosis?

A
  • Expression of charged sugar molecules (also reduces inflamation) on outer surface of cell membranes (recognised by macrophages to enhance phagocytosis)
  • Protein cleavage by proteases (capsases)
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19
Q

How does DNA fragmentation differ in normal DNA, apoptotic DNA and necrosis DNA?

A
  • Normal is a thick band that doesn’t travel far
  • Apoptotic shows characteristic laddering
  • Necrosis looks like one large smear (non-specific so no laddering)
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20
Q

What is metamorphosis + give examples?

A

Apoptosis causing tadpoles tail loss, and interdigital web loss (mouse paw development)

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21
Q

In which condition does metamorphosis not take place in human?

A

Syndactyly

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22
Q

Examples of apoptosis

A
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23
Q

Which factors promote survival of a cell?

A

Cell-cell / cell-matrix contacts
Growth factors
Cytokines

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24
Q

Which factors promote apoptosis of a cell?

A

Disruption of cell-cell/cell-matric contacts.
Lack of growth factors
Death domain ligands
DNA damaging agents

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25
Q

What are the 2 types of apoptosis?

A

Intrinsic and extrinsic (relative to cell not body)

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26
Q

Give examples of intrinsic apoptosis

A 
DNA damage - p53 dependent pathway
Interruption of cell cycle
Inhibition of cell cycle
Viral infection (once virus has entered cell)
Change in redox state
27
Q

Give examples of extrinsic apoptosis

A

Withdrawal of survival factors e.g. mitogens
Extracellular signal (e.g. TNF)
T cell or NK (natural killer) cells e.g. Granzyme

28
Q

What are capsases?

A

Cysteine protease (enzyme) required in apoptosis, both intrinsic and extrinsic pathway the same from capsase step.

Cysteine aspartate specific proteases

29
Q

What do caspases work generally?

A

They form an activation cascade (one cleaves the next) and activates them. (initially inactive).
Signal apmilfication - alot starting from a few

30
Q

What is the general mechanism of caspases?

A

An inactive caspase (procaspase) is activated by cleavage (+ prodomain released). The active caspase reassembles to form another active caspase allowing it to continue other procaspases.

31
Q

What are initiator caspases and effector caspases and how do their numbers vary?

A

Initiator caspases are a few molecules.
Effector caspases are activated by initiator caspases and signal amplification there casues a lot more effector caspases activation.

32
Q

What do the effector caspases do?

A

Effector caspases cleave cytosolic proteins first, other effector caspases activated further on cleave nuclear lamina.

33
Q

How do caspases cause apoptosis?

A

Many caspases form cuts on substrates that are very important genes e.g. to form nuclear envelope, dna repair/replication. Without which cell death occurs.

34
Q

What is the external effect of caspase activation?

A

Characteristic morphological changes such as shrinkage and chromatin condensation.
DNA fragmentation and plasma membrane blebbing.
Vesicles budding and cytoplasm shrinkage.

35
Q

How are initiator caspases activated?

A

Initiator caspases activate themselves when in close proximity. Activation rings initiator caspases together.

36
Q

How does extrinsic apoptosis start?

A

It is induced by ligand binding to receptors causing receptor dimerisation which leads to caspase activation.

LIGAND INDUCED MULTIMERISATION

37
Q

What are the proteins involved in ligand induced multimerisation (extrinsic apoptosis)?

A

Receptor, death adapter (intermediate protein) and procaspase (inactive caspase)

38
Q

What are the domains in the receptor of ligand induced multimerisation (extrinsic apoptosis)?

A

Ligand binding domain and death domain

39
Q

What are the domains in the death adapter induced multimerisation (extrinsic apoptosis)?

A

Death domain and death effector domain

40
Q

What are the domains in the procaspase of ligand induced multimerisation (extrinsic apoptosis)?

A

death effector domain and procaspase (catalytic part) domain

41
Q

What are the general steps in ligand induced multimerisation (extrinsic apoptosis)?

A

1) The ligand binds to the ligand binding domain of the receptor.
2) This causes the death domain of the receptor to bind to the death domain of the death adapter.
3) The death effector domain of the death adapter binds to the death effector domain of the procaspase.
4) Protease domains of multiple procaspases in close proximity allows autoproteloysis and caspase is activated. (Caspase leaves the DISC complex)

42
Q

What are the steps in ligand induced multimerisation (extrinsic apoptosis) in the example of TNF?

A

TNF (tumour necrosis factor) is a ligand - binds to tumour necrosis receptor in the cell membrane.

