Lecture 17 - Autophagy 1 Flashcards
What is (macro)autophagy ?
Involves the degradation and recycling of cellular components. Invovles the formation of specialised double-membrane structures called (autophagosomes, which enclose portions of cytoplasm, organelles, or protein aggregates.
A mechanism to digest intracellular material.
It delivers cytoplasmic waste materials to the lysosome
What are the main steps of autophagy?
- Initiation
- Nucleation
- Elongation (Phagophore)
4.Closure (autophagosome)
Lysosome - Fusion
- Acidification and maturation
- Degradation and recycling (Autolysosome)
What are the 2 main sets of pathways for intracellular degradation?
- The Ubiquitin/ proteasome system (UPS)
- Autophagy
How can autophagy be selective ?
There are many different tyoes including :
Mitophagy - degradation of mitochondria
Reticulophagy
Nucleophagy
Lipophagy - degradation of lipid droplets
Xenophagy - degrades microorgansisms
Why do cells need degradation/ autophagy?
Recyclying nutrients, damaged protein/organelle removel, cellular remodelling and intracellular pathogen removal
It is an evolutionary conserved survival mechanism
What occurs during Ubiquitin system ?
Certain cargo proteins are targeted for degradation by Ubiquitin attachment. Ubs is a small protein. Ubs is recognised by proteasome and fed through and degraded.
Non-lusosomal
Degrades individual proteins
Major turnover route for short-lived proteins
What are the 3 compartments of Autophagy ?
Macroautophagy
Chaperone-Mediated Autophagy
Microautophagy
What are the features of Macrophagy pathway ?
Lysosomal
Bulk digestion pathway
can remove whole organelles
Molecules released can support metabolism
What are the features of chaperone-mediated autophagy/ microautophagy?
Lysosomal
Only degrades individual proteins
Important in aging
Turns over specific, generally long-lived proteins
Relatively low capacity
What is useful about Nutirent recycling?
Autophagy is upregulated under starvation.
Causes non-selective bulking
Cells lacking autophagy die under starvation
Autophagy-deficient mice die during neonatal starvation
Cancer calls in solid tumours need autophagy to survive
What is useful about cellular remodelling ?
Autophagy is the ONLY mechanism to degrade organelles at once.
Essential to form some specific cell types e.g.
Erythropoiesis - red blood cell differentiation
Removal of sperm-derived mitochondria
What is useful about the removal of damaged components ?
Cellular components accumulate damage over time.
Mechanical damage
Damaged mitochondria selectively removed
Ageing and neurodegenerative disease:
Cells continuously acquire damage
Lysosomal capacity decreases as we age
Reduced autophagy is the major reason for age-related degeneration
Long-lived or highly metabolic cells such as neurons and muscles most susceptible. Muscle dystrophy
Cancer
Can autophagy make you live longer?
If you restrict calorifc intake you can increase autophagy and therefore increase damage repair - The dietary restriction hypothesis. This increase in damage repair hypothetically stops aging.
Expirements used C.elegans (worms) to test this
What is useful about killing intracellular pathogens?
Problem is that Many pathogens escape into the cytoplasm, by being taking up by phagasomes but can prevent maturation of phagosomes. In the cytocol the pathogens are able to easily grow and burst out
Without autophagy = cells more sensitive to infection
Tuberculosis
MRSA
Viruses
What are the 4 man roles of autophagy ?
Recycling nutrients
Cellualer remodellin
Intracellu;ar pathogen removel
Damaged proteins
How did we discover the pathway ?
Discoverd a mitochondria within a lysosme in 1963. Without knowledge of molecular machinery.
Then in 1992 another man found the same thing in yeast. Instead of many lysosomes yeast have only one central vacuole.
WHat did idntifying the Atg genes allow ?
DISRUPTED AUTOPHAGY TO INVESTIGATE ITS FUNCTION
It was a start on dissecting how the machinery works
Observation of autophagy in live cells
WHat did idntifying the Atg genes allow ?
ISRUPTED AUTOPHAGY TO INVESTIGATE ITS FUNCTION]
It was a start on dissecting how the machinery works
Observation of autThophagy in live cells
Whta re the main proteins and genes involved in autopjagy
- ULK1 kinase requird for helping start the antire autophay pathwya off
- PI3K - defines where autophagasomes form
- 10 gene complex - Controls addition of new lipid to it
- SNARES regulate fusion of phagasomes with lysosomes
How can autophagy be selective aka when the person is starving?
Uses 2 thing
Ubibiquitin tag-cell will be targeted
Adaptor proteins - scaffolding protein with 2 domains. Atg8 (LC3) is a small portion that gets lipide and incorporated into the membrane and Ubiquitin tag.
The adaptor will drag anything ubiquitinated
