Autophagy is a cellular process where cytoplasmic components are engulfed and degraded in the lysosome or vacuole. There are three main types of autophagy: chaperone-mediated autophagy, macroautophagy, and microautophagy. Macroautophagy involves the formation of a double-membrane vesicle called the autophagosome that delivers cytoplasmic cargo to the lysosome. Autophagy plays an important role in cellular homeostasis and survival during starvation. Defects in autophagy are associated with cancer, neurodegenerative diseases, and other disorders. While autophagy generally promotes survival, excessive autophagy may lead
here is some information about autophagy, how it happend, when it happend and it's mechanism.
and some information about it's effect on cancer and some disorders.
MULTIFACETED ROLES OF AUTOPHAGY IN CANCER & NEURODEGENERATIVE DISORDERSPHARMA IQ EDUCATION
1. What is Autophagy
2. Overview of the mechanisms lying behind autophagy
3. Mechanism of autophagy
4. Physiological role of autophagy
5. Role of Autophagy in cancer
6. Autophagy in tumor suppression
7. Autophagy in tumor promotion
8. Role of Autophagy in neurodegenerative diseases
9. Mechanism of autophagy in neurodegenerative disorders
10. Conclusion
11. References
12. Thank You
here is some information about autophagy, how it happend, when it happend and it's mechanism.
and some information about it's effect on cancer and some disorders.
MULTIFACETED ROLES OF AUTOPHAGY IN CANCER & NEURODEGENERATIVE DISORDERSPHARMA IQ EDUCATION
1. What is Autophagy
2. Overview of the mechanisms lying behind autophagy
3. Mechanism of autophagy
4. Physiological role of autophagy
5. Role of Autophagy in cancer
6. Autophagy in tumor suppression
7. Autophagy in tumor promotion
8. Role of Autophagy in neurodegenerative diseases
9. Mechanism of autophagy in neurodegenerative disorders
10. Conclusion
11. References
12. Thank You
Molecular mechanisms of Autophagy and its Role in Plant Immunity SystemsMonuj Gogoi
Details of Autophagy Mechanisms and its roles for plant diseases management.
Numbers of papers were selected for the preparation of this presentation. So Thanks to all authors those are published.
Autophagy the housekeeper in every cellfathi neana
Autophagy is a catabolic process involving the degradation of a cell’s own components through the lysosomal machinery. It is a tightly regulated process that plays a normal part in cell growth, development, and homeostasis, helping to maintain a balance between the synthesis, degradation, and subsequent recycling of cellular products.
It is a major mechanism by which a starving cell reallocates nutrients from unnecessary processes to more-essential processes. Autophagy is an evolutionarily conserved mechanism of cellular self-digestion in which proteins and organelles are degraded through delivery to lysosomes. Defects in this process are implicated in numerous human diseases including cancer.
Content-
1. Background
2. Introduction
3. Difference between apoptosis and necrosis
4. Apoptosis in biologic processes
5. Apoptosis in pathologic processes
6. Morphologic features
7. Techniques to identify and count apoptotic cells
8. Biochemical changes
9. Molecular mechanism of apoptosis
10. Recent advancement and emerging trends in apoptosis
11. References
Autophagy Lecture from HNO Skill Development Centrerandzee7
Autophagy is the natural, conserved degradation of the cell that removes unnecessary or dysfunctional components through a lysosome-dependent regulated mechanism. It allows the orderly degradation and recycling of cellular components. Although initially characterized as a primordial degradation pathway induced to protect against starvation, it has become increasingly clear that autophagy also plays a major role in the homeostasis of non-starved cells. Defects in autophagy have been linked to various human diseases, including neurodegeneration and cancer, and interest in modulating autophagy as a potential treatment for these diseases has grown rapidly.
Molecular mechanisms of Autophagy and its Role in Plant Immunity SystemsMonuj Gogoi
Details of Autophagy Mechanisms and its roles for plant diseases management.
