Autophagy Flashcards
Autophagy
mechanism to digest intracellular material
Why do cells need degradation?
homeostasis
removing damaged components
signalling
recycling nutrients
reprogramming cells for differentiation
What are the different mechanisms of degradation?
ubiquitin/proteosome system
macroautophagy
chaperone-mediated autophagy
microautophagy
Proteosome
non-lysosomal
degrades individual proteins
major turnover route for short lived proteins
Macroautophagy
lysosomal
bulk digestion pathway
can remove whole organelles
molecules released can support metabolism
Chaperone mediated autophagy
lysosomal
only degrades individual proteins
turns over specific generally long lived proteins and relatively low capacity
Nutrient recycling
autophagy is rapidly upregulated under starvation which causes non-selective bulk degradation of the cytosol
wihout autophagy cells die under starvation
cancer cells in solid tumours need it to survive
Cellular remodelling
autophagy is the only mechanism to degrade organelles and is essential to from specific cell types
Removal of damaged components
cellular componnents accumulate damage over time
cell are continuously damaged and reduced autophagy is part of age related degeneration
What cells are most susceptible to age related reductions in autophagy?
long lived metabolic cells
neurons and muscle
What processes require organelle autophagy to form specific cell types?
erythropoiesis
removal of sperm derived mitochondria
Dietary restriction hypothesis
starvation/exercise → increase in autophagy → increase in damage repair
Damaged protein/organelle removal in disease
ageing, muscular dystrophy, neurodegeneration, cancer
Intracellular pathogen removal examples
tuberculosis, MRSA and viruses
What happens when neuronal cells lack autophagy?
accumulation of ubiquitinated aggregates
increased apoptosis and necrosis
Huntingtons disease
caused by polyglutamine (polyQ) expansion in the huntingtin protein:
midfolding and aggregation → ubiquitination → aggresome formation/ proteosomal degradation → autophagic degradation
Parkinsons disease
main neuropathology is aggregates of a-synuclein or lewy bodies
complex genetics but a-synuclein is rarely mutated
a-synuclein
normally degraded by chaperone mediated autophagy
mutated versions block this causing toxicity in parkinsons
What else accumulates in parkinsons disease?
damaged mitochondria
may be caused by mitochondrial derived oxidative damage as they are the main source of ROS
PINK1
mitochondrial kinase which shows loss of function mutation in some sporadic early onset parkinsons
PARKIN
cytosolic E3 ubiquitin ligase
mutated in half of autosomal recessive parkinsons and a some of sporadic early onset
How is autophagy tumour recessive?
decrease in damaged organelles
protein toxicity and ROS stops oxidative stress and DNA damage, and therefore tumorigenesis
Beclin 1
monoallelically deleted in 40-75% of ovarian, breast and prostate carcinomas
Where is autophagy unregulated?
in hypoxic, nutrient poor tumour regions
How is lack of autophagy related to cancer?
cancer can be caused by accumulation of DNA damage
How is autophagy anti-oncogenic?
cell homeostasis
damage removal
reduced ROS and genotoxicity
reduced inflammation
How can autophagy be pro-oncogenic?
survival during oxygen or nutrient storage
prevention of apoptosis
survival during chemotherapy
Autophagy based therapies
blocking survival to metabolic stress with autophagy inhibitors
inhibiting autophagy to increase apoptosis during chemo
elevating autophagy to remove damage and prevent cancer
