Lecture 20 - Autophagy 1

Question 1

What is autophagy?

Answer 1

(macro) autophagy - mechanism to digest intracellular material

Question 2

Why do cells need degradation?

Answer 2

• homeostasis
• signalling
• removing damaged components
• recycling nutrients
• reprogramming cells (differentiation)

Question 3

What are the multiple mechanisms of degradation?

Answer 3

• the ubiquitin/proteasome system (UPS)
• Macro autophagy
• Chaperone-mediated autophagy
• Microautophagy

Question 4

How does degradation occur via the ubiquitin/proteasome system (UPS)?

Answer 4

• Ubiquitin tag is degraded by proteasome
• Non-lysosomal
• Degrades individual proteins
• Major turnover route for short-lived proteins

Question 5

How does degradation occur via maroautophagy?

Answer 5

• lysosomal
• bulk digestion pathway
• can remove whole organelles
• molecules released can support metabolism

Question 6

How does degradation occur via chaperone-mediated autophagy/microautophagy?

Answer 6

• Lysosomal
• Only degrades individual proteins
• Turns over specific, generally long-lived proteins
• relatively low capacity

Question 7

What are the 4 functions of (macro)autophagy?

Answer 7

• nutrient recycling
• cellular remodelling
• removal of damaged components
• killing intracellular pathogens

Question 8

Describe nutrient recycling in (macro) autophagy?

Answer 8

Autophagy is rapidly upregulated under starvation. This causes non-selective bulk degradation of the cytosol.

Cells lacking autophagy die under starvation

Autophagy-deficient mice die during neonatal starvation

Cancer cells in solid tumours need autophagy to survive

This also happens in humans between meals e.g. liver to supply amino acids

Question 9

What occurs during cellular remodelling?

Answer 9

Autophagy is the only mechanism to degrade organelles. It is essential to form some specific cell types.

• Erythropoiesis (red blood cell differentiation)
• Removal of sperm-derived mitochondria

Question 10

What occurs during removal of damaged components?

Answer 10

Cellular components accumulate damage over time

Question 11

Explain ageing and neurodegenerative disease

Answer 11

• cells continuously acquire damage
• lysosomal capacity decrease as we age
• reduced autophagy is the major reason for age-related degeneration
• long-lived or highly metabolic cells such as neurons and most susceptible to reduced autophagy

Question 12

Can autophagy make you live longer?

Answer 12

The dietary restriction hypothesis:

Starvation/exercise –> increased autophagy –> increased damage repair

Question 13

How does autophagy in physiology in physiology disease relate to recycling nutrients?

Answer 13

cancer cells use the process of autophagy to survive when faced with nutrient deprivation

Question 14

How does autophagy in physiology & disease relate to damaged protein/organelle removal?

Answer 14

Ageing, muscular dystrophy, neurodegeneration, cancer

Question 15

How does autophagy in physiology & disease relate to cellular remodelling?

Answer 15

Erythrocyte differentiation, removing sperm-derived mitochondria

Question 16

How does autophagy in physiology & disease relate to intracellular pathogen removal?

Answer 16

tuberculosis, MRSA, viruses

Question 17

How could prevention of autophagy prevent cancer?

Answer 17

As these cells may use autophagy

Question 18

How may autophagy prevent cancer?

Answer 18

Through prevention of ageing, muscular dystrophy etc.

Question 19

What does stimulation of autophagy lead to?

Answer 19

Removal of tuberculosis

Question 20

What does inhibition of autophagy lead to?

Answer 20

Increased susceptibility to MRSA

Question 21

Describe the process of producing a autolysosome

Answer 21

1. Phagophore (includes expansion and closure)
2. Autophagosome
   3.Fusion of lysosome
3. Acidification and maturation
4. Autolysosome (degradation)

Question 22

How were the identification of ATG (autophagy-related genes) allowed?

Answer 22

• disruption of autophagy to investigate its function
• a start on dissecting the machinery
• observation of autophagy in live cells

Question 23

How many proteins & genes are involved in the autophagy machinery?

Answer 23

Approximately 40

Question 24

What 3 components can the proteins and genes involved in autophagy machinery be broken into?

Answer 24

• Regulation - cells need to be able to decide how many autophagosomes to make and where - e.g. AMPK detect ATP levels, mTORC1 detects amino acid levels - both input into ULK1 complex
• Addition of a membrane
• SNAREs

Question 25

How does selective autophagy occur?

Answer 25

Through a family of adaptor proteins