Numbers of papers were selected for the preparation of this presentation. So Thanks to all authors those are published.
Autophagy the housekeeper in every cellfathi neana
Autophagy is a catabolic process involving the degradation of a cell’s own components through the lysosomal machinery. It is a tightly regulated process that plays a normal part in cell growth, development, and homeostasis, helping to maintain a balance between the synthesis, degradation, and subsequent recycling of cellular products.
It is a major mechanism by which a starving cell reallocates nutrients from unnecessary processes to more-essential processes. Autophagy is an evolutionarily conserved mechanism of cellular self-digestion in which proteins and organelles are degraded through delivery to lysosomes. Defects in this process are implicated in numerous human diseases including cancer.
Content-
1. Background
2. Introduction
3. Difference between apoptosis and necrosis
4. Apoptosis in biologic processes
5. Apoptosis in pathologic processes
6. Morphologic features
7. Techniques to identify and count apoptotic cells
8. Biochemical changes
9. Molecular mechanism of apoptosis
10. Recent advancement and emerging trends in apoptosis
11. References
Autophagy Lecture from HNO Skill Development Centrerandzee7
Autophagy is the natural, conserved degradation of the cell that removes unnecessary or dysfunctional components through a lysosome-dependent regulated mechanism. It allows the orderly degradation and recycling of cellular components. Although initially characterized as a primordial degradation pathway induced to protect against starvation, it has become increasingly clear that autophagy also plays a major role in the homeostasis of non-starved cells. Defects in autophagy have been linked to various human diseases, including neurodegeneration and cancer, and interest in modulating autophagy as a potential treatment for these diseases has grown rapidly.
Basic structural and functional unit of life
Understanding of cell morphology is critical to the study of biochemistry.
Divided and classified in many ways.
One common classification method is absence or presence of a cell nucleus.
Autophagy is an essential catabolic pathway by which cytoplasmic materials are delivered to and degraded in the lysosome. This highly regulated pathway is physiologically essential, ensuring nutrient recycling, and cellular and organismal homeostasis during stress. It is activated by various endogenous and exogenous stimuli.
The chapter contain detail descriptions regarding structures and functions of different cell organelles of plant and animal cells which is helpful to UG and PG students of Science. Cell is the basic unit of structure and function in all living organisms. The basic constituents of plant and animal cells are the same,
viz nucleic acid, proteins, carbohydrates, lipids and various inorganic substances
They organized in the same fundamental manner. The shape of plant cell is rectangular and that of animal cell is round with irregular appearance. Cell organelles various membrane bound structures that are
found within a cell such as nucleus, plastids, mitochondria,
endoplasmic reticulum etc.
Similar to autophagy- survival and cell death. (20)
This pdf is about the Schizophrenia.
For more details visit on YouTube; @SELF-EXPLANATORY;
https://www.youtube.com/channel/UCAiarMZDNhe1A3Rnpr_WkzA/videos
Thanks...!
Multi-source connectivity as the driver of solar wind variability in the heli...Sérgio Sacani
The ambient solar wind that flls the heliosphere originates from multiple
sources in the solar corona and is highly structured. It is often described
as high-speed, relatively homogeneous, plasma streams from coronal
holes and slow-speed, highly variable, streams whose source regions are
under debate. A key goal of ESA/NASA’s Solar Orbiter mission is to identify
solar wind sources and understand what drives the complexity seen in the
heliosphere. By combining magnetic feld modelling and spectroscopic
techniques with high-resolution observations and measurements, we show
that the solar wind variability detected in situ by Solar Orbiter in March
2022 is driven by spatio-temporal changes in the magnetic connectivity to
multiple sources in the solar atmosphere. The magnetic feld footpoints
connected to the spacecraft moved from the boundaries of a coronal hole
to one active region (12961) and then across to another region (12957). This
is refected in the in situ measurements, which show the transition from fast
to highly Alfvénic then to slow solar wind that is disrupted by the arrival of
a coronal mass ejection. Our results describe solar wind variability at 0.5 au
but are applicable to near-Earth observatories.
