AUTOPHAGY LINKS TO VARIOUS DISEASES

1. AUTOPHAGY LINKS TO VARIOUS
DISEASES

2. CONTENTS
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Introduction
Types of autophagy
Dual role of autophagy
Autophagy in cancer cells
Autophagosome formation
Diseases and autophagy role
Role of autophagy in diabetes and diabetic complications
Role of autophagy in diabetic neuropathy

3. Introduction
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Definition:
• Autophagy is a normal physiological process in the
body that deals with destruction of cells in the body.
• It maintains homeostasis or normal functioning by protein
degradation and turnover of the destroyed cell organelles
for new cell formation.

4. Types of Autophagy
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There are three different forms of autophagy that are
commonly described
1. Macroautophagy
2. Microautophagy
3. Chaperone – mediated autophagy
Micro Autophagy
Cytosolic components are directly taken up by the
lysosome itself through invagination of the lysosomal
membrane.
Macro Autophagy
Delivery of cytoplamic cargo to the
intermediatery of a double membrane bound vesicle ,
referred as an autophagosome, that fuses with the

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Chaperone – Mediated Autophagy
Targeted proteins are traslocated across the
lysosomal membrane in a complex with chaperone
proteins (such as Hsc-70) that are recognised by the
lysosomal membrane receptor LAMP-2A, resulting in
their unfolding and degradation

6. Autophagy Role In Cancer
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 Autophagy is a survival-promoting pathway that captures, degrades,
and recycles intracellular proteins and organelles in lysosomes.
 Although in some contexts autophagy suppresses tumorigenesis ,
and most contexts autophagy facilitates tumorigenesis.
 Cancers can up regulate autophagy to survive micro environmental
stress and to increase growth and aggressiveness.
 Mechanisms by which autophagy promotes cancer include
suppressing induction of the p53 tumour suppressor protein and
maintaining metabolic function of mitochondria.

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Tumour suppression by Autophagy in mouse liver
Autophagy deficiency
( Atg7or Becn1 Atg5)
P62accumulation
Mitochondrial defects
Oxidative stress
DNA damage
Cell death
Chronic tissue damage
Inflammation
Oncogenic signaling
Genome instability
Tumour initiation
Tumour promotion by Autophagy
Deregulated prolifiration
(KRASG12D or BRAFV600E)
Autophagy
Oxidative stress
ER stress
Mitochondrial function
Metabolism
Stress tolerance
Tumour promotion
zz

8. AUTOPHAGOSOME FOMATION
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DISEASES
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Five steps are involved in the autophagic pathways have been
identified:
1. Nucleation
2. Elongation
3. Closure
4. Fusion
5. Degradation
Nucleation
Isolated membrane appears in a cytosol.
Elongation
It is characterized by membrane bending and increase in the
size of the phagophore.
Closure
The autophagosome membrane wraps around the cytosolic
components.
Fusion
The fusion of autophagosome with a lysosome to form an
autolysosome.

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 Degradation : the autolysosome is degraded by
lysosomal hydrolases.

10. Diseases and Autophagy
role
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AUTOPHAGY
CANCER
CELL DEATH
INNATE IMMUNE
SYSTEM
CARDIOMYOPATHY
TYPE II DIABETES
AGING
INFECTIOUS DISEASES
NEURODEGENERATIVE
DISEASES

11. ROLE OF AUTOPHAGY IN
DIABETES AND DIABETIC
COMPLICATIONS
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12. )12
AMPK improves autophagy activity
Diabetic complicationsDiabetes
Pancreatic β
cells
Skeletal
muscle
insulin
activity
Liver
gluconeogen
esis
Diabetes
cardiomyopa
thy
Diabetes
nephropath
y
AMPK
RHEB
mTORC1
ULK1
Autophagy
AMPK
FoxO3
Gene
expressio
n
(LC3
beclin1)
Autophag
y
AMPK
ULK1
Autophag
y
AMPK
TSC1
MTORC
1
Autopha
gy
LKB1,CaMKK
AMPK
TSC1/2
mTORC1
ULK1
Autophagy

13. Role of Autophagy in Diabetic
Neuropathy
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Role of autophagy in diabetes can by done by two
ways
1. Protein aggregation and Endoplasmic
Reticulum(ER) stress in Diabetic
Neuropathy(DN).
2. Oxidative stress and mitotoxicity in Diabetic
Neuropathy(DN).

14. Protein aggregation and ER stress in
DN
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• As the path physiology of DN revolves around one of the unifying
mechanism i.e., reactive oxygen species (ROS) resulting in oxidative
stress, there exists a propensity of protein misfolding and aggregation.
• Proteins are highly susceptible to the modifications by ROS ROS
induced protein modifications might be reversible such as S-
glutathionylation and S-nitrosation.
• But irreversible protein modifications such as carbonylation results in
protein misfolding and aggregation depending on the severity of
• carbonylation.
• Both ER and Ubiquitin proteasome system (UPS) acts as quality control
systems for proteins deregulated under hyperglycemic conditions .
• ER requires reduced environment for oxidative folding of proteins.
• The reduced environment is maintained by antioxidants such as reduced
glutathione.

15. Oxidative stress and Mitotoxicity in
Diabetic Neuropathy
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• Mitochondrial dysfunction mainly occur either due to
synthesis of damaged electron transport chain(ETC)
components or due to enhanced ROS generation from
ETC.
• Later one occurs due to enhanced supply of NADH to ETC
which causes partial reduction of molecular oxygen to
superoxide in hyperglycemic state.
• It was well proved from the studies on diabetic rats that
hyperglycemia caused impairment in the function of ETC
enzyme complexes and some enzymes of tricarboxylic
acid(TCA) cycle.
 As a result of failure of mitochondrial function and
metabolism reduced ATP generation occurs and thus leads
to bioenergetic crisis followed by necrosis .

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 Mitochondrial dysfunction in hyperglycemia is also
associated with Ca2+ dyshomeostasis.
 Elevated levels of intramitochondrial Ca2+ levels make
mitochondria to work faster by stimulating TCA enzymes and
thus enhances the generation of ROS further .

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18. Interventions targeting at autophagy
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19. Repurposed Drug Targets in Autophagy
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 Rapamycin or chloroquine are studied as autophagy modulators in
clinical trials for lung diseases.
 For example : chloroquine, which inhibits autophagy-mediated cell
survival in tumour cells, is used as an intervention for patients with
small cell lung cancer in a clinical trial.
 Interventions using hydrochloroquine and other anticancer drugs such
as erlotinib are used for non-small cell lung cancer in two clinical trials.
 paradox may used due to the differential roles of autophagy in
different stages of tumorigenesis .

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 Lymphangioleiomyomatosis (LAM), a progressive lung
disease caused by mutation in the tuberous sclerosis
genes (tsc), is associated with inappropriate activation of
mTOR signaling, which regulates cellular growth and
lymphangiogenesis
 For example : Chloroquine is also used with rapamycin for
patients with LAM.