Autophagy Flashcards

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1
Q

What are the 2 main mechanisms of degradation?

A

The Ubiquitin/ Proteosome system (UPS), or Autophagy

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2
Q

How does the Ubiquitin System degrade material?

A

Ubiquitin targets specific proteins and this is recognised and degraded by a proteosome.

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3
Q

What is The Ubiquitin System often used for and why?

A

Signalling, as a specific protein can be degraded quickly (major turnover route for short-lived proteins).

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4
Q

What are the 3 types of Autophagy, and which is the main one?

A
  1. Macroautophagy (most common, the word autophagy almost always just refers to this)
  2. Chaperone-mediated autophagy
  3. Microautophagy
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5
Q

What are the mechanisms of Macroautophagy in 4 steps?

A
  1. Phagophore forms by expansion.
  2. Autophagosome forms by closure of phagophore.
  3. Autolysosome forms by fusion of lysosome and autophagosome (the cytosol acidifies here)
  4. Degradation of the materials inside the autolysosome by hydrolases and proteases.
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6
Q

What are 5 reasons cells need degradation?

A
  1. Homeostasis
  2. Signalling (used to down or up regulate)
  3. Reprogramming cells (allows different cells to have different cytosolic components/ differentiate)
  4. Removing damaged components
  5. Recycling nutrients (e.g. starvation)
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7
Q

How does Chaperone-mediated autophagy occur?

A

LAMP-2A receptor on lysosome recognises proteins and can enter it directly to be destroyed.

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8
Q

How does Microautophagy occur?

A

Cargo can be engulfed directly by lysosome membrane.

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9
Q

Which type of cell degradation doesn’t require lysosomes present?

A

The Ubiquitin/ proteasome system (UPS) uses proteosomes.

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10
Q

Why would The Ubiquitin/ proteasome system (UPS) be inefficient at degrading a lot of material at once?

A

As one proteosome degrades one protein at a time, many proteosomes would be needed.

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11
Q

What degradation pathway is most suitable for bulk digestion and removal of whole organelles?

A

Macroautophagy can degrade many proteins at once as well as whole organelles such as mitochondria.

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12
Q

What degradation pathway is most suitable for quick turnover of short lived proteins?

A

The Ubiquitin/ proteasome system (UPS), e.g. for signalling.

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13
Q

What degradation pathways are most suitable for long-lived proteins?

A

Chaperone-mediated autophagy and Microautophagy

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14
Q

Does the Chaperone-mediated autophagy and Microautophagy degrade individual proteins or bulk?

A

Individual proteins

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15
Q

What are the 4 key functions of Autophagy?

A
  1. Nutrient recycling
  2. Cellular remodelling
  3. Removal of damaged components
  4. Killing intracellular pathogens (mainly TB and salmonella in phagosome)
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16
Q

What is the effect of starvation of autophagy?

A

Autophagy is rapidly upregulated, as the digested material can be recycled.

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17
Q

What is an advantage to degradation with lysosomes?

A

The molecules released can support metabolism.

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18
Q

Why do cancer cells need autophagy to survive?

A

As cancer cells often undergo starvation due to having a lack of solid blood supply.

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19
Q

Why is (Macro) Autophagy used for cellular remodelling?

A

As this is the only mechanism to degrade whole organelles.

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20
Q

What are 2 examples of cellular remodelling by (Macro) Autophagy?

A
  1. Erythropoiesis (red blood cell differentiation)
    >Red blood cells have no organelles, the nucleus is ejected by the mitochondria are cleared by autophagy.
  2. Removal of sperm-derived mitochondria
    >In fertilised egg mitochondria is removed from sperm via autophagy.
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21
Q

What are two ways mitochondria can be damaged and what happens to them once damaged?

A

> During exercise can sustain mechanical damage, or due to ROS can be chemically damaged.

> Autophagosomes degrade them.

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22
Q

What happens in terms of autophagy while we age?

A

Autophagy capacity decreases (as lysosomal capacity decreases), so cell damage accumulates quicker than at it can be removed.

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23
Q

Why are muscle and neuronal cells more susceptible to build up of damaged cells when aging?

A

As they are longer lived cells and highly active, so have more mechanical damage and more chance of mutation. So when autophagy capacity decreases, damaged cells will build up.