Richard's aventures in two entangled wonderlandsRichard Gill
Since the loophole-free Bell experiments of 2020 and the Nobel prizes in physics of 2022, critics of Bell's work have retreated to the fortress of super-determinism. Now, super-determinism is a derogatory word - it just means "determinism". Palmer, Hance and Hossenfelder argue that quantum mechanics and determinism are not incompatible, using a sophisticated mathematical construction based on a subtle thinning of allowed states and measurements in quantum mechanics, such that what is left appears to make Bell's argument fail, without altering the empirical predictions of quantum mechanics. I think however that it is a smoke screen, and the slogan "lost in math" comes to my mind. I will discuss some other recent disproofs of Bell's theorem using the language of causality based on causal graphs. Causal thinking is also central to law and justice. I will mention surprising connections to my work on serial killer nurse cases, in particular the Dutch case of Lucia de Berk and the current UK case of Lucy Letby.
Slide 1: Title Slide
Extrachromosomal Inheritance
Slide 2: Introduction to Extrachromosomal Inheritance
Definition: Extrachromosomal inheritance refers to the transmission of genetic material that is not found within the nucleus.
Key Components: Involves genes located in mitochondria, chloroplasts, and plasmids.
Slide 3: Mitochondrial Inheritance
Mitochondria: Organelles responsible for energy production.
Mitochondrial DNA (mtDNA): Circular DNA molecule found in mitochondria.
Inheritance Pattern: Maternally inherited, meaning it is passed from mothers to all their offspring.
Diseases: Examples include Leber’s hereditary optic neuropathy (LHON) and mitochondrial myopathy.
Slide 4: Chloroplast Inheritance
Chloroplasts: Organelles responsible for photosynthesis in plants.
Chloroplast DNA (cpDNA): Circular DNA molecule found in chloroplasts.
Inheritance Pattern: Often maternally inherited in most plants, but can vary in some species.
Examples: Variegation in plants, where leaf color patterns are determined by chloroplast DNA.
Slide 5: Plasmid Inheritance
Plasmids: Small, circular DNA molecules found in bacteria and some eukaryotes.
Features: Can carry antibiotic resistance genes and can be transferred between cells through processes like conjugation.
Significance: Important in biotechnology for gene cloning and genetic engineering.
Slide 6: Mechanisms of Extrachromosomal Inheritance
Non-Mendelian Patterns: Do not follow Mendel’s laws of inheritance.
Cytoplasmic Segregation: During cell division, organelles like mitochondria and chloroplasts are randomly distributed to daughter cells.
Heteroplasmy: Presence of more than one type of organellar genome within a cell, leading to variation in expression.
Slide 7: Examples of Extrachromosomal Inheritance
Four O’clock Plant (Mirabilis jalapa): Shows variegated leaves due to different cpDNA in leaf cells.
Petite Mutants in Yeast: Result from mutations in mitochondrial DNA affecting respiration.
Slide 8: Importance of Extrachromosomal Inheritance
Evolution: Provides insight into the evolution of eukaryotic cells.
Medicine: Understanding mitochondrial inheritance helps in diagnosing and treating mitochondrial diseases.
Agriculture: Chloroplast inheritance can be used in plant breeding and genetic modification.
Slide 9: Recent Research and Advances
Gene Editing: Techniques like CRISPR-Cas9 are being used to edit mitochondrial and chloroplast DNA.
Therapies: Development of mitochondrial replacement therapy (MRT) for preventing mitochondrial diseases.
Slide 10: Conclusion
Summary: Extrachromosomal inheritance involves the transmission of genetic material outside the nucleus and plays a crucial role in genetics, medicine, and biotechnology.
Future Directions: Continued research and technological advancements hold promise for new treatments and applications.
Slide 11: Questions and Discussion
Invite Audience: Open the floor for any questions or further discussion on the topic.
