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L2 Molecular Cell Biology > Autophagy > Flashcards

Autophagy Flashcards

1
Q

What is autophagy?

A

A mechanism to digest intracellular material

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2
Q

Why do cells need degradation? (5)

A
  • Homeostasis
  • Removing damaged components
  • Signalling (degrade receptors)
  • Recycling nutrients
  • Reprogramming cells (differentiation)
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3
Q

What are the 2 main mechanisms of degradation?

A
  • The ubiquitin/proteasome system (UPS)
  • Autophagy
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4
Q

How does the UPS pathway work? (2)

A
  • Target proteins are tagged with ubiquitin
  • Ubiquitin tag is recognised by the proteasome and the protein is degraded
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5
Q

What are the 3 types of autophagy?

A
  • Macroautophagy
  • Microautophagy
  • Chaperone-mediated autophagy
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6
Q

What is macroautophagy? (2)

A
  • Vesicle is formed de novo (autophagosome) in the cytosol which engulfs material to be degraded
  • Autophagosome fuses with a lysosome and degrades the material
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7
Q

What is microautophagy? (2)

A
  • Lysosome membrane invaginates to engulf material
  • Material is degraded in the lysosome
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8
Q

What is chaperone-mediated autophagy? (2)

A
  • LAMP2 receptor on the lysosome recognises specific amino acid tags on target proteins
  • Targets fed into the lysosome and degraded
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9
Q

What are the features of proteasomal degradation? (3)

A
  • No lysosomes involved
  • Degrades individual proteins
  • Major turnover route for short-lived proteins (e.g. signalling proteins)
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10
Q

What are the features of macroautophagy? (4)

A
  • Lysosomal
  • Bulk digestion pathway
  • Can remove whole organelles
  • Molecules released can support metabolism (proteins, lipids etc.)
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11
Q

What are the features of chaperone-mediated autophagy? (4)

A
  • Lysosomal
  • Degrades individual proteins
  • Turnover route for specific long-lived proteins
  • Relatively low capacity
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12
Q

What are the functions of macroautophagy? (4)

A
  • Nutrient recycling
  • Cellular remodelling
  • Removal of damaged components
  • Killing intracellular pathogens
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13
Q

How is macroautophagy used for nutrient recycling? (2)

A
  • Autophagy is rapidly upregulated under starvation
  • Bulk degradation of the cytosol to create nutrients to keep the cells alive
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14
Q

Why do cancer cells need autophagy?

A

Tumour cells have restricted blood supply (hypoxic, limited nutrient access) so need to do autophagy to survive

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15
Q

How is macroautophagy used for cellular remodelling? (3)

A
  • Autophagy is the only mechanism to degrade entire organelles
  • Removal of mitochondria etc. is required in erythropoiesis
  • Removal of sperm-derived mitochondria in the fertilised egg (mitochondria is maternally inherited)
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16
Q

What is erythropoiesis?

A

Red blood cell formation

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17
Q

How is macroautophagy used to remove damaged components? (2)

A
  • Cellular components accumulate damage over time e.g. mitochondria oxidative damage
  • Damage removed by autophagy
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18
Q

How is autophagy linked to ageing and neurodegenerative disease? (3)

A
  • Lysosomal capacity decreases as we age
  • Reduced autophagy is the major reason for age-related degeneration
  • Long-lived or highly metabolic cells (neurons and muscle) are most susceptible
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19
Q

What is the dietary restriction hypothesis? (2)

A
  • Starvation upregulates autophagy in cells
  • Increased damage repair extends lifespan
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20
Q

How is macroautophagy used to kill intracellular pathogens? (3)

A
  • Many pathogens evade the immune system and escape into the cytosol
  • Cells can use autophagy to have a second go at getting rid of infection
  • However some pathogens can prevent vesicle fusion with the lysosome so the pathogen is safe within the vesicle
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21
Q

Why is it hard to know how to manipulate autophagy? (4)

A
  • Autophagy needs to be inhibited/upregulated in different situations
  • Cancer: need to inhibit autophagy to kill tumour cells
  • Neurodegeneration: need to upregulate autophagy to remove damage
  • Pathogens: inhibit/upregulate depending on the pathogen
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22
Q

How was autophagy discovered? (4)

A
  • Mitochondria within a lysosome observed by electron microscopy, named autophagy
  • Later observed in yeast, 15 autophagy genes identified
  • Disruption of atg genes used to investigate its functions
  • Machinery identified and autophagy observed in live cells
23
Q

Which proteins are involved in autophagy? (4)

A
  • ULK1 complex required to start autophagy
  • PIK3 complex makes a specific lipid on the surface of the phagophore
  • Multiple genes involved in adding lipids to the membrane as it forms
  • SNAREs required for fusion of autophagosomes with lysosomes
24
Q

How can autophagy be selective? (3)

A
  • The UBD of an adaptor protein binds to a ubiquitinated protein
  • The AIM binds to Atg8 on the inside of the autophagosome membrane to drag the cargo inside for degradation
  • Some specific proteins contain AIMs anyway which are naturally selected for degradation by autophagosomes
25
Q

What is the structure of adaptor proteins? (2)

A
  • Ubiquitin binding domain (UBD)
  • Atg8 (LC3) interacting motif (AIM)
26
Q

What is the marker for autophagosome membranes?

A

Atg8 (LC3)

27
Q

What is a phagophore?

A

A double-membrane structure that expands around the cargo and seals to form a double-membrane vesicle called an autophagosome

28
Q

What common feature is seen in neurodegenerative diseases?