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24
Q

What is the dietary restriction hypothesis?

A

Starvation -> Increase autophagy -> Damage repair (upregulating autophagy can increase damage repair)

25
Q

What are 2 pathogens which can easily escape phagocytes?

A

TB and Salmonella

26
Q

How does TB manipulate macrophages?

A

Stops phagosome from fusing with lysosomes (inside macrophages), so can be free in cytosol and feed on nutrients

27
Q

How does autophagy help the immune system and what would happen without its AID?

A

> Used to degrade faulty phagolysosome (e.g. manipulated by TB) a long with the pathogen inside it.

> Without autophagy, cells are a lot more vulnerable to infection from certain pathogens like TB.

28
Q

In what case would we want to inhibit autophagy to treat a disease?

A

To starve cancer cells

29
Q

In what 4 cases would we want to increase autophagy?

A
  1. In aging patients
  2. Muscular dystrophy
  3. Neurodegeneration
  4. To prevent cancer forming in the first place
30
Q

Do we want to increase or decrease autophagy for pathogen removal?

A

It varies for each pathogen, as for TB we would increase autophagy

31
Q

What method was used to identify 15 autophagy genes?

A

Genetic screens on yeast

32
Q

What are the 4 pathways which regulate autophagy and what do they do?

A
  1. ULK1 complex
    >Kinase that turns autophagy on or off (when to make autosomes or not) based off of AMPK signals on nutrient availability.
  2. P13K (kinase)
    >Defines where autophagosomes form (based off of lipids)
  3. Lipidation of autophagosome (controlled by 10 genes)
    >Regulates elongation of autophagosome.
  4. SNAREs
    >Specific SNAREs on autophagosome and lysosome mediate their fusion.
33
Q

In starvation is autophagy specific?

A

No, it is more random; vesicles collect as much as they can for recycling due to lack of nutrients.

34
Q

How is selective autophagy done in 2 ways?

A
  1. Ubiquitin tag added to target protein. Adaptor protein (has Ubiquitin and Atg8 binding sites) binds to Ubiquitin and drags the protein into the autophagosome and binds to Atg8.
  2. Or proteins can directly bind to Atg8 without ubiquitin present.
35
Q

What is Atg8?

A

Atg8 is a protein incorporated on both sides of autophagosome membrane

36
Q

Why is autophagy referred to as a housekeeping process?

A

As it keeps cell cleans by digesting unwanted proteins.

37
Q

What is a clear indication that a mitochondrion is damaged?

A

If they don’t have correct electrochemical gradient across it.

38
Q

What accumulates in cells that lack autophagy?

A

Ubiquitin aggregates

39
Q

Why are neurons particularly sensitive to failure of autophagy?

A

As they have long active lives and are large cells that transport over distances.

40
Q

What are the aggregates in a) Huntington’s b) Parkinson’s c) Alzheimer’s neurodegenerative diseases called?

A

a) Huntingtin b) α-synuclein (Lewy bodies) c) Amyloid β

41
Q

Why do different ubiquitin aggregates form in different neurodegenerative diseases?

A

All have dying neurons, but it is different subtypes of neurons dying in different cells as there are different reasons causing the aggregates.

42
Q

What causes Huntington’s disease and why is it more frequent in older people?

A

Having 35 or more polyglutamine (polyQ) expansions in Huntingtin protein causes higher frequency of misfolding in the protein due to the longer sequence length. As you age and autophagy capacity decreases, more of these aggregates don’t get degraded.

43
Q

How is Huntington’s disease degraded by autophagy in 4 steps and what issues can lead to Huntington’s disease?

A

1) Misfolding and aggregation of Huntingtin due to high polyglutamine (polQ) number.

2) Ubiquitination of misfolded proteins leads proteasomal degradation of individual misfolded proteins.

3) If misfolded proteins build up, adaptor proteins bind to multiple ubiquitins to combine aggregates into agrosomes.

4) Autophagosome degrades agrosome.

> Issues in a combination of these steps can lead to Huntington’s.

44
Q

What type of genetic disease is Parkinson’s?

A

Sporadic

45
Q

What is the rare type of mutations cause Parkinson’s?

A

Secondary mutations that effect turn over of α-synuclein (Lewy bodies).

46
Q

Describe the mutation which causes Parkinson’s disease by α-synuclein aggregates?