Deep Behavioral Phenotyping in Systems Neuroscience for Functional Atlasing a...Ana Luísa Pinho
Functional Magnetic Resonance Imaging (fMRI) provides means to characterize brain activations in response to behavior. However, cognitive neuroscience has been limited to group-level effects referring to the performance of specific tasks. To obtain the functional profile of elementary cognitive mechanisms, the combination of brain responses to many tasks is required. Yet, to date, both structural atlases and parcellation-based activations do not fully account for cognitive function and still present several limitations. Further, they do not adapt overall to individual characteristics. In this talk, I will give an account of deep-behavioral phenotyping strategies, namely data-driven methods in large task-fMRI datasets, to optimize functional brain-data collection and improve inference of effects-of-interest related to mental processes. Key to this approach is the employment of fast multi-functional paradigms rich on features that can be well parametrized and, consequently, facilitate the creation of psycho-physiological constructs to be modelled with imaging data. Particular emphasis will be given to music stimuli when studying high-order cognitive mechanisms, due to their ecological nature and quality to enable complex behavior compounded by discrete entities. I will also discuss how deep-behavioral phenotyping and individualized models applied to neuroimaging data can better account for the subject-specific organization of domain-general cognitive systems in the human brain. Finally, the accumulation of functional brain signatures brings the possibility to clarify relationships among tasks and create a univocal link between brain systems and mental functions through: (1) the development of ontologies proposing an organization of cognitive processes; and (2) brain-network taxonomies describing functional specialization. To this end, tools to improve commensurability in cognitive science are necessary, such as public repositories, ontology-based platforms and automated meta-analysis tools. I will thus discuss some brain-atlasing resources currently under development, and their applicability in cognitive as well as clinical neuroscience.
4. Cytoplasmic material- engulfed within double
membrane vesicles – degraded.
Vesicle contain- mitochondria , ER and lysosomal
enzymes.
In a conference on lysosome in 1963, Christian de
duva- coined –autophagy –eating one self.
Why would cell digest itself ???
5.
6. Starvation condition – enhance the formation of such
vesicles. Amino acids – end product – degradation
process- inhibit their formation.
Autophagy – strategy – evolved – cell survival – low
nutrient condition.
Double membrane vesicle- now called as
autophagosome.
7.
8. A self-digesting mechanism- removal of long lived
proteins, damaged organelles and malformed
proteins.
Portion of the cell content- delivered to lysosome or
vacuole – degradation.
Induced at nutrient starvation- bulk degradation.
9. Defective in autophagy – reduced amino acids –
inability to synthesis of protein.
Important for cellular housekeeping as it may remove
exhausted, redundant or unwanted components.
10. It is divided into – 3 general types.
Depending- mechanism- intracellular materials are
delivered into lysosome for degradation.
They are:
◦ Chaperone mediated autophagy
◦ Macroautophagy
◦ Microautophagy
11. CMA- yet only described in mammals and involved in
degradation of single soluble proteins.
Micro and macro autophagy- wide range of eukaryotes-
degrade portion of cytoplasm- may include cell
organelles.
13. Process that results in selective degradation- cytosolic
proteins.
Key proteins in CMA-
Hsc70 [cytosol]
Hsc73 [lysosomal lumen]
LAMP-2A [lysosomal membrane protein]
Very complex and specific pathway.
14.
15. Cytosolic Hsc70 recognizes and unfolds substrate
protein that have a specific sequence (KFERQ- like
motif).
Form Hsc70 cargo complex- moves to lysosomal
membrane- binds to cytosolic LAMP-2A.
Hsc73 pull the substrate protein into the lysosome.
16. Cytosolic Hsc70 dissociates from its cargo –
translocation of the substrate and recycles to the
cytosol.
It is significantly different from other types of
autophagy because it translocates protein material in a
one by one manner.
Selective about what material crosses a lysosomal
barrier.