A

Ubiquitinated protein aggregates

29
Q

What proteinopathy is seen in Huntington’s disease?

A

Huntingtin aggregates

30
Q

What proteinopathy is seen in Alzheimer’s disease?

A

Amyloid β plaques

31
Q

What proteinopathy is seen in Parkinson’s

A

α-synuclein aggregates

32
Q

What causes Huntington’s disease? (4)

A
  • Polyglutamine expansion (polyQ) in the Huntingtin protein causes misfolding
  • Aggregates of misfolded polyQ Huntingtin are normally ubiquitinated and degraded by the proteosome
  • Too much build up results in aggresomes forming which are targeted by autophagy
  • More glutamine repeats correlates with earlier onset of disease
33
Q

What could be the mechanism of toxicity in Huntington’s? (6)

A
  • Loss of the normal function of Huntingtin (function unknown)
  • Toxic microaggregates (oligomers)
  • Toxic aggresomes
  • Proteosome damage
  • Adaptor sequestration (adaptor proteins held in the aggresomes)
  • Interacting protein sequestration
34
Q

What causes Parkinson’s disease?

A

Aggregates of α-synuclein (Lewy bodies) build up in dopaminergic neurons causing death of dopaminergic neurons

35
Q

What are the differences between Huntington’s and Parkinson’s? (3)

A
  • Huntington’s is caused by a single gene but Parkinson’s has complex genetics
  • Huntington’s runs in families but only a small percentage of Parkinson’s cases are familial
  • Huntington’s is caused by a Huntingtin mutation but in Parkinson’s α-synuclein is rarely mutated
36
Q

How is α-synuclein normally degraded? (2)

A
  • Chaperone-mediated autophagy
  • Recognised by LAMP2 receptor and transported directly into the lysosome
37
Q

How can mutations in α-synuclin cause familial Parkinson’s? (3)

A
  • A53T mutation causes α-synuclein to block the LAMP2 receptor, therefore can’t enter the lysosome
  • α-synuclein builds up and forms aggregates which are targeted by autophagy
  • Aggregates overwhelm autophagy, accumulate and cause disease
38
Q

What is the leading hypothesis for the cause of Parkinson’s? (2)

A
  • Damaged mitochondria accumulate in Parkinson’s, source of ROS which causes damage
  • Parkinson’s is caused by mitochondrial-derived oxidative damage
39
Q

What proteins are mutated in sporadic cases of Parkinson’s? (2)

A
  • PINK1
  • PARKIN
40
Q

What is PINK1? (3)

A
  • Mitochondrial kinase
  • Loss of function in sporadic early-onset Parkinson’s
  • Responds to mitochondrial damage
41
Q

What is PARKIN? (3)

A
  • E3 ubiquitin ligase (tags target proteins with ubiquitin)
  • Associated with early-onset Parkinson’s
  • Responds to mitochondrial damage
42
Q

How do PINK1 and PARKIN work normally? (2)

A
  • PINK1 and PARKIN recognise damaged mitochondria and ubiquitinate
  • Damaged mitochondria are targeted by mitophagy
43
Q

What is mitophagy?

A

Degradation of damaged mitochondria via autophagy

44
Q

What happens when PINK1/PARKIN are mutated? (3)

A
  • Damaged mitochondria accumulate and generate ROS
  • ROS causes oxidative damage, protein misfolding and damage to organelles
  • Ultimately leads to neuronal death in Parkinson’s
45
Q

How is autophagy linked to cancer? (2)

A
  • Autophagy protects cells from damaged organelles/ROS/protein toxicity which prevents DNA damage
  • Without autophagy, DNA damage can lead to cancer
46
Q

Which autophagy gene mutation is associated with cancer?

A

Atg6 gene (Beclin 1) deletion in high proportion of ovarian, breast and prostate cancers

47
Q

How are autophagy and apoptosis linked in normal cells? (3)

A
  • Autophagy suppresses apoptosis
  • When the cell is surviving, Beclin1 is encouraging autophagy and Bcl2 is on the mitochondria blocking apoptosis
  • When the cell wants to die, Beclin1 directly interacts with Bcl2 to remove it from the mitochondria, favours apoptosis over autophagy
48
Q

What largely causes apoptosis? (2)

A
  • Mitochondrial membrane permeabilisation and release of caspases into the cytosol
  • Regulated by Bcl protein family
49
Q

What does Bcl2 do? (2)

A
  • Present on the mitochondrial membrane
  • Prevents the release of caspases and blocks apoptosis
50
Q

What does Beclin1 do?

A

Involved in making autophagosomes for autophagy

51
Q

Why is autophagy a concern in cancer? (3)

A
  • Autophagy is upregulated in cancer cells to keep them alive
  • This causes inhibition of apoptosis
  • This drives tumour survival and chemotherapy resistance
  • Inhibit autophagy to activate apoptosis?
52
Q

How is autophagy anti-oncogenic? (4)

A
  • Removes damage
  • Reduces ROS
  • Reduces inflammation
  • Prevents DNA damage
53
Q

How is autophagy pro-oncogenic? (3)

A
  • Promotes survival during oxygen/nutrient shortage
  • Inhibits apoptosis
  • Promotes chemotherapy resistance
54
Q

How could autophagy be manipulated to tackle cancer? (3)

A
  • Inhibit autophagy to block tumour survival
  • Inhibit autophagy to increase apoptosis during chemotherapy
  • Activate autophagy to remove damage and prevent cancer

L2 Molecular Cell Biology (13 decks)

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