A

α-synuclein with A53T mutation blocks LAMP2 receptor (is chaperone mediated as uses ubiquitin) when taken up by lysosome. This means other α-synuclein proteins cannot be degraded by this Chaperone-mediated autophagy pathway. Causes accumulation of α-synuclein called Lewy Bodies.

47
Q

In someone with a working autophagy system, how are α-synuclein aggregates degraded?

A

Via Chaperone-mediated autophagy, where α-synuclein proteins are taken up by LAMP2 receptors into lysosomes for degradation.

48
Q

What is a more common cause for Parkinson’s disease than α-synuclein aggregates?

A

Parkinson’s may be caused by mitochondrial-derived oxidative damage. As mitochondria damaged by reactive oxygen species (ROS) accumulate in cells if autophagy capacity is sub-optimal.

49
Q

What are the 2 enzymes than can be mutated to cause Parkinson’s via mitochondrial disfunction and what is the effect of these mutations?

A

1) PINK1 (mitochondrial kinase)

2) PARKIN (Cytosolic E3 ubiquitin ligase).

> Mutations in these proteins mean mitochondria will not be degraded.

50
Q

How do PINK1 and PARKIN enzymes respond to mitochondrial damage?

A

Kinase and Ubiquitin ligase recognise depolarised mitochondria and tag with ubiquitin on surface so autophagosomes can target and degrade.

51
Q

How does Reactive Oxygen Species (ROS) cause damage to mitochondria?

A

Mitochondria damaged by ROS have misfolded proteins due to oxidative damage, but carry on working (if not degraded by autophagy system) producing more ROS which causes more oxidative damage (degenerative positive feedback loop) which can damage other organelles.

52
Q

What is overall concept of how cancer is caused?

A

Cancer is caused by accumulation of DNA damage disrupting normal homeostatic function.

53
Q

What are the 2 main causes of DNA damage in our cells?

A

DNA damage is often caused by ROS from damaged mitochondria and damaged organelles in cells.

54
Q

How does autophagy protect cells from developing cancer?

A

As DNA damage is often caused by ROS from damaged mitochondria and damaged organelles in cells, if autophagy removes these damaged organelles and mitochondria then this reduces the chances of DNA damage in cells and cancer is caused by an accumulation of DNA damage.

55
Q

What mutation causes ovarian, breast and prostate cancer carcinomas?

A

Atg6 autophagy gene (Beclin 1) is deleted, reducing autophagy capacity so DNA damage builds up.

56
Q

What are 3 ways autophagy is Pro-oncogenic (helps cancers)?

A

1) Autophagy is unregulated in hypoxic, nutrient poor tumour conditions as cancerous cells at first don’t have vasculature so can use autophagy to survive starvation (by recycling material) before vascularization occurs.

2) Upregulation of autophagy blocks apoptotic pathway as Beclin1 does not bind to Bcl2.

3) Helps survival during chemotherapy.

> Don’t want autophagy once cancer is present (as promotes survival)

57
Q

How does the autophagy pathway and apoptotic pathway interact?

A

Beclin1 is a protein which makes PI3P leading to autophagosome formation in the autophagy pathway. Blc2 is normally bound to mitochondria which blocks the initiation of the apoptotic pathway. When not too much autophagy is taking place, Beclin1 and Blc2 bind bringing Blc2 away from mitochondria triggering apoptosis while turning off autophagosome formation (Decreased autophagy -> Increased apoptosis, Increased autophagy -> Decreased apoptosis)

58
Q

What are 4 ways autophagy is anti-oncogenic (stops cancers)?

A

1) Maintains cell homeostasis.

2) Removal of damaged organelles, causing less DNA damage and mutations

3) Reducing ROS/ genotoxicity by degrading damaged mitochondria.

4) Reducing inflammation

(Want autophagy before cancer develops, it prevents DNA damage and therefore stops cancers)

59
Q

What are 3 strategies for autophagy as a therapeutic?

A

1) Block autophagy so tumour starves in early stages (lack of recycling of material when no venus structure is present).

2) Inhibit autophagy to increase apoptosis during chemotherapy.

3) Increase autophagy (from exercise or a drug), would prevent diseases in the first place as would reduce DNA damage in the first place that cause cancers and neurodegenerative diseases.