17. Main pathway
Eradicate damaged cell organelles or unused proteins.
It could be selective or non selective.
Involves- autophagasome- around organelle.
Travels through cytoplasm to vacuole - fuse.
In vacuole – contents degraded via acidic lysosomal
hydrolases.
18. Double membrane- isolates –like organelles, soluble
cytosolic proteins, protein aggregates- degradation.
Structure – autophagosome.
Outer membrane – fuses with vacuole- uptake of cargo-
inner autophagosomal membrane.
Various protein – macroautophagy.
19. Serine/threonine protein kinase TOR – signaling of
nutrient limitation.
TOR- cell growth , cell cycle progression, nutrient
import and protein synthesis.
Normal growth- TOR is active – hyperphosphorylation
of Atg13- modulates Atg1 activity.
Nitrogen stravation- TOR inactivated-
hypophosphorylation of Atg13- affinity of Atg13 for
Atg1.
20. Atg1 – regulating different steps in autophagosome
formation.
Nitrogen starvation stimulates formation Atg1-Atg13
complex- larger regulatory protein complex- induction
of macroautophagy.
21.
22. Phophatidylinositol 3 kinase(PI 3K) complex mediates
vesicle nucleation.
After induction by Atg1 complex- cascade of reaction
occurs resulting in initiation of autophagosome
formation.
In yeast- start at pre-autophagosomal structure(PAS).
PAS- localized in peri vacuolar region- almost all Atg
proteins assemble.
23. In Saccharomyces cerevisiae, 16 ATG genes -identified
– autophagosome formation and most of these proteins-
localized to the PAS.
Once phagophore - formed – membrane structure
expands – isolate material to be degraded.
This process involves two reaction-
Atg12-Atg5-Atg16 conjugation
Atg8 processing
24.
25. Atg7 activates Atg12 and transfers it to Atg10 .
Atg10 helps to bind Atg 12 to Atg5 then to Atg16.
This forms Atg12-Atg5-Atg16 complex.
The complex induces curvature into the growing
phagophore through recruitment of processed Atg8.
26.
27. Atg8 is a cytosolic protein that, upon induction of autophagy,
is proteolytically cleaved by Atg4 (Atg4, a cysteine protease).
Its is activated by Atg7 ( adding carboxyterminal
glycine residue)
Atg8 transferred to Atg3( Carrier) and
phos-phatidylethanolamine (PE) is added – forms Atg8-PE.
(Atg12-Atg5-Atg16) locates Atg8-PE into the growing
phagophore.
28. Atg8-PE associated- double autophagosome membrane- inner
& outer membrane.
Closure - Atg8 protein in outer membrane- recycled to PAS.
Inner membrane- degraded with cargo.
Atg12-Atg5-Atg16 complex- cover only outside- recycled
upon completion of autophagosome.
29. Outer membrane – autophagosome- fuses with
vacuole- inner membrane together with cargo
degraded.
Once degraded- macro molecules – released to
cytosol – through various permease including Atg22.
30.
31. 1). Cvt pathway:
Protein transport route- only in yeast.
Molecular mechanisms- overlap with macroautophagy.
It is biosynthetic pathway- responsible for sorting of
two hydrolases, aminopeptidase 1 and alpha
mannosidase 1 to the vacuole.
32. 2). Macropexophagy :
Peroxisomes- recent class of subcellular organelles-
eukaryotic cells- but are the 1st organelles – selective
organelle degradation by autophagy has been
described.
Selective peroxisomes degradation by
autophagy(pexophagy)
33. 3). Reticulophagy:
ER – site of folding and modification of proteins.
In case of folding stress- volume of ER and protein
content- involved in protein folding and modification
increases.
Stress response- part of ER – selectively isolated by
double membrane vesicles.
ER containing autophagosome- fuses with vacuole –
releases content into it for degradation.
Electron microscopy- reticulophagy- highly selective-
no cytosol & other organelle included into degradation
vesicles.