Death domains brought together (dimerisation) and FADD (FAS associated protein with death domain) binds to the death domain of the receptor.

Procaspase 8 binds to death domain of death adapters binding protease domains of procaspase in close proximity (multimerisation forms DISC complex)

Autoproteolysis occurs and caspase activation occurs. Now it can lead the membrane and induce caspase cascade in cytoplasm.

43
Q

What is a DISC?

A

Death inducing signal complex (all the regions of the dimerisation have bound to form a multiprotein complex)

44
Q

What causes intrinsic apoptosis?

A

Cytochrome C released from mitochondria.

45
Q

When is cytochrome c involved in extrinsic apoptosis?

A

Growth factor withdrawl (extrinsic apoptosis) uses cytochrome C.

46
Q

What is cytochrome C?

A

Mitochondrial matrix protein released in reponse to oxidative stress

47
Q

How does cytochrome C lead to apoptosis?

A

permeabillity transition releases cytochrome C induces apoptosis

48
Q

What are the proteins involved in cytochrome C induced apoptosis (intrinsic apoptosis)?

A

APAF1 - Apoptotic protease activating factor (similair to death adapter)
Procaspase 9

49
Q

What are the domains of APAF1?

A

Cyctochrome C binding site
APAF domain
Caspase recruitment domain (CARD)

50
Q

What are the domains in procaspase 9?

A

Caspase recruitment domain (CARD)

Protease domain

51
Q

What is the common domain between APAF 1 and procaspase 9?

A

Caspase recruitment domain (CARD)

52
Q

What are the general steps in cytochrome c induced apoptosis (intrinsic apoptosis)?

A

1) Cytochrome c binds to cytochrome c binding domain of APAF1
2) Dimerisation of APAF 1
3) CARD domain of procaspase 9 binds to CARD domain of APAF 1 = multimerisation (apoptosome complex formed)
4) Protease domains of procaspase 9 in close proximity induces autoproteolysis and activated caspase released from apoptosome

53
Q

What proteins regulate cytochrome release from mitochondria?

A

BCL-2 family proteins forms a pore in mitochondriol membrane for cytochrome C to be released

54
Q

Are BCL-2 protein family pro or anti apoptotic?

A

Both (some proteins anti-apoptotic and some pro-apoptotic)

55
Q

Which proteins in BCL-2 family are pro-apoptotic? - facilitate cytochrome C release and therefore cell death

A

Bax, Bad, Bid

56
Q

Which proteins in BCL-2 family are anti-apoptotic? - repress cytochrome C release and therefore cell death

A

BCL-2, BCL-XL

57
Q

Where are BCL-2 family proteins found?

A

Some are membrane proteins and others are in the mitochondral matrix

58
Q

What happens is only BAX is present?

A

Bax is a membrane protein that forms a pore so is pro-apoptotic and releases cytochrome C.

59
Q

What happens if BAX and BCL-2 is present?

A

BCL-2 is anti-apoptotic and blocks the Bax protein pore so cytochrome remains in the mitochondria.

60
Q

What happens if BAX, BCL-2 and BAD is present?

A

Although BCL-2 blocks the BAX pore, BAD is pro-apoptotic and is not a membranous protein so binds to BCL-2 and displaces it (stronger than BCL-2 and BAX association) allowing cytochrome C to be released through the Bax pore.

61
Q

What regulates BCL-2 family proteins?

A

Gene transcription and post-translational modification e.g. phosphorylation

62
Q

How does TP53 control intrinsic apoptosis? (cytochrome c induced) + mechanism

A
  • Induces apoptosis
    TP53 drives transcription for BAX proteins. More BAX proteins inserted into membrane so new pore are formed (even if existing ones are blocked by BCL-2).
    Cytochrome C now released through new BAX pores.
63
Q

How does phosphorylation regulate intrinsic apoptosis? (cytochrome c pathway)

A

Phosphorylation by growth factors prevent apoptosis. Growth factors are pro-survival, inhibiting it induces apoptosis.

64
Q

What is the mechanism of action of growth factors and phosphorylation in both cell survival and apoptosis?

A

Survival
Survivial signals causes growth factors (Akt/PKB) to phosphrylate BAD so BAD unavailable to bind to BCL-2 and displace it. Cytochrome C not released and cell curvives

Intrinsic apoptosis
Loss of survival signals = dephosphorylation of BAD. BAD displaces BCL-2 and cytochrome C can be released through BAX pores = apoptosis.

Molecular Basis of Disease (29 decks)

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