Degrade damaged portion of ER
34. Mediated by direct engulfment of vacuolar cytoplasmic
cargo.
It is responsible for degradation of various cellular
components- vacuolar membrane.
Like macroautophagy, it is induced in yeast cells that
experience nitrogen starvation via the TOR signaling
complex.
35. In addition to TOR- it is controlled – 2nd regulatory
complex, EGO complex.
It is non selective process.
But there are 3 selective microautophagic pathway:
◦ micropexophagy (cluster of peroxisomes)
◦ piecemeal microautophagy
◦ micromitophagy
36. Piecemeal microautophagy:
Nucleus belong to the organelles which can be
subjected to autophagic degradation.
PMN(Piecemeal nucleus autophagy)- minor portion is
degraded.
Isolated by vacuolar membrane- degraded in vacuole-
resembles microautophagy.
37. Mitophagy :
Selective degradation of mitochondria.
Occurs to defective mitochondria- damage or stress.
Occurrence of mitophagy is not limited to damaged
mitochondria but also involves undamaged ones.
38.
39. Autophagy – essential for survival under starvation
condition.
Function – illustrated by – observation that knock out
mice- autophagy blocked in all tissues- death after
birth.
Ability- survive – neonatal starvation period.
In mammals- autophagy occurs at low constitutive
levels- important- preventing the accumulation of
damaged and malfunctional cell components.
40. Enhanced – starvation & increase in the unwanted
components in the cell.
Act as defense – by removing invading pathogens.
Defects in autophagy – serious disease.
Mutation in genes encoding protein of (ATG genes)-
abolish autophagy and cause disease.
Deregulation – affect human health- spotty skin
pigmentation and endocrine tumors – defect in TOR
signaling pathway.
41. Two major function of autophagy- human heath-
Recycling of cell material during starvation
Cellular housekeeping
42. Defects or deregulation cause-
1. Cancer
2. Neurodegenerative disease
3. Lysosomal storage disease
4. Ageing and ageing related diseases.
43. Strong links – autophagy and cancer.
Autophagy suppresses – primary tumor growth.
But it is required for tumor maintenance and
progression on the other hand.
Mutation affect – TOR signaling.
Tumor suppressor gene- inhibition of TOR signaling-
stimulate autophagy.
Oncogene proteins- activate TOR.
Several observation- enhanced autophagy tumor
suppressor. Defect in autophagy promote tumor.
44. Some cytotoxic drugs used for the treatment of cancer
can engage ACD.
Critical to understand the pathways regulating these
events.
Autophagy-control - cell death and survival programs.
Induction of autophagy in cancer cells represents a
double-edged sword.
45. Autophagy is crucial for neuronal homeostasis.
Prevent accumulation of protein aggregates.
Evidence for the vital role of autophagy- studies- mice
lacking Atg5 or Atg7 showed severe neurodegeneration
in the CNS.
Huntington's disease and several age-related diseases,
like Alzheimer and Parkinson.
46. Lysosomal storage diseases are generally caused by a
defect in specific lysosomal hydrolases.
In Pompe disease, glycogen accumulates in multiple
tissues- skeletal and cardiac muscle, as a results of a
deficiency of lysosomal acid alpha-glucosidase
47. Macroautophagy - in cellular defense against pathogens
(bacteria, viruses, parasites).
In addition- autophagy is also implicated in immunity
and chronic inflammation disease.
The recent finding that mutations in Atg16 may be
related to Crohn disease, a chronic inflammatory bowel
disease.
48.
49. New era of autophagy research began in 1990s when
several groups of scientist discovered ATG genes-
yeast.
Ohsumi and Michael thumm examined starvation
induced non-selective autophagy.
Meantime- Daniel J klionsky – cytoplasm-to- vacuole
targeting(cvt) pathway- form of selective autophagy.
soon found – they were also looking for the same
pathway, just from different angles.
50. The genes discovered by these and other yeast groups
were given different names ( APG, AUT, CVT, GSA,
PAG, PAZ & PDD).
The unified nomenclature was advacated in 2003 by the
yeast researcher to denote autophagy genes.
The 2016 noble prize in physiology/ medicine was
awarded to Yoshinori ohsumi.
His contribution to autophagy research is well
recognized.
51. Knowledge of ATG genes provide scientists more
convenient tools to dissect functions of autophagy in
human health and disease.
52.
53. 1) Todde V, Veenhuis M and Klei IJ (2008). Autophagy:
principle and significance in health and disease. Biochimica
et Biophysica Acta 1792 (2009)3 -13.
2) Mowers EE, Sharifi MN and Macleod KF(2016). Autophagy
in cancer metastasis. Oncogene (2017) 36, 1619–1630.
3) Fulda S (2017) Autophagy in Cancer Therapy. Front. Oncol.
7:128.
4) Zhangyuan Yin, Clarence Pascual and Daniel J. Klionsky
(2016). Autophagy: machinery and regulation. Microbial
Cell 3(12): 588-596. doi: 10.15698/mic2016.12.546
54.
55. Autophagy - eukaryotic cell death and apoptosis.
Some cases - the same proteins control -autophagy
and apoptosis.
Apoptotic signaling - autophagy and conversely
autophagy- apoptosis (cell death mechanisms).
The molecular connections between autophagy and
cell death are complicated.
Play important roles in health and many diseases
allow new ways to prevent or treat disease.
56. Role for autophagy- accepted- cellular survival.
Autophagy – associated- cell death pathways-
apoptosis.
Autophagy -regulated program associated with survival
or stress adaptation.
Increased autophagosome- coincident in cells that are
dying.
Excess activation of autophagy- contribute - apoptotic
cell death through unchecked degradative processes.
57. Morphological and biochemical - autophagy and apoptosis -
different.
Cells undergoing autophagy display an increase- autophagic
vesicles.
While partial chromatin condensation appears-autophagic
cells-DNA fragmentation occur.
58. “Autophagic cell death” - programmed cell death.
autophagic, or type II - programmed cell death.
Large numbers of autophagic vacuoles -observed in dying
cells of animals.
Contribution of autophagy to cell death -studied - Drosophila -
apoptosis machinery-involved-death of multiple cell types.
Apoptotic cell death-caspase-dependent and characterized-
internucleosomal DNA cleavage.
Caspase activation and DNA fragmentation occur very late-
autophagic cell death .
59. Factors - regulate apoptosis pathways -also - potential to effect
regulatory activity-factors-regulate autophagy -vice-versa .
Mammalian cell death- multiple mechanisms - deliberate
suicide -clearly programmed -accidental or the result of
damage.
Autophagic cell death - based on the frequent observation that
cell death -accompanied -high levels- autophagosomes and
active autophagy.
Cells that will die induce autophagy before they die- doesn’t
implicate a causal relationship between the autophagy and cell
death.
60. High levels of autophagy- indication – cell- attempting-
survive-inducing autophagy -when this effort fails -
death occurs.
So, does autophagy kill cells and, if so, how?
One situation - autophagy - cell death - where the cell -
no ability -activate canonical apoptosis- preferred
mechanism of death.
61. Examples was described in cells from BAX and BAK double
knockout mice- lack - main proteins - regulate the release of
mitochondrial proteins -apoptosis.
Cells -severely compromised-apoptosis and do not display any
activation of pro-apoptotic caspases-still die in response -DNA
damaging agents.
This non-apoptotic death-dependent-autophagy.
In the absence- apoptosis- DNA damage activates- autophagy-
kills the cells.
62. The major concern with these example- represent a very
artificial situation.
Normal cells are probably never as defective in apoptosis as
BAX/BAK double knockout.
Autophagy-induce-cell death - cells use this pathway-die
because -no other option rather – indication- autophagy - a
death mechanism-promote death -cells under more normal
circumstances.
63. However it is important to note that even in these cases,
it does not necessarily follow that autophagy alone kills
the cells.
Autophagy dependent cell death -physiological
conditions-largely- autophagy making other death
pathways
64. Autophagy- induced -specific tissues -starvation - Drosophila
melanogaster.
In contrast-starvation induced-survival-oriented autophagy,
programmed autophagy-involved- removal-tissues- observed
in Drosophila .
During metamorphosis- pulses of the steroid hormone 20-
hydroxyecdysone (ecdysone) signal for old tissues-such as the
larval salivary glands and midgut-degraded - programmed
autophagic cell death.
65. During the larval -pupal transition-Drosophila midgut shrink
drastically-size.
A pulse of ecdysone -onset - puparium formation triggers -cell
size reduction- within 4 hrs – midgut- died.
High levels of autophagy -detected during this process
when autophagy genes-mutated-midgut cells fail to degrade.
66. Inhibition of autophagy genes-dying midgut also disrupts
mitochondrial clearance-implicating a role for mitophagy in
this process.
Midgut cell death- independent of apoptosis, as the inhibition
of caspases -no effect - induction of autophagy or cell death.
Thus, in the destruction of the midgut, autophagy is necessary
but apoptosis is non-essential.
67. Destruction of the Drosophila larval salivary glands –occurs-
larval to pupal transition.
Another pulse of ecdysone - 12 h after puparium formation
signals- total degradation- salivary glands.
High levels-autophagy -induced - process and genetic
inhibition of autophagy results in incomplete degradation of
the gland.
68. Caspases are involved-degradation of glands-inhibition of
caspases -results in incomplete gland degradation.
Autophagy and caspases- blocked- removal-salivary glands is
further delayed compared with when either of these pathways-
blocked individually.
Thus, autophagy and apoptosis function in parallel in salivary
gland degradation.
69. The core autophagy machinery- required for autophagosome
formation. This distinction has important practical
implications.
Suppose we wanted to block disease-associated apoptosis
where autophagy is involved
In a case like that in fly oocytes where autophagic flux and
degradation –substrate- required - alter sensitivity to apoptosis.
Sufficient-block-degradation step without affecting
autophagosome formation-order to get the result you want.
70. Can be done-inactivating lysosome-have drugs- chloroquine.
If autophagy-promoting apoptosis -because autophagosomes
serve- platform upon which caspase activation -achieved then
just blocking- lysosome wouldn’t have any effect.
Instead in this case-need to prevent formation-
autophagosomes if -want to prevent apoptosis.
71. During Drosophila oogenesis, autophagy controls
developmental cell death -selectively degrading the protein
dBruce-functions to inhibit caspase activation .
Thus, it promotes cell death-degrading –target-acts as a
negative regulator of caspase activity -stimulating higher
levels of caspase activity, i.e. being a form of apoptosis .
Some developmental cell death-flies occurs-autophagy
dependent but caspase-independent manner .
72. In this case-underlying target-degraded-autophagy and which
causes the caspase-independent death is unclear.
Here autophagy controls cell death by promoting caspase
activation and subsequent apoptosis.
It shows that developmentally programmed cell deaths can
involve autophagy working alongside apoptosis, autophagy
controlling apoptosis and autophagy working on its own with
no involvement of the apoptosis machinery.
73.
74.
75.
76. It is clear- autophagy- promote cell death.
we still lack a detailed understanding .
However while it makes sense that they should exist, the full
spectrum of such molecules is unknown.
Play important roles in health and many diseases
allow new ways to prevent or treat disease.
77. Without knowing what autophagy has to degrade in order to
cause cell death, one cannot claim to understand mechanisms
of autophagy dependent death.
The functional contribution of autophagy to cell death has
been a subject of great controversy.
The reason for controversy appears to be related to the
historical focus on autophagy as a cell survival process.
In addition, until relatively recently limited empirical studies
had been done to test whether autophagy genes